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A number of news items and case reports describing complex behaviours (e.g. sleep driving, sleep cooking, sleep eating, sleep conversations, sleep sex) associated with the use of hypnosedative medications have recently received considerable attention. Regulatory agencies examining these reports have subsequently issued warnings regarding the potential of hypnosedative agents to produce complex behaviours. Despite these warnings, little is known about the likelihood, presentation, treatment or prevention of hypnosedative-induced complex behaviours. The purpose of this review is to evaluate the published evidence regarding the clinical presentation, incidence, mechanism and management of sleep-related behaviours induced by nonbenzodiazepine receptor agonists (NBRAs).Review of the literature identified ten published case reports of NBRA-induced complex behaviours involving 17 unique patients. Fifteen of the 17 patients described in the case reports had taken zolpidem, one had taken zaleplon and one had taken zopiclone. The complex behaviours most commonly reported were sleep eating, sleepwalking with object manipulation, sleep conversations, sleep driving, sleep sex and sleep shopping. Elevated serum concentrations resulting from increased medication dose or drug-drug interactions appeared to play a role in some but not all cases. Sex, age, previous medication exposure and concomitant disease states were not consistently found to be related to the risk of experiencing a medication-induced complex behaviour.From a pharmacological standpoint, enhancement of GABA activity at GABAA receptors (particularly alpha1-GABAA receptors) is a possible mechanism for hypnosedative complex behaviours and amnesia. Evidence suggests that complex behaviour risk may increase with both dose and binding affinity at alpha1-GABAA receptors. The amnesia that accompanies complex behaviours is possibly due to inhibition of consolidation of short- to long-term memory, suggesting that the risk may extend to non-GABAergic hypnosedatives. While amnesia and GABA-related receptor actions are the most frequently discussed mechanisms for complex behaviours in the literature, they do not fully explain such behaviours, suggesting that other mechanisms and factors probably play a role.A number of potential strategies are available to manage or prevent hypnosedative-induced complex behaviours. These include lowering the dose of, or stopping, the offending hypnosedative, switching to a different hypnosedative, treating patients with other classes of medications, using nonpharmacological treatment strategies for patients with sleep disorders, examining drug regimens for potential drug interactions that may predispose patients to experiencing complex behaviours, administering hypnosedative medications appropriately and selecting patients more carefully for treatment in terms of their likelihood of experiencing medication adverse effects. [ABSTRACT FROM AUTHOR]

Background: Answering calls in the literature, we developed and introduced an evidence-based tool for surgeons facing errors in the operating room: the STOPS framework (stop, talk to you team, obtain help, plan, succeed). The purpose of this research was to assess the impact of presenting this psychological tool on resident coping in the operating room and the related outcome of burnout while examining sex differences., Methods: In a natural experiment, general surgery residents were invited to attend 2 separate educational conferences regarding coping with errors in the operating room. Three months later, all residents were asked to fill out a survey assessing their coping in the operating room, level of burnout, and demographics. We assessed the impact of the educational intervention by comparing those who attended the coping conferences with those who did not attend., Results: Thirty-five residents responded to the survey (65% response rate, 54% female respondents, 49% junior residents). Our hypothesized moderated mediation model was supported. Sex was found to moderate the impact of the STOPS framework-female residents who attended the coping educational conference reported higher coping self-efficacy, whereas attendance had no statistically significant impact on male levels of coping self-efficacy. In turn, higher coping self-efficacy was associated with lower levels of burnout., Conclusion: Our results suggest that there is evidence of efficacy in this instruction-female residents presented this material report higher levels of coping in the operating room compared to those who did not receive the framework. Further, increase in coping ability was associated with reduced levels of burnout for both genders., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Rationale: Recent research has called for further resident training in coping with errors and adverse events in the operating room. To the best of our knowledge, there currently exists no evidence-based curriculum or training on this topic., Materials and Methods: Synthesizing three prior studies on how experienced surgeons react to errors and adverse events, we developed the STOPS framework for handling surgical errors and adverse events (Stop, Talk to your team, Obtain help, Plan, Succeed). This material was presented to residents in two teaching sessions., Results and Conclusion: In this paper, we describe the presentation of, and the uniformly positive resident reaction to, the STOPS framework: an empirically based psychological tool for surgeons who experience operative errors or adverse events., (Copyright © 2023 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

IL-17-producing antigen-specific human T cells elicit potent antitumor activity in mice. Yet, refinement of this approach is needed to position it for clinical use. While activation signal strength regulates IL-17 production by CD4 + T cells, the degree to which T cell antigen receptor (TCR) and costimulation signal strength influences Th17 immunity remains unknown. We discovered that decreasing TCR/costimulation signal strength by incremental reduction of αCD3/costimulation beads progressively altered Th17 phenotype. Moreover, Th17 cells stimulated with αCD3/inducible costimulator (ICOS) beads produced more IL-17A, IFNγ, IL-2, and IL-22 than those stimulated with αCD3/CD28 beads. Compared with Th17 cells stimulated with the standard, strong signal strength (three beads per T cell), Th17 cells propagated with 30-fold fewer αCD3/ICOS beads were less reliant on glucose and favored the central carbon pathway for bioenergetics, marked by abundant intracellular phosphoenolpyruvate (PEP). Importantly, Th17 cells stimulated with weak αCD3/ICOS beads and redirected with a chimeric antigen receptor that recognizes mesothelin were more effective at clearing human mesothelioma. Less effective CAR Th17 cells generated with high αCD3/ICOS beads were rescued by overexpressing phosphoenolpyruvate carboxykinase 1 (PCK1), a PEP regulator. Thus, Th17 therapy can be improved by using fewer activation beads during manufacturing, a finding that is cost effective and directly translatable to patients., Competing Interests: Declaration of interests C.M.P. has a patent for the expansion of Tc17 and Th17 cells using the inducible costimulator agonist and inducible costimulator ligand-expressing artificial antigen-presenting cells and beads. C.M.P. is a cofounder of Ares Immunotherapy and has received research funding through a sponsored research agreement between the Medical University of South Carolina and Lycera Corporation, Thermo Fisher Scientific, and Obsidian Therapeutics and through a sponsored research agreement between Emory University and Vaccinex, Inc. G.B.L. has consulted for ProDa Biotech, LLC, and received compensation. G.B.L. has received research funding through a sponsored research agreement between Emory University and Merck and Co., Bristol-Myers Squibb, Boehringer-Ingelheim, and Vaccinex, Inc. J.L.R. is a founder and equity holder in Tmunity Therapeutics, which is now part of Kite, a Gilead Company. J.L.R. received research support from Tmunity Therapeutics., (Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

The substantial gap in electoral participation between upper and lower socioeconomic status (SES) groups has long been a vexing problem for modern democracies and one that demands explanation. Following separate bodies of scholarship that suggest (1) socioeconomic disadvantage diminishes health and (2) poor health demobilizes eligible voters, this paper proposes that health serves as a pathway through which social inequality manifests in disparities in electoral participation. This paper tests this hypothesis by analyzing U.S. presidential election data, in which structural equation modeling was used to decompose the association between SES and turnout, through health. Results show that health mediates approximately 20% of the relationship between SES and electoral participation. These findings imply a political explanation for the endurance of population health disparities; they may self-sustain by disproportionately limiting the political voice of the disadvantaged, for whom more egalitarian social and health policy would be most beneficial., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

4-1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNγ production. The ability to induce potent antitumor activity by stimulating 4-1BB on tumor-specific cytotoxic T cells makes 4-1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4-1BB function when co-engaged with the tumor-associated antigen 5T4. ALG.APV-527 was built on the basis of the ADAPTIR bispecific platform with optimized binding domains to 4-1BB and 5T4 originating from the ALLIGATOR-GOLD human single-chain variable fragment library. The epitope of ALG.APV-527 was determined to be located at domain 1 and 2 on 4-1BB using X-ray crystallography. As shown in reporter and primary cell assays in vitro, ALG.APV-527 triggers dose-dependent 4-1BB activity mediated only by 5T4 crosslinking. In vivo, ALG.APV-527 demonstrates robust antitumor responses, by inhibiting growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response. ALG.APV-527 has an antibody-like half-life in cynomolgus macaques and was well tolerated at 50.5 mg/kg. ALG.APV-527 is uniquely designed for 5T4-conditional 4-1BB-mediated antitumor activity with potential to minimize systemic immune activation and hepatotoxicity while providing efficacious tumor-specific responses in a range of 5T4-expressing tumor indications as shown by robust activity in preclinical in vitro and in vivo models. On the basis of the combined preclinical dataset, ALG.APV-527 has potential as a promising anticancer therapeutic for the treatment of 5T4-expressing tumors., (©2022 The Authors; Published by the American Association for Cancer Research.)

Affective polarization-the tendency for individuals to exhibit animosity toward those on the opposite side of the partisan divide-has increased in the United States in recent years. This article presents evidence that this trend may have consequences for Americans' health. Structural equation model analyses of nationally representative survey data from Pew Research Center's American Trends Panel (n = 4,685) showed heterogeneous relationships between affectively polarized attitudes and self-rated health. On one hand, such attitudes were directly negatively associated with health such that the polarized political environment was proposed to operate as a sociopolitical stressor. Simultaneously, affective polarization was positively associated with political participation, which in turn was positively associated with health, although the direct negative effect was substantially larger than the indirect positive one. These results suggest that today's increasingly hostile and pervasive form of partisanship may undermine Americans' health even as it induces greater political engagement.

CD137 (4-1BB; TNFSR9) is an activation-induced surface receptor that through costimulation effects provide antigen-primed T cells with augmented survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being utilised for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cell is superior to that provided in-trans in terms of T cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mouse and human. Cis ligation of CD137 relative to the TCR-CD3 complex results in more intense canonical and non-canonical NF-κB signaling and provides a more robust induction of cell cycle and DNA damage repair gene expression programs. Here we report that the superiority of cis versus trans CD137-costimulation is readily observed in vivo and is relevant for understanding the immunotherapeutic effects of CAR T cells and CD137 agonistic therapies currently undergoing clinical trials, which may provide costimulation either in cis or in trans., (© 2021. The Author(s).)

Background: Bile duct injury (BDI) during cholecystectomy requiring biliary enteric reconstruction (BER) is associated with increased risk of postoperative mortality and substantive increases in costs of care. The impact of the timing of repair on overall costs of care is poorly understood., Materials and Methods: The Healthcare Cost and Utilization Project Florida State databases (2006-2015) were queried to identify patients undergoing BER within 1-y of cholecystectomy performed for benign biliary disease. Patients were then categorized by the time interval between cholecystectomy to BER: early (≤3 d), intermediate (4 d to 6 wk), or delayed (>6 wk). By repair timing strategy, 1-y outcomes were aggregated, including charges, inpatient costs, aggregate length of stay, and inpatient mortality., Results: Of 563,887 patients undergoing cholecystectomy, 1168 required a BER (0.21%) within 1-y of cholecystectomy. Early BER was performed in 560 patients (47.9%), intermediate BER in 439 patients (37.6%), and delayed BER in 169 (14.5%) patients. On multivariable analysis adjusting for patient, procedure, and facility factors, intermediate BER demonstrated an increased risk of mortality (odds ratio 2.04, 95% confidence interval [CI]: 1.16-3.56) and increased aggregate inpatient cost (+$12,472; 95% CI: $6421-$18,524) relative to early BER. There was no notable difference in adjusted risk of inpatient mortality between the early and delayed BER cohorts (odds ratio 0.90; 95% CI: 0.32-1.25), but delayed BER was associated with increased aggregate inpatient costs (+$45,111; 95% CI: $36,813-$53,409)., Conclusions: When compared with delayed BER, early repair was associated with shorter aggregate inpatient hospitalization without increased postoperative mortality. Intermediate timing of repair is associated with increased costs and risk of mortality., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The accessibility of adoptive T-cell transfer therapies (ACT) is hindered by the cost and time required for product development. Here we describe a streamlined ACT protocol using Th17 cells expanded only 4 days ex vivo . While shortening expansion compromised cell yield, this method licensed Th17 cells to eradicate large tumors to a greater extent than cells expanded longer term. Day 4 Th17 cells engrafted, induced release of multiple cytokines including IL6, IL17, MCP-1, and GM-CSF in the tumor-bearing host, and persisted as memory cells. IL6 was a critical component for efficacy of these therapies via its promotion of long-term immunity and resistance to tumor relapse. Mechanistically, IL6 diminished engraftment of FoxP3 + donor T cells, corresponding with robust tumor infiltration by donor effector over regulatory cells for the Day 4 Th17 cell product relative to cell products expanded longer durations ex vivo . Collectively, this work describes a method to rapidly generate therapeutic T-cell products for ACT and implicates IL6 in promoting durable immunity of Th17 cells against large, established solid tumors. SIGNIFICANCE: An abbreviated, 4-day ex vivo expansion method licenses Th17 cells to confer long-lived immunity against solid malignancies via induction of systemic IL6 in the host. See related commentary by Fiering and Ho, p. 3795 ., (©2020 American Association for Cancer Research.)

How naturally arising human CD4 + T helper subsets affect cancer immunotherapy is unclear. We reported that human CD4 + CD26 high T cells elicit potent immunity against solid tumors. As CD26 high T cells are often categorized as T H 17 cells for their IL-17 production and high CD26 expression, we posited these populations would have similar molecular properties. Here, we reveal that CD26 high T cells are epigenetically and transcriptionally distinct from T H 17 cells. Of clinical importance, CD26 high and T H 17 cells engineered with a chimeric antigen receptor (CAR) regressed large human tumors to a greater extent than enriched T H 1 or T H 2 cells. Only human CD26 high T cells mediated curative responses, even when redirected with a suboptimal CAR and without aid by CD8 + CAR T cells. CD26 high T cells cosecreted effector cytokines, produced cytotoxic molecules, and persisted long term. Collectively, our work underscores the promise of CD4 + T cell populations to improve durability of solid tumor therapies., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: Many patients with erectile dysfunction (ED) after radical prostatectomy (RP) improve with conservative therapy but some do not; penile prosthesis implantation rates have been sparsely reported, and have used nonrepresentative data sets., Aim: To characterize rates and timing of penile prosthesis implantation after RP and to identify predictors of implantation using a more representative data set., Methods: The Healthcare Cost and Utilization Project State Inpatient and State Ambulatory Surgery databases for Florida from 2006 to 2015 were used. Patients undergoing RP (2006-2012) were tracked longitudinally for penile prosthesis implantation. Patient and clinical data were analyzed using multivariable logistic regression., Outcomes: The primary outcome was risk-adjusted predictors of prosthesis implantation, and the secondary outcome was predictors of the highest quartile of time between RP and penile prosthesis., Results: Of 29,288 men who had RP, 1,449 (4.9%) patients underwent subsequent prosthesis. The mean time from RP to prosthesis was 2.6 years (median: 2.1; interquartile range [IQR]: 1.2-3.5). Adjusted predictors of prosthesis implantation included open RP (odds ratio [OR]: 1.5, P < .01), African American race (OR: 1.7, P < .01) or Hispanic ethnicity (OR: 3.2, P < .01), and Medicare (OR: 1.4, P < .01) insurance. Oler patients (age >70 years; OR: 0.7, P < .01) and those from the highest income quartile relative to the lowest (OR: 0.8, P < .05) were less likely to be implanted. Adjusted predictors of longer RP-to-implantation time (highest quartile: median: 4.7 years; IQR: 3.9-6.0 years) included open RP (OR: 1.78, P < .01), laparoscopic RP (OR: 4.67, P < .01), Medicaid (OR: 3.03, P < .05), private insurance (OR: 2.57, P < .01), and being in the highest income quartile (OR: 2.52, P < .01)., Clinical Implications: These findings suggest ED treatment healthcare disparities meriting further investigation; upfront counseling on all ED treatment modalities and close monitoring for conservative treatment failure may reduce lost quality of life years., Strengths & Limitations: This study is limited by its use of administrative data, which relies on accurate coding and lacks data on ED questionnaires/prior treatments, patient-level cost, and oncologic outcomes. Quartile-based analysis of income and time between RP and prosthesis limits the conclusions that can be drawn., Conclusion: Less than 5% of post-RP patients undergo penile prosthesis implantation, with open RP, Medicare, African American race, and Hispanic ethnicity predicting post-RP implantation; living in the wealthiest residential areas predicts lower likelihood of implantation compared to the least wealthy areas. Patients with the longest time between RP and prosthesis are more likely to live in the wealthiest areas or have undergone open/laparoscopic RP relative to robotic RP. Bajic P, Patel PM, Nelson MH, et al. Penile Prosthesis Implantation and Timing Disparities After Radical Prostatectomy: Results From a Statewide Claims Database. J Sex Med 2020;17:1175-1181., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Distinct lineages of T cells can act in response to various environmental cues to either drive or restrict immune-mediated pathology. Here, we identify the RNA binding protein, poly(C)-binding protein 1 (PCBP1) as an intracellular immune checkpoint that is up-regulated in activated T cells to prevent conversion of effector T (T eff ) cells into regulatory T (T reg ) cells, by restricting the expression of T eff cell-intrinsic T reg commitment programs. This was critical for stabilizing T eff cell functions and subverting immune-suppressive signals. T cell-specific deletion of Pcbp1 favored T reg cell differentiation, enlisted multiple inhibitory immune checkpoint molecules including PD-1, TIGIT, and VISTA on tumor-infiltrating lymphocytes, and blunted antitumor immunity. Our results demonstrate a critical role for PCBP1 as an intracellular immune checkpoint for maintaining T eff cell functions in cancer immunity., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: Little is known regarding the impact of minimally invasive approaches to pancreatoduodenectomy on the aggregate costs of care for patients undergoing pancreatoduodenectomy., Methods: We queried the Healthcare Cost and Utilization Project State Inpatient Database to identify patients undergoing elective laparoscopic or open pancreatoduodenectomy between 2014 and 2016., Results: In this database, 488 (10%) patients underwent elective laparoscopic; 4,544 (90%) underwent open pancreatoduodenectomy. On adjusted analysis, the risk of perioperative morbidity and overall duration of hospitalization for patients undergoing elective laparoscopic were identical to those for patients undergoing open pancreatoduodenectomy. Patients undergoing elective laparoscopic in low (+$10,399, 95% confidence interval [$3,700, $17,098]) and moderate to high (+$4,505, 95% confidence interval [$528, $8,481]) volume centers had greater costs than those undergoing open pancreatoduodenectomy in the same centers. In very high-volume centers (>127 pancreatoduodenectomies/year), aggregate costs of care for patients undergoing elective laparoscopic were essentially identical to those undergoing open pancreatoduodenectomy in the same centers (+$815, 95% confidence interval [-$1,530, $3,160])., Conclusion: Rates of morbidity and overall duration of hospitalization for patients undergoing elective laparoscopic are not different than those undergoing open pancreatoduodenectomy. At low to moderate and high-volume centers, elective laparoscopic is associated with greater aggregate costs of care relative to open pancreatoduodenectomy. At very high-volume centers, elective laparoscopic is cost-neutral., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: We sought to determine the socioeconomic and patient factors that influence the utilization of urethroplasty and location of management in the treatment of male urethral stricture disease., Methods: A retrospective review using the Healthcare Cost and Utilization Project State Inpatient and Ambulatory Surgery and Services Databases for California and Florida was performed. Adult men with a diagnosis of urethral stricture who underwent treatment with urethroplasty or endoscopic dilation/urethrotomy between 2007 and 2011 in California and 2009 and 2014 in Florida were identified by ICD-9 or CPT codes. Patients were categorized based on whether they had a urethroplasty or serial dilations/urethrotomies. Patients were assessed for age, insurance provider, median household income by zip code, Charlson Comorbidity Index, race, prior stricture management, and location of the index procedure. A multivariable logistic regression model was fit to assess factors influencing treatment modality (urethroplasty vs endoscopic management) and location (teaching hospital vs non-teaching hospital)., Results: Twenty seven thousand, five hundred and sixty-eight patients were identified that underwent treatment for USD. 25,864 (93.8%) treated via endoscopic approaches and 1704 (6.2%) treated with urethroplasty. Factors favoring utilization of urethroplasty include younger age, lower Charlson Comorbidity score, higher zip code median income quartile, private insurance, prior endoscopic treatment, and management at a teaching hospital., Conclusion: Socioeconomic predictors of urethroplasty utilization include higher income status and private insurance. Patient-specific factors influencing urethroplasty were younger age and fewer medical comorbidities. A primary driver of urethroplasty utilization was treatment at a teaching hospital. Older and Hispanic patients were less likely to seek care at these facilities.

Background: Previous evaluations of the oncologic efficacy of minimally invasive approaches to total gastrectomy in gastric adenocarcinoma have been limited by sample size and duration of follow-up., Methods: We queried the National Cancer Database to identify patients undergoing robotic and laparoscopic or open total gastrectomy for gastric adenocarcinoma between 2010 and 2015. Propensity score matching was used to adjust for patient, tumor, and treating facility factors. Kaplan-Meier survival functions were used to compare overall survival. Secondary outcomes included margin status, lymph node sampling, mortality, readmission, and length of stay., Results: In the study, 3,213 (72.2%) patients underwent open total gastrectomy; 1,238 (27.8%) minimally invasive total gastrectomy. Patients undergoing minimally invasive total gastrectomy were more likely to be treated at academic (49.5% vs 57.8%, P < .05) and high-volume centers (21.6% vs 28.4%, P < .05). Propensity score matching yielded 1,238 open and 1,238 minimally invasive well-matched total gastrectomies. Minimally invasive was associated with a decreased median length of stay (10 vs 9 days; P < .01). Rates of positive surgical margins, 30-day readmission, 90-day mortality and overall survival were identical between matched cohorts (P > .1)., Conclusion: Minimally invasive approaches to total gastrectomy provide perioperative oncologic outcomes and overall survival rates that are identical to those for open total gastrectomy but are associated with reduced length of stay., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Minimally invasive colectomy is associated with improved length of stay and decreased postoperative morbidity. Little is known regarding the impact of prolonged operative time on the benefits afforded by minimally invasive colectomy., Methods: The American College of Surgeons National Surgical Quality Improvement Program procedure targeted colectomy dataset was queried to identify elective right and left colectomies performed between 2011 and 2017. Multivariable modeling was used to compare rates of composite 30-day death or serious morbidity, overall morbidity, mortality, anastomotic leak, surgical site infection, and length of stay for prolonged minimally invasive cases to those for average duration open cases., Results: A total of 16,602 right colectomies and 36,557 left colectomies were identified. Median operative times for open and minimally invasive right colectomies were 107 min and 129 min (P < .01), while that for open left colectomies was 128 min and 156 min for minimally invasive left colectomies (P < .01). Cohorts were stratified by quartiles of operative time with the highest (fourth) quartile defined as a prolonged operating time. When compared with an average duration open colectomy, prolonged minimally invasive right colectomies and left colectomies were associated with decreased risk-adjusted rates of overall morbidity, surgical site infection, and with lesser lengths of stay (P < .05). Prolonged minimally invasive left colectomies were also associated with improved rates of composite 30-day death or serious morbidity relative to average open left colectomies (odds ratio 0.66, 95% confidence interval, 0.54-0.79)., Conclusion: Prolonged operating times of an minimally invasive approach do not obviate the benefits of an minimally invasive approach to colectomy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cancer immunotherapy is recently considered the most promising treatment for human patients with advanced tumors and could be effectively combined with conventional therapies such as chemotherapy or radiotherapy. Patients with hematological malignancies and melanoma have benefited greatly from immunotherapies such as, adoptive cell transfer therapy, experiencing durable remissions and prolonged survival. In the face of increasing enthusiasm for immunotherapy, particularly for the administration of tumor-specific T lymphocytes, the question arises whether this method could be employed to improve treatment outcomes for canine patients. It is warranted to determine whether veterinary clinical trials could support comparative oncology research and thus facilitate the development of new cell-based therapies for humans. Herein, we discuss adoptive transfer of T lymphocytes and lymphokine-activated cells for application in veterinary oncology, in the context of human medicine achievements. Furthermore, we discuss potential benefits of using domestic dog as a model for immunotherapy and its advantages for translational medicine. We also focus on an emerging genome-editing technology as a useful tool to improve a T cells' phenotype.

Introduction: We detail the process of developing a workload calculation model (WCM) for a highly integrated curriculum delivered by team-based learning, rationale for workload multipliers, and preliminary results of our effort to implement the WCM., Methods: Our WCM includes teaching, service, and scholarship, with a time buffer. The WCM utilizes multipliers for most work activities (teaching and service). For other activities, a fixed number of hours per year was used. The WCM was set up using Microsoft Excel. The development of the WCM was an iterative process in collaboration with the school's Faculty Affairs Committee, each department, and then individually with all faculty members., Results: The WCM had three sections. A section each for teaching and service workload calculations and a dashboard section to summarize workload calculations per department that added in time for scholarship and a buffer calculation (to allow flexibility for faculty). Teaching included classroom, experiential, and academic advising, all of which had unique multipliers. Service included committee work at all levels and student organization advising. A fourth section for time spent at individual faculty practice sites. Calculations were kept consistent between departments for most activities., Conclusion: We developed a novel WCM to accommodate all of the major areas of workload for faculty at a private institution. The unique approach to building it included representing teaching in a highly integrated curriculum delivered via team-based learning and creating a buffer category to allow for workload individualization. The WCM is actively used in our school to proactively manage workload., (Copyright © 2018 Elsevier Inc. All rights reserved.)

CD8 + T lymphocytes mediate potent immune responses against tumor, but the role of human CD4 + T cell subsets in cancer immunotherapy remains ill-defined. Herein, we exhibit that CD26 identifies three T helper subsets with distinct immunological properties in both healthy individuals and cancer patients. Although CD26 neg T cells possess a regulatory phenotype, CD26 int T cells are mainly naive and CD26 high T cells appear terminally differentiated and exhausted. Paradoxically, CD26 high T cells persist in and regress multiple solid tumors following adoptive cell transfer. Further analysis revealed that CD26 high cells have a rich chemokine receptor profile (including CCR2 and CCR5), profound cytotoxicity (Granzyme B and CD107A), resistance to apoptosis (c-KIT and Bcl2), and enhanced stemness (β-catenin and Lef1). These properties license CD26 high T cells with a natural capacity to traffic to, regress and survive in solid tumors. Collectively, these findings identify CD4 + T cell subsets with properties critical for improving cancer immunotherapy.

Phosphatidylinositol-3-kinase p110δ (PI3Kδ) inhibition by Idelalisib (CAL-101) in hematological malignancies directly induces apoptosis in cancer cells and disrupts immunological tolerance by depleting regulatory T cells. Yet, little is known about the direct impact of PI3Kδ blockade on effector T cells from CAL-101 therapy. Herein, we demonstrate a direct effect of p110δ inactivation via CAL-101 on murine and human CD8 + T cells that promotes a strong undifferentiated phenotype (elevated CD62L/CCR7, CD127, and Tcf7). These CAL-101 T cells also persisted longer after transfer into tumor bearing mice in both the murine syngeneic and human xenograft mouse models. The less differentiated phenotype and improved engraftment of CAL-101 T cells resulted in stronger antitumor immunity compared to traditionally expanded CD8 + T cells in both tumor models. Thus, this report describes a novel direct enhancement of CD8 + T cells by a p110δ inhibitor that leads to markedly improved tumor regression. This finding has significant implications to improve outcomes from next generation cancer immunotherapies.

Cancer-associated thrombocytosis has long been linked to poor clinical outcome, but the underlying mechanism is enigmatic. We hypothesized that platelets promote malignancy and resistance to therapy by dampening host immunity. We show that genetic targeting of platelets enhances adoptive T cell therapy of cancer. An unbiased biochemical and structural biology approach established transforming growth factor β (TGFβ) and lactate as major platelet-derived soluble factors to obliterate CD4 + and CD8 + T cell functions. Moreover, we found that platelets are the dominant source of functional TGFβ systemically as well as in the tumor microenvironment through constitutive expression of the TGFβ-docking receptor glycoprotein A repetitions predominant (GARP) rather than secretion of TGFβ per se. Platelet-specific deletion of the GARP-encoding gene Lrrc32 blunted TGFβ activity at the tumor site and potentiated protective immunity against both melanoma and colon cancer. Last, this study shows that T cell therapy of cancer can be substantially improved by concurrent treatment with readily available antiplatelet agents. We conclude that platelets constrain T cell immunity through a GARP-TGFβ axis and suggest a combination of immunotherapy and platelet inhibitors as a therapeutic strategy against cancer., (Copyright © 2017, American Association for the Advancement of Science.)

ICOS costimulation generates Th17 cells with durable memory responses to tumor. Herein, we found that ICOS induces PI3K/p110δ/Akt and Wnt/β-catenin pathways in Th17 cells. Coinhibiting PI3Kδ and β-catenin altered the biological fate of Th17 cells. Th17 cells inhibited of both pathways expressed less RORγt, which, in turn, reduced their ability to secrete IL-17. Unexpectedly, these cells were more effective (than uninhibited cells) at regressing tumor when infused into mice, leading to long-term curative responses. PI3Kδ inhibition expanded precursor Th17 cells with a central memory phenotype that expressed nominal regulatory properties (low FoxP3), while β-catenin inhibition enhanced Th17 multifunctionality in vivo. Remarkably, upon TCR restimulation, RORγt and IL-17 rebounded in Th17 cells treated with PI3Kδ and β-catenin inhibitors. Moreover, these cells regained β-catenin, Tcf7, and Akt expression, licensing them to secrete heightened IL-2, persist, and eradicate solid tumors without help from endogenous NK and CD8 T cells. This finding shines a light on ways to repurpose FDA-approved drugs to augment T cell-based cancer immunotherapies.

Background: Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC)., Methods: We generated autologous DCs from the peripheral blood of HLA-A2 + patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV.A2). Patients received four intradermal injections of 1 × 10 7 peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 μg/Kg on vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31, 37, and 45. Our key objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells., Results: Twelve patients underwent apheresis: nine patients with metastatic disease, and three patients with locally advanced unresectable disease. Vaccines were successfully manufactured from all individuals. We found that this treatment was well-tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the eight patients who underwent imaging on day 56, four patients experienced stable disease while four patients had disease progression. The median overall survival was 7.7 months. One patient survived for 28 months post leukapheresis. MHC class I -tetramer analysis before and after vaccination revealed effective generation of antigen-specific T cells in three patients with stable disease., Conclusion: Vaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC., Trial Registration: NCT01410968 ; Name of registry: clinicaltrials.gov; Date of registration: 08/04/2011).

Objective. To determine the frequency distribution of pharmacy students across Emotionally Intelligent Leadership Inventory (EILI) measures. Methods. The EILI was administered to 235 pharmacy students at two schools. The instrument was systematically compared to the 2013 CAPE Outcomes and analyzed by confirmatory factor analysis. Results. The EILI has primary connections with pharmacy competencies related to interprofessional communication and leadership. The three facets of the EILI were verified for internal consistency (Context, α=.78; Self, α=.74; Others, α=.79). Student scores were the highest for the consciousness of self facet, with a mean score of 31.4 out of 40. Conclusion. The EILI shows promise as an instrument for use in assessing pharmacy students' emotional intelligence and leadership skills.

Adoptive immunotherapy for solid tumors relies on infusing large numbers of T cells to mediate successful antitumor responses in patients. While long-term rapid-expansion protocols (REPs) produce sufficient numbers of CD8 + T cells for treatment, they also cause decline in the cell's therapeutic fitness. In contrast, we discovered that IL-17-producing CD4 + T cells (Th17 cells) do not require REPs to expand 5,000-fold over 3 weeks. Also, unlike Th1 cells, Th17 cells do not exhibit hallmarks of senescence or apoptosis, retaining robust antitumor efficacy in vivo. Three-week-expanded Th17 cells eliminated melanoma as effectively as Th17 cells expanded for 1 week when infused in equal numbers into mice. However, treating mice with large recalcitrant tumors required the infusion of all cells generated after 2 or 3 weeks of expansion, while the cell yield obtained after 1-week expansion was insufficient. Long-term-expanded Th17 cells also protected mice from tumor rechallenge including lung metastasis. Importantly, 2-week-expanded human chimeric antigen receptor-positive (CAR + ) Th17 cells also retained their ability to regress human mesothelioma, while CAR + Th1 cells did not. Our results indicate that tumor-reactive Th17 cells are an effective cell therapy for cancer, remaining uncompromised when expanded for a long duration owing to their resistance to senescence., Competing Interests: Conflict of interest: The authors have declared that no conflict of interest exists.

Adoptive T cell transfer (ACT) can mediate objective responses in patients with advanced malignancies. There have been major advances in this field, including the optimization of the ex vivo generation of tumor-reactive lymphocytes to ample numbers for effective ACT therapy via the use of natural and artificial antigen presenting cells (APCs). Herein we review the basic properties of APCs and how they have been manufactured through the years to augment vaccine and T cell-based cancer therapies. We then discuss how these novel APCs impact the function and memory properties of T cells. Finally, we propose new ways to synthesize aAPCs to augment the therapeutic effectiveness of antitumor T cells for ACT therapy.

Cancer immunotherapy is one the most effective approaches for treating patients with tumors, as it bolsters the generation and persistence of memory T cells. In preclinical work, it has been reported that adoptively transferred CD4+ and CD8+ lymphocytes that secrete IL-17A (i.e., Th17 and Tc17 cells) regress tumors to a greater extent than IFN-γ(+)Th1 or Tc1 cells in vivo. Herein, we review the mechanisms underlying how infused Th17 and Tc17 cells regress established malignancies in clinically relevant mouse models of cancer. We also discuss how unique signaling cues--such as co-stimulatory molecules (ICOS and 41BB), cytokines (IL-12 and IL-23) or pharmaceutical reagents (Akt inhibitors, etc.)--can be exploited to bolster the therapeutic potential of IL-17(+) lymphocytes with an emphasis on using this knowledge to improve next-generation clinical trials for patients with cancer.

The CAPE 2013 Outcomes answered the call for increased student leadership development (SLD) by identifying leadership as a desired curricular goal. To meet this outcome, colleges and schools of pharmacy are advised to first identify a set of SLD competencies aligned with their institution's mission and goals and then organize these competencies into a SLD framework/model. Student leadership development should be integrated vertically and horizontally within the curriculum in a deliberate and longitudinal manner. It should include all student pharmacists, begin at the point of admission, and extend beyond extracurricular activities. The school's assessment plan should be aligned with the identified SLD competencies so student learning related to leadership is assessed. To accomplish these recommendations, a positive environment for SLD should be cultivated within the school, including administrative backing and resources, as well as support among the broader faculty for integrating SLD into the curriculum.

Background: Lymphodepletion enhances adoptive T cell transfer (ACT) therapy by activating the innate immune system via microbes released from the radiation-injured gut. Microbial components, such as LPS, are key mediators of total body irradiation (TBI) enhancement, but our ability to strategically use these toll-like receptor (TLR) agonists to bolster the potency of T cell-based therapies for cancer remains elusive. Herein, we used TLR4 agonist LPS as a tool to address how and when to use TLR agonists to effectively improve cancer immunotherapy., Methods: To determine the mechanisms of how innate immune activation via lymphodepletion potentiated antitumor T cell immunity, we utilized the pmel-1 melanoma mouse model. B16F10-bearing mice were preconditioned with 5Gy TBI and given a tripartite ACT therapy (consisting of transferred pmel-1 CD8(+) T cells, vaccination with fowlpox encoding gp100, and IL-2) along with TLR4 agonist LPS. The timing of LPS administration and the requirement of individual components of the tripartite therapy were evaluated based on tumor growth and the phenotype of recovered splenocytes by flow cytometry. We also evaluated the role of non-toxic and clinically used TLR4 and TLR9 agonists-monophosphoryl lipid A (MPL) and CpG Oligodeoxynucleotide (CpG ODN), respectively- for ACT therapy., Results: Here we report that while exogenous administration of LPS was able to enhance adoptively transferred CD8(+) T cells' tumor destruction, LPS treatment alone did not replace individual components of the tripartite ACT regimen, or obviate TBI. Moreover, we found that sequentially administering LPS during or one day prior to ACT therapy compromised tumor regression. In contrast, administering LPS after ACT potentiated the antitumor effectiveness of the regimen, thereby supporting the expansion of transferred tumor-specific CD8(+) T cells over host CD4(+) T cells. We also found that non-toxic TLR agonists MPL and CpG potentiated the antitumor activity of infused CD8(+) T cells. Finally, TBI was no longer needed to regress tumors in mice who were depleted of host CD4(+) T cells, given a tripartite ACT regimen and then treated with low dose LPS., Conclusions: Collectively, our results identify how and when to administer TLR agonists to augment T cell-based immunotherapy in the absence or presence of host preconditioning for treatment of advanced malignancies. Our findings have clinical implications for the design of next generation immune-based therapies for patients with cancer.

Purpose: The adoptive cell transfer (ACT) of CD8(+) T cells is a promising treatment for advanced malignancies. Lymphodepletion before ACT enhances IFNγ(+)CD8(+) T cell (Tc0)-mediated tumor regression. Yet, how lymphodepletion regulates the function and antitumor activity of IL17A(+)CD8(+) T cells (Tc17) is unknown., Experimental Design: To address this question, pmel-1 CD8(+) T cells were polarized to secrete either IL17A or IFNγ. These subsets were then infused into mice with B16F10 melanoma that were lymphoreplete [no total body irradiation (TBI)], or lymphodepleted with nonmyeloablative (5 Gy) or myeloablative (9 Gy with hematopoietic stem cell transplantation) TBI. The activation of innate immune cells and function of donor T-cell subsets were monitored in recipient mice., Results: Tc17 cells regress melanoma in myeloablated mice to a greater extent than in lymphoreplete or nonmyeloablated mice. TBI induced functional plasticity in Tc17 cells, causing conversion from IL17A to IFNγ producers. Additional investigation revealed that Tc17 plasticity and antitumor activity were mediated by IL12 secreted by irradiated host dendritic cells (DC). Neutralization of endogenous IL12 reduced the antitumor activity of Tc17 cells in myeloablated mice, whereas ex vivo priming with IL12 enhanced their capacity to regress melanoma in nonmyeloablated animals. This, coupled with exogenous administration of low-dose IL12, obviated the need for host preconditioning, creating curative responses in nonirradiated mice., Conclusions: Our findings indicate that TBI-induced IL12 augments Tc17 cell-mediated tumor immunity and underline the substantial implications of in vitro preparation of antitumor Tc17 cells with IL12 in the design of T-cell immunotherapies., (©2015 American Association for Cancer Research.)

The importance of emotional intelligence (EI) for effective teamwork and leadership within the workplace is increasingly apparent. As suggested by the 2013 CAPE Outcomes, we recommend that colleges and schools of pharmacy consider EI-related competencies to build self-awareness and professionalism among students. In this Statement, we provide two examples of the introduction of EI into pharmacy curricula. In addition, we provide a 4-phase process based on recommendations developed by EI experts for structuring and planning EI development. Finally, we make 9 recommendations' to inform the process of including EI in pharmacy curricula.

The inducible costimulator (ICOS) plays a key role in the development of Th17 cells, but its role in the development and antitumor activity of IL-17-producing CD8(+) T cells (Tc17) remains unknown. We found that ICOS costimulation was important for the functional maintenance, but not differentiation, of Tc17 cells in vitro. Blocking the ICOS pathway using an antagonist mAb or by using recipient mice genetically deficient in the ICOS ligand reduced the antitumor activity of adoptively transferred Tc17 cells. Conversely, activating Tc17 cells with an ICOS agonist in vitro enhanced their capacity to eradicate melanoma and induce autoimmune vitiligo when infused into mice. However, ICOS stimulation did not augment the antitumor activity of IL-2 expanded T cells. Additional investigation revealed that ICOS stimulation not only increased IL-2Rα, CXCR3, and IL-23R expression on Tc17 cells, but also dampened their expression of suppressive molecule CD39. Although Tc17 cells activated with an ICOS agonist cosecreted heightened IL-17A, IL-9, and IFN-γ, their therapeutic effectiveness was critically dependent on IFN-γ production. Depletion of IL-17A and IL-9 had little impact on antitumor Tc17 cells activated with an ICOS agonist. Collectively, our work reveals that the ICOS pathway potentiates the antitumor activity of adoptively transferred Tc17 cells. This work has major implications for the design of vaccine, Ab and cell-based therapies for autoimmunity, infectious disease, and cancer., (Copyright © 2015 by The American Association of Immunologists, Inc.)

The microbiota plays a key role in regulating the innate and adaptive immune system. Herein, we review the immunological aspects of the microbiota in tumor immunity in mice and man, with a focus on toll-like receptor (TLR) agonists, vaccines, checkpoint modulators, chemotherapy, and adoptive T cell transfer (ACT) therapies. We propose innovative treatments that may safely harness the microbiota to enhance T cell-based therapies in cancer patients. Finally, we highlight recent developments in tumor immunotherapy, particularly novel ways to modulate the microbiome and memory T cell responses to human malignancies.

The immune system is designed to discriminate between self and tumor tissue. Through genetic recombination, there is fundamentally no limit to the number of tumor antigens that immune cells can recognize. Yet, tumors use a variety of immunosuppressive mechanisms to evade immunity. Insight into how the immune system interacts with tumors is expanding rapidly and has accelerated the translation of immunotherapies into medical breakthroughs. Herein, we appraise novel strategies that exploit the patient's immune system to kill cancer. We review various forms of immune-based therapies, which have shown significant promise in patients with hematologic malignancies, including (i) conventional monoclonal therapies like rituximab; (ii) engineered monoclonal antibodies called bispecific T-cell engagers; (iii) monoclonal antibodies and pharmaceutical drugs that block inhibitory T-cell pathways (i.e. PD-1, CTLA-4, and IDO); and (iv) adoptive cell transfer therapy with T cells engineered to express chimeric antigen receptors or T-cell receptors. We also assess the idea of using these therapies in combination and conclude by suggesting multi-prong approaches to improve treatment outcomes and curative responses in patients., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

T helper 17 (Th17) cells play a complex and controversial role in tumor immunity and have been found to exhibit a fluctuating identity within the context of cancer. The recent, expanding literature on these cells attests to their puzzling nature, either promoting or suppressing tumor growth depending on the malignancy and course of therapeutic intervention investigated. This review addresses several newly appreciated factors that may help delineate Th17 cells' immunological properties in the context of cancer. Several reports suggest that inflammatory signals induced in the tumor milieu regulate the functional fate and antitumor activity of Th17 cells. Recent findings also point to significant alterations in Th17 cells due to their interplay with regulatory T lymphocytes and cytotoxic CD8(+) T cells within the tumor microenvironment. Finally, an appreciation for the stem cell-like properties of Th17 cells that augment their persistence and activity emerges from recent reports. The impact of these factors on Th17 cells' antitumor efficacy and how these factors may be exploited to improve cancer therapies will be discussed.

The rs1061170T/C variant encoding the Y402H change in complement factor H (CFH) has been identified by genome-wide association studies as being significantly associated with age-related macular degeneration (AMD). However, the precise mechanism by which this CFH variant impacts the risk of AMD remains largely unknown. Oxidative stress plays an important role in many aging diseases, including cardiovascular disease and AMD. A large amount of oxidized phospholipids (oxPLs) are generated in the eye because of sunlight exposure and high oxygen content. OxPLs bind to the retinal pigment epithelium and macrophages and strongly activate downstream inflammatory cascades. We hypothesize that CFH may impact the risk of AMD by modulating oxidative stress. Here we demonstrate that CFH binds to oxPLs. The CFH 402Y variant of the protective rs1061170 genotype binds oxPLs with a higher affinity and exhibits a stronger inhibitory effect on the binding of oxPLs to retinal pigment epithelium and macrophages. In addition, plasma from non-AMD subjects with the protective genotype has a lower level of systemic oxidative stress measured by oxPLs per apolipoprotein B (oxPLs/apoB). We also show that oxPL stimulation increases expression of genes involved in macrophage infiltration, inflammation, and neovascularization in the eye. OxPLs colocalize with CFH in drusen in the human AMD eye. Subretinal injection of oxPLs induces choroidal neovascularization in mice. In addition, we show that the CFH risk allele confers higher complement activation and cell lysis activity. Together, these findings suggest that CFH influences AMD risk by modulating oxidative stress, inflammation, and abnormal angiogenesis.

Background: Mirtazapine is a commonly used antidepressant with a well-known ability to produce sedation. At the same time, its sleep-promoting effects in patients with major depressive disorder (MDD) are relatively unclear. The purpose of this article is to provide clinicians with a detailed review of mirtazapine's sleep effects in patients with MDD., Methods: A literature search was conducted for studies involving mirtazapine in depressed patients that specifically assessed sleep., Results: Twenty-three studies met selection criteria and were included in this review. Of the 15 studies that included a general assessment of sleep, all noted improvement from baseline with mirtazapine. Twelve of the 23 trials were randomized, blinded, and controlled. Mirtazapine was superior to placebo but did not clearly differentiate itself from other antidepressants, with the exception of venlafaxine. Eight studies used detailed measures of sleep and consistently reported that mirtazapine produced significant improvement in sleep efficiency, total sleep time, and sleep quality. Few investigations combined detailed assessments of sleep along with a comparator antidepressant., Conclusion: Mirtazapine is an antidepressant with sleep-promoting effects significantly greater than placebo, similar to tricyclic antidepressants, and somewhat similar to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. These effects must be balanced with mirtazapine's ability to cause sedation-related side effects.

Type I interferons (IFNs) are critical for controlling pathogenic virus infections and can enhance immune responses. Hence their impact on the effectiveness of live-attenuated vaccines involves a balance between limiting viral antigen expression and enhancing the development of adaptive immune responses. We examined the influence of type I IFNs on these parameters following immunization with RepliVAX WN, a single-cycle flavivirus vaccine (SCFV) against West Nile virus (WNV) disease. RepliVAX WN-immunized mice produced IFN-α and displayed increased IFN-stimulated gene transcription in draining lymph nodes (LN). SCFV gene expression was over 100 fold-higher on days 1-3 post-infection in type I IFN receptor knockout mice (IFNAR(-/-)) compared to wild-type (wt) mice indicating a profound IFN-mediated suppression of SCFV gene expression in the wt animals. IFNAR(-/-) mice produced nearly equivalent levels of WNV-specific serum IgG and WNV-specific CD4(+) T cell responses compared to wt mice. However, significantly higher numbers of WNV-specific CD8(+) T cells were produced by IFNAR(-/-) mice and a significantly greater percentage of these T cells from IFNAR(-/-) mice produced only IFN-γ following antigen-specific re-stimulation. This altered cytokine expression was not associated with increased antigen load suggesting the loss of type I IFN receptor signaling was responsible for the altered quality of the CD8(+) effector T cell response. Together, these results indicate that although type I IFN is not essential for the intrinsic adjuvanting of RepliVAX WN, it plays a role in shaping the cytokine secretion profiles of CD8(+) effector T cells elicited by this SCFV., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

CD8(+) T cells are important for resolution of HSV-2 lesions from the female genital epithelium. It is uncertain whether optimal clearance of viruses such as HSV-2 that cause a limited, non-systemic infection solely requires expression of effector functions by infiltrating CD8(+) T lymphocytes, or if the clearance rate is reflective of the expression level of critical effector functions. To address this, CD8(+) T cells from normal OT-I mice or OT-I mice deficient in IFNγ (IFNγ(-/-)) or the IFNγ receptor (IFNγR(-/-)) were activated in vitro in the presence of IFNγ or IL-4 to generate a series of effector populations (Tc1 and Tc2-like respectively) that secreted different levels of IFNγ and expressed different levels of HSV-specific cytolytic function. Compared with Tc1 cells, Tc2-like cells produced the type 2 cytokines IL-4 and IL-5, exhibited decreased IFNγ secretion, diminished proliferation in vitro, and decreased antigen-specific cytolysis in vivo. Clearance of an ovalbumin-expressing HSV-2 strain (HSV-2 tk(-) OVA) by adoptively transferred Tc2-like cells was delayed relative to Tc1 cell recipients. Because donor Tc2-like cells proliferated in vivo and infiltrated the infected genital epithelium similar to Tc1 cells, the diminished virus clearance by Tc2-like effector cells correlated with reduced expression of critical effector functions. Together, these results suggest that high level expression of protective T cell functions by effector T cells is necessary for optimal clearance of HSV-2 from the genital epithelium. These results have important implications for vaccines designed to elicit CD8(+) T cells against viruses such as HSV-2 that infect the genital tract., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

We recently reported that immunization with RepliVAX WN, a single-cycle West Nile virus (WNV) vaccine, protected mice against WNV challenge. We have extended these studies by characterizing the RepliVAX WN-elicited antibody and T cell responses. WNV-specific IgG antibody responses comprised predominantly of IgG(2c) and IgG(2b) subclasses were detected 8 months after immunization. Vigorous WNV-specific CD4(+) and CD8(+) T cell responses directed at both structural and nonstructural WNV proteins were detected which were characterized by cytolytic activity and secretion of IFN-γ and TNF-α. Importantly, RepliVAX WN immunization resulted in vigorous CD8(+) memory T cell responses detected at 8 months after immunization., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Purpose: Age-related macular degeneration (AMD) is the most common cause of irreversible central vision loss worldwide. Research has linked AMD susceptibility with dysregulation of the complement cascade. Typically, complement factor H (CFH), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3) are associated with AMD. In this paper, we investigated the association between complement factor D (CFD), another factor of the complement system, and advanced AMD in a Caucasian population., Methods: Six single nucleotide polymorphisms (SNPs), rs1683564, rs35186399, rs1683563, rs3826945, rs34337649, and rs1651896, across the region covering CFD, were chosen for this study. One hundred and seventy-eight patients with advanced AMD and 161 age-matched normal controls were genotyped. Potential positive signals were further tested in another independent 445 advanced AMD patients and 190 controls. χ2 tests were performed to compare the allele frequencies between case and control groups., Results: None of the six SNPs of CFD was found to be significantly associated with advanced AMD in our study., Conclusions: Our findings suggest that CFD may not play a major role in the genetic susceptibility to AMD because no association was found between the six SNPs analyzed in the CFD region and advanced AMD.

Interferon gamma (IFNgamma) is important for immune resistance to herpes simplex virus (HSV) infection. To examine the influence of IFNgamma on the development of HSV-specific immune responses and test for IFNgamma-independent adaptive immune mechanisms of protection, IFNgamma-deficient mice (IFNgamma(-/-)) were immunized with thymidine kinase-deficient HSV-2 (HSV-2 333tk(-)). HSV-specific cellular and humoral responses were elicited in immunized IFNgamma(-/-) mice resulting in increased resistance relative to non-immune C57BL/6J (B6) mice following challenge with fully virulent HSV-2. CD8(+) T cells from IFNgamma(-/-) mice displayed cytotoxic activity and secreted TNFalpha. HSV-specific CD4(+) T cells from immunized IFNgamma(-/-) mice secreted IL-4, TNFalpha, and IL-17, but unlike T cells from HSV-immune B6 mice, could not clear virus from genital tissue following adoptive transfer. HSV-immune IFNgamma(-/-) mice produced predominantly IgG(1) HSV-specific antibodies while immune B6 mice produced predominantly IgG(2c) antibodies. Transfer of equivalent amounts of HSV-specific antibodies from either strain to naïve mice imparted equivalent early resistance against infection of the genital epithelia. However, protection against neurological symptoms mediated by immune B6 antibodies was superior late in infection. Taken together, these results demonstrate that the limited resistance of HSV-immune IFNgamma(-/-) mice to HSV-2 infection resulted from the action of HSV-specific Ab rather than IFNgamma-independent effector functions of T cells. Further, protection against neurological manifestations of HSV-2 infection was superior in mice receiving Ab from immune B6 mice suggesting that Ab-mediated protective mechanisms involving IFNgamma-induced IgG subclasses were more effective once virus had spread to neural tissues., (2009 Elsevier Ireland Ltd. All rights reserved.)

Repair of beta-globin pre-mRNA rendered defective by a thalassemia-causing splicing mutation, IVS2-654, in intron 2 of the human beta-globin gene was accomplished in vivo in a mouse model of IVS2-654 thalassemia. This was effected by a systemically delivered splice-switching oligonucleotide (SSO), a morpholino oligomer conjugated to an arginine-rich peptide. The SSO blocked the aberrant splice site in the targeted pre-mRNA and forced the splicing machinery to reselect existing correct splice sites. Repaired beta-globin mRNA restored significant amounts of hemoglobin in the peripheral blood of the IVS2-654 mouse, improving the number and quality of erythroid cells.

Breast cancer remains a leading cause of disease and death among women throughout the world. Despite advances in drug therapy, development of novel and improved drugs for breast cancer continues to be of great interest. Lapatinib is a novel dual receptor tyrosine kinase inhibitor that is a selective and potent inhibitor of ErbB-1 and ErbB-2 tyrosine kinases, both of which are growth promoting factors overexpressed in some breast cancers. Cell-based assays have proven lapatinib to be a potent inhibitor of ErbB-1 and ErbB-2 activation and breast cancer cell proliferation. In pharmacokinetic studies, lapatinib has shown mostly linear elimination kinetics over the daily dose range of 10-1600 mg and is metabolized by CYP3A4/5 and CYP2C19. Phase I, II, and III clinical trials involving lapatinib as monotherapy or in combination have shown promise for the treatment of advanced and metastatic breast cancer. Drug-drug interactions may occur secondary to concomitant administration of either CYP450 inhibitors or inducers. While lapatinib appear to be a promising addition to breast cancer therapy, several questions remain to be answered before its optimal role is elucidated.

Arginine-rich cell-penetrating peptides (CPPs) are promising transporters for intracellular delivery of antisense morpholino oligomers (PMO). Here, we determined the effect of L-arginine, D-arginine and non-alpha amino acids on cellular uptake, splice-correction activity, cellular toxicity and serum binding for 24 CPP-PMOs. Insertion of 6-aminohexanoic acid (X) or beta-alanine (B) residues into oligoarginine R8 decreased the cellular uptake but increased the splice-correction activity of the resulting compound, with a greater increase for the sequences containing more X residues. Cellular toxicity was not observed for any of the conjugates up to 10 microM. Up to 60 microM, only the conjugates with > or = 5 Xs exhibited time- and concentration-dependent toxicity. Substitution of L-arginine with D-arginine did not increase uptake or splice-correction activity. High concentration of serum significantly decreased the uptake and splice-correction activity of oligoarginine conjugates, but had much less effect on the conjugates containing X or B. In summary, incorporation of X/B into oligoarginine enhanced the antisense activity and serum-binding profile of CPP-PMO. Toxicity of X/B-containing conjugates was affected by the number of Xs, treatment time and concentration. More active, stable and less toxic CPPs can be designed by optimizing the position and number of R, D-R, X and B residues.