Idiopathic nodular glomerulosclerosis: A case report and literature review.

This paper reports a 49-year-old male patient with a long-term smoking history who developed renal insufficiency and proteinuria in the range of nephropathy without diabetes. Renal biopsy showed nodular glomerulosclerosis with vitreous degeneration of arterioles and moderate and severe proliferation of glomerular mesangial cells and matrix. The patient was diagnosed with idiopathic nodular glomerulosclerosis. After treatment with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) drugs, the level of albuminuria decreased rapidly, and renal function remained stable. The clinical manifestations and pathological features of 122 cases of idiopathic nodular glomerulosclerosis reported from 1999 to August 2023 were analyzed, retrospectively.

Molecular Classification of Endometrial Endometrioid Carcinoma With Microcystic Elongated and Fragmented Pattern.

The studies on the molecular classification of endometrioid carcinoma (EC) with microcystic, elongated, and fragmented (MELF) pattern invasion are limited. In this study, 77 cases of ECs with MELF patterns in Chinese women were collected. The molecular classification of the fifth edition of the World Health Organization was used to classify the molecular subtypes using immunohistochemistry staining (mismatch repair [MMR]-immunohistochemistry: MSH2, MSH6, MLH1, and PMS2; p53) and Sanger sequencing targeted POLE . The results showed that the prevalence of the 4 molecular subtypes in EC with MELF pattern was 6.5% (5/77) for POLE mutation, 20.8% (16/77) for MMR deficient, 11.7% (9/77) for p53-mutant, and 61.0% (47/77) for no specific molecular profile. The clinicopathological characteristics of each subtype were compared. The p53-mutant and no specific molecular profile subgroups were associated with higher International Federation of Gynecology and Obstetrics stage and International Federation of Gynecology and Obstetrics grade, deeper myometrial invasion, lymphovascular space invasion, lymph node metastasis, and absence of tumor-infiltrating lymphocytes, whereas the POLE mutation and MMR deficient subgroups were associated with lower aggressive features and prominent tumor-infiltrating lymphocytes. Progression-free survival showed that the p53-mutant and no specific molecular profile subgroups had a poorer prognosis than the POLE mutation and MMR deficient subgroups. However, lymph node metastasis was an independent factor associated with a higher risk of disease recurrence in multivariate analysis. In conclusion, ECs with MELF patterns can be divided into 4 molecular subtypes with discrepancies in aggressive clinicopathological characteristics and tumor-infiltrating lymphocytes. Molecular classification has clinical significance in a morpho-molecular approach for ECs with MELF patterns.

proBDNF/p75NTR promotes rheumatoid arthritis and inflammatory response by activating proinflammatory cytokines.

P75 pan-neurotrophin receptor (p75NTR) is an important receptor for the role of neurotrophins in survival and death of neurons during development and after nerve injury. Our previous research found that the precursor of brain-derived neurotrophic factor (proBDNF) regulates pain as an inflammatory mediator. The current understanding of the role of proBDNF/p75NTR signaling pathway in inflammatory arthritis pain and rheumatoid arthritis (RA) is unclear. We recruited 20 RA patients, 20 healthy donors (HDs), and 10 osteoarthritis (OA) patients. Hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) of proBDNF and p75NTR in synovial membrane were performed and evaluated. We next examined the mRNA and protein expression of proBDNF/p75NTR signaling pathway in peripheral blood mononuclear cells (PBMCs) and synovial tissue. ELISA and flow cytometry were assessed between the blood of RA patients and HD. To induce RA, collagen-induced arthritis (CIA) were induced in mice. We found over-synovitis of RA synovial membrane compared to OA controls in histologic sections. P75NTR and sortilin mRNA, and proBDNF protein level were significantly increased in PBMCs of RA patients compared with the HD. Consistently, ELISA showed that p75NTR, sortilin, tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interleukin-10 (IL-10) levels in the serum of RA patients were increased compared with HD and p75NTR, sortilin were positively correlated with Disease Activity Score in 28 joints (DAS28). In addition, using flow cytometry we showed that the increased levels of proBDNF and p75NTR characterized in CD4+ and CD8+ T cells of RA patients were subsequently reversed with methotrexate (MTX) treatment. Furthermore, we found pathological changes, inflammatory pain, upregulation of the mRNA and protein expression of proBDNF/p75NTR signaling pathway, and upregulation of inflammatory cytokines in spinal cord using a well-established CIA mouse model. We showed intravenous treatment of recombinant p75ECD-Fc that biologically blocked all inflammatory responses and relieved inflammatory pain of animals with CIA. Our findings showed the involvement of proBDNF/p75NTR pathway in the RA inflammatory response and how blocking it with p75ECD-Fc may be a promising therapeutic treatment for RA.

Improved diagnosis of thyroid cancer aided with deep learning applied to sonographic text reports: a retrospective, multi-cohort, diagnostic study.

OBJECTIVE: Large volume radiological text data have been accumulated since the incorporation of electronic health record (EHR) systems in clinical practice. We aimed to determine whether deep natural language processing algorithms could aid radiologists in improving thyroid cancer diagnosis. METHODS: Sonographic EHR data were obtained from the EHR database. Pathological reports were used as the gold standard for diagnosing thyroid cancer. We developed thyroid cancer diagnosis based on natural language processing (THCaDxNLP) to interpret unstructured sonographic text reports for thyroid cancer diagnosis. We used the area under the receiver operating characteristic curve (AUROC) as the primary metric to measure the performance of the THCaDxNLP. We compared the performance of thyroid ultrasound radiologists aided with THCaDxNLP vs. those without THCaDxNLP using 5 independent test sets. RESULTS: We obtained a total number of 788,129 sonographic radiological reports. The number of thyroid sonographic data points was 132,277, 18,400 of which were thyroid cancer patients. Among the 5 test sets, the numbers of patients per set were 439, 186, 82, 343, and 171. THCaDxNLP achieved high performance in identifying thyroid cancer patients (the AUROC ranged from 0.857-0.932). Thyroid ultrasound radiologists aided with THCaDxNLP achieved significantly higher performances than those without THCaDxNLP in terms of accuracy (93.8% vs. 87.2%; one-sided t-test, adjusted P = 0.003), precision (92.5% vs. 86.0%; P = 0.018), and F1 metric (94.2% vs. 86.4%; P = 0.007). CONCLUSIONS: THCaDxNLP achieved a high AUROC for the identification of thyroid cancer, and improved the accuracy, sensitivity, and precision of thyroid ultrasound radiologists. This warrants further investigation of THCaDxNLP in prospective clinical trials.

Downregulation of DNMT3a expression by RNAi and its effect on NF-κBs expression of thymic epithelial cells.

OBJECTIVE: To understand the characteristics of DNA methyltransferase 3a (DNMT3a) in thymoma associated Myasthenia Gravis reveal its transcriptional regulator network as while as analyze the effect of DNMT3a on Rel/ nuclear factor-kappaB family (RelA/RelB) and its downstream autoimmune regulatory factor (Aire). METHODS: Tissues of 30 patients with thymoma, with or without myasthenia gravis (MG), were collected and the DNMT3a protein expression were evaluated through immunohistochemistry. We performed mRNA expression profiling microarray detection and analysis, and integrated the analysis by constructing protein-protein interaction networks and the integration with other database. We identified molecular difference between low and high DNMT3a in the thymoma by heatmap. We also performed PCR validation in thymoma tissues. The DNMT3a-shRNA plasmid was transfected into TEC cells, and these cells were treated with 5-aza-2-deoxycytidine, a blocker of DNMT3a. After the down-regulation of DNMT3a in TEC cells, the transcript and protein levels of RelA, RelB, Aire, and CHRNA3 were evaluated by western blotting. In addition, changes in gene expression profiles were screened through microarray technology. We performed differential gene analysis in the thymoma cohort by heatmap with R (v.4.3.0) software. RESULTS: In 30 matched tissue specimens, the expression of DNMT3a protein in thymoma with MG was lower than that in thymoma. Through mRNA expression profiling analysis, we constructed a co-expression network of DNMT3a and found direct interaction between IKZF1 and DNMT3a, and this co-expression relationship was overlappted with Cistrome DB database. We found up-regulation of 149 mRNAs and repression of 177 mRNAs in thymoma with MG compared with thymoma. Gene ontology and pathway analysis show the involvement of a multitude of genes in the mis-regulation of MG-related pathways. RNA interference significantly reduced the level of mRNA of DNMT3a, which proved that plasmid DNMT3a was effective. In comparison to the control group, the levels of DNMT3a, Aire, and CHRNA3 mRNA and protein in TEC cells transfected with DNMT3a-shRNA interference plasmid were significantly decreased, while the expression level of RelA and RelA/RelB was significantly increased. CONCLUSIONS: Our study reveals the DNMT3a-NF-κB pathway has a major effect on MG, and can be used as a marker for diagnosis as well as a target for MG treatment.

IL-37 Confers Anti-Tumor Activity by Regulation of m6A Methylation.

N6-methyladenosine (m6A) is a common transcriptomic modification in cancer. Recently, it has been found to be involved in the regulation of non-small cell lung cancer (NSCLC) formation and metastasis. Interleukin 37 (IL-37) plays a crucial protective role in lung cancer. In our previous studies, we found that IL-37 is a potential novel tumor suppressor by inhibiting IL-6 expression to suppress STAT3 activation and decreasing epithelial-to-mesenchymal transition. Moreover, we found that treatment of IL-37 in lung cancer cells induced widespread and dynamic RNA m6A methylation. The effects of RNA m6A methylation of IL-37 treatment require further study. However, the functions of RNA m6A methylation of IL-37 treatment still await elucidation. Using MeRIP-seq and RNA-seq, we uncovered a unique m6A methylation profile in the treatment of IL-37 on the A549 cell line. We also showed the expression of m6A writers METTL3, METTL14, and WTAP and erasers ALKBH5 and FTO in A549 cells and lung cancer tissues after the treatment of IL-37. This study showed that IL-37 could lead to changes in m6A methylation level and related molecule expression level in A546 cells and may downregulate the proliferation by inhibiting Wnt5a/5b pathway in A549 cells. We conclude that IL-37 suppresses tumor growth through regulation of RNA m6A methylation in lung cancer cells.

Alteration in gene expression profiles of thymoma: Genetic differences and potential novel targets.

BACKGROUND: This study was conducted to investigate the gene expression profiles associated with thymoma to better understand the molecular mechanism underlying the pathogenesis of thymoma. METHODS: Eight patients with thymomas (type A, AB, B1, and B2) and four controls with thymic cysts were analyzed using microarray profiling to identify changes in gene expression. RESULTS: Across all of our samples, 2319 messenger RNAs were upregulated and 2776 were downregulated in thymomas relative to thymic cysts. Gene ontology and pathway analyses revealed that a large number of genes participate in cellular functions, among which MHC class II protein complex assembly, assembly with peptide antigen, calcium activated phosphatidylcholine scrambling, and release of cytoplasmic sequestered NF-κB were dysregulated, whereas intestinal immune network for immunoglobulin A production, cytokine-cytokine receptor interaction, the calcium signaling pathway, and pathways related to autoimmune diseases were downregulated. CONCLUSIONS: Our results revealed gene expression differences between thymomas and thymic cysts, and identified key candidate genes/pathways that might be used as diagnostic markers and potential therapeutic targets to treat cancer metastasis.

A novel subtype of primary prostatic adenocarcinoma: A case report.

The present study reports the novel case of an 81-year-old male with prostatic adenocarcinoma (PAC), whose histopathological study revealed a pure urothelial carcinoma (UC) that originated, however, from the prostatic glandular epithelium. The levels of serum prostate-specific antigen (PSA) were extraordinarily high in this patient. An MRI scan indicated a prostatic neoplasm and no malignant changes were observed in the bladder or other areas of the urinary tract. Hematoxylin and eosin-stained sections revealed a diagnosis of pure UC with no other form of differentiation (typical adenocarcinoma or squamous differentiation). The immunohistochemical findings were positive for PSA and P504S, and negative for CK7, CK20, 34ßE12 and p63. A diagnosis of primary PAC (solid carcinoma) originating from the prostate was made based on the clinical, histopathological and immunohistochemical observations. This case was susceptible to diagnostic errors, however, a novel subtype of primary PAC was identified and termed the UC-like subtype.