Search

Jennifer S Carew, Kevin R Kelly, Steffan T NawrockiThe Department of Medicine and Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX, USAAbstract: Autophagy is an evolutionarily conserved lysosomal degradation pathway that eliminates cytosolic proteins, macromolecules, organelles, and protein aggregates. Activation of autophagy may function as a tumor suppressor by degrading defective organelles and other cellular components. However, this pathway may also be exploited by cancer cells to generate nutrients and energy during periods of starvation, hypoxia, and stress induced by chemotherapy. Therefore, induction of autophagy has emerged as a drug resistance mechanism that promotes cancer cell survival via self-digestion. Numerous preclinical studies have demonstrated that inhibition of autophagy enhances the activity of a broad array of anticancer agents. Thus, targeting autophagy may be a global anticancer strategy that may improve the efficacy of many standard of care agents. These results have led to multiple clinical trials to evaluate autophagy inhibition in combination with conventional chemotherapy. In this review, we summarize the anticancer agents that have been reported to modulate autophagy and discuss new developments in autophagy inhibition as an anticancer strategy.Keywords: autophagy, chloroquine, lucanthone, cancer, apoptosis

p53 activation is a primary mechanism underlying pathological responses to DNA damaging agents such as chemotherapy and radiotherapy. Our recent animal studies showed that low dose arsenic (LDA)-induced transient p53 inhibition selectively protected normal tissues from chemotherapy-induced toxicity. Study objectives were to: 1) define the lowest safe dose of arsenic trioxide that transiently blocks p53 activation in patients and 2) assess the potential of LDA to decrease hematological toxicity from chemotherapy. Patients scheduled to receive minimum 4 cycles of myelosuppressive chemotherapy were eligible. For objective 1, dose escalation of LDA started at 0.005 mg/kg/day for 3 days. This dose satisfied objective 1 and was administered before chemotherapy cycles 2, 4, and 6 for objective 2. p53 level in peripheral lymphocytes was measured on day 1 of each cycle by ELISA assay. Chemotherapy cycles 1, 3, and 5 served as the baseline for the subsequent cycles of 2, 4, and 6 respectively. If p53 level for the subsequent cycle was lower (or higher) than the baseline cycle, p53 was defined as "suppressed" (or "activated") for the pair of cycles. Repeated measures linear models of CBC in terms of day, cycle, p53 activity and interaction terms were used. Twenty-six patients treated with 3 week cycle regimens form the base of analyses. The mean white blood cell, hemoglobin and absolute neutrophil counts were significantly higher in the "suppressed" relative to the "activated" group. These data support the proof of principle that suppression of p53 could lead to protection of bone marrow in patients receiving chemotherapy.This trial is registered in ClinicalTrials.gov. Identifier: NCT01428128.

Recently, tramadol and its active metabolite, O-desmethyltramadol (M1), have been studied as analgesic agents in various traditional veterinary species (e.g., dogs, cats, etc.). This study explores the pharmacokinetics of tramadol and M1 after intravenous (IV) and oral (PO) administration in rhesus macaques (Macaca mulatta), a nontraditional veterinary species. Rhesus macaques are Old World monkeys that are commonly used in biomedical research. Effects of tramadol administration to monkeys are unknown, and research veterinarians may avoid inclusion of this drug into pain management programs due to this limited knowledge. Four healthy, socially housed, adult male rhesus macaques (Macaca mulatta) were used in this study. Blood samples were collected prior to, and up to 10 h post-tramadol administration. Serum tramadol and M1 were analyzed using liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic analysis was performed. Tramadol clearance was 24.5 (23.4-32.7) mL/min/kg. Terminal half-life of tramadol was 111 (106-127) min IV and 133 (84.9-198) min PO. Bioavailability of tramadol was poor [3.47% (2.14-5.96%)]. Maximum serum concentration of M1 was 2.28 (1.88-2.73) ng/mL IV and 11.2 (9.37-14.9) ng/mL PO. Sedation and pruritus were observed after IV administration.

This study reports the pharmacokinetics of buprenorphine in conscious rhesus macaques (Macaca mulatta) after intravenous (i.v.) and intramuscular (i.m.) administration. Four healthy, opioid-naïve, socially housed, adult male macaques were used. Buprenorphine (0.03 mg/kg) was administered intravenously as a bolus or intramuscularly on separate occasions. Blood samples were collected prior to, and up to 24 h, postadministration. Serum buprenorphine concentrations were analyzed with liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic analysis was performed with commercially available software. Mean residence time in the i.v. study as compared to the i.m. study was 177 (159-189) vs. 185 (174-214) min, respectively [median (range)]. In the i.v. study, concentration back-extrapolated to time zero was found to be 33.0 (16.8-57.0) ng/mL [median (range)]. On the other hand, the maximum serum concentration found in the i.m. study was 11.8 (6.30-14.8) ng/mL [median (range)]. Rhesus macaques maintained concentrations >0.10 ng/mL for over 24 h in the i.v. study and over 12 h in the i.m. study. Bioavailability was found to be 68.1 (59.3-71.2)% [median (range)]. No significant adverse effects were observed in the monkeys at the 0.03 mg/kg dose of buprenorphine during either study.

Abstract Background This cross‐sectional study explored how masculinity beliefs may influence colorectal cancer (CRC) screening participation among ethnic subgroups of screening‐age–eligible (45–75 years) Hispanic/Latino men. Methods Using a consumer panel, we recruited self‐identified Hispanic/Latino men fluent in English or Spanish, and residing in Florida, New York, or Texas. The Masculinity Barriers to Medical Care (MBMC) scale and its six subscales were used to assess masculinity beliefs. Multivariable logistic regression was used to estimate the association between MBMC and CRC screening participation, adjusting for Hispanic/Latino subgroup, marital status, survey language, age group, and health insurance status. Results were then stratified by Hispanic/Latino subgroup. Results Of the participants (n=611), approximately 31% identified as Puerto Rican, 30% as other Hispanic/Latino, 26% as Mexican, and 14% as Cuban; 63% had ever been screened for CRC. We found no differences in the prevalence of screening participation by Hispanic/Latino subgroup. The majority of participants had completed both a stool‐based test and an exam‐based screening test (29.3%). After adjusting for confounding, MBMC reduced the odds of screening participation. Slight MBMC‐subscale differences were observed by Hispanic/Latino subgroup. For example, higher scores on the Restrictive Emotionality subscale were associated with a lower likelihood of screening participation among Puerto Rican men, but higher odds of screening for Cuban men. Conclusions Masculinity barriers to CRC screening may exist. Tailored interventions to address masculinity barriers among specific Latino subgroups may improve CRC screening uptake in this population.

Ex vivo autologous hematopoietic stem cell lentiviral-based gene therapy with betibeglogene autotemcel has been studied in patients with transfusion-dependent β-thalassemia in Phase III clinical trials (HGB-207 and HGB-212), with 90% of patients reaching transfusion independence (TI). Here, we explore manufacturing parameters, drug product quality attributes, and limited patient characteristics that had an impact on clinical efficacy in HGB-207 and HGB-212. Retrospective analysis revealed that the peripheral blood vector copy number (VCN) was related to TI, with a strong correlation between peripheral blood VCN at 6 months and gene therapy–derived therapeutic protein (HbAT87Q) expression at 6 months (correlation coefficient, 0.8681; p

ABSTRACT A 39‐year‐old female with a history of kidney transplant presented to the endocrinology clinic for osteoporosis evaluation after sustaining an ankle fracture from a fall. Her kidney transplant regimen (mycophenolate mofetil 360 mg twice a day, tacrolimus 0.5 mg every morning and 0.5–1 mg every evening, prednisone 5 mg/day) and baseline creatinine (1.0–1.2 mg/dL) had been stable for several years. After an appropriate secondary workup, she was started on abaloparatide 80 μg subcutaneous daily injections for osteoporosis. She had a good initial biochemical response to therapy. However, 5 months after abaloparatide initiation she was found to have a new elevation in serum creatinine (1.17 to 1.69 mg/dL) despite stable serum tacrolimus trough levels, and two new human leukocyte antigen (HLA) antibodies (anti‐HLA antibodies detected to Cw7 and DP28). Abaloparatide was stopped due to concern for immunogenicity. There was no evidence of rejection on kidney biopsy and she was restabilized on her transplant regimen with a new baseline creatinine of 1.3–1.6 mg/dL. The patient was subsequently started on teriparatide 20 μg daily subcutaneous injections for 2 years with good biochemical response, significant improvement in bone mineral density, and stable transplant regimen without additional signs of immunogenicity or rejection. This is the first case report to raise concern about immunogenicity with abaloparatide in solid organ transplant recipients. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

G0/G1 switch gene 2 (G0S2) is known to inhibit lipolysis by inhibiting adipose triglyceride lipase (ATGL). In this report, we dissect the role of G0S2 in ER+ versus ER- breast cancer. Overexpression of G0S2 in ER- cells increased cell proliferation, while G0S2 overexpression in ER+ cells decreased cell proliferation. Transcriptome analysis revealed that G0S2 mediated distinct but overlapping transcriptional responses in ER- and ER+ cells. G0S2 reduced genes associated with an epithelial phenotype, especially in ER- cells, including CDH1, ELF3, STEAP4 and TACSTD2, suggesting promotion of the epithelial-mesenchymal transition (EMT). G0S2 also repressed estrogen signaling and estrogen receptor target gene signatures, especially in ER+ cells, including TFF1 and TFF3. In addition, G0S2 overexpression increased cell migration in ER- cells and increased estrogen deprivation sensitivity in ER+ cells. Interestingly, two genes downstream of ATGL in fat utilization and very important in steroid hormone biosynthesis, HMGCS1 and HMGCS2, were downregulated in G0S2 overexpressing ER+ cells. In addition, HSD17B11, a gene that converts estradiol to its less estrogenic derivative, estrone, was highly upregulated in G0S2 overexpressing ER+ cells, suggesting G0S2 overexpression has a negative effect on estradiol production and maintenance. High expression of G0S2 and HSD17B11 was associated with improved relapse-free survival in breast cancer patients while high expression of HMGSC1 was associated with poor survival. Finally, we deleted G0S2 in breast cancer-prone MMTV-PyMT mice. Our data indicates a complex role for G0S2 in breast cancer, dependent on ER status, that may be partially mediated by suppression of the estrogen signaling pathway.

Healthcare continues toward team-based approaches in which multiple disciplines collaborate to ensure holistic patient care. National standards for intraprofessional collaboration guide curriculum design for entry-level occupational therapy (OT) and occupational therapy assistant (OTA) programs to ensure students acquire specific skills and knowledge needed for current OT practices. Effective intraprofessional collaboration includes effective communication, respect, trust, and understanding of role delineation, which students prefer to learn in experiential, face-to-face formats. The purpose of this study was to examine OT and OTA students’ perspectives of participating in an educational escape room (EER) as a novel experience for intraprofessional education. Investigators created an EER with a healthcare plot and conducted it at two sites with 76 students, who had 60 minutes to solve puzzles based on OT/OTA knowledge to “escape” the room. Seventy-five students provided feedback on the EER in an online survey. Participants enjoyed working together in the EER, and felt it was a fun way to apply learned skills. They reported that collaboration was a key benefit and that this learning approach made them feel like equal contributors and created a sense of accomplishment. OT educators should consider including novel game-based learning activities such as EERs in their programs and in collaboration with other programs.

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C>T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell–derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC–derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.

Introduction Historically, heterogeneous outcome assessments have been used to measure recovery of consciousness in patients with disorders of consciousness (DoC) following traumatic brain injury (TBI), making it difficult to compare across studies. To date, however, there is no comprehensive review of clinical outcome assessments that are used in intervention studies of adults with DoC. The objective of this scoping review is to develop a comprehensive inventory of clinical outcome assessments for recovery of consciousness that have been used in clinical studies of adults with DoC following TBI.Methods and analysis The methodological framework for this review is: (1) identify the research questions, (2) identify relevant studies, (3) select studies, (4) chart the data, (5) collate, summarise and report results and (6) consult stakeholders to drive knowledge translation. We will identify relevant studies by searching the following electronic bibliographic databases: PubMed, Scopus, EMBASE, PsycINFO and The Cochrane Library (including Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and Cochrane Methodology Register). Criteria for article inclusion are published in the English-language, peer-reviewed studies of interventions aimed at facilitating recovery of consciousness among adults (> 18 years) with DoC following a severe TBI, published from January 1986 to December 2020. Articles meeting inclusion criteria at this stage will undergo a full text review. We will chart the data by applying the WHO International Classification of Functioning, Disability and Health Framework to identify the content areas of clinical outcome assessments. To support knowledge translation efforts, we will involve clinicians and researchers experienced in TBI care throughout the project from conceptualisation of the study through dissemination of results.Ethics and dissemination No ethical approval is required for this study as it is not determined to be human subjects research. Results will be presented at national conferences and published in peer-reviewed journals.Trial registration number CRD42017058383.

Liver test abnormalities have been described during severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection causing coronavirus disease 2019. Most of them consist of elevation of the aminotransferases that resolve once the infection subsides. There are several reports of autoimmune hepatitis developing after vaccination against COVID-19 and one case of autoimmune hepatitis following COVID-19 infection. We present a patient that was not vaccinated against COVID-19 and developed resistant de novo autoimmune hepatitis following COVID-19 infection requiring aggressive immunosuppression.

BACKGROUND Wolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODS Based on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTS Dantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects.CONCLUSION This study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02829268FUNDING NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

Low-glycemic index diets and exercise independently improve glucose tolerance and reduce diabetes risk. However, the combined effect of a low-glycemic index diet and exercise on inflammation and glucose metabolism is not known. Therefore, we randomized 28 insulin-resistant adults (age: 66 ± 1 y; BMI: 34.2 ± 0.7 kg · m(-2)) to a 12-wk, low (LGI = 40) or high- (HGI = 80) glycemic index diet plus aerobic exercise (5 d · wk(-1), 60 min · d(-1), 80-85% heart rate(max)) intervention. All food and fluids were provided during the study. Inflammation was assessed from cytokine (TNFα and IL-6) secretion using peripheral blood mononuclear cells (MNC) stimulated overnight with LPS. Glycemic response was determined following ingestion of a 75-g glucose solution. Fasting blood samples were collected for additional cytokine [TNFα, IL-6, and monocyte chemoattractant protein 1 (MCP-1)] analysis. Both interventions decreased BMI (P < 0.001), fasting plasma glucose (P = 0.01), and insulin (P = 0.02). The glycemic response was reduced only in the LGI group (P = 0.04). Plasma and MNC-derived TNFα secretion were reduced in the LGI group (P = 0.02) but increased in the HGI group (P = 0.02). Secretion of IL-6 from MNC and plasma IL-6 and MCP-1 concentrations were reduced in the LGI group. The change in MNC-derived TNFα (r = 0.43; P = 0.04) and plasma MCP-1 (r = 0.44; P = 0.04) correlated with decreases in the glycemic response. These data highlight the importance of diet composition in the treatment and prevention of inflammation and hyperglycemia. A low-glycemic index diet has antiinflammatory and antidiabetogenic effects when combined with exercise in older, obese prediabetics. [ABSTRACT FROM AUTHOR]

Objective: Restoration of insulin secretion is critical for the treatment of type 2 diabetes. Exercise and diet can alter glucose-induced insulin responses, but whether this is due to changes in beta-cell function per se is not clear. The mechanisms by which lifestyle intervention may modify insulin secretion in type 2 diabetes have also not been examined but may involve the incretin axis.Research Design and Methods: Twenty-nine older, obese (aged 65 +/- 1 years; BMI 33.6 +/- 1.0 kg/m(2)) subjects, including individuals with newly diagnosed type 2 diabetes (obese-type 2 diabetic) and individuals with normal glucose tolerance (obese-NGT), underwent 3 months of nutritional counseling and exercise training. beta-Cell function (oral glucose-induced insulin secretion corrected for insulin resistance assessed by hyperinsulinemic-euglycemic clamps) and the role of glucose-dependent insulinotropic polypeptide (GIP) were examined.Results: After exercise and diet-induced weight loss (-5.0 +/- 0.7 kg), oral glucose-induced insulin secretion was increased in the obese-type 2 diabetic group and decreased in the obese-NGT group (both P < 0.05). When corrected for alterations in insulin resistance, the change in insulin secretion remained significant only in the obese-type 2 diabetic group (1.23 +/- 0.26 vs. 2.04 +/- 0.46 arbitrary units; P < 0.01). Changes in insulin secretion were directly related to the GIP responses to oral glucose (r = 0.64, P = 0.005), which were augmented in the obese-type 2 diabetic group and only moderately suppressed in the obese-NGT group.Conclusions: After lifestyle-induced weight loss, improvements in oral glucose-induced insulin secretion in older, obese, nondiabetic subjects seem to be largely dependent on improved insulin sensitivity. However, in older obese diabetic patients, improved insulin secretion is a consequence of elevated beta-cell function. We demonstrate for the first time that changes in insulin secretion after lifestyle intervention may be mediated via alterations in GIP secretion from intestinal K-cells. [ABSTRACT FROM AUTHOR]

Context: Hyperglycemia resolves quickly after bariatric surgery, but the underlying mechanism and the most effective type of surgery remains unclear.Objective: To examine glucose metabolism and beta-cell function in patients with type 2 diabetes mellitus (T2DM) after two types of bariatric intervention; Roux-en-Y gastric bypass (RYGB) and gastric restrictive (GR) surgery.Design: Prospective, nonrandomized, repeated-measures, 4-week, longitudinal clinical trial.Patients: In all, 16 T2DM patients (9 males and 7 females, 52+/-14 years, 47+/-9 kg m(-2), HbA1c 7.2+/-1.1%) undergoing either RYGB (N=9) or GR (N=7) surgery.Outcome Measures: Glucose, insulin secretion, insulin sensitivity at baseline, and 1 and 4 weeks post-surgery, using hyperglycemic clamps and C-peptide modeling kinetics; glucose, insulin secretion and gut-peptide responses to mixed meal tolerance test (MMTT) at baseline and 4 weeks post-surgery.Results: At 1 week post-surgery, both groups experienced a similar weight loss and reduction in fasting glucose (P<0.01). However, insulin sensitivity increased only after RYGB, (P<0.05). At 4 weeks post-surgery, weight loss remained similar for both groups, but fasting glucose was normalized only after RYGB (95+/-3 mg 100 ml(-1)). Insulin sensitivity improved after RYGB (P<0.01) and did not change with GR, whereas the disposition index remained unchanged after RYGB and increased 30% after GR (P=0.10). The MMTT elicited a robust increase in insulin secretion, glucagon-like peptide-1 (GLP-1) levels and beta-cell sensitivity to glucose only after RYGB (P<0.05).Conclusion: RYGB provides a more rapid improvement in glucose regulation compared with GR. This improvement is accompanied by enhanced insulin sensitivity and beta-cell responsiveness to glucose, in part because of an incretin effect. [ABSTRACT FROM AUTHOR]

Abstract Background High throughput sequencing has become an important technology for studying expression levels in many types of genomic, and particularly transcriptomic, data. One key way of analysing such data is to look for elements of the data which display particular patterns of differential expression in order to take these forward for further analysis and validation. Results We propose a framework for defining patterns of differential expression and develop a novel algorithm, baySeq, which uses an empirical Bayes approach to detect these patterns of differential expression within a set of sequencing samples. The method assumes a negative binomial distribution for the data and derives an empirically determined prior distribution from the entire dataset. We examine the performance of the method on real and simulated data. Conclusions Our method performs at least as well, and often better, than existing methods for analyses of pairwise differential expression in both real and simulated data. When we compare methods for the analysis of data from experimental designs involving multiple sample groups, our method again shows substantial gains in performance. We believe that this approach thus represents an important step forward for the analysis of count data from sequencing experiments.

Abstract Background Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences. Methods To better understand long-term effects and pathogenesis of this common, persistent brain infection, mice were infected at a time in human years equivalent to early to mid adulthood and studied 5–12 months later. Appearance, behavior, neurologic function and brain MRIs were studied. Additional analyses of pathogenesis included: correlation of brain weight and neurologic findings; histopathology focusing on brain regions; full genome microarrays; immunohistochemistry characterizing inflammatory cells; determination of presence of tachyzoites and bradyzoites; electron microscopy; and study of markers of inflammation in serum. Histopathology in genetically resistant mice and cytokine and NRAMP knockout mice, effects of inoculation of isolated parasites, and treatment with sulfadiazine or αPD1 ligand were studied. Results Twelve months after infection, a time equivalent to middle to early elderly ages, mice had behavioral and neurological deficits, and brain MRIs showed mild to moderate ventricular dilatation. Lower brain weight correlated with greater magnitude of neurologic abnormalities and inflammation. Full genome microarrays of brains reflected inflammation causing neuronal damage (Gfap), effects on host cell protein processing (ubiquitin ligase), synapse remodeling (Complement 1q), and also increased expression of PD-1L (a ligand that allows persistent LCMV brain infection) and CD 36 (a fatty acid translocase and oxidized LDL receptor that mediates innate immune response to beta amyloid which is associated with pro-inflammation in Alzheimer's disease). Immunostaining detected no inflammation around intra-neuronal cysts, practically no free tachyzoites, and only rare bradyzoites. Nonetheless, there were perivascular, leptomeningeal inflammatory cells, particularly contiguous to the aqueduct of Sylvius and hippocampus, CD4+ and CD8+ T cells, and activated microglia in perivascular areas and brain parenchyma. Genetically resistant, chronically infected mice had substantially less inflammation. Conclusion In outbred mice, chronic, adult acquired T. gondii infection causes neurologic and behavioral abnormalities secondary to inflammation and loss of brain parenchyma. Perivascular inflammation is prominent particularly contiguous to the aqueduct of Sylvius and hippocampus. Even resistant mice have perivascular inflammation. This mouse model of chronic T. gondii infection raises questions of whether persistence of this parasite in brain can cause inflammation or neurodegeneration in genetically susceptible hosts.

Chromosomal rearrangements (CR) initiate leukemogenesis in approximately 50 % of acute myeloid leukemia (AML) patients; however, limited targeted therapies exist due to a lack of accurate molecular and genetic biomarkers of refractory mechanisms during treatment. Here, we investigated the pathological landscape of treatment resistance and relapse in 16 CR-AML patients by monitoring cytogenetic, RNAseq, and genome-wide changes among newly diagnosed, refractory, and relapsed AML. First, in FISH-diagnosed KMT2A (MLL gene, 11q23)/AFDN (AF6, 6q27)-rearrangement, RNA-sequencing identified an unknown CCDC32 (15q15.1)/CBX3 (7p15.2) gene fusion in both newly diagnosed and relapsed samples, which is previously unknown in KMT2A/AFDN-rearranged AML patients. Second, the unreported CCDC32/CBX3 gene fusion significantly affected the expression of wild-type genes of both CCDC32 (essential for embryonic development) and CBX3 (an oncogene for solid tumors) during the relapse, as demonstrated by Quantitative PCR analyses. Third, we further confirmed the existence of triple biomarkers - KMT2A/AFDN (AF6, 6q27) rearrangement, the unknown CCDC32 (15q15.1)/CBX3 (7p15.2) gene fusion and chimeric RNA variants (treatment-resistant leukemic blasts harboring distinct breakpoints) in a 21-year-old male patient of rapid relapsed/refractory AML. Most intriguingly, in this work regarding 16 patients, patients 7 and 20 initially showed the KMT2A/AFDN gene fusion; upon relapse, patient 20 did not show this fusion. On the other hand, patient 7 retained the KMT2A/AFDN fusion at diagnosis and during the relapse, only identified by PCR and Sanger's Sequencing, not by cytogenetics. Interestingly, the chimeric CCDC32/CBX3 gene fusion persisted in the 21-year-old male patient over the diagnostic and relapse phases. Most intriguingly, the overexpression of CCDC32/CBX3 fusion gene in AML patient-specific MV4-11 cells confirms the functional validation, providing experimental evidence of the biological impact of the CCDC32/CBX3 fusion on AML pathogenesis and treatment resistance by promoting cell cycle progression, a mechanism through which AML evolves to become treatment-resistant. All these might exhort differential resistance to treatment. Thus, we found that prognostic and predictive triple biomarkers - KRAS mutated, dual fusions (KMT2A/AFDN, CCDC32/CBX3), and chimeric variants - might evolve with a potential oncogenic role of subclonal evolution for poor clinical outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: One rationale for dichoptic amblyopia therapy is that it may promote recovery of binocular function. Yet data on binocular outcomes in anisometropic amblyopia following dichoptic therapy are sparse. We report factors associated with pre- and post-treatment binocular function in anisometropic amblyopia, and examine binocular function in children who recover normal visual acuity compared to those with residual amblyopia., Methods: Baseline and outcome stereoacuity and binocular function (BF) scores were pooled across 185 children (3-12 years of age) with anisometropic amblyopia who participated in one of eight clinical trials of contrast-rebalanced dichoptic amblyopia treatment conducted at a single site. Associations of baseline variables (visual acuity, suppression, type and amount of anisometropia, prior treatment) with baseline and outcome stereoacuity and BF scores were analyzed, as well the association between improvement in visual acuity with improvement in stereoacuity and BF scores., Results: Better baseline stereoacuity and BF score were associated with better baseline visual acuity, less baseline suppression, less anisometropia, and anisometropia due to astigmatism. Better outcome stereoacuity and BF score were associated with better baseline stereoacuity and BF score, more improvement in visual acuity, less anisometropia, and anisometropia due to astigmatism. Children aged 3-6 years who recovered normal visual acuity with dichoptic treatment had better stereoacuity and BF score outcomes than those with residual amblyopia., Conclusions: Dichoptic therapy is an effective amblyopia treatment. Although there was no substantive advantage in promoting binocular function, stereoacuity outcomes were similar to those previously reported for patching and Bangerter filters., (Copyright © 2025 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

This final analysis from the phase 4 BYOND trial reports outcomes with bosutinib in patients with previously treated chronic myeloid leukemia (CML); 163 patients with CML resistant/intolerant to previous tyrosine kinase inhibitors received bosutinib (starting dose: 500 mg QD). At study completion (median follow-up, 47.8 months), 48.1% (n = 75/156) of patients with Philadelphia chromosome-positive chronic phase CML were still receiving treatment. Among evaluable patients, 71.8% (95% CI, 63.9-78.9) and 59.7% (95% CI, 51.4-67.7) attained or maintained major molecular response (MMR) and molecular response (MR) 4 , respectively, at any time on treatment. The majority of patients achieved a deeper molecular response relative to baseline while on bosutinib. Kaplan-Meier probabilities (95% CI) of maintaining MMR and MR 4 at 36 months were 87.2% (78.0-92.7) and 80.7% (69.4-88.1), respectively. At 48 months, the Kaplan-Meier overall survival rate was 88.3% (95% CI, 81.8-92.6); there were 17 deaths, including 2 that were considered CML related. Long-term adverse events (AEs) were consistent with the known safety profile of bosutinib, and no new safety issues were identified. The management of AEs through dose reduction maintained efficacy while improving tolerability. These results support the use of bosutinib in patients with previously treated CML.ClinicalTrials.gov, NCT02228382., (© 2024. The Author(s).)

Retinal pigment epithelial (RPE) cells are exclusive to the retina, critically multifunctional in maintaining the visual functions and health of photoreceptors and the retina. Despite their vital functions throughout lifetime, RPE cells lack regenerative capacity, rendering them vulnerable which can lead to degenerative retinal diseases. With advancements in stem cell technology enabling the differentiation of functional cells from pluripotent stem cells and leveraging the robust autocrine and paracrine functions of RPE cells, extracellular vesicles (EVs) secreted by RPE cells hold significant therapeutic potential in supplementing RPE cell activity. While previous research has primarily focused on the trophic factors secreted by RPE cells, there is a lack of studies investigating miRNA, which serves as a master regulator of gene expression. Profiling and defining the functional role of miRNA contained within RPE-secreted EVs is critical as it constitutes a necessary step in identifying the optimal phenotype of the EV-secreting cell and understanding the biological cargo of EVs to develop EV-based therapeutics. In this study, we present a comprehensive profile of miRNA in small extracellular vesicles (sEVs) secreted during RPE maturation following differentiation from human embryonic stem cells (hESCs); early - stage hESC-RPE (20-21 days in culture), mid - stage hESC-RPE (30-31 days in culture) and late - stage hESC-RPE (60-61 days in culture). This exploration is essential for ongoing efforts to develop and optimize EV-based intraocular therapeutics utilizing RPE-secreted EVs, which may significantly impact the function of dysfunctional RPE cells in retinal diseases., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Journal of Extracellular Biology published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Introduction: Shooting simulations provide an excellent opportunity to train use-of-force decisions in controlled environments. Recently, military and law enforcement organizations have expressed a growing desire to integrate physiological measurement into simulations for training and feedback purposes. Although participants can easily wear physiological monitors in these scenarios, direct implementation into training may not be simple. Theoretical problems exist in the ultra-short heart rate variability windows associated with use-of-force training, and practical problems emerge as existing scenario libraries at training organizations were not designed for physiological monitoring., Methods: The current study explored the challenges and possibilities associated with direct implementation of physiological monitoring into an existing library of firearms training scenarios. Participants completed scenarios in a shooting simulator using existing military training scenarios while wearing a device to monitor their heart rate., Results: The results revealed lower heart rate variability (approximately 6%) occurred in scenarios where participants did not have to fire weapons, indicating that don't-shoot scenarios may actually impose more cognitive stress on shooters. Additional evidence further demonstrated how both behavioral and physiological factors could be used concomitantly to predict unintentionally firing on non-hostile actors. However, behavioral measures were more predictive (e.g., β  = .221) than physiological measures (e.g., β  = -.132) when the latter metrics were limited to specific scenarios. Qualitative results suggest that simply applying physiological monitoring to existing shooting simulations may not yield optimal results because it would be difficult to directly integrate physiological measurement in a meaningful way without re-designing some elements of the simulations, the training procedure, or both., Discussion: Future use-of-force shooting simulations should consider designing novel scenarios around the physiological measurement rather than directly implementing physiological assessments into existing libraries of scenarios., Competing Interests: Author Andrew E. Jensen was employed by Leidos, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Biggs, Jensen and Kelly.)

Introduction: Winter warfare training (WWT) is a critical component of military training that trains warfighters to operate effectively in extreme environments impacted by snow and mountainous terrain. These environmental factors can exacerbate the disruption to the hormone milieu associated with operating in multi-stressor settings. To date, there is limited research on the physiological responses and adaptations that occur in elite military populations training in arduous environments. The purpose of this study was to quantify hormone responses and adaptations in operators throughout WWT., Materials and Methods: Participants engaged in baseline laboratory metrics at their home station, Fort Carson, located in Colorado (CO) prior to WWT, for one week in Montana (MT) and one week in Alaska (AK). WWT periods were separated by approximately one month. Blood was collected upon wake at baseline (CO) and on the first and last day of WWT at each location (MT and AK). Plasma was analyzed for stress, metabolic, and growth-related hormones via enzyme-linked immunoassay (ELISA). Sleep quality was assessed via the Pittsburg Sleep Quality Index (PSQI) at baseline (CO) and on the first day of training in MT and AK. Cognitive function was evaluated using the Defense Automated Neurobehavioral Assessment (DANA) at baseline (CO) and on the first and last day of WWT in both MT and AK., Results: Fourteen US Army operators in 10th Special Forces Group (SFG) Operational Detachment participated in winter warfare training (WWT; age: 31.5 years; 95%CI[28.1, 34.3]; height: 180.6 cm; 95%CI[177.3, 183.4]; weight: 87.4 kg.; 95%CI[80.6, 97.7]; body fat: 18.9%; 95%CI[13.7, 23.1]; male: n=13; female: n=1). Plasma adrenocorticotropic hormone (ACTH) levels increased from baseline (19.9 pg/mL; 95%CI[8.6, 24.2])  to pre-WWT (26.9 pg/mL; 95%CI [16.2, 37]; p=0.004), decreased from pre-  (26.9 pg/mL; 95%CI [16.2, 37]) to post-WWT in MT (22.3 pg/mL; 95% CI [8, 23.7]; p=0.004;), and increased from pre-  (25 pg/mL; 95%CI[ 28.4) to post-WWT (36.6 pg/mL; 95%CI [17.9, 48.9]) in AK (p=0.005). Plasma cortisol levels decreased from pre- (174 ng/mL; 95%CI[106.2, 233.6])  to post-WWT (94.5 ng/mL; 95%CI[54.8, 101.7]) in MT (p=0.001) and, conversely, increased from pre- (123.1 ng/mL; 95%CI[97.5, 143.9]) to post-WWT  (162.8 ng/mL; 95%CI[128, 216.7]) in AK (p<0.001). Alterations in growth-related hormones (insulin-like growth factor 1 [IGF-1], insulin-like growth factor binding protein 3 [IGFBP-3],  and sex hormone binding globulin [SHBG]) were observed throughout WWT (p<0.05). The Total Testosterone / Cortisol ratio (TT / CORT; molar ratio) was lower pre-WWT in MT (0.04; 95%CI[0.01,0.04) compared to baseline in CO (0.07; 95%CI[0.04, 0.07]; p=0.042). Triiodothyronine (T3) levels increased from pre-  (101.7 ng/dL; 95%CI[93.7, 110.4]) to post-WWT  (117.8 ng/dL; 95%CI[105.1, 129.4]) in MT (p=0.042). No differences in sleep quality were reported between locations (CO, MT, and AK). Alterations in cognitive function were exhibited between locations and during WWT in both MT and AK (p<0.05)., Conclusions: Over the course of WWT, elite operators experienced alterations in stress, metabolic, and growth-related hormones, as well as cognitive performance. The increase in stress hormones (i.e., ACTH and cortisol) and reduction in cognitive performance following training in AK are suggestive of heightened physiological strain, despite similarities in physical workload, self-reported sleep quality, and access to nutrition. The variation in hormone levels documented between MT and AK may stem from differences in environmental factors, such as lower temperatures and harsh terrain. Further research is warranted to provide more information on the combined effects of military training in extreme environments on operator health and performance., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Abstract: Schram, B, Orr, R, Niederberger, B, Givens, A, Bernards, J, and Kelly, KR. Cardiovascular demand differences between male and female US Marine recruits during progressive loaded hikes. J Strength Cond Res 38(8): e454-e458, 2024-Despite having to carry the same occupational load, female soldiers tend to be lighter than male soldiers. The aim of this study was to determine the differences in cardiovascular load between female and male US Marine recruits during progressive load carriage hikes. United States Marine Corps recruits (565 male recruits; 364 female recruits) completed 6 loaded hikes over 6 weeks (1: 10 kg, 30 minutes; 2: 10 kg, 45 minutes; 3: 15 kg, 30 minutes, 4: 15 kg, 45 minutes; 5: 20 kg, 30 minutes; 6: 20 kg, 45 minutes) during which cardiovascular response was measured. Average heart rate (HRavg), HR maximum (HRmax), and pace were measured via a wrist-worn physiological monitor. Independent sample t -tests were conducted to compare between sexes, with significance set at 0.008 after adjusting for multiple comparisons. The average female recruit had significantly lower body mass (BM) compared with the average male recruit ( p < 0.001) and thus carried a significantly heavier relative load. (10 kg ∼17%, 15 kg ∼25%, 20 kg ∼33%, p < 0.001). There were no significant differences in pace in any hike, and no significant differences were found in HRavg or HRmax when comparing female and male Marines during Hike 1. For female Marines, HRavg was significantly higher compared with male Marines during Hike 2 (+6.5 b·min -1 , p < 0.001) and Hike 3 (+7.4 b·min -1 , p < 0.001), and both HRavg and HRmax were significantly higher in Hike 4 (+11.9 b·min -1 , +8.4 b·min -1 , p < 0.001), Hike 5 (+7.7 b·min -1 , +7.9 b·min -1 , p < 0.001), and Hike 6 (+6.9 b·min -1 , +7.1 b·min -1 , p < 0.001), respectively. Female Marines endured greater cardiovascular demand compared with male Marines during load carriage events when carrying loads greater than 15 kg (∼25% BM)., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the National Strength and Conditioning Association.)

Background: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies., Patients and Methods: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle., Results: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway., Conclusion: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations., Competing Interests: Disclosure MYK is a consultant for AbbVie, Inc., Genentech, Inc., and F. Hoffmann La-Roche; is an advisory board member for F. Hoffmann La-Roche; holds shares from Reata Pharmaceuticals; has received honoraria from Amgen, AbbVie, Inc., and Genentech, Inc.; and has received research funding from AbbVie, Inc., Genentech, Inc., Eli Lilly, Cellectis, Calithera, Stemline, Threshold, Flexus Biosciences, Novartis, Ablynx, and Agios. MD, MO, JW, WH, DD, and HH are employees of Genentech, Inc. and may hold Roche stock or stock options. NGD has received research funding from Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Inc., Astellas, Daiichi Sankyo, AbbVie, Inc., Hanmi, Trovagene, Fate Therapeutics, Amgen, Novimmune, GlycoMimetics, Trillium, Kite Pharma, Aptose, Shattuck Labs, KAHR, ArcellX, Sanofi, Sumitomo, and ImmunoGen; and has served in a consulting or advisory role for Daiichi Sankyo, Bristol-Myers Squibb, Arog Pharmaceuticals, Pfizer, Novartis, Jazz Pharmaceuticals, Celgene, AbbVie, Inc., Astellas, Genentech, Inc., Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck Labs, ArcellX, Kite Pharma, Sumitomo, Caribou Biosciences, Sanofi, Rigel, Aptose, KURA, GlycoMimetics, and Agios. JSG has received research funding (for trials) from AbbVie, Inc., Genentech, Inc., Pfizer, Prelude, and AstraZeneca; and has served on advisory boards for AbbVie, Inc., Astellas, Bristol-Myers Squibb and Servier. BAJ is a consultant/advisor for AbbVie, Inc., Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Inc., Gilead, GlycoMimetics, Jazz Pharmaceuticals, Kymera, Pfizer, Rigel, Servier, and Takeda; protocol steering committee for GlycoMimetics; data monitoring committee for Gilead; travel reimbursement/support from Rigel; and research funding to his institution from AbbVie, Inc., Amgen, Arog Pharmaceuticals, Aptose, BMS, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma Therapeutics, Forty-Seven, Genentech, Inc./Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz Pharmaceuticals, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, and Treadwell. KWLY is a consultant for Astex, Bristol-Myers Squibb/Celgene, F. Hoffmann-La Roche, Novartis, Otsuka, Paladin, Pfizer, Shattuck Labs, Taiho, and Takeda; has received honorarium from AbbVie, Inc. and Novartis; and has received research funding from Astex, Forma Therapeutics, F. Hoffmann-La Roche, Genentech, Inc., Geron, Janssen, Jazz Pharmaceuticals, MedImmune, Novartis, Onconova, and Tolero. KRK, NV, SP, AT, AP, PF, and GV declare no competing financial interests. SA reports non-financial support from Roche/Genentech, Inc. during the conduct of the study; and has received personal fees from Roche Canada, Pfizer, Bristol-Myers Squibb, Palladin, and Lundbeck outside of the submitted work. GJR consulted for AbbVie, Inc., Amgen, Argenx, AstraZeneca, Bluebird Bio, Blueprint Medicines, Bristol-Myers Squibb, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses Pharma, GlaxoSmithKline, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Novartis, Pfizer, Roche, Syndax, Takeda (IRC Chair), and Telix Pharma; and has received research funding from Janssen. DAP has received research funding from AbbVie, Inc. and has served as a consultant or advisory board member for AbbVie, Inc. and Genentech, Inc. JMB consulted for AbbVie, Inc., Bristol-Myers Squibb, Astex, Pfizer, Astellas, Taiho, and Jazz Pharmaceuticals. BLP has received research funding from Ambit Biosciences, Genentech, Inc., F. Hoffmann-La Roche, Jazz Pharmaceuticals, Novartis, Pfizer, and Cornerstone Pharmaceuticals; and is a consultant for Cornerstone Pharmaceuticals. RLO has received research support for trials from Astellas, Pfizer, Genentech, Inc., Daiichi Sankyo, and Cellectis; and consulted for AbbVie, Inc., Astellas, and Actinium. GM is a consultant for AbbVie, Inc., Celgene, Roche, Janssen, Astellas, Pfizer, and Incyte. W-JH is a former employee of Genentech, Inc. and may hold Roche stock; and is a current employee of Prelude Therapeutics. MGO is an employee of F. Hoffmann-La Roche and may hold stock or stock options. MA consulted for Amgen, AstraZeneca, Daiichi Sankyo, Syndax, GlycoMimetics, Oncoceutics, and Aptose; has received research funding from F. Hoffmann-La Roche, AstraZeneca, Amgen, Daiichi Sankyo, Jazz Pharmaceuticals, GlycoMimetics; and holds stock from Reata, Oncoceutics/Chimerix and Aptose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Understanding the cellular composition of a disease-related tissue is important in disease diagnosis, prognosis, and downstream treatment. Recent advances in single-cell RNA-sequencing (scRNA-seq) technique have allowed the measurement of gene expression profiles for individual cells. However, scRNA-seq is still too expensive to be used for large-scale population studies, and bulk RNA-seq is still widely used in such situations. An essential challenge is to deconvolve cellular composition for bulk RNA-seq data based on scRNA-seq data. Here, we present DeepDecon, a deep neural network model that leverages single-cell gene expression information to accurately predict the fraction of cancer cells in bulk tissues. It provides a refining strategy in which the cancer cell fraction is iteratively estimated by a set of trained models. When applied to simulated and real cancer data, DeepDecon exhibits superior performance compared to existing decomposition methods in terms of accuracy., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Dysfunction of the retinal pigment epithelium (RPE) is a common shared pathology in major degenerative retinal diseases despite variations in the primary etiologies of each disease. Due to their demanding and indispensable functional roles throughout the lifetime, RPE cells are vulnerable to genetic predisposition, external stress, and aging processes. Building upon recent advancements in stem cell technology for differentiating healthy RPE cells and recognizing the significant roles of small extracellular vesicles (sEV) in cellular paracrine and autocrine actions, we investigated the hypothesis that the RPE-secreted sEV alone can restore essential RPE functions and rescue photoreceptors in RPE dysfunction-driven retinal degeneration. Our findings support the rationale for developing intravitreal treatment of sEV. We demonstrate that intravitreally delivered sEV effectively penetrate the full thickness of the retina. Xenogenic intraocular administration of human-derived EVs did not induce acute immune reactions in rodents. sEV derived from human embryonic stem cell (hESC)-derived fully differentiated RPE cells, but not sEV-depleted conditioned cell culture media (CCM minus sEV), rescued photoreceptors and their function in a Royal College of Surgeons (RCS) rat model. This model is characterized by photoreceptor death and retinal degeneration resulting from a mutation in the MerTK gene in RPE cells. From the bulk RNA sequencing study, we identified 447 differently expressed genes in the retina after hESC-RPE-sEV treatment compared with the untreated control. Furthermore, 394 out of 447 genes (88%) showed a reversal in expression toward the healthy state in Long-Evans (LE) rats after treatment compared to the diseased state. Particularly, detrimental alterations in gene expression in RCS rats, including essential RPE functions such as phototransduction, vitamin A metabolism, and lipid metabolism were partially reversed. Defective photoreceptor outer segment engulfment due to intrinsic MerTK mutation was partially ameliorated. These findings suggest that RPE-secreted sEV may play a functional role similar to that of RPE cells. Our study justifies further exploration to fully unlock future therapeutic interventions with sEV in a broad array of degenerative retinal diseases.

Purpose: The purpose of this study was to assess motion-defined form perception, including the association with clinical and sensory factors that may drive performance, in each eye of children with deprivation amblyopia due to unilateral cataract., Methods: Coherence thresholds for orientation discrimination of motion-defined form were measured using a staircase procedure in 30 children with deprivation amblyopia and 59 age-matched controls. Visual acuity, stereoacuity, fusion, and interocular suppression were also measured. Fixation stability and fellow-eye global motion thresholds were measured in a subset of children., Results: Motion-defined form coherence thresholds were elevated in 90% of children with deprivation amblyopia when viewing with the amblyopic eye and in 40% when viewing with the fellow eye. The deficit was similar in children with a cataract that had been visually significant at birth (congenital) and in children for whom the cataract appeared later in infancy or childhood (developmental). Poorer motion-defined form perception in amblyopic eyes was associated with poorer visual acuity, poorer binocular function, greater interocular suppression, and the presence of nystagmus. Fellow-eye deficits were not associated with any of these factors, but a temporo-nasal asymmetry for global motion perception in favor of nasalward motion suggested a general disruption in motion perception., Conclusions: Deficits in motion-defined form perception are common in children with deprivation amblyopia and may reflect a problem in motion processing that relies on binocular mechanisms.

Purpose: Isolating extracellular vesicles (EVs) with high yield, replicable purity, and characterization remains a bottleneck in the development of EV therapeutics. To address these challenges, the current study aims to establish the necessary framework for preclinical and clinical studies in the development of stem cell-derived intraocular EV therapeutics., Methods: Small EVs (sEVs) were separated from the conditioned cell culture medium (CCM) of the human embryogenic stem cell-derived fully polarized retinal pigment epithelium (hESC-RPE-sEV) by a commercially available microfluidic tangential flow filtration (TFF) device ExoDisc (ED) or differential ultracentrifugation (dUC). The scaling and concentration capabilities and purity of recovered sEVs were assessed. Size, number, and surface markers of sEVs were determined by orthogonal approaches using multiple devices., Results: ED yielded higher numbers of sEVs, ranging from three to eight times higher depending on the measurement device, compared to dUC using the same 5 mL of CCM input. Within the same setting, the purity of ED-recovered hESC-RPE-sEVs was higher than that for dUC-recovered sEVs. ED yielded a higher concentration of particles, which is strongly correlated with the input volume, up to 10 mL (r = 0.98, P = 0.016). Meanwhile, comprehensive characterization profiles of EV surface markers between ED- and dUC-recovered hESC-RPE-sEVs were compatible., Conclusions: Our study supports TFF as a valuable strategy for separating sEVs for the development of intraocular EV therapeutics. However, there is a growing need for diverse devices to optimize TFF for use in EV preparation. Using orthogonal approaches in EV characterization remains ideal for reliably characterizing heterogeneous EV.

Background: During periods of high-volume vigorous exercise, United States Marine Corps recruits often experience musculoskeletal injuries. While the program of instruction (POI) for basic training is a defined training volume, the total workload of boot camp, including movements around the base, is unknown., Objective: The present study aimed to quantify the daily total workload, energy expenditure, and sleep during basic recruit training at Marine Corps Recruit Depot (MCRD) San Diego., Methods: Eighty-four male recruits from MCRD San Diego wore wrist wearable physiological monitors to capture their complete workload (mileage from steps), energy expenditure, and sleep throughout the 10-week boot camp., Results: Marine recruits traveled an average of 11.5±3.4 miles per day (M±SD), expended 4105±823 kcal per day, and slept an average of 5 : 48±1 : 06 hours and minutes per night. While the POI designates a total of 46.3 miles of running and hiking, the actual daily average miles yielded approximately 657.6±107.2 miles over the 10-week boot camp., Conclusion: Recruit training requires high physical demand and time under tension due to the cumulative volume of movements around base in addition to the POI planned physical training.

The functional distinction between vision-for-perception and vision-for-action is a key aspect of understanding the primate visual system. While this dissociation has been well-established in adulthood, its development and dependence on typical visual experience remain unclear. To address these questions, we examined two groups of children: typically developed children and those with amblyopia, who presumably have a sub-optimal visual experience. The Ponzo illusion, known to impact perception but not visuomotor behaviors across age groups, was employed to assess the extent of dissociation. Participants engaged in two tasks involving the Ponzo illusion: a grasping task (vision-for-action) and a manual estimation task (vision-for-perception), with objects placed on the "close" and "far" surfaces of the illusion. Typically developed children displayed grasping movements that were unaffected by the illusion, as their grasping apertures were scaled based on object size, independent of its location. In contrast, children with amblyopia exhibited a clear susceptibility to the illusion, showing larger apertures for objects placed on the 'far' surface of the illusion, and smaller apertures for objects placed on the 'close' surface. Interestingly, both groups of children demonstrated similar susceptibility to the illusion during the perceptual task, with objects placed on the far surface being perceived as longer compared to objects placed on the close surface. These findings shed light on the impact of atypical visual development on the emergence of the dissociation between perception and action, highlighting the crucial role of typical visual experience in establishing this distinction., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Purpose: Our preclinical studies showed that the oncolytic reovirus formulation pelareorep (PELA) has significant immunomodulatory anti-myeloma activity. We conducted an investigator-initiated clinical trial to evaluate PELA in combination with dexamethasone (Dex) and bortezomib (BZ) and define the tumor immune microenvironment (TiME) in patients with multiple myeloma treated with this regimen., Patients and Methods: Patients with relapsed/refractory multiple myeloma (n = 14) were enrolled in a phase Ib clinical trial (ClinicalTrials.gov: NCT02514382) of three escalating PELA doses administered on Days 1, 2, 8, 9, 15, and 16. Patients received 40 mg Dex and 1.5 mg/m2 BZ on Days 1, 8, and 15. Cycles were repeated every 28 days. Pre- and posttreatment bone marrow specimens (IHC, n = 9; imaging mass cytometry, n = 6) and peripheral blood samples were collected for analysis (flow cytometry, n = 5; T-cell receptor clonality, n = 7; cytokine assay, n = 7)., Results: PELA/BZ/Dex was well-tolerated in all patients. Treatment-emergent toxicities were transient, and no dose-limiting toxicities occurred. Six (55%) of 11 response-evaluable patients showed decreased paraprotein. Treatment increased T and natural killer cell activation, inflammatory cytokine release, and programmed death-ligand 1 expression in bone marrow. Compared with nonresponders, responders had higher reovirus protein levels, increased cytotoxic T-cell infiltration posttreatment, cytotoxic T cells in significantly closer proximity to multiple myeloma cells, and larger populations of a novel immune-primed multiple myeloma phenotype (CD138+ IDO1+HLA-ABCHigh), indicating immunomodulation., Conclusions: PELA/BZ/Dex is well-tolerated and associated with anti-multiple myeloma activity in a subset of responding patients, characterized by immune reprogramming and TiME changes, warranting further investigation of PELA as an immunomodulator., (©2023 The Authors; Published by the American Association for Cancer Research.)

Wearables are lightweight, portable technology devices that are traditionally used to monitor physical activity and workload as well as basic physiological parameters such as heart rate. However recent advances in monitors have enabled better algorithms for estimation of caloric expenditure from heart rate for use in weight loss as well as sport performance. can be used for estimating energy expenditure and nutritional demand. Recently, the military has adopted the use of personal wearables for utilization in field studies for ecological validity of training. With popularity of use, the need for validation of these devices for caloric estimates is needed to assist in work-rest cycles. Thus the purpose of this effort was to evaluate the Polar Grit X for energy expenditure (EE) for use in military training exercises. Polar Grit X Pro watches were worn by active-duty elite male operators ( N = 16; age: 31.7 ± 5.0 years, height: 180.1 ± 6.2 cm, weight: 91.7 ± 9.4 kg). Metrics were measured against indirect calorimetry of a metabolic cart and heart rate via a Polar heart rate monitor chest strap while exercising on a treadmill. Participants each performed five 10-minute bouts of running at a self-selected speed and incline to maintain a heart rate within one of five heart rate zones, as ordered and defined by Polar. Polar Grit X Pro watch had a good to excellent interrater reliability to indirect calorimetry at estimating energy expenditure (ICC = 0.8, 95% CI = 0.61-0.89, F (74,17.3) = 11.76, p < 0.0001) and a fair to good interrater reliability in estimating macronutrient partitioning (ICC = 0.49, 95% CI = 0.3-0.65, F (74,74.54) = 2.98, p < 0.0001). There is a strong relationship between energy expenditure as estimated from the Polar Grit X Pro and measured through indirect calorimetry. The Polar Grit X Pro watch is a suitable tool for estimating energy expenditure in free-living participants in a field setting and at a range of exercise intensities., (© Journal of Sports Science and Medicine.)

Introduction: Little data exist on the effect of extremely cold-water diving on thermo-metabolic hormone secretion. Moreover, the impact of repetitive dives on the stress response is unknown. The purpose of this study was to determine the effects of two daily bouts of cold-water diving on the hormonal and metabolic profile of elite military personnel and to measure the stress response., Methods: Healthy, male, Norwegian Special Forces operators (n = 5) volunteered for this study. Physiological and hormone data were analyzed prior to and following twice-daily Arctic dives (3.3°C)., Results: Core temperature was maintained (p > .05), whereas skin temperature was significantly reduced over the course of each dive (p < .01). Pairwise comparisons revealed adrenocorticotropic hormone (ACTH) and cortisol concentration significantly decreased across both dives and days (p < .001). Adrenaline and noradrenaline significantly increased across both time and day (p < .001). Leptin, testosterone, and IGF-1 significantly decreased over time but recovered between days., Conclusion: The main findings of this effort are that there is a rapid sympathetic-adreno-medullary (SAM/SNS) response to cold-water diving and a suppression of the hypothalamic-pituitary-adrenal (HPA) axis and hormones related to repair and recovery. While the sample size was too small to determine the role of SAM/SNS, HPA, and thyroid hormone effect on thermoregulation, it addresses a gap in our understanding of physiological adaptions that occurs in extreme environments., (2023.)

Poor control of intermittent exotropia may be used as an indication for surgery. However, control fluctuates during the day and from day to day. The standardized triple office control score (mean of three scores on a 6-point ordinal scale) is representative of repeated assessments throughout the day, but lacks validation against an objective measure of eye movements. We report the agreement between the triple office control score measured by the referring eyecare professional and lab-measured vergence instability using an EyeLink video eye tracker. Near and distance triple office control scores were moderately correlated with vergence instability. Near, but not distance, triple office control score was moderately correlated with the percentage of time intermittent exotropia was manifest during EyeLink recording. Larger triple office control scores for intermittent exotropia provide a meaningful description of larger vergence instability, supporting its use in clinical decisions and as a measure in clinical trials., (Copyright © 2023 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Contrast-rebalanced dichoptic games and videos have been shown to be an effective treatment for childhood amblyopia. Whether the visual acuity gains achieved with these binocular treatments are long-lasting has not been determined. In this prospective cohort study of 100 consecutive amblyopic children who improved by ≥0.2 logMAR or obtained ≤0.2 logMAR amblyopic eye visual acuity during a binocular treatment clinical trial, risk of recurrence was 24% (95% CI, 16%-35%) at up to 3 years' follow-up according to Kaplan-Meier survival analysis, which accounts for censored, truncated, and missing data. Risk of recurrence was similar among children who required additional treatment for residual amblyopia after 4-8 weeks of dichoptic treatment (n = 62 [19%]; 95% CI, 10%-34%) and those who did not (n = 38 [32%]; 95% CI, 18%-52%; P = 0.12). There was no association between recurrence and age, visual acuity at the end of binocular treatment, stereoacuity, or ocular alignment. In a secondary analysis to compare rates of recurrence with published data, risk of recurrence in the subset of children who had no additional treatment for residual amblyopia (28%) was similar to the reported recurrence after cessation of successful patching and atropine (24%) at 12 months. Children with successful binocular treatment of amblyopia require monitoring for recurrence of amblyopia., (Copyright © 2023 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Abstract: Jensen, AE, Bernards, JR, Hamilton, JA, Markwald, RR, Kelly, KR, and Biggs, AT. Do not shoot me: potential consequences of force-on-force training modulate the human stress response. J Strength Cond Res 37(9): 1761-1769, 2023-Close-quarters combat (CQC) engagements trigger the "fight-or-flight" response, activating the sympathetic nervous system and hypothalamic-pituitary-adrenal axis in response to perceived threats. However, it has yet to be shown if a force-on-force (FoF) CQC training environment will lead to adaptations in the physiological stress response or performance. United States Marines and Army infantry personnel participated in a 15-day CQC training program. The CQC program focused heavily on FoF training with the use of nonlethal training ammunition (NLTA). Data collections occurred on training days 1 and 15, during a simulated FoF-hostage rescue (HR) scenario and photorealistic target drill. For the FoF-HR, subjects were instructed to clear the shoot house, rescue the hostage, and only shoot hostile threat(s) with NLTA. The photorealistic target drills were similar, but replaced the role players in the FoF-HR with paper targets. Salivary alpha-amylase (sAA) and salivary cortisol were obtained immediately before entering and exiting the shoot house. Time to completion significantly decreased, between days 1 and 15, for both the FoF-HR and the photorealistic drills by 67.7 and 54.4%, respectively ( p < 0.05). Analyses revealed that the change in sAA, nonsignificantly, doubled from day 1 to 15 during FoF-HR ( p > 0.05), whereas the change in sAA decreased during the photorealistic drills across days ( p < 0.05). Cortisol was significantly higher during the FoF-HR in comparison to the photorealistic drills ( p < 0.05). These data suggest that potential consequences of FoF training heighten the stress response in conjunction with enhanced performance., (Copyright © 2023 National Strength and Conditioning Association.)

Purpose: To evaluate a closed-cell wet-suit for thermal protective capability during extreme cold water exposure at various depths. Methods: Thirteen (n = 13) elite military divers who were tasked with cold-water training, participated in this study. To mimic various depths, the Ocean Simulation Facility (OSF) at the Navy Experimental Diving Unit (NEDU) was pressurized to simulate dive depths of 30, 50, and 75fsw. Water temperature remained at 1.8-2.0°C for all dives. Four divers dove each day and used the MK16 underwater breathing apparatus with gas mixes of either N202 (79:21) or HeO2 (88:12). Mean skin temperature (T SK ) (Ramanathan, 1964), core temperature (Tc), hand and foot readings were obtained every 30 min for 30 and 50fsw and every 15 min during the 75fsw dive. Results: T C was significantly reduced across all dives ( p = 0.004); however, was preserved above the threshold for hypothermia (post dive Tc = 36.5 ± 0.4). There was no effect of gas mix on T C . T SK significantly decreased ( p < 0.001) across all dives independent of depth and gas. Hand and foot temperatures resulted in the termination of three of the dives. There were no significant main effects for depth or gas, but there were significant main effects for time on hand temperature ( p < 0.001) and foot temperature ( p < 0.001). Conclusion: Core temperature is maintained above threshold for hypothermia. Variatioins in T C and T SK are a function of dive duration independent of depth or gas for a closed-cell wet-suit in cold water at various depths. However, both hand and foot temperatures reached values at which dexterity is compromised., Competing Interests: Authors LP, AJ, and JB were employed by the Leidos, Inc. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (At least a portion of this work is authored by Karen R. Kelly on behalf of the U.S. Government and as regards Dr. Kelly and the U.S. Government, is not subject to copyright protection in the United States. Foreign and other copyrights may apply.)

Basic training is centered on developing the physical and tactical skills essential to train a recruit into a Marine. The abrupt increase in activity and energy expenditure in young recruits may contribute to high rates of musculoskeletal injuries, to which females are more susceptible. To date, the total workload of United State Marine Corps (USMC) bootcamp is unknown and should include movement around the military base (e.g., to and from dining facilities, training locations, and classrooms). Thus, the purpose of this effort was to quantify workload and caloric expenditure, as well as qualitatively assess the impact of female reproductive health and injury rates in female recruits. Female recruits (n = 79; age: 19.1 ± 0.2 years, weight: 59.6 ± 0.8 kg, height: 161.6 ± 0.7 cm) wore physiological monitors daily throughout 10 weeks of USMC bootcamp. Physical fitness test scores, physiological metrics from wearables, injury data, and menstrual cycle information were obtained. Female recruits on average expended 3096 ± 9 kcal per day, walked 11.0 ± 0.1 miles per day, and slept 5:43 ± 1:06 h:min per night throughout the 10 weeks of bootcamp. About one-third (35%) of female recruits sustained an injury. In a subset of females that were not taking birth control and had previously been menstruating, 85% experienced cycle dysfunction during boot camp. High levels of physical activity and caloric expenditure, coupled with the stress of a new environment and insufficient sleep, may lead to alterations in female reproductive cycles and musculoskeletal injuries in young USMC recruits.

This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1 to 5 in 28-day cycles, followed by dosing schedule optimization (n = 6) to evaluate reduced venetoclax schedules (21-/14-day dosing). Common adverse events (occurring in ≥40% of patients) included diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). During DE, across all doses, composite complete remission (CRc; CR + CR with incomplete blood count recovery + CR with incomplete platelet count recovery) rate was 26.0% and morphologic leukemia-free state (MLFS) rate was 12%. For anticipated recommended phase 2 doses (venetoclax 600 mg + idasanutlin 150 mg; venetoclax 600 mg + idasanutlin 200 mg), the combined CRc rate was 34.3% and the MLFS rate was 14.3%. Pretreatment IDH1/2 and RUNX1 mutations were associated with higher CRc rates (50.0% and 45.0%, respectively). CRc rate in patients with TP53 mutations was 20.0%, with responses noted among those with co-occurring IDH and RUNX1 mutations. In 12 out of 36 evaluable patients, 25 emergent TP53 mutations were observed; 22 were present at baseline with low TP53 variant allele frequency (median 0.0095% [range, 0.0006-0.4]). Venetoclax-idasanutlin showed manageable safety and encouraging efficacy in unfit patients with R/R AML. IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were preexisting. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations. This trial was registered at www.clinicaltrials.gov as #NCT02670044., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Significance: Amblyopic children read 25% slower than their peers during binocular silent reading., Purpose: We compared binocular reading to fellow eye reading to determine whether slow reading in amblyopic children is due to binocular inhibition; that is, the amblyopic eye is interfering during binocular reading., Methods: In a cross-sectional study, 38 children with amblyopia and 36 age-similar control children who completed grades 1 to 6 were enrolled. Children silently read grade-appropriate paragraphs during binocular reading and fellow eye reading while wearing ReadAlyzer eye-tracking goggles (Compevo AB, Stockholm, Sweden). Reading rate, number of forward saccades, number of regressive saccades, and fixation duration were analyzed between groups and between viewing conditions. We also examined whether sensory factors (amblyopia severity, stereoacuity, suppression) were related to slow reading., Results: For amblyopic children, binocular reading versus fellow eye reading did not differ for reading rate (176 ± 60 vs. 173 ± 53 words per minute, P = .69), number of forward saccades (104 ± 35 vs. 97 ± 33 saccades/100 words, P = .18), number of regressive saccades (21 ± 15 vs. 22 ± 13 saccades/100 words, P = .75), or fixation duration (0.31 ± 0.06 vs. 0.32 ± 0.07 seconds, P = .44). As expected, amblyopic children had a slower reading rate and more forward saccades than control children during binocular reading and fellow eye reading. Slow reading was not related to any sensory factors., Conclusions: Binocular reading did not differ from fellow eye reading in amblyopic children. Thus, binocular inhibition is unlikely to play a role in slow binocular reading and is instead a fellow eye deficit that emerges from a disruption in binocular visual experience during development., Competing Interests: Conflict of Interest Disclosure: None of the authors have reported a financial conflict of interest., (Copyright © 2023 American Academy of Optometry.)