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Come help us celebrate the new pecan harvest season! The Royalty Pecan Harvest Festival is a free public event hosted by Royalty Pecan Farms with the help of community volunteers and sponsors. Our mission is to promote and celebrate local culture, healthy living, and agritourism while offering an educational and entertaining experience. We will be hosting a 5&10K Run that morning through the orchard. This year we are adding a Bier and Wine- garten, along with a big screen displaying the out of town Texas A&M football game.
The festival grounds are located behind our gift shop on Texas Hwy 21 between Bryan/College Station and Caldwell. Our extended lawn overlooks 500 acres of lush pecan trees with the College Station city skyline on the horizon. In addition to shopping and enjoying the festivities, we encourage visitors to bring their own camp chairs, blankets, Frisbees, balls, or kites and enjoy our backyard! Just remember to take your things with you when you leave.


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London Improv is a bit over-excited about tomorrow. You see, we get to watch a group of fantastic improvisers hit the stage and do something completely new and original.
The Milk Monitors are of fine pedigree, featuring performers from the very well respected Oxford Imps, amongst others. We've seen the likes of Cariad Lloyd, Amy Cooke-Hodgson and Rachel Parris on stage, and to be honest if there was a comedy version of sexual attraction we'd have to go and have a lie down. And check out those dashing costumes too, these gentlemen and women don't do things by halves. Get me a fan.
The Milk Monitors fine form is that of one of Britain's best-loved novelists, Jane Austen. They'll improvise a whole new story before your very eyes, so if you're someone who needs a bit more culture in your life but don't want to have to read an actual victorian book; then this is pretty much a necessity. And we know for a fact that the players involved will add faster pace than a speeding carriage and more belly laughs than a Scottish gent with a quart o' whiskey. Can't wait.
The Milk Monitors are doubling up with superb long-form group and regular performers on the London improv stage: 8bit, so it's going to be both anarchic and anachronistic. Which is pleasurable on a linguistic level if nothing else.
We are very much looking forward to seeing you there.
Cordially yours,
London Improv
Wednesday 6th July
Time: Doors 7:30pm, Show 8pm - 10pm with interval.
Cost: £5 on the door.
Where: The Miller, 96 Snowsfields Road, London Bridge, London, SE1 3SS.

subset: commoncrawl


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Quorn Sausage Cassoulet
Try this delicious recipe for sausage cassoulet - using Quorn Garlic and Parsley Sausages cooked in wine with onion, celery and carrots.
- 1 pack Quorn Wild Garlic & Parsley Sausages
- 1 tbsp olive oil
- 1 medium onion, chopped
- 2 sticks of celery, diced
- 1 carrot, diced
- 4 cloves of garlic, crushed
- 1 bouquet garni
- A few sprigs of thyme
- A handful of fresh parsley, chopped
- 2 large tomatoes, cut into 8's,
- 300ml vegetable stock
- 150ml dry or medium white wine400g tin of cannellini, borlotti or haricot beans, or a mix
- 2 tbsp fresh breadcrumb
- Salt, black pepper and lime juice to season
- Preheat the oven to 170C/325F/Gas Mark 3
- Heat half of the oil and add the onion, celery and carrots for 5 minutes or until softened. Add the garlic, bouquet garni, parsley, half of the thyme, wine and stock and beans and bring to the boil then place in an ovenproof container and cook in the middle of the oven for 40 minutes.
- Heat the remaining oil in a large frying pan and gently fry the sausages until browned, remove and set aside
- Remove the cassoulet from the oven, add the Quorn Wild Garlic & Parsley Sausages, season with salt and black pepper and a squeeze of lime juice.
- Stir in the tomatoes. Sprinkle the breadcrumbs and the remaining thyme over and bake for a further 20 minutes or until the beans are softened. Remove the bouquet garni before serving
Serve with a green salad


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Skinny Pills are the manufacturer Maxine's answer to a fat burning supplement just for women. They are meant to fight off overzealous appetites, boost your overall energy, burn fat, and even help you focus as you diet. The manufacturer has ties to Max, a well known supplement brand from Australia. Maxine's products are made only with women in mind however.
Now, let's see what Skinny Pills have in store:
1 – The Active Ingredients
The first ingredient in Skinny Pills is L-carnitine. This compound is highly useful for boosting metabolism and energy. It isn't going to be as useful for people that are already relatively healthy however. There's also an acetyl form of the compound that can boost cognitive ability.
Next up is white willow bark extract. Bark from white willows has been a long standing pain relief remedy. It can also help prolong some of the other ingredients' effects.
Ginger root powder and cayenne pepper are also among the ingredients list. The first helps with limiting your appetite. The less likely you are to binge on food at random intervals, the easier it will be to lose weight. The second is mostly beneficial given its capsaicin, a powerful fat oxidation and metabolism booster.
Raspberry ketones are also found in Skinny Pills. This is a common ingredient used to help flavour and scent certain foods. There haven't been a lot of human studies yet, but it's been shown to help burn fat in early trials with other animals.
As with many supplements of this kind, these pills also include caffeine. This gives yet another layer to the energizing and fat burning capabilities of the supplement. It can be addictive however!
Beta-Phenylethylamine, Tyrosine, and Dandelion root round out the ingredients list. The first is a mild mood enhancer that should help you keep positive throughout the many frustrations of attempting to lose weight. The second can help you fight off fatigue and also focus more easily. Lastly, dandelion root has the ability to help you cut down through slight dehydration. Be sure to drink plenty of water to counterbalance the negative effects of this!
2 – Who Should Take Skinny Pills?
Skinny pills are obviously only meant for females. They are especially useful for athletes. They can easily help anyone on a strict diet and exercise regimen however.
3 – How Are They Taken?
Skinny pills are only taken once a day. It's recommended that they be taken with a meal. Lunch time is also best since it isn't advisable to take them close to bed time.
4 – Potential Side Effects
Caffeine is addictive and can also lead to upset stomachs. In extreme cases, they can even increase your heartbeat too much. You might also run into problems with the capsaicin and beta-phenylethylamine reacting poorly with existing medication or causing headaches. You should consult with a doctor to make sure you can handle all of the ingredients listed above.
5 – In Conclusion
The ingredients in Skinny Pills are all quite effective at helping burn fat. Only having to take them once a day is also quite simple. But you might find that the ingredients aren't provided in quite a potent enough dose however.
You will need to take quite a few servings to get the desired weight loss effect.


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More than 4 out of 5 Workers Now Protected from Secondhand Smoke
American Lung Association calls on remaining 22 states to pass smokefree laws and protect workers from the harms of secondhand smoke
(October 12, 2017) - CHICAGO
For more information please contact:
Allison MacMunn
[email protected]
Statement of Harold P. Wimmer, National President and CEO of the American Lung Association, in response to the Centers for Disease Control and Prevention (CDC) study on "Changes in Self-Reported Smokefree Workplace Policy Coverage Among Employed Adults—United States, 2003 and 2010–2011" published today in the journal Nicotine & Tobacco Research:
"Today's report shows significant progress in the effort to protect Americans from the dangers of secondhand smoke. Overall, the number of U.S. workers covered by smokefree workplace policies increased from 77.7 percent to 82.8 percent. Twenty-one states saw a substantial increase in workers covered by smokefree policies. While great gains were seen in the food service industry and particularly among bartenders and wait staff, food service workers are still more likely to have a workplace without a smokefree policy.
"Over a decade ago, the U.S. Surgeon General found there is no safe level of exposure to secondhand smoke. Secondhand smoke causes lung cancer, COPD, heart disease and worsens existing health conditions including asthma. Today's study shows that while substantial increases in smokefree workplaces have occurred over the past seven years, gaps still exist – leaving workers exposed to dangerous secondhand smoke just so they can put food on the table.
"Everyone deserves the chance to lead a healthy life, and that means having a safe work environment free from the health harms associated with secondhand smoke. While the Lung Association is proud that 28 states and the District of Columbia have passed comprehensive smokefree laws, we will continue our efforts to pass smokefree air laws in all 50 states because everyone deserves to breathe clean air."
About the American Lung Association
The American Lung Association is the leading organization working to save lives by improving lung health and preventing lung disease, through research, education and advocacy. The work of the American Lung Association is focused on four strategic imperatives: to defeat lung cancer; to improve the air we breathe; to reduce the burden of lung disease on individuals and their families; and to eliminate tobacco use and tobacco-related diseases. For more information about the American Lung Association, a holder of the coveted 4-star rating from Charity Navigator and a Gold-Level GuideStar Member, or to support the work it does, call 1-800-LUNGUSA (1-800-586-4872) or visit: Lung.org.
Sign up for the latest lung health news sent right to your inbox.
Join more than 500,000 people who receive research updates, inspiring stories, health information and more.


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Teens @ Living Hope
Middle school and high school students are integrated into the life and ministry of Living Hope. We're glad to have teens who volunteer in just about all areas of the church's life. They're not just the church of tomorrow… They're the church of today!
We're currently looking for a part-time youth pastor to help take this to the next level. If you know someone we should be talking to, or if you have questions, please let us know!
Until then, the students are meeting with Pastor Rich on Tuesday nights, 7:15-8:30, for games, prayer, Bible discussion, and plotting to do good together. If you're in middle school or high school, we'd love to have you drop in!
Find Us…
1115 Calumet Ave.
Valparaiso, IN 46383
(across from Old Fairgrounds Park between Evans & Harrison)
Come As You Are
If there's one place where you can take off the mask, let down your guard, and just be yourself, it's church: a community of grace, where nobody is perfect and everybody depends on the help of God and each other to live better each day than the day before.
If that sounds good to you, we invite you to come check it out.


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Taghmon's big goals bonanza
Taghmon-Camross 3-10 Horeswood 2-11
The rise of the Intermediate title-holders continued in O'Kennedy Park, New Ross, on Saturday when Taghmon-Camross claimed their second huge scalp with a Group B win that sent former kingpins Horeswood crashing out of the Tom Doyle Supplies Senior football championship.
With Oylegate-Glenbrien blazing a trail in hurling in their first season back in the top flight, the Jason Ryan-trained side are doing likewise and are now unbeaten since receiving a lesson from St. Martin's on day one four months ago.
And while this win hasn't quite booked their quarter-final place, even one point against St. James' will be enough to do so. Even at that, it would take a cruel run of results from the Taghmon-Camross perspective to deny them the knockout spot their efforts deserve.
Horeswood couldn't say they weren't forewarned after their rivals shocked champions Gusserane a fortnight ago, and they're now left battling for survival.
They can't reach the last eight, but they can still avoid the relegation final if they beat Fethard by a decent margin and Taghmon-Camross do them a big favour against St. James', who are currently two points above them and five points better off on scoring difference.
This game was effectively won and lost in an amazing four minutes at the start of the second-half when Taghmon-Camross scored 3-1 without reply to transform a 1-7 to 0-5 interval deficit into a 3-6 to 1-7 lead.
A mere 16 seconds had elapsed when Barry O'Gorman's delivery from the throw-in was gathered by Luke Sinnott who fed Stephen O'Gorman for a morale-boosting goal.
Horeswood were asleep and, after Eoin Doyle pointed on the next attack, the net rippled again in the 32nd minute when a Darren Carty mark led to a composed finish from his brother, Ian, at the second attempt after his initial shot was blocked.
It didn't end there for Taghmon-Camross, because Ian Carty then turned provider for Anthony Breen to career through from midfield and beat Conor Swaine for the third time in under four minutes.
There was still a long way to go though, and Horeswood hit back midway through the third quarter after opposing netminder Seán O'Gorman was black-carded for taking down Declan Murphy.
Amazingly, Jack Dunne's first act was to save P.J. Banville's spot-kick, but there was a reprieve for the attacking side as referee Barry Redmond ordered a re-take and this time David Shannon tucked it away into the corner (3-6 to 2-7).
The experience of beating Gusserane a fortnight before clearly emboldened Taghmon-Camross though as they reacted with a brace of pointed frees from Seamus McLoughlin, while Stephen O'Gorman fired another goal chance wide.
Horeswood were fighting for their lives at this stage, and it showed as David Shannon (free), Leigh O'Brien and Declan Murphy brought them back to within one point (3-8 to 2-10) with nine minutes left.
Significantly though, Taghmon-Camross refused to surrender the lead as Luke Sinnott and P.J. Banville (free) swapped points before Anthony Breen kicked a beauty from a Stephen O'Gorman feed in the 59th minute (3-10 to 2-11).
They still had four added minutes to survive, but Horeswood had nothing left to offer after Banville blazed a free to the right and wide.
The experienced attacker had been a key figure in the early stages as he linked up effectively with county Minor Seán Nolan down the left flank.
They accounted for 1-5 between them in the first quarter as Horeswood surged clear by seven points but, after recovering from an early deficit of six last time out against St. James', they threw a better advantage away this time around.
It may have taken the Taghmon-Camross mentors 15 minutes to recognise the threat and move Alan Nolan on to Banville, but it was still timely as the deadly duo weren't nearly as effective thereafter.
Banville (free) and Nolan had pointed early on, with Stephen O'Gorman hitting back before Horeswood goaled for the first time in the tenth minute.
Banville sold a dummy and laid a pass on a plate at the far post for Nolan who palmed home, and another run of points from Banville, Nolan and Banville again left Taghmon-Camross with that 1-5 to 0-1 deficit.
Three points on the trot from Seamus McLoughlin (free), Chris Cullen and Ian Carty saw them settle, and the gap was down to a more manageable 1-7 to 0-5 by half-time after another McLoughlin free sandwiched scores from Declan Murphy and a fine effort on the run by David Larkin.
It seemed like the Horeswood backs had stayed in the dressing-room when play resumed, and Taghmon-Camross took full advantage to make a second major statement in the space of 13 days.
Taghmon-Camross: Seán O'Gorman; David O'Keeffe, Alan Nolan (capt.), Shane Doyle; Stephen Stafford, Mark O'Gorman, Darren Carty; Barry O'Gorman, Anthony Breen (1-1); Chris Cullen (0-1), Stephen O'Gorman (1-1), Eoin Doyle (0-1); Seamus McLoughlin (0-4 frees), Luke Sinnott (0-1), Ian Carty (1-1). Subs. - Jack Dunne for S. O'Gorman, black card (37), Michael O'Gorman for Cullen (57), Shane Lacey for O'Keeffe, inj. (60+2).
Horeswood: Conor Swaine; Barry Hearn, Ryan Harris, Steven Collins; Kevin Parker, David Larkin (capt., 0-1), Eddie Shiely; Shane O'Hanlon, Paddy Murphy; Johnny Keating, Leigh O'Brien (0-1), Seán Nolan (1-2); Declan Murphy (0-2), David Shannon (1-1, 1-0 pen., 0-1 free), P.J. Banville (0-4, 2 frees). Subs. - Jim Wall for Shannon (51), Seán Stafford for Parker (58), Michael O'Hanlon for Keating, inj. (60+2).
Referee: Barry Redmond (Clonard).
Wexford People


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Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine.
Methods and Findings
We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH) responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002), decrease in prostate specific antigen (PSA) slope (p = 0.016), and a two-fold increase in PSA doubling time (p = 0.003) were identified when we compared data before and after vaccination.
An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine. (ClinicalTrials.gov number NCT00289341).
Trial Registration
ClinicalTrials.gov NCT00289341
Citation: Frank MO, Kaufman J, Tian S, Suárez-Fariñas M, Parveen S, Blachère NE, et al. (2010) Harnessing Naturally Occurring Tumor Immunity: A Clinical Vaccine Trial in Prostate Cancer. PLoS ONE 5(9): e12367. https://doi.org/10.1371/journal.pone.0012367
Editor: Torbjorn Ramqvist, Karolinska Institutet, Sweden
Received: March 1, 2010; Accepted: June 22, 2010; Published: September 1, 2010
Copyright: © 2010 Frank et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Burroughs Wellcome Fund and Doris Duke Foundation (MLA), the National Institutes of Health (NIH) (R01 CA85784 to RBD), the Rockefeller University Hospital Clinical and Translational Science Awards (CTSA)(grant UL1 RR024143) from the National Center for Research Resources at the NIH, the Leslie Misrock Memorial Fund, and David H. Koch. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Tumor immunity in patients with paraneoplastic neurologic disorders (PND) have been studied with the hope of uncovering principles that can be applied to the general population of cancer patients[1], [2]. These studies demonstrated tumor antigen-specific CD8+ T cells in the peripheral blood of PND patients[3], [4], but also generated a paradox. PND antigens are normally expressed in the brain, and are ectopically expressed in tumors, but are not expressed in dendritic cells (DCs) that are necessary to prime naïve T cell responses.[5] Based on observations made with lupus antigens[6], we hypothesized that apoptotic cells might serve as an effective means of antigen transfer into DCs and presentation on MHC I for the activation of CD8+ T cells[7]. This proved to be correct for both tumor[3] and viral antigens[8], and it is likely that phagocytosis of apoptotic cells serve as a general means by which the immune system surveys antigens throughout life. Insights from studying natural tumor immunity in PND provide a compelling base upon which to model clinical studies[2], [9], [10].
Several observations support the suggestion that apoptotic tumor cells may serve as a potent source of antigen for stimulating host immune responses in vivo. Theoretically, all potential tumor antigens within an apoptotic tumor cell, and multiple epitopes from each antigen, can be cross-presented by DCs, where processed antigen may be placed on all (typically six) MHC I alleles. This offers considerable advantages over peptide-pulsed DC protocols, in which the investigator must have knowledge of the tumor antigen and must choose specific MHC I-restricted peptides for antigen stimulation. Antigen presentation from apoptotic cells has been estimated to be 10,000–50,000 more efficient than free peptide in loading the MHC molecules of a DC[11], [12]. Apoptotic material is processed by a natural pathway: apoptotic cells are internalized by DC-restricted receptors, including the αvβ5 integrin receptor[13], then processed within DCs by distinct pathways[14]. These DCs then generate both MHC I and MHC II peptide epitopes[13], leading to the activation of both CD8+ and CD4+ T cells. Since the ability of DCs cross-presenting apoptotic cells to activate effector CD8+ T cells requires signals from CD4 helper cells[15], the ability of apoptotic material to be loaded on both MHC I and MHC II molecules is of particular importance in considering its potential in immunotherapy.
DCs presenting apoptotic tumor cells stimulate T cell responses in animals and in vitro[16]. Clinically, several studies have used killed tumor cells in vaccine trials, including glial[17]–[21], prostate[22], melanoma[23], breast[24], ovarian[25] and pediatric solid tumor cells[26] (reviewed in [9], [16], [27]). These studies have not focused on apoptotic death per se, but rather have killed tumor cells by various means (e.g. freeze-thawing, or large amounts of UVB and gamma irradiation), leading to incompletely characterized mixtures of necrotic and apoptotic cell death. Interpretation of these studies is complicated by controversy regarding the immunogenic potency of different forms of dead cells[28]. Nonetheless, some trials have indicated the potential for immunologic and clinical responses to autologous DC presenting dead tumor cells[19], [23]. Here we set out to more precisely test the relationship between induction of PND-like tumor immune responses and development of a clinical vaccine. We induced apoptotic death of LNCaP prostate cancer cells, and allowed them to be phagocytosed by autologous DCs generated from prostate cancer patients' peripheral blood monocytes; such DCs were previously shown to stimulate both CD8+ and CD4+ T cells in vitro[29], and in a B16 mouse melanoma model DCs cross-presenting apoptotic tumor were effective in preventing tumor growth (Blachere et al., unpublished data). Here we report the safety and immunogenicity of DC/apoptotic LNCaP prostate tumor cells in a controlled study of 24 prostate cancer patients.
Study Population
Twenty-four consecutive eligible patients were vaccinated with DC/LNCaP, together with control vaccinations. A total of 28.4–78.9 million (average 50.3 million) DCs cross-presenting apoptotic LNCaP tumor cells were given per patient, divided over 4 doses, each 2 weeks apart (Figure 1). At the time of study entry, 11 of 12 patients in Arm 1 and 10 of 12 patients in Arm 2 had only biochemical relapse with no other evidence of metastatic disease (Table 1). The mean age of patients was 62.5±6.7 and 65.7±9.2 years and the mean Gleason score at study entry was 7.25 and 7.17 in Arms 1 and 2, respectively.
Patients were screened and randomized into 1 of 2 arms, each with 12 patients. Patients in both arms were blind during the vaccine/placebo phases until Week 8. Patients in Arm 1 continued into the post-vaccine phase while patients in Arm 2 crossed over into the vaccine phase before entering post-vaccine phase.
DC vaccine characteristics
DCs were cocultured with LNCaP or LNCaP-M1 cells that were >90% apoptotic (Figure 2). All DC vaccine preparations administered met criteria for viability and maturity (Table 2 and Figure 2). DC function was monitored by allo-MLR; DCs stimulated 2×105 allogeneic T cells to incorporate ≥105 CPM of 3H-thymidine on day 5 after an 18-hour 3H thymidine pulse (data not shown).
UV irradiation (+UV) specifically induced apoptosis in LNCaP cells as indicated by 96% Caspatag+ TOPRO+ staining 38 hours post UV. DC cocultured with apoptotic LNCaP cells (Vaccine) are mature, with >96% CD83 positive cells. Data shown is representative of all 24 vaccines prepared.
The incidence of injection-site and systemic reactions to vaccine are presented in Table 3. No vaccine related serious adverse events were observed. Only 1 toxicity was significantly different between the placebo and vaccine groups in the single blind phase of the study: grade 1 or 2 injections site reactions that occurred in 11 of 12 patients in the vaccine group (p<0.001), attributable to vaccine (but not placebo) generating DTH-like responses. There was no symptomatic evidence of autoimmune disease in any patient, including vasculitis, thyroiditis, colitis, neurologic disease, endocrinopathy or cardiomyopathy.
Immune response
All patients who received the DC/keyhole limpet hemocyanin (KLH) vaccine had a positive DTH response to KLH. None of the 24 patients had a response to LNCaP lysate at baseline (week 0). All 24 patients were given LNCaP lysate as part of DTH panels at weeks 3, 5, 7, and 9. Sixteen of 24 patients (67%) had a DTH response to LNCaP lysate in at least 1 of these 4 time points, with the highest proportion of patients (54.2%) responding to LNCaP lysate at 2 weeks after the last booster (week 9). Responses were maintained in 9 of 13 patients (69%) at 22 weeks after the last booster (week 29, Figure 3). The responses to LNCaP lysate were statistically significant at all time points with a 95% confidence interval. Normal saline, given as a control, was negative at all time points in all patients.
Vaccine induced DTH response to LNCaP cell lysates injected intradermally were measured at the indicated times. Week 1 was baseline, at which time no patients had DTH responses (data not shown). DTH responses were considered positive at ≥5 mm erythema read at 48 hours after placement. Bars indicate the number of patients with positive responses at each time point. Error bars represent 95% confidence intervals. Dotted line represents trend of percentage of patients with positive responses at each time point. Statistically significant positive DTH responses to LNCaP cell lysate appeared at Week 3 (first time point after baseline) and responses were still present in 9 of 13 patients (69%) at 22 weeks after the last booster dose (Week 29).
A 3H thymidine proliferation assay was used to assess the reactivity of T cells to KLH protein and to prostate tumor cells (either those used in vaccination (LNCaP) or to another prostate tumor cell line (PC3)). Negative control antigens included autologous monocytes and an irrelevant cell line (3T3). 3T3 infected with influenza was used as positive control. T cells were collected at week 0 (pre-vaccine) leukapheresis and week 13 (post-vaccine) leukapheresis (Figure 1). To be valid, each individual proliferation assay must have had a detectable influenza response pre- and post-vaccine. Two of 24 patients had no detectable influenza response and thus were excluded from analysis. The 22 evaluable patients, considered as a group, had no statistically significant difference in T cell response to influenza, pre- versus post-vaccine (p = 0.310, data not shown). There was a statistically significant T cell response to KLH post-vaccine vs pre-vaccine (p = 0.008), as well as to apoptotic LNCaP (p = 0.017) and apoptotic PC3 tumor cells (p = 0.011) (Figure 4a). There were no statistically significant differences in pre- vs post-vaccine T cell responses to antigen presenting cells (APCs) alone (p = 0.160), to control antigens, 3T3 (p = 0.070) or autologous monocytes (p = 0.156) (Table 4, Figure 4a and data not shown).
Comparison of pre- and post-vaccine bulk T cell responses to prostate antigen. a. Apoptotic tumor cells (LNCaP and PC3, or an irrelevant cell line (3T3)) or KLH protein were co-cultured with patient peripheral blood monocytes and syngeneic bulk T cells obtained from patients pre- or post-vaccination. Monocytes without exogenous antigen (No Ag) or apoptotic 3T3 cells (Ctrl Ag), served as negative controls. Proliferation was assessed on day 5 after an 18-hour 3H thymidine pulse. Data is presented for 22 of 24 patients. The difference in proliferation (post- minus pre-vaccine) for each antigen group is shown in box plots. Values reported are average counts per minute (CPM) of triplicate wells. The median difference for each antigen group is shown by the line in the box. Each patient who is an outlier is indicated by a unique symbol. Statistically significant differences in pre-vaccine vs. post-vaccine T cell proliferative responses were found for KLH (p = 0.008), LNCaP (p = 0.017) and PC3 (p = 0.011). b. Bulk T cells obtained post-vaccination were stained with CFSE and cultured with DCs cross-presenting prostate antigens, LNCaP and PC3, or an irrelevant cell line (293 cells, Ctrl Ag). Cell proliferation on day 5, assessed by CFSE dye dilution, is shown on the x-axis and CD8 expression is shown on the y-axis. Percentages shown represent CD8+ cells that have divided within the bulk T cell population. Four of five additional patients tested showed similar CD8+ responses; data shown are for patient #15.
Based on the DTH data (Figure 3) and the 3H thymidine proliferation data (Figure 4a), we calculated and ranked a DTH index and a proliferation index to determine if there was an association between the two. A positive correlation was found (0.55 using the Spearman rank correlation test (p = 0.008)), indicating that patients who had positive DTH responses to LNCaP lysate also tended to have T cell proliferation responses to apoptotic LNCaP cells in vitro.
The proliferation response was also assessed by CFSE dye dilution assay[30]. In 5 of 6 patients, a CD8+ T cell response specific for prostate antigens was observed (Figure 4b and data not shown). We confirmed that all six patients tested also had a CD4+ T cell response to prostate antigens.
We considered the possibility that the increased T cell proliferation response post vaccination could relate to a decline in regulatory T cells in circulation. To determine the percent of CD4+ T cells that are T regulatory cells in pre- and post-vaccinated blood samples, PBMCs were stained and assessed for Foxp3 expression (Figure 5). No difference (p = 0.924) was found in Foxp3 expression comparing pre- and post-vaccination CD4+ T cells from 15 patients (Table 4).
a. FACS profile of Foxp3 expression in pre- and post-vaccinated peripheral blood gated on CD4+ T cells. A representative patient (#13) is shown. b. Box plots of the percent Foxp3+ cells (gated on CD4+ T cells) pre and post-vaccination in 15 representative patients, including those across the whole range of proliferative responses and changes in PSA slope. The median is shown by the +. Outliers are indicated by •. No difference in pre-vaccine vs. post-vaccine T cell expression of Foxp3 (p = 0.924) was observed.
PSA response
The prostate specific antigen doubling time (PSADT) was calculated for each patient during each phase of study. The median doubling time during the pre-vaccine phase was 4.5 months, and this increased to 5.4 and 8.9 months during the vaccine and post-vaccine phases respectively. There were statistically significant differences in PSADT between the pre- and post-vaccine phases (p = 0.003) and between the vaccine and post-vaccine phases (p<0.001) but not between the pre-vaccine and vaccine phases (p = 0.915).
We also compared the slope of the PSA rise between the 3 study phases. Eighteen of 23 (78%) evaluable patients had a decrease in PSA slope between the pre- and post-vaccine phases. When considering all 23 patients, there was a statistically significant decrease in the PSA slope between the pre-vaccine and post-vaccine phases of −0.093/month (p = 0.016, Figure 6 and Table 5). There was no statistical difference in PSA slope between the pre-vaccine and vaccine phases (−0.018/month, p = 0.681) or the vaccine and post-vaccine phases (−0.075/month, p = 0.098). We evaluated whether this PSA slope change might result from the development of serum anti-PSA antibodies. Pre- and post-vaccine serum was assessed by measuring serum antibody reactivity to purified PSA protein on Western blot, using PSA monoclonal antibodies as a positive control. We found no evidence for antibody reactivity to PSA (data not shown). Nonetheless, we cannot rule out that antibodies are not detectable due to antigen/antibody complexes being formed and that these somehow aided in clearing PSA from the serum.
Graph of the average log2 (PSA) slope per study phase (solid line); for comparison, an extrapolation of the pre-vaccine average log2 (PSA) slope is shown (dotted line). Based on the linear spline model, the average change in PSA slope of 23 patients from pre- to post-vaccine phases is −0.093/month (p = 0.016). One patient's PSA values were not included in the analysis as his pre-vaccine values were affected by other treatment near the start of study participation. Three other patients started other treatment either during or after vaccination; PSA values obtained after this point were not included in the analysis.
We then stratified the study population with two more fixed effects on a mixed model and conducted a likelihood ratio test; the patients that had a DTH response to LNCaP lysate had a significantly different PSA slope change when compared to those that had no DTH response to LNCAP lysate (p = 0.004). Sixteen of 24 patients had DTH responses to LNCaP in at least one time point. This group of patients had a statistically significant change in PSA slope between the pre-vaccine and post-vaccine phases (−0.105/month, p = 0.020, Table 6). Eight of 24 patients had no response to LNCaP lysate at any time point, and these patients had no statistically significant change in slope between the pre-and post-vaccine phases (−0.033/month, p = 0.631). When we stratified the study population into 2 groups based on PSA value at study entry, the likelihood ratio test indicated a significantly different PSA slope change between these two groups (p<0.001). With the mixed model, we found that those who had a PSA ≥1 ng/ml at study entry (15 patients) had a significant PSA slope change between pre- to post-vaccine phase (−0.099/month, p = 0.031, Table 6) while the patient subgroup that had a PSA <1 ng/ml at study entry (8 patients) did not (−0.078/month, p = 0.279). Taken together, these data demonstrate that the study patients taken as a group had a significant reduction in the rate of rise of PSA after vaccination, and that this effect was particularly evident in those with immunologic response and more readily measurable disease.
Patients with PND develop effective tumor suppression of common cancer types[2] that are likely to be triggered by immune recognition of ectopic expression of neuronal proteins by those cancers. To trigger such immune responses, we hypothesized and demonstrated that apoptotic tumor serves as a potent source of antigen for presentation by APCs[7], [29]. The focus of this study was to evaluate the safety and immunogenicity of mimicking this means of triggering tumor immunity by using prostate cancer patients' DCs cross-presenting apoptotic tumor cells as a cancer vaccine.
Despite the conceptual link between the development of apoptotic cells as a vaccine and tumor immunity in PND, we found no evidence that this approach triggered autoimmune disease in our patients. We did note small ANA elevations post vaccine in 5 patients (titer of 1∶160 in one patient, ≤1∶80 in four patients) which resolved over time in 4/5 patients. However, we also noted that of 7 patients with detectable ANA levels pre-vaccination, 5 became lower after vaccination. Statistical analysis of ANA changes pre versus post vaccine/placebo in Arm 1 versus Arm 2 revealed no significant differences (Fisher's exact test), and we conclude that ANA changes were not clinically meaningful; moreover, such transient responses have commonly been seen in DC based vaccines[26], [31], [32]. One reason that we chose prostate cancer as an initial tumor for study using this vaccine approach is that these tumors are rarely associated with PND. Despite the safety of the vaccine here, caution is warranted in extending this approach to patients harboring tumors known to be associated with PND (for example gynecologic tumors expressing the cdr2 or Nova antigens and small cell lung cancers expressing the Hu antigen)[1], [2].
Our dendritic cell/apoptotic tumor vaccine was immunogenic. Sixty-seven percent of patients developed DTH responses to LNCaP antigens. Furthermore, these DTH responses were positively correlated with post-vaccine bulk T cell proliferation responses. This high level of immunogenicity was similar to that reported in other studies of peptide-pulsed or tumor cell associated DC vaccines. Importantly, these responses included CD8+ T cell responses to prostate tumor cells (Figure 4b). This is significant, as a critical determinant of successful tumor vaccines is likely to be induction of CD8+ T cell responses[33]. The ability to detect such responses here is consistent with the observation that cross-presentation of apoptotic cells are able to stimulate naïve and memory CD8+ T cell responses to tumor cells[3] or to virally infected cells[8] ex vivo. Due to the nature of the disease, autologous tumor cells were not available for testing T cell responses. However, both the CD4 and CD8 proliferation responses were detected to prostate tumor cell lines, despite the high background responses seen in T cells post vaccination (Figure 4a). Such background responses have been seen before in DC-based vaccines and are of uncertain etiology[34], and may be reflected in transient increases in ANA seen in some patients. It is likely that patients had variable immune responses to tumor vaccination, either resulting from intrinsic differences in immune repertoire, or from actions of the tumor itself to modify patient immune responses[35].
Significantly, we found that PSA slopes decreased and PSADT increased after vaccination in our patient population as a whole (p = 0.016). We hypothesized that if this correlation was related to the immunogenicity of the vaccine, PSA changes should be present in the subset of patients showing immunogenic response to vaccine but not in those who do not. In fact, patients who had DTH responses to LNCaP after vaccination had significant decreases in PSA slope (p = 0.020), compared to patients who did not have DTH responses (p = 0.631). Taken together, our data suggests that the changes seen in PSA slope represent an immune response to patient tumor cells in vivo.
Although variable immunologic and clinical responses have been reported to vaccines using dead tumor cells as a source of antigen, these studies have not focused on using pure, well-defined populations of apoptotic tumor cells. We used UV-B irradiation to induce apoptotic (not necrotic) death in >90% of the prostate cell line used for the vaccine; nonetheless, our side-effect profile was very low, similar to other tumor vaccines. Most other studies have used gamma irradiation or freeze-thawing, generating variable mixtures of apoptotic and necrotic cells, which may underlie differences in immunogenic potential[28].
Taken together, the results presented in this study provide initial safety and immunogenicity data for a vaccine mimicking what we believe is a critical trigger for naturally occurring effective tumor immune responses seen in PND patients. These responses correlate with a clinically relevant response to patient tumor, as assessed by highly statistically significant effects on PSA slope and doubling time. These observations suggest that this vaccination approach warrants further exploration as a safe and potent means of triggering tumor immune response in the general population of cancer patients. Future vaccine modifications to be considered are the addition of immune adjuvants during vaccine preparation ex vivo or in conjunction with vaccine administration in vivo[9], [36], or the use of autologous tumor as a source of apoptotic antigen. In addition, a safe means of vaccinating against prostate (or other) cancers may serve in a synergistic manner with other immune-stimulating agents, such as CTLA4-Ig, which are showing promise in combined immunotherapies in prostate[37] and other cancers[38].
The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1.
Patients and Study Design
Ethics Statement.
The study was approved by The Rockefeller University Institutional Review Board (RDA-0466) and the FDA (IND 10710). Written consent was obtained from all patients. No de novo cell lines were generated in this study.
Study Design.
The study was conducted at the Rockefeller University in New York; twenty-four patients aged 53 to 81 were enrolled between November 2003 and February 2006. All authors vouch for the completeness and accuracy of the data and its analysis and participated in writing the article.
Twenty-four patients were randomly assigned to one of two arms for the purpose of assessing vaccine safety, our primary endpoint (Figure 1). All patients were blinded. Twelve patients assigned to Arm 1 received vaccine followed by 3 vaccine boosts at 2-week intervals, for a total of four injections over eight weeks, and were unblinded after the last booster. Twelve patients assigned to Arm 2 received placebo (vehicle (5% DMSO in saline)) for each of four injections, were unblinded, crossed over to the vaccine phase, and received vaccine followed by 3 boosts at 2-week intervals. After the last booster, patients in both groups were followed for up to 22 weeks. All time points in both arms up to and including the day of the first vaccination with DC vaccine were considered pre-vaccine phase. All time points from the first booster through the first follow up visit after the final vaccination (week 9) was considered vaccine phase. All remaining time points in the study were considered to be post-vaccine phase. Safety data was compared between the 2 arms of the study, while immune and PSA data were assessed by comparisons made between pre- and post-vaccine phases in all 24 patients.
Patient Selection and Vaccination.
Patients were eligible to participate if they provided informed consent, had biopsy proven prostate cancer and progressive disease: PSA documented to be rising on 3 occasions, either despite castrate testosterone levels (below 50 ng/dl) or despite definitive local therapy (prostatectomy, radiation, etc.). Exclusion criteria included prior biologic therapy with dendritic cells, autoimmune disease, or significant major organ disease.
DC vaccines were given together with DTH panels and patients were closely observed for one hour. Patients returned to clinic at 48 hours, at which time they were examined clinically and their DTH responses were read. Vaccines were administered at a cell dose ranging from 2−10×106 DCs/vaccination, given subcutaneously in the inner aspect of the upper arm, approximately 6–8 cm from the axillary lymph nodes. Patients received one priming and three biweekly booster vaccinations. During the first two injections, patients also received 2−10×106 DC/KLH.
Vaccine was manufactured in a BSL-2 facility maintained and independently audited to meet Good Tissue Practice specifications. To prepare autologous DCs, peripheral blood mononuclear cells (PBMCs) were obtained by leukapheresis, adhered to endotoxin free tissue-culture dishes (Falcon), and differentiated in vitro to immature DCs over six days in RPMI-1640 supplemented with 1% autologous plasma, GM-CSF (180 ng/ml; Bayer HealthCare Pharmaceuticals) and IL-4 (10 mg/ml; R&D Systems) as described[29], [39]. LNCaP prostate tumor cells were obtained from the American Type Cell Culture and a master cell bank was made and screened by BioReliance Corporation (Rockville, MD) to rule out contamination or adventitious agents. LNCaP cells from the master stock (frozen in Aim V media (Invitrogen) plus BSE-free fetal bovine serum (20% FBS; HyClone) and 5% DMSO (Edward Life Sciences)) were expanded in Aim V media/1% FBS, and cells were treated with UV-B irradiation such that >90% of cells underwent apoptotic death (Caspatag positive, as described[29]). Immature DCs and apoptotic LNCaP were co-cultured at a ratio of 1∶1 for 36–48 hours in the presence of PGE2 (20 mM; Sigma) and TNF-α (150 ng/ml; R&D Systems) to mature DCs as described[40]. DCs pulsed with KLH (2.5 µg/ml, biosyn) provided a positive control for DC function. All patients were also immunized with 2−10×106 DCs cross-presenting apoptotic LNCaP producing the M1 antigen as a potential positive control (DC/LNCaP-M1), but only four patients were HLA A2.1+ and tetramer analysis did not show boosted M1 responses post vaccination in these patients (data not shown). The quality and viability of the vaccine was monitored by flow cytometry; to pass release criteria the HLA-DR (DC) cell fraction had to be >70% CD83+, <15% CD14+ and <20% Propidium Iodide (PI) + (Serologicals). All antibodies were purchased from BD Pharmingen. Sterility was tested by gram stain, by culture for bacterial and fungal contamination (BacT/ALERT, Biomereux), and by DNA fluorochrome for mycoplasma (Bionique Testing Laboratories, Inc.). The LAL method (Associates of Cape Cod) was used to test for endotoxin. The final product was divided into 4 equal aliquots, each containing 2−10×106 DCs each. The first aliquot was given as a "fresh" dose; all other aliquots were frozen and thawed prior to administration.
Clinical and Immunomonitoring
Clinical Monitoring.
Patients were monitored at each study visit by history, physical examination, and by laboratory evaluations including CBC, chemistries, and urinalysis, for any adverse effects. The National Cancer Institute Common Toxicity Criteria version 3 was used to grade toxicities. Patients were also asked to maintain a diary of local injection site reactions and systemic adverse events for one week following each vaccination.
To assess for clinical response, PSA levels were measured in the serum using MSA Bayer Immuno I or IEA Tosoh Nexia assays at each study visit. The PSA slope was calculated for each phase of the study (pre-vaccine, vaccine, and post-vaccine phases) using a linear mixed model with two knots representing the change in slope in each phase of the study. In addition, for each phase of study for each patient, a PSA doubling time (PSADT) was calculated using the formula: 1 divided by the slope log2 PSA derived from this linear spline model.
A DTH panel was placed intradermally at weeks 1 (vaccine), 3 (Boost #1), 5 (Boost #2), 7 (Boost #3), 9, 17 and 29 to assess for T cell responses. The panel included lysate of 105 LNCaP cells (in 0.1 ml normal saline), 0.05 mg KLH, candida or tetanus toxoid (whichever the patient had responses to at baseline, as positive control), and saline (as negative control). Responses were considered positive if erythema was equal to or greater than 5 mm at 48 hours post implantation.
We evaluated immunogenicity outcomes against apoptotic LNCaP and PC3 (another prostate cancer tumor cell line) by 3H thymidine or CFSE proliferation assays as described[29] with the following modifications. In the 3H thymidine assay, autologous monocytes (CD14+ cells) were used as APCs. 3T3 cells, an irrelevant cell line, were used as the negative control antigen and influenza infected (strain A/P/R8) 3T3 cells were used as a positive control for both pre-vaccine and post-vaccine T cell responses. 3T3 cells were obtained from the American Type Cell Culture. In the CFSE assay, DCs cross-presenting prostate tumor antigens or 293 cells (irrelevant cell line used as negative control antigen) were used as APCs and cultured with T cells stained with CFSE (Vibrant CFDA SE Cell Tracer Kit, Invitrogen). On day 5, T cells were stained with anti-CD8 conjugated antibody (Becton Dickinson) and analyzed using FlowJo software. All cell lines were UV-B irradiated to induce apoptotic death three hours prior to co-culture with APCs[29].
To assess for correlations between patients who had a DTH response to LNCaP lysate and those who had T cell proliferation responses to apoptotic LNCaP in vitro, patients were ranked by a DTH index and a T cell (3H thymidine) proliferation index. The DTH index was calculated as the number of positive DTH responses to LNCaP lysate divided by the total number of DTH time points for each patient. The T cell proliferation index was calculated as the post-vaccine LNCaP response (CPM) minus 2 standard deviations, divided by post-vaccine 3T3 response (CPM) plus 2 standard deviations.
FACS staining of regulatory T cells was done by surface staining with anti-CD4-FITC (Becton Dickinson) followed by intracellular staining with anti-Foxp3-APC (eBioscience, clone PCH101) per manufacturers instructions. For analysis, PBMCs were gated on CD4+ T cells and the percentage of Foxp3+ cells was determined (FlowJo).
Statistical Analysis
The protocol called for 12 patients to be recruited to each of two arms, which would have 90% power to detect an increase in cumulative serious adverse events (SAEs) from 5% in the placebo group to 50% in the vaccine group at the 10% level. All adverse events were analyzed using Fisher's exact test to compare placebo and vaccine phase. Significance of DTH responses to LNCaP cell lysate was determined by the exact binomial test with 95% confidence intervals. To analyze pre- to post- T cell proliferation data (per antigen) for study subjects as a group, a two-sampled paired t-test was used with 95% confidence intervals. The Spearman rank correlation test was used to determine if those that had DTH responses to LNCaP lysate also had T cell proliferation responses to apoptotic LNCaP in vitro. The paired t-test was used to compare the percentage of pre- vs post-vaccine Foxp3+ cells in PBMCs with 95% confidence intervals. In all of the above tests, the differences or correlation were deemed statistically significant if the p-value was less than 0.05.
To model the evolution of PSA (in log-scale) during the three study phases (pre-vaccine, vaccine, and post-vaccine phases), a mixed linear spline model was used. Two knots (one at the start of the vaccine phase and the other at the start of the post-vaccine phase) were used to directly quantify the differences in slopes between each phase. To account for the heterogeneous treatment effect and the repeated measures structure, random effects are incorporated into the model. For the general model, random effects for the intercept, slope and the first knot were considered. To determine if there was any difference in PSA slopes between those that did have an immunologic response (DTH responders to LNCaP lysate) and those that did not (DTH non-responders to LNCaP lysate), a second model, stratified by these response indicators (with separate knots for the two groups), was fitted and the likelihood ratio test was conducted. Similarly, a third model was fitted, this time, stratified by PSA at study start of <1 ng/ml or ≥1 ng/ml. The models with stratification were then compared to the general model. All models were fitted and hypotheses were tested using the lme package from R (www.R-project.org). The Wilcoxon matched-paired signed rank test was used to determine statistical significance of the difference in PSADT between phases (www.fon.hum.uva.nl/service/statistics/signed_rank_test.html). A PSADT can be a positive number as a result of rising PSA levels or a negative number as a result of declining PSA levels. For the purpose of statistical analysis, negative PSADT (indicating declining PSAs) were replaced with 9999 months to represent an infinitely long doubling time so that they rank higher than any value for which doubling time was a positive number. Differences were deemed significant if the p-value was less than 0.05.
Supporting Information
Checklist S1.
Consort checklist.
Protocol S1.
FDA-approved IND 10710 protocol.
We thank Michel Sadelain for helpful discussions, members of the Darnell laboratory for critical discussion and review of the manuscript, members of the Rockefeller University Hospital Nursing Staff for their compassionate care of the study participants, members of the MSKCC clinical and research nurses, Gabrielle Aruz, Anthony Delacruz, and Tracy Smart-Curley, for their assistance with study patients, Sarah Schlesinger and Mary Marovich for help drafting SOPs, Stephen Paget for advice regarding relevance of ANAs, and Denise Larone for help with release criteria. The authors are grateful for extraordinary support from David Koch. RBD is an Investigator of the Howard Hughes Medical Institute.
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- 34. Palucka AK, Connolly J, Ueno H, Kohl J, Paczesny S, et al. (2005) Spontaneous proliferation and type 2 cytokine secretion by CD4+T cells in patients with metastatic melanoma vaccinated with antigen-pulsed dendritic cells. J Clin Immunol 25: 288–295.
- 35. Bui JD, Schreiber RD (2007) Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes? Curr Opin Immunol 19: 203–208.
- 36. Zang X, Allison JP (2007) The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res 13: 5271–5279.
- 37. Fong L, Kwek SS, O'Brien S, Kavanagh B, McNeel DG, et al. (2009) Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res 69: 609–615.
- 38. Peggs KS, Quezada SA, Korman AJ, Allison JP (2006) Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr Opin Immunol 18: 206–213.
- 39. Sallusto F, Lanzavecchia A (1994) Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 179: 1109–1118.
- 40. Rieser C, Bock G, Klocker H, Bartsch G, Thurnher M (1997) Prostaglandin E2 and tumor necrosis factor alpha cooperate to activate human dendritic cells: synergistic activation of interleukin 12 production. J Exp Med 186: 1603–1608.


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- Thursday April 6th, 2017 :: 10:12 a.m. PDT
Impending Storm System
The National Weather Service is predicting potentially significant rainfall activity in your area starting Thursday evening. Your area is of particular concern due to the Loma Fire Burn Scar and the identified concern of soil instability along the Llagas Creek. Please review the safety information that may have been distributed in your area regarding landslide and mud/debris flow hazards at Casa Loma Rd. and the Chual Spur.
Please visit the following link for additional information:
County of Santa Clara
55 W Younger Ave
San Jose, CA 95110
Emergency: 9-1-1
Non-emergencies: 408-808-7800


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HTACCESS redirection file needed
I need someone to generate a small HTACCESS redirection file. The site is on Linux.
Please see attached Excel file.
Please only apply if you have dev experience and have done HTACCESS files before.
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Need this today if possible.
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What: Five powerful products from certified-organic natural anti-aging line Skin 2 Skin Care. You'll get:
White Tea Anti-Aging Face Wash
Anti-Aging Revitalizing Eye Gel
Un-Wrinkle Forehead & Crow's Feet
If you can't wait to win, shop the site now and get 15% off your order with coupon code SheFinds, and an additional 10% off when you register as a VIP Member. Plus, you'll get free ground shipping in the 48 contiguous United States. Pretty good deal.
Why: Skin 2 Skin Care's natural and organic products are all specifically formulated to make skin look healthy and youthful. They fight fine lines, wrinkles and sun damage, and even use replenishable ingredients – no petroleum, mineral oil, or synthetic fragrance.
This comprehensive prize includes everything you'll need to keep your skin looking young (or make it look a lot younger). From cleansing to moisturizing to spot treatments, this regimen is a luxurious way to get great-looking skin.
How: Browse the products on the site, then come back here and tell us what you'd want to try in the comments section below. If it's not one in the prize pack (or even if it is), take advantage of the 25% discount and free shipping you can get when you buy it!
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1. Post a comment about your favorite product on Skin2SkinCare.com.
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5. No prize substitutions.
6. You must be 18 years old or older to enter and a resident of the USA.
7. No purchase necessary.
8. Void where prohibited.
9. Click here for the full rules.


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Certified Tutor
I'm a native of Oklahoma City, Oklahoma and a recent UC Davis graduate. I'm a sports enthusiast, avid music fan, shoe fanatic, traveler, and I love to hike.
If asked to describe myself in three words, I'd say ethical, relatable, and progressive-minded. Further, I enjoy assisting students throughout various stages of the writing process. As a Senior Writing Tutor at UC Davis, I had the privilege of tutoring students from various cultures, disciplines of study, and levels of education.
Being that I'm not far removed from school, I understand how utterly frustrating and mind-numbing the writing process can be. Through it all, I encourage students: find your voice and remain creative throughout the writing process. I am both well-qualified and thrilled to help guide your journey to becoming a better writer. It's imperative to your future success, and that isn't a responsibility I take lightly. I look forward to meeting you!
Harrison's Qualifications
Education & Certification
Undergraduate Degree: University of California-Davis - Bachelor in Arts, African American and African Studies
Sports, traveling, avid music fan, hiking, and hanging out with friends
Tutoring Subjects
College English
Comparative Literature
High School English
What is your teaching philosophy?
Find your voice and remain creative.
What might you do in a typical first session with a student?
Introduce ourselves and get to know each other.
How can you help a student become an independent learner?
By helping the student grow his/her knowledge base and instilling confidence.
How would you help a student stay motivated?
By celebrating success and finding ways to improve.
If a student has difficulty learning a skill or concept, what would you do?
Reimagine the skill or concept and approach it from a different angle.
How do you help students who are struggling with reading comprehension?
Break the piece into sections and review the most pertinent info in each section. Many students try to remember everything as opposed to employing strategy.
What strategies have you found to be most successful when you start to work with a student?
Getting to know the student foremost. Also, understanding his or her strengths is essential to developing his or her weaknesses.
How would you help a student get excited/engaged with a subject that they are struggling in?
By making learning a playful competition. I'd test the student's knowledge, and if the student correctly answered "x" number of questions out of "y," he or she wins.
What techniques would you use to be sure that a student understands the material?
I'd produce test-level practice questions and talk through why each answer is or isn't correct. I'd also employ verbal quizzing.
How do you build a student's confidence in a subject?
Repetition, encouragement, and fun.
How do you evaluate a student's needs?
By observation and asking the student directly.
How do you adapt your tutoring to the student's needs?
I take time in each session to build their strengths and in turn their confidence--before addressing the not-so-strengths and working to improve them.
What types of materials do you typically use during a tutoring session?
Laptop, pen, and paper.


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Organic Fernleaf Dill Seedling
Anethum graveolens
This aromatic herb attracts beneficial insects in the garden, and is beautiful swaying in the wind. It is great for pickling, of course, and we often serve it with salmon. We recently enjoyed a salad with dill seeds and could taste a bit of citrus in them.
Space each plant four inches apart in a bed with four hours of sun. Water well when young; once established the dill's deep taproot makes it very drought tolerant. Dill reseeds each year.
Out Stock


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As you can see it is working perfectly with my config using Linux Mint 19.2 Tina 64bit Cinnamon Live USB installer.
The config is Dell Vostro 5481 + WD15 130W dock + 2xP2217
How do you make it work?
I have dell vostro 5481 but no matter what I try it most often does not even work with one monitor. I am thinking about selling it cheaper than i bought 😞
I have xubuntu 18 and windows 10
I did nothing special. It just works. Also with windows 10. The laptop has the latest BIOS and the dock has the latest firmware and it is working out of the box. I am using the HDMI and DP ports of the dock. If it doesn't work for you with the same devices and same conditions that may mean that some of them are faulty. Mine is also not perfect as I have to plug it in the dock twice every time to make it work as I mentioned in the topic starter but then it is working perfectly.
Thanks a lot for giving it a try!
I will buy a WD15 then.
Really appreciate it!
Best regards!
You're welcome. In return you should check if you will experience the same behaviour as I described in the topic starter.
thanks for your helpful contributions to this topic
I've just noticed this thread re: Vostro 5481 + WD15 dock + 130W PSU. I have the same setup. I'm running BIOS version 2.2 with Windows 10 Pro 1903. It's all working fine except for the behaviour on power-up. I have the Vostro 5481 in a stand (with the lid closed) and have the start on power applied BIOS setting. Only the USB-C connector is in the laptop, everything else on the desk (keyboard, mouse, ethernet and monitor) is connected to the WD15.
On applying power via the PSU & Dock, the laptop starts, and all connected devices start OK, except for the monitor (connected via either HDMI or Mini-Displayport), also the light on the USB-C plug at the laptop end does not light up. I can fix things by unplugging the USB-C and then plugging it in again, the monitor now works and the light on the USB-C plug lights up.
This sounds similar to the behaviour detailed by other users on this thread. I'd be interested if anyone has a proper fix (perhaps updating the Vostro 5481 BIOS or the firmware on the WD15) ?


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Lance Stroll
Logo Design, Graphic Design, Typography
Identity for Lance Stroll, a Canadian racing driver who started his first season in Formula 1 in 2017 with Williams. A contemporary, distinctive and cutting-edge monogram and logotype were developed to bring his true DNA to life — as both the racer and the man. The dynamic and italicised typography and the cut angles hint towards the race circuit and the aerodynamic shape of the car. Designed at MSL.


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Totally "Tub"ular!
When this vacant Garden City property, listed for sale by a local realtor, suffered from a trash can fire, extensive cleaning and deodorization services were required due to the heavy amount of smoke and soot throughout the home. The owner wanted the property back on the market quickly and SERVPRO of Dearborn Heights North/East Garden City was called in to expedite the cleanup. Utilizing SERVPRO's proven cleaning techniques, the home was promptly and properly cleaned and deodorized. The homeowner was thrilled with the results and the home was back on the market within two weeks and sold within a month. At SERVPRO, we work to make it "Like it never even happened."


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2nd Amend.
Our military overwhelmingly wants concealed carry rights on base
It would be nice to just issue a proclamation here today that all soldiers should be able to carry on base.
There was an unusual Rasmussen survey this month which provided a glimpse into one segment of the population we don't hear from often enough. Our nation's military almost uniformly (pun not intended) wants the right to arm themselves while on base. Unfortunately, what seems like common sense at the most basic level is highly controversial in politics, particularly among the Democrat leadership. Our own Katie Pavlich touched on this at Town Hall with some of the pertinent background.
After watching the slaughter at the Ft. Hood terror attack in 2009, the second Ft. Hood shooting in 2014 and most recently in Chattanooga, soldiers stationed at bases and posts here at home are fed up with the military's "gun free" zone policy.
Current Department of Defense policy states, "It is DoD policy to limit and control the carrying of firearms by DoD military and civilian personnel. The authorization to carry firearms shall be issued only to qualified personnel when there is a reasonable expectation that life or DoD assets will be jeopardized if firearms are not carried."
After Chattanooga, this policy was even more dumbfounding. The FBI had been warning military service members about potential lone wolf terror attacks for nearly a year, yet didn't allow those stationed in recruitment centers any means to protect themselves.
The results of this survey are pretty much as obvious as discovering that water is wet, but as I noted above, it's something of a rare glimpse. You don't often see our active duty soldiers, sailors and airmen piping up on matters of political debate, and unless things have changed significantly since I was in the service, that fact is by design. Personnel are actively discouraged from spouting off, particularly when their opinions could be seen as contrary to the leadership, established rules or the Commander in Chief. If that sounds unfair to civilian ears you really need to consider the absolute requirement for discipline and respect for the chain of command in a functional military. Free thinking on matters of policy and tactics is not only discouraged, but seen as corrosive.
Still, our troops are human beings, each with their own opinions, and most of them doubtless follow the news of the days. I have to wonder if this desire for self-protection – widely opposed by Democrats – is only a smaller symptom of a larger trend. The Washington Post reported this month that recent veterans completing their terms of military service are far more Republican than they used to be.
We found that military service did move the needle to the right, even after controlling for age and other demographic factors. Veterans in general were more likely to vote for John McCain and Mitt Romney, more likely to call themselves Republicans, more likely to hold conservative positions on the "Don't Ask, Don't Tell" repeal, and more likely to dislike Obamacare. About half of non-veteran men voted for Obama, but only about 35 percent of male veterans voted for Obama in 2008 and 2012…
But that section of the analysis is for all veterans. They already seemed to tilt to the Right traditionally, but the newest crop is accelerating the pace.
A closer look at which veterans exhibit distinctive attitudes reveals that recent, younger veterans are more likely to be Republicans and vote for GOP candidates. We ran a statistical model that examined veteran attitudes and vote choice for each decade of age. While veterans in their 20s are not numerous—only about 6 percent of American men this age served—they are particularly likely to prefer and identify with Republicans.
Sign up for our daily email and get the stories everyone is talking about.


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Explore your creative side while developing better writing skills in this exciting 10-week course. Students will participate in several different creative writing exercises and workshops. In this class, you will have an opportunity to share your writing and get feedback from your peers. This class will also feature a close study of many different short stories from various genres.
Teacher: Mr. Joseph Shey Weaver
Shey Weaver was born in Anchorage, Alaska and spent his childhood living in many small villages including North Pole and Kotzebue. He graduated from the University of Georgia with a BA in English. He also went to Relay Graduate School in New York City, where he received a Masters of Arts in Teaching. In NYC, he briefly worked on Broadway and played guitar, bass, and drums in several unpopular rock bands. Prior to working for Lakeland University, he worked for Tokyo Metropolitan University and Japan College of Foreign Language.


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You are here
Petronas to export world's 1st LNG from floating production unit
[SINGAPORE] Malaysia's Petronas is about to export the world's first liquefied natural gas (LNG) produced from a floating production unit, according to shipping data and people familiar with the matter, beating rivals like Royal Dutch Shell in a race that has cost developers billions of dollars.
The Petronas Floating LNG Satu (PFLNG Satu), sitting off the coat of Bintulu on Malaysia's Borneo island, is currently loading LNG into the 144,000 cubic metre capacity LNG tanker Seri Camellia, according to trade sources and shipping data in Thomson Reuters Eikon.
"Now, Satu is loading up a tanker, which will leave within the next day or two, making Satu the world's first LNG that was produced from a floating platform," one source close to the matter said, declining to be named due to the commercial sensitivity of the deal.
Eikon data shows that the LNG tanker arrived on March 25 and has started loading the LNG cargo. Traders with knowledge of the matter said that PFLNG Satu's first export cargo was heading for South Korea.
Petronas declined to comment.
The Satu facility, which is estimated to have cost as much as US$10 billion, arrived in those waters last year, preparing for first operations.
Other producers currently developing floating LNG production facilities include Royal Dutch Shell, which with the over US$12 billion Prelude FLNG is building the world's biggest maritime vessel for use in Australia.
Japan's Inpex is building a similarly big FLNG unit as part of the US$37 billion Ichthys export project, also for use in Australia.
Both these hugely expensive projects have been plagued by delays, allowing Petronas to become the first company to produce LNG from a floating production unit.
The huge development costs have led some to question whether FLNG units on this scale will be ordered again in future.
The LNG industry is undergoing huge change as the biggest ever flood of new supply is hitting the market, with volumes coming mainly from Australia and the United States.
The oversupply resulted in a more than 70 per cent fall in Asian spot LNG prices LNG-AS from their 2014 peaks to around US$5.50 per million British thermal units (mmBtu).
The Satu project's progress boosts Petronas' credibility as a firm able to engineer and execute cutting-edge projects, said Prasanth Kakaraparth, senior upstream analyst at energy consultancy Wood Mackenzie.
"Petronas enters a super-elite club of global players with FLNG capability," said Mr Kakaraparth.
"But with spot prices looking to trend below US$5/mmbtu, this is a very tough environment to be bringing on new supply."


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TORONTO -- Former NHL player and general manager John
Ferguson Sr., died Saturday after a lengthy fight with prostate
cancer. He was 68.
Ferguson was one of the toughest players to lace up skates in
the NHL and remained a big part of the sport as a GM, coach and
scout at the highest level.
Ferguson, the father of current Maple Leafs GM John Ferguson
Jr., went from being a tough guy on the ice to a powerful man in
the executive chair. He played eight NHL seasons from 1963-71, all
with the Montreal Canadiens, and was a Stanley Cup champion five
Ferguson was diagnosed with prostate cancer in September 2005,
and thought he had beaten the disease, but a recurrence took his
"My father battled cancer with the same spirit in which he
played the game of hockey," Ferguson Jr., said in a release. "He
showed courage, strength, class and tremendous character. He had
deep appreciation for the support he'd received from so many people
beginning with his initial diagnosis.
"My father's spirit will continue to live on in all of us whose
lives he touched."
Ferguson was GM and coach of the New York Rangers for two
tumultuous years until 1978 and GM of the Winnipeg Jets, both in
the WHA and NHL, from 1979-88 -- briefly serving as coach. He was
the manager of Windsor Raceway between hockey jobs before becoming
director of player personnel for the Ottawa Senators from 1992-95.
Ferguson was a senior scout for the San Jose Sharks from 1995 until
his death.
"John Ferguson was one of the most beloved figures to ever
represent the Sharks, as well as the entire National Hockey
League," Sharks GM Doug Wilson said in a statement. "His sense of
class, grace and love of the game of hockey is legendary among
those who were fortunate enough to know and work with him."
And his determination was unmatched.
Ferguson, also a standout on the lacrosse field, would crash
creases and drop the gloves when necessary. Along with his 145
goals -- an average of 18 a season -- and 158 assists, he amassed
1,214 penalty minutes in 500 regular-season games.
"There was no more passionate competitor, as a player, as a
coach or as an executive, than John Ferguson," NHL commissioner
Gary Bettman said in a statement. "He was tough, he wanted the
best for his teams, his teammates and his players, and his country,
and would stop at nothing to try to help them win.
"His fight against cancer was every bit as fierce as his
competitive drive on and off the ice. The League has lost a great
hockey man."
Ferguson was more than just a bodyguard for Montreal's stars, but
because of his reputation as a tough-as-nails combatant -- he got
into his first fight 12 seconds into his first NHL game -- it is
often forgotten that in his first season he led NHL rookies in
scoring and was runner-up for rookie of the year honors.
Ferguson scored two goals after fighting Ted Green in his first
game and was regarded as hockey's unofficial heavyweight champion
until he retired. He played much of his rookie season on a line
with Jean Beliveau, who won the Hart Trophy as league MVP that
Ferguson scored the Stanley Cup-winning goal in 1969, capping a
season in which he had 29 goals and a plus-30 rating. The 5-foot-11,
190-pound left winger was a force in the playoffs. In 85 postseason
games, No. 22 scored 20 goals and assisted on 18 others. Ferguson,
a two-time All-Star, once was dared to fight Canadian heavyweight
boxing champion George Chuvalo. He was willing to enter the ring
but the Canadiens wouldn't allow it.
Ferguson was an assistant coach on Canada's team in the 1972
Summit Series. Standing behind the bench watching Valeri Kharlamov
fly around the ice, Ferguson frowned and said, "He's killing us."
Bobby Clarke then went out and slashed Kharlamov across an ankle,
thus limiting the Russian's effectiveness.
In addition to his son, Ferguson is survived by wife, Joan.


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Envipco Holding N.V.
Below you will find information from the register publication of inside information. The information has been provided by the organisation.
- Registration date 06 aug 2018 - 02:25
- Statutory name Envipco Holding N.V.
- Title Envipco awarded with contract in Greece
Date last update: 11 December 2019


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Are you a creative student?
Have you heard of 3D additive manufacturing and are interested to learn more?
E-Civis and ECDL Romania offer you the opportunity for a free course in 3D printing. Become one of the few Romanian 3D designers and bring innovation in your field of work!
We are selecting 12 girl students in different university specialization in Bucharest for a certified ECDL 3D printing course – endorsed by the ECDL Foundation.
The Course will take place during the period 11 – 22 December between 17:00 – 20:00.


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Lahore: Provincial Minister for Social Welfare and Bait-ul-Mall, Syed Haroon Ahmed Sultan Bukhari has said that Provincial Social Welfare Department will complete four mega projects of women welfare at a cost of 413.72 million rupees in the province while five ongoing mega projects will become functional in June and Rs. 384.749 million have been spent on these projects.
He expressed these views while addressing a high level meeting of the department today. DG Social Welfare, Director Planning and other officers were present on the occasion.
The Minister said that four new mega projects to be completed include setting up of old age home in Multan at a cost of Rs. 28.267 million, establishment of industrial home and construction of building in Vehari with Rs. 44.442 million, building of shelter homes in five cities including Okara, Attock, Jhelum Chakwal and Mandi Bahauddin and construction of Qasar-e-Bahbood in Faisalabad and Sialkot with Rs. 192.483 billion.
The Minister informed that besides setting up of children home in Faisalabad, bagger home and old age home building in Lahore, upgradation of social welfare training institute and repair and reconstruction of buildings of Dar-ul-Aman in 34 districts will be completed during the end of current fiscal year. He said that Rs. 384.749 million have been spent on all these projects.
The Minister said that on the instructions of Punjab Chief Minister, Provincial Social Welfare Department will be made a role model department of the province.


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Holed – Site Rip
42 videos | 71.1 GB
It's new, it's looking good, it got me gaping at the butt-banging anal and it's set to grow. It's Holed and it's amazing quality ass-action. The whole thing is easy to use and for everyone into anal action, this is the latest site to see.


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If you are looking for a plushie of our mascot, Minty Sketch, you're at the right page!
She stands at approximately 12 inches tall, 7 inches long and 3 inches wide. And really, really soft.
She weighs about 0.23 kg/0.5 lbs, so you should have no problems carrying her around if you want to.


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Tonight with the encouragment of Brenda I leaned how to use Picassa. And here is proof - a collage of some of the window photos on my hard drive.
Fun to do? Yes. Helpful in narrowing down my quilt design? Um no!
It may not be helpful, but it sure is pretty. :-)
It really is amazing that a window can be so much more than a hole in a wall!
What an intriguing arrangement. I have been using Picasa for several years and am a loyal user. Picasa 3 has some great features that I have been longing for.
Beautiful windows! I really need to get our more. I've been stuck behind vinyl clad for too long.
I really like the one that looks like a geometric eye. That would make a fabulous window quilt with a twist :)