Extragonadal germ cell tumors: A clinicopathologic study with emphasis on molecular features, clinical outcomes and associated secondary malignancies.

Extragonadal germ cell tumors (EGCTs) are rare, representing <5% of all germ cell tumors (GCTs). Whilst EGCTs share morphological and immunohistochemical features with their gonadal counterparts, they tend to be more aggressive and are frequently associated with secondary somatic malignancies. The aim of our study was to evaluate the clinical, morphological and immunohistochemical features, and to analyze tumors for chromosomal abnormalities of 12p, in addition to any novel genetic alterations, in a series of EGCTs. Seventy-seven EGCTs were included. Anterior mediastinum was the most common anatomic site, followed by central nervous system, retroperitoneum, sacroccygeal area, and neck. Whole genome SNP array identified isochromosome 12p in 26% of tumors. Additional cytogenetic abnormalities included the presence of gain of chr 21 in 37% of tumors. Somatic-type malignancies were identified in 8% of patients. Disease progression (metastasis and/or recurrence) was documented in 8 patients, most of whom died from their relapse. Three patients who died of disease had somatic-type malignancies. Mediastinal seminomas had a significantly better overall survival when compared to mediastinal non-seminomatous GCTs. Our study demonstrates that EGCTs share similar histologic features, but diverse clinical outcomes compared to their gonadal counterparts. Outcomes vary according to anatomic location and histologic subtypes. Our data corroborate that somatic-type malignancies are frequently encountered in mediastinal EGCTs and that their presence portends a poorer prognosis.

Advances in the mechanism of inflammasomes activation in herpes virus infection.

Herpesviruses, prevalent DNA viruses with a double-stranded structure, establish enduring infections and play a part in various diseases. Despite their deployment of multiple tactics to evade the immune system, both localized and systemic inflammatory responses are triggered by the innate immune system's recognition of them. Recent progress has offered more profound understandings of the mechanisms behind the activation of the innate immune system by herpesviruses, specifically through inflammatory signaling. This process encompasses the initiation of an intracellular nucleoprotein complex, the inflammasome associated with inflammation.Following activation, proinflammatory cytokines such as IL-1ß and IL-18 are released by the inflammasome, concurrently instigating a programmed pathway for cell death. Despite the structural resemblances between herpesviruses, the distinctive methods of inflammatory activation and the ensuing outcomes in diseases linked to the virus exhibit variations.The objective of this review is to emphasize both the similarities and differences in the mechanisms of inflammatory activation among herpesviruses, elucidating their significance in diseases resulting from these viral infections.Additionally, it identifies areas requiring further research to comprehensively grasp the impact of this crucial innate immune signaling pathway on the pathogenesis of these prevalent viruses.

Development and application of an indirect ELISA for detection of antibodies against emerging atypical porcine pestivirus.

BACKGROUND: Atypical porcine pestivirus (APPV) is a newly discovered swine pestivirus, which can cause congenital tremor and high mortality in newborn piglets and subclinical infection in adult pigs, leading to significant impacts on the pig industry. Currently, there is no approved serological method to assess APPV infection status in pig farms. METHODS: In this study, the envelope glycoprotein E2 of APPV was highly expressed in suspension HEK293 cells, and further an indirect enzyme-linked immunosorbent assay based on the recombinant E2 protein (E2-iELISA) was developed and evaluated. RESULTS: The reaction parameters of the E2-iELISA were optimized, and the cutoff value was determined to be 0.2 by analyzing S/P values of 165 negative sera against APPV that were confirmed by virus neutralization test (VNT). Specificity test showed that the method had no cross-reaction with other common swine viruses. The E2-iELISA was evaluated using a panel of swine sera, and showed high sensitivity (113/120, 94.2%) and specificity (65/70, 92.9%), and the agreement rate with VNT was 93.7% (178/190). Subsequently, the E2-iELISA was utilized to investigate the seroprevalence of APPV in pig herds of China. When detecting 1368 pig serum samples collected from nine provinces in China, the overall seroprevalence of APPV was 73.9% (1011/1368). CONCLUSION: Our findings suggest that the E2-iELISA is specific and sensitive, and could be a valuable tool for serological surveillance of APPV infection in pigs.

Clinical effect of roxadustat vs. erythropoietin in non-dialysis CKD with diabetes: a single center propensity score matching analysis.

PURPOSE: Renal anemia is a common complication of chronic kidney disease. Currently, recombinant human erythropoietin and roxadustat are the main treatments. In China, diabetic kidney disease is the primary cause of chronic kidney disease. However, high-quality evidence on the efficacy of roxadustat in patients with non-dialysis-dependent chronic kidney disease and diabetes mellitus is scarce. This study aimed to assess the clinical effect of roxadustat in such patients. METHODS: Patients with non-dialysis-dependent anemia and diabetes mellitus who received roxadustat or recombinant human erythropoietin for ≥ 4 weeks were enrolled. We compared baseline characteristics, including age, gender, hypertension, and hemoglobin level, and then employed a 1:3 ratio propensity score matching. The primary efficacy outcomes were changes in hemoglobin levels. After propensity score matching, 212 patients were analyzed, including the roxadustat (n = 53) and recombinant human erythropoietin (n = 159) groups. Baseline characteristics were comparable, including hemoglobin level, estimated glomerular filtration rate, and glycated hemoglobin A1c (p > 0.05). RESULTS: After 4, 12, and 24 weeks of treatment, the median hemoglobin levels in the roxadustat group were 97.5 g/L, 104 g/L, and 106.5 g/L, respectively, significantly surpassing the corresponding levels in the recombinant human erythropoietin group at 91 g/L, 94.5 g/L, and 94.5 g/L (p = 0.002, p = 0.025, p = 0.006, respectively). Additionally, subgroup analysis demonstrated better treatment efficacy of roxadustat patients with elevated high-sensitivity C-reactive protein and low albumin levels. CONCLUSION: In Chinese patients with anemia and diabetes not on dialysis, roxadustat efficiently and rapidly improved and maintained hemoglobin levels unaffected by elevated high-sensitivity C-reactive protein and low albumin levels.

Section E6.1-6.6 of the American College of Medical Genetics and Genomics (ACMG) Technical Laboratory Standards: Cytogenomic studies of acquired chromosomal abnormalities in neoplastic blood, bone marrow, and lymph nodes.

Cytogenomic analyses of acquired clonal chromosomal abnormalities in neoplastic blood, bone marrow, and/or lymph nodes are instrumental in the clinical management of patients with hematologic neoplasms. Cytogenetic analyses assist in the diagnosis of such disorders and can provide important prognostic information. Furthermore, cytogenetic studies can provide crucial information regarding specific genetically defined subtypes of these neoplasms that may have targeted therapies. At time of relapse, cytogenetic analysis can confirm recurrence of the original neoplasm, detect clonal disease evolution, or uncover a new unrelated neoplastic process. This section deals specifically with the technical standards applicable to cytogenomic studies of acquired clonal chromosomal abnormalities in neoplastic blood, bone marrow, and/or lymph nodes. This updated Section E6.1-6.6 supersedes the previous Section E6 in Section E: Clinical Cytogenetics of the American College of Medical Genetics and Genomics Technical Standards for Clinical Genetics Laboratories.

Section E6.7-6.12 of the American College of Medical Genetics and Genomics (ACMG) Technical Laboratory Standards: Cytogenomic studies of acquired chromosomal abnormalities in solid tumors.

Clinical cytogenomic studies of solid tumor samples are critical to the diagnosis, prognostication, and treatment selection for cancer patients. An overview of current cytogenomic techniques for solid tumor analysis is provided, including standards for sample preparation, clinical and technical considerations, and documentation of results. With the evolving technologies and their application in solid tumor analysis, these standards now include sequencing technology and optical genome mapping, in addition to the conventional cytogenomic methods, such as G-banded chromosome analysis, fluorescence in situ hybridization, and chromosomal microarray analysis. This updated Section E6.7-6.12 supersedes the previous Section E6.5-6.8 in Section E: Clinical Cytogenetics of the American College of Medical Genetics and Genomics Standards for Clinical Genetics Laboratories.

Genome sequencing unveils blaKPC-2-harboring plasmids as drivers of enhanced resistance and virulence in nosocomial Klebsiella pneumoniae.

The threat posed by Klebsiella pneumoniae in healthcare settings has worsened due to the evolutionary advantages conferred by blaKPC-2-harboring plasmids (pKPC-2). However, the specific evolutionary pathway of nosocomial K. pneumoniae carrying pKPC-2 and its transmission between patients and healthcare environments are not yet well understood. Between 1 August and 31 December 2019, 237 ST11 KPC-2-producing-carbapenem-resistant K. pneumoniae (CRKP) (KPC-2-CRKP) were collected from patient or ward environments in an intensive care unit and subjected to Illumina sequencing, of which 32 strains were additionally selected for Nanopore sequencing to obtain complete plasmid sequences. Bioinformatics analysis, conjugation experiments, antimicrobial susceptibility tests, and virulence assays were performed to identify the evolutionary characteristics of pKPC-2. The pKPC-2 plasmids were divided into three subgroups with distinct evolutionary events, including Tn3-mediated plasmid homologous recombination, IS26-mediated horizontal gene transfer, and dynamic duplications of antibiotic resistance genes (ARGs). Surprisingly, the incidence rates of multicopy blaKPC-2, blaSHV-12, and blaCTX-M-65 were quite high (ranging from 27.43% to 67.01%), and strains negative for extended-spectrum ß-lactamase tended to develop multicopy blaKPC-2. Notably, the presence of multicopy blaSHV-12 reduced sensitivity to ceftazidime/avibactam (CZA), and the relative expression level of blaSHV-12 in the CZA-resistant group was 6.12 times higher than that in the sensitive group. Furthermore, a novel hybrid pKPC-2 was identified, presenting enhanced virulence levels and decreased susceptibility to CZA. This study emphasizes the notable prevalence of multicopy ARGs and provides a comprehensive insight into the intricate and diverse evolutionary pathways of resistant plasmids that disseminate among patients and healthcare environments.IMPORTANCEThis study is based on a CRKP screening program between patients and ward environments in an intensive care unit, describing the pKPC-2 (blaKPC-2-harboring plasmids) population structure and evolutionary characteristics in clinical settings. Long-read sequencing was performed in genetically closely related strains, enabling the high-resolution analysis of evolution pathway between or within pKPC-2 subgroups. We revealed the extremely high rates of multicopy antibiotic resistance genes (ARGs) in clinical settings and its effect on resistance profile toward novel ß-lactam/ß-lactamase inhibitor combinations, which belongs to the last line treatment choices toward CRKP infection. A novel hybrid pKPC-2 carrying CRKP with enhanced resistance and virulence level was captured during its clonal spread between patients and ward environment. These evidences highlight the threat of pKPC-2 to CRKP treatment and control. Thus, surveillance and timely disinfection in clinical settings should be practiced to prevent transmission of CRKP carrying threatful pKPC-2. And rational use of antibiotics should be called for to prevent inducing of pKPC-2 evolution, especially the multicopy ARGs.

Effects of Mineralocorticoid Receptor Antagonists for Chronic Kidney Disease: A Systemic Review and Meta-Analysis.

BACKGROUND: Mineralocorticoid receptor blockade could be a potential approach for the inhibition of chronic kidney disease (CKD) progression. The benefits and harms of different mineralocorticoid receptor antagonists (MRAs) in CKD are inconsistent. OBJECTIVES: The aim of the study was to summarize the benefits and harms of MRAs for CKD patients. METHODS: We searched MEDLINE, EMBASE, and the Cochrane databases for trials assessing the effects of MRAs on non-dialysis-dependent CKD populations. Treatment and adverse effects were summarized using meta-analysis. RESULTS: Fifty-three trials with 6 different MRAs involving 22,792 participants were included. Compared with the control group, MRAs reduced urinary albumin-to-creatinine ratio (weighted mean difference [WMD], -90.90 mg/g, 95% CI, -140.17 to -41.64 mg/g), 24-h urinary protein excretion (WMD, -0.20 g, 95% CI, -0.28 to -0.12 g), estimated glomerular filtration rate (eGFR) (WMD, -1.99 mL/min/1.73 m2, 95% CI, -3.28 to -0.70 mL/min/1.73 m2), chronic renal failure events (RR, 0.86, 95% CI, 0.79-0.93), and cardiovascular events (RR, 0.84, 95% CI, 0.77-0.92). MRAs increased the incidence of hyperkalemia (RR, 2.04, 95% CI, 1.73-2.40) and hypotension (RR, 1.80, 95% CI, 1.41-2.31). MRAs reduced the incidence of peripheral edema (RR, 0.65, 95% CI, 0.56-0.75) but not the risk of acute kidney injury (RR, 0.94, 95% CI, 0.79-1.13). Nonsteroidal MRAs (RR, 0.66, 95% CI, 0.57-0.75) but not steroidal MRAs (RR, 0.20, 95% CI, 0.02-1.68) significantly reduced the risk of peripheral edema. Steroidal MRAs (RR, 5.68, 95% CI, 1.26-25.67) but not nonsteroidal MRAs (RR, 0.52, 95% CI, 0.22-1.22) increased the risk of breast disorders. CONCLUSIONS: In the CKD patients, MRAs, particularly in combination with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, reduced albuminuria/proteinuria, eGFR, and the incidence of chronic renal failure, cardiovascular and peripheral edema events, whereas increasing the incidence of hyperkalemia and hypotension, without the augment of acute kidney injury events. Nonsteroidal MRAs were superior in the reduction of more albuminuria with fewer peripheral edema events and without the augment of breast disorder events.

A study on the factors influencing the utilization of public health services by China's migrant population based on the Shapley value method.

BACKGROUND: The health of migrants has received significant global attention, and it is a particularly significant concern in China, which has the largest migrant population in the world. Analyzing data on samples from the Chinese population holds practical significance. For instance, one can delve into an in-depth analysis of the factors impacting (1) the health records of residents in distinct regions and (2) the current state of family doctor contracts. This study explores the barriers to access these two health services and the variations in the effects and contribution magnitudes. METHODS: This study involved data from 138,755 individuals, extracted from the 2018 National Migration Population Health and Family Planning Dynamic Monitoring Survey database. The theoretical framework employed was the Anderson health service model. To investigate the features and determinants of basic public health service utilization among the migrant population across different regions of China, including the influence of enabling resources and demand factors, x2 tests and binary logistic regression analyses were conducted. The Shapley value method was employed to assess the extent of influence of each factor. RESULTS: The utilization of various service types varied among the migrant population, with significant regional disparities. The results of the decomposition of the Shapley value method highlighted variations in the mechanism underlying the influence of propensity characteristics, enabling resources, and demand factors between the two health service types. Propensity characteristics and demand factors were found to be the primary dimensions with the highest explanatory power; among them, health education for chronic disease prevention and treatment was the most influential factor. CONCLUSION: To better meet the health needs of the migrant population, regional barriers need to be broken down, and the relevance and effectiveness of publicity and education need to be improved. Additionally, by considering the education level, demographic characteristics, and mobility characteristics of the migrant population, along with the relevant health policies, the migrant population needs to be guided to maintain the health records of residents. They should also be encouraged to sign a contract with a family doctor in a more effective manner to promote the equalization of basic health services for the migrant population.

Isolation and Molecular Characterization of Atypical Porcine Pestivirus Emerging in China.

Atypical porcine pestivirus (APPV) is a recently discovered and very divergent species of the genus Pestivirus within the family Flaviviridae, which causes congenital tremor (CT) in newborn piglets. In this study, an APPV epidemiological investigation was conducted by studying 975 swine samples (562 tissue and 413 serum samples) collected from different parts of China from 2017 to 2021. The results revealed that the overall positive rate of the APPV genome was 7.08% (69/975), among which 50.7% (35/69) of the samples tested positive for one or more other common swine viruses, especially porcine circovirus type 2 (PCV2) with a coinfection rate of 36.2% (25/69). Subsequently, a novel APPV strain, named China/HLJ491/2017, was isolated in porcine kidney (PK)-15 cells for the first time from a weaned piglet that was infected with both APPV and PCV2. The new APPV isolate was confirmed by RT-PCR, sequencing, immunofluorescence assay, and transmission electron microscopy. After clearing PCV2, a pure APPV strain was obtained and further stably propagated in PK-15 cells for more than 30 passages. Full genome sequencing and phylogenetic analysis showed that the China/HLJ491/2017 strain was classified as genotype 2, sharing 80.8 to 97.6% of its nucleotide identity with previously published APPV strains. In conclusion, this study enhanced our knowledge of this new pestivirus and the successful isolation of the APPV strain provides critical material for the investigation of the biological and pathogenic properties of this emerging virus, as well as the development of vaccines and diagnostic reagents.

Plasma D-dimer levels are associated with disease progression in diabetic nephropathy: a two-center cohort study.

BACKGROUND: This study aimed to investigate the relationship between plasma D-dimer levels, clinicopathological features, and clinical outcomes in patients with biopsy-proven diabetic nephropathy (DN). METHODS: A total of 137 patients with biopsy-proven DN were enrolled in this two-center cohort study. Patients were stratified into tertiles based on plasma D-dimer levels. We investigated the relationship between plasma D-dimer levels and clinical outcomes, including a composite of death, a 40% decline in estimated glomerular filtration rate (e-GFR) from baseline, or end-stage renal disease (ESRD) (defined as e-GFR < 15 mL/min/1.73 m2 or need for renal replacement therapy including hemodialysis, peritoneal dialysis, or kidney transplantation), assessed using Cox regression models with adjustment for confounders. RESULTS: At baseline, the mean age was 52.61 ± 11.63 years, and the mean e-GFR was 58.02 ± 28.77 mL/min/1.73 m2. During a median 26-month follow-up period, 65 (47% of patients) achieved clinical outcomes. Compared with the low plasma D-dimer level group, those with higher plasma D-dimer levels were more likely to have higher 24-h proteinuria (p = .002), lower e-GFR (p = .001), lower hemoglobin (p = .001), a higher glomerular lesion class (p = .03), and higher interstitial fibrosis and tubular atrophy (IFTA) scores (p = .002). After adjustment for demographic, DN-specific covariates, and treatments, it was observed that a higher tertile of plasma D-dimer was nonlinearly associated with an increased risk of the clinical outcomes (Hazard Ratio (HR) for tertile 2 vs. 1, 1.7; 95% Confidence Interval (CI), 0.80-3.75; HR for tertile 3 vs. 1, 2.2; 95% CI, 0.93-5.27; p for trend = .001) in the Cox proportional hazards models. CONCLUSION: In this study, DN patients with higher levels of plasma D-dimer had higher 24-h proteinuria, lower e-GFR, a higher glomerular lesion class, and higher IFTA scores. Furthermore, a high level of plasma D-dimer was nonlinearly associated with DN progression.

Aspirin intervention before ICU admission reduced the mortality in critically ill patients with acute kidney injury: results from the MIMIC-IV.

Background: Aspirin, with its pleiotropic effects such as anti-inflammatory and anti-platelet aggregation, has been widely used for anti-inflammatory, analgesic, and cardiovascular diseases. However, the association between the use of aspirin before the intensive care unit (ICU) and clinical outcomes in critically ill patients with acute kidney injury (AKI) is unknown. Methods: Patients with AKI in this retrospective observational study were selected from the Marketplace for Medical Information in Intensive Care IV (MIMIC-IV). The association between aspirin intervention and 30-day mortality was assessed using Cox proportional hazards model. Logistic regression models were used to assess the association of aspirin intervention with the risks of intracranial hemorrhage, gastrointestinal bleeding and blood transfusion. The propensity score matching (PSM) method was adopted to balance the baseline variables. Sensitivity analysis was performed to validate the results by multiple interpolations for the missing data. Results: The study included 4237 pre-ICU aspirin users and 9745 non-users. In multivariate models, we found a decreased risk of mortality in those who received aspirin before ICU compared to those who did not (30-day:hazard ratio [HR], 0.70; 95% CI, 0.62-0.79; p < 0.001; 90-day:HR, 0.70; 95% CI, 0.63-0.77, p < 0.001; 180-day:HR, 0.72; 95%CI,0.65-0.79, p < 0.001). This benefit was consistent in the post-PSM analyses, sensitivity analyses, and subgroup analyses. Moreover, aspirin intervention was associated with a reduced risk of intracranial hemorrhage and gastrointestinal bleeding (HR, 0.16; 95% CI, 0.10-0.25; p < 0.001; HR, 0.59; 95% CI, 0.38-0.88, p = 0.012) after being adjusted by relating covariates, whereas with a increased risk of blood transfusion (HR, 1.28; 95% CI, 1.16-1.46; p < 0.001). Conclusion: Patients with AKI treated with aspirin before ICU admission might have reduced 30-day, 90-day and 180-day mortality without increasing the risk of intracranial hemorrhage (ICH) or gastrointestinal bleeding, but may increase the risk of transfusion.

Acute kidney injury in patients with cancer receiving anti-PD-1/PD-L1 antibodies: incidence, risk factors, and prognosis.

Anti-PD-1/PD-L1 antibodies are widely used in anti-cancer therapy. While they have improved cancer prognoses, immune-related adverse events, which can cause acute kidney injury (AKI), cannot be ignored. The purpose of this retrospective cohort study was to assess the incidence, risk factors, and prognosis of AKI associated with anti-PD-1/PD-L1 antibodies. Patients who received anti-PD-1/PD-L1 antibody treatment at our hospital between January 2018 and December 2022 were enrolled. Clinical information, combined medications, concomitant diseases, tumor types, and laboratory indicators were collected from patient records, and the incidence of AKI was determined. The risk factors for AKI were assessed using univariate and multivariate logistic regression analyses. Overall, 1418 patients were enrolled. The median follow-up time was 112 days and 92 (6.5%) developed AKI. The median time from the initial anti-PD-1/PD-L1 antibody treatment to AKI was 99.85 days. Head and neck cancer and combined use of diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), lower hemoglobin level, and other types of chemotherapeutic drugs were independent risk factors for AKI. The complete recovery, partial recovery, non-recovery, and unknown AKI rates were 7.6%, 28.3%, 52.2%, and 11.9%, respectively. Kidney biopsies were performed on two patients with AKI and pathology confirmed diagnosis of acute tubulointerstitial nephritis. In this cohort, AKI was not uncommon in patients treated with anti-PD-1/PD-L1 antibodies; therefore, it is necessary to monitor renal function and identify AKI early, especially in patients with head and neck tumors. Improving anemia and minimizing the use of diuretics, NSAIDs, and chemotherapeutics may reduce AKI.

Lessons from 801 clinical TFE3/TFEB fluorescence in situ hybridization assays performed on renal cell carcinoma suspicious for MiTF family aberrations.

OBJECTIVES: Fluorescence in situ hybridization (FISH) assays for the detection of chromosomal rearrangements involving TFE3 and TFEB are considered the gold standard for the diagnosis of MiTF family altered renal cell carcinoma (MiTF-RCC). We reviewed 801 clinical TFE3/TFEB FISH assays performed at our tertiary-level institution between 2014 and 2023 on kidney tumors suspicious at the morphologic or biomarker level for MiTF aberrations. METHODS: We summarized and analyzed clinical information, TFE3/TFEB FISH results, and available biomarker staining results in a cohort of 453 consecutive kidney tumor cases suspicious for MiTF-RCC. RESULTS: In total, 61 of 434 (14%) kidney tumors were confirmed for TFE3 translocation; 10 of 367 cases (2.7%) were confirmed for TFEB translocation. Since TFEB amplification interpretation was implemented in our service line, 20 of 306 cases (6.5%) were diagnosed with TFEB amplification. Importantly, TFE3 and TFEB rearrangements were never co-detected within the same kidney tumor. Patients with TFEB amplification were significantly older (P < .001) than patients with TFE3 or TFEB translocation. Kidney tumors with TFEB amplification were seen to be at least 3 times as common as those with TFEB translocation. CONCLUSIONS: Clinical TFE3/TFEB FISH assays successfully identified and confirmed rare MiTF-RCC with TFE3 and TFEB rearrangements. Although morphologic and biomarker features associated with a kidney tumor may be suggestive of MiTF-RCC, clinical TFE3/TFEB FISH assays are crucial for a confirmation and definitive subclassification of patients with MiTF-RCC.

T-Cell Prolymphocytic Leukemia With t(X;14)(q28;q11.2): A Clinicopathologic Study of 15 Cases.

OBJECTIVES: T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell leukemia usually characterized by inv(14)(q11.2q32)/t(14;14)(q11.2;q32). In this study, we aimed to investigate the clinicopathologic features and molecular profile of T-PLL associated with t(X;14)(q28;q11.2). METHODS: The study group included 10 women and 5 men with a median age of 64 years. All 15 patients had a diagnosis of T-PLL with t(X;14)(q28;q11.2). RESULTS: All 15 patients had lymphocytosis at initial diagnosis. Morphologically, the leukemic cells had features of prolymphocytes in 11 patients, small cell variant in 3, and cerebriform variant in 1. All 15 patients had hypercellular bone marrow with an interstitial infiltrate in 12 (80%) cases. By flow cytometry, the leukemic cells were surface CD3+/CD5+/CD7+/CD26+/CD52+/TCR α/ß+ in 15 (100%) cases, CD2+ in 14 (93%) cases, CD4+/CD8+ in 8 (53%) cases, CD4+/CD8- in 6 (40%) cases, and CD4-/CD8 + in 1 (7%) case. At the cytogenetic level, complex karyotypes with t(X;14)(q28;q11.2) were seen in all 15 patients assessed. Mutational analysis showed mutations of JAK3 in 5 of 6 and STAT5B p.N642H in 2 of 6 patients. Patients received variable treatments, including 12 with alemtuzumab. After a median follow-up of 17.2 months, 8 of 15 (53%) patients died. CONCLUSIONS: T-PLL with t(X;14)(q28;q11.2) frequently shows a complex karyotype and mutations involving JAK/STAT pathway, and it is an aggressive disease with a poor outcome.

High-grade B-cell lymphoma with concurrent MYC rearrangement and 11q aberrations: clinicopathologic, cytogenetic, and molecular characterization of 4 cases.

High-grade B-cell lymphoma with 11q aberrations (LBL-11q) resembles Burkitt lymphoma (BL), is negative for MYC rearrangement, and harbors chromosome 11q aberrations. Rare cases of high-grade B-cell lymphoma with concurrent MYC rearrangement and 11q aberrations (HGBCL-MYC-11q) have been described. In this study, we report the clinicopathologic, cytogenetic, and molecular findings in 4 such cases. Diagnoses were made on tissue or bone marrow biopsies. Karyotype, fluorescence in situ hybridization, genomic microarray analyses, and next-generation sequencing were performed. All patients were male (median age, 39 years). Three cases were diagnosed as BL, while one was diagnosed as diffuse large B-cell lymphoma. Karyotypes (available in 2 patients) were complex. In 1 patient, copy number analysis showed gains at 1q21.1-q44 and 13q31.3 and loss of 13q34, abnormalities typically seen in BL. All of our cases showed 2 or more mutations that are recurrent in BL, including ID3, TP53, DDX3X, CCND3, FBXO1, and MYC. Two cases showed a GNA13 mutation, commonly seen in LBL-11q. Cases of HGBCL-MYC-11q display overlapping morphologic and immunophenotypic, as well as cytogenetic and molecular features between BL and LBL-11q, with a mutational landscape enriched for mutations recurrent in BL. Concurrent MYC rearrangement with 11q abnormalities is important to recognize, especially as it has implications for their classification.

Osteoblast Jmjd3 regulates osteoclastogenesis via EphB4 and RANKL signalling.

BACKGROUND: Osteoblasts suppress osteoclastogenesis during the reversal phase of bone remodelling and the mechanism needs to be further investigated. Here, we investigated the role of histone demethylase Jumonji domain-containing 3 (Jmjd3) in osteoblasts on regulating osteoclastogenesis. METHODS: Jmjd3 expression was silenced in osteoblasts. Osteoblasts and osteoclasts were co-cultured in direct or indirect contact ways, and osteoclastogenesis was determined by tartrate-resistant acid phosphatase (TRAP) staining and Western blotting. Additionally, Ephrin receptor B4 (EphB4) and receptor activator of nuclear factor-kappa Β ligand (RANKL) expression were quantified in osteoblasts via real-time PCR, Western blotting, and enzyme-linked immunosorbent assay. Subsequently, EphB4 was overexpressed in osteoblasts and RANKL expression and osteoclastogenesis was quantified. RESULTS: Osteoclastogenesis and marker protein expression levels was promoted when osteoclasts were co-cultured with Jmjd3-silenced osteoblasts. Silencing of Jmjd3 expression in osteoblasts decreased EphB4 expression, owing to suppression of demethylation of H3K27me3 on the promoter region of EphB4. Whereas RANKL expression was upregulated in Jmjd3-silenced osteoblasts. Overexpression of EphB4 in osteoblasts inhibited osteoclastogenesis and RANKL expression. CONCLUSION: Jmjd3 in osteoblasts is a crucial regulator of osteoblast-to-osteoclast communication through EphB4-EphrinB2, RANKL-RANK and EphB4-RANKL signalling axes, suggesting the pivotal role of Jmjd3 in bone remodelling process in bone destruction disease such as chronic apical periodontitis.

VALPROIC ACID INHIBITS CLASSICAL MONOCYTE-DERIVED TISSUE FACTOR AND ALLEVIATES HEMORRHAGIC SHOCK-INDUCED ACUTE LUNG INJURY IN RATS.

ABSTRACT: Background: Monocytes and monocyte-derived tissue factor (TF) promote the development of sepsis-induced acute lung injury (ALI). Classical monocytes (C-Mcs) can be induced to express TF. Valproic acid (VPA) alleviates hemorrhagic shock (HS)-induced ALI (HS/ALI) and inhibits TF expression in monocytes. We hypothesized that C-Mcs and C-Mc-derived TF promoted HS/ALI and that VPA could inhibit C-Mc-derived TF expression and attenuate HS/ALI. Methods: Wistar rats and THP-1 cells were used to evaluate our hypothesis. Monocyte subtypes were analyzed by flow cytometry; mRNA expression was measured by fluorescence quantitative polymerase chain reaction; protein expression was measured by Western blotting, immunofluorescence, or immunohistology; inflammatory cytokines levels were measured by enzyme-linked immunosorbent assay; and ALI scores were used to determine the degree of ALI. Results: The blood %C-Mcs and C-Mcs/non-C-Mcs ratios, monocyte TF levels, serum and/or lung inflammatory cytokine levels, and ALI scores of HS rats were significantly increased ( P < 0.05). After monocyte depletion and thrombin inhibition, the inflammatory cytokine levels and ALI scores were significantly decreased ( P < 0.05). VPA reduced the %C-Mcs and C-Mc/non-C-Mc ratios, TF expression, inflammatory cytokine levels, and ALI scores during HS ( P < 0.05) and inhibited HS-induced monocyte Egr-1 and p-ERK1/2 expression ( P < 0.05). VPA inhibited hypoxia-induced TF expression in THP-1 cells by regulating the p-ERK1/2-Egr-1 axis. Conclusion: C-Mcs and C-Mc-derived TF accelerate the development of HS/ALI by increasing thrombin production. VPA inhibits HS-induced C-Mc production of TF by regulating the p-ERK1/2-Egr-1 axis and alleviates HS/ALI.

Development and validation of a nomogram for predicting pulmonary infection in patients receiving immunosuppressive drugs.

Objective: Pulmonary infection (PI), a severe complication of immunosuppressive therapy, affects patients' prognosis. As part of this study, we aimed to construct a pulmonary infection prediction (PIP) model and validate it in patients receiving immunosuppressive drugs (ISDs). Methods: Totally, 7,977 patients being treated with ISDs were randomised 7:3 to the developing (n = 5,583) versus validation datasets (n = 2,394). Our predictive nomogram was established using the least absolute shrinkage and selection operator (LASSO) and multivariate COX regression analyses. With the use of the concordance index (C-index) and calibration curve, the prediction performance of the final model was evaluated. Results: Among the patients taking immunosuppressive medication, PI was observed in 548 (6.9%). The median time of PI occurrence after immunosuppressive therapy was 123.0 (interquartile range: 63.0, 436.0) days. Thirteen statistically significant independent predictors (sex, age, hypertension, DM, malignant tumour, use of biologics, use of CNIs, use of methylprednisolone at 500 mg, use of methylprednisolone at 40 mg, use of methylprednisolone at 40 mg total dose, use of oral glucocorticoids, albumin level, and haemoglobin level) were screened using the LASSO algorithm and multivariate COX regression analysis. The PIP model built on these features performed reasonably well, with the developing C-index of 0.87 (sensitivity: 85.4%; specificity: 81.0%) and validation C-indices of 0.837, 0.829, 0.832 and 0.830 for predicting 90-, 180-, 270- and 360-day PI probability, respectively. The decision curve analysis (DCA) and calibration curves displayed excellent clinical utility and calibration performance of the nomogram. Conclusion: The PIP model presented herein could aid in the prediction of PI risk in individual patients who receive immunosuppressive treatment and help personalise clinical decision-making.

Comparison of efficacy of roxadustat and erythropoietin for the treatment of renal anemia in patients with chronic kidney disease: a retrospective study.

Background: Renal anemia is a common complication in patients with end-stage renal disease (ESRD). Both roxadustat and recombinant human erythropoietin (rhEPO) are alternative option for patients with renal anemia. However, the adverse events of rhEPO limited the wide use of it and the concrete difference of real clinical efficacy of rhEPO and roxadustat was still uncertain. This study aimed to assess the clinical efficacy of roxadustat for improving renal anemia in patients with chronic kidney disease. Methods: A retrospective cohort study of 790 consecutive patients with renal anemia treated with roxadustat and rhEPO was conducted at the Zhejiang Provincial People's Hospital. Patients were classified into two groups: roxadustat (n=95) and rhEPO (n=695). Baseline characteristics were compared in two groups. After propensity-score matching at a 1:3 ratio, we compared the efficacy of roxadustat and rhEPO in improving anemia, mainly using the Mann-Whitney U test. The follow-up period lasted 24 weeks. Results: The baseline characteristics were comparable between the two groups after propensity-score matching. There were no significant differences in the hemoglobin levels and estimated glomerular filtration rates (eGFRs) of the two groups before roxadustat or rhEPO treatment (P>0.05). The hemoglobin level after 4 weeks of treatment was 96 g/L in the roxadustat group, and the increase from baseline was 10 g/L; in the rhEPO group, these values were 87 and 6 g/L, respectively (P<0.001). After 12 weeks of treatment, the hemoglobin level and change from baseline were 105 and 15 g/L in the roxadustat group and 94 and 11 g/L in the rhEPO group, respectively (P<0.001). Similar results were observed after 24 weeks of treatment; the hemoglobin level and change from baseline were 105 and 17 g/L in the roxadustat group and 97 and 14 g/L in the rhEPO group (P=0.001). Conclusions: This retrospective study demonstrated that orally administered roxadustat improved hemoglobin levels more than rhEPO in patients with CKD and anemia.