Development of Functional Human NK Cells in an Immunodeficient Mouse Model with the Ability to Provide Protection against Tumor Challenge

Studies of human NK cells and their role in tumor suppression have largely been restricted to in vitro experiments which lack the complexity of whole organisms, or mouse models which differ significantly from humans. In this study we showed that, in contrast to C57BL/6 Rag2−/−/γc−/− and NOD/Scid mice, newborn BALB/c Rag2−/−/γc−/− mice can support the development of human NK cells and CD56+ T cells after intrahepatic injection with hematopoietic stem cells. The human CD56+ cells in BALB/c Rag2−/−/γc−/− mice were able to produce IFN-γ in response to human IL-15 and polyI:C. NK cells from reconstituted Rag2−/−/γc−/− mice were also able to kill and inhibit the growth of K562 cells in vitro and were able to produce IFN-γ in response to stimulation with K562 cells. In vivo, reconstituted Rag2−/−/γc−/− mice had higher survival rates after K562 challenge compared to non-reconstituted Rag2−/−/γc−/− mice and were able to control tumor burden in various organs. Reconstituted Rag2−/−/γc−/− mice represent a model in which functional human NK and CD56+ T cells can develop from stem cells and can thus be used to study human disease in a more clinically relevant environment

An epitope-specific DerG-PG70 LEAPS vaccine modulates T cell responses and suppresses arthritis progression in two related murine models of rheumatoid arthritis

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The effects of combination canagliflozin and glucagon-like peptide-1 receptor agonist therapy on intermediate markers of cardiovascular risk in the CANVAS program

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) reduce cardiovascular events, and improve intermediate markers of cardiometabolic health, in those with type 2 diabetes. We investigated these effects in the CANVAS Program. Methods and results: The CANVAS Program comprised 2 double-blind, randomized, placebo-controlled trials (CANVAS and CANVAS-R) done in patients with type 2 diabetes and elevated cardiovascular risk. Effects were estimated using mixed-effects models for continuous measures and Cox regression models for other outcomes. Randomized treatment by subgroup interaction terms were used to compare effects of canagliflozin versus placebo across subgroups defined by baseline use of GLP1-RA. There were 10,142 participants, of whom 407 (4%) were using GLP1-RA therapy at baseline. Those using GLP1-RA at baseline were less likely to have a history of cardiovascular disease (60.4% vs 65.8%), had a longer duration of diabetes (152 vs 13.5 years) and a higher body mass index (BMI; 35.6 vs 31.8 kg/m(2)) but were otherwise similar. There were greater reductions with canagliflozin versus placebo for HbA1c (-0.75% versus -0.58%; P = .0091), SBP (-6.26 versus -3.83 mmHg; P = .0018), and body weight (-3.79 versus -2.18 kg; P <.0001) in those on baseline GLP1-RA therapy. Effects across subgroups were similar for UACR (P = .21), eGFR slope (A - .72), major adverse cardiac events (P = .94) and total serious adverse events (P = .74). Conclusions: There may be a synergistic effect of SGLT2 inhibition when used on a background of GLP1-RA for intermediate cardiometabolic markers. (C) 2020 Elsevier B.V. All rights reserved

TLR10 Senses HIV-1 Proteins and Significantly Enhances HIV-1 Infection

Toll-like receptors (TLRs) play a crucial role in innate immunity and provide a first line of host defense against invading pathogens. Of the identified human TLRs, TLR10 remains an orphan receptor whose ligands and functions are poorly understood. In the present study, we sought to evaluate the level of TLR10 expression in breast milk (BM) and explore its potential function in the context of HIV-1 infection. We evaluated HIV-1-infected (Nigerian: n = 40) and uninfected (Nigerian: n = 27; Canadian: n = 15) BM samples for TLR expression (i.e., TLR10, TLR2, and TLR1) and report here that HIV-1-infected BM from Nigerian women showed significantly higher levels of TLR10, TLR1, and TLR2 expression. Moreover, the level of TLR10 expression in HIV-1-infected BM was upregulated by over 100-fold compared to that from uninfected control women. In vitro studies using TZMbl cells demonstrated that TLR10 overexpression contributes to higher HIV-1 infection and proviral DNA integration. Conversely, TLR10 inhibition significantly decreased HIV-1 infection. Notably, HIV-1 gp41 was recognized as a TLR10 ligand, leading to the induction of IL-8 and NF-κBα activation. The identification of a TLR10 ligand and its involvement in HIV-1 infection enhances our current understanding of HIV-1 replication and may assist in the development of improved future therapeutic strategies

Early Change in Albuminuria with Canagliflozin Predicts Kidney and Cardiovascular Outcomes:A Post Hoc Analysis from the CREDENCE Trial

Background The association between early changes in albuminuria and kidney and cardiovascular events is primarily based on trials of renin-angiotensin system blockade. It is unclear whether this association occurs with sodium-glucose cotransporter 2 inhibition. Methods TheCanagliflozin and Renal Events inDiabeteswith EstablishedNephropathy Clinical Evaluation (CREDENCE) trial enrolled 4401 patients with type 2 diabetes and CKD (urinary albumin-creatinine ratio [UACR].300 mg/g). This post hoc analysis assessed canagliflozin's effect on albuminuria and how early change in albuminuria (baseline to week 26) is associated with the primary kidney outcome (ESKD, doubling of serum creatinine, or kidney death), major adverse cardiovascular events, and hospitalization for heart failure or cardiovascular death. Results Complete data for early change in albuminuria and other covariates were available for 3836 (87.2%) participants in the CREDENCE trial. Compared with placebo, canagliflozin lowered UACR by 31% (95% confidence interval [95% CI], 27% to 36%) at week 26, and significantly increased the likelihood of achieving a 30% reduction in UACR ( odds ratio, 2.69; 95% CI, 2.35 to 3.07). Each 30% decrease in UACR over the first 26 weeks was independently associated with a lower hazard for the primary kidney outcome (hazard ratio [HR], 0.71; 95% CI, 0.67 to 0.76; P,0.001), major adverse cardiovascular events (HR, 0.92; 95% CI, 0.88 to 0.96; P,0.001), and hospitalization for heart failure or cardiovascular death (HR, 0.86; 95% CI, 0.81 to 0.90; P,0.001). Residual albuminuria levels at week 26 remained a strong independent risk factor for kidney and cardiovascular events, overall and in each treatment arm. Conclusions In people with type 2 diabetes and CKD, use of canagliflozin results in early, sustained reductions in albuminuria, which were independently associated with long-term kidney and cardiovascular outcomes

Access Impediments to Health Care and Social Services Between Anglophone and Francophone African Immigrants Living in Philadelphia with Respect to HIV/AIDS

Objectives To describe the social and cultural differences between Anglophone and Francophone African immigrants which define the impediments that Francophone African immigrants face trying to access health and human services in Philadelphia, Pennsylvania. Methods Surveys and personal interviews were administered to participants in social events, community meetings, and health centers. A Chi-squared analysis was used to contrast the communities. Results Francophone Africans demonstrated less acculturation, education, English fluency, and more legal documentation problems, and thus face greater challenges accessing health care. Anglophone Africans had a higher level of acculturation, fewer language problems, and perceived fewer barriers in accessing health care than Francophone Africans. Conclusions Educating new immigrants, through a more culturally sensitive infectious disease treatment and prevention program, is integral to achieving a higher access and utilization rates of available services; especially in recent Francophone immigrants. A larger study is needed to extend the findings to other cities where immigrants with similar backgrounds or acculturation issues reside

The effects of canagliflozin on heart failure and cardiovascular death by baseline participant characteristics:Analysis of the CREDENCE trial

Heart failure is prevalent in those with type 2 diabetes and chronic kidney disease, and is associated with significant mortality and morbidity. In the CREDENCE trial, canagliflozin reduced the risk of hospitalization for heart failure (HHF) or cardiovascular (CV) death by 31%. In the current analysis we sought to determine whether the effect of canagliflozin on HHF/CV death differed in subgroups defined by key baseline participant characteristics. Cox regression models were used to estimate hazard ratios and 95% confidence intervals. Canagliflozin was associated with a reduction in the relative risk of HHF/CV death regardless of age, sex, history of heart failure or CV disease, and the use of loop diuretics or glucagon-like peptide-1 receptor agonists (all p(interaction) > .114). The absolute benefit of canagliflozin was greater in those at highest baseline risk, such as those with CV disease (50 fewer events/1000 patients treated over 2.5 years vs. 20 fewer events in those without CV disease) or advanced kidney disease (estimated glomerular filtration rate [eGFR] 30-45 mL/min/1.73m(2): 61 events prevented/1000 patients treated over 2.5 years vs. 23 events in eGFR 60-90 mL/min/1.73m(2)). Canagliflozin consistently reduces the proportional risk of HHF/CV death across a broad range of subgroups with greater absolute benefits in those at highest baseline risk

Risk factors for late bowel and bladder toxicities in NRG Oncology prostate cancer trials of high-risk patients: A meta-analysis of physician-rated toxicities

Purpose: A meta-analysis of sociodemographic variables and their association with late (\u3e180 days from start of radiation therapy[RT]) bowel, bladder, and clustered bowel and bladder toxicities was conducted in patients with high-risk (clinical stages T2c-T4b or Gleason score 8-10 or prostate-specific antigen level \u3e20) prostate cancer. Methods and materials: Three NRG trials (RTOG 9202, RTOG 9413, and RTOG 9406) that accrued from 1992 to 2000 were used. Late toxicities were measured with the Radiation Therapy Oncology Group Late Radiation Morbidity Scale. After controlling for study, age, Karnofsky Performance Status, and year of accrual, sociodemographic variables were added to the model for each outcome variable of interest in a stepwise fashion using the Fine-Gray regression models with an entry criterion of 0.05. Results: A total of 2432 patients were analyzed of whom most were Caucasian (76%), had a KPS score of 90 to 100 (92%), and received whole-pelvic RT+HT (67%). Of these patients, 13 % and 16% experienced late grade ≥2 bowel and bladder toxicities, respectively, and 2% and 3% experienced late grade ≥3 bowel and bladder toxicities, respectively. Late grade ≥2 clustered bowel and bladder toxicities were seen in approximately 1% of patients and late grade ≥3 clustered toxicities were seen in 2 patients ( Conclusions: Patients with high-risk prostate cancer who receive whole-pelvic RT+LT HT are more likely to have a grade ≥2 bowel toxicity than those who receive prostate-only RT. LT bowel and bladder toxicities were infrequent. Future studies will need to confirm these findings utilizing current radiation technology and patient-reported outcomes

Cardiorenal protective effects of canagliflozin in CREDENCE according to glucose lowering

INTRODUCTION: Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain. RESEARCH DESIGN AND METHODS: We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components. RESULTS: HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60-90, 45-59, and 30-44 mL/min/1.73 m2, overall HbA1c (canagliflozin vs placebo) decreased by -0.24%, -0.14%, and -0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control. CONCLUSIONS: The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.22