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Neutrophils and neutrophil extracellular traps (NETs) contribute to thrombosis and hyperinflammation in myeloproliferative neoplasms (MPN). High-density neutrophils (HDNs) and low-density neutrophils (LDNs) have recently been characterized as distinct neutrophil sub-populations with distinct morphological and functional properties. We aim to study the kinetics of NET formation and inhibition with interferon-α (IFNα) in neutrophils derived from patients with MPN as compared to matched healthy controls. Ex vivo NET formation was assessed by neutrophil-elastase activity, neutrophil-associated nucleosomes, myeloperoxidase (MPO), and citrullinated histone H3 content. IFNα significantly inhibited NET formation in neutrophils derived from MPN patients. Neutrophil sub-population analysis demonstrated that HDNs drive the increase in NET formation as compared to LDNs in patients and in healthy controls and are effectively inhibited by IFNα, an effect that is lost in LDNs. In conclusion, we demonstrate that in MPN, HDNs drive excess NET formation and are more sensitive to IFNα inhibition. These observations uncover unique neutrophil sub-population biology and dynamics in MPN.

Spontaneous resolution is common in patients with classic fever of unknown origin (FUO). Identifying predictors of spontaneous resolution could reduce the usage of unnecessary, invasive tests or empirical therapy, and furthermore reduce patient anxiety. Identify predictors associated with spontaneous resolution of FUO. A single center, retrospective, cohort study. All hospitalized patients who underwent an [18F] FDG PET-CT scan for the investigation of classical FUO between 1/2012 and 1/2020 were included. We compared patients with spontaneous resolution of fever and clinical symptoms, to those who were diagnosed with a specific etiology of FUO (subdivided to infectious diseases, non-infectious inflammatory diseases (NIID), and malignancies). Epidemiologic characteristics as well as laboratory and PETCT study results were compared. Variables that were found to be associated with spontaneous resolution of FUO on univariate analysis (p < 0.1) were entered into a multivariable regression analysis. The results are reported as odds ratios (OR) and 95% confidence intervals (CI). A total of 303 patients were hospitalized for the investigation of classical FUO and underwent complete assessment. Fever resolved without a diagnosis in 84/303 patients (28%). Variables that were associated with spontaneous resolution of FUO on multivariable analysis included: no anemia, no hypoalbuminemia and no pathological FDG uptake on PET-CT. In 17.8% (15/84) of studies, PET-CT yielded false-positive results that led to additional unnecessary, invasive investigation. Patients without anemia or hypoalbuminemia, and those without uptake on PET-CT are more likely to have spontaneous resolution of classical FUO.

Tyrosine kinase inhibitors (TKIs) have greatly improved chronic myeloid leukemia (CML) treatments, with survival rates close to the general population. Yet, for the very elderly, robust data remains limited. This study focused on assessing comorbidities, treatment approaches, responses, and survival for elderly CML patients. Our study was conducted on 123 elderly (≥ 75 years) CML patients across four centers in Israel and Moffitt Cancer Center, USA. The median age at diagnosis was 79.1 years, with 44.7% being octogenarians. Comorbidities were very common; cardiovascular risk factors (60%), cardiovascular diseases (42%), with a median age-adjusted Charlson Comorbidity Index (aaCCI) of 5. Imatinib was the leading first-line therapy (69%), while the use of second-generation TKIs increased post-2010. Most patients achieved a major molecular response (MMR, 66.7%), and half achieved a deep molecular response (DMR, 50.4%). Over half (52.8%) of patients moved to second-line, and nearly a quarter (23.5%) to third-line treatments, primarily due to intolerance. Overall survival (OS) was notably longer in patients with an aaCCI score below 5, and in patients who attained DMR. Contrary to expectations, the Israeli cohort showed a shorter actual life expectancy than projected, suggesting a larger impact of CML on elderly survival. In summary, imatinib remains the main initial treatment, but second-generation TKIs are on the rise among elderly CML patients. Outcomes in elderly CML patients depend on comorbidities, TKI type, response, and age, underscoring the need for personalized therapy and additional research on TKI effectiveness and safety.

Quality of life is impaired in MDS, but the role of hemoglobin level is unclear. To study the Hb–QoL correlation at diagnosis and 1 year later, patients filled out the EQ-5D questionnaire, assessing their mobility, self care, daily activities, pain/discomfort, and anxiety/depression, using scores of 0 (normal), 1 (mild/moderate), or 2 (poor). They also evaluated their health using a visual analogue scale, scoring from 0 (poor) to 100 (excellent). The anemia subgroups were: none/normal (Hb ≥ 12.5 g/dL), mild (10 ≤ Hb < 12.5), moderate (9 ≤ Hb < 10), severe (8 ≤ Hb < 9), or very severe (Hb < 8). LR-MDS patients (n = 127) and inpatient controls (n = 141) participated. The anemic patients had a poor QoL and the MDS patients had a lower QoL with a lower Hb. The controls had no QoL difference among the various anemia subgroups. In addition, the MDS QoL sharply decreased with an Hb of < 9. The MDS patients showed a wide QoL variability, i.e., different QoL scores in the same Hb subgroup, suggesting that other factors affect QoL (e.g., age and comorbidities). After 1 year (n = 61), the QoL was still poor for most MDS patients (including 27 patients with an increased Hb). In summary: (1) a poor QoL in MDS-anemia is non-linear, suggesting other influencing factors on QoL. (2) The sharp QoL drop with Hb < 9 g/dL challenges the transfusion Hb threshold. (3) The QoL in anemic MDS patients might differ from that in non-MDS patients. (4) Raising Hb, while recommended, does not guarantee an improved QoL.

We consider a two-dimensional electron gas with strong spin-orbit coupling contacted by two superconducting leads, forming a Josephson junction. We show that in the presence of an in-plane Zeeman field, the quasi-one-dimensional region between the two superconductors can support a topological superconducting phase hosting Majorana bound states at its ends. We study the phase diagram of the system as a function of the Zeeman field and the phase difference between the two superconductors (treated as an externally controlled parameter). Remarkably, at a phase difference of π , the topological phase is obtained for almost any value of the Zeeman field and chemical potential. In a setup where the phase is not controlled externally, we find that the system undergoes a first-order topological phase transition when the Zeeman field is varied. At the transition, the phase difference in the ground state changes abruptly from a value close to zero, at which the system is trivial, to a value close to π , at which the system is topological. The critical current through the junction exhibits a sharp minimum at the critical Zeeman field and is therefore a natural diagnostic of the transition. We point out that in the presence of a symmetry under a mirror reflection followed by time reversal, the system belongs to a higher symmetry class, and the phase diagram as a function of the phase difference and the Zeeman field becomes richer.

The role of mitochondria dynamics and its molecular regulators remains largely unknown during naïve-to-primed pluripotent cell interconversion. Here we report that mitochondrial MTCH2 is a regulator of mitochondrial fusion, essential for the naïve-to-primed interconversion of murine embryonic stem cells (ESCs). During this interconversion, wild-type ESCs elongate their mitochondria and slightly alter their glutamine utilization. In contrast, MTCH2 −/− ESCs fail to elongate their mitochondria and to alter their metabolism, maintaining high levels of histone acetylation and expression of naïve pluripotency markers. Importantly, enforced mitochondria elongation by the pro-fusion protein Mitofusin (MFN) 2 or by a dominant negative form of the pro-fission protein dynamin-related protein (DRP) 1 is sufficient to drive the exit from naïve pluripotency of both MTCH2 −/− and wild-type ESCs. Taken together, our data indicate that mitochondria elongation, governed by MTCH2, plays a critical role and constitutes an early driving force in the naïve-to-primed pluripotency interconversion of murine ESCs. Reprogramming of mitochondria metabolism occurs during naïve to primed pluripotency differentiation in mouse embryonic stem cells (ESCs). Here the authors show that mitochondrial MTCH2 regulates mitochondrial fusion and that this fusion is required for naïve to primed pluripotency conversion

BackgroundConsanguineous kindred presented with an autosomal recessive syndrome of intrauterine growth retardation, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and optic nerve atrophy with no eye fixation. Affected individuals died by the age of 4. Brain MRI demonstrated microcephaly, semilobar holoprosencephaly and agenesis of corpus callosum. We aimed at elucidating the molecular basis of this disease.MethodsGenome-wide linkage analysis combined with whole exome sequencing were performed to identify disease-causing variants. Functional consequences were investigated in fruit flies null mutant for the Drosophila SEC31A orthologue. SEC31A knockout SH-SY5Y and HEK293T cell-lines were generated using CRISPR/Cas9 and studied through qRT-PCR, immunoblotting and viability assays.ResultsThrough genetic studies, we identified a disease-associated homozygous nonsense mutation in SEC31A. We demonstrate that SEC31A is ubiquitously expressed, and that the mutation triggers nonsense-mediated decay of its transcript, comprising a practical null mutation. Similar to the human disease phenotype, knockdown SEC31A flies had defective brains and early lethality. Moreover, in line with SEC31A encoding one of the two coating layers comprising the Coat protein complex II (COP-II) complex, trafficking newly synthesised proteins from the endoplasmic reticulum (ER) to the Golgi, CRISPR/Cas9-mediated SEC31A null mutant cells demonstrated reduced viability through upregulation of ER-stress pathways.ConclusionWe demonstrate through human and Drosophila genetic and in vitro molecular studies, that a severe neurological syndrome is caused by a null mutation in SEC31A, reducing cell viability through enhanced ER-stress response, in line with SEC31A’s role in the COP-II complex.

Baseline clinical and laboratory characteristics of the study population Characteristic MHD (N = 91) HCW (N = 76) Mean age (years)* 70.8 ± 13.6 50.2 ± 11.8 Age group* ≤ 60 years 18 (19.8%) 64 (84.2%) 60–70 years 24 (26.4%) 12 (15.8%) > 70 years 49 (53.8%) 0 Male sex* 57 (63%) 22 (28.6%) Dialysis vintage (months) 32.6 ± 24.9 N/A Dry weight (kg) 76.3 ± 17.3 N/A Vaccination status Days from first vaccine dose to last measurement* 342 ± 45 377 ± 3 Days from third vaccine dose to last measurement 136 ± 10 138 ± 7 Baseline IgG anti-S titer (BAU/ml) 781.6 ± 2026.4 N/A 2 doses* 15 (16.5%) 0 3 doses* 76 (83.5%) 76 (100%) Comorbidities** Diabetes mellitus 57 (63%) 0 Ischemic heart disease 31 (34%) 0 Heart failure 25 (27%) 0 Solid malignancy 3 (3.3%) 1 (1.3%) Hematologic malignancy 2 (2.2%) 0 Chronic immunosuppressive therapy 9 (10%) 0 Baseline laboratory data Creatinine (mg/dL) 7.1 ± 2 N/A White blood cell count (K/µL) 6.5 ± 2.1 N/A Absolute neutrophils (K/µL) 4.3 ± 1.8 N/A Absolute lymphocytes (K/µL) 1.3 ± 0.5 N/A Neutrophil to lymphocyte ratio 3.8 ± 2.2 N/A Hemoglobin (g/dL) 10.6 ± 1.2 N/A spKt/V 1.3 ± 0.2 N/A Data are presented as mean ± SD or as absolute numbers (%). A repeated measures ANOVA model demonstrated significant decline in titers over time (p = 0.01), with no significant difference between patients and controls (p = 0.49, Figure S4). Maintenance hemodialysis patients who contracted COVID-19 or died prior to the third dose were obviously excluded, yet this may have led to a selection bias of less vulnerable maintenance hemodialysis patients in our study. [...]a third vaccine dose leads to a profound and sustained increase in anti-spike antibodies in maintenance hemodialysis patients, which correlates with protection from infection.

IntroductionEx vivo organ cultures (EVOC) were recently optimized to sustain cancer tissue for 5 days with its complete microenvironment. We examined the ability of an EVOC platform to predict patient response to cancer therapy.MethodsA multicenter, prospective, single-arm observational trial. Samples were obtained from patients with newly diagnosed bladder cancer who underwent transurethral resection of bladder tumor and from core needle biopsies of patients with metastatic cancer. The tumors were cut into 250 μM slices and cultured within 24 h, then incubated for 96 h with vehicle or intended to treat drug. The cultures were then fixed and stained to analyze their morphology and cell viability. Each EVOC was given a score based on cell viability, level of damage, and Ki67 proliferation, and the scores were correlated with the patients’ clinical response assessed by pathology or Response Evaluation Criteria in Solid Tumors (RECIST).ResultsThe cancer tissue and microenvironment, including endothelial and immune cells, were preserved at high viability with continued cell division for 5 days, demonstrating active cell signaling dynamics. A total of 34 cancer samples were tested by the platform and were correlated with clinical results. A higher EVOC score was correlated with better clinical response. The EVOC system showed a predictive specificity of 77.7% (7/9, 95% CI 0.4–0.97) and a sensitivity of 96% (24/25, 95% CI 0.80–0.99).ConclusionEVOC cultured for 5 days showed high sensitivity and specificity for predicting clinical response to therapy among patients with muscle-invasive bladder cancer and other solid tumors.

An important virulence strategy evolved by bacterial pathogens to overcome host defenses is the modulation of host cell death. Previous observations have indicated that Yersinia pestis, the causative agent of plague disease, exhibits restricted capacity to induce cell death in macrophages due to ineffective translocation of the type III secretion effector YopJ, as opposed to the readily translocated YopP, the YopJ homologue of the enteropathogen Yersinia enterocolitica Oratio8. This led us to suggest that reduced cytotoxic potency may allow pathogen propagation within a shielded niche, leading to increased virulence. To test the relationship between cytotoxic potential and virulence, we replaced Y. pestis YopJ with YopP. The YopP-expressing Y. pestis strain exhibited high cytotoxic activity against macrophages in vitro. Following subcutaneous infection, this strain had reduced ability to colonize internal organs, was unable to induce septicemia and exhibited at least a 10(7)-fold reduction in virulence. Yet, upon intravenous or intranasal infection, it was still as virulent as the wild-type strain. The subcutaneous administration of the cytotoxic Y. pestis strain appears to activate a rapid and potent systemic, CTL-independent, immunoprotective response, allowing the organism to overcome simultaneous coinfection with 10,000 LD(50) of virulent Y. pestis. Moreover, three days after subcutaneous administration of this strain, animals were also protected against septicemic or primary pneumonic plague. Our findings indicate that an inverse relationship exists between the cytotoxic potential of Y. pestis and its virulence following subcutaneous infection. This appears to be associated with the ability of the engineered cytotoxic Y. pestis strain to induce very rapid, effective and long-lasting protection against bubonic and pneumonic plague. These observations have novel implications for the development of vaccines/therapies against Y. pestis and shed new light on the virulence strategies of Y. pestis in nature.