interacts_with DB00087?
Therapeutic implications of variable expression of P31358 on clonal cytotoxic T cells in CD8+ large granular lymphocyte leukemia . BACKGROUND : T-cell large granular lymphocytic leukemia is a clonal proliferation of cytotoxic T-lymphocytes which often results in severe cytopenia . Current treatment options favor chronic immunosuppression . DB00087 , a humanized monoclonal antibody against glycophosphatidylinositol-anchored P31358 , is approved for patients refractory to therapy in other lymphoid malignancies . DESIGN AND METHODS : We retrospectively examined treatment outcomes in 59 patients with CD8+ T-cell large granular lymphocytic leukemia , 41 of whom required therapy . Eight patients with severe refractory cytopenia despite multiple treatment regimens had been treated with subcutaneous alemtuzumab as salvage therapy . Flow cytometry was used to monitor expression of glycophosphatidylinositol-anchored P31358 , P08174 , and P13987 as well as to characterize T-cell clonal expansions by T-cell receptor variable beta-chain ( Vbeta ) repertoire . RESULTS : Analysis of the effects of alemtuzumab revealed remissions with restoration of platelets in one of one patient , red blood cell transfusion independence in three of five patients and improvement of neutropenia in one of three , resulting in an overall response rate of 50 % ( 4/8 patients ) . Clonal large granular lymphocytes exhibited decreased P31358 expression post-therapy in patients refractory to treatment . Samples of large granular lymphocytes collected prior to therapy also unexpectedly had a significant proportion of P31358 -negative cells while a healthy control population had no such P31358 deficiency ( p=0.026 ) . CONCLUSIONS : While alemtuzumab may be highly effective in large granular lymphocytic leukemia , prospective serial monitoring for the presence of P31358 -deficient clonal cytotoxic T-lymphocytes should be a component of clinical trials investigating the efficacy of this drug . P31358 deficiency may explain lack of response to alemtuzumab , and such therapy may confer a survival advantage to glycophosphatidylinositol-negative clonal cytotoxic T-lymphocytes . Ex vivo expansion and long-term hematopoietic reconstitution ability of sorted P28906 + P13987 + cells from patients with paroxysmal nocturnal hemoglobinuria . Autologous bone marrow transplantation ( ABMT ) for paroxysmal nocturnal hemoglobinuria ( PNH ) remains difficult so far . To expand residual normal P28906 (+) P13987 (+) cells isolated from patients with PNH and observe the long-term hematopoietic reconstruction ability of the expanded cells both ex vivo and in vivo , P28906 (+) P13987 (+) cells from 13 PNH patients and P28906 (+) cells from 11 normal controls were separated from bone marrow mononuclear cells first by immunomagnetic microbeads and then by flow cytometry autoclone sorting . The cells were then cultivated under different conditions . The long-term hematopoietic supporting ability of expanded P28906 (+) P13987 (+) cells was evaluated by long-term culture in semi-solid medium in vitro and long-term engraftment in irradiated severe combined immunodeficiency ( SCID ) mice in vivo . The best combination of hematopoietic growth factors for ex vivo expansion was P21583 + P08700 + P05231 + FL + Tpo + Epo . The most suitable time for harvest was on day 7 . P28906 (+) P13987 (+) PNH cells retained strong colony-forming capacity even after expansion . The survival rate , complete blood cell count recovery on day 90 , and human P08575 expression in different organs were similar between the irradiated SCID mice transplanted with expanded P28906 (+) P13987 (+) PNH cells and those with normal P28906 (+) cells ( P > 0.05 ) both in primary and secondary transplantation . These data provided a new potential way of managing PNH with ABMT . Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c-kit receptor . Mouse pluripotent hematopoietic stem cells ( PHSC ) were fractionated based on size and density using counterflow centrifugal elutriation ( CCE ) . These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage-specific markers ( Lin- ) followed by positive sorting for c-kit expression . The cells were characterized for their functional and biochemical properties . We defined a subpopulation of c-kit-positive cells that expressed high numbers of c-kit receptors ( c-kitBR ) . One hundred c-kitBR cells from either low- or higher-density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1-W/Wv ( W/Wv ) recipients , whereas no PHSC were found in cells with low ( c-kitDULL ) or no ( c-kitNEG ) c-kit expression . Lin- c-kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 ( Rho ) . The PHSC were concentrated in Lin- c-kitBR RhoDULL cells and the number of Lin- c-kitBR RhoBR cells correlated directly with the number of day 12 colony-forming unit-spleen ( CFU- P28222 ) in each fraction . We were not able to enrich further for PHSC using monoclonal antibodies to the cell-surface markers AA4.1 or P01730 , which have been used by others to isolate PHSC . The small , low-density Lin- c-kitBR subset contained PHSC and few CFU- P28222 . This enabled us to assay PHSC for expression of the flk-2 gene , which encodes a tyrosine kinase receptor present on fetal liver PHSC . Purified RNA from the low-density Lin- c-kitBR subset did not contain flk-2 mRNA . We suggest that AA4.1 , P01730 and flk-2 are expressed as stage-specific markers on PHSC in cell cycle . Activation of T cells via P08174 : recruitment of early components of the CD3-TCR pathway is required for P60568 secretion . It was previously reported that the glycosylphosphatidylinositol ( P06744 ) -anchored P08174 molecule provides a co-stimulatory signal for T lymphocytes and is constitutively associated with the Src-related kinase p56lck . The present studies were undertaken to clarify the mechanism of action of P08174 in T cells . We describe the failure of cross-linking of P08174 alone to induce both the elevation of the intracellular calcium concentration and the tyrosine phosphorylation of P98160 -gamma in CD3+ Jurkat cells . By contrast , it is sufficient to induce the phosphorylation of tyrosine residues on p56lck , the TCR-zeta chain as well as Q7Z2W4 -70 . Surprisingly , the observed TCR-zeta and Q7Z2W4 -70 tyrosine phosphorylations appear delayed compared to stimulation via CD3 . DB01373 ionophore A23187 in combination with cross-linked P08174 mAb initially caused an acceleration in the kinetic of these two phosphorylation events , followed by P60568 secretion . Furthermore , transfection of the cytoplasmic domain of TCR-zeta in CD3- Jurkat cells , using a CD16-zeta chimera , demonstrates that P08174 -mediated T-cell activation depends on the expression of this chain of the CD3-TCR complex . P04150 antagonism disrupts the reconsolidation of social reward-related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play-induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play-induced CPP . DB00834 did not affect social play-induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK-801 modestly affected the reconsolidation of social play-induced CPP . However , the reconsolidation of social play-induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward-related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward-related memories only partially overlap with those underlying the reconsolidation of other reward-related memories . [ Endometrial cancer in young women -- clinical and molecular aspects ] . OBJECTIVES : The aim the study was to compare two groups of endometrial cancer patients ( below and above 45 years of age ) in the aspect of clinicopathological and molecular data . MATERIAL AND METHODS : The study encompassed 456 primary tumour samples retrospectively collected from a cohort of endometrial cancer patients , primarily treated by surgery Molecular analysis covered : copy number variations of 10 genes ( P11388 , P00533 , P04626 , P21860 , Q15303 , MYC , P24385 , P03372 , P42336 , O60216 ) analyzed by quantitative PCR ; mRNA expression of 6 genes ( Q13296 , RAD27 , Q01196 , O95863 , O43623 , O43490 ) analyzed with the use of reverse transcription quantitative PCR ; protein expression analysis of 8 markers ( P06401 , P03372 ; P00533 , P04626 , P21860 , Q15303 , P11388 , pAKT1 ) performed with the use of immunohistochemistry . RESULTS : The younger group of patients was characterized by less frequent hypertension ( p < 0.00007 ) , less frequent myometrial infiltration ( p=0.002 ) and longer overall survival ( p=0.003 ) . Apart from O60216 gene aberrations , which were more frequent in younger patients ( p=0.02 ) , the study revealed no statistically significant differences between the groups . CONCLUSIONS : The study showed no molecular differences in the profile of younger and older endometrial cancer patients . Data on both the prognostic and predictive significance of O60216 in endometrial cancer are still insufficient . The clinical profile of younger patients with endometrial carcinoma was slightly better when compared to elderly patients . Younger patients were characterized by longer overall survival . A mechanistic rationale for combining alemtuzumab and rituximab in the treatment of ALL . B-lineage acute lymphoblastic leukemia ( ALL ) may express P31358 and P11836 . DB00087 ( ALM ) and rituximab ( RTX ) are therapeutic antibodies directed against P31358 and P11836 , respectively , but showed limited activity against ALL in clinical trials . The mechanisms for the impaired responses remained unclear . We studied expression of P31358 and P11836 on ALL cells and found that most cases coexpressed P31358 and P11836 . However , distinct P31358 -negative ( P31358 (-) ) subpopulations were detected in most cases as the result of defective glycophosphatidyl-inositol anchoring . Although ALM efficiently eradicated P31358 -positive ( P31358 (+) ) cells in NOD/scid mice engrafted with primary human ALL , P31358 (-) subclones escaped therapy . In the same model , RTX showed limited activity resulting from occurrence of P11836 down-modulation . However , P31358 (-) cells concurrently lacked the glycophosphatidyl-inositol-anchored complement regulators P08174 and P13987 and showed increased susceptibility to RTX-mediated complement-dependent cytotoxicity in vitro . At the same time , ALM was shown to inhibit down-modulation of P11836 in response to RTX by depleting the trogocytic capacity of phagocytic cells . Probably because of these complementary mechanisms , combined administration of ALM and RTX induced complete responses in vivo . Based on these data , we propose a mechanistic rationale for combined application of RTX and ALM in ALL . Real life experience with alemtuzumab treatment of patients with lower-risk P43034 and a hypocellular bone marrow . Immunosuppressive therapy is a therapeutic option for selected low-risk myelodysplastic syndromes ( P43034 ) patients . Besides standard treatment protocols that include ATG and Q13216 , the humanized P31358 antibody alemtuzumab has been shown to have efficacy in P43034 treatment . We report our experience with alemtuzumab in nine P43034 RCMD patients . All patients had a hypocellular bone marrow with a blast count < 5 % and were classified as intermediate-1 according to the IPSS . We found a response in five patients ( 60 % ) ; three patients achieved a complete remission 3 and 6 months after the treatment with alemtuzumab , and two patients showed a haematological improvement . DB00087 was administered in a 10-mg dosage for 10 days . Treatment was well tolerated , and no severe side effects were observed . We could confirm the finding that the alemtuzumab is effective and save selected P43034 patients . Due to the promising results , further studies , especially with regard to long-term survival and risk of leucemic progression should be initiated . Immunotherapy of murine leukemia following non-myeloablative conditioning with naïve or G- P04141 mobilized blood or bone marrow stem cells . Allogeneic stem cell transplantation ( P09683 ) is the treatment of choice for a large number of hematologic malignancies . Its major advantage over conventional chemotherapy lies in the graft-versus-leukemia ( GVL ) effects mediated by allo- or tumor-reactive donor lymphocytes given in the course of P09683 or post transplantation as donor lymphocyte infusions ( DLI ) . The benefits of cell-mediated immunotherapy over myeloablative radiochemotherapy have also made it possible to reduce the intensity of conditioning regimens . Mobilized peripheral blood has proved preferable to bone marrow ( BM ) as a source of stem cells for transplantation , since it provides a larger number of stem cells on the one hand and immunologically competent lymphocytes on the other . The use of granulocyte colony stimulating factor ( DB00099 ) , which is necessary to mobilize and increase the number of stem cells , may down-regulate the GVL effect by suppression of donor effector T lymphocytes by inducing Th1 --> Th2 cytokine switch . It has previously been shown that GVL effects may be amplified by both in vivo and in vitro activation of donor lymphocytes with human recombinant interleukin-2 ( rIL-2 ) . Our studies using a leukemic murine model prepared for transplantation with low intensity conditioning prior to infusion of G- P04141 -mobilized peripheral blood stem cells ( PBSC ) have demonstrated that mobilization of blood cells with G- P04141 and in vivo treatment with rIL-2 following low-intensity conditioning enhances the GVL effects and prolongs survival of recipients inoculated with P24385 . Activation of donor lymphocytes with rIL-2 may thus be useful for amplifying GVL effects following mobilization with DB00099 . Identification of campath-1 ( P31358 ) as novel drug target in neoplastic stem cells in 5q-patients with P43034 and AML . PURPOSE : The P31358 -targeted antibody alemtuzumab induces major clinical responses in a group of patients with myelodysplastic syndromes ( P43034 ) . The mechanism underlying this drug effect remains unknown . EXPERIMENTAL DESIGN : We asked whether neoplastic stem cells ( NSC ) in patients with P43034 ( n = 29 ) or acute myelogenous leukemia ( AML ; n = 62 ) express P31358 . RESULTS : As assessed by flow cytometry , P31358 was found to be expressed on NSC-enriched P28906 (+)/ P28907 (-) cells in 8/11 patients with P43034 and isolated del(5q) . In most other patients with P43034 , P31358 was weakly expressed or not detectable on NSC . In AML , P28906 (+)/ P28907 (-) cells displayed P31358 in 23/62 patients , including four with complex karyotype and del(5q) and one with del(5q) and t(1;17;X) . In quantitative PCR ( qPCR ) analyses , purified NSC obtained from del(5q) patients expressed P31358 mRNA . We were also able to show that P31358 mRNA levels correlate with EVI1 expression and that P01111 induces the expression of P31358 in AML cells . The P31358 -targeting drug alemtuzumab , was found to induce complement-dependent lysis of P28906 (+)/ P28907 (-)/ P31358 (+) NSC , but did not induce lysis in P31358 (-) NSC . DB00087 also suppressed engraftment of P31358 (+) NSC in NSG mice . Finally , P31358 expression on NSC was found to correlate with a poor survival in patients with P43034 and AML . CONCLUSIONS : The cell surface target Campath-1 ( P31358 ) is expressed on NSC in a group of patients with P43034 and AML . P31358 is a novel prognostic NSC marker and a potential NSC target in a subset of patients with P43034 and AML , which may have clinical implications and may explain clinical effects produced by alemtuzumab in these patients . Cytoplasmic and nuclear estrogen binding capacity in the rat uterus during treatment with danazol and testosterone . DB01406 , testosterone and dihydrotestosterone ( DB02901 ) were tested as competitors for estrogen receptors on immature rat uterus cytosol . No competitive binding could be demonstrated for any of these steroids . After that , prepubertal Wistar rats were exposed to danazol , testosterone or propylene glycol ( control ) for 3 days or 17 days . After the appropriate exposure to medication , the animals were killed . Both danazol and testosterone appeared to be uterotropic after 3 days of treatment , although the increase in the uterine weight was significant only in the danazol-treated group ( p less than 0.05 ) . This effect was lost after 17 days of treatment . P03372 binding assays were done on the cytosolic and nuclear fractions of the homogenized uterine tissue of each group . The estrogen binding capacity of cytosols was increased in both the danazol ( p less than 0.05 ) and the testosterone ( p less than 0.01 ) groups after 3 days of treatment . A parallel increase was found in the nuclear fraction of both groups . After 17 days of treatment , the comparison between the 3 groups showed no differences in the cytosolic or nuclear estrogen binding capacity . The information provided by this study suggests that some effects of danazol may be due to an androgenic action and that may be associated to increases in the free fraction of testosterone . Inflammatory protein serum amyloid A1 marks a subset of conventional renal cell carcinomas with fatal outcome . BACKGROUND : Conventional renal cell carcinoma ( RCC ) is the most common renal cancer . As the metastatic conventional RCC is practically incurable , there is a need for markers to estimate the tumour aggressiveness . OBJECTIVE : To identify and characterise new marker(s) associated with the poor prognosis of conventional RCC . DESIGN , SETTING , AND PARTICIPANTS : RNA from 24 conventional RCCs was analysed for global gene expression by Affymetrix U133 Plus 2.0 arrays . Tissue microarrays containing 224 renal tumours including 87 conventional RCCs were used for immunohistochemistry . Cell lines Q92769 , HD48 , HA344 and HA465 established in our laboratory were used for invasion assay and zymography . MEASUREMENTS : Serum amyloid A 1 ( P0DJI8 ) was found to be upregulated in conventional RCCs and it has been analysed by quantitative RT-PCR and immunohistochemistry on TMAs to establish the correlation between P0DJI8 protein expression and patient survival by uni and multivariate analysis . The effect of P0DJI8 on tumour cell behaviour in vitro has also been examined by invasion assay and zymography . RESULTS AND LIMITATIONS : P0DJI8 RNA is expressed in conventional RCC samples of patients with poor prognosis . Immunohistochemistry of 72 conventional RCCs with a 5 yr follow up showed a correlation between P0DJI8 expression and the clinical outcome of disease . Stimulation of conventional RCC cell lines with recombinant P0DJI8 increased the expression of metalloproteinase ( MMP ) -9 and the invasive potential of tumour cells . Limitation of the study is a relatively small number ( 72 ) of patients having follow up . CONCLUSION : P0DJI8 seems to be a useful marker to estimate the prognosis of conventional RCCs . CD8 T cells and P12830 in host responses against oropharyngeal candidiasis . BACKGROUND : Oropharyngeal candidiasis ( OPC ) is the most common oral infection in HIV(+) persons . Previous studies suggest a role for CD8(+) T cells against OPC when P01730 (+) T cells are lost , but enhanced susceptibility to infection occurs when CD8(+) T-cell migration is inhibited by reduced tissue P12830 . OBJECTIVE : To conduct a longitudinal study of tissue CD8(+) T-cells and P12830 expression before , during , and after the episodes of OPC . METHODS : Oral fungal burden was monitored and tissue was evaluated for CD8(+) T cells and P12830 over a 1-year period in HIV(+) persons with a history of , or an acute episode of , OPC . RESULTS : While longitudinal analyses precluded formal interpretations , point prevalence analyses of the data set revealed that when patients experiencing OPC were successfully treated , tissue P12830 expression was similar to that in patients who had not experienced OPC , and higher numbers of CD8(+) T cells were distributed throughout OPC(-) tissue under normal expression of P12830 . CONCLUSION : These results suggest that ( 1 ) reduction in tissue P12830 expression in patients with OPC(+) is not permanent , and ( 2 ) high numbers of CD8(+) T cells can be distributed throughout OPC(-) tissue under normal P12830 expression . Together , these results extend our previous studies and continue to support a role for CD8(+) T cells in host defense against OPC . Quantifying Lipari-Szabo modelfree parameters from 13CO NMR relaxation experiments . It is proposed to obtain effective Lipari-Szabo order parameters and local correlation times for relaxation vectors of protein (13)CO nuclei by carrying out a (13)CO-R(1) auto relaxation experiment , a transverse (13)CO Q13216 /13CO-13Calpha Q13216 /dipolar cross correlation and a transverse (13)CO Q13216 /(13)CO-(15)N Q13216 /dipolar cross correlation experiment . Given the global rotational correlation time from (15)N relaxation experiments , a new program COMFORD ( CO-Modelfree Fitting Of Relaxation Data ) is presented to fit the (13)CO data to an effective order parameter S2CO , an effective local correlation time and the orientation of the Q13216 tensor with respect to the molecular frame . It is shown that the effective S2CO is least sensitive to rotational fluctuations about an imaginary Calpha-Calpha axis and most sensitive to rotational fluctuations about an imaginary axis parallel to the NH bond direction . As such , the Calpha-Calpha information is fully complementary to the (15)N relaxation order parameter , which is least sensitive to fluctuations about the NH axis and most sensitive to fluctuations about the Calpha-Calpha axis . The new paradigm is applied on data of Ca(2+) saturated P62158 , and on available literature data for Ubiquitin . Our data indicate that the S2CO order parameters rapport on slower , and sometimes different , motions than the (15)N relaxation order parameters . The CO local correlation times correlate well with the calmodulin 's secondary structure . Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : DB08907 is a sodium glucose co-transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : (14)C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human , rat , or mouse SGLT2 or P13866 ; (3)H-2-deoxy-d-glucose uptake in Q9BTT4 myoblasts ; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT(G) ) in vehicle or canagliflozin-treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg/kg lowered RT(G) from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT(G) . DB08907 dose-dependently decreased BG concentrations in db/db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : DB08907 lowered RT(G) and increased UGE , improved glycemic control and beta-cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity . DB00087 induction and steroid-free maintenance immunosuppression in pancreas transplantation . DB00087 is a humanized anti- P31358 antibody that depletes lymphocytes and has been increasingly used as induction agent in transplantation . The impact of alemtuzumab induction immunosuppression in pancreas transplantation was evaluated , with particular reference to steroid avoidance in maintenance . A total of 100 patients who received 102 pancreas transplants ( 83 simultaneous kidney-pancreas [ SPK ] , 15 pancreas after kidney transplantation [ PAK ] and 4 pancreas transplant alone [ P03951 ] ) were included . All patients received two doses of 30-mg alemtuzumab i.v. with tacrolimus ( trough level 8-12 ng/mL ) and mycophenolate mofetil ( DB00688 ,1g/day ) with no maintenance steroids . This analysis included 62 male and 38 female recipients , with mean ( +/-SD ) age of 42 ( +/-7.6 ) years . Median follow-up was 17 months ( range 8-41 months ) . One-year patient , pancreas and kidney graft survival ( actuarial ) was 97 % , 89 % and 94 % , respectively . Overall incidence of rejection was 25 % . Side effects of alemtuzumab administration included thrombocytopenia ( 14 % ) , pulmonary edema ( 2 % ) and rash ( 1 % ) . Twenty-five percent required reoperations ( 12 % for bleeding ) . Infectious complications included Cytomegalovirus ( CMV,6.8 % ) BK viruria ( 3.8 % ) , fungal infections ( 4 % ) , primary varicella ( 1 % ) and posttransplant lymphoproliferative disorders ( PTLD,1 % ) . Eighty-three percent did not require any steroids posttransplant . These results indicate that alemtuzumab is safe and enables pancreas transplantation to be carried out without maintenance steroids in 83 % of cases and acceptable rejection rate . No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( DB00422 ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to DB00422 in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between DB00422 responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of DB00422 among adults with ADHD . Chemoimmunotherapy in acute lymphoblastic leukemia . ALL blast cells express a variety of specific antigens e.g. P15391 , P11836 , P20273 , P20138 , and P31358 , which serve as targets for Monoclonal Antibodies ( MoAbs ) . So far , the most experience is available for anti- P11836 ( rituximab ) , which has been combined with chemotherapy for treatment of mature B-ALL/Burkitt 's lymphoma . Studies with rituximab have also been completed in B-precursor ALL . Another antigen , P15391 , is of great interest due to a very high rate of expression in ALL . It can be targeted by a bispecific monoclonal antibody , DB09052 , directed against P15391 and CD3 . Smaller studies or case reports are also available for the anti P31358 antibody ( DB00087 ) , for anti P20273 ( DB04958 ) or anti P20138 ( Gemtuzumab ) . Available data demonstrate that MoAb therapy in ALL is a highly promising targeted treatment . However , several details for an optimal treatment approach e.g. the required level of antigen expression , timing , schedule , dosage and stage of disease still need to be defined . Bloodstream infections in organ transplant recipients receiving alemtuzumab : no evidence of occurrence of organisms typically associated with profound T cell depletion . BACKGROUND : DB00087 is a humanized monoclonal antibody directed against P31358 , a cell surface antigen expressed on B and T lymphocytes , monocytes and NK cells . Its use results in a profound decrease in P01730 positive T lymphocytes . DB00087 is used as induction immunosuppression and therapy for rejection in organ transplant recipients in some centers . We followed a cohort of 449 consecutive transplant recipients who received alemtuzumab to determine the occurrence of bloodstream infections , particularly those previously associated with decrease in P01730 positive T lymphocytes . PATIENTS AND METHODS : Fifteen percent ( 69/449 ) patients had at least one episode of bloodstream infection . However , no patient had bacteremia with Streptococcus pneumoniae , Listeria monocytogenes , non-typhoidal Salmonella or Mycobacterium avium complex . Fungaemia was rare , occurring in 1.5 % of patients . The most common organisms isolated from the blood were Staphylococcus aureus ( 21 episodes ) , coagulase negative Staphylococcus ( 14 episodes ) , Klebsiella pneumoniae ( 12 episodes ) , Enterococcus faecium ( 11 episodes ) , Pseudomonas aeruginosa ( 10 episodes ) , Enterococcus faecalis ( 9 episodes ) and Escherichia coli ( 7 episodes ) . DISCUSSION : We conclude that although alemtuzumab use is associated with profound P01730 positive T lymphocyte depletion , alemtuzumab does not seem to be associated with an increased risk of bloodstream infection with pathogens typically seen in other disorders of P01730 cell depletion , such as acquired immunodeficiency syndrome . Long-term follow-up of symptomatic patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia treated with the anti- P31358 monoclonal antibody alemtuzumab . P31358 is expressed on malignant cells in lymphoplasmacytic lymphoma ( P06858 ) , including IgM-secreting Waldenström macroglobulinemia ( WM ) . We examined the activity of alemtuzumab in 28 symptomatic P06858 ( 27 IgM and 1 IgA ) patients . The median prior number of therapies for these patients was 2 ( range , 0-5 ) and 43 % had refractory disease . Patients received alemtuzumab at 30 mg IV 3 times weekly for up to 12 weeks after test dosing , and also received hydrocortisone , acyclovir , and Bactrim or equivalent prophylaxis . Patients had a complete response ( n = 1 ) , a partial response ( n = 9 ) , or a MR ( n = 11 ) for an overall and major response rate of 75 % and 36 % , respectively . Median serum Ig decreased from 3510 to 1460 mg/dL ( P < .001 at best response ) . With a median follow-up of 64 months , the median time to progression was 14.5 months . Hematologic and infectious complications , including CMV reactivation , were more common in previously treated patients and were indirectly associated with 3 deaths . Long-term follow-up revealed late-onset autoimmune thrombocytopenia ( AITP ) in 4 patients at a median of 13.6 months after therapy , which contributed to 1 death . DB00087 is an active therapy in patients with P06858 , but short- and long-term toxicities need to be carefully weighed against other available treatment options . Late AITP is a newly recognized complication of alemtuzumab in this patient population . This study is registered at www.clinicaltrials.gov as NCT00142181 . [ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 -1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM-101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol-17 beta ( E2 ) + P01133 than control . However , E2+ P01133 did not stimulate the growth of IK cell than P01133 significantly . DB01406 ( D ) and D+ P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D+ P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2+ P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 . The Mek1 phosphorylation cascade plays a role in meiotic recombination of Schizosaccharomyces pombe . Mek1 is a Chk2/Rad53/Cds1-related protein kinase that is required for proper meiotic progression of Schizosaccharomyces pombe . However , the molecular mechanisms of Mek1 regulation and Mek1 phosphorylation targets are unclear . Here , we report that Mek1 is phosphorylated at serine-12 ( P28222 ) , Q92748 and threonine-15 ( T15 ) by Rad3 ( ATR ) and/or Tel1 ( Q13315 ) kinases that are activated by meiotic programmed double-strand breaks ( DSBs ) . Mutations of these sites by alanine replacement caused abnormal meiotic progression and recombination rates . Phosphorylation of these sites triggers autophosphorylation of Mek1 ; indeed , alanine replacement mutations of Mek1-T318 and -T322 residues in the activation loop of Mek1 reduced Mek1 kinase activity and meiotic recombination rates . Substrates of Mek1 include Mus81-T275 , Rdh54- Q8NHM4 and Rdh54-T673 . Mus81-T275 is known to regulate the Mus81 function in DNA cleavage , whereas Rdh54-T6A/T673A mutant cells showed abnormal meiotic recombination . Taken together , we conclude that the phosphorylation of Mek1 by Rad3 or Tel1 , Mek1 autophosphorylation and Mus81 or Rdh54 phosphorylation by Mek1 regulate meiotic progression in S. pombe . P04150 and histone deacetylase-2 mediate dexamethasone-induced repression of P98088 gene expression . Airway occlusion in obstructive airway diseases is caused in part by the overproduction of secretory mucin glycoproteins through the up-regulation of mucin ( MUC ) genes by inflammatory mediators . Some pharmacological agents , including the glucocorticoid dexamethasone ( DB00514 ) , repress mucin concentrations in lung epithelial cancer cells . Here , we show that DB00514 reduces the expression of P98088 , a major airway mucin gene , in primary differentiated normal human bronchial epithelial ( NHBE ) cells in a dose-dependent and time-dependent manner , and that the DB00514 -induced repression is mediated by the glucocorticoid receptor ( GR ) and two glucocorticoid response elements ( GREs ) in the P98088 promoter . The pre-exposure of cells to DB00834 , a GR antagonist , and mutations in either the GRE3 or GRE5 cis-sites abolished the DB00514 -induced repression . Chromatin immunoprecipitation ( ChIP ) assays showed a rapid temporal recruitment of GR to the GRE3 and GRE5 cis-elements in the P98088 promoter in NHBE and in A549 cells . Immunofluorescence showed nuclear colocalization of GR and histone deacetylase-2 ( Q92769 ) in P98088 -expressing NHBE cells . ChIP also showed a rapid temporal recruitment of Q92769 to the GRE3 and GRE5 cis-elements in the P98088 promoter in both cell types . The knockdown of Q92769 by Q92769 -specific short interfering RNA prevented the DB00514 -induced repression of P98088 in NHBE and A549 cells . These data demonstrate that GR and Q92769 are recruited to the GRE3 and GRE5 cis-sites in the P98088 promoter and mediate the DB00514 -induced cis repression of P98088 gene expression . A better understanding of the mechanisms whereby glucocorticoids repress P98088 gene expression may be useful in formulating therapeutic interventions in chronic lung diseases . Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender-dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 -length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E(2) ) binding was similar , E(2) stimulated proliferation only in cells from females , and this response was inhibited by anti-estrogens 4-hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E(2) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element-driven reporter gene was stimulated by E(2) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E(2) in two out of five adenocarcinoma cell lines from females , but none from males . E(2) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF-7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males . Class I HDACs are mediators of smoke carcinogen-induced stabilization of P26358 and serve as promising targets for chemoprevention of lung cancer . DNA methylation is an early event in bronchial carcinogenesis and increased DNA methyltransferase ( P26358 )1 protein expression is a crucial step in the oncogenic transformation of epithelia . Here , we investigate the role of class I histone deacetylases ( HDAC ) 1 to 3 in the stabilization of P26358 protein and as a potential therapeutic target for lung cancer chemoprevention . Long-term exposure of immortalized bronchial epithelial cells ( HBEC-3KT ) to low doses of tobacco-related carcinogens led to oncogenic transformation , increased HDAC expression , cell-cycle independent increased P26358 stability , and DNA hypermethylation . Overexpression of HDACs was associated with increased P26358 stability and knockdown of HDACs reduced P26358 protein levels and induced P26358 acetylation . This suggests a causal relationship among increased class I HDACs levels , upregulation of P26358 protein , and subsequent promoter hypermethylation . Targeting of class I HDACs with valproic acid ( DB00313 ) was associated with reduced HDAC expression and a profound reduction of P26358 protein level . Treatment of transformed bronchial epithelial cells with DB00313 resulted in reduced colony formation , demethylation of the aberrantly methylated Q96HF1 promoter , and derepression of Q96HF1 transcription . These data suggest that inhibition of HDAC activity may reverse or prevent carcinogen-induced transformation . Finally , immunohistochemistry on human lung cancer specimens revealed a significant increase in P26358 , Q13547 , Q92769 , and O15379 expression , supporting our hypotheses that class I HDACs are mediators of P26358 stability . In summary , our study provides evidence for an important role of class I HDACs in controlling the stability of P26358 and suggests that HDAC inhibition could be an attractive approach for lung cancer chemoprevention . Pathological study on the relationship between C4d , P13987 and C5b-9 in acute renal allograft rejection . In order to evaluate the activation or inhibition of the later phases of classical complement cascade in renal allograft presenting with acute rejection , particularly with C4d deposition on the peritubular capillary ( PTC ) , we observed the expression of P13987 and C5b-9 on the PTC . Subjective cases were divided into two groups , an acute rejection group , of 4 males and 6 females , and a normal donor group , of 5 males and 5 females . Renal biopsies were performed at the onset of acute rejection and at the transplant operation , before reperfusion . C4d deposition on PTC was found in three of 10 cases ( 30 % ) with biopsy proven acute rejection , whereas P13987 on PTC was positively expressed in all of the rejection cases . Although C5b-9 was not observed on PTC in the acute rejection group , it was intensively deposited on the tubular basement membrane ( P98088 ) in five cases , including the three with positive C4d on PTC . In the normal donor group , P13987 on PTC was intensively observed , whereas C5b-9 was weakly expressed on P98088 . P13987 , a complement regulatory factor , works as an inhibitory factor against the formation of C5b-9 , a membrane attack complex . From our data , we noted the dissociation between the depositions of C4d and C5b-9 on PTC . The substantially expressed P13987 on PTC may affect this dissociation between C4d and C5b-9 on PTC . The intensive deposition of C5b-9 on P98088 in acute rejection cases may suggest an independent immunological injury attacking tubular cells . DB00087 in allogeneic hematopoetic stem cell transplantation . INTRODUCTION : With the use of reduced-intensity conditioning ( RIC ) , early toxicity of allogeneic stem cell transplantation ( P09683 ) has been much reduced . Graft-versus-host disease ( GvHD ) causes morbidities and mortality . DB00087 is a mAb directed against P31358 . When administered prior to transplant , it leads to T-cell depletion . Incorporation of alemtuzumab in RIC results in low rates of GvHD and treatment-related mortality ( TRM ) in haematological diseases , even in the setting of mismatched-donor transplantation . AREAS COVERED : The use of alemtuzumab for GvHD prophylaxis in P09683 . The benefit of alemtuzumab-based conditioning is partially offset by increased disease relapse due to impaired graft-versus-tumor effect ( GvT ) and by slower immune reconstitution , necessitating special precautions . While GvHD is prevented with alemtuzumab , post- P09683 interventions are often required . Most studies find that alemtuzumab-based conditioning results in decreased chronic GvHD and TRM , but also in decreased progression-free survival . Overall survival after 3 - 5 years is usually equivalent and quality of life may be improved because of a lower incidence of sequelae of chronic GvHD . Many aspects of alemtuzumab treatment are under investigation . EXPERT OPINION : DB00087 reduces GvHD and TRM after P09683 . Use of alemtuzumab requires awareness and strict management of the risk of opportunistic infections and of an increased risk of disease recurrence . Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations : relevance for early adoptive immunotherapy and infectious complications . Persistence of alemtuzumab at lympholytic concentrations after reduced-intensity conditioning allogeneic stem cell transplantations ( RITs ) could impair immune reconstitution and reduce donor T-cell-mediated graft-versus-leukemia/lymphoma ( GVL ) effects , derived from the graft or subsequent adoptive immunotherapy . We have studied the pharmacokinetics of alemtuzumab in 2 different groups : Q92963 ( 100 mg alemtuzumab in vivo over 5 days ) and myeloablative allografts ( 20 mg alemtuzumab added in vitro to the stem cells prior to return ) . DB00087 concentrations in Q92963 patients were in excess of that required to kill infused donor P31358 + cells at the time of transplantation and remained at potentially lympholytic levels ( > 0.1 microg/mL ) for approximately 56 days after transplantation , 26 days longer than for the myeloablative group . Total lymphocyte counts were significantly lower in the Q92963 group persisting beyond 6 months after transplantation ( P =.005 ) , and median absolute P01730 counts higher than 200 x 106/L were delayed until 9 months after transplantation . DB00087 in peripheral T-cell malignancies . The humanized monoclonal antibody CAMPATH-1H ( alemtuzumab ) binds to the P31358 antigen , a glycoprotein that is widely expressed on normal and malignant B- and T-lymphocytes . Over the past 5 years , a number of trials have demonstrated that alemtuzumab has clinical activity in mature T-cell diseases such as T-cell prolymphocytic leukemia ( T-PLL ) and cutaneous T-cell lymphoma ( CTCL ) . In heavily pretreated relapsed/refractory patients alemtuzumab induced responses in more than two thirds of T-PLL and more than 50 % of CTCL patients . Responding patients had improved survival compared to nonresponders . DB00087 is particularly effective in clearing malignant lymphocytes from peripheral blood and bone marrow and may therefore facilitate stem-cell transplantation ( P09683 ) in selected patients . The toxicity profile for the antibody is acceptable ; the major complications are infusional reactions , which generally subside after the first 1-2 weeks of therapy , and prolonged lymphopenia associated with reactivation of viruses . These can be minimized by careful monitoring and the use of prophylactic therapy . Future studies will be directed toward : alternative routes ( subcutaneous ) and schedules of administration ; use as first-line therapy ; combination strategies with conventional chemotherapy ; and use of alemtuzumab to purge minimal residual bone-marrow disease prior to P09683 . Interaction of tacrolimus(FK506) and its metabolites with FKBP and calcineurin . DB00864 (FK506) is a strong immuno-suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2+ , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con-A response inhibiting activities of 7 metabolites . C15-demethylated metabolite(M-3) needed higher quantity to compete in Con-A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation . t(1;3)(p36; P38936 ) is a recurring therapy-related translocation . Chromosome bands 1p36 and 3p21 are known to be recurring breakpoints in therapy-related ( t- ) leukemia . We identified a recurring translocation , t(1;3)(p36; P38936 ) , in eight patients with various hematologic malignancies : three patients with ALL , one with chronic myelogenous leukemia ( CML ) in accelerated phase ( AP ) , two with P43034 , and two with AML(M3) . Five of the eight patients had a history of chemotherapy , including alkylating agents in three , before the translocation was detected . In two of these five patients , the t(1;3)(p36; P38936 ) emerged only at relapse or in the accelerated phase of CML . The karyotypes of the patients were complex , including -7 and structural abnormalities of 5q , 6q , 7q , 9p , and 11q23 . Survival time varied among patients ( 25 days to more than 16 years ) . Using Q5TCZ1 with 13 1p35-36 cosmid probes ( tel-FB12- P35218 -G7-FD2- P21554 -ED8-FD9-G32- P48751 -G50-AD8-GG4-G43-cen ) , we delineated the 1p36 breakpoint in two patients with P43034 and ALL as lying between FB12 and FD2 ( between BAC47P3 and PAC963K15 ) , with a small deletion near the breakpoint in both cases . In the patient with P43034 , there was also a deletion at 3p21.3 , as detected with the cosmid probe cosNRL9 . The results of the present study suggest that t(1;3)(p36; P38936 ) in hematologic diseases is associated with prior exposure to mutagens , including alkylating agents . Down-regulation of lipoprotein lipase increases glucose uptake in Q9BTT4 muscle cells . Thiazolidinediones ( TZDs ) are synthetic hypoglycemic agents used to treat type 2 diabetes . TZDs target the peroxisome proliferator activated receptor-gamma ( P37231 ) and improve systemic insulin sensitivity . The contributions of specific tissues to TZD action , or the downstream effects of P37231 activation , are not very clear . We have used a rat skeletal muscle cell line ( Q9BTT4 cells ) to demonstrate that TZDs directly target P37231 in muscle cells . TZD treatment resulted in a significant repression of lipoprotein lipase ( P06858 ) expression in Q9BTT4 cells . This repression correlated with an increase in glucose uptake . Down-regulation of P06858 message and protein levels using siRNA resulted in a similar increase in insulin-dependent glucose uptake . Thus , P06858 down-regulation improved insulin sensitivity independent of TZDs . This finding provides a novel method for the management of insulin resistance . [ The first case of single pancreas transplantation in Hungary ] . Simultaneous pancreas kidney ( SPK ) transplantation is the only routinely used therapeutic option which can provide insulin independence , euglycemia and good renal replacement for type I diabetes mellitus patients with end stage renal disease . Several patients have some complications of diabetes without renal failure . For these patients pancreas transplantation alone is a therapeutic option . The first pancreas transplantation alone was performed 6 years after the launch of our pancreas transplant program . The patient was a 40-years-old man . Enteric drainage was used with portal venous drainage . Anti P60568 . R antibody , daclizumab was given as prolonged induction therapy . In spite of the technical and immunological difficulties there were neither technical failures nor acute rejection . 3 years after the transplantation the patient has a good quality of life without insulin therapy with excellent renal function . CONCLUSION : P03951 transplant is a routinely used therapeutic option with good survival rate and good quality of life for type I diabetes mellitus patients without end stage renal disease . The transcriptional coactivator DRIP/mediator complex is involved in vitamin D receptor function and regulates keratinocyte proliferation and differentiation . Mediator is a multisubunit coactivator complex that facilitates transcription of nuclear receptors . We investigated the role of the mediator complex as a coactivator for vitamin D receptor ( P11473 ) in keratinocytes . Using P11473 affinity beads , the vitamin D receptor interacting protein ( DRIP ) /mediator complex was purified from primary keratinocytes , and its subunit composition was determined by mass spectrometry . The complex included core subunits , such as Q15648 /MED1 ( MED1 ) , that directly binds to P11473 . Additional subunits were identified that are components of the RNA polymerase II complex . The functions of different mediator components were investigated by silencing its subunits . The core subunit MED1 facilitates P11473 activity and regulating keratinocyte proliferation and differentiation . A newly described subunit Q13503 also has a role in promoting keratinocyte proliferation and differentiation , whereas Q9BTT4 has an inhibitory role . Blocking MED1/ Q13503 expression caused hyperproliferation of keratinocytes , accompanied by increases in mRNA expression of the cell cycle regulator cyclin D1 and/or glioma-associated oncogene homolog . Blocking MED1 or Q13503 expression also resulted in defects in calcium-induced keratinocyte differentiation , as indicated by decreased expression of differentiation markers and decreased translocation of P12830 to the membrane . These results show that keratinocytes use the transcriptional coactivator mediator to regulate P11473 functions and control keratinocyte proliferation and differentiation . Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab ( anti- P31358 monoclonal antibody ) in patients with relapsing-remitting multiple sclerosis . DB00087 ( anti- P31358 mAb ) provides long-lasting disease activity suppression in relapsing-remitting multiple sclerosis ( RRMS ) . The objective of this study was to characterize the immunological reconstitution of T cell subsets and its contribution to the prolonged RRMS suppression following alemtuzumab-induced lymphocyte depletion . The study was performed on blood samples from RRMS patients enrolled in the CARE-MS II clinical trial , which was recently completed and led to the submission of alemtuzumab for U.S . Food and Drug Administration approval as a treatment for RRMS . DB00087 -treated patients exhibited a nearly complete depletion of circulating P01730 (+) lymphocytes at day 7 . During the immunological reconstitution , P01730 (+)CD25(+)CD127(low) regulatory T cells preferentially expanded within the P01730 (+) lymphocytes , reaching their peak expansion at month 1 . The increase in the percentage of TGF-β1- , P22301 - , and P05112 -producing P01730 (+) cells reached a maximum at month 3 , whereas a significant decrease in the percentages of Th1 and Th17 cells was detected at months 12 and 24 in comparison with the baseline . A gradual increase in serum P13232 and P05112 and a decrease in Q16552 , Q96PD4 , Q9HBE4 , Q9GZX6 , and IFN-γ levels were detected following treatment . In vitro studies have demonstrated that P13232 induced an expansion of P01730 (+)CD25(+)CD127(low) regulatory T cells and a decrease in the percentages of Th17 and Th1 cells . In conclusion , our results indicate that differential reconstitution of T cell subsets and selectively delayed P01730 (+) T cell repopulation following alemtuzumab-induced lymphopenia may contribute to its long-lasting suppression of disease activity . DNA methyltransferase inhibitors in acute myeloid leukemia : discovery , design and first therapeutic experiences . INTRODUCTION : DNA methylation is an epigenetic change mediated by DNA methyltranferases ( DNMTs ) , which are promising epigenetic targets for the treatment of acute myeloid leukemia ( AML ) . This is evidenced by the two P26358 inhibitors ( azacitidine and decitabine ) approved by the Food and Drug Administration of the United States for the treatment of high-risk myelodysplastic syndromes and the first clinical data available in AML . AREAS COVERED : This paper reviews data from the international literature regarding the design , sites of impact and pharmacodynamic characteristics of P26358 inhibitors , and their first clinical experiences in AML . EXPERT OPINION : The strongest advances in epigenetic therapy have been in the treatment of AML . There are now an increasing number of P26358 inhibitors . These agents may be potentially administered at different times of leukemia therapy : before or instead of chemotherapy , as maintenance therapy , prior to allogeneic stem cell transplant ( P09683 ) or after relapse following P09683 . P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . DB00351 ( 160 mg/day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen-receptor ( ER ) level was greater than 10 fmols/mg of protein in 28 patients , and the progesterone-receptor ( PR ) level was greater than 10 fmols/mg of protein in 26 patients . ER and PR levels , age , and disease-free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone . Mutation of beta-catenin and its protein accumulation in solid and cystic tumor of the pancreas associated with metastasis . P35222 serves not only as a structural component of the P12830 -mediated cell-cell adhesion system , but also as a signaling molecule of the Wnt/wingless pathway . Mutations of beta-catenin and aberrant expression of its protein have been identified in a number of different types of human malignancies . To determine the role of beta-catenin in solid and cystic tumor ( P09683 ) of the pancreas , a rare neoplasm usually observed in young females , we examined three primary tumors and one corresponding liver metastatic tumor presented in pediatric patients . Single strand conformation polymorphism and neucleotide sequencing analysis confirmed a TCT right curved arrow TTT somatic mutation at codon 37 changing serine to phenylalanine in one of the primary tumors and its corresponding metastatic tumor . Immunohistochemical analysis displayed abnormally strong nuclear and widespread cytoplasmic expression of beta-catenin in these tumors with the mutation . Our observations suggest that , in some SCTs of the pancreas presented in the pediatric age group , mutated beta-catenin has an important oncogenic effect . Sporadic breast carcinomas with somatic P38398 gene deletions share genotype/phenotype features with familial breast carcinomas . BACKGROUND : High frequencies of loss of heterozygosity ( LOH ) are found in familial breast carcinomas with BRCA mutations . Although LOH of P38398 does not coincide with somatic P38398 mutations , reduced P38398 protein expression and hypermethylation indicate the involvement of P38398 in sporadic carcinogenesis . To further investigate the role of BRCA we determined LOH of P38398 and correlated this with LOH in other breast cancer-associated regions . MATERIALS AND METHODS : A total of 105 sporadic breast carcinomas were analysed for LOH in the regions of P38398 , P51587 , P04637 , Caveolin1 , " putative BRCA3 " , P60484 , Q13315 and P12830 and correlated it with clinicopathological features . RESULTS : We found an overall increase of LOH in carcinomas with simultaneous LOH of P38398 . Significantly higher LOH rates were detected in the regions of P04637 ( 80 % : 34.7 % ; p < 0.005 ) , 8q21 ( 72.7 % : 30.6 % ; p < 0.010 ) and 10q22-23 ( 21.1 % : 5.9 % ; p=0.043 ) . Moreover , estrogen receptor-negative carcinomas revealed LOH of P38398 more frequently than estrogen receptor-positive carcinomas ( 39 % : 12 % ; p=0.003 ) . CONCLUSION : These data indicate that LOH of P38398 coincides with a defect of the DNA repair pathway . Therefore , LOH of P38398 determines a subgroup of sporadic breast carcinomas sharing genotype/phenotype features with familial breast carcinomas . Novel and emerging drugs for rarer chronic lymphoid leukaemias . Rarer chronic lymphoid leukaemias represent a challenge to the clinicians due to the limited information on their pathogenesis , difficulties on setting up prospective clinical trials and to their refractoriness to drugs used in the most common form of chronic lymphocytic leukaemia ( CLL ) . In this review all these issues are addressed in three B-cell leukaemias : B-cell prolymphocytic leukaemia ( B-PLL ) , hairy cell leukaemia ( HCL ) and HCL-variant and three T-cell leukaemias : T-cell prolymphocytic leukaemia ( T-PLL ) , T-cell large granular lymphocytic leukaemia ( T-cell LGLL ) and adult T-cell leukaemia lymphoma ( ATLL ) . Data will be presented on the natural history , current therapies and emerging drugs potentially useful in the treatment of patients with these leukaemias . Emphasis is made on : 1- the novel agents targeting a variety of B and T-cell antigens expressed on the surface of the leukaemic cells ; these are either unconjugated monoclonal antibodies ( McAb ) such as DB00073 ( anti- P11836 ) , the second and third generation of anti- P11836 McAbs , DB00087 ( anti- P31358 ) , Siplizumab ( anti- P06729 ) , DB00111 ( anti-CD25 ) and KW-0761 , an anti-chemokine receptor 4 ( CCR4 ) or McAbs conjugated to toxins such as P20273 linked to the pseudomonas exotoxin or radiolabelled McAb ; 2- the use of new purine nucleosides such as nelarabine and 3- agents targeting deregulated genes in the leukaemic cells from these diseases such as the Poly ( ADP-ribose ) polymerase ( PARP ) Olarapib in T-PLL with deregulation of the ataxia telangiectasia mutated ( Q13315 ) gene . Data of phase I and II clinical studies with these agents as well as the potential and current use of other drugs are outlined . Targeting Q01196 / Q06455 -histone deacetylase repressor complex : a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in Q01196 / Q06455 -positive acute myeloid leukemia cells . In t(8;21) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) -containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( DB00313 ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . DB00313 causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i.e. , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that DB00313 treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i.e. , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase-dependent apoptosis . Taken together , these data support the notion that DB00313 might effectively target Q01196 / Q06455 -driven leukemogenesis through disruption of aberrant Q13547 function and that DB00313 should be integrated in novel therapeutic approaches for Q01196 / Q06455 -positive AML . DB00087 in the treatment of chronic lymphocytic leukemia . DB00087 is a humanized therapeutic monoclonal antibody ( MAb ) that recognizes the P31358 antigen , expressed on normal and neoplastic lymphocytes , monocytes , and natural killer cells . In 2001 , alemtuzumab was approved in the US and Europe to treat B-cell chronic lymphocytic leukemia ( CLL ) that had been treated previously with alkylating agents and was refractory to fludarabine . In heavily pretreated patients this MAb is able to produce response rates of about 40 % , and in symptomatic , previously untreated patients response rates of more than 80 % can be achieved . DB00087 can also be used in patients with CLL as a preparative regimen for stem cell transplantation ( P09683 ) and to prevent graft versus host disease . Moreover its in vivo use before or after P09683 may also potentially result in depletion of residual leukemia cells , especially in the autologous setting . Adverse events associated with alemtuzumab include acute first-dose reaction , hematologic toxicity , and infectious complications . Usually they are predictable , manageable , and acceptable in the context of CLL . However , in a significant percentage of patients , cytomegalovirus reactivation occurs during alemtuzumab therapy , and routine weekly monitoring with the polymerase chain reaction methodology is indicated . Moreover , antiviral and antibacterial prophylaxis is mandatory . Deficiency of a phosphatidylinositol-anchored cell adhesion molecule influences haemopoietic progenitor binding to marrow stroma in chronic myeloid leukaemia . The interactions between haemopoietic progenitor cells and marrow stromal cells that are essential for the regulation of normal haemopoiesis are defective in chronic phase chronic myeloid leukaemia ( CML ) . The presence of primitive progenitor cells ( blast colony-forming cells , Bl- Q15814 ) in the blood of patients with CML is reflected by their reduced capacity to bind to marrow derived stromal layers in vitro . Whereas normal bone marrow Bl- Q15814 bind irreversibly to cultured stromal layers ( and none are found in normal blood ) , the Bl- Q15814 in CML bind transiently and then detach . The normal cell adhesion mechanism is partially sensitive to treatment with phosphatidylinositol-specific phospholipase C ( Pl- P98160 ) , indicating the participation of a phosphatidylinositol ( Pl ) -linked structure ; however , when CML cells were treated with Pl- P98160 it had no effect on progenitor binding . Two other Pl-linked structures , decay-accelerating factor ( P08174 ) and lymphocyte function associated antigen-3 ( LFA-3 ) were normally expressed on P28906 positive CML cells and normally susceptible to Pl- P98160 treatment . The treatment of normal cells with Pl- P98160 , to mimic the situation in CML , resulted in the indiscriminate and inefficient binding of Bl- Q15814 to stroma . Moreover , treatment of the normal cells with 5637 conditioned medium ( CM ) , which contains haemopoietic growth factors , also reduced the binding capacity of normal Bl- Q15814 ; 5637CM treatment did not alter the expression of P08174 . It is proposed that a Pl-linked cell adhesion molecule ( P62158 ) is deficient in CML as a consequence of the constitutive activation of P00519 kinase whilst , in normal cells , CAMs attached in this manner are responsible for efficient adhesion to stroma and are regulated by growth factors . Allogeneic stem cell transplantation using alemtuzumab-containing regimens in severe aplastic anemia . DB00087 , a humanized anti- P31358 , IgG1 monoclonal antibody , is used to reduce graft-versus- host disease ( GVHD ) and aid engraftment after allogeneic haemopoietic stem cell transplant ( HSCT ) . Its associated low incidence of GVHD makes it an attractive alternative to anti-thymocyte globulin ( ATG ) in transplant conditioning regimen for severe aplastic anaemia ( P0DJI8 ) . We have reviewed the use of alemtuzumab-based conditioning regimen for HSCT in P0DJI8 and show that it results in sustained haematological engraftment , a very low incidence of chronic GVHD without an increase in viral infections . Intriguingly , alemtuzumab appears to induce tolerance post-HSCT with the findings of stable mixed T cell chimerism with full donor myeloid chimerism and the absence of chronic GVHD , and which persist on withdrawal of post-graft immunosuppression . Finally , its low toxicity profile may permit future application of HSCT to older patients with P0DJI8 who fail to respond to immunosuppressive therapy . DB00087 in the treatment of refractory acute rejection and bronchiolitis obliterans syndrome after human lung transplantation . Despite substantial improvements in early survival after lung transplantation , refractory acute rejection ( RAR ) and bronchiolitis obliterans syndrome ( BOS ) remain major contributors to transplant-related morbidity and mortality . We have utilized alemtuzumab , a humanized anti- P31358 antibody which results in potent lymphocyte depletion , in consecutive patients with RAR ( n = 12 ) or BOS ( n = 10 ) . All patients failed conventional treatment with methylprednisolone and antithymocyte globulin and received strict infection prophylaxis . DB00087 significantly improved histological rejection scores in RAR . Total rejection grade/biopsy was 1.98 +/- 0.25 preceding alemtuzumab versus 0.33 +/- 0.14 posttreatment , p-value < 0.0001 ( with a similar number of biopsies/patient per respective time interval ) . Freedom from BOS was observed in 65 % of RAR patients 2 years after alemtuzumab treatment . Although there was no statistically significant change in forced expiratory volume in 1 second ( FEV1 ) before and after alemtuzumab treatment in patients with BOS , a stabilization or improvement in BOS grade occurred in 70 % of patients . Patient survival 2 years after alemtuzumab for BOS was 69 % . Despite a dramatic decline in P01730 counts in alemtuzumab-treated patients , only one patient developed a lethal infection . Thus , we provide the first evidence that alemtuzumab is a potentially useful therapy in lung transplant recipients with RAR or BOS . [ DB00087 , a monoclonal antibody against P31358 : hopes and fears ] . P31358 , an antigen expressed on immune cells including mature T lymphocytes , is thought to be involved in immunomodulatory mechanisms . DB00087 is a humanized monoclonal antibody against P31358 , which causes a marked and long-term decrease in immune cells , especially P01730 -positive T lymphocytes . A few randomized clinical trials have revealed the efficacy of alemtuzumab to be much greater than that of interferon-β in patients with relapsing-remitting multiple sclerosis . However , the development of other autoimmune disorders , including autoimmune thyroid disorders and thrombocytic purpura , because of alemtuzumab application has been considered an obstacle in its widespread use . Targeted deletion of cannabinoid receptors P21554 and CB2 produced enhanced inflammatory responses to influenza A/PR/8/34 in the absence and presence of Delta9-tetrahydrocannabinol . We have previously reported that Delta-9-tetrahydrocannabinol ( Delta(9)-THC ) -treated mice challenged with influenza virus A/PR/8/34 ( PR8 ) developed increased viral hemagglutinin 1 ( H1 ) mRNA levels and decreased monocyte and lymphocyte recruitment to the pulmonary airways when compared with mice challenged with PR8 alone . The objective of the present study was to examine the role of cannabinoid ( CB(1)/CB(2) ) receptors in mediating the effects of Delta(9)-THC on immune and epithelial cell responses to PR8 . In the current study , Delta(9)-THC-treated CB(1)/CB(2) receptor null ( CB(1)-/-/CB(2)-/- ) and wild-type mice infected with PR8 had marked increases in viral H1 mRNA when compared with CB(1)-/-/CB(2)-/- and wild-type mice challenged with PR8 alone . However , the magnitude of the H1 mRNA levels was greatly reduced in CB(1)-/-/CB(2)-/- mice as compared with wild-type mice . In addition , Delta(9)-THC-treated CB(1)-/-/CB(2)-/- mice infected with PR8 had increased P01730 + T cells and P01579 in bronchoalveolar lavage fluid with greater pulmonary inflammation when compared with Delta(9)-THC-treated wild-type mice infected with PR8 . Delta(9)-THC treatment of CB(1)-/-/CB(2)-/- mice in the presence or absence of PR8 challenge also developed greater amounts of mucous cell metaplasia in the affected bronchiolar epithelium . Collectively , the immune and airway epithelial cell responses to PR8 challenge in Delta(9)-THC-treated CB(1)-/-/CB(2)-/- and wild-type mice indicated the involvement of CB(1)/CB(2) receptor-dependent and -independent mechanisms . DB00087 for the prevention and treatment of graft-versus-host disease . DB00087 is a humanized monoclonal antibody against the P31358 antigen , which is expressed on the surface of various hematopoietic cells such as B and T lymphocytes , and has been widely used for preventing acute graft-versus-host disease ( GVHD ) in allogeneic stem cell transplantation ( P09683 ) . Administration of 100 mg alemtuzumab before transplantation has resulted in a low incidence of acute GVHD in HLA-matched and mismatched transplantation from either related or unrelated donors . However , because alemtuzumab could remain in the blood at the lympholytic level 1-2 months after transplantation , immune reconstitution was substantially delayed , leading to a high incidence of viral infection and relapse . A dose reduction of alemtuzumab was attempted in a reduced-intensity conditioning setting to facilitate immune reconstitution , and this resulted in earlier immune reconstitution , but the clinical benefits were unclear . The dose of alemtuzumab and the timing of its administration should be optimized to maximize the benefit of acute GVHD suppression and minimize the risk of infection and relapse . Another strategy to facilitate immune reconstitution and augment anti-tumor effects is donor cell infusion of T and NK cells . Although there is accumulating evidence regarding the use of alemtuzumab for acute GVHD prevention , information on the salvage treatment for steroid-refractory acute and chronic GVHD is still limited . In vivo cytokine responses to interleukin-2 immunotherapy after autologous stem cell transplantation in children with solid tumors . The potent immunostimulatory cytokine interleukin-2 ( P60568 ) has been extensively investigated for its potential to induce anti-tumor immunity in a number of tumor models . Only recently the complex interplay of mutually suppressive or supportive cytokines of the P60568 -induced network of cytokines has been better characterized . The aim of this study was to assess which of these in vitro findings are reproducible in vivo in recipients of stem cell transplants ( P09683 ) , since in these patients long- lasting impairments in cytokine inducibility have been described . We have therefore studied the kinetics of putative modulators and mediators of P60568 -induced immune activation , namely IL-1beta , P05112 , P05113 , P22301 , IL-12 , soluble P48023 ( sFasL ) , and GM- P04141 during P60568 therapy . All patients were children or adolescents suffering from solid tumors with poor prognosis who received three 5-day courses of high-dose intravenous P60568 as an adjuvant to their radio-chemotherapy and autologous P09683 . While IL-1beta , P05112 and IL-12 were not , and sFasL was only mildly affected by the P60568 therapy , we observed a consistent and early rise of P22301 , P05113 , and GM- P04141 . These increases were rapidly reversible after discontinuation of P60568 therapy . The inducibility of P22301 , P05113 and GM- P04141 was more pronounced with increasing time from the P09683 , and in the third cycle reached an order of magnitude as in high-dose P60568 patients without P09683 . Together with the abundant in vitro data , these findings may help devise a combination immunotherapy permitting stronger anti-tumor effects , but lesser adverse effects . Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . We observed that the intracellular calcium content of P. bainier 229-7 mycelia was increased in response to exposure to high external Ca(2+) concentrations . Both ginsenoside Rd biotransformation and β-glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca(2+) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92.44 % was observed and maximal β-glucosidase activity of 0.1778 U was reached in a 72-h biotransformation . The Ca(2+) channel blocker Verapamil blocked the trans-membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β-glucosidase activity and ginsenoside Rd content decreased by 36.0 and 29.2 % respectively after a 72-h incubation in the presence of 0.05 mM P62158 ( P62158 ) antagonist DB00850 . These results suggest that both Ca(2+) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β-glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi . Cytokine-induced beta-galactoside alpha-2,6-sialyltransferase in human endothelial cells mediates alpha 2,6-sialylation of adhesion molecules and P20273 ligands . Sialic acids decorating blood and cell surface proteins can play important roles in various biological processes . The inflammatory cytokines tumor necrosis factor-alpha ( P01375 ) and interleukin-1 , as well as bacterial lipopolysaccharide , can activate vascular endothelium , increasing expression of several surface glycoproteins . Here we show that treatment of cultured human endothelial cells ( O14777 ) with P01375 , interleukin-1 , or lipopolysaccharide causes increased expression of the enzyme beta-galactoside alpha-2,6-sialytransferase ( alpha 2-6STN ) . P01375 was most effective , inducing a 3.5-fold enhancement of cell-associated sialytransferase activity by 72 h . In addition , activated O14777 secreted a large portion of the induced sialyltransferase activity into the medium . Analysis of labeled O14777 showed both a relative and an absolute increase of alpha 2,6-linked sialic acid on N-linked oligosaccharides after P01375 stimulation . This coincided with increased expression of endothelial glycoproteins bearing N-linked glycans with alpha 2,6-linked sialic acid detected by the lectin Sambucus nigra agglutinin . The cytokine-inducible endothelial cell adhesion molecules P16581 , P05362 , and P19320 are among these glycoprotein substrates for alpha 2-6STN . These changes also correlated with a substantial increase in binding sites for P20273 beta , a mammalian lectin known to recognize oligosaccharides carrying multiple copies of alpha 2,6-linked sialic acid . Northern analysis revealed increased levels of mRNA encoding alpha 2-6STN . Thus , activation of endothelial cells during inflammatory and immunological processes may induce alpha 2-6STN , which can participate in sialylation of other activation-dependent molecules . In vivo alemtuzumab enables haploidentical human leukocyte antigen-mismatched hematopoietic stem-cell transplantation without ex vivo graft manipulation . BACKGROUND : DB00087 , a humanized monoclonal antibody directed against human P31358 , has a strong lympholytic effect . This study evaluates the safety of unmanipulated peripheral blood stem-cell transplantation from two or three loci-mismatched related donors using alemtuzumab in vivo . METHODS : A total body irradiation-based regimen was used in young patients , whereas those 50 years or older received fludarabine-based conditioning . DB00087 was added to these regimens by intravenous infusion at 0.2 mg/kg per day for 6 days ( days -8 to -3 ) . RESULTS : We treated 12 patients with a median age of 49.5 years . Eight patients demonstrated active disease , and four patients demonstrated acute leukemia in high-risk remission . All achieved neutrophil engraftment a median of 17.5 days after transplantation with complete donor-type chimerism . The cumulative incidence of grades III to IV acute graft-versus-host disease was only 9 % . Infection-related deaths were not observed . CD3+/ P01730 + and CD3+/CD8+ T cells were strongly suppressed within 2 months after transplantation , but recovered on day 90 . Relapse was observed in five of eight patients who underwent transplantation for active disease , whereas none of the three patients who underwent transplantation in first remission had a relapse . CONCLUSIONS : We conclude that in vivo alemtuzumab enables haploidentical hematopoietic stem-cell transplantation without ex vivo graft manipulation . [ A colorimetric method of O14777 toxin hemolysis test for diagnosis of paroxysmal nocturnal hemoglobinuria ] . The purpose of the study is to establish a colorimetric method of O14777 toxin hemolysis test for diagnosis of paroxysmal nocturnal hemoglobinuria ( PNH ) . RBCs from normal persons and patients with PNH and non-PNH anemia were treated with O14777 toxin secreted by Aeromonas hydrophila J-1 strain and the absorbance at 630 nm was measured to quantitate the extent of hemolysis . The results demonstrated that the RBCs from PNH patients showed resistance to the toxin hemolysis , which was in accord with the percentages of P13987 (-) cells , while the RBCs from normal persons and non-PNH anemic patients were nearly totally lysed . It is concluded that the method can be considered as a simple , specific and reliable method for the diagnosis of PNH . [ Measurement of rifampicin and clarithromycin in serum by high-performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug-metabolizing enzymes , making drug interactions a very important clinical problem . DB01211 ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug-metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high-performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC/MS/MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r=0.975 , p < 0.01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC/MS/MS analysis ( r=0.995 , p < 0.01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations . Increased levels of Candida albicans mannan-specific T-cell-derived antigen binding molecules in patients with invasive candidiasis . In addition to cytokines , P01730 + T cells have been found to secrete soluble , T-cell-derived antigen binding molecules ( TABMs ) . These antigen-specific immunoproteins are thought to have immunoregulatory properties in the suppression of cell-mediated immunity ( CMI ) because they often associate with interleukin-10 ( P22301 ) and transforming growth factor beta . Decreased CMI causes susceptibility to infections caused by organisms which are normally nonpathogenic . In this situation , e.g. , Candida albicans saprophytism may develop into invasive candidiasis . The difficult diagnosis of invasive candidiasis is based on the findings obtained from blood cultures and with tissue biopsy specimens , with some additional diagnostic value gained by the detection of Candida albicans mannan antigenemia and antimannan antibodies . In the present study , Candida albicans mannan-specific TABM ( P62158 -TABM ) levels in the sera of patients with invasive candidiasis ( n = 11 ) , Candida colonization ( n = 11 ) and noncolonization ( n = 10 ) , recurrent vulvovaginal candidiasis ( n = 30 ) , and atopic eczema dermatitis syndrome ( n = 59 ) and healthy controls ( n = 30 ) were analyzed . For 14 participants , the effect of mannan stimulation on TABM production and gamma interferon ( P01579 ) and P05112 mRNA expression by peripheral blood lymphocytes was also studied . It was demonstrated that P62158 -TABM production was the highest in patients with invasive candidiasis and that P62158 -TABM levels could distinguish Candida-colonized patients from noncolonized patients . In addition , the P62158 -TABM level was directly related to mRNA expression for P05112 but not P01579 . These results reinforce the view that TABMs are associated with decreased CMI , immunoregulation , and the T-helper cell 2-type immune response . DB00087 as a bridge to allogeneic P09683 in atypical hemophagocytic lymphohistiocytosis . BACKGROUND : A 39-year-old woman with no relevant medical or family history was admitted to hospital with episodic fever , which persisted despite antibiotic therapy . Other notable findings at admission were splenomegaly , pancytopenia , hyponatremia , elevated levels of liver enzymes , hyperferritinemia and hypofibrinogenemia . INVESTIGATIONS : Physical examination , laboratory tests , rheumatic marker serology , pathogen detection assays , complete blood counts , measurement of levels of ferritin , fibrinogen , triglycerides and soluble CD25 , natural killer cell functional studies , P14222 mutation analysis , renal biopsy , bone marrow biopsy , CT imaging of the chest and abdomen . DIAGNOSIS : Idiopathic , atypical hemophagocytic lymphohistiocytosis . MANAGEMENT : Initial treatment with antibiotics was followed by immunosuppressive therapy ( including intravenous immunoglobulin , ciclosporin , infliximab , corticosteroids and etoposide ) . Remission was achieved by treatment with the anti- P31358 monoclonal antibody , alemtuzumab , after which allogeneic stem-cell transplantation ( with reduced-intensity conditioning treatment and graft-versus-host disease prophylaxis ) resulted in a definitive cure .