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European Myeloma Network Group Review and consensus statement on primary plasma cell leukemia
No full textBackgroundPrimary plasma cell leukemia (PPCL) is the most aggressive disorder among plasma cell malignancies, with new diagnostic criteria recently established by the International Myeloma Working Group. Studies have shown that PPCL patients receiving a combination of novel agents, but not eligible for transplantation, may have a median survival up to 2 years, extended to 3 years or more in those undergoing transplant procedures. These findings remain unsatisfactory, particularly if compared with progresses obtained in multiple myeloma.DesignA European Myeloma Network (EMN) expert panel reviewed the most recent literature and selected the areas of major concern in the management of PPCL by generating and rank ordering key questions using the criterion of clinical relevance. Multistep procedures were utilized to achieve a consensus on recommendations. The Delphi questionnaire method was used and a consensus of at least 80% was reached for all final statements.ResultsAn extended overview of current biological, clinical, prognostic, and therapeutic aspects of PPCL, including ongoing and close to start clinical trials, is presented. Furthermore, updated guidelines for the management of PPCL and practical recommendations are provided, in the context of current knowledge about this disease, also looking at possible future perspectives to ameliorate the outcome of these patients.ConclusionsPPCL still remains an unmet clinical need. Notwithstanding, some not negligible progresses have been recently achieved. The European Myeloma Network panel strongly support ongoing and planned clinical trials, as well as biological studies based on novel technologies, strategies, and treatment options that could represent breakthroughs we have been waiting for too long
Signaling activation and modulation in extrafollicular B cell responses
No full textThe differentiation of naive follicular B cells into either the germinal center (GC) or extrafollicular (EF) pathway plays a critical role in shaping the type, affinity, and longevity of effector B cells. This choice also governs the selection and survival of autoreactive B cells, influencing their potential to enter the memory compartment. During the first 2–3 days following antigen encounter, initially activated B cells integrate activating signals from T cells, Toll-like receptors (TLRs), and cytokines, alongside inhibitory signals mediated by inhibitory receptors. This integration modulates the intensity of signaling, particularly of the PI3K/AKT/mTOR pathway, which plays a central role in guiding developmental decisions. These early signaling events determine whether B cells undergo GC maturation or differentiate rapidly into antibody-secreting cells (ASCs) via the EF pathway. Dysregulation of these signaling pathways—whether through excessive activation or defective regulatory mechanisms—can disrupt the balance between GC and EF fates, predisposing individuals to autoimmunity. Accordingly, aberrant PI3K/AKT/mTOR signaling has been implicated in the defective selection of autoreactive B cells, increasing the risk of autoimmune disease. This review focuses on the signaling events in newly activated B cells, with an emphasis on the induction and regulation of the PI3K/AKT/mTOR pathway. It also highlights gaps in our understanding of how alternative B cell fates are regulated. Both the physiological context and the implications of inborn errors of immunity (IEIs) and complex autoimmune conditions will be discussed in this regard
Double carbapenemases in Klebsiella pneumoniae blood isolates: dissemination in a single medical center via multiple plasmids and a variety of highly efficient clones
No full textAcquisition of multiple carbapenemase genes by Klebsiella pneumoniae (Kp) is an emerging public health threat. Here, we aim to elucidate the population structure of Kp blood isolates carrying two different carbapenemase genes and identify the mechanism facilitating their dissemination. The study was conducted in a tertiary healthcare center between 2014 and 2022. Twenty-four patients with bacteremia caused by Kp carrying two different carbapenemase genes were identified. All 24 blood isolates were analyzed by short-read genome sequences supplemented by long reads in a selected number of isolates. All isolates carried blaKPC (23 blaKPC-2, 1 blaKPC-3) and blaVIM-1 genes, along with a variety of antimicrobial resistance determinants. The isolates were clustered in six clonal lineages (ST39, ST147, ST323, ST258, ST3035, and ST340). Long-read genome sequences demonstrated that each carbapenemase gene was located in a separate group of plasmids: the blaKPC-2 on a fusion of IncFIB(pQil) and IncFII(K) plasmids, the blaKPC-3 on IncX3, the blaVIM-1 on IncC, or a fusion of the IncFIB(pNDM-Mar) and IncHI1B(pNDM-MAR) plasmids. Comparison of plasmid content of eight isolates carrying a single carbapenemase gene from a previous study with eight isolates carrying two carbapenemase genes from the present study, matched by clonal lineages, revealed that the second carbapenemase gene was acquired by addition of another plasmid. Identical plasmids were found within the same lineage and across lineages. These findings suggest that dissemination of carbapenemase genes in our hospital setting was driven by multiple plasmids across a variety of highly efficient clones
Retrieval-augmented generation improves precision and trust of a GPT-4 model for emergency radiology diagnosis and classification: a proof-of-concept study
No full textObjectivesThis study evaluated the effect of enhancing a GPT-4 model with retrieval-augmented generation on its ability to diagnose and classify traumatic injuries based on radiology reports.Materials and methodsIn this prospective proof-of-concept study, we used retrieval-augmented generation as a zero-shot learning approach to provide expert knowledge from the RadioGraphics top ten reading list for trauma radiology to the GPT-4 model, creating the context-aware TraumaCB. Radiological report findings of 50 traumatic injuries were independently generated by two radiologists. The performance of the TraumaCB compared to the generic GPT-4 was evaluated by three board-certified radiologists, assessing the accuracy and trustworthiness of the chatbot responses in the 100 reports created.ResultsThe TraumaCB achieved 100% correct diagnoses, 96% correct classification, and 87% correct grading, outperforming the generic GPT-4 with 93% correct diagnoses, 70% correct classification, and 48% correct grading. TraumaCB sources consistently achieved a median rating of 5.0 for explanation and trust. Challenges encountered mainly involved traumatic injuries lacking widely accepted classification systems.ConclusionAugmenting a commercial GPT-4 model with retrieval-augmented generation improves its diagnostic and classification capabilities, positioning it as a valuable tool for efficiently assessing traumatic injuries across various anatomical regions in trauma radiology
Digestive exophagy as a novel mechanism of amyloid-[beta] degradation by microglial lysosomes
No full textMicroglia are known to be involved in the modulation of amyloid-β (Aβ) plaques in Alzheimer’s disease (AD). In a recent study, Jacquet et al. describe how microglia degrade larger Aβ aggregates by forming lysosomal synapses, further implicating the microglial release of lysosomal Aβ, amongst other processes, in the growth and spread of fibrillary Aβ
KDM5C and KDM5D mutations have different consequences in clear cell renal cell carcinoma cells
No full textKDM5C is commonly mutated in clear cell renal cell carcinomas (ccRCC) in men but rarely in women. Introducing KDM5C mutation into two male and two female KDM5C wild-type ccRCC cell lines caused different phenotypes and non-overlapping transcriptional consequences, indicative of context-dependent functions of KDM5C. We identify that loss of the Y chromosome, harbouring the KDM5C homologue KDM5D, occurs in most male KDM5C mutant ccRCCs. Mutation of KDM5D in male 786-O cells prevented xenograft tumour formation and this phenotype was unexpectedly rescued by co-mutation of KDM5C, consistent with the co-occurrence of KDM5C mutation and loss of the Y chromosome in ccRCC. Transcriptional analyses showed that KDM5C and KDM5D regulate the expression of both overlapping as well as distinct sets of genes. While KDM5C and KDM5D bind to at least some overlapping genomic sites, gene expression changes induced by KDM5C or KDM5D mutation are apparently unrelated to the direct functions of these proteins at the relevant gene promoters or enhancers. Our findings identify similarities and differences in KDM5C and KDM5D functions, challenging the idea that KDM5D in male cells functions equivalently to the second KDM5C allele in female cells, and implicate an interplay between KDM5C mutation and Y chromosome loss in ccRCC development in men
Mutism in Han Kang’s "Greek Lessons" - a reading from a psychiatric perspective
No full textDer Nobelpreis für Literatur 2024 wurde der südkoreanischen Schriftstellerin Han Kang (*1970) verliehen für – wie es in der Begründung der Jury hieß – „ihre intensive Prosa, die sich historischen Traumata stellt und die Zerbrechlichkeit des menschlichen Lebens aufzeigt“ [6]. Einer ihrer Romane, der sich mit einer psychopathologischen Reaktion auf ein persönliches Trauma befasst, trägt den Titel „Griechischstunden“ [5]. Eingebettet in eine Liebesgeschichte wird hier die völlige Aufhebung der Fähigkeit zur mündlichen Sprachproduktion im Sinne eines Mutismus dargestellt. Die namenlos bleibende Protagonistin aus Seoul hat innerhalb weniger Monate sowohl ihre Mutter als auch den Kampf um das Sorgerecht für ihren neunjährigen Sohn und in diesem Zuge auch ihre Stimme verloren. Die Frau nimmt Unterricht in Altgriechisch und entwickelt über die Zeit eine Liebesbeziehung mit ihrem Griechischlehrer, der seinerseits zunehmend erblindet
