A cardiac rehabilitation program for breast cancer survivors: A feasibility study

Purpose: The purpose of this study was to determine the feasibility and preliminary efficacy of a cardiac rehabilitation (CR) intervention in the breast cancer population. Methods: This single-arm feasibility study evaluated a 14-week CR intervention program in breast cancer survivors. Feasibility was defined as completion of at least 30/36 sessions of the program without serious adverse events (SAE) in 80% of patients. Secondary endpoints included the change in VO2 max, cardiovascular disease (CVD) risk factors, Duke Activity Secondary Index (DASI), Brief Fatigue Inventory (BFI), and QLQ-C30. All outcomes were reported as mean change and compared using paired Results: A total of 25 patients were enrolled in the study. 18 patients of the 25 enrolled (72%) completed the 14 weeks program without SAE. The overall adherence to the study protocol was 60%. Of the 18 participants who did not withdraw from the program, 15 (83%) adhered to the study protocol and completed 30 or more sessions. There was a nonsignificant improvement in VO2 max (mean Δ0.5, Conclusion: A CR intervention in breast cancer survivors had high adherence in those who were able to complete the 14-week program. The program significantly improved patient reported physical activity, fatigue, and quality of life (QoL), without significant improvement in CVD risk factors. Implications for cancer patients are that early implementation of a CR program should be considered by practitioners as it improves QoL and exercise tolerance in breast cancer survivors

Whole-Genome SNP Association in the Horse: Identification of a Deletion in Myosin Va Responsible for Lavender Foal Syndrome

Lavender Foal Syndrome (LFS) is a lethal inherited disease of horses with a suspected autosomal recessive mode of inheritance. LFS has been primarily diagnosed in a subgroup of the Arabian breed, the Egyptian Arabian horse. The condition is characterized by multiple neurological abnormalities and a dilute coat color. Candidate genes based on comparative phenotypes in mice and humans include the ras-associated protein RAB27a (RAB27A) and myosin Va (MYO5A). Here we report mapping of the locus responsible for LFS using a small set of 36 horses segregating for LFS. These horses were genotyped using a newly available single nucleotide polymorphism (SNP) chip containing 56,402 discriminatory elements. The whole genome scan identified an associated region containing these two functional candidate genes. Exon sequencing of the MYO5A gene from an affected foal revealed a single base deletion in exon 30 that changes the reading frame and introduces a premature stop codon. A PCR–based Restriction Fragment Length Polymorphism (PCR–RFLP) assay was designed and used to investigate the frequency of the mutant gene. All affected horses tested were homozygous for this mutation. Heterozygous carriers were detected in high frequency in families segregating for this trait, and the frequency of carriers in unrelated Egyptian Arabians was 10.3%. The mapping and discovery of the LFS mutation represents the first successful use of whole-genome SNP scanning in the horse for any trait. The RFLP assay can be used to assist breeders in avoiding carrier-to-carrier matings and thus in preventing the birth of affected foals

Ethnic and Racial Differences in Self-reported Symptoms, Health Status, Activity Level, and Missed Work at 3 and 6 Months Following SARS-CoV-2 Infection

INTRODUCTION: Data on ethnic and racial differences in symptoms and health-related impacts following SARS-CoV-2 infection are limited. We aimed to estimate the ethnic and racial differences in symptoms and health-related impacts 3 and 6 months after the first SARS-CoV-2 infection. METHODS: Participants included adults with SARS-CoV-2 infection enrolled in a prospective multicenter US study between 12/11/2020 and 7/4/2022 as the primary cohort of interest, as well as a SARS-CoV-2-negative cohort to account for non-SARS-CoV-2-infection impacts, who completed enrollment and 3-month surveys ( RESULTS: Following SARS-CoV-2 infection, the majority of symptoms were similar over time between ethnic and racial groups. At 3 months, Hispanic participants were more likely than non-Hispanic participants to report fair/poor health (OR: 1.94; 95%CI: 1.36-2.78) and reduced activity (somewhat less, OR: 1.47; 95%CI: 1.06-2.02; much less, OR: 2.23; 95%CI: 1.38-3.61). At 6 months, differences by ethnicity were not present. At 3 months, Other/Multiple race participants were more likely than white participants to report fair/poor health (OR: 1.90; 95% CI: 1.25-2.88), reduced activity (somewhat less, OR: 1.72; 95%CI: 1.21-2.46; much less, OR: 2.08; 95%CI: 1.18-3.65). At 6 months, Asian participants were more likely than white participants to report fair/poor health (OR: 1.88; 95%CI: 1.13-3.12); Black participants reported more missed work (OR, 2.83; 95%CI: 1.60-5.00); and Other/Multiple race participants reported more fair/poor health (OR: 1.83; 95%CI: 1.10-3.05), reduced activity (somewhat less, OR: 1.60; 95%CI: 1.02-2.51; much less, OR: 2.49; 95%CI: 1.40-4.44), and more missed work (OR: 2.25; 95%CI: 1.27-3.98). DISCUSSION: Awareness of ethnic and racial differences in outcomes following SARS-CoV-2 infection may inform clinical and public health efforts to advance health equity in long-term outcomes

Ultrapotent Broadly Neutralizing Human-llama Bispecific Antibodies against HIV-1

Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV‐1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion‐stabilized HIV‐1 envelope (Env) trimer, BG505 DS‐SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4‐binding site (CD4bs) of vulnerability. Two of the vaccine‐elicited CD4bs‐targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a‐hinge region and human IgG1‐constant region (G36×3‐IgG2a and R27×3‐IgG2a), neutralized 96% of a multiclade 208‐strain panel at geometric mean IC80s of 0.314 and 0.033 µg mL−1, respectively. Cryo‐EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV‐1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2‐apex‐targeting broadly neutralizing antibody, CAP256V2LS. The resultant human‐llama bispecific antibody CAP256L‐R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV‐1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn‐Fc mice similar to the parent CAP256V2LS. Vaccine‐elicited llama nanobodies, when combined with V2‐apex broadly neutralizing antibodies, may therefore be able to fulfill anti‐HIV‐1 therapeutic and prophylactic clinical goals

Characterization and intracellular localization of putative Chlamydia pneumoniae effector proteins

We here describe four proteins of Chlamydia pneumoniae, which might play a role in host-pathogen interaction. The hypothetical bacterial proteins CPn0708 and CPn0712 were detected in Chlamydia pneumoniae-infected host cells by indirect immunofluorescence tests with polyclonal antisera raised against the respective proteins. While CPn0708 was localized within the inclusion body, CPn0712 was identified in the inclusion membrane and in the surrounding host cell cytosol. CPn0712 colocalizes with actin, indicating its possible interaction with components of the cytoskeleton. Investigations on CPn0809 and CPn1020, two Chlamydia pneumoniae proteins previously described to be secreted into the host cell cytosol, revealed colocalization with calnexin, a marker for the ER. Neither CPn0712, CPn0809 nor CPn1020 were able to inhibit host cell apoptosis. Furthermore, transient expression of CPn0712, CPn0809 and CPn1020 by the host cell itself had no effect on subsequent infection with Chlamydia pneumoniae. However, microarray analysis of CPn0712-expressing host cells revealed six host cell genes which were regulated as in host cells infected with Chlamydia pneumoniae, indicating the principal usefulness of heterologous expression to study the effect of Chlamydia pneumoniae proteins on host cell modulation

The VLA/ALMA Nascent Disk and Multiplicity (VANDAM) Survey of Orion Protostars. I. Identifying and Characterizing the Protostellar Content of the OMC-2 FIR4 and OMC-2 FIR3 Regions

We present ALMA (0.87~mm) and VLA (9~mm) observations toward OMC2-FIR4 and OMC2-FIR3 within the Orion integral-shaped filament that are thought to be the nearest regions of intermediate mass star formation. We characterize the continuum sources within these regions on $\sim$40~AU (0\farcs1) scales and associated molecular line emission at a factor of $\sim$30 better resolution than previous observations at similar wavelengths. We identify six compact continuum sources within OMC2-FIR4, four in OMC2-FIR3, and one additional source just outside OMC2-FIR4. This continuum emission is tracing the inner envelope and/or disk emission on less than 100~AU scales. HOPS-108 is the only protostar in OMC2-FIR4 that exhibits emission from high-excitation transitions of complex organic molecules (e.g., methanol and other lines) coincident with the continuum emission. HOPS-370 in OMC2-FIR3 with L~$\sim$~360~\lsun, also exhibits emission from high-excitation methanol and other lines. The methanol emission toward these two protostars is indicative of temperatures high enough to thermally evaporate methanol from icy dust grains; overall these protostars have characteristics similar to hot corinos. We do not identify a clear outflow from HOPS-108 in \twco, but find evidence of interaction between the outflow/jet from HOPS-370 and the OMC2-FIR4 region. The multitude of observational constraints indicate that HOPS-108 is likely a low to intermediate-mass protostar in its main mass accretion phase and it is the most luminous protostar in OMC2-FIR4. The high resolution data presented here are essential for disentangling the embedded protostars from their surrounding dusty environments and characterizing them

The impact of regular physical activity on fatigue, depression and quality of life in persons with multiple sclerosis

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to compare fatigue, depression and quality of life scores in persons with multiple sclerosis who do (Exercisers) and do not (Non-exercisers) regularly participate in physical activity.</p> <p>Methods</p> <p>A cross-sectional questionnaire study of 121 patients with MS (age 25–65 yr) living in Queensland, Australia was conducted. Physical activity level, depression, fatigue and quality of life were assessed using the International Physical Activity Questionnaire, Health Status Questionnaire Short Form 36, Becks Depression Inventory and Modified Fatigue Impact Scale.</p> <p>Results</p> <p>52 participants performed at least two 30-min exercise sessions·wk^-1(Exercisers) and 69 did not participate in regular physical activity (Non-exercisers). Exercisers reported favourable fatigue, depression and quality of life scores when compared to Non-exercisers. Significant weak correlations were found between both leisure-time and overall reported physical activity levels and some subscales of the quality of life and fatigue questionnaires. Additionally, some quality of life subscale scores indicated that regular physical activity had a greater benefit in subjects with moderate MS.</p> <p>Conclusion</p> <p>Favourable fatigue, depression and quality of life scores were reported by persons with MS who regularly participated in physical activity, when compared to persons with MS who were classified as Non-exercisers.</p

The clinical significance of inflammatory cytokines in primary cell culture in endometrial carcinoma

Endometrial cancer is the most common malignancy of the female genital tract, and the incidence and mortality rates from this disease are increasing. Although endometrial carcinoma has been regarded as a tissue‐specific disease mediated by female sex steroid pathways, considerable evidence implicates a role for an inflammatory response in the development and propagation of endometrial cancer. We hypothesized that if specific patterns of cytokine expression were found to be predictive of adverse outcome, then selective receptor targeting may be a therapeutic option. This study was therefore undertaken to determine the relationship between cytokine production in primary cell culture and clinical outcome in endometrial adenocarcinoma. Fresh endometrial tissues were fractionated into epithelial and stromal fractions and cultured. After 6–7 days, supernatants were collected and cells enumerated. Batched aliquots were assayed using ELISA kits specific for CSF‐1, GMCSF, G‐CSF, TNF‐α, IL‐6, IL‐8, and VEGF. Data were compared using ANOVA, Fisher's exact, and log rank tests. Increased epithelial VEGF production was observed more often in tumors with Type 2 variants (p = 0.039) and when GPR30 receptor expression was high (p = 0.038). Although increased stromal VEGF production was detected more often in grade 3 endometrioid tumors (p = 0.050), when EGFR expression was high (p = 0.003), and/or when ER/PR expression was low (p = 0.048), VEGF production did not correlated with overall survival (OS). Increased epithelial CSF‐1 and TNF‐α production, respectively, were observed more often in tumors with deep myometrial invasion (p = 0.014) and advanced stage (p = 0.018). Increased CSF‐1 (89.5% vs. 42.9%, p = 0.032), TNF‐α (88.9% vs. 42.9%, p = 0.032, and IL‐6 (92.3% vs. 61.5%, p = 0.052) also correlated with low OS. In Cox multivariate models, CSF‐1 was an independent predictor of low survival when stratified by grade (p = 0.046) and histology (p = 0.050), and TNF‐α, when stratified by histology (p = 0.037). In this study, high CSF‐1, TNF‐α, and IL‐6 production rates identified patients at greatest risk for death, and may signify patients likely to benefit from receptor‐specific therapy

LIM and SH3 Protein -1 Modulates CXCR2-Mediated Cell Migration

BACKGROUND: The chemokine receptor CXCR2 plays a pivotal role in migration of neutrophils, macrophages and endothelial cells, modulating several biological responses such as angiogenesis, wound healing and acute inflammation. CXCR2 is also involved in pathogenesis of chronic inflammation, sepsis and atherosclerosis. The ability of CXCR2 to associate with a variety of proteins dynamically is responsible for its effects on directed cell migration or chemotaxis. The dynamic network of such CXCR2 binding proteins is termed as "CXCR2 chemosynapse". Proteomic analysis of proteins that co-immunoprecipitated with CXCR2 in neutrophil-like dHL-60 cells revealed a novel protein, LIM and SH3 protein 1 (LASP-1), binds CXCR2 under both basal and ligand activated conditions. LASP-1 is an actin binding cytoskeletal protein, involved in the cell migration. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that CXCR2 and LASP-1 co-immunoprecipitate and co-localize at the leading edge of migrating cells. The LIM domain of LASP-1 directly binds to the carboxy-terminal domain (CTD) of CXCR2. Moreover, LASP-1 also directly binds the CTD of CXCR1, CXCR3 and CXCR4. Using a site-directed and deletion mutagenesis approach, Iso323-Leu324 of the conserved LKIL motif on CXCR2-CTD was identified as the binding site for LASP-1. Interruption of the interaction between CXCR2-CTD and LIM domain of LASP-1 by dominant negative and knock down approaches inhibited CXCR2-mediated chemotaxis. Analysis for the mechanism for inhibition of CXCR2-mediated chemotaxis indicated that LASP-1/CXCR2 interaction is essential for cell motility and focal adhesion turnover involving activation of Src, paxillin, PAK1, p130CAS and ERK1/2. CONCLUSIONS/SIGNIFICANCE: We demonstrate here for the first time that LASP-1 is a key component of the "CXCR2 chemosynapse" and LASP-1 interaction with CXCR2 is critical for CXCR2-mediated chemotaxis. Furthermore, LASP-1 also directly binds the CTD of CXCR1, CXCR3 and CXCR4, suggesting that LASP-1 is a general mediator of CXC chemokine mediated chemotaxis. Thus, LASP-1 may serve as a new link coordinating the flow of information between chemokine receptors and nascent focal adhesions, especially at the leading edge. Thus the association between the chemokine receptors and LASP-1 suggests to the presence of a CXC chemokine receptor-LASP-1 pro-migratory module in cells governing the cell migration