Notes

Patterns involving transfusion stress within an unselected human population associated with sufferers using myelodysplastic syndromes: A new population-based examine.
Goodpasture's syndrome is a rare vasculitis associated with anti-glomerular basement membrane (anti-GBM) autoantibodies that target type IV collagen found in the basement membranes of glomeruli and alveoli. We present a case of a 79-year-old man with seronegative Goodpasture's syndrome with predominant respiratory symptoms and mild acute kidney injury that initially improved. Final diagnosis was made by immunofluorescent staining on open lung biopsy which also revealed concomitant organising pneumonia. GSK2636771 mouse The patient underwent treatment with corticosteroids, cyclophosphamide, haemodialysis and plasmapheresis. This was an atypical presentation wherein the patient only exhibited pulmonary symptoms early in the course of illness in the setting of negative anti-GBM antibody serum testing, which made diagnosis challenging. With this case, we emphasise that clinicians should have a high suspicion for Goodpasture's syndrome in the setting of unexplained severe pulmonary or renal disease despite negative anti-GBM antibody testing.Tuberculosis (TB), a significant cause of morbidity and mortality worldwide, is particularly relevant in low/middle-income countries like India, where the disease is endemic. The female reproductive system is very vulnerable to this infection with, the clinical presentation being utterly silent in most patients. Symptoms of TB in pregnancy may initially be attributed to the gravidity itself besides temporary concealment of associated weight loss by the normally occurring weight gain during the pregnancy. Untreated TB may cause pregnancy loss by either placental damage or direct harm to both the mother and child. We report a case of latent disseminated TB in a young immunocompetent female that was revealed in the postpartum state (after full-term stillbirth delivery at home) as 20 ileal perforations secondary to intestinal TB. Due to ongoing sepsis and delayed presentation to the hospital, the patient could not be salvaged despite the best possible efforts.Glandular odontogenic cyst (GOC) is a very rare jaw cyst accounting for 0.2% of all odontogenic cysts. It presents usually in adults with a slight male predominance. It shows radiological, histopathological and even immunohistochemical overlap with low grade intraosseous mucoepidermoid carcinoma (MEC) but their distinction is crucial. A 57-year-old woman with bilocular radiolucency in the anterior mandible crossing the midline is described here. Microscopy features were consistent with glandular odontogenic cyst but multiple MEC-like islands were seen in the capsule, creating a diagnostic head trip with low grade intraosseous MEC. However, the absence of cellular atypia and epidermoid and intermediate cells led to a final diagnosis of GOC, with close follow-up of the patient recommended. This rare finding shows the relation between GOC and MEC or the origin of MEC from GOC.Cancer evolution determines molecular and morphologic intratumor heterogeneity and challenges the design of effective treatments. In lung adenocarcinoma, disease progression and prognosis are associated with the appearance of morphologically diverse tumor regions, termed histologic patterns. However, the link between molecular and histologic features remains elusive. Here, we generated multiomics and spatially resolved molecular profiles of histologic patterns from primary lung adenocarcinoma, which we integrated with molecular data from >2,000 patients. The transition from indolent to aggressive patterns was not driven by genetic alterations but by epigenetic and transcriptional reprogramming reshaping cancer cell identity. A signature quantifying this transition was an independent predictor of patient prognosis in multiple human cohorts. Within individual tumors, highly multiplexed protein spatial profiling revealed coexistence of immune desert, inflamed, and excluded regions, which matched histologic pattern composition. Our results provide a detailed molecular map of lung adenocarcinoma intratumor spatial heterogeneity, tracing nongenetic routes of cancer evolution. SIGNIFICANCE Lung adenocarcinomas are classified based on histologic pattern prevalence. However, individual tumors exhibit multiple patterns with unknown molecular features. We characterized nongenetic mechanisms underlying intratumor patterns and molecular markers predicting patient prognosis. Intratumor patterns determined diverse immune microenvironments, warranting their study in the context of current immunotherapies.This article is highlighted in the In This Issue feature, p. 1307.The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors that harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair-deficient (RRD) cancers, which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for RAS/MAPK mutations (P = 10-8). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient-derived RRD tumors, and these tumors responded to MEK inhibition in vitro and in vivo. Treatment of patients with RAS/MAPK hypermutant gliomas reveals durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways, resulting in favorable response to targeted therapies. SIGNIFICANCE Tumors harboring a single RAS/MAPK driver mutation are targeted individually for therapeutic purposes. We find that in RRD hypermutant cancers, mutations in the RAS/MAPK pathway are enriched, highly expressed, and result in sensitivity to MEK inhibitors. Targeting an oncogenic pathway may provide therapeutic options for these hypermutant polyclonal cancers.This article is highlighted in the In This Issue feature, p. 1307.Adoptive cell therapy (ACT) for cancer shows tremendous potential; however, several challenges preclude its widespread use. These include poor T-cell function in hostile tumor microenvironments, a lack of tumor-specific target antigens, and the high cost and poor scalability of cell therapy manufacturing. Creative genome-editing strategies are beginning to emerge to address each of these limitations, which has initiated the next generation of cell therapy products now entering clinical trials. CRISPR is at the forefront of this revolution, offering a simple and versatile platform for genetic engineering. This review provides a comprehensive overview of CRISPR applications that have advanced ACT. SIGNIFICANCE The clinical impact of ACT for cancer can be expanded by implementing specific genetic modifications that enhance the potency, safety, and scalability of cellular products. Here we provide a detailed description of such genetic modifications, highlighting avenues to enhance the therapeutic efficacy and accessibility of ACT for cancer. Furthermore, we review high-throughput CRISPR genetic screens that have unveiled novel targets for cell therapy enhancement.Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.See related commentary by Bornhauser and Bourquin, p. 1322.This article is highlighted in the In This Issue feature, p. 1307.The inability of CAR T-cells to sustain their effector function after repeat exposure to tumor cells is a major obstacle to their success in patients with solid tumors. To overcome this limitation, we designed a novel chimeric cytokine receptor to create an autocrine loop that links activation-dependent GM-CSF production by CAR T-cells to IL18 receptor signaling (GM18). Expression of GM18 in CAR T-cells enhanced their effector function in an antigen- and activation-dependent manner. In repeat stimulation assays, which mimic chronic antigen exposure, CAR.GM18 T-cells had a significant greater ability to expand and produce cytokines in comparison to their unmodified counterparts targeting EphA2 or HER2. In vivo, CAR.GM18 T-cells induced tumor regression at cell doses at which standard CAR T-cells were ineffective in two solid tumor xenograft models. Thus, our study highlights the potential of hijacking cytokines that are physiologically secreted by T-cells to bolster their antitumor activity.The capsule of Bacillus anthracis is composed of a d isomer poly-γ-glutamic acid polymer, which is especially nonstimulatory to dendritic cells, even more so than similar mixed d, l isomer polymers from nonpathogenic Bacillus species. Capsule is an essential virulence factor for B. anthracis, protecting the bacilli from phagocytosis by innate immune cells. In this study, we demonstrate that encapsulation provides a further pathogenic advantage by shielding more inflammatory Ags on the bacillus surface, thereby reducing dendritic cell responses. We exposed human immature dendritic cells (DCs) to increasing multiplicities of infection (MOIs) of killed B. anthracis bacilli from the fully encapsulated wild-type Ames strain (WT) and an isogenic capsule-deficient strain (capA mutant). Both strains elicited robust cytokine responses, but IL-23, TNF-α, and IL-10 were significantly reduced in response to the encapsulated WT compared with capA mutant up to an MOI of 15. capA mutant bacilli could induce phenotypic maturation of immature DCs with upregulation of MHC classes I and II, CD83, and CCR7 at an MOI of 3.75, whereas encapsulated WT bacilli still did not induce significant upregulation of MHC classes I and II at an MOI of 15. DCs exposed to capA mutant bacilli (MOI 3.75) exhibited CCR7-dependent chemotaxis that was comparable to that of LPS-stimulated controls, whereas DCs exposed to encapsulated WT bacilli exhibited significantly less chemotaxis. We conclude that capsule shields more inflammatory surface Ags, delaying development of an adaptive immune response by reducing TNF-α, thereby inhibiting DC maturation.
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