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PurposeIncreased activity of STAT3 is associated with progression of head and neck squamous cell carcinoma (HNSCC). Upstream activators of STAT3, such as JAKs, represent potential targets for therapy of solid tumors, including HNSCC. In this study, we investigated the anticancer effects of ruxolitinib, a clinical JAK1/2 inhibitor, in HNSCC preclinical models, including patient-derived xenografts (PDX) from patients treated on a window-of-opportunity trial.Experimental designHNSCC cell lines were treated with ruxolitinib, and the impact on activated STAT3 levels, cell growth, and colony formation was assessed. PDXs were generated from patients with HNSCC who received a brief course of neoadjuvant ruxolitinib on a clinical trial. The impact of ruxolitinib on tumor growth and STAT3 activation was assessed.ResultsRuxolitinib inhibited STAT3 activation, cellular growth, and colony formation of HNSCC cell lines. Ruxolitinib treatment of mice bearing an HNSCC cell line-derived xenograft significantly inhibited tumor growth compared with vehicle-treated controls. The response of HNSCC PDXs derived from patients on the clinical trial mirrored the responses seen in the neoadjuvant setting. Baseline active STAT3 (pSTAT3) and total STAT3 levels were lower, and ruxolitinib inhibited STAT3 activation in a PDX from a patient whose disease was stable on ruxolitinib, compared with a PDX from a patient whose disease progressed on ruxolitinib and where ruxolitinib treatment had minimal impact on STAT3 activation.ConclusionsRuxolitinib exhibits antitumor effects in HNSCC preclinical models. Baseline pSTAT3 or total STAT3 levels in the tumor may serve as predictive biomarkers to identify patients most likely to respond to ruxolitinib.

Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected [CD4.sup.+] T cells. We engineered an anti-PD-1 chimeric antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239-infected rhesus macaques (RMs). Adoptive transfer of anti-PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti-PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of [PD- 1.sup.+] memory T cells in blood and tissues, including lymph node [CD4.sup.+] follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of [CD8.sup.+] memory T cells. These data indicate anti-PD-1 CAR T cells depleted [PD-1.sup.+] T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary., Introduction HIV infects cells of the immune system through interaction with CD4, CCR5, and CXCR4 and establishes long-lasting infections that develop into the acquired immunodeficiency syndrome if left untreated. With [...]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) with CCR5- donor cells is the only treatment known to cure HIV-1 in patients with underlying malignancy. This is likely due to a donor cell-mediated graft-versus-host effect targeting HIV reservoirs. Allo-HSCT would not be an acceptable therapy for most people living with HIV due to the transplant-related side effects. Chimeric antigen receptor (CAR) immunotherapies specifically traffic to malignant lymphoid tissues (lymphomas) and, in some settings, are able to replace allo-HSCT. Here, we quantified the engraftment of HSC-derived, virus-directed CAR T cells within HIV reservoirs in a macaque model of HIV infection, using potentially novel IHC assays. HSC-derived CAR cells trafficked to and displayed multilineage engraftment within tissue-associated viral reservoirs, persisting for nearly 2 years in lymphoid germinal centers, the brain, and the gastrointestinal tract. Our findings demonstrate that HSC-derived CAR+ cells reside long-term and proliferate in numerous tissues relevant for HIV infection and cancer.

The purpose of this study is to evaluate how the five variables that measure servant leadership (Altruistic Calling, Emotional Healing, Persuasive Mapping, Organizational Stewardship, and Team Learning) impact on teachers' perception of principal Wisdom. Participants were from fifteen moderate-need elementary schools located in southern New York State counties. One hundred and sixty-two teachers responded to a 36 item survey instrument. A structural equation model was used to evaluate which of the variables influenced wisdom. It was found that Altruistic Calling served as a mediator of Team Learning and Emotional Healing. Wisdom is predicted by Altruistic Calling (ß = 0.331), Persuasive Mapping (ß =0.195), and Organizational Stewardship (ß = 0.424). The three variables accounted for 81.4% of teachers' perception of principal wisdom. It is recommended that organizations that are interested in developing principal wisdom invest their developmental efforts into Altruistic Calling and Organizational Stewardship.

Coccidioides immitis and C. posadasii are soil-dwelling fungi that cause the disease coccidioidomycosis, also known as Valley fever (1). Since coccidiomycosis was first recorded in 1892, the disease has become [...]

[This corrects the article DOI: 10.1371/journal.ppat.1006753.].

Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. However, significant limitations are persistence and whether peripheral T cell-based products can respond to malignant or infected cells that may reappear months or years after treatment remains unclear. Hematopoietic Stem/Progenitor Cells (HSPCs) are capable of long-term engraftment and have the potential to overcome these limitations. Here, we report the use of a protective CD4 chimeric antigen receptor (C46CD4CAR) to redirect HSPC-derived T-cells against simian/human immunodeficiency virus (SHIV) infection in pigtail macaques. CAR-containing cells persisted for more than 2 years without any measurable toxicity and were capable of multilineage engraftment. Combination antiretroviral therapy (cART) treatment followed by cART withdrawal resulted in lower viral rebound in CAR animals relative to controls, and demonstrated an immune memory-like response. We found CAR-expressing cells in multiple lymphoid tissues, decreased tissue-associated SHIV RNA levels, and substantially higher CD4/CD8 ratios in the gut as compared to controls. These results show that HSPC-derived CAR T-cells are capable of long-term engraftment and immune surveillance. This study demonstrates for the first time the safety and feasibility of HSPC-based CAR therapy in a large animal preclinical model.

Topological crystalline insulators (TCIs) can exhibit unusual, quantized electric phenomena such as fractional electric polarization and boundary-localized fractional charge.sup.1-6. This quantized fractional charge is the generic observable for identification of TCIs that lack clear spectral features.sup.5-7, including ones with higher-order topology.sup.8-11. It has been predicted that fractional charges can also manifest where crystallographic defects disrupt the lattice structure of TCIs, potentially providing a bulk probe of crystalline topology.sup.10,12-14. However, this capability has not yet been confirmed in experiments, given that measurements of charge distributions in TCIs have not been accessible until recently.sup.11. Here we experimentally demonstrate that disclination defects can robustly trap fractional charges in TCI metamaterials, and show that this trapped charge can indicate non-trivial, higher-order crystalline topology even in the absence of any spectral signatures. Furthermore, we uncover a connection between the trapped charge and the existence of topological bound states localized at these defects. We test the robustness of these topological features when the protective crystalline symmetry is broken, and find that a single robust bound state can be localized at each disclination alongside the fractional charge. Our results conclusively show that disclination defects in TCIs can strongly trap fractional charges as well as topological bound states, and demonstrate the primacy of fractional charge as a probe of crystalline topology. It is experimentally shown that crystallographic defects may trap fractional charges, as well as topological states, in the bulk of topological crystalline insulators., Author(s): Christopher W. Peterson [sup.1] , Tianhe Li [sup.2] , Wentao Jiang [sup.1] , Taylor L. Hughes [sup.2] , Gaurav Bahl [sup.3] Author Affiliations: (1) Department of Electrical and Computer [...]

Eco‐evolutionary experiments are typically conducted in semi‐unnatural controlled settings, such as mesocosms; yet inferences about how evolution and ecology interact in the real world would surely benefit from experiments in natural uncontrolled settings. Opportunities for such experiments are rare but do arise in the context of restoration ecology—where different "types" of a given species can be introduced into different "replicate" locations. Designing such experiments requires wrestling with consequential questions. (Q1) Which specific "types" of a focal species should be introduced to the restoration location? (Q2) How many sources of each type should be used—and should they be mixed together? (Q3) Which specific source populations should be used? (Q4) Which type(s) or population(s) should be introduced into which restoration sites? We recently grappled with these questions when designing an eco‐evolutionary experiment with threespine stickleback (Gasterosteus aculeatus) introduced into nine small lakes and ponds on the Kenai Peninsula in Alaska that required restoration. After considering the options at length, we decided to use benthic versus limnetic ecotypes (Q1) to create a mixed group of colonists from four source populations of each ecotype (Q2), where ecotypes were identified based on trophic morphology (Q3), and were then introduced into nine restoration lakes scaled by lake size (Q4). We hope that outlining the alternatives and resulting choices will make the rationales clear for future studies leveraging our experiment, while also proving useful for investigators considering similar experiments in the future. [ABSTRACT FROM AUTHOR]

Sixteen jurisdictions in the United States prohibit payday lending through stringent usury laws or well‐established nonprofitable 36% interest rate caps. Yet over one in 10 consumers residing in these jurisdictions borrowed payday loans in the past 5 years. This raises questions about actual policy implementation and enforcement. We employ data from the 2018 National Financial Capability Study to investigate if associations between payday lending prohibitions and payday borrowing differ by degree of enforcement. We find that nuances in degree of enforcement among restrictive states are not associated with payday borrowing likelihoods. However, these nuances appear when examining payday borrowing frequency, particularly when controlling for consumers' financial circumstances and when conditioning on alternative financial services consumers. We consistently note the highest borrowing behaviors for states sans regulation. Policymakers may consider strengthening enforcement in cases where the primary goal is preventing or reducing payday borrowing. [ABSTRACT FROM AUTHOR]

The retraction of medical articles periodically occurs in most medical journals and can involve multiple article types. These retractions are beneficial if they remove flawed or fraudulent information from the medical literature. However, retractions may also decrease confidence in the medical literature and require significant amounts of time by editors. One publisher (Hindawi) announced that it will retract over 1200 articles. Given this, the PubMed database was searched to identify retracted publications on or related to COVID-19, and articles retracted by journals sponsored by the publisher Hindawi were then identified. These journals retracted 25 articles and, in most cases, did not provide an exact explanation about the particular problem(s) resulting in the retraction. The time to retraction was 468.7 ± 109.8 days (median = 446 days). These articles had 9.3 ± 9.9 citations. Analysis of the titles and abstracts of the articles suggests that their removal from the medical literature would have limited effects on the near-term management decisions during the COVID-19 pandemic. Nevertheless, retraction of medical articles creates uncertainty in medical care and science and in the public regarding the validity of medical research and related publications and the level of professionalism of the individuals submitting these articles. [ABSTRACT FROM AUTHOR]

Abstract--Stocks of red snapper (Lutjanus campechanus) exhibited a dramatic decline in abundance in the northern Gulf of Mexico (GOM) between 1960 and 1991; management regulations implemented since 1991 have resulted [...]

Over the past decade, chimeric antigen receptor (CAR) T cells have emerged as the prototype gene therapy for B cell leukemias. These so-called living drugs are derived from a patient's own cells, reprogrammed to recognize and destroy cancer cells, and then reintroduced into the body. The huge success of this therapy for cancer is rooted in pioneering clinical and preclinical studies, established more than three decades ago, focused on persistent HIV-1 infection. In this issue of theJCI, Bingfeng Liu et al. revisit HIV-specific CAR T cells in an important clinical study that supports broader application of this groundbreaking therapy. Although curative endpoints were not achieved, these findings lay the foundation for augmented approaches applying combinatorial technologies including antigen supplementation., CAR T cells from HIV to cancer and back CAR T cell therapies were first described in the early 1990s as a treatment for antiretroviral therapy-suppressed (ART-suppressed) people living with [...]