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At least 25 were killed in a riot which saw protestors fighting Ukrainian police. This is said to be the most violence the ex-Soviet republic has seen since their independence. On Tuesday thousands of police armed with stun grenades and water cannons rushed at protestors camped out in Kiev's Independence Square.
Ukrainian President Viktor Yanukovych released a statement Wednesday blaming the opposition for the country's violence.
"Oppositional leaders neglected the main principle of democracy – the power is gained not on the streets or squares, but at the polls," Yanukovych said. "I have repeatedly told them – the elections will be soon. If people vote for you, you will have power. If people do not vote for you, you will not have power. But it should happen legally, under the Constitution of Ukraine.
"They have crossed the line after calling people for weapon," the President continued. "It is a flagrant violation of law. The perpetrators must stand before the court that will determine their punishment. It is not my whim, it is my duty as a guarantor of the Constitution - to ensure public peace in the country and justice for everyone."
Of those killed was Ukrainian journalist Vyacheslav Veremiy. The journalist was killed by a group of paid government "helpers" whose sole purpose is to create disorder in the country. Witnesses say these helpers are armed with bats and guns.
Veremiy was attacked at around 2 a.m. Wednesday when his taxi was ambushed by a group of armed thugs near a police station. The driver and passenger in the car were beaten while Veremiy was shot in the chest.
European leaders are set to address the violence on Thursday in Brussels. French President Francois Hollande says he is in favor of EU sanctions against the Ukraine.
"Whoever is responsible for decisions that lead to bloodshed in the center of Kiev or elsewhere in Ukraine will need to consider that Europe's previous reluctance for sanctions must be rethought," Hollande was quoted as saying in the French press.
Germany also came out in favor of sanctions. Foreign Minister Frank-Walter Steinmeier says the option is on the table due to the escalation in violence. This comes as a surprise as Germany had originally rejected any calls for sanctions.
Riots also broken out in Venezuela although the opposition has recently surrendered. Their leader, Leopoldo Lopez, is due in court on Wednesday and may face charges for allegedly provoking violence during protests against the socialist government.
Five were killed in these Venezuelan protests against President Nicolas Maduro's government.
[Source: President Viktor Yanukovych, USA Today]


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Should I study calculus watching youtube videos or reading the book?
There are very good youtube videos but also the classic massive calculus books. Sometimes I watch a video and don't remember anything., but reading a math book take hours.The same for physics.. So what is your advice?
6 Answers
- 1 month ago
I found that problem solving was the only thing that really helped me learn calculus. Do the homework problems, and then do them over again, and them do them a third time. A crashing bore when you could be out partying. Watching videos is just like doing "programmed instruction".... Uh huh, yeah, uh huh, yeah.....when you get an actual problem you have no clue Do you want to learn it or not? Do the problems alot if you do. You will be shocked and surprised about how much sense it begins to make.
- formengLv 61 month ago
It depends on what your goal is. I would recommend Khan academy as a starter. Math books do a lot of proving theorems that are not necessary for people other than mathematicians and engineers. Actually, I have a MSEE and I never did much proving of theorems in my work. But you'll need to know about it if you expect to get a masters degree.
- qrkLv 71 month ago
Depends on how you learn. The first first semester of calculus (derivatives) can easily be learned by reading the book. This will take about 1 to 1.5 months if you are serious about it. Integral calculus is a bit harder, but can be learn straight from the book. There are lots of tricks involved with integral calc where having a teacher is helpful if they are a good instructor. For both semesters, you need to solve lots of problems, at least 10+ per day.
- oil field trashLv 71 month ago
All the way through engineering in college I found reading the book and attending the lectures was the best combination. Since the classes work is in steps you don't have to read the whole book at once but just the part that matches the lectures.
- How do you think about the answers? You can sign in to vote the answer.
- DixonLv 71 month ago
You will only find out by trying both. My experience is that if I start with a book I can follow it but I don't really see the bigger picture beyond each step, whereas as a spoken explanation gives me a good sense of the overall ideas. But then after a lecture it is good to have a book because otherwise there is no reference that you quickly dive into. And when I have had the time I found that even tho reading first didn't completely sink in, it was much easier to follow a spoken lecture.
- 1 month ago
In general, everyone learns in either one of or a combination of four methods:
Kinesthetic (learning by doing, like moving stuff around or building things)
Practice will always help you learn, but you can help yourself by knowing how it is you remember things. If you don't remember stuff from a video, it's likely learning by listening isn't really your best method. But, if you learn by reading/writing, what you could do is have the video running and write down notes as you do it, or you could watch part of the video then look in your book for practice questions and do a few of those, and take it chunk by chunk. If you try mixing up different types of learning (listening to a video and drawing a diagram/writing it down or writing down elements of the equation on little bits of paper and physically moving them around) you might pick things up a little better and make your learning more interactiveSource(s): I learned I was a visual learner a week before my final exams, I thought I was a Reading/Writing learner then I realised I was remembering phrases from their positioning on the page I wrote them on instead of remembering the actual words themselves

subset: commoncrawl


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Metro Detroit Award Winning Wedding Planners creating fabulous wedding experiences for busy and stressed couples. We handle the details bringing your dreams to fruition. Farmington, MI 248.408.4602 ~ email@example.com ~ www.yourethebride.com Michigan Event Planner Romantic, Simple Elegant, Traditional Weddings, Detroit Day of Coordinator, Detroit Michigan Weddings, Wedding Management ~ Brand Influencer ~ Weddings, Events, Home Decor, Beauty + Style
Sunday, September 5, 2010
Alice in Wonderland anyone?
Here are some ways you can have a Alice in wonderland theme wedding:
A Mad Hatter wedding cake
Have an outdoor or garden wedding reception
You can serve cups of teas as your guests arrive (just like the Mad Hatter's tea party!)
Get your servers or waiting attendants to wear the Mad Hatter's Hat or Alice's blue and white dress combo!)
For your wedding favors, you can have personalized tea bags or tea cups.
If you are a wedding/event professional don't forget about the upcoming NACE meeting on October 20th that is going to feature this theme. I can't wait to see it!!
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DOUBLE Surgical Scrub Sink
Features of DOUBLE Surgical Scrub Sink:-
- Automatic/foot operated scrub sink. It is an advanced compact fully stainless steel scrub sink which offers two scrub stations.
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Item Code: CMP2SSMFHC14-4
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Delivery Time: 10


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Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line–derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers. Mol Cancer Ther; 15(1); 60–71. ©2015 AACR.
Cancer cells acquire several stochastic characteristics that provide growth and survival advantages (1). Multiple cellular factors affecting these processes, including tumor suppressor and oncogenic proteins (2–4), are deregulated in cancer, perturbing their natural function. One manner in which these proteins may be dysregulated is via mislocalization within the cell. Exportin 1 (XPO1; or chromosome maintenance region 1, CRM1) is the prominent nuclear export receptor that controls nucleo-cytoplasmic localization of many proteins (2) and is overexpressed in many cancer types both solid and hematologic in origin, including multiple myeloma as shown by us and others (4–6), promoting aberrant cytoplasmic accumulation of its cargo. Small molecule, selective inhibitors of nuclear export (SINE) force nuclear retention of deregulated targets by preventing XPO1/cargo interaction, thereby reestablishing normal tumor suppressive functions and rendering cancer cells responsive to other chemotherapeutics. We and others have demonstrated the cytotoxic effects of SINE in multiple myeloma (4–7). Currently, multiple phase I/II clinical trials are enrolling to test the efficacy of the orally available SINE, selinexor, in patients with advanced stage pancreatic, prostate, salivary gland, and rectal cancers, glioblastoma, melanoma, non-Hodgkin's lymphoma, acute myeloid leukemia, and relapsed/refractory multiple myeloma (R/R multiple myeloma).
Despite significant advances in treatment options, multiple myeloma remains incurable and the majority of patients will relapse and become refractory to most agents. Proteasome inhibitors (PI), including the second-generation irreversible PI carfilzomib, and immunomodulatory agents are among several classes of drugs that have improved the rate and duration of patient responses (8). Both classes of drugs target not only the myeloma tumor cell but also the bone marrow microenvironment, the latter of which supports tumor cell growth and drug resistance, likely contributing to their efficacy when used together. Despite the success of combination treatment regimens using these drugs, many patients fail to achieve a durable response, necessitating further investigation into novel therapeutic options.
The induction of cell death and autophagy are underlying commonalities highlighted by the cellular effects of PI and SINE. Recently, autophagy emerged as a myeloma cell death pathway and alternate to the ubiquitin–proteasome pathway by which excess and/or dysfunctional proteins and organelles are degraded and recycled (9–13). RNA knockdown of XPO1 is sufficient to induce autophagy (14) and is cytotoxic to myeloma cells (4), and, similarly, SINE compounds induce the degradation of XPO1 protein. PI promote accumulation and aggregation of proteins destined to be degraded by the proteasome, and these excess proteins are instead degraded via the autophagic machinery. Myeloma cells require basal autophagy for survival and perturbing the balance between limited and hyperactive autophagy promotes apoptosis-independent cell death (12). Given the known effects of both SINE and PI on apoptosis, the established effects of PI on autophagy, and the putative effects of SINE on autophagy, we hypothesized that the combination of selinexor and carfilzomib could augment the antimyeloma activity of either agent alone and sought to determine cellular mechanisms by which these drugs exert their effects.
Materials and Methods
Cell lines and patient samples
Human myeloma cell lines (HMCL) were obtained from the American Type Culture Collection (ATCC) in the last 3 years and authentication was not performed. HMCL and patient plasma cells (PC) were cultured in RPMI 1640, 10% FBS, and antibiotics in a 5% CO2 humidified incubator. Carfilzomib-resistant RPMI 8226/Dox40 cells were previously described (15, 16). PC were purified from multiple myeloma patient bone marrow aspirates using immunomagnetic positive selection of CD138+ cells (Stem Cell Technology) and determined to be >80% enriched by examining Wright-Giemsa stained cytospins. After Institutional Review Board approval, informed consent to treatment and sample procurement was obtained from patients.
Detection of autophagy and aggresome formation
Autophagy was monitored in live cells using the Cyto-ID Autophagy Detection Kit (Enzo Life Sciences) according to manufacturer recommendations by fluorescence microscopy.
Aggresome formation was detected in fixed cells using the ProteoStat Aggresome Detection Kit (Enzo Life Sciences) according to the manufacturer's recommendations. Images were captured using a Panoramic Scan whole slide scanner (Cambridge Research and Instrumentation) and analyzed using 3DHistech software. Fold changes in the mean fluorescence intensity (FI; determined using ImageJ software) from the Hoescht and aggresome dye signals were calculated from ten random fields from each slide/treatment and determined by [(FI aggresome dye)/(FI Hoescht)].
Immunofluorescence microscopy
HMCL were cytospun onto slides, fixed in formaldehyde (4% in 1× PBS), permeabilized with methanol, and quenched overnight with sodium borohydride (2 mg/mL in PBS). Slides were blocked with 2% BSA in PBS, incubated with primary antibody for 2 hours at room temperature, washed, and incubated in secondary antibody for 1 hour at room temperature while protected from light. After washing, slides were mounted with coverslips and images were captured using a Zeiss Axioplan upright fluorescence microscope equipped with a CCD camera (Sensys) and pseudocolored using IPLab imaging software (Becton Dickinson).
MTT assay
HMCL were plated in 96-well plates at 4 × 105 cells/mL after drug dilutions were made and treated for 72 hours. MTT (thiazolyl blue tetrazolium bromide; Amresco) was added and incubated for up to 6 hours at 37°C. Cells were lysed and absorbance was read at 570 nm on a Tecan Safire microplate reader.
GST pull-down
GST pull-downs were performed as previously described (17) using MM1.S cells (2 × 107) left untreated or treated with selinexor (50 nmol/L) and carfilzomib (50 nmol/L) for 18 hours.
Murine xenograft study
NOD-SCID mice were inoculated subcutaneously with 1 × 107 NCI H929 cells. When tumors reached a mean volume of 100 mm3, mice were randomized into groups of eight and treated with vehicle (0.6% Pluronic F-68, 0.6% PVP in water), selinexor (5 or 10 mg/kg) thrice weekly per os, or twice weekly carfilzomib (1.5 or 3 mg/kg) intravenously, alone or in combination. Weights were recorded daily and tumor volume was measured thrice weekly. Animals with greater than 13% weight loss were rested from dosing until weight loss recovered to no more than 5%. This study was carried out by Pharmamodels LLC in accordance with the guidelines for animal welfare and with the approval of the IACUC.
Statistical analysis
GraphPad Prism software was used for calculation of all statistics of significance and IC50 values. Combination indices were determined using Calcusyn software (Biosoft).
SINE and PI treatment both induce hallmarks of apoptosis and autophagy
First, we tested the effects of XPO1 inhibition alone and in combination with carfilzomib on induction of autophagy markers. Characteristically, autophagy involves sequestration of cytoplasmic contents into double-membrane vesicles, known as autophagosomes, for delivery to lysosomes and degradation. Formation of autophagy-associated membranes can be monitored by the processing and accumulation of microtubule-associated light chain 3 (LC3), a protein that undergoes lipidation and cleavage upon insertion into nascent membranes (18). RPMI 8226 and MM1.S cells were treated up to 96 hours with either selinexor or carfilzomib alone and in combination. In response to selinexor alone, Western blot analysis revealed prompt processing and accumulation of LC3 II (Fig. 1A) and sequestosome 1 (p62), an LC3-interacting protein and scavenger of ubiquitinated proteins fated for degradation via autophagy that is also consumed by autophagy (19). Caspase-10 levels decreased modestly during the course of treatment, which is associated with the induction of autophagy in myeloma cells (12). Treatment with carfilzomib also promoted LC3 II processing, accumulation and degradation of p62 and LC3 II, and loss of caspase-10, albeit in a faster time frame than selinexor. IRF4, a transcriptional regulator of caspase-10, BCLAF1, and Bcl-2 expression were impaired, which may enhance autophagy induction (20). Combination treatment with SINE and PI accelerated these effects, which were similarly demonstrated in response to prolonged pan-caspase inhibition, a myeloma cell autophagy inducer (Supplementary Fig. S1; ref. 12).
Next, we examined the morphology of myeloma cell lines treated with each inhibitor alone and in combination after Wright-Giemsa staining. Features of both autophagy and apoptosis were prominent in all three myeloma cell lines. Both selinexor and carfilzomib alone promoted accumulation of cytoplasmic vacuoles, marginalization and degradation of nuclear material, and breakdown of cell membranes and blebbing of cellular contents (Fig. 1B), which occurred faster in the presence of both. MM1.S cells loaded with a dye that recognizes autophagosome formation demonstrated a moderate increase in dye accumulation with either drug alone and this effect occurred faster with the combination (Fig. 1C). We also monitored aggresome formation, which is enhanced in the setting of diminished proteasome activity (21), and detected a significant increase in response to either inhibitor alone and with the combination (Fig. 1D and Supplementary Fig. S2). These data support our hypothesis that SINE and PI have common cellular effects, warranting further investigation into their interaction.
Synergistic antimyeloma activity of selinexor and carfilzomib
Next, we tested the effects of combined treatment with selinexor and carfilzomib on myeloma cell viability. Statistical analysis of MTT assays determined drug combination indices (CI) to be less than 1 in response to treatment with both selinexor and carfilzomib in three myeloma cell lines, indicating a synergistic relationship (Fig. 2A). Western blot analysis of MM1.S cells treated with the combination demonstrated augmented activation of caspase-8, -9, and -3 and increased PARP cleavage as compared with single-agent treatment (Fig. 2B). We detected concomitant accumulation of LC3 II and loss of caspase-10, further supporting that induction of autophagy correlates with activation of apoptotic machinery. Importantly, we investigated the effects of selinexor and carfilzomib in PC derived from R/R multiple myeloma patients who failed on combination treatment regimens that included carfilzomib. Western blot analyses demonstrated that PC from three of the four R/R multiple myeloma patients responded well to either selinexor or carfilzomib alone, and clearly had enhanced markers for autophagy (patient 7) and apoptosis (patients 7, 8, and 9) when the combination was used. Interestingly, PC from patient 10, who progressed on a carfilzomib-containing regimen, did not have a robust response to carfilzomib as a single agent, but responded to selinexor (Fig. 2C and Supplementary Fig. S3). To test the effects of these drugs in a more defined setting of drug resistance, we also assessed the cytotoxicity of SINE and PI in a subclone of RPMI 8226 cells (16), Dox40, which were created by continuous exposure to doxorubicin and subsequently found to overexpress the multidrug resistance p-glycoprotein and are cross-resistant to PI (15, 16, 22). Although selinexor alone was able to reduce the viability of the Dox40 cells, there were no additive or synergistic effects of the combination (Fig. 2D).
We further investigated the effects of selinexor and carfilzomib in a murine myeloma xenograft model. Although treatment with either carfilzomib or selinexor alone reduced growth of xenografts, the combination of both drugs completely abrogated tumor growth (Fig. 2E). Single-agent treatment was well-tolerated; however, two mice from the highest dose combination group had to be rested from treatment due to excessive weight loss (Supplementary Fig. S4). Antitumor responses of all nine treatment groups are shown in Supplementary Fig. S5. Altogether, these data underscore the potent synergistic antimyeloma effects of selinexor and carfilzomib and provide preclinical rationale for deploying this drug combination for multiple myeloma treatment.
Role of caspase-10 activation in SINE/PI-induced cell death
Next, we investigated the mechanism of cell death induced by combined XPO1 and proteasome inhibition. We focused on caspase-10 because it was recently highlighted as a key cell survival factor for all genotypes of myeloma (12) and is less well characterized due to its absence from the rodent lineage. Our results thus far suggest that full-length caspase-10 levels decrease in response to selinexor or carfilzomib treatment, which possibly accounts for increased autophagy because caspase-10 limits autophagy in HMCL (12). Examination of other caspases shows cleavage and activation of the caspase-10 ortholog caspase-8, and caspase-9 and -3. To determine if caspase-10 is also activated in response to selinexor and carfilzomib, we assayed its protease activity and the presence of cleaved/activated fragments and found both increase with either selinexor or carfilzomib alone, and significantly so with the combination (Fig. 3A). As an initiator caspase in the context of certain death receptor apoptotic pathways (23), we sought to determine whether caspase-10 enzymatic activity was necessary for activation of other caspases. We monitored protease activity of caspase-1 (negative control), -3, -8, -9, and -10 in response to combined selinexor/carfilzomib treatment and also cotreated cells with a peptide inhibitor of caspase-10, Q-AEVD-OPH (Fig. 3B). Inhibition of caspase-10 catalytic activity abolished SINE/PI-induced caspase activity as well as PARP cleavage (Fig. 3B and inset).
In response to certain stimuli, caspase-9 can promote caspase-10 activation (24). Therefore, we also monitored the effects of the caspase-9 inhibitor LEHD.fmk on SINE/PI-induced caspase activation. Western blot analysis showed that, although LEHD.fmk affected caspase-9 activation at the lowest dose (10 μmol/L), activation of caspase-3, -8, and -10 was only modestly impaired (Fig. 3C). Furthermore, unlike caspase-10 inhibition, PARP cleavage could not be abrogated even at the highest dose of LEHD.fmk (100 μmol/L). We also tested the effects of siRNA-mediated inhibition of caspase-9 expression and found that loss of caspase-9 had no effect on activation of caspase-3, -8, and -10 and PARP cleavage (Fig. 3D). We monitored overall cell viability in response to cotreatment with either LEHD.fmk, Q-AEVD-OPH, or pan-caspase inhibitor Q-VD-OPH and found that while all three inhibitors were able to significantly protect against selinexor/carfilzomib-induced cell death, caspase-10 inhibition more significantly reversed cell death than either pan- or caspase-9 inhibition (Fig. 3E). Treatment with each inhibitor alone had no significant effect on cell viability (Supplementary Fig. S6). Importantly, CRISPR-mediated stable knockdown of caspase-10 prevented apoptosis in response to single agent and combined SINE/PI treatment (Fig. 3F). Together, these results underscore the novel role of caspase-10 as a key upstream caspase in the context of SINE/PI-induced apoptosis.
Novel mechanism of intracellular caspase-10 activation
During proteasome inhibition, and by extension autophagy, ubiquitinated caspase-8 forms an apoptosis-inducing complex on intracellular membranes that depends on LC3 and p62 (25, 26). p62 has a newly-appreciated role in modulating cell fate by interacting with key signaling proteins marked by ubiquitination and can promote apoptosis or survival depending on the stimulus (27). Given the high degree of homology between caspase-8 and -10, we wanted to determine whether there was any relationship between caspase-10 and p62 or LC3. MM1.S cells were treated with SINE/PI and CHAPS-soluble and insoluble fractions, the latter containing intracellular membranes derived from autophagosomes, were analyzed by Western blot. We were struck by the presence of "preactivated" cleaved caspase-10, -8, and -9 exclusively in the insoluble fractions of untreated cells, yet only a minor presence of the corresponding full-length caspase (Fig. 4A). Levels of p62 were also detectable, albeit by long exposure (not shown), and LC3 I was cytoplasmic, whereas LC3 II, which becomes embedded in nascent autophagosomes, was predominantly in the insoluble fraction. Upon treatment with selinexor/carfilzomib, we detected dramatically increased levels of cleaved/active forms of caspase-10, -8, and -9 almost exclusively in the CHAPS-insoluble fraction. Caspase-3 did not have membrane-associated "preactivated" amounts in untreated cells and its distribution was markedly less exclusively separated upon selinexor/carfilzomib treatment. Total levels of p62 dramatically increased in response to SINE/PI treatment, and its distribution was comparably spread between the CHAPS-soluble and insoluble fractions. Two fragments of p62 appeared in the insoluble fraction and the molecular weights correspond to previously-identified caspase-cleaved products (28). Q-AEVD-OPH cotreatment suppressed activation of all caspases, as shown in Fig. 3B, and impaired p62 cleavage, but had no effect on LC3 processing or accumulation. Q-AEVD-OPH alone was not able to reduce the levels of "preactivated" caspase-10, -9, and -8 below that of mock-treated cells, suggesting that relocalization and recruitment to intracellular membranes may influence caspase activation.
To further explore this intriguing and novel relationship between p62 and caspase-10, we assessed their subcellular distribution and ability to interact. Using immunofluorescence microscopy, untreated cells showed diffuse, occasional punctate staining of caspase-8 and -10 and p62. However, selinexor/carfilzomib-treated cells demonstrated overt intracellular punctate staining and colocalization of caspase-10 and -8 with p62 (Fig. 4B). Detection of cell surface expression of Fas and its lack of colocalization with p62-containing puncta further supports the intracellular nature of these aggregates (Supplementary Fig. S7). GST-tagged p62 associated with full-length endogenous caspase-10 and presumably full-length caspase-8 modified by ubiquitination from untreated cell lysates, as well as LC3 II and poly-ubiquitinated proteins, but not LC3I or caspase-9 or -3 (Fig. 4C). Interestingly, despite their colocalization, the association between caspase-8 and -10 and GST-p62 was lost in lysates from selinexor/carfilzomib-treated cells; however, the presence of LC3 II and poly-ubiquitinated proteins increased.
Next, we tested the effects of LY294002 (LY), a PI3K inhibitor that blocks autophagosome membrane nucleation, on the distribution of caspases and autophagy players. LY treatment alone reduced levels of "preactivated" caspase-8 and -10 and accumulation of LC3 II in the insoluble fraction and pretreatment with LY prior to SINE/PI modestly reduced cleavage and redistribution of caspase-8 and -10 and p62 to the insoluble fraction (Fig. 5A). siRNA-mediated knockdown of Beclin 1, a key upstream autophagy initiator (29), impaired redistribution and activation of caspase-10 and -8 (Fig. 5B). Interestingly, p62 levels were dramatically reduced, which could account for diminished caspase-10 and -8 recruitment and activation, although more work is needed to determine specifically how impaired Beclin 1 expression influences caspase-10 and -8 activation beyond the potential inhibition of autophagosome formation.
Together, these results suggested that perhaps p62 plays a role in promoting assembly of caspase-activating complexes along intracellular/autophagic membranes and that caspase-10 is a novel upstream caspase activator in the setting of combined XPO1 and proteasome inhibition.
Combined selinexor/carfilzomib treatment overcomes cytoprotective autophagy
Because autophagy can be cytoprotective in the setting of limited nutrients or other cell-stressing conditions (11) yet also serve as a myeloma cell death pathway, we wanted to determine the contribution of autophagy to the overall lethal effects of SINE/PI. We tested the effects of bafilomycin, which blocks the final steps of autophagy by preventing lysosomal acidification, on apoptosis induction and cell viability. High doses of bafilomycin had minimal effects on apoptosis either alone or with combination SINE/PI treatment, but promoted LC3 II accumulation as expected (Fig. 6A and left inset Fig. 6B) and reduced overall cell viability (right inset Fig. 6B). We assessed differences in cell viability at sublethal yet autophagy-inhibiting doses of bafilomycin in combination with increasing doses of selinexor/carfilzomib, but did not detect significant changes, suggesting that autophagy may not provide a cytoprotective effect in the setting of strong commitment to apoptosis promoted by the combination of SINE and PI (Fig. 6B). These data show that, in this context, autophagy is neither protective against nor additive to selinexor/carfilzomib-induced cell death.
To further explore the relationship between the induction of apoptosis and autophagy, we performed a time course with SINE/PI and assessed caspase activation, cleavage of apoptotic substrates, and LC3 processing. We also assessed levels of total Akt and its activation state given its pivotal role in myeloma cell survival and drug resistance (30), and its ability to limit autophagy (31). Interestingly, we found simultaneous activation of caspase-10, -8, -9, and -3 and cleavage of both PARP and Akt beginning 6 hours after treatment (Fig. 6C), which may account for the rapid phenotypic changes associated with apoptosis and autophagy seen in Fig. 1B and C. Akt is cleaved during apoptosis, resulting in its inactivation and subsequent induction of autophagy (31, 32). Levels of active Ser473 phosphorylated Akt increased until 8 hours, when Akt cleavage peaked, then declined to baseline levels. p62 levels accumulated until 16 hours when we saw a dramatic increase and its cleavage. LC3 II accumulated early at 2 hours, suggesting autophagy-associated membrane formation may precede apoptosis induction, until 16 hours when the presence of LC3 I was no longer detectable and LC3 II levels began to decrease, likely due to autophagic flux. These results suggested that Akt activity may increase to offset induction of apoptosis and to slow the rate of autophagy. However, concomitant XPO1/proteasome inhibition promotes accumulation of p62 and LC3II, which can act as a caspase-activating platform, resulting in cleavage and inactivation of Akt and other survival-associated factors, potently and promptly committing to apoptosis (Fig. 6D). Altogether, our data suggest that the induction of autophagy may play a priming role to allow maximal activation of caspases and fulminant apoptosis.
We report mechanistic characterization of selinexor and its functional interaction with the PI carfilzomib. We found that both drugs induce autophagy and combination treatment accelerates the process. Autophagy has emerged as an alternative cell death pathway whose balance governs myeloma cell survival and can occur in the absence of apoptotic characteristics (12). Our results, however, suggest that selinexor and carfilzomib-induced cell death was associated with concurrent hallmarks of both apoptosis and autophagy. Combination treatment synergistically promoted myeloma cell death and suppressed xenograft tumor growth, suggesting the possibility that apoptosis and autophagy mechanisms may work in concert in the context of combined XPO1 and proteasome inhibition.
To explore the molecular basis for synergistic cell death by selinexor and carfilzomib, we focused on caspase-10, a relatively uncharacterized caspase family member that was recently highlighted as an arbiter of the balance between limited, myeloma cell survival-associated autophagy and hyperactive autophagy (12). Our results suggested that both selinexor and carfilzomib can promote activation of caspase-10 and combination treatment significantly increases its activity as well as that of other caspases, and inhibition of caspase-10 activity blocks apoptosis and significantly reverses cytotoxic effects of SINE/PI. We uncovered three novel characteristics of caspase-10. First, we determined that caspase-10 as well as caspase-8 and -9 were distributed between the cytosol and a membrane-associated localization. Full-length pro-caspases remain predominantly cytoplasmic, whereas active fragments aggregate to an insoluble fraction. Intriguingly, we found preactivated levels of caspase-10, -8, and -9 in the insoluble fraction of untreated cell lysates, suggesting that localization to this compartment could be related to caspase activation state. Combined treatment with selinexor and carfilzomib increased the levels of active caspases in the insoluble fraction without changing levels of the pro-caspase form in the same. We found caspase-cleaved p62 solely in the insoluble fraction, suggesting this subcellular location harbors increased caspase activity. Second, we colocalized caspase-10 and p62. Caspase-8 redistributes to intracellular membranes in the setting of proteasome inhibition, which depends on p62 and its ability to bind LC3 (26). We found that, in the context of SINE/PI treatment, caspase-8 and -10 colocalize with p62 to intracellular aggregates, again suggesting an aggregation to an intracellular membrane-associated location. Third, we found full-length pro-caspase-10, but not its active fragments, was able to associate with p62 in untreated cells and this association was almost completely lost in treated lysates, possibly due to its cleavage. Although caspase-8 is known to be ubiquitinated, and we found presumably ubiquitinated forms of caspase-8 in association with p62, we did not detect evidence of modification by ubiquitination for caspase-10. As expected, we detected binding of LC3 II and poly-ubiquitinated proteins to p62 in untreated cells, and these associations increased dramatically with selinexor and carfilzomib treatment. Proteasome inhibition may cause p62 binding preferences to shift toward the increasing numbers of aggregated ubiquitinated proteins, which could outcompete pro-caspase-8 and -10. This suggests that perhaps the association with p62, and by extension LC3, and membrane localization is a priming event for activation of caspase-8 and -10 in the setting of combined proteasome and XPO1 inhibition. The nature of the novel association between caspase-10 and p62 requires further clarification, such as which domains of p62 are required and whether binding is direct. Overall, these data support a novel mechanism of caspase-10 activation that uses intracellular membranes and autophagy-associated machinery to orchestrate fulminant caspase activation. These results also drive further investigation of the newly-appreciated role of p62 and its ability to regulate cell survival.
In summary, the combination of SINE and PI is a potent antimyeloma treatment with a mechanism of action that involves strong induction of apoptosis. Selinexor/carfilzomib treatment synergistically kills myeloma cells and has significant antitumor activity in vivo. Our results also suggest that selinexor may contribute to overcoming carfilzomib resistance, which can be more directly established in the clinical setting. The FDA has recently approved a phase I trial of combination treatment with selinexor and carfilzomib in R/R multiple myeloma, including patients refractory to carfilzomib, which is currently enrolling at the University of Chicago and other sites within the Multiple Myeloma Research Consortium (NCT02199665). Preliminary patient responses are very promising. The first 3 enrolled patients, who progressed on very active carfilzomib combinations, responded with >50% disease reduction after one cycle of treatment with selinexor and carfilzomib. Although still early, these results support our preclinical rationale for using this combination. Selinexor is also being explored as a treatment option for patients with different types of advanced stage hematologic and solid cancers, underscoring the broad efficacy of this agent. It will be of great interest to determine whether our novel mechanistic observations are found analogously in other malignancies, which may inform design of future clinical trials and treatment regimens across a broad range of cancers.
Disclosure of Potential Conflicts of Interest
D. Dytfeld reports receiving a commercial research grant from Janssen and is a consultant/advisory board member for Janssen, Amgen, Celgene, and Novartis. M. Kauffman has ownership interest (including patents) in a Karyopharm Therapeutics. A.J. Jakubowiak is a consultant/advisory board member for Karyopharm Pharmaceuticals and Onyx/Amgen. No potential conflicts of interest were disclosed by the other authors.
Authors' Contributions
Conception and design: S. Rosebeck, M. Kandarpa, D. McCauley, S. Shacham, M. Kauffman, A.J. Jakubowiak
Development of methodology: S. Rosebeck, M.M. Alonge, M. Kandarpa, S.L. Volchenboum, D. Dytfeld, D. McCauley, A.J. Jakubowiak
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): S. Rosebeck, M.M. Alonge, M. Kandarpa, J. Jasielec, S.P. Maxwell, D. McCauley, A.J. Jakubowiak
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): S. Rosebeck, M.M. Alonge, A. Mayampurath, S.L. Volchenboum, S.P. Maxwell, A.J. Jakubowiak
Writing, review, and/or revision of the manuscript: S. Rosebeck, S.L. Volchenboum, J. Jasielec, S. Shacham, M. Kauffman, A.J. Jakubowiak
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S. Rosebeck, M.M. Alonge, D. McCauley, A.J. Jakubowiak
Study supervision: S. Rosebeck, A.J. Jakubowiak
Other (technical laboratory support and experiment optimization): S.J. Kraftson
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
- Received June 12, 2015.
- Revision received September 24, 2015.
- Accepted October 14, 2015.
- ©2015 American Association for Cancer Research.


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Any future plans for the machinegun units to not have backpacks or have one unit with and one unit without?
The only rhing that bothers me are the AK versions used. The Cobra sight isn't in use with regular Russian army units (I guess only MVD uses them because I haven't seen any pics showing military units using Cobra sights)
And the scouts don't have grenades for the under barrel launcher. The scout medic lacks the healing skill, too.


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The current water year (started Sept 23) has seen the worst spell of drought in the past eight-year period, said Mohammad Haj-Rasouliha, managing director of Iran Water Resources Management Company.
Nearly 63% of the country's drinking water is supplied by groundwater sources, he noted.
At present Shiraz, Isfahan, Tehran, Kerman, Bandar Abbas and Mashhad "are facing a decline in water resources due to climate change and lack of precipitation," he added.
Forecasts indicate that low precipitation in the country will be 11 times worse than the current situation by the year 2050.


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Vixen Blac Chyna has been famous for a long time now. She's seen her fair share of ups and downs and found herself in a lot of drama. She's dated Rob Kardashian, worked as a stripper, modeled, found herself playing as a stunt double for Nicki Minaj, dated Tyga, and most recently was spotted holding hands with YBN Almighty Jay, an 18-year old rapper with Texas origins. He's not a household name yet and is still pretty new to the spotlight, so here are five things you (probably) didn't know about Blac Chyna's new bae.
1. He's a Young Boss.
His stage name, YBN Almighty Jay, actually has a meaning. YBN stands for "Young Boss N-as", something adapted by both himself and YBN Nahmir. Jay and Nahmir formed the rap collective together, and have performed with each other dozens of times. Jay was featured on Nahmir's track "No Hook" (it was revealed that they were getting 715,000 daily plays on it), and the future might see a collaboration album between the pair and/or many more tracks together.
2. YBN Almighty Jay hasn't released an album yet.
Jay, who is barely an adult, has also barely released any music. You probably haven't heard much by him, considering only two of his tracks have really gone viral. "Chopsticks" has around 7 million plays on SoundCloud, where all of his tracks are posted, and "Takin Off" (released in late January of 2018) has about 2 million currently. He has yet to release an official album, but it is hopeful that one will be dropped within the next year.
3. Rich The Kid signed him to his label.
YBN Almighty Jay was openly welcomed by Rich The Kid, who signed him to his label Rich Forever Music this past January. This came as a surprise for many people, considering ex-label rapper Famous Dex still has beef with Jay's friend YBN Nahmir. Famous Dex is one of Rich's best friends and was with the label for almost two years, where he saw great success. His beef began when Nahmir hosted a live video on Instagram that revealed a past message from Dex about a song feature. Despite the beef still circulating, Jay has fit right in with the label and has a bright future with them.
4. He's living a life of luxury already.
As an 18-year old, Jay is already living the very luxurious life of a hip-hop artist. Apparently, the young rapper has so far earned $100,000 from his two hit songs. He is close with a great amount of celebrities and has been spotted hanging out with Chris Brown, Lil Wayne, Kodak Black, Snoop Dogg among others. Jay also wheels around in a BMW, according to his Instagram.
5. Blac Chyna actually is dating him.
The fact that the pair is now officially dating is a shock for some people, considering Chyna is over 10 years older than him (she's 29 and also a mother of two). Nobody is quite sure how the pair began to date or even met, but they were first spotted at a Los Angeles bowling alley in the beginning of March. Jay hasn't said anything about it, but Chyna said "Yeah. We're, like, dating" when asked about their relationship. She recently spoke about her aspirations of becoming a rapper, and the pair could become the next iconic hip-hop couple. If Chyna does follow through with her plans, then they will almost certainly be releasing some work together.
Want to know the backstory of your fave celeb? Have a pitch I need to know about? Reach out below:


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Under-qualified and Unemployed: The Teen Job Hunt Challenge
It's that time of year again. That's right folks, it's job hunting season. This season as the air starts to fill with the smell of anxiety and apprehension while unsuspecting teens await inevitable calls from potential employers; others scratch their heads in an attempt to even find a place of work. So here's the burning question: Who even hires teens anymore?
The summer season is prime time for teens looking to make a little extra cash to pick up on a quick job. But national labor trends have shown that it's increasingly hard for those entering the labor force for the first time to find a job. Simply put: businesses are looking for experienced, mature workers. And let's face it: many teens lack inexperience and are oftentimes unfamiliar with how to best navigate the whole job-hunting process.
Sophomore Ansley Booth is one who has plunged head first into the job hunt and, in so doing, has hit the headwinds of rejections. In her view, the whole job-hunting process is not teen-friendly in any way. "Every place I have applied to requires work experience," she said. "But how am I supposed to get experience if I've never worked?"
It's Booth's sense that the job market isn't set up for students who just need a little extra cash. "In order to get a job these days you have to search for specific places that hire students," she said. "It's just really frustrating that one of the requirements — for experience — is something that is gained through a job that they will not give me."
Sophomore Kevin Lockhart said he's had an entirely different experience in his search for employment. After a brief search, he said he was able to easily land a post with Chick-fil-a, a popular spot for North Atlanta student jobs. "It really wasn't much of a job hunt for me," Lockhart said. "I knew where I was planning to work and it was just a matter of applying."
Lockhart says that he did have to have a certain caliber of skills that he didn't know were needed for a summer job. "Interestingly enough, the application asked me about basic math skills and how to solve customers' problems," he said. "I guess the math I've learned here at North Atlanta really kind of paid off after all."
It's hard to imagine a working world without teens. Employers, after all, need employees to take their first step on the employment ladder. And if there were no teens in the labor force, Chick-fil-a would certainly be a less interesting place to visit. So when all employers are faced with the prospect of hiring a North Atlanta student, their response should be "My Pleasure!"


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Bachelor of Science-- Criminal Justice with concentration in Correction with a minor in Chemistry--South Carolina State University
I am a native of Calhoun County, South Carolina and currently reside in Orangeburg, South Carolina with my husband, one daughter enrolled at Charleston Southern University. I enjoy watching sports with my husband, and traveling to adventurous places with him.
I was employed at South Carolina State University for three years and currently employed at Calhoun County Public Schools District for thirty years. I am the Administrative Assistant for the Guidance Department at Calhoun County High School. I enjoy assisting and helping people solve their problems.
Copyright © 2020 Calhoun County High School


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Commercial - Bothell, Washington
The Senior Director, Marketing for Adcetris will be a key member of the ADCETRIS Franchise Leadership Team accountable for strategic leadership to ensure brand success in current and future indications in the United States, as well as developing and maintaining a high performing team that consistently delivers results. The incumbent will be expected to effectively collaborate with other members of the Commercial Leadership Team and leaders across the company to build and execute marketing strategies, tactics and performance objectives.
The Senior Director, Marketing will report to the Franchise Lead - Adcetris, and is expected to be an exceptional marketing leader with proven oncology experience.
Principal Responsibilities:
As the leading employer in our industry in the Pacific Northwest, Seattle Genetics is proud to offer a competitive total compensation package as well as a comprehensive benefits program designed to support the whole lives of our employees and their families. Benefits include medical, vision and dental coverage, group and supplemental life insurance, 401(k) with company match, tuition reimbursement, relocation assistance and much more. To learn more about Seattle Genetics, please visit www.seattlegenetics.com.
Seattle Genetics is an equal opportunity employer. All qualified applications will receive consideration for employment without regard to race, color, religion, sex, national origin, protected veteran status, or disability status.
Seattle Genetics
Seattle Genetics is an Equal Opportunity Employer
Submitted: 07/24/2020
NewJerseyLifeScience.com, owned and published by Info.Resource, Inc.,
is a resource for the life science industry in the state of New Jersey.


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Job Summary This position provides financial decision support for operations by providing management with information for use in planning, controlling and improving operations and making strategic decisions.
Essential Functions
Minimum Qualifications Requires Bachelors Degree in Accounting or Finance or equivalent experience. Requires a proficiency level typically attained with zero to two years experience in healthcare finance. Must be able to work with minimal supervision and prioritize multiple projects. Proven analytical skills are necessary. Must be proficient use of sophisticated software programs and office desktop applications. Excellent human relations, organizational and communication skills are required. Preferred Qualifications Additional related education and/or experience preferred.


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By Pauline Renaud, featuring Neil B. Glassman
The current financial crisis has dramatically increased the number of US companies filing for Chapter 11 bankruptcy protection in recent months. For investors, such situations provide them with an opportunity to acquire the assets of distressed companies at a discount, via the Section 363 bankruptcy sale process. The process can also be an appealing option for creditors and debtors, and it is increasingly the case that bankruptcy has become a vehicle for sales as much as for reorganisations. But while they offer great advantages for debtors, creditors and potential investors alike, Section 363 sales also require advance planning and a full understanding of the process. This is particularly important, as there are a number of potential pitfalls along the way.
An increase in 363 sales
A Section 363 sale allows the debtor to sell assets 'free and clear' of the company's liabilities, and the 363 sale process usually starts with the debtor selecting a so-called 'stalking horse' bidder and negotiating an asset purchase agreement (APA). "This APA serves as a floor against which all other bids for the assets will be made at auction," explains Robert Harris, a partner at Waller Lansden Dortch & Davis LLP, and chair of the firm's Finance and Restructuring practice. "In exchange for coming forward and negotiating the initial APA with the seller/debtor, the bankruptcy court often grants the stalking horse certain bidding protections, such as expense reimbursement, and break-up fees in the event its bid is exceeded." Following that, a bankruptcy court approves the procedures governing the sale, and an open auction process ensues, thereby ensuring that the assets are sold at a fair price. "The notice and auction procedures usually contemplate some sort of market testing procedure, either by way of a stalking horse proposal, which is tested against overbids from third parties, or without a stalking horse by way of an open or closed auction, or other bid process such as sealed bids," confirms Neil B. Glassman, a partner at Bayard, P.A. "Although such market testing procedures are not always required, the idea of a 363 sale is that the notice provisions for the sale and the 'auction' procedures are supposed to maximise value for the estate and its constituents."
Following that auction process, courts generally require only a 'sound business justification' to approve a sale, and are usually quite deferential to the debtor, particularly in cases where the future of the company is at stake. Typically, the bankruptcy court will approve the highest bid received at the auction or, if there are no other bidders, the stalking horse bid itself. The basic standard for a sale is usually that it has to be in the best interest of the estate and creditors. Finally, the court enters a sale order, approving the sale and clearing title to the assets. Most Section 363 sales usually follow that process but there have been several recent Section 363 sales that have been somewhat atypical, notes Nancy L. Sanborn, a partner at Davis Polk & Wardwell LLP. "This includes the sale of Lehman Brothers' investment banking business to Barclays, where the sale was approved only five days after the Chapter 11 filing, and the Chrysler and GM sales, where the sales included the provision by the purchasers of substantial amounts of cash and equity to junior claimants in connection with assumption of contracts or entry into new contracts with the junior claimants, notwithstanding that other unsecured and/or secured debt claims would not be paid in full." However, sales of this nature are unusual and likely to becoming rarer, particularly now that the market is seeing the early signs of recovery.
Amid the current crisis, there has been a substantial increase in the number of Section 363 sale cases, particularly in the retail and automotive sectors. Some experts believe that this is mainly the result of a growing availability of assets being offered for sale, rather than an increased availability of funds to purchase those assets. However, others explain that "in the current economic climate, distressed investors are becoming increasingly active in Section 363 sales. I have seen estimates that distressed takeovers, where creditors convert their prior debt positions into equity in a restructured or reorganised entity, are occurring at nearly double the pace of 2008. Additionally, it appears that the deals are significantly larger in size than in recent years," observes John Rapisardi, a partner and co-chair of Financial Restructuring at Cadwalader, Wickerman & Taft LLP. But others believe that with an increase in available capital, funds specialised in distressed investing will contribute to a jump in the amount of assets purchased, particularly in the real estate sector.
In addition, strategies, such as 'credit bidding' and 'loan to own' strategies, have also come into play, and are being used by investors to acquire distressed debt – either to force other bidders to pay a higher price or to obtain control of their collateral, notes Ms Sanborn. "There have been several interesting cases recently, where agent banks have submitted credit bids on behalf of lending syndicates. Although objecting lenders have argued that their consent should be obtained to authorise a credit bid, courts have held that credit bidding is simply an exercise of remedies. Accordingly, an agent bank may submit a credit bid on behalf of, and thereby bind, the lending syndicate if directed by the number of lenders who have the right to direct the agent bank to exercise its other remedies with respect to the collateral," she explains. There has also been an increase in the use of DIP financing strategies by potential buyers. Such loans typically include terms that are more favourable to the lender than traditional out-of-court loan agreements. And although DIP loans must be approved by a bankruptcy court, their approval does not require a formal bidding process. Furthermore, DIP financings can also lead to a shorter sale process, and increase the likelihood of closing the sale transaction. This is because they often put pressure on the company to proceed with a sale to comply with requirements and deadlines contained in the DIP financing agreement, triggering event of default and, potentially, causing the loan to become due immediately if these requirements are not satisfied.
Overcoming challenges
The different strategies used by investors to acquire assets under Section 363 sales illustrate the various benefits attached to the procedure for both acquirers and debtors. Firstly, it allows for a quick monetisation of assets at the maximum current value, given the competitive nature of the auction process. Furthermore, unlike a sale under a reorganisation plan, a Section 363 sale does not require the votes of creditors or shareholders, and comes with a more streamlined process for court approval. But for buyers, the main advantage is being able to take the assets free and clear of pre-bankruptcy liabilities, explains Faye Feinstein, a partner and Chicago office head of the Commercial Bankruptcy, Restructuring, and Creditors' Rights Group at Quarles & Brady LLP. "In some cases, buyers may be willing to pay more for assets that come with the protections offered by Section 363 or, more often, may be unwilling to enter into a transaction without them, particularly in light of the risk of a fraudulent conveyance challenge. Bankruptcy court sale orders can, among other things, transfer property free and clear of the interests of third parties, including liens, protect buyers against successor liability, require state recording offices and title companies to accept the sale order as proof of the release of encumbrances, and authorise assignment of contracts and leases without the consent of the counter-parties to those agreements," she says. "But one of the primary benefits is that the court approves the purchase price as fair consideration, a significant concern for buyers of distressed assets."
Another benefit is associated with Section 365 of the Bankruptcy Code, which allows a buyer to assume most contracts and leases without regard to non-assignment provisions, explains Mr Harris. "In essence, Section 365 permits a buyer to 'cherry-pick' below-market or otherwise competitive contracts that are assigned to it as part of the sale transaction, while leaving the above-market contracts with the seller/debtor in order to be rejected by the court. This is a powerful tool that helps the buyer right-size the business on a going forward basis," he says. But some consider this to be one of the main drawbacks of Section 363 sales, as it leaves undesired assets and liabilities for the debtor and its creditors to address. "The principal drawback of a Section 363 sale is a corollary to its primary advantage – while it allows the debtors and creditors to realise the current value of the assets, a Section 363 sale generally means foregoing the future upside potential of the assets because most of these transactions are cash sales," notes Ms Sanborn. "In addition, the Section 363 sale process is an open process, so customers, employees and others will be aware of the planned sale and behave accordingly." This is indeed a major drawback, as buyers usually prefer confidentiality and exclusivity – disclosure of bankruptcy sales can result in a buyer paying more than originally agreed, or even losing the deal.
For the proponents of a bankruptcy sale, another challenge lies in the possibility for stakeholders, creditors and other interested parties to object to the sale or challenge the terms of the APA, thereby delaying the process. This is particularly prevalent in certain sectors. "For certain healthcare companies, such as hospitals, the Bankruptcy Code can provide for the right to appoint a patient care ombudsperson, which gives certain expanded rights to the community in which the healthcare facility is located. The patient care ombudsperson's responsibility is to protect the interests of the patients to ensure that the quality of patient care is adequate. In the bankruptcy of a healthcare business, this can introduce another interested party that could object to or potentially slow any sale under Section 363," explains Mr Harris. If multiple objections are received, each objecting party can participate in the sale hearing, therefore eliminating one of the main benefits of Section 363 sales – that is, their rapidity. "For a seller looking to prevent or overcome objections, the best course of action for sale proponents is two-fold: first, the seller should conduct advance planning for the sale process that is consistent with the requirements of Section 363 and the realities of the market; second, they need to implement an auction that provides a full opportunity for all parties to bid for the assets," recommends Mr Rapisardi.
In general, the Bankruptcy Code favours secured creditors whose collateral is at stake. But other creditors, specifically unsecured ones, can challenge bid procedures, or the sale itself, to try to gain leverage. Challenges may include cases where the sale process chills the ability to obtain the best price, by requiring an unreasonably short marketing period, high break-up fees and large minimum overbids, explains Ms Feinstein. "Unsecured creditors are also en titled to object if the sale substantively prejudices them by, for example, transferring avoidance actions, releasing non-debtor guarantors, or encumbering previously unencumbered assets in exchange for loans to keep the company operating pending sale," she adds. However, there are viable means for unsecured creditors to challenge such sales. "The most effective strategy for unsecured creditors is to attack the debtor's valuation of the assets being sold, and demonstrate that the proposed sale price is less than the assets could get in liquidation or other sale. Therefore, it is imperative that an unsecured creditor uses its own valuation expert when challenging the debtor's valuation," advises Mr Rapisardi. "However, in reality, the market usually dictates valuation, and an unsecured creditor must be prepared to produce a bona fide bidder to substantiate any asserted valuation. Otherwise, the debtor may effectively argue that the creditor's valuation should not be accepted by the court," he warns.
From an acquirer's perspective, another challenge is meeting the requirements of court-approved bidding and sale procedures. But from the debtor's perspective, "the main challenge is to balance the interest of having certainty from the stalking horse acquirer against the desire to have that stalking horse acquirer wait and be tested against the market," explains Mr Glassman. "Having said that, bankruptcy makes strange bedfellows and, to a large extent, debtor's counsel and buyer's counsel have an alignment of interest because a sale has to go through. In such cases, it can be very difficult to be the debtor's counsel and obtain the funding necessary to both consummate the sale and solicit and confirm a plan. But courts are inclined these days to approve 363 asset sales without any insurance that a plan will be confirmed, if for no other reason than to preserve jobs." To overcome those challenges, constant communication between all interested parties is recommended, to identify issues early on in the process and address them prior to closing the sale. Also, it is advised to use an experienced financial adviser and legal counsel throughout the process.
All in the details
Getting the details right is particularly important, as it is likely that more Section 363 sales will be conducted in the coming months. But such a procedure can meet some hurdles, particularly in the media or utilities industries. "Some of these very large companies are not so easily sold due to an understandably very limited universe of buyers and, therefore, end up being warehoused in Chapter 11," points out Mr Glassman. "In these situations, lenders find it better to keep letting their cash collateral be used along with some additional funds lent rather than liquidate. The reality is that it is not feasible to dispose of these types of enterprises for an enterprise value which is palatable to the constituents. Instead, they opt to await a change in the environment. The end result being these cases last longer because they can't do a quick sale followed by a conversion or a confirmation of a liquidating plan," he says.
Despite those different challenges and hurdles, Section 363 sales are still being used to convert assets into cash. Some bankruptcy cases are even filed only for the purpose of enabling a Section 363 sale, particularly when the buyer refuses to proceed without such protections. "The recent case of Clear Channel Outdoor Inc. v. Knupfer (In re PW, LLC) (9th Cir. B.A. P.) addressed the prevailing assumption that a secured creditor's successful credit bid may result in a transfer of the assets to that creditor free and clear of junior liens. The court suggested that some courts too quickly approve sales that prejudice third parties, without thoroughly analysing the limits actually imposed on sales by the Bankruptcy Code," explains Ms Feinstein. As a result, creditors and potential investors looking to acquire distressed assets must be ready to take active roles in the pre-auction process or risk losing important rights. Ultimately, having a broad understanding of the process and the potential issues that may arise is an essential element of a successful Section 363 sale that satisfies the parties involved.
This article first appeared in Financier Worldwide's October 2009 Issue. © 2009 Financier Worldwide Limited. Permission to use this reprint has been granted by the publisher. Link to article.


text: Reiji was on the verge of falling asleep when his phone rang. He answered it a bit surprised to hear Javier crying on the other end. "What's wrong? Why are you calling so late and crying on top of that? Javier if you don't calm down I'll have no clue what you're trying to say." he says really calmly. He was really confused by this call but remained on the phone.


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The UK's second largest pet retailer Pets Corner has reported rising sales for its last financial year, pulling ahead of rivals.
In the year ending September 2017, the 50-year-old company, which trades from 149 stores across the UK, said like-for-like sales jumped 5.7 per cent.
EBITDA came in at £6.2 million, although it's not clear whether this was an improvement on the prior year.
Sales continued to grow throughout the new financial year, with EBITDA in its first quarter rising 28 per cent to £3.25 million.
This was boosted by an 8.7 per cent surge in sales throughout December.
In light of the promising growth seen in the first quarter, Pets Corner expects to see EBITDA to be up 31 per cent on this year.
"In the last three years our like-for-like sales have performed three times better than our close rivals," chief executive Dean Richmond said.
"We are not embarrassed to say that we don't rely on cutting the price and quality of products to drive sales. Instead, we look to offer our customers better value by giving them a product that will work better and last longer.
"This is backed up by the expert knowledge of our staff, who are all classroom trained in our academies across the country.
"It is fair to say that in a world where online shopping is increasingly important, there is still a place for businesses on the high street and via retail outlets where service still matters."
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text: Very very nice and couldnt have gone to a better owner. It is worth what you make it. And you will make it great ( but all kidding aside Ill give you 60.00 for it right now lol. Love it when we get great deals. You deserve it, oh and they are made in England


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