Infection pre-Ad26.COV2.S-vaccination primes greater class switching and reduced CXCR5 expression by SARS-CoV-2-specific memory B cells

Neutralizing antibodies strongly correlate with protection for COVID-19 vaccines, but the corresponding memory B cells that form to protect against future infection are relatively understudied. Here we examine the effect of prior SARS-CoV-2 infection on the magnitude and phenotype of the memory B cell response to single dose Johnson and Johnson (Ad26.COV2.S) vaccination in South African health care workers. Participants were either naïve to SARS-CoV-2 or had been infected before vaccination. SARS-CoV-2-specific memory B-cells expand in response to Ad26.COV2.S and are maintained for the study duration (84 days) in all individuals. However, prior infection is associated with a greater frequency of these cells, a significant reduction in expression of the germinal center chemokine receptor CXCR5, and increased class switching. These B cell features correlated with neutralization and antibody-dependent cytotoxicity (ADCC) activity, and with the frequency of SARS-CoV-2 specific circulating T follicular helper cells (cTfh). Vaccination-induced effective neutralization of the D614G variant in both infected and naïve participants but boosted neutralizing antibodies against the Beta and Omicron variants only in participants with prior infection. In addition, the SARS-CoV-2 specific CD8+ T cell response correlated with increased memory B cell expression of the lung-homing receptor CXCR3, which was sustained in the previously infected group. Finally, although vaccination achieved equivalent B cell activation regardless of infection history, it was negatively impacted by age. These data show that phenotyping the response to vaccination can provide insight into the impact of prior infection on memory B cell homing, CSM, cTfh, and neutralization activity. These data can provide early signals to inform studies of vaccine boosting, durability, and co-morbidities

Methods of induction of labour: a systematic review

<p>Abstract</p> <p>Background</p> <p>Rates of labour induction are increasing. We conducted this systematic review to assess the evidence supporting use of each method of labour induction.</p> <p>Methods</p> <p>We listed methods of labour induction then reviewed the evidence supporting each. We searched MEDLINE and the Cochrane Library between 1980 and November 2010 using multiple terms and combinations, including labor, induced/or induction of labor, prostaglandin or prostaglandins, misoprostol, Cytotec, 16,16,-dimethylprostaglandin E2 or E2, dinoprostone; Prepidil, Cervidil, Dinoprost, Carboprost or hemabate; prostin, oxytocin, misoprostol, membrane sweeping or membrane stripping, amniotomy, balloon catheter or Foley catheter, hygroscopic dilators, laminaria, dilapan, saline injection, nipple stimulation, intercourse, acupuncture, castor oil, herbs. We performed a best evidence review of the literature supporting each method. We identified 2048 abstracts and reviewed 283 full text articles. We preferentially included high quality systematic reviews or large randomised trials. Where no such studies existed, we included the best evidence available from smaller randomised or quasi-randomised trials.</p> <p>Results</p> <p>We included 46 full text articles. We assigned a quality rating to each included article and a strength of evidence rating to each body of literature. Prostaglandin E2 (PGE2) and vaginal misoprostol were more effective than oxytocin in bringing about vaginal delivery within 24 hours but were associated with more uterine hyperstimulation. Mechanical methods reduced uterine hyperstimulation compared with PGE2 and misoprostol, but increased maternal and neonatal infectious morbidity compared with other methods. Membrane sweeping reduced post-term gestations. Most included studies were too small to evaluate risk for rare adverse outcomes.</p> <p>Conclusions</p> <p>Research is needed to determine benefits and harms of many induction methods.</p

Physician career satisfaction within specialties

<p>Abstract</p> <p>Background</p> <p>Specialty-specific data on career satisfaction may be useful for understanding physician workforce trends and for counseling medical students about career options.</p> <p>Methods</p> <p>We analyzed cross-sectional data from 6,590 physicians (response rate, 53%) in Round 4 (2004-2005) of the Community Tracking Study Physician Survey. The dependent variable ranged from +1 to -1 and measured satisfaction and dissatisfaction with career. Forty-two specialties were analyzed with survey-adjusted linear regressions</p> <p>Results</p> <p>After adjusting for physician, practice, and community characteristics, the following specialties had significantly higher satisfaction levels than family medicine: pediatric emergency medicine (regression coefficient = 0.349); geriatric medicine (0.323); other pediatric subspecialties (0.270); neonatal/prenatal medicine (0.266); internal medicine and pediatrics (combined practice) (0.250); pediatrics (0.250); dermatology (0.249);and child and adolescent psychiatry (0.203). The following specialties had significantly lower satisfaction levels than family medicine: neurological surgery (-0.707); pulmonary critical care medicine (-0.273); nephrology (-0.206); and obstetrics and gynecology (-0.188). We also found satisfaction was significantly and positively related to income and employment in a medical school but negatively associated with more than 50 work-hours per-week, being a full-owner of the practice, greater reliance on managed care revenue, and uncontrollable lifestyle. We observed no statistically significant gender differences and no differences between African-Americans and whites.</p> <p>Conclusion</p> <p>Career satisfaction varied across specialties. A number of stakeholders will likely be interested in these findings including physicians in specialties that rank high and low and students contemplating specialty. Our findings regarding "less satisfied" specialties should elicit concern from residency directors and policy makers since they appear to be in critical areas of medicine.</p

The molecular diversity of Luminal A breast tumors

Breast cancer is a collection of diseases with distinct molecular traits, prognosis, and therapeutic options. Luminal A breast cancer is the most heterogeneous, both molecularly and clinically. Using genomic data from over 1,000 Luminal A tumors from multiple studies, we analyzed the copy number and mutational landscape of this tumor subtype. This integrated analysis revealed four major subtypes defined by distinct copy-number and mutation profiles. We identified an atypical Luminal A subtype characterized by high genomic instability, TP53 mutations, and increased Aurora kinase signaling; these genomic alterations lead to a worse clinical prognosis. Aberrations of chromosomes 1, 8, and 16, together with PIK3CA, GATA3, AKT1, and MAP3K1 mutations drive the other subtypes. Finally, an unbiased pathway analysis revealed multiple rare, but mutually exclusive, alterations linked to loss of activity of co-repressor complexes N-Cor and SMRT. These rare alterations were the most prevalent in Luminal A tumors and may predict resistance to endocrine therapy. Our work provides for a further molecular stratification of Luminal A breast tumors, with potential direct clinical implications. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10549-013-2699-3) contains supplementary material, which is available to authorized users

Isatin-benzoazine molecular hybrids as potential antiproliferative agents: synthesis and in vitro pharmacological profiling

Hatem A Abdel-Aziz,1 Wagdy M Eldehna,2 Adam B Keeton,3 Gary A Piazza,3 Adnan A Kadi,4 Mohamed W Attwa,4 Ali S Abdelhameed,4 Mohamed I Attia4,5 1Department of Applied Organic Chemistry, National Research Centre, Giza, 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt; 3Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA; 4Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 5Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Giza, Egypt Abstract: In continuation of our endeavor with respect to the development of potent and effective isatin-based anticancer agents, we adopted the molecular hybridization approach to design and synthesize four different sets of isatin-quinazoline (6a&ndash;f and 7a&ndash;e)/phthalazine (8a&ndash;f)/quinoxaline (9a&ndash;f) hybrids. The antiproliferative activity of the target hybrids was assessed towards HT-29 (colon), ZR-75 (breast) and A-549 (lung) human cancer cell lines. Hybrids 8b&ndash;d emerged as the most active antiproliferative congener in this study. Compound 8c induced apoptosis via increasing caspase 3/7 activity by about 5-fold in the A-549 human cancer cell line. In addition, it exhibited an increase in the G1 phase and a decrease in the S and G2/M phases in the cell cycle effect assay. Furthermore, it displayed an inhibitory concentration 50% value of 9.5 &micro;M against multidrug-resistant NCI-H69AR lung cancer cell line. The hybrid 8c was also subjected to in vitro metabolic investigations through its incubation with rat liver microsomes and analysis of the resulting metabolites with the aid of liquid chromatography-mass spectrometry. Keywords: isatins, hybridization approach, antiproliferative, apoptosi

Inhibition of the Lysophosphatidylinositol Transporter ABCC1 Reduces Prostate Cancer Cell Growth and Sensitizes to Chemotherapy

Expression of ATP-binding cassette (ABC) transporters has long been implicated in cancer chemotherapy resistance. Increased expression of the ABCC subfamily transporters has been reported in prostate cancer, especially in androgen-resistant cases. ABCC transporters are known to efflux drugs but, recently, we have demonstrated that they can also have a more direct role in cancer progression. The pharmacological potential of targeting ABCC1, however, remained to be assessed. In this study, we investigated whether the blockade of ABCC1 affects prostate cancer cell proliferation using both in vitro and in vivo models. Our data demonstrate that pharmacological inhibition of ABCC1 reduced prostate cancer cell growth in vitro and potentiated the effects of Docetaxel in vitro and in mouse models of prostate cancer in vivo. Collectively, these data identify ABCC1 as a novel and promising target in prostate cancer therapy