Proteomic analysis of meiosis and characterization of novel short open reading frames in the fission yeast Schizosaccharomyces pombe.

Meiosis is the process by which haploid gametes are produced from diploid precursor cells. We used stable isotope labeling by amino acids in cell culture (SILAC) to characterize the meiotic proteome in the fission yeast Schizosaccharomyces pombe. We compared relative levels of proteins extracted from cells harvested around meiosis I with those of meiosis II, and proteins from premeiotic S phase with the interval between meiotic divisions, when S phase is absent. Our proteome datasets revealed peptides corresponding to short open reading frames (sORFs) that have been previously identified by ribosome profiling as new translated regions. We verified expression of selected sORFs by Western blotting and analyzed the phenotype of deletion mutants. Our data provide a resource for studying meiosis that may help understand differences between meiosis I and meiosis II and how S phase is suppressed between the two meiotic divisions

Pulmonary nodules in African migrants caused by chronic schistosomiasis

Schistosomiasis is a neglected tropical disease that can cause mainly hepatic and genitourinary damage, depending on the species. Involvement of the lungs has been commonly described in acute infection (Katayama syndrome) and chronic infection (pulmonary hypertension). Although rarely reported in the scientific literature, cases of lung nodules due to chronic schistosome infection are also possible and are probably more frequent than commonly thought. Here we report seven cases of African migrants who were diagnosed with chronic schistosomiasis and pulmonary nodules due to deposition of schistosome eggs, and we compare our findings to the case reports found in the scientific literature. We discuss the management of these patients in a non-endemic setting, beginning with a first fundamental step that is to include parasitic infections, namely schistosomiasis, in the differential diagnosis of pulmonary nodules in African immigrants. All patients responded to antiparasitic treatment with praziquantel after a relatively short time. We therefore conclude that lung biopsies and other invasive procedures (performed in the first cases to rule out other potential causes, such as tuberculosis or malignant nodules) can be avoided or postponed

KarMMa-7, a Phase 1/2, Dose-Finding and Dose-Expansion Study of Combination Therapies with Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy for Relapsed/Refractory Multiple Myeloma (RRMM)

Abstract Background Patients (pts) with RRMM previously exposed to immunomodulatory agents, proteasome inhibitors (PIs), and anti-CD38 antibodies were reported to have poor outcomes with subsequent therapy, and deep and durable responses were uncommon (Chari et al. N Engl J Med 2019, Lonial et al. Lancet Oncol 2019, Richardson et al. J Clin Oncol 2020). This highlighted the need for treatments capable of improving responses for such pts. Ide-cel, a BCMA-directed CAR T cell therapy, showed a favorable safety profile and frequent, deep, durable responses in heavily pretreated pts with RRMM (Raje et al. N Engl J Med 2019, Munshi et al. N Engl J Med 2021), and was approved in the US for pts with ≥ 4 prior lines of therapy including an immunomodulatory agent, a PI, and an anti-CD38 antibody. Long-term results from the pivotal phase 2 KarMMa study showed ide-cel induced an overall response rate (ORR) of 73% (33% complete response [CR] rate) with a median duration of response (DOR) of 10.9 months; median overall survival (OS) was 24.8 months (Anderson et al. ASCO 2021 Poster 8016). Combining ide-cel with other agents may enhance efficacy, resulting in long-term clinical benefits for pts. Agents in development include iberdomide (CC-220), an oral, potent novel cereblon E3 ligase modulator (CELMoD ®) compound with direct tumoricidal and immune-stimulatory effects that has shown promising activity in heavily pretreated pts (van de Donk et al. ASH 2020 Abstract 724), and BMS-986405, a gamma secretase inhibitor that blocks shedding of surface BCMA to enhance antitumor activity of BCMA-directed CAR+ T cells (Cowan et al. ASH 2019 Abstract 204). Standard treatments for RRMM include daratumumab + pomalidomide + dexamethasone (DPd)andpomalidomide + bortezomib + low-dose dexamethasone (PVd). This dose-finding safety and efficacy study will assess ide-cel in combination with these agents in pts with RRMM. Methods KarMMa-7 (NCT04855136) is an exploratory, open-label, multicenter, phase 1/2 study. Eligible pts are ≥ 18 years with measurable MM, who have received either ≥ 3 or 1-3 prior regimens depending on treatment arm/cohort (Figure). Pts must have achieved at least a minimal response to a prior treatment, have disease progression during, or within 6 months of completing, their last treatment, and have an ECOG performance status of 0 or 1. Enrollment is up to approximately 415 pts. The study consists of two parts: dose finding for combination agents (phase 1) and dose expansion at the recommended phase 2 dose (RP2D) determined in phase 1 (phase 2). Pts are enrolled into 3 treatment arms (non-randomized allocation; Figure): arm A, ide-cel + iberdomide (± dexamethasone), in cohorts 1 and 2 (per pt population), as maintenance therapy (subcohort a), or as both concurrent and maintenance therapy (subcohorts b and c; schedules differ); arm B, ide-cel + BMS-986405 as concurrent therapy; arm C, ide-cel + DPdor PVd as maintenance therapy. Following leukapheresis, bridging therapy may be administered subject to restrictions. Lymphodepletion with fludarabine (30 mg/m 2/day) and cyclosphosphamide (300 mg/m 2/day) occurs for 3 consecutive days followed by 2 rest days before ide-cel infusion. Ide-cel target dose is 450 x 10 6 (± 20%) CAR+ T cells for all study arms. Combination agents are prespecified to be administered before, concurrently with, and/or following ide-cel infusion. Primary objectives include evaluation of safety (dose-limiting toxicity rate), RP2D determination, schedule optimization for combination agents administered with ide-cel (phase 1), and assessment of efficacy (CR rate) of combination regimens (phase 2). Secondary objectives are additional safety (adverse events) and efficacy (ORR, progression-free survival [PFS], OS, time to response, DOR, time to next treatment, PFS after next therapy) parameters, feasibility of maintenance therapy, and characterizing pharmacokinetics of ide-cel. At the end of phase 1, interim analysis will be performed to determine the RP2D. The primary analysis for efficacy and safety will be in phase 2 when all pts have a minimum follow-up of 15 months. Pts will be followed for a maximum of 2 years after the last pt receives first combination agent, or after the last pt receives any study treatment, in the respective cohorts, whichever occurs later. Recruitment began in June 2021 and is ongoing in the United States and Spain. Study support bluebird bio and Celgene, a Bristol-Myers Squibb Company Figure 1 Figure 1. Disclosures Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Berdeja: Poseida, Sanofi, Teva: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; Lilly, Novartis: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; Abbvie, Acetylon, Amgen: Research Funding; EMD Sorono, Genentech: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Clínica Universidad de Navarra: Current Employment; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Jagannath: Bristol Myers Squibb: Consultancy; Janssen Pharmaceuticals: Consultancy; Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Lonial: Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria; Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Gipson: Bristol Myers Squibb: Current Employment. Caia: Bristol Myers Squibb: Current Employment. Martin: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Yang: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company. Pittari: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Mateos: Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Oncopeptides: Honoraria; AbbVie: Honoraria; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Neither iberdomide nor BMS-986405 are approved, and all combinations of agents with ide-cel are off-label. These drugs and combinations of drugs are being investigated for treatment of relapsed/refractory multiple myeloma. </jats:sec

A Longitudinal Multiinstitutional Study of Vulvar Lichen Sclerosus: From Childhood to Perimenopause

objective: the main outcome of this study was the evaluation of clinical characteristics, comorbidities, and therapeutic approaches in patients with vulvar lichen sclerosus (VLS) aged from childhood to perimenopause. secondly, it was intended to compare these characteristics according to the menarchal status. methods: patients less than 45 years of age with a diagnosis of VLS from January 2002 to June 2022 in 10 referral centers were included in this retrospective longitudinal study. the univariate analysis compared the dependent variables according to menarchal status. results: one hundred eighty-six patients met the inclusion criteria. at diagnosis, between 25% and 40% of premenarchal patients reported signs related to subepithelial hemorrhage. a significantly greater presence of bleeding (p &lt; .005), easy bruising (p = .028), fissures (p = .008), petechiae/splinter hemorrhages (p &lt; .001), and bleeding/blistering or open sores (p = .011) was observed in premenarchal patients with respect to the postmenarchal group. the perineum (p = .013) and the perianal region (p &lt; .001) were significantly more involved in the premenarchal group. topical calcineurin inhibitors were more used in the premenarchal population (p = .004), whereas vitamin e oil and moisturizers were more used in the postmenarchal population (p = .047). conclusions: vulvar lichen sclerosus is a chronic condition that can cause vulvar changes that result in severe morbidity and affects sexual function and quality of life, even before menopause. vulvar lichen sclerosus continues to be misdiagnosed in this population. this may lead to an average delay from symptom onset to diagnosis. evaluating clinical manifestations of VLS in premenarchal and postmenarchal age allowed us to find different clinical characteristics between the 2 periods suggestive of the diagnosis