N6-methyladenosine (m6A) is one of the most prevalent and conserved RNA modifications. It controls several biological processes, including the biogenesis and function of circular RNAs (circRNAs), which are a class of covalently closed-single stranded RNAs. Several studies have revealed that proteotoxic stress response induction could be a relevant anticancer therapy in Acute Myeloid Leukemia (AML). Furthermore, a strong molecular interaction between the m6A mRNA modification factors and the suppression of the proteotoxic stress response has emerged. Since the proteasome inhibition leading to the imbalance in protein homeostasis is strictly linked to the stress response induction, we investigated the role of Bortezomib (Btz) on m6A regulation and in particular its impact on the modulation of m6A-modified circRNAs expression. Here, we show that treating AML cells with Btz downregulated the expression of the m6A regulator WTAP at translational level, mainly because of increased oxidative stress. Indeed, Btz treatment promoted oxidative stress, with ROS generation and HMOX-1 activation and administration of the reducing agent N-acetylcysteine restored WTAP expression. Additionally, we identified m6A-modified circRNAs modulated by Btz treatment, including circHIPK3, which is implicated in protein folding and oxidative stress regulation. These results highlight the intricate molecular networks involved in oxidative and ER stress induction in AML cells following proteotoxic stress response, laying the groundwork for future therapeutic strategies targeting these pathways.

BACKGROUND: Follicular lymphoma (FL) is characterized by t(14;18)(q32;q21) involving the IGH and BCL2 genes. However, 10-15% of FLs lack the BCL2 rearrangement. These BCL2-rearrangement-negative FLs are clinically, pathologically, and genetically heterogeneous. The biological behavior and histological transformation of such FLs are not adequately characterized. Here, we report the first case of t(14;18)-negative FL that rapidly progressed to plasmablastic lymphoma (PBL).
METHODS: A previously healthy 51-year-old man presented with leg swelling. Computed tomography (CT) showed enlarged lymph nodes (LNs) throughout the body, including both inguinal areas. Needle biopsy of an inguinal LN suggested low-grade B-cell non-Hodgkin lymphoma. Excisional biopsy of a neck LN showed proliferation of centrocytic and centroblastic cells with follicular and diffuse growth patterns. Immunohistochemical analysis showed that the cells were positive for CD20, BCL6, CD10, and CD23. BCL2 staining was negative in the follicles and weak to moderately positive in the interfollicular areas. BCL2 fluorescence in situ hybridization result was negative. Targeted next-generation sequencing (NGS) revealed mutations in the TNFRSF14, CREBBP, STAT6, BCL6, CD79B, CD79A, and KLHL6 genes, without evidence of BCL2 or BCL6 rearrangement. The pathologic and genetic features were consistent with t(14;18)-negative FL. Two months after one cycle of bendamustine and rituximab chemotherapy, the patient developed left flank pain. Positron emission tomography/CT showed new development of a large hypermetabolic mass in the retroperitoneum. Needle biopsy of the retroperitoneal mass demonstrated diffuse proliferation of large plasmablastic cells, which were negative for the B-cell markers, BCL2, BCL6, and CD10; they were positive for MUM-1, CD138, CD38, and C-MYC. The pathologic findings were consistent with PBL. The clonal relationship between the initial FL and subsequent PBL was analyzed via targeted NGS. The tumors shared the same CREBBP, STAT6, BCL6, and CD79B mutations, strongly suggesting that the PBL had transformed from a FL clone. The PBL also harbored BRAF V600E mutation and IGH::MYC fusion in addition to IGH::IRF4 fusion.
CONCLUSIONS: We propose that transformation or divergent clonal evolution of FL into PBL can occur when relevant genetic mutations are present. This study broadens the spectrum of histological transformation of t(14;18)-negative FL and emphasizes its biological and clinical heterogeneity.

BACKGROUND: Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor outcomes, especially in older AML patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer drug because it selectively induces the extrinsic apoptosis of tumor cells without affecting normal cells. However, clinical trials have shown that the responses of patients to TRAIL are significantly heterogeneous. It is necessary to explore predictable biomarkers for the preselection of AML patients with better responsiveness to TRAIL. Here, we investigated the critical role of tumor protein p53 inducible nuclear protein 2 (TP53INP2) in the AML cell response to TRAIL treatment.
METHODS: First, the relationship between TP53INP2 and the sensitivity of AML cells to TRAIL was determined by bioinformatics analysis of Cancer Cell Line Encyclopedia datasets, Cell Counting Kit-8 assays, flow cytometry (FCM) and cell line-derived xenograft (CDX) mouse models. Second, the mechanisms by which TP53INP2 participates in the response to TRAIL were analyzed by Western blot, ubiquitination, coimmunoprecipitation and immunofluorescence assays. Finally, the effect of TRAIL alone or in combination with the BCL-2 inhibitor venetoclax (VEN) on cell survival was explored using colony formation and FCM assays, and the effect on leukemogenesis was further investigated in a patient-derived xenograft (PDX) mouse model.
RESULTS: AML cells with high TP53INP2 expression were more sensitive to TRAIL in vitro and in vivo. Gain- and loss-of-function studies demonstrated that TP53INP2 significantly enhanced TRAIL-induced apoptosis, especially in AML cells with nucleophosmin 1 (NPM1) mutations. Mechanistically, cytoplasmic TP53INP2 maintained by mutant NPM1 functions as a scaffold bridging the ubiquitin ligase TRAF6 to caspase-8 (CASP 8), thereby promoting the ubiquitination and activation of the CASP 8 pathway. More importantly, simultaneously stimulating extrinsic and intrinsic apoptosis signaling pathways with TRAIL and VEN showed strong synergistic antileukemic activity in AML cells with high levels of TP53INP2.
CONCLUSIONS: Our findings revealed that TP53INP2 is a predictor of responsiveness to TRAIL treatment and supported a potentially individualized therapeutic strategy for TP53INP2-positive AML patients.

The main finding that 18F-FDG PET imaging can reveal in patients with leukemias is the presence of bone marrow (BM) infiltration in both acute or chronic forms. This ability can influence and guide the use of BM biopsy but also assess to therapy response. Additionally 18F-FDG PET imaging has been reported as particularly useful for the diagnosis of leukemias in patients with non specific symptoms. In the case of acute leukemias it revealed also a role for the evaluation of extramedullary forms while in the case of chronic forms a role for the assessment of Richter transformation has been reported.

OBJECTIVE: To identify determinants of puerperal sepsis among postpartum women attending East Shoa Zone public hospitals, Central Ethiopia, 2023.
METHODS: An institutional-based, unmatched case-control study was conducted from 19 June 2023 to 4 September 2023, in East Shoa Zone public hospitals.
METHODS: 495 postpartum women (100 cases and 395 controls) were selected using systematic sampling techniques. Data were collected through face-to-face interviews and from medical charts using a pretested, structured questionnaire. The AOR with its corresponding 95% CI was used to identify determinant variables. Findings were presented in texts and tables.
METHODS: The medical charts of participants were reviewed to identify those who had developed puerperal sepsis.
RESULTS: Anaemia (AOR 6.05; 95% CI 2.57 to 14.26), undernourishment (AOR 4.43; 95% CI 1.96 to 10.01), gestational diabetes mellitus (AOR 3.26; 95% CI 1.22 to 8.74), postpartum haemorrhage (AOR 3.17; 95% CI 1.28 to 7.87), obstructed labour (AOR 2.76; 95% CI 1.17 to 6.52), multiparity (AOR 2.54; 95% CI 1.17 to 5.50), placenta previa (AOR 2.27; 95% CI 1.11 to 4.67) and vaginal examination ≥5 times (AOR 2.19; 95% CI 1.05 to 4.54) were the independent determinants of puerperal sepsis in this study.
CONCLUSIONS: This study found that gestational diabetes mellitus, anaemia, undernourishment, placenta previa, obstructed labour, postpartum haemorrhage and five or more per-vaginal examinations during labour were the determinants of puerperal sepsis. Therefore, it is recommended that obstetric care providers strictly adhere to guidelines on the number of vaginal exams that should be performed throughout labour and that they perform these exams using the appropriate infection-prevention techniques. In addition, they should provide comprehensive health education on nutrition during pregnancy and postnatal periods and the importance of iron supplements.

BACKGROUND: Thrombocytopenia is common for patients in the intensive care unit (ICU) and is associated with adverse outcomes. ICU thrombocytopenia in pediatric patients who underwent cardiac surgeries with cardiopulmonary bypass (CPB) is inadequately studied.
OBJECTIVE: We aimed to investigate the incidence, risk factors, and prognostic role of ICU thrombocytopenia after congenital cardiac surgeries with CPB.
METHODS: A retrospective study involving 11761 patients was conducted. Patients were categorized into four groups of thrombocytopenia based on platelet counts tested during ICU: non (> 150×109/L), mild (100-150×109/L), moderate (50-100×109/L), and severe (< 50×109/L). Logistic and Cox regression analyses were utilized to explore the risk factors of thrombocytopenia and the association of ICU thrombocytopenia with 30-day mortality.
RESULTS: ICU thrombocytopenia was observed in 4007 patients (34.1%), with mild, moderate, and severe thrombocytopenia occurring in 2773 (23.6%), 987 (8.4%), and 247 (2.1%) patients, respectively. Younger age, cyanotic CHD, CPB duration, and preoperative laboratory findings (red blood cell, thrombocytopenia, red cell distribution width, hematocrit, coagulation disorder) were identified as independent risk factors of ICU thrombocytopenia. Patients with moderate [HR: 11.38 (3.02-42.87), p<0.001] and severe thrombocytopenia [HR: 49.54 (13.11-187.14), p<0.001] had a significantly higher risk of 30-day mortality. Furthermore, with the increase in the severity of ICU thrombocytopenia, there was an incremental increase in the incidence of postoperative critical bleeding and thrombosis, perioperative blood transfusions, length of ICU stays, and duration of mechanical ventilation.
CONCLUSIONS: ICU thrombocytopenia occurred in one-third of children after congenital cardiac surgery with CPB, and it was associated with multiple adverse outcomes.

BACKGROUND: In Senegal, anemia prevalence among women of reproductive age (WRA) decreased from 59% in 2005 to 54% in 2017. However, determinants of reduction in disease burden under challenging public health conditions have not been studied.
OBJECTIVE: To conduct a systematic in-depth assessment of the quantitative and qualitative determinants of anemia reduction among WRA in Senegal between 2005 and 2017.
METHODS: Standard Exemplars in Global Health methodology was used for quantitative analyses using Senegal\'s Demographic and Health Surveys. Qualitative analyses included a systematic literature review, program/policy analysis, and interviews with key stakeholders. A final Oaxaca-Blinder decomposition analysis (OBDA) evaluated the relative contribution of direct and indirect factors.
RESULTS: Among non-pregnant women (NPW), mean hemoglobin (Hb) increased from 11.4 g/dL in 2005 to 11.7 g/dL in 2017 (p<0.0001), corresponding to a 5%-point decline in anemia prevalence (58% to 53%). However, inequities by geographical region, household wealth, women\'s educational attainment, urban compared to rural residence, and antenatal care (ANC) during last pregnancy continue to persist. During this time period, several indirect nutrition programs were implemented, with stakeholders acknowledging the importance of these programs, but agreeing there needs to be more consistency, evaluation, and oversight for them to be effective. Our OBDA explained 59% of the observed change in mean Hb, with family planning (25%), malaria prevention programs (17%), use of iron and folic acid (IFA) during last pregnancy (17%), and improvement in women\'s empowerment (12%) emerging as drivers of anemia decline, corroborating our qualitative and policy analyses.
CONCLUSIONS: Despite a reduction in anemia prevalence, anemia remains a severe public health problem in Senegal. To protect the gains achieved to date, as well as accelerate reduction in WRA anemia burden, focused efforts to reduce gender and social disparities, and improve coverage of health services, such as family planning, IFA, and antimalarial programs, are needed.

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OBJECTIVE: Crystalglobulinemia is a rare syndrome characterized by intravascular crystallization of monoclonal immunoglobulins (MIgs). Data on kidney involvement are limited to case reports. This series characterizes the clinicopathologic spectrum of crystalglobulin-induced nephropathy (CIN).
METHODS: Case series.
METHODS: Nineteen CIN cases were identified from the nephropathology archives of Mayo Clinic and Columbia University. CIN was defined by intravascular (extracellular) MIg crystals visible by light (LM) and electron microscopy (EM).
RESULTS: Among the cases, 68% were male and 65% were Caucasian (median age 56 years). Most patients presented with severe AKI (median creatinine 3.5 mg/dL), hematuria, and mild proteinuria (median 1.1 g). Common extrarenal manifestations were constitutional (67%), cutaneous (56%), and rheumatologic (50%). Fifty percent of cases had hypocomplementemia. The hematologic disorders were monoclonal gammopathy of renal significance (MGRS) (72%), lymphoma (17%), or myeloma (11%), with 65% of these disorders discovered concomitantly with CIN. All patients had MIg identified on SPEP/SIF (IgGκ in 65%). The sFLC ratio was outside the renal range in 40%, and bone marrow biopsy detected the responsible clone in 67%. On LM, crystals involved glomeruli (100%) and vessels (47%), often with an inflammatory reaction (89%) and fibrin (58%). All cases exhibited crystal substructures (mostly paracrystalline) by EM. Immunofluorescence (IF) on paraffin embedded tissue was more sensitive than frozen tissue (92% versus 47%) for demonstrating the crystal composition (IgGκ in 63%). Follow up (median 20 months) was available in 16 patients. Eighty-one percent received steroids, 44% plasmapheresis, 38% hemodialysis, and 69% chemotherapy. Ninety-percent of patients who received clone-directed therapy achieved kidney recovery vs. 20% of those who did not (p=0.017).
CONCLUSIONS: Retrospective design, small sample size.
CONCLUSIONS: CIN is a rare cause of nephropathy associated with lymphoplasmacytic disorders (mostly MGRS) and typically presents with severe AKI and extrarenal manifestations. Diagnosis often requires IF performed on paraffin embedded kidney tissue. Prompt initiation of clone-directed therapy, coupled with corticosteroids and plasmapheresis, may lead to recovery of kidney function.

Leukemia is an incurable disease; it exhibits strong resistance to chemotherapy and other therapies, and it represents the most common childhood cancer and mortality. The cytotoxic of amygdalin (AMG) against the cell line of human monocytic leukemia (THP-1) was recorded, before determining other pharmacological effects. The cells were exposed to AMG for 24 hr at 37°C at different concentrations, the cytotoxic effect was determined via the MTT assay. The cells and the supernatant were collected for analyzing the oxidant/antioxidant status, apoptotic markers, and anti-microbial activity. Results showed a marked anti-proliferative cytotoxic effect of AMG which is concentration and time-dependent, the lipid peroxidation content was significantly decreased while the total thiol was increased in the treated cell line, significant up-regulation of Caspase-3 (Cas-3) and Bcl-2-associated X protein (BAX) and down-regulation of B-cell lymphoma 2 (Bcl-2). Furthermore, The bacterial activity was detected via Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), and Disc Diffusion assays, while the antifungal evaluation was done by the Minimum Fungicidal Concentration (MFC). Antimicrobial experiments revealed that AMG exerted potent, broad-spectrum antimicrobial effects toward a diversity of dangerously infecting pathogens. In conclusion; the prevailing research suggests that AMG is an effective anticarcinogenic and antimicrobial substance. The utilization of AMG subsequently in masks or wound dressings to prevent bacterial & fungal infections, including mucormycosis following COVID-19, as well as infections caused by penicillium and aspergillus, is a highly effective strategy in combating resistant microorganisms.