Association of p60c-src with endosomal membranes in mammalian fibroblasts.

We have examined the subcellular localization of p60c-src in mammalian fibroblasts. Analysis of indirect immunofluorescence by three-dimensional optical sectioning microscopy revealed a granular cytoplasmic staining that co-localized with the microtubule organizing center. Immunofluorescence experiments with antibodies against a number of membrane markers demonstrated a striking co-localization between p60c-src and the cation-dependent mannose-6-phosphate receptor (CI-MPR), a marker that identifies endosomes. Both p60c-src and the CI-MPR were found to cluster at the spindle poles throughout mitosis. In addition, treatment of interphase and mitotic cells with brefeldin A resulted in a clustering of p60c-src and CI-MPR at a peri-centriolar position. Biochemical fractionation of cellular membranes showed that a major proportion of p60c-src co-enriched with endocytic membranes. Treatment of membranes containing HRP to alter their apparent density also altered the density of p60c-src-containing membranes. Similar density shift experiments with total cellular membranes revealed that the majority of membrane-associated p60c-src in the cell is associated with endosomes, while very little is associated with plasma membranes. These results support a role for p60c-src in the regulation of endosomal membranes and protein trafficking

Uptake of the multi-arm multi-stage (MAMS) adaptive platform approach: a trial-registry review of late-phase randomised clinical trials

BACKGROUND: For medical conditions with numerous interventions worthy of investigation, there are many advantages of a multi-arm multi-stage (MAMS) platform trial approach. However, there is currently limited knowledge on uptake of the MAMS design, especially in the late-phase setting. We sought to examine uptake and characteristics of late-phase MAMS platform trials, to enable better planning for teams considering future use of this approach. DESIGN: We examined uptake of registered, late-phase MAMS platforms in the EU clinical trials register, Australian New Zealand Clinical Trials Registry, International Standard Randomised Controlled Trial Number registry, Pan African Clinical Trials Registry, WHO International Clinical Trial Registry Platform and databases: PubMed, Medline, Cochrane Library, Global Health Library and EMBASE. Searching was performed and review data frozen on 1 April 2021. MAMS platforms were defined as requiring two or more comparison arms, with two or more trial stages, with an interim analysis allowing for stopping of recruitment to arms and typically the ability to add new intervention arms. RESULTS: 62 late-phase clinical trials using an MAMS approach were included. Overall, the number of late-phase trials using the MAMS design has been increasing since 2001 and been accelerated by COVID-19. The majority of current MAMS platforms were either targeting infectious diseases (52%) or cancers (29%) and all identified trials were for treatment interventions. 89% (55/62) of MAMS platforms were evaluating medications, with 45% (28/62) of the MAMS platforms having at least one or more repurposed medication as a comparison arm. CONCLUSIONS: Historically, late-phase trials have adhered to long-established standard (two-arm) designs. However, the number of late-phase MAMS platform trials is increasing, across a range of different disease areas. This study highlights the potential scope of MAMS platform trials and may assist research teams considering use of this approach in the late-phase randomised clinical trial setting. PROSPERO REGISTRATION NUMBER: CRD42019153910

Parametric hazard rate models for long-term sickness absence

PURPOSE: In research on the time to onset of sickness absence and the duration of sickness absence episodes, Cox proportional hazard models are in common use. However, parametric models are to be preferred when time in itself is considered as independent variable. This study compares parametric hazard rate models for the onset of long-term sickness absence and return to work. METHOD: Prospective cohort study on sickness absence with four follow-up years of 53,830 employees working in the private sector in the Netherlands. The time to onset of long-term (>6 weeks) sickness absence and return to work were modelled by parametric hazard rate models. RESULTS: The exponential parametric model with a constant hazard rate most accurately described the time to onset of long-term sickness absence. Gompertz-Makeham models with monotonically declining hazard rates best described return to work. CONCLUSIONS: Parametric models offer more possibilities than commonly used models for time-dependent processes as sickness absence and return to work. However, the advantages of parametric models above Cox models apply mainly for return to work and less for onset of long-term sickness absence

Characterization and Comparison of 2 Distinct Epidemic Community-Associated Methicillin-Resistant Staphylococcus aureus Clones of ST59 Lineage.

Sequence type (ST) 59 is an epidemic lineage of community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) isolates. Taiwanese CA-MRSA isolates belong to ST59 and can be grouped into 2 distinct clones, a virulent Taiwan clone and a commensal Asian-Pacific clone. The Taiwan clone carries the Panton-Valentine leukocidin (PVL) genes and the staphylococcal chromosomal cassette mec (SCCmec) VT, and is frequently isolated from patients with severe disease. The Asian-Pacific clone is PVL-negative, carries SCCmec IV, and a frequent colonizer of healthy children. Isolates of both clones were characterized by their ability to adhere to respiratory A549 cells, cytotoxicity to human neutrophils, and nasal colonization of a murine and murine sepsis models. Genome variation was determined by polymerase chain reaction of selected virulence factors and by multi-strain whole genome microarray. Additionally, the expression of selected factors was compared between the 2 clones. The Taiwan clone showed a much higher cytotoxicity to the human neutrophils and caused more severe septic infections with a high mortality rate in the murine model. The clones were indistinguishable in their adhesion to A549 cells and persistence of murine nasal colonization. The microarray data revealed that the Taiwan clone had lost the ø3-prophage that integrates into the β-hemolysin gene and includes staphylokinase- and enterotoxin P-encoding genes, but had retained the genes for human immune evasion, scn and chps. Production of the virulence factors did not differ significantly in the 2 clonal groups, although more α-toxin was expressed in Taiwan clone isolates from pneumonia patients. In conclusion, the Taiwan CA-MRSA clone was distinguished by enhanced virulence in both humans and an animal infection model. The evolutionary acquisition of PVL, the higher expression of α-toxin, and possibly the loss of a large portion of the β-hemolysin-converting prophage likely contribute to its higher pathogenic potential than the Asian-Pacific clone

Dynamics of multi-stage infections on networks

This paper investigates the dynamics of infectious diseases with a nonexponentially distributed infectious period. This is achieved by considering a multistage infection model on networks. Using pairwise approximation with a standard closure, a number of important characteristics of disease dynamics are derived analytically, including the final size of an epidemic and a threshold for epidemic outbreaks, and it is shown how these quantities depend on disease characteristics, as well as the number of disease stages. Stochastic simulations of dynamics on networks are performed and compared to output of pairwise models for several realistic examples of infectious diseases to illustrate the role played by the number of stages in the disease dynamics. These results show that a higher number of disease stages results in faster epidemic outbreaks with a higher peak prevalence and a larger final size of the epidemic. The agreement between the pairwise and simulation models is excellent in the cases we consider

Gender differences in the association between self-rated health and hypertension in a Korean adult population

<p>Abstract</p> <p>Background</p> <p>Self-rated health (SRH) has been reported as a predictor of mortality in previous studies. This study aimed to examine whether SRH is independently associated with hypertension and if there is a gender difference in this association.</p> <p>Methods</p> <p>16,956 community dwelling adults aged 20 and over within a defined geographic area participated in this study. Data on SRH, socio-demographic factors (age, gender, marital status, education) and health behaviors (smoking status, alcohol consumption, physical activity) were collected. Body mass index and blood pressure were measured. Logistic regression models were used to determine a relationship between SRH and hypertension.</p> <p>Results</p> <p>32.5% of the participants were found to have hypertension. Women were more likely than men to rate their SRH as poor (<it>p </it>< 0.001), and the older age groups rated their SRH more negatively in both men and women (<it>p </it>< 0.001). While the multivariate-adjusted odds ratio (OR, 95% CI) of participants rating their SRH as very poor for hypertension in men was OR 1.70 (1.13-2.58), that in women was OR 2.83 (1.80-4.44). Interaction between SRH and gender was significant (<it>p </it>< 0.001).</p> <p>Conclusions</p> <p>SRH was independently associated with hypertension in a Korean adult population. This association was modified by gender.</p

Exploratory Case‐Control Analysis of Psychosocial Factors and Adult Periodontitis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141163/1/jper1060.pd

Chromogranin A, a significant prognostic factor in small cell lung cancer

Chromogranin A (CgA) is a protein present in neuroendocrine vesicles. Small cell lung cancer (SCLC) is considered a neuroendocrine tumour. It is possible to demonstrate CgA expression in SCLC by immunohistochemical methods. Since CgA is released to the circulation it might also work as a clinical tumour marker. We used a newly developed two-site enzyme-linked immunosorbent assay for CgA in plasma from 150 newly diagnosed patients with SCLC. Follow-up was for a minimum of 5 years. Thirty-seven per cent of the patients had elevated pretreatment values and the values were significantly related to stage of disease. Multivariable analysis by Cox's proportional hazard model including nine known prognostic factors disclosed performance status as the most influential prognostic factor followed by stage of disease, CgA and LDH. A simple prognostic index (PI) could be established based on these four pretreatment features. In this way the patients could be separated into three groups with significant different prognosis. The median survival and 95% confidence intervals for the three groups were as follows: 424 days (311–537), 360 days (261–459) and 174 days (105–243). © 1999 Cancer Research Campaig

Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial.

PURPOSE: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.CRU