-
Journal of the Endocrine Society Jul 2024Activation of fibroblast growth factor receptor 1 (FGFR1) signaling improves the metabolic health of animals and humans, while inactivation leads to diabetes in mice....
CONTEXT
Activation of fibroblast growth factor receptor 1 (FGFR1) signaling improves the metabolic health of animals and humans, while inactivation leads to diabetes in mice. Direct human genetic evidence for the role of FGFR1 signaling in human metabolic health has not been fully established.
OBJECTIVE
We hypothesized that individuals with naturally occurring variants ("experiments of nature") will display glucose dysregulation.
METHODS
Participants with rare variants and noncarrier controls. Using a recall-by-genotype approach, we examined the β-cell function and insulin sensitivity of 9 individuals with rare deleterious variants compared to 27 noncarrier controls, during a frequently sampled intravenous glucose tolerance test at the Reproductive Endocrine Unit and the Harvard Center for Reproductive Medicine, Massachusetts General Hospital. -mutation carriers displayed higher β-cell function in the face of lower insulin sensitivity compared to controls.
CONCLUSION
These findings suggest that impaired FGFR1 signaling may contribute to an early insulin resistance phase of diabetes pathogenesis and support the candidacy of the FGFR1 signaling pathway as a therapeutic target for improving the human metabolic health.
PubMed: 38957656
DOI: 10.1210/jendso/bvae118 -
Journal of the Endocrine Society Jul 2024Rabson-Mendenhall syndrome (RMS) is a rare autosomal, recessive disorder characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene.... (Review)
Review
AIMS
Rabson-Mendenhall syndrome (RMS) is a rare autosomal, recessive disorder characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. This study aims to analyze the clinical features and gene mutations in RMS, which have not been extensively studied.
METHODS
PubMed, Embase, the China National Knowledge Infrastructure, and Wanfang were searched for "Rabson-Mendenhall syndrome" or "Black acanthosis hirsutism insulin resistance syndrome."
RESULTS
A total of 42 cases from 33 articles were included. The body mass index ranged from 18.50 to 20.00 kg/m with an average of 16.00 kg/m. There were no overweight (25.00∼29.90 kg/m) or obese (≥30.00 kg/m) patients. Acanthosis was present in 29 cases (29/42, 69.05%); growth retardation in 25 cases (25/42, 59.52%); dental anomalies including absence of teeth, crowding, and malocclusion in 23 cases (23/42, 54.76%); and hirsutism in 17 cases (17/42, 40.48%). The average glycosylated hemoglobin was 9.35%, and the average fasting blood-glucose was 8.44 mmol/L; the mean fasting insulin was 349.96 μIU/mL, and the average fasting C-peptide was 6.00 ng/mL. Diabetes was reported in 25 cases (25/33, 75.76%) all of which were diagnosed before 23 years old. All 42 patients had recorded gene mutations, with 22 patients (22/42, 52.38%) having ≥ 2 mutations and 20 cases (20/42, 47.62%) having only 1 mutation. No statistical differences were found in clinical features and laboratory parameters between patients with different mutations.
CONCLUSION
The study indicates that RMS should be considered in young patients with hyperinsulinemia, hyperglycemia with low weight, acanthosis nigricans, growth retardation, dental anomalies, and hirsutism.
PubMed: 38957655
DOI: 10.1210/jendso/bvae123 -
Cureus Jul 2024Lung cancer metastasizing to the colon is exceedingly rare and can present similarly to colorectal cancer. It is crucial to conduct further evaluations using...
Lung cancer metastasizing to the colon is exceedingly rare and can present similarly to colorectal cancer. It is crucial to conduct further evaluations using immunohistochemical (IHC) stains and genomic testing to differentiate between the two and provide appropriate treatment without delay. Lung cancer generally has a poor prognosis, especially in cases with distant metastases. Although gastrointestinal (GI) metastases from lung cancer have been reported, cases of lung cancer manifesting as colon metastasis are extremely rare, with only a few instances documented.
PubMed: 38957515
DOI: 10.7759/cureus.63665 -
Frontiers in Immunology 2024Hemophagocytic lymphohistiocytosis (HLH) is an immune dysfunction characterized by an exaggerated and pathological inflammatory response, potentially leading to systemic... (Review)
Review
Hemophagocytic lymphohistiocytosis (HLH) is an immune dysfunction characterized by an exaggerated and pathological inflammatory response, potentially leading to systemic inflammatory reactions and multiple-organ failure, including renal involvement. HLH can be classified as primary or secondary, with primary HLH associated with genetic mutations affecting cell degranulation capacity, and secondary HLH often linked to infections, tumors, and autoimmune diseases. The pathogenesis of HLH is not fully understood, but primary HLH is typically driven by genetic defects, whereas secondary HLH involves the activation of CD8+ T cells and macrophages, leading to the release of inflammatory cytokines and systemic inflammatory response syndrome (SIRS). The clinical presentation of HLH includes non-specific manifestations, making it challenging to differentiate from severe sepsis, particularly secondary HLH due to infections. Shared features include prolonged fever, hepatosplenomegaly, hematopenia, hepatic dysfunction, hypertriglyceridemia, and hypofibrinogenemia, along with histiocytosis and hemophagocytosis. However, distinctive markers like dual hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated sCD25 levels may aid in differentiating HLH from sepsis. Indeed, no singular biomarker effectively distinguishes between hemophagocytic lymphohistiocytosis and infection. However, research on combined biomarkers provides insights into the differential diagnosis. Renal impairment is frequently encountered in both HLH and sepsis. It can result from a systemic inflammatory response triggered by an influx of inflammatory mediators, from direct damage caused by these factors, or as a consequence of the primary disease process. For instance, macrophage infiltration of the kidney can lead to structural damage affecting various renal components, precipitating disease. Presently, tubular necrosis remains the predominant form of renal involvement in HLH-associated acute kidney injury (HLH-AKI). However, histopathological changes may also encompass interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Treatment approaches for HLH and sepsis diverge significantly. HLH is primarily managed with repeated chemotherapy to eliminate immune-activating stimuli and suppress hypercellularity. The treatment approach for sepsis primarily focuses on anti-infective therapy and intensive symptomatic supportive care. Renal function significantly influences clinical decision-making, particularly regarding the selection of chemotherapy and antibiotic dosages, which can profoundly impact patient prognosis. Conversely, renal function recovery is a complex process influenced by factors such as disease severity, timely diagnosis, and the intensity of treatment. A crucial aspect in managing HLH-AKI is the timely diagnosis, which plays a pivotal role in reversing renal impairment and creating a therapeutic window for intervention, may have opportunity to improve patient prognosis. Understanding the clinical characteristics, underlying causes, biomarkers, immunopathogenesis, and treatment options for hemophagocytic lymphohistiocytosis associated with acute kidney injury (HLH-AKI) is crucial for improving patient prognosis.
Topics: Lymphohistiocytosis, Hemophagocytic; Humans; Acute Kidney Injury; Critical Care; Biomarkers
PubMed: 38957461
DOI: 10.3389/fimmu.2024.1396124 -
Frontiers in Immunology 2024Targeted therapy and immunotherapy are both important in the treatment of non-small-cell lung cancer (NSCLC). Accurate diagnose and precise treatment are key in...
Targeted therapy and immunotherapy are both important in the treatment of non-small-cell lung cancer (NSCLC). Accurate diagnose and precise treatment are key in achieving long survival of patients. fusion is a rare oncogenic factor, whose optimal detection and treatment are not well established. Here, we report on a 32-year-old female lung adenocarcinoma patient with positive PD-L1 and negative driver gene detected by DNA-based next-generation sequencing (NGS). A radical resection of the primary lesion after chemotherapy combined with PD-1 checkpoint inhibitor administration indicated primary immuno-resistance according to her pathological response and rapid relapse. A rare was detected by RNA-based NGS, which was confirmed by fluorescence hybridization. Multiplex immunofluorescence revealed a PD-L1 related heterogeneous immunosuppressive microenvironment with little distribution of CD4+ T cells and CD8+ T cells. Savolitinib therapy resulted in a progression-free survival (PFS) of >12 months, until a new secondary resistance mutation in p.D1228H was detected by re-biopsy and joint DNA-RNA-based NGS after disease progression. In this case, fusion NSCLC was primarily resistant to immunotherapy, sensitive to savolitinib, and developed secondary p.D1228H mutation after targeted treatment. DNA-RNA-based NGS is useful in the detection of such molecular events and tracking of secondary mutations in drug resistance. To this end, DNA-RNA-based NGS may be of better value in guiding precise diagnosis and individualized treatment in this patient population.
Topics: Humans; Female; Adenocarcinoma of Lung; Adult; Lung Neoplasms; High-Throughput Nucleotide Sequencing; Proto-Oncogene Proteins c-met; Oncogene Proteins, Fusion; Drug Resistance, Neoplasm; Immune Checkpoint Inhibitors
PubMed: 38957460
DOI: 10.3389/fimmu.2024.1386561 -
PNAS Nexus Jul 2024The Fanconi anemia (FA) repair pathway governs repair of highly genotoxic DNA interstrand crosslinks (ICLs) and relies on translesion synthesis (TLS). TLS is facilitated...
The Fanconi anemia (FA) repair pathway governs repair of highly genotoxic DNA interstrand crosslinks (ICLs) and relies on translesion synthesis (TLS). TLS is facilitated by REV1 or site-specific monoubiquitination of proliferating cell nuclear antigen (PCNA) (PCNA-Ub) at lysine 164 (K164). A but not mutation renders mammals hypersensitive to ICLs. Besides the FA pathway, alternative pathways have been associated with ICL repair (1, 2), though the decision making between those remains elusive. To study the dependence and relevance of PCNA-Ub in FA repair, we intercrossed mice. A combined mutation ( ) was found embryonically lethal. RNA-seq of primary double-mutant (DM) mouse embryonic fibroblasts (MEFs) revealed elevated levels of replication stress-induced checkpoints. To exclude stress-induced confounders, we utilized a knock-down to obtain a model to study ICL repair in depth. Regarding ICL-induced cell toxicity, cell cycle arrest, and replication fork progression, single-mutant and DM MEFs were found equally sensitive, establishing PCNA-Ub to be critical for FA-ICL repair. Immunoprecipitation and spectrometry-based analysis revealed an unknown role of PCNA-Ub in excluding mismatch recognition complex MSH2/MSH6 from being recruited to ICLs. In conclusion, our results uncovered a dual function of PCNA-Ub in ICL repair, i.e. exclude MSH2/MSH6 recruitment to channel the ICL toward canonical FA repair, in addition to its established role in coordinating TLS opposite the unhooked ICL.
PubMed: 38957451
DOI: 10.1093/pnasnexus/pgae242 -
MicroPublication Biology 2024The transcription factor is required in for patterning the eye-antennal disk. At the adult stage, is strongly expressed in Johnston's Organ (JO) neurons, the antennal...
The transcription factor is required in for patterning the eye-antennal disk. At the adult stage, is strongly expressed in Johnston's Organ (JO) neurons, the antennal auditory organ. Using RNAi-mediated knockdown of using a strong neuronal driver, we find a significant reduction in electrophysiological responses to auditory stimuli, recorded from the antennal nerve. This reduction can be accounted for by knockdown in the auditory subset of JO neurons, with no effect of knockdown in JO neuron subsets associated with wind or gravity detection. Conversely, knockdown in JO sense organ precursors had no effect on hearing. Mosaic animals with antennal clones of the null mutation showed morphological defects in the antenna, and significant auditory electrophysiological defects. Our results are consistent with two distinct functions for in the antenna, including an early patterning function in the eye-antennal disk, and a later neural differentiation function in the JO neurons.
PubMed: 38957438
DOI: 10.17912/micropub.biology.001229 -
Frontiers in Oncology 2024Microsatellite instability (MSI) is a genetic marker that is useful in the detection and treatment of Lynch syndrome (Sd). Although conventional techniques such as...
INTRODUCTION
Microsatellite instability (MSI) is a genetic marker that is useful in the detection and treatment of Lynch syndrome (Sd). Although conventional techniques such as immunohistochemistry (IHC) and polymerase chain reaction (PCR) are the standards for MSI detection, the advent of next-generation sequencing (NGS) has offered new possibilities, especially with circulating DNA.
CASE REPORT
We present the case of a 26-year-old patient with Lynch Sd and a -mutated metastatic colon cancer. The discordant MSI results between the conventional methods and NGS posed challenges in making treatment decisions. Subsequent NGS analysis revealed a high MSI status, leading to participation in an immunotherapy trial, with remarkable clinical response.
CONCLUSION
This case emphasizes the importance of comprehensive molecular profiling and strong interdisciplinary collaborations, especially in cases with ambiguous MSI results.
PubMed: 38957326
DOI: 10.3389/fonc.2024.1396869 -
Frontiers in Oncology 2024Lynch syndrome (LS) is an inherited cancer predisposition syndrome characterized by a high risk of colorectal and extracolonic tumors. Germline pathogenic variants (GPV)...
INTRODUCTION
Lynch syndrome (LS) is an inherited cancer predisposition syndrome characterized by a high risk of colorectal and extracolonic tumors. Germline pathogenic variants (GPV) in the gene are associated with <15% of all cases. The pseudogene presents high homology with , challenging molecular diagnosis by next-generation sequencing (NGS). Due to the high methodological complexity required to distinguish variants between and , most laboratories do not clearly report the origin of this molecular finding.
OBJECTIVE
The aim of this study was to confirm the GPVs detected by NGS in regions of high homology segments of the gene in a Brazilian sample.
METHODS
An orthogonal and gold standard long-range PCR (LR-PCR) methodology to separate variants detected in the gene from those detected in the pseudogene.
RESULTS
A total of 74 samples with a GPV detected by NGS in exons with high homology with pseudogene were evaluated. The most common was NM_000535.6:c.2182_2184delinsG, which was previously described as deleterious mutation in a study of African-American patients with LS and has been widely reported by laboratories as a pathogenic variant associated with the LS phenotype. Of all GPVs identified, only 6.8% were confirmed by LR-PCR. Conversely, more than 90% of GPV were not confirmed after LR-PCR, and the diagnosis of LS was ruled out by molecular mechanisms associated with
CONCLUSION
In conclusion, the use of LR-PCR was demonstrated to be a reliable approach for accurate molecular analysis of variants in segments with high homology with . We highlight that our laboratory is a pioneer in routine diagnostic complementation of the gene in Brazil, directly contributing to a more assertive molecular diagnosis and adequate genetic counseling for these patients and their families.
PubMed: 38957325
DOI: 10.3389/fonc.2024.1390221 -
Biological Psychiatry Global Open... Jul 2024Sex-differential biology may contribute to the consistently male-biased prevalence of autism spectrum disorder (ASD). Gene expression differences between males and...
BACKGROUND
Sex-differential biology may contribute to the consistently male-biased prevalence of autism spectrum disorder (ASD). Gene expression differences between males and females in the brain can indicate possible molecular and cellular mechanisms involved, although transcriptomic sex differences during human prenatal cortical development have been incompletely characterized, primarily due to small sample sizes.
METHODS
We performed a meta-analysis of sex-differential expression and co-expression network analysis in 2 independent bulk RNA sequencing datasets generated from cortex of 273 prenatal donors without known neuropsychiatric disorders. To assess the intersection between neurotypical sex differences and neuropsychiatric disorder biology, we tested for enrichment of ASD-associated risk genes and expression changes, neuropsychiatric disorder risk genes, and cell type markers within identified sex-differentially expressed genes (sex-DEGs) and sex-differential co-expression modules.
RESULTS
We identified 101 significant sex-DEGs, including Y-chromosome genes, genes impacted by X-chromosome inactivation, and autosomal genes. Known ASD risk genes, implicated by either common or rare variants, did not preferentially overlap with sex-DEGs. We identified 1 male-specific co-expression module enriched for immune signaling that is unique to 1 input dataset.
CONCLUSIONS
Sex-differential gene expression is limited in prenatal human cortex tissue, although meta-analysis of large datasets allows for the identification of sex-DEGs, including autosomal genes that encode proteins involved in neural development. Lack of sex-DEG overlap with ASD risk genes in the prenatal cortex suggests that sex-differential modulation of ASD symptoms may occur in other brain regions, at other developmental stages, or in specific cell types, or may involve mechanisms that act downstream from mutation-carrying genes.
PubMed: 38957312
DOI: 10.1016/j.bpsgos.2024.100321