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One major challenge in the development of cancer therapeutics is the selective delivery of the drugs to their cellular targets. In the case of pancreatic cancer, the σ-2 receptor is a unique target that triggers apoptosis upon activation. We have previously developed a series of chemical compounds with high affinity for the σ-2 receptor and showed rapid internalization of the ligands. One particular specific ligand of the σ-2 receptor, SV119, binds to pancreatic cancer cells and induces target cell death in vitro and in vivo. In this study, we characterized the ability of SV119 to selectively deliver other death-inducing cargos to augment the cytotoxic properties of SV119 itself. When conjugated to SV119, small molecules that are known to interfere with intracellular prosurvival pathways retained their ability to induce cell death, the efficiency of which was enhanced by the combinatorial effect of SV119 delivered with its small molecule cargo. Our findings define a simple platform technology to increase the tumor-selective delivery of small molecule therapeutics via σ-2 ligands, permitting chemotherapeutic synergy that can optimize efficacy and patient benefit. Cancer Res; 72(1); 201–9. ©2011 AACR.

BACKGROUND An increasing number of mental health apps (MHapps) are being developed that focus on youth. Additionally, youth report being high users of technologies generally and MHapps specifically. Little is known, however, about youth’s perspectives on MHapps and methods to better involve youth in the process of providing feedback on apps. OBJECTIVE The goal of this study was to develop a process for eliciting youth perspectives on MHapps in a structured and collaborative way. We also sought to identify early learnings on aspects of MHapps and youths’ use of them that might facilitate discovery, activation, or engagement in MHapps. METHODS We created a series of five focus groups sessions that would introduce youth to different categories of MHapps (cognitive behavior therapy apps, mindfulness apps, miscellaneous). Within each category, we select four MHapps and participants would choose one to use for the week and provide feedback through both between-session and in-session activities. At the end of completing all five of the focus groups, participants completed a brief questionnaire to gather their impressions of the apps they had used. RESULTS We identified several aspects regarding MHapps that were important to youth. Youth wanted apps that were youth-centric, simple, could integrate with their offline lives, and also were relatable and accessible. We also found that the mindfulness apps we assigned to youth were viewed most favorably but that cognitive-behavioral therapy apps were viewed as more impactful. CONCLUSIONS Eliciting youth feedback on MHapps is critical if these apps are going to serve a role in supporting their mental health and wellbeing. We identified factors that were important to youth and refined a process for collecting feedback. Future work could go broader, i.e., recruiting larger samples of more diverse youth, or deeper, i.e., collecting more information from each youth around interests, needs, barriers, or facilitators or better understanding the various impacts of MHapps using qualitative and quantitative measures. Nevertheless, this study advances formative understanding of how youth might be viewing these tools. CLINICALTRIAL N/A

Multiple trials have demonstrated a survival benefit for adjuvant chemotherapy after resection of pancreatic adenocarcinoma. This study aimed to identify the rate for completion of adjuvant chemotherapy, factors associated with completion, and its impact on survival after surgical resection. The Surveillance Epidemiology and End Results Medicare-linked data was used to identify patients who underwent upfront resection for pancreatic adenocarcinoma from 2004 to 2013. Billing codes were used to quantify receipt and completion of chemotherapy. Factors associated with completion of chemotherapy were identified using multivariable regression. Kaplan–Meier and Cox proportional-hazards modeling were used to examine survival. The inclusion criteria were met by 2440 patients. Of these patients, 65% received no adjuvant chemotherapy, 28% received incomplete therapy, and 7% completed chemotherapy. The factors associated with chemotherapy completion were nodal metastases and treatment at a National Cancer Institute-designated cancer center (p ≤ 0.05). Comorbidities decreased the odds of completion (p ≤ 0.05). The median overall survival (OS) was 14 months for the patients who received no adjuvant chemotherapy, 17 months for those who received incomplete adjuvant chemotherapy, and 22 months for those who completed adjuvant chemotherapy (p ≤ 0.05). More recent diagnosis, comorbidities, T stage, nodal metastases, and no adjuvant chemotherapy were associated with an increased hazard ratio for death (p ≤ 0.05). Evaluation of 15 or more nodes and completion of chemotherapy decreased the hazard ratio for death (p ≤ 0.05). Only 7% of the Medicare patients who underwent upfront resection for pancreatic cancer completed adjuvant chemotherapy, yet completion of adjuvant chemotherapy was associated with improved OS. Completion of adjuvant chemotherapy should be the goal after upfront resection, but neoadjuvant chemotherapy may ensure that patients receive systemic chemotherapy.

BACKGROUND People with obsessive-compulsive disorder (OCD) have faced unique challenges during the COVID-19 pandemic. Research from the first two months of the pandemic suggests that a small proportion of people with OCD experienced worsening in their OCD symptoms since the pandemic began, whereas the rest experienced either no change or an improvement in their symptoms. However, as society-level factors relating to the pandemic have evolved, the effects of the pandemic on people with OCD have likely changed as well, in complex and population-specific ways. Therefore, this study contributes to a growing body of knowledge on the impact of the COVID-19 pandemic on people and demonstrates how differences across studies might emerge when studying specific populations at specific timepoints. OBJECTIVE This study aimed to assess how members of online OCD support communities felt the COVID-19 pandemic had affected their OCD symptoms, around 3 months after the pandemic began. METHODS We recruited participants from online OCD support communities for our brief survey. Participants indicated how much they felt their OCD symptoms had changed since the pandemic began and how much they felt that having OCD was making it harder to deal with the pandemic. RESULTS We collected survey data from June through August 2020 and received a total of 196 responses, some of which were partial responses. Among the nonmissing data, 65.9% (108/164) of the participants were from the United States and 90.5% (152/168) had been subjected to a stay-at-home order. In all, 92.9% (182/196) of the participants said they experienced worsening of their OCD symptoms since the pandemic began, although the extent to which their symptoms worsened differed across dimensions of OCD; notably, symmetry and completeness symptoms were less likely to have worsened than others. Moreover, 95.5% (171/179) of the participants felt that having OCD made it difficult to deal with the pandemic. CONCLUSIONS Our study of online OCD support community members found a much higher rate of OCD symptom worsening than did other studies on people with OCD conducted during the current COVID-19 pandemic. Factors such as quarantine length, location, overlapping society-level challenges, and differing measurement and sampling choices may help to explain this difference across studies.

We conducted a survey of adults with OCD during COVID-19, but found a much higher rate of OCD symptom worsening than similar studies did. Here, we describe our study and discuss potential reasons for these differing patterns of results.

To identify patient and health care provider characteristics associated with receipt of a high amount of prescribed opioids at postpartum discharge.This was a retrospective case-control study of all opioid-naïve women delivering at a single, high-volume tertiary care center between December 1, 2015, and November 30, 2016. Inpatient, outpatient, pharmacy, and billing records were queried for clinical, prescription, and health care provider (training, age, gender) data. The discharging health care provider, whether an opioid prescription was provided, and the details of any opioid prescription were determined. A high amount of prescribed opioids was defined as morphine milligram equivalents greater than the 90th percentile (determined as 300 morphine milligram equivalents for vaginal and 500 morphine milligram equivalents for cesarean delivery). Multivariable logistic regression models with random effects were used to identify patient and health care provider factors independently associated with receipt of a high amount of prescribed opioids at discharge. Findings were analyzed separately by mode of delivery.The analysis included 12,362 women. High amounts of opioids were prescribed for 636 of 9,038 (7.0%) women who delivered vaginally and 241 of 3,288 (7.3%) of those delivering by cesarean. In multivariable analysis, patient factors associated with receipt of a high amount of prescribed opioids at discharge after a vaginal delivery included nulliparity, intrapartum neuraxial anesthesia, major laceration, and infectious complication. Discharge by a trainee physician was associated with decreased odds of receiving a high amount of opioids (8.5% vs 1.9%; adjusted odds ratio [OR] 0.08, 95% CI 0.01-0.53). For women who underwent cesarean delivery, the only patient factor associated with receipt of a high amount of prescribed opioids was hemorrhage. Discharge by a trainee physician was associated with decreased odds of being provided a high-amount opioid prescription (7.9% vs 0.4%; adjusted OR 0.01, 95% CI 0.00-0.36).Even after adjusting for patient factors, discharge by a trainee physician is significantly associated with decreased odds of a high amount of prescribed opioids at postpartum discharge.

Introduction. This paper focuses on knowledge generation and the way in which it is transferred from universities to industry. Most well reputed universities have several departments and university-run enterprises that engage in research. The purpose of these research units is to help universities provide breakthrough innovation through the generation of new knowledge. Problem Statement. For this we chose to study China's University Technology Transfer Offices (UTTOs) to gather concrete evidence of university knowledge generation for commercial use in industry. The objective of this study is get indepth information about the role of UTTOs in the transfer of such knowledge. Purpose. The generation of new knowledge contributes to the field of science and technology; in turn, industry can use this knowledge to produce new innovative products or improve existing ones. This study aims to identify the process of knowledge transfer from universities to industry in China. Materials and Methods. Our study was carried out as a qualitative case study in the Anhui province of China. Data was mainly collected through semi-structured interviews with technology transfer experts working in technology transfer offices. Collected data were analyzed using a knowledge transfer model with six phases: 1) awareness, 2) acquisition, 3) transformation, 4) association, 5) application, and 6) feedback. Results. In China, universities and their research groups dominate in the generation and commercialization of research results, with UTTOs acting as technology bridges between the two parties, as well as providing legal and business services. Conclusions. This paper contributes by offering a detailed description of the knowledge transfer process and specifically the role and activities of UTTOs. This research also helps Chinese and international researchers currently carrying out research on the technology transfer process in China. Вступ. Висвітлено питання генерації знань та способу їх передачі від університетів у промисловість. Найвідоміші університети мають кілька департаментів та підприємств, які займаються дослідженнями. Мета цих підрозділів полягає в тому, щоб допомогти університетам забезпечити інноваційні рішення шляхом створення нових знань. Проблематика. Генерація нових знань сприяє розвитку галузі науки та техніки, які, у свою чергу, використовуються промисловістю для виробництва нових інноваційних продуктів або вдосконалення вже існуючих. На прикладі роботи департаментів трансферу технологій (ДТТ) в університетах Китаю вивчено роботу та зібрано конкретні факти генерації знань для комерційного використання в промисловості. Мета. Отримання детальної інформації про роль ДТТ у передачі знань від університетів до промисловості в Китаї. Матеріали та методи. Дослідження проведено в китайській провінції Аньхой (Аньхуей). Збір даних виконували за допомогою напівструктурованих інтерв’ю з фахівцями з передачі технологій, які працюють в офісах департаментів передачі технологій. В подальшому їх аналізували за допомогою моделі передачі знань, яка передбачає шість етапів: поінформованість, придбання, перетворення, зв’язок ідей, застосування та зворотній зв’язок. Результати. Університети Китаю та їх дослідницькі групи домінують у виробництві та комерціалізації результатів досліджень, а ДТТ відіграють роль технологічних мостів між двома сторонами, а також надають юридичні та бізнес-послуги. Висновки. Стаття містить детальний опис процесу передачі знань та, зокрема, висвітлює роль та діяльність ДТТ Китаю, що може бути корисним китайським та міжнародним науковцям у проведенні досліджень процесу передачі технологій. Введение. Раскрыто вопрос генерации знаний и способа их передачи от университетов в промышленность. Самые известные университеты имеют несколько департаментов и предприятий, которые занимаются исследованиями. Цель этих подразделений лежит в том, чтобы помочь университетам обеспечить инновационные решения путем создания новых знаний. Проблематика. Генерация новых знаний способствует развитию отрасли науки и техники, которые, в свою очередь, используются промышленностью для производства новых инновационных продуктов или усовершенствования уже существующих. На примере работы департаментов трансфера технологий (ДТТ) в университетах Китая изучено работу и собрано конкретные факты генерации знаний для коммерческого использования в промышленности. Цель. Получение детальной информации о роли ДТТ в передаче знаний от университетов к промышленности в Китае. Материалы и методы. Исследование проведено в китайской провинции Аньхой (Аньхуей). Сбор данных производили с помощью полуструктурированных интервью специалистов с передачи технологий, которые работают в офисах департаментов передачи технологий. В дальнейшем их анализировали с помощью модели передачи знаний, которая предусматривает шесть этапов: информированность, получение, преобразование, связь идей, использование и обратная связь. Результаты. Университеты Китая и их исследовательские группы доминируют в производстве и коммерциализации результатов исследований, а ДДТ играют роль технологических мостов между двумя сторонами, а также предлагают юридические и бизнес-услуги. Выводы. Статья содержит детальное описание процесса передачи знаний и, в частности, раскрывает роль и деятельность ДТТ Китая, что может быть полезным китайским и международным ученым при проведении исследований процесса передачи технологий.

Purpose Environment is an independent factor affecting quality of life. Studies suggest that health practices consider having an impact on quality of life. The purpose of the present paper was to examine the association between environmental conditions and quality of life, and how individual health practices affected this association. Methods Participants aged 20 or above were recruited from 11 tertiary planning units in the centre of Kowloon. These tertiary planning units were selected as they represent the overall living environment in Hong Kong, with older poorer urban areas alongside relatively affluent districts. A mediation analysis was implemented using multiple linear regressions to examine the effects of environmental conditions on quality of life. The predictor variables included sociodemographic and environmental conditions, health practices and health service utilisation. Results Of the eligible 607 participants, 390 females and 217 males with a mean age of 47.4 were included for analysis. Physical, psychological and environmental factors were conducive and connected to quality of life. After adjusting for fruit and vegetable intake, gender, education level and chronic illness, perceived stress and sleep quality had significant mediating effects. Conclusion Environment is an important factor that affects the overall well-being of individuals. The interaction of environmental quality with individual variables, specifically stress and sleep is extremely important when assessing its impact on the quality of life. The findings of this study support the importance of individual stress and sleep in mediating the relationship between the environment and quality of life.

BACKGROUND: Chemotherapy for high grade gliomas (HGG) is limited by the blood-brain-barrier (BBB). Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal-irinotecan (Onivyde) showed to be a superior delivery route for anti-tumor activity in animal models. An advance of this trial is the development and use of real time CED, which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents, monitoring delivery into the brain and affording for corrective action. METHODS: This is a 3 + 3 single dose escalation trial with 2 cohorts: 20mg/ml and 40mg/ml. Onivyde and GAD were co-infused via the same catheters in a one-time delivery. The total volume of infusate, and consequently total dose, were personalized based on the patient’s tumor volume, and ranged from 20–680 mg of Onivyde, given via up to 4 catheters. Tumor diameters were allowed to be 1 – 4 cm, with injection volumes ranging from 2 – 17 mL of infusate. RESULTS: 10 patients have been treated on this protocol, all in under 5 hours. There were 7 GBs, 2 anaplastic astrocytomas, and 1 oligoastrocytoma. Seven patients lived over a year after treatment, which is remarkable since median survival rates for multiply recurrent: GBs = 8 months, AAs = 11 months. Utilizing imaging software, we correlated pre-infusion modeling of the drug distribution with post-infusion imaging. A number of technical challenges were overcome by real time monitoring; the total volume of distribution (Vd), and the Vd to volume infused (Vi) ratio for each infusion was ~2. CONCLUSIONS: Image-guided distribution allows for safe real-time placement and adjustment of CED cannula of Onivyde into patient’s brains. Such methods allow for maximum tumor coverage and warrant further studies with repeat dosing.

Introduction Kawasaki disease (KD) is a major cause of acquired heart disease in children, and there is limited information on postmortem findings in the pediatric population in Canada. Cases For a 15-year time span (January 2000-March 2015), we had 2 cases of KD presented to the Department of Forensic Pathology at Hamilton General Hospital. Discussion There were common cardiac findings including presence of giant coronary artery aneurysms and microscopic changes occurring within the coronary arteries and the myocardium. Evidence of old infarction was present in both heart specimens, but acute infarction was noted in one of the specimens. Conclusions This case series documents postmortem findings that outline cardiac complications of KD including aneurysms, thrombotic events, and infarcts. In addition to addressing the medical complications of KD, it is also important to address the psychosocial effect due to its impact on quality of life.

There is a growing population of women who have or will undergo hematopoietic stem cell transplant for a variety of malignant and benign conditions. Gynecologists play an important role in addressing the gynecologic and reproductive health concerns for these women throughout the transplant process. As women undergo cell transplantation, they should avoid becoming pregnant and are at risk of uterine bleeding. Thus, counseling about and implementing hormonal treatments such as gonadotropin-releasing hormone agonists, combined hormonal contraceptives, and progestin-only methods help to achieve therapeutic amenorrhea and can serve as contraception during the peritransplant period. In this commentary, we summarize the timing, risks, and benefits of the hormonal options just before, during, and for the year after hematopoietic stem cell transplantation.

c-Met and receptor originated from nantes (RON) are structurally related transmembrane phosphotyrosine kinase receptors. c-Met and RON show increased expression or activity in a variety of tumors leading to tumor progression and may play a role in acquired resistance to therapy. Although often co-expressed, the distinct functional roles of c-Met and RON are not fully understood. c-Met and RON form both activated homodimers and heterodimers with themselves and other families of phosphotyrosine kinase receptors. Inhibitors for c-Met and RON including small molecular weigh kinase inhibitors and neutralizing antibodies are in pre-clinical investigation and clinical trials. Several of the tyrosine kinase inhibitors have activity against both c-Met and RON kinases whereas the antibodies generally are target specific. As with many targeted agents used to treat solid tumors, it is likely that c-Met/RON inhibitors will have greater benefit when used in combination with chemotherapy or other targeted agents. A careful analysis of c-Met/RON expression or activity and a better elucidation of how they influence cell signaling will be useful in predicting which tumors respond best to these inhibitors as well as determining which agents can be used with these inhibitors for combined therapy.

Sepsis is a heterogeneous syndrome comprising a highly diverse and dynamic mixture of hyperinflammatory and compensatory anti-inflammatory immune responses. This immune phenotypic diversity highlights the importance of proper patient selection for treatment with the immunomodulatory drugs that are entering clinical trials. To better understand the serial changes in immunity of critically ill patients and to evaluate the potential efficacy of blocking key inhibitory pathways in sepsis, we undertook a broad phenotypic and functional analysis of innate and acquired immunity in the same aliquot of blood from septic, critically ill nonseptic, and healthy donors. We also tested the ability of blocking the checkpoint inhibitors programmed death receptor-1 (PD-1) and its ligand (PD-L1) to restore the function of innate and acquired immune cells. Neutrophil and monocyte function (phagocytosis, CD163, cytokine expression) were progressively diminished as sepsis persisted. An increasing frequency in PD-L1+-suppressor phenotype neutrophils [low-density neutrophils (LDNs)] was also noted. PD-L1+ LDNs and defective neutrophil function correlated with disease severity, consistent with the potential importance of suppressive neutrophil populations in sepsis. Reduced neutrophil and monocyte function correlated both with their own PD-L1 expression and with PD-1 expression on CD8+ T cells and NK cells. Conversely, reduced CD8+ T cell and NK cell functions (IFN-γ production, granzyme B, and CD107a expression) correlated with elevated PD-L1+ LDNs. Importantly, addition of antibodies against PD-1 or PD-L1 restored function in neutrophil, monocyte, T cells, and NK cells, underlining the impact of the PD-1:PD-L1 axis in sepsis-immune suppression and the ability to treat multiple deficits with a single immunomodulatory agent.

Background Sepsis remains a leading cause of death in most intensive care units. Many deaths in sepsis are due to nosocomial infections in patients who have entered the immunosuppressive phase of the disorder. One cause of immunosuppression in sepsis is T-cell exhaustion mediated by programmed cell death-1 (PD-1) interaction with its ligand (PD-L1). Studies demonstrated that blocking the interaction of PD-1 with PD-L1 with knockout mice or inhibitory antibodies reversed T-cell dysfunction and improved sepsis survival. This study assessed the efficacy of a novel short-acting peptide (compound 8) that inhibits PD-1:PD-L1 signaling in a clinically relevant second-hit fungal sepsis model. Methods Mice underwent cecal ligation and puncture to induce peritonitis. Three days later, mice received intravenous injection of Candida albicans. Forty-eight hours after Candida infection, mice were treated with compound 8 or inactive peptide. The effect of Candida infection on expression of coinhibitory molecules, PD-1, and PD-L1 were quantitated by flow cytometry on CD4+ cells, CD8+ cells, natural killer (NK) cells, and natural killer T-cells (NKT). The effect of compound 8 on survival was also examined. Results Four days after fungal infection, PD-1 and PD-L1 expressions were markedly increased on CD4+, NK, and NKT cells in septic versus sham-operated mice (%PD-1 on CD4+, 11.9% versus 2.8%; and %PD-L1 on NKT, 14.8% versus 0.5%). Compared with control, compound 8 caused a 2-fold increase in survival from 30% to 60%, P Conclusions Compound 8 significantly improved survival in a clinically relevant immunosuppressive model of sepsis. These results support immunoadjuvant therapy targeting T-cell exhaustion in this lethal disease.

Background Despite appropriate therapy, Candida bloodstream infections are associated with a mortality rate of approximately 40 %. In animal models, impaired immunity due to T cell exhaustion has been implicated in fungal sepsis mortality. The purpose of this study was to determine potential mechanisms of fungal-induced immunosuppression via immunophenotyping of circulating T lymphocytes from patients with microbiologically documented Candida bloodstream infections. Methods Patients with blood cultures positive for any Candida species were studied. Non-septic critically ill patients with no evidence of bacterial or fungal infection were controls. T cells were analyzed via flow cytometry for cellular activation and for expression of positive and negative co-stimulatory molecules. Both the percentages of cells expressing particular immunophenotypic markers as well as the geometric mean fluorescence intensity (GMFI), a measure of expression of the number of receptors or ligands per cell, were quantitated. Results Twenty-seven patients with Candida bloodstream infections and 16 control patients were studied. Compared to control patients, CD8 T cells from patients with Candidemia had evidence of cellular activation as indicated by increased CD69 expression while CD4 T cells had decreased expression of the major positive co-stimulatory molecule CD28. CD4 and CD8 T cells from patients with Candidemia expressed markers typical of T cell exhaustion as indicated by either increased percentages of or increased MFI for programmed cell death 1 (PD-1) or its ligand (PD-L1). Conclusions Circulating immune effector cells from patients with Candidemia display an immunophenotype consistent with immunosuppression as evidenced by T cell exhaustion and concomitant downregulation of positive co-stimulatory molecules. These findings may help explain why patients with fungal sepsis have a high mortality despite appropriate antifungal therapy. Development of immunoadjuvants that reverse T cell exhaustion and boost host immunity may offer one way to improve outcome in this highly lethal disorder.

One major challenge in the development of cancer therapeutics is the selective delivery of the drugs to their cellular targets. In the case of pancreatic cancer, the σ-2 receptor is a unique target that triggers apoptosis upon activation. We have previously developed a series of chemical compounds with high affinity for the σ-2 receptor and showed rapid internalization of the ligands. One particular specific ligand of the σ-2 receptor, SV119, binds to pancreatic cancer cells and induces target cell death in vitro and in vivo. In this study, we characterized the ability of SV119 to selectively deliver other death-inducing cargos to augment the cytotoxic properties of SV119 itself. When conjugated to SV119, small molecules that are known to interfere with intracellular prosurvival pathways retained their ability to induce cell death, the efficiency of which was enhanced by the combinatorial effect of SV119 delivered with its small molecule cargo. Our findings define a simple platform technology to increase the tumor-selective delivery of small molecule therapeutics via σ-2 ligands, permitting chemotherapeutic synergy that can optimize efficacy and patient benefit. Cancer Res; 72(1); 201–9. ©2011 AACR.

Purpose: A subpopulation of pancreatic ductal adenocarcinoma (PDAC) cells is thought to be inherently resistant to chemotherapy or to give rise to tumor cells that become resistant during treatment. Here we determined the role of CD44 expression and its isoforms as a marker and potential target for tumor cells that give rise to invasive and gemcitabine-resistant tumors. Experimental Design: RT-PCR, Western blotting, and DNA sequencing was used to determine CD44 isoform and expression levels. Flow cytometry was used to sort cells on the basis of their CD44 expression level. CD44 expression was knocked down using shRNA. Tumorigenic properties were determined by clonogenic and Matrigel assays, IHC, tumor growth in vivo using luciferase imaging and by tumor weight. Results: We identified an invasive cell population that gives rise to gemcitabine-resistant tumors. These cancer cells express a high level of CD44 standard isoform and have an EMT phenotype (CD44s/EMT). In vivo, CD44s/EMT engraft and expand rapidly and give rise to tumors that express high levels of CD44 isoforms that contain multiple exon variants. CD44low-expressing cells show continued sensitivity to gemcitabine in vivo and knockdown of CD44 in CD44s/EMT cells increases sensitivity to gemcitabine and decreases invasiveness. Conclusions: PDAC cells expressing high levels of CD44s with a mesenchymal-like phenotype were highly invasive and developed gemcitabine resistance in vivo. Thus, initial targeting CD44 or reversing the CD44high phenotype may improve therapeutic response. Clin Cancer Res; 22(22); 5592–604. ©2016 AACR.

A ampliação das ações de promoção da saúde na Estratégia Saúde da Família pode contribuir para a construção da integralidade, mas, ainda persistem lacunas de tecnologias para instrumentalizar os profissionais a analisarem os potenciais de saúde da população. O objetivo deste estudo é sintetizar as contribuições do WHOQOL-bref para instrumentalizar ações de promoção da saúde na Estratégia Saúde da Família. Foi realizada uma metassíntese qualitativa a partir de pesquisas realizadas pelo grupo Modelos tecnoassistenciais e a promoção da saúde com o uso do WHOQOL-bref e sua interface com a promoção da saúde. As sínteses das cinco pesquisas mostraram que existem relações conceituais entre os domínios do WHOQOL-bref e a promoção da saúde, legitimando este como um instrumento para a promoção da saúde. A utilização do WHOQOL-bref pode facilitar o vinculo e o cuidado longitudinal na Estratégia Saúde da Família.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is one of the critical inhibitory regulators of early stages of T-cell activation and proliferation, which opposes the actions of CD28-mediated costimulation. Anti-CTLA-4 therapy has been effective clinically in enhancing immunity and improving survival in patients with metastatic cancer. Sepsis is a lethal condition that shares many of the same mechanisms of immune suppression with cancer. Given the similarities in immune defects in cancer and sepsis, we examined the ability of anti-CTLA-4 antibody to block apoptosis, reverse the immunosuppression of sepsis, and improve survival in the cecal ligation and puncture model. Mice underwent sham or cecal ligation and puncture, and spleens harvested at various time points after surgery. Expression of CTLA-4 on CD4, CD8, and regulatory T cells was quantitated. Anti-CTLA-4 was administrated 6 and 24 h after surgery. Spleens were harvested at 48 h after surgery, and apoptosis and cytokine production determined. Seven-day survival studies were also conducted. Expression of CTLA-4 on CD4, CD8, and regulatory T cells increased during sepsis. Anti-CTLA-4 therapy decreased sepsis-induced apoptosis but had little effect on proinflammatory or anti-inflammatory cytokines. There was a dose-dependent effect of anti-CTLA-4 on survival. At high dose, anti-CTLA-4 worsened survival, but at lower doses, survival was significantly improved. Survival in sepsis depends on the proper balance between the proinflammatory and anti-inflammatory/immunologic systems. Anti-CTLA-4-based immunotherapy offers promise in the treatment of sepsis, but care must be used in the timing and dose of administration of the drug to prevent adverse effects.

Previous studies in ovine uterine arteries have demonstrated that sex steroid hormones upregulate extracellular signal–regulated kinase 1/2 expression and downregulate the protein kinase C signaling pathway, resulting in the attenuated myogenic tone in pregnancy. The present study tested the hypothesis that chronic hypoxia during gestation inhibits the sex steroid-mediated adaptation of extracellular signal–regulated kinase 1/2 and protein kinase C signaling pathways and increases the myogenic tone of uterine arteries. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep that had been maintained at sea level (≈300 m) or exposed to high-altitude (3801 m) hypoxia for 110 days. In contrast to the previous findings in normoxic animals, 17β-estradiol and progesterone failed to suppress protein kinase C–induced contractions and the pressure-induced myogenic tone in uterine arteries from hypoxic animals. Western analyses showed that the sex steroids lost their effects on extracellular signal–regulated kinase 1/2 expression and phospho- extracellular signal–regulated kinase 1/2 levels, as well as the activation of protein kinase C isozymes in uterine arteries of hypoxic ewes. In normoxic animals, pregnancy and the sex steroid treatments significantly increased uterine artery estrogen receptor-α and progesterone receptor B expression. Chronic hypoxia selectively downregulated estrogen receptor-α expression in uterine arteries of pregnant animals and eliminated the upregulation of estrogen receptor-α in pregnancy or by the steroid treatments observed in normoxic animals. The results demonstrate that, in the ovine uterine artery, chronic hypoxia in pregnancy inhibits the sex steroid hormone–mediated adaptation of decreased myogenic tone by downregulating estrogen receptor-α expression, providing a mechanism linking hypoxia and maladaptation of uteroplacental circulation and an increased risk of preeclampsia in pregnancy.

This study examined the fate of dendritic cells (DCs) and macrophages (M Phi) in vivo in a murine model of sepsis. Wild-type, knockout, and transgenic mice were used to examine the role of Bcl-2 family members on the regulation of splenic DCs and M Phi survival. Bim knockout (Bim) mice and mice overexpressing Bcl-2 in selected hematopoietic cells were used: (a) overexpression of Bcl-2 in all hematopoietic cells using a vav promoter (Vav-Bcl-2) and (b) overexpression of Bcl-2 in all Major histocompatibility complex (MHC) class I cells (H-2K-Bcl-2). Mice underwent sham surgery or cecal ligation and puncture, and absolute numbers of splenic DCs and M Phi were determined. Importantly, two distinct M Phi populations, that is, well-differentiated "mature" M Phi population and a less differentiated "immature," "monocyte-like" (IM Phi) population were identified that demonstrated differential susceptibility to apoptosis. In wild-type mice, sepsis induced a 64% +/- 7% and a 77% +/- 3% decrease in absolute cell numbers of splenic DCs and IM Phi, respectively (n = 7, P < 0.05). Mature M Phi were not depleted in sepsis. No significant cell depletion was evident in Vav-Bcl-2, H-2K-Bcl-2, or Bim mice. We conclude that sepsis induces a major depletion of developing M Phi as well as DCs, and this depletion may be an important mechanism of immune suppression in sepsis.

Lymphocytes help determine whether gut epithelial cells proliferate or differentiate but are not known to affect whether they live or die. Here, we report that lymphocytes play a controlling role in mediating gut epithelial apoptosis in sepsis but not under basal conditions. Gut epithelial apoptosis is similar in unmanipulated Rag-1−/− and wild-type (WT) mice. However, Rag-1−/− animals have a 5-fold augmentation in gut epithelial apoptosis following cecal ligation and puncture (CLP) compared to septic WT mice. Reconstitution of lymphocytes in Rag-1−/− mice via adoptive transfer decreases intestinal apoptosis to levels seen in WT animals. Subset analysis indicates that CD4+ but not CD8+, γδ, or B cells are responsible for the antiapoptotic effect of lymphocytes on the gut epithelium. Gut-specific overexpression of Bcl-2 in transgenic mice decreases mortality following CLP. This survival benefit is lymphocyte dependent since gut-specific overexpression of Bcl-2 fails to alter survival when the transgene is overexpressed in Rag-1−/− mice. Further, adoptively transferring lymphocytes to Rag-1−/− mice that simultaneously overexpress gut-specific Bcl-2 results in improved mortality following sepsis. Thus, sepsis unmasks CD4+ lymphocyte control of gut apoptosis that is not present under homeostatic conditions, which acts as a key determinant of both cellular survival and host mortality.—Stromberg, P. E., Woolsey, C. A., Clark, A. T., Clark, J. A., Turnbull, I. R., McConnell, K. W., Chang, K. C., Chung, C.-S., Ayala, A., Buchman, T. G., Hotchkiss, R. S., Coopersmith, C. M. CD4+ lymphocytes control gut epithelial apoptosis and mediate survival in sepsis.