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Genomic structural variants (SVs) greatly impact human health, but much is unknown about the mechanisms that generate the largest class of nonrecurrent alterations. Common fragile sites (CFSs) are unstable loci that provide a model for SV formation, especially large deletions, under replication stress. We study SV junction formation as it occurs in human cell lines by applying error-minimized capture sequencing to CFS DNA harvested after low-dose aphidicolin treatment. SV junctions form throughout CFS genes at a 5-fold higher rate after cells pass from G2 into M-phase. Neither SV formation nor CFS expression depend on mitotic DNA synthesis (MiDAS), an error-prone form of replication active at CFSs. Instead, analysis of tens of thousands of de novo SV junctions combined with DNA repair pathway inhibition reveal a primary role for DNA polymerase theta (POLQ)-mediated end-joining (TMEJ). We propose an important role for mitotic TMEJ in nonrecurrent SV formation genome wide. The mechanisms of nonrecurrent structural variant (SV) formation are poorly understood. Here, the authors sequenced thousands of SV junctions as they formed at common fragile sites in human cell lines to reveal a primary role for DNA polymerase theta-mediated end joining activated during mitosis.

Cancer related cognitive impairments have been subjectively reported and objectively detected in breast cancer patients treated with chemotherapy and are known to have a profound negative impact on productivity, psychosocial well-being and overall quality of life. Moderate levels of walking are known to be of benefit to the psychosocial well-being of those affected by breast cancer and for managing cognitive impairment in healthy adults, children, and the elderly. The purpose of this study is to investigate the effects of a home-based, self-managed, moderate intensity walking intervention on subjective and objective cognitive functioning in breast cancer patients undergoing chemotherapy. A home-based, self-managed intervention that consisted of moderate levels of walking was compared to usual care among breast cancer patients treated with chemotherapy in a randomised controlled trial. Outcome measures included changes in subjective (CFQ) and objectively detected cognitive functioning (Stroop, SART and two subscales from the WAIS- Digit Span and Block Design). Fifty participants were randomised to either the intervention group (n = 25), who completed 12 weeks of moderate intensity walking, or to the control group (n = 25) mid-way through chemotherapy. Compared with the control group, the self-managed walking intervention had positive effects on perceived cognitive function but not on sustained attention, executive function, memory or visual spatial skills when assessed objectively using neuropsychological measures. This home-based, self-managed intervention is beneficial for protecting against perceived cognitive decline in breast cancer patients treated with chemotherapy. There is a need for further research to objectively assess cognitive decline within this population with larger sample sizes of patients. Current Controlled Trials ISRCTN50709297.

Alice in Wonderland syndrome (AIWS) is a rare neurological disorder characterized by perceptual distortions, including alterations in body image perception and time perception. This case report presents a 94-year-old female patient who exhibited visual and auditory hallucinations, including macropsia (perception of objects as larger than their actual size), suggestive of AIWS, following an ischemic stroke. Despite initial suspicions of AIWS, imaging revealed chronic infarcts in the posterior right parietal lobe and the left occipital lobe, suggesting a stroke etiology. Management focused on symptomatic treatment with quetiapine, which effectively alleviated visual and auditory hallucinations, paranoia, and psychosis. This case explores the importance of thorough diagnostic evaluation to distinguish between post-stroke hallucinations versus those associated with AIWS. Additionally, it highlights the need for further research to expand on the mechanisms and optimal management strategies for AIWS, particularly in the context of stroke and other neurological conditions.

BackgroundCheckMate 817, a phase 3B study, evaluated flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic non-small cell lung cancer (NSCLC). Here, in this research, we report on first-line treatment in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 (cohort A) and special populations (cohort A1: ECOG PS 2; or ECOG PS 0–1 with untreated brain metastases, renal impairment, hepatic impairment, or controlled HIV infection).MethodsCohorts A and A1 received nivolumab 240 mg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary endpoint was the incidence of grade 3–4 and grade 5 immune-mediated adverse events (IMAEs; adverse events (AEs) deemed potentially immune-related, occurring <100 days of last dose, and treated with immune-modulating medication (except endocrine events)) and treatment-related select AEs (treatment-related AEs with potential immunological etiology requiring frequent monitoring/intervention, reported between first dose and 30 days after the last dose) in cohort A; efficacy endpoints were secondary/exploratory. In cohort A1, safety/efficacy assessment was exploratory.ResultsThe most common grade 3–4 IMAEs were pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%) in cohort A (N=391) and diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%) in cohort A1 (N=198). The most common grade 3–4 treatment-related select AEs were hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events in cohort A and gastrointestinal (4.0%), skin (3.5%), and endocrine (3.0%) events in cohort A1. No grade 5 IMAEs or treatment-related select AEs occurred. Treatment-related deaths occurred in 4 (1.0%) and 3 (1.5%) patients in cohorts A and A1, respectively. Three-year overall survival (OS) rates were 33.7% and 20.5%, respectively.ConclusionsFlat-dose nivolumab plus weight-based ipilimumab was associated with manageable safety and durable efficacy in cohort A, consistent with data from phase 3 metastatic NSCLC studies. Special populations of cohort A1 including patients with ECOG PS 2 or ECOG PS 0–1 with untreated brain metastases had manageable treatment-related toxicity and clinically meaningful 3-year OS rate.Trial registration numberNCT02869789.

Introduction: Sarcoidosis is a T-helper cell mediated disease characterized by granulomatous inflammation. We posited that unsupervised clustering of various features in sarcoidosis would establish phenotypes associated with inflammatory activity measured by 18FDG-PET/CT. Our goal was to identify unique features capable of distinguishing clusters and subsequently examine the relationship with FDG avidity to substantiate their potential use as markers for sarcoidosis inflammation. Methods: We performed a retrospective study of a diverse, but primarily African American, cohort of 58 subjects with biopsy proven sarcoidosis followed at the University of Illinois Bernie Mac Sarcoidosis Center and Center for Lung Health who underwent 18FDG-PET/CT scan. Demographic, therapeutic, radiographic, and laboratory data were utilized in unsupervised cluster analysis to identify sarcoidosis phenotypes. The association between clusters, their defining features, and quantitative measurements on 18FDG-PET/CT was determined. The relevance of these features as markers of 18FDG-PET/CT inflammatory activity was also investigated. Results: Clustering determined three distinct phenotypes: (1) a predominantly African American cluster with chronic, quiescent disease, (2) a predominantly African American cluster with elevated conventional inflammatory markers, advanced pulmonary disease and extrathoracic involvement, and (3) a predominantly Caucasian cluster characterized by reduced lymphocyte counts and acute disease. In contrast to the chronic quiescent cluster, Clusters 2 and 3 were defined by significantly greater FDG avidity on 18FDG-PET/CT. Despite similarly increased inflammatory activity on 18FDG-PET/CT, Clusters 2, and 3 differed with regards to extrathoracic FDG avidity and circulating lymphocyte profiles, specifically CD4+ T-cells. Notably, absolute lymphocyte counts and CD4+ T-cell counts were found to predict 18FDG-PET/CT inflammatory activity by receiver operating curve analysis with a 69.2 and 73.42% area under the curve, respectively. Conclusions: Utilizing cluster analysis, three distinct phenotypes of sarcoidosis were identified with significant variation in race, disease chronicity, and serologic markers of inflammation. These phenotypes displayed varying levels of circulating inflammatory cells. Additionally, reduction in lymphocytes, specifically CD4+ T-cells, was significantly related to activity on 18FDG-PET/CT. Though future studies are warranted, these findings suggest that peripheral lymphocyte counts may be considered a determinant of sarcoidosis phenotypes and an indicator of active inflammation on 18FDG-PET/CT.

Fine-needle aspiration (FNA) aids in the diagnosis of thyroid nodules. The expression of previously implicated genes was examined to potentially discriminate between benign and malignant thyroid samples. Patients included for study had cytology demonstrating follicular cells of undetermined significance, atypical cells of undetermined significance, follicular neoplasm, or suspicion of malignancy with one of the following postoperative diagnoses: follicular thyroid adenomas, follicular thyroid carcinomas, or follicular variant of papillary thyroid carcinomas (FV-PTCs). FNA and tumor expression of human telomerase reverse transcriptase (hTERT), high-mobility group A2 (HMGA2), and trefoil factor 3/3-galactoside-binding lectin (T/G ratio) were analyzed. T/G ratios were not significantly different in the malignant and benign groups. HMGA2 was overexpressed in carcinoma states; however, only FV-PTCs were significant (P = .006). Tumor hTERT expression was detected in 25% of follicular thyroid carcinomas, whereas 5% of FV-PTCs and 10% of follicular thyroid adenomas had expression. FNA aspirates showed similar results. Although HMGA2 and hTERT showed differential expression, they did not consistently differentiate benign from malignant. Further study based on global gene expression is needed to identify markers that could serve as a diagnostic tool.

ObjectivesTo evaluate the demographic and comorbid risk factors for cerebrovascular disease (CVD) hospitalization in patients with retinal artery occlusion (RAO) and study the impact on hospitalization outcomes.MethodsWe conducted a retrospective cross-sectional study using the Nationwide Inpatient Sample (NIS, 2019). We included 62,255 adults (age 18-65 years) with the primary diagnosis of CVD. The study sample was divided by the co-diagnosis of RAO (N=1,700). A logistic regression model was used to evaluate the odds ratio (OR) of association for risk factors leading to CVD hospitalization in patients with RAO, with the non-RAO cohort as the reference category.ResultsThe majority of the CVD patients with RAO were elderly (51-65 years, 68%), females (54%), and whites (47%). Yet, demographics did not significantly impact the association with CVD hospitalization between RAO and non-RAO patients. There was a significant difference in the geographic distribution of CVD hospitalizations with RAO, with the highest prevalence in the East North Central Atlantic (21%) and South Atlantic (18%) regions, and the lowest in the Mountain (4%) and East South Central (4%) regions. Comorbid diabetes with complications (69%), and complicated hypertension (55%) were most prevalent in patients with RAO thereby increasing the risk for CVD hospitalization by 7.8 (95% CI 6.9-8.8) and 1.8 times (95% CI 1.6-1.9), respectively. Patients with RAO and having major severity of illness were at increased risk of CVD hospitalization (OR 2.8, 95% CI 1.9-3.9). Patients with RAO had a significant difference in adverse disposition, including transfer to the skilled nursing facility (SNF)/intermediate care facility (ICF) (32% vs. 24%) and requiring home health care (16% vs. 11%) compared to non-RAO patients.ConclusionThe prevalence of RAO in CVD hospitalization was 2.7%, and demographics did not have any impact on the increasing risk of CVD. Comorbid diabetes (by 685%) and hypertension (by 78%) potentially increase the risk of CVD hospitalization in patients with RAO. These patients have a major severity of illness, leading to an adverse disposition. This calls for a collaborative care model to improve the quality of life in these at-risk patients with RAO.

This study aims to investigate the factors affecting on English speech of undergraduate students at the SMIU, Karachi. The study prospects two aspects as outcomes of the study, one to discover what are the major issues and hindrances and another one to find their solutions for developing techniques and skills to gain confidence while speaking English as a second language in ESL classroom and in public. It will further investigate as how to help develop a wonderful speech free from speech anxiety. The study administered Likert Scale as a tool for data collection. Forty participating students were recruited from the department of Computer Science, Sindh Madressatul Islam University, Karachi. Speech anxiety is a common phenomenon amongst the students in the second language classrooms. Second language i.e., English, however, has become the lingua franca of the world. It is no longer the language of only native Britishers and Americans, rather, it is a widely spoken language by most people living in every nook & corner of the world. This study investigates as to how ESL learners turn out as nervous speakers while speaking English. Findings of the study suggest that speech anxiety seems to be an unavoidable phenomenon for ESL learners as the data reveal. In addition, this study is associated with the previous studies that there is a moderate level of Foreign Language Speech Anxiety (FLSA) amongst the Pakistani English speakers. Since English is taught from the primary level and every literate person almost understands and speaks English. Pakistani English language speakers should speak without speech anxiety, though it seems to be a part of human nature being nervous while speaking English as a second language. The students should learn how to manage speech anxiety by welcoming it and try to overcome it not by mindless imitation but by being natural in English speech.

This study investigated the Trk receptor family as a therapeutic target in pancreatic ductal adenocarcinoma and assessed their prognostic significance. Global gene expression analysis was investigated in prospectively collected pancreatic ductal adenocarcinomas that had either undergone neoadjuvant chemoradiation or were treated by surgery. PANC-1 and MIA-PaCa-2 cell lines were investigated to establish whether fractionated radiation altered expression of four neuroendocrine genes and whether this resulted in subsequent changes in radiosensitivity. A specific inhibitor of TrkA, B, and C, AstraZeneca 1332, was investigated in vitro and in vivo in combination with radiation. A tissue microarray was constructed from 77 pancreatic ductal adenocarcinoma patients who had undergone neoadjuvant chemoradiation and the Trk receptor, and neurogenic differentiation 1 expression was assessed and correlated with overall survival. A total of 99 genes were identified that were differentially expressed in the chemoradiation patients with neuroendocrine genes and pathways, in particular the neurogenic differentiation 1 and Trk receptor family, being prominent. Fractionated radiation upregulated the expression of neuroendocrine genes, and AstraZeneca 1332 treatment in vitro enhanced radiosensitivity. No added effect of AstraZeneca 1332 was observed in vivo. Trk receptor expression varied between isoforms but did not correlate significantly with clinical outcome. Radiation treatment upregulated neuroendocrine gene expression but the Trk receptor family does not appear to be a promising treatment target.

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with -mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with -mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).