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PubMed2026

Efficacy of Proton Pump Inhibitor Therapy for Nocturnal GERD Symptoms and Associated Sleep Disturbances: A Systematic Review of Randomized Controlled Trials.

GOALS: A systematic review was conducted to evaluate the efficacy and safety of proton pump inhibitor (PPI) therapy in relieving nocturnal reflux symptoms and sleep disturbances. BACKGROUND: Nocturnal gastroesophageal reflux disease (GERD) is commonly associated with sleep disturbances. The benefits of PPI therapy for GERD-related nocturnal reflux and sleep disturbance remain unclear. STUDY: We searched the MEDLINE, EMBASE, and Cochrane CENTRAL databases from inception to March 1, 2026, for randomized controlled trials (RCTs) in adults with GERD and sleep disturbances that compared any PPI to placebo or an alternative therapy. The primary outcome was the proportion of patients experiencing relief from nighttime heartburn. Secondary outcomes included relief from GERD-related sleep disturbances, changes in subjective sleep quality, work productivity, and treatment-emergent adverse events (TEAEs). RESULTS: Five RCTs involving 1495 patients met the inclusion criteria. Three placebo-controlled trials consistently showed that PPI therapy improved nighttime heartburn relief and GERD-related sleep disturbances compared with placebo. Subjective sleep quality and sleep-related daytime functioning also generally improved with PPI therapy. However, the findings were more heterogeneous across trials because of differences in study populations, comparators, and outcome measures. Across the placebo-controlled studies, TEAEs were generally similar between the PPI and placebo groups. CONCLUSIONS: PPI therapy was associated with improvement in nighttime heartburn and reflux-related sleep disturbances, especially in patients with reflux-driven nocturnal symptoms. The available evidence also suggests potential improvement in subjective sleep quality and sleep-related daytime functioning.

Humans↗

PubMed2026

Causal Relationships Between Modifiable Risk Factors and Gastroesophageal Reflux Disease: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: Gastroesophageal reflux disease (GERD) is a prevalent digestive disorder, yet the causal roles of modifiable risk factors remain unclear. This study aims to investigate the causal relationships between 28 modifiable risk factors (including obesity traits, mental health disorders, sleep traits, metabolic comorbidities, and serum parameters) and GERD using two-sample Mendelian randomization (MR). Gastroesophageal reflux disease (GERD). Our findings aim to inform targeted prevention and treatment strategies for GERD. METHODS: This study obtained data from extensive genome-wide association studies (GWAS). Pooled data associated with gastroesophageal reflux associations were obtained from the 23andMe Research team's research, which included a total of 129,080 cases of gastroesophageal reflux and 473,524 controls of European ancestry. We conducted a univariable Mendelian randomization (MR) analysis to ascertain whether genetic evidence of exposure demonstrated a statistically significant association with the risk of GERD. Subsequently, a multivariable MR analysis was carried out to estimate the independent effects of the exposures on GERD. RESULTS: Univariable MR analysis utilizing extensive GWAS data suggested that genetic factors such as BMI, Waist circumference, Arm fat mass (left and right), Leg fat mass (left and right), Attention Deficit and Hyperactivity Disorder (ADHD), Major Depressive Disorder (MDD), Schizophrenia, Negative emotions (including nervousness, anxiety, tension, or depression), Insomnia, Sleep apnea syndrome, Sleep duration, and Snoring, as well as Total cholesterol levels and Apolipoprotein B levels, are associated with the development of GERD. Multivariate Mendelian randomization of BMI and Negative emotion as correction factors showed that Waist circumference, Arm fat mass (left and right), Leg fat mass (left and right), ADHD, Insomnia, Sleep apnea syndrome, and Snoring were associated with an increased risk of GERD (p< 0.05). Conversely, longer sleep duration was associated with a reduced risk of GERD (p< 0.05). DISCUSSION: This MR study reveals novel causal mechanisms in GERD pathogenesis: (1) Peripheral adiposity (arm/leg fat mass) exerts independent effects beyond central obesity, indicating site-specific fat distribution significance; (2) ADHD emerges as a distinct psychiatric risk factor independent of mental disorders; (3) Sleep apnea operates through BMI-independent pathways. Collectively, these findings redefine GERD pathophysiology, highlighting fat depot specificity and brain-gut interactions as critical mechanistic drivers. CONCLUSION: Overall, our findings suggest that multiple risk factors are associated with the risk of GERD. These results provide a theoretical basis for controlling body weight and plasticity, improving sleep habits, and preventing and timely seeking medical attention to reduce the occurrence of psychiatric disorders, which will be important strategies to prevent and alleviate GERD.

Humans↗

PubMed2025

Mendel randomization confirmed gastroesophageal reflux disease may increase the risk of mental disorders.

BACKGROUND: The potential causal relationship between gastroesophageal reflux disease (GERD) and mental disorder was analyzed using the mendelian randomization (MR) method. METHODS: Data are derived from genome-wide association study (GWAS) summary data, using gastroesophageal reflux disease (GERD) as the exposure factor. Single nucleotide polymorphisms (SNPs) significantly associated with GERD were selected as instrumental variables (IVs), and mental disorders (bipolar disorder, major depression, Alzheimer's disease, anorexia nervosa, anxiety, and obsessive-compulsive disorder) were used as outcome variables. The inverse variance weighted (IVW) method is used as the main analysis method, and MR-Egger regression, weighted median (WM) method, simple mode and weighted mode are used as supplementary methods for Mendelian randomization (MR) analysis. Cochran's Q test and P value are used to quantify heterogeneity, MR-Egger regression was used to evaluate the multilevel effect test of SNPs, and leave-one-out method to determine whether there are potential SNPs, and to evaluate the stability of the results. Odds ratio (OR) and 95% confidence interval (CI) were used as effect indicators to evaluate whether there is a causal relationship between GERD and mental disorders. RESULTS: IVW demonstrated a causal relationship between GERD and bipolar disorder (OR = 1.70, 95%CI = 1.39-2.09, P < 0.05) and anorexia nervosa (OR = 0.71, 95%CI = 0.52-0.99, P < 0.05). Furthermore, there is a weak causal relationship between GERD and major depression (OR = 1.01, 95%CI = 1.01-1.02, P < 0.05) and anxiety (OR = 1.01, 95%CI = 1.01-1.01, P < 0.05). Similarly, there is no evidence of a causal relationship between GERD and Alzheimer's disease (OR = 0.95, 95%CI = 0.87-1.03, P > 0.05) or obsessive-compulsive disorder (OR = 0.95, 95%CI = 0.67-1.36, P > 0.05). Cochran's Q test for heterogeneity shows that there is no significant heterogeneity (P > 0.05) for bipolar disorder, anxiety, and obsessive-compulsive disorder. However, major depression, Alzheimer's disease, and anorexia nervosa have some degree of heterogeneity (P < 0.05). Horizontal pleiotropic analysis showed that the P values for six mental disorders (0.750, 0.296, 0.154, 0.798, 0.893, 0.451) were all greater than 0.05. Leave-one-out analysis and funnel plot showed that MR analysis results can be considered relatively stable. All F are > 10, indicating no weak IVs bias. CONCLUSION: GERD can obviously increase the risk of bipolar disorder; the increased risk of anxiety disorder is very slight. There is no clear evidence to support the causal relationship between GERD and four other mental disorders, including major depression, Alzheimer's disease, anorexia nervosa, and obsessive-compulsive disorder.

Humans↗

PubMed2024

Leisure television watching exerts a causal effect on gastroesophageal reflux disease: evidence from a two-step mendelian randomization study.

BACKGROUND: Previous studies have shown that physical activity (PA) and leisure sedentary behaviors (LSB, including leisure television watching) are linked to gastroesophageal reflux disease (GERD). However, the associations between PA/LSB and GERD remain controversial. In this study, we aimed to reveal whether these associations reflect causal relationships and reveal the potential mechanisms of these relationships using bidirectional and two-step Mendelian randomization (MR) analyses. METHODS: We obtained genome-wide association study (GWAS) summary statistics for PA/LSB, four common risk factors (including cigarettes smoked per day, alcoholic drinks per week, triglycerides, total cholesterol) and GERD from published GWASs. A bidirectional MR analysis was performed to identify causal relationships between PA/LSB and GERD. Then, a series of sensitivity analyses were performed to verify the robustness of the results. Finally, a mediation analysis via two-step MR was conducted to investigate any effects explained by common risk factors in these relationships. RESULTS: Genetically predicted per 1-SD increase in leisure time television watching significantly increased the risk of GERD in the bidirectional MR analysis (OR = 1.33; 95% CI: 1.14-1.56; P = 2.71 × 10- 4). Sensitivity analyses successfully verified the robustness of the causal relationship. Further mediation analysis showed that this effect was partly mediated by increasing cigarettes smoked per day, with mediated proportions of 18.37% (95% CI: 11.94-39.79%). CONCLUSION: Our findings revealed a causal relationship between leisure television watching and an increased risk of GERD, notably, the causal effect was partially mediated by cigarettes smoked per day. These findings may inform prevention and management strategies directed toward GERD.

Humans↗

PubMed2026

Shared genetic architecture of obesity and gastroesophageal reflux disease.

Obesity is identified as a risk factor of gastroesophageal reflux disease (GERD). This study aims to elucidate the shared genetic architecture of obesity-related phenotypes and GERD. Based on the publicly available genome-wide association studies' datasets, this genome-wide pleiotropic association study was conducted with various genetic approaches (including linkage disequilibrium score regression, high-definition likelihood inference for genetic correlations, pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation, Bayesian colocalization, summary-based Mendelian randomization, and multi-marker analysis of genomic annotation analysis) sequentially to unravel the genetic associations from single-nucleotide polymorphism to gene levels, and to reveal the underlying shared genetic architecture between obesity-related phenotypes and GERD. This study discovered shared genetic mechanisms between GERD and several obesity-related phenotypes, including arm fat percentage (left), arm fat percentage (right), leg fat percentage (left), leg fat percentage (right), trunk fat percentage, waist-to-hip ratio, and body mass index. Significant genetic correlations were observed by linkage disequilibrium score regression and high-definition likelihood inference for genetic correlations, with multiple associated pleiotropic loci and their mapped genes identified by pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation, Bayesian colocalization, summary-based Mendelian randomization, and multi-marker analysis of genomic annotation analysis. Additionally, several brain tissues were identified to be linked to both obesity and GERD by multi-marker analysis of genomic annotation. This research provided strong evidence of genetic correlations and brought novel insights into the underlying genetic connections and shared genetic architectures of obesity and GERD.

Humans↗

PubMed2026

Late hiatal hernia after Roux-en-Y gastric bypass: a systematic review.

Obesity is a global public health issue. This condition is linked to gastroesophageal reflux disease (GERD) and hiatal hernia (HH), both of which are exacerbated by increased intra-abdominal pressure. Roux-en-Y gastric bypass (RYGB) is one of the most widely performed techniques for treating obesity and is considered a versatile option suitable for most patients. The development of a symptomatic HH and pouch migration can lead to various symptoms and complications. PubMed, EMBASE, and Cochrane Central were searched for studies with late HH after RYGB. We pooled outcomes for symptom resolution. Secondary outcomes were recurrence rate and operation characteristics (mesh use, cruroplasty, gastropexy, reoperation, length of stay, and operative time). A meta-analysis could not be conducted due to significant heterogeneity in HH. HH following RYGB presents with GERD (39-93.6%), obstructive symptoms (29%-88%), and abdominal pain (28.6%-71%). Diagnostic methods include endoscopy, computed tomography scans, and upper gastrointestinal series. Surgical management varies, with primary cruroplasty being the most common approach, sometimes incorporating mesh or fundoplication. Postoperative symptom resolution rates range from 42.9% to 100%, with HH recurrence occurring in 5%-6.54% of cases. Follow-up durations varied, showing improvement in most patients, though some continued to experience reflux and dysphagia HH contributes to obstructive and reflux symptoms, with contrast-enhanced imaging offering the highest diagnostic accuracy. Bioabsorbable mesh may reduce recurrence, highlighting the need for long-term monitoring.

Humans↗

PubMed2025

Genome-Wide Association Analyses of HPV16 and HPV18 Seropositivity Identify Susceptibility Loci for Cervical Cancer.

Infection by high-risk human papillomavirus is known to exacerbate cervical cancer development. The host immune response is crucial in disease regression. Large-scale genetic association studies for cervical cancer have identified few susceptibility variants, mainly at the human leukocyte antigen locus on chromosome 6. We hypothesized that the host immune response modifies cervical cancer risk and performed three genome-wide association analyses for HPV16, HPV18 and HPV16/18 seropositivity in 7814, 7924, and 7924 samples from the UK Biobank, followed by validation genotyping in the German Cervigen case-control series of cervical cancer and dysplasia. In GWAS analyses, we identified two loci associated with HPV16 seropositivity (6p21.32 and 15q26.2), two loci associated with HPV18 seropositivity (5q31.2 and 14q24.3), and one locus for HPV16 and/or HPV18 seropositivity (at 6p21.32). MAGMA gene-based analysis identified HLA-DQA1 and HLA-DQB1 as genome-wide significant (GWS) genes. In validation genotyping, the genome-wide significant lead variant at 6p21.32, rs9272293 associated with overall cervical disease (OR = 0.86, p = 0.004, 95% CI = 0.78-0.95, n = 3710) and HPV16 positive invasive cancer (OR = 0.73, p = 0.005, 95% CI = 0.59-0.91, n = 1431). This variant was found to be a robust eQTL for HLA-DRB1, HLA-DQB1-AS1, C4B, HLA-DRB5, HLA-DRB6, HLA-DQB1, and HLA-DPB1 in a series of cervical epithelial tissue samples. We additionally genotyped twenty-four HPV seropositivity variants below the GWS threshold out of which eleven variants were found to be associated with cervical disease in our cohort, suggesting that further seropositivity variants may determine cervical disease outcome. Our study identifies novel genomic risk loci that associate with HPV type-specific cervical cancer and dysplasia risk and provides evidence for candidate genes at one of the risk loci.

Humans↗

PubMed1975

[X-ray studies of the brain as a basis for stereotaxy (author's transl)].

All attempts to reconstruct the topography of the brain in the living from studies of animal material are handicapped by technical difficulties. The best method is to compare exact X-ray pictures, which have been taken under stereotactic conditions. From a large collection of such X-rays the authors have composed contours of the internal table of the skull and of the ventricles, which best match the brains, selected for the Schaltenbrand-Bailey sterotactic atlas. For practical purposes these contours were combined with the transparent overlays for the nomenclature and the border lines of the different parts of the basal ganglia, which have been used in the myelin sections part of the atlas. A comparison of our sagittal series with the new X-ray findings shows, that the sagittal schemata of the atlas represent an extreme variation in the position of the Meynert axis and of the contours of the 4th ventricle. We have chosen a new axis system for the hindbrain, which corresponds to the average of our brains in constructing a new set of typical overlays for the atlas. The contour of the posterior fossa had to be completed. An independent axis system dor the structures of the 4th ventricle was developed, consisting of the base of the 4th ventricle, and a tangent, to the upper contour of the pons. In sterotactic procedures the axis systems for the forebrain and the hindbrain should be used independently. The results obtained are the basis for a new series of lantern slides which can be projected against the X-ray pictures with the Würzburg stereotactic equipment. In the course of this investigation we discovered a source of error. When air enters the puncture hole of the dura, the brain may sink back, so with the patient lying on his back, all structures may shift a few millimeters towards the occipital region. When the patient is lying on his side, as during an approach to the amygdala through the planum temporale, the ventricular system may collapse, so that almost no air is visible in the ventricles and the 3rd ventricle may appear to be in the lower hemisphere, the dislocation being more than 5-8 mm. But filling the ventricle with air through the ventricular catheter is sufficient to blow up the brain and to restore the normal topography.

Brain↗

PubMed2026

Optical genome mapping improves structural variant detection and characterization in syndromic and neurogenetic disorders.

Optical Genome Mapping (OGM) offers superior resolution compared to standard diagnostic methods such as karyotyping and FISH, enabling the detection of nearly all types of chromosomal aberrations with non-centromeric breakpoints. This study evaluated OGM's potential to enhance the genetic findings in unsolved cases of neurogenetic and syndromic disease requiring further investigation after standard genetic testing. In 10 patients with various neurogenetic diagnoses, OGM confirmed all structural findings previously detected by karyotyping, chromosomal microarray (CMA), and/or NGS. Moreover, OGM provided additional structural insights in five cases, such as identifying a novel candidate gene in a patient with a balanced translocation, redefining of breakpoint regions in familial translocations, characterization of complex rearrangements, and revising of initial diagnostic interpretations. Most importantly, we present OGM results for three individuals with ring chromosomes 18, 20, and 22, highlighting the need to adjust filter settings and to incorporate the rare variant pipeline for accurate detection. Based on our experiences, we propose a strategic approach for identifying ring chromosomes using OGM. On the other hand, OGM did not identify causative variants in three unsolved cases with strong clinical suspicion of hereditary neuropathy. In summary, while OGM did not yield new insights for hereditary neuropathy, it provided additional or refined information in 6 out of 10 cases with other syndromic diseases. These findings underscore the value of OGM in increasing the diagnostic yield and precision of genetic testing.

Humans↗

PubMed2026

Futibatinib after non-covalent FGFR inhibitors in FGFR2-rearranged intrahepatic cholangiocarcinoma: clinical activity and resistance patterns.

PURPOSE: The optimal sequencing of non-covalent and covalent FGFR inhibitors in FGFR2-rearranged intrahepatic cholangiocarcinoma (iCCA) remains undefined. Futibatinib, an irreversible FGFR1-4 inhibitor, may retain activity in the setting of acquired resistance to non-covalent FGFR inhibitors, but data on the patterns of acquired alterations are limited. METHODS: We conducted a retrospective multicenter study across three European centers including patients with advanced FGFR2-rearranged iCCA treated with futibatinib after progression on non-covalent FGFR inhibitors. Clinical outcomes and safety were evaluated. Available genomic profiling at progression was analyzed to characterize resistance mechanisms and their association with outcomes. RESULTS: Sixteen patients were included. Median progression-free survival (mPFS) with prior non-covalent FGFR inhibitors was 10.2 months (95% CI 7.0-15.5), with an objective response rate (ORR) of 60.0%. Among patients with post-progression genomic profiling (n = 11), all harbored FGFR2 resistance mutations, with polyclonal alterations (≥2) in 45.5%. A higher burden of FGFR2 mutations and the presence of co-alterations were associated with shorter mPFS on non-covalent inhibitors. Futibatinib was administered at a median of fourth-line therapy. ORR was 31.3% and disease control rate was 50.0%. Median PFS and overall survival were 4.5 months (95% CI 2.0-9.1) and 9.9 months (95% CI 5.7-not reached), respectively. Notably, outcomes with futibatinib were independent of the number of acquired FGFR2 resistance mutations, and the adverse impact of co-alterations appeared attenuated. Safety was consistent with the known profile. CONCLUSIONS: Futibatinib demonstrates clinically meaningful activity after progression on non-covalent FGFR inhibitors, supporting its use in FGFR2-rearranged iCCA, including in the post-non-covalent inhibitor setting. The distinct resistance patterns provide a biological rationale for the continued efficacy of covalent FGFR inhibition. Prospective studies incorporating longitudinal molecular profiling are needed to optimize treatment sequencing.

Drug resistance↗

PubMed2026

Utility of monocyte-derived cells to investigate immune-mediated drug-induced liver injury.

Immune-mediated drug-induced liver injury (DILI) is triggered or exacerbated by the immune system mounting an attack against the drug or its metabolites. The array of in vitro assays for evaluating drug immune liability is limited, highlighting a significant gap in effectively predicting and understanding immune-mediated hepatotoxicity. We aimed to investigate whether monocytes differentiated with the Metaheps (MH) protocol could provide insights into the molecular mechanisms of immune-mediated DILI. MH were generated from monocytes of healthy volunteers (HV) and DILI patients. MH phenotypic characterization was performed by proteomics and qPCR. MH sensitivity to drugs associated with immune-mediated DILI was assessed by lactate dehydrogenase (LDH) assay. Drug-induced LDH release by DILI-derived MH was compared to the upper limit of the 95% CI calculated from HV-derived MH cells treated with the same drug. The 95% CI determined in HV-derived MH was set as the sensitivity threshold for the specific drug. MH cells retain the expression of several immune-related proteins of the parental monocytes and activate a pro-inflammatory response upon exposure to lipopolysaccharide. For all MH (6 out of 6) generated from patients with penicillin-induced DILI, the LDH release upon re-challenge was above the threshold. The sensitivity of MH generated from seven patients with immune checkpoint inhibitor (ICI)-induced hepatotoxicity was ICI-dependent, responding to nivolumab and/or ipilimumab (4 out of 5), but not to pembrolizumab (0 out of 2). Additionally, DILI-derived MH were not sensitive to non-DILI drugs. In conclusion, monocyte-derived cells may serve as an additional tool for drug-specific mechanistic studies of immune-mediated DILI.

Humans↗

PubMed2025

E2F1 induces a G0-G1 reentry transcriptional program without changing chromatin accessibility.

Quiescent cells actively repress cell-cycle genes via chromatin-based mechanisms to maintain a non-dividing state, yet remain poised to reenter upon stimulation. E2F1, a canonical activator of cell-cycle genes, is sufficient to induce reentry from quiescence, but how it overcomes chromatin-mediated repression remains unclear. Here, we show that inducible E2F1 expression triggers exit from quiescence and progression through the cycle without changes in chromatin accessibility, by harnessing regulatory elements with limited, pre-existing accessibility. Using time-resolved transcriptomics, we demonstrate that E2F1 induces an accelerated transcriptional program compared to serum. Unlike serum, which triggers broad chromatin remodeling, E2F1-induced activation occurs in a context of limited accessibility. ChIP-seq reveals that E2F1 directly binds target sites in quiescent cells to upregulate canonical genes. Biochemical reconstitution shows that E2F1 binds nucleosomes and accesses internal E2F sites within histone-wrapped DNA. These findings suggest that E2F1 can engage nucleosome-associated DNA and initiate transcription without major chromatin reorganization, redefining transcription factor-chromatin dynamics during cell fate transitions and establishing E2F1 as a potent regulator of cell-cycle reentry.

Journal Article↗

PubMed2026

Cardiac mitochondrial proteome of lean, healthy Ossabaw minipigs with predisposition to metabolic syndrome versus that of Göttingen minipigs.

Ossabaw minipigs differ from other (mini)pig strains by their genetic predisposition to develop full metabolic syndrome and their nonresponsiveness to cardioprotective interventions, even before developing the diseased phenotype. Previous DNA sequencing data revealed differences in a cluster of mitochondrial protein-coding genes between Ossabaw and Göttingen minipigs-a large animal model without such a genetic predisposition and a responsiveness to cardioprotection. Alterations in mitochondrial protein composition affect mitochondrial function, and mitochondria play a crucial role in the development of metabolic syndrome and for cardioprotection. Therefore, we aimed to compare the cardiac mitochondrial proteome between lean Ossabaw minipigs with a healthy phenotype and Göttingen minipigs to gain initial insights into potential differences in mitochondrial protein composition and function. Cardiac mitochondria (left ventricular tissue) of both minipig strains (male/female pigs) were isolated, and the proteome was analyzed by liquid chromatography-tandem mass spectrometry. An unbiased, nonhypothesis-driven proteome analysis identified 97% overlap in the proteome. Among the 3% of differentially expressed proteins, 19 were related to mitochondrial metabolism, 8 to transcription and translation, 3 to small molecule transport, 2 to oxidative phosphorylation, and 1 to dynamics and surveillance. These small differences in protein composition were associated with an altered mitochondrial energy turnover-ATP production was reduced by 49% in Ossabaw compared with Göttingen minipig mitochondria. This proteome analysis provides a broader basis to understand how genetic alterations result in changes of the mitochondrial proteome and function, which might be relevant for the development and progression of metabolic syndrome and/or the primordial nonresponsiveness to cardioprotection in Ossabaw minipigs.NEW & NOTEWORTHY Our comprehensive cardiac mitochondrial proteome of Ossabaw and Göttingen minipigs is a valuable resource for cardiac biomedical research. Moreover, our proteome analysis provides a broader basis for understanding how genetic alterations result in changes of the mitochondrial proteome and support a mechanistic link between subtle, strain-specific mitochondrial proteomic signatures and altered mitochondrial energy turnover. These changes may be relevant for the development and progression of metabolic syndrome and/or primordial nonresponsiveness to cardioprotection in Ossabaw minipigs.

Animals↗

PubMed2026

FLT3-ITD Induces CMTM6 and Enhances Immune Escape in Acute Myeloid Leukemia.

UNLABELLED: FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations are frequent in acute myeloid leukemia (AML) and are associated with a high risk of relapse. CKLF-like MARVEL transmembrane domain containing member 6 (CMTM6) stabilizes PD-L1 surface expression and modulates tumor immunity in solid cancer. In this study, we found a role for FLT3-induced CMTM6 in hematologic malignancies. FLT3 drove CMTM6 and PD-L1 expression in AML cells, whereas FLT3 inhibition reduced expression of CMTM6 and PD-L1. In three distinct allogeneic hematopoietic cell transplantation mouse models, transplantation of Cmtm6-deficient FLT3-ITD+ leukemia cells resulted in prolonged survival, reduced leukemia burden, enhanced T-cell effector function, and decreased expression of T-cell exhaustion markers compared with Cmtm6-proficient FLT3-ITD+ leukemia cells. Furthermore, combination therapy with anti-PD-L1 and tandutinib significantly improved survival, suppressed leukemia cell expansion, and augmented the anti-leukemia T-cell response in mice bearing FLT3-ITD+ leukemia. Mechanistically, protein-protein interaction of FLT3 and CMTM6 within their transmembrane domains, which was not phosphorylation dependent, enhanced CMTM6 stability in leukemia cells, whereas FLT3-ITD did not increase CMTM6 and PD-L1 expression at the RNA level. Furthermore, CMTM6 upregulation and protein interaction with FLT3 were validated in primary leukemia cells from two independent cohorts of patients with FLT3-ITD+ AML. Collectively, these findings uncover FLT3-mediated stabilization of CMTM6 in AML cells, which results in enhanced PD-L1 cell surface expression and leukemia immune escape. SIGNIFICANCE: Activation of the CMTM6/PD-L1 axis in FLT3-ITD-driven acute myeloid leukemia mediates immunosuppression, providing the basis for potential inhibition of this pathway to harness antitumor immunity.

Animals↗

PubMed2026

Proteomics profiling of serum and liver in GSD Ia and Ib patients: insights into complication mechanisms and circulation biomarkers.

BACKGROUND: Glycogen Storage Disease (GSD) Types Ia and Ib are rare metabolic diseases caused by gene variants in G6PC1 and SLC37A4, respectively. Although life-threatening fasting hypoglycemia can be controlled by a strict diet, patients often suffer from multiple metabolic abnormalities and severe long-term complications. However, the underlying mechanisms remain incompletely understood, and there is a lack of effective monitoring biomarkers. Therefore, the aims of this study are to investigate the pathological mechanisms of the disease and disease complications in GSD I and identify potential protein biomarkers. METHODS: Comprehensive untargeted proteomics was performed on 18 GSD Ia and 8 GSD Ib sera samples from patients with 21 matched control sera, complemented by liver 3 GSD Ia samples and 1 GSD Ib sample from patient liver tissues, compared to 10 donor liver samples. RESULTS: We identified 415 proteins in total. Significantly changed (FDR < 0.05) were observed in 158 (38%) proteins for GSD Ia vs Control, 116 (28%) for GSD Ib vs. Control, and 151 (36%) for GSD Ia vs. Ib. Pathway analysis revealed distinct alterations in serum/plasma, with 58, 32, and 29 significantly changed biological processes (FDR < 0.05) in these three comparisons, respectively. The coagulation pathway was the most significantly changed one in the GSD Ia patients. Immune response-associated proteins, especially immunoglobulins, were increased in GSD Ib specifically. Proteins related to liver injury, cholesterol, and amyloidosis were altered in two subtypes, though more pronounced in GSD Ia. Potential biomarkers with significant alterations both in the circulation and in the liver tissue were identified specifically for monitoring GSD I subtypes and prognosing liver deterioration, namely APOC1 and CD5L to distinguish between GSD Ia and Ib and ALDOB for the presence of hepatocellular carcinoma (HCC) in GSD Ia patients. CONCLUSIONS: These findings provide new insights into the differences between the two GSD I subtypes and the pathogenesis of GSD I-related complications, as well as highlighting the potential of protein circulating biomarkers for monitoring complication progression in GSD I and assessing HCC risk in GSD Ia patients.

Humans↗

PubMed2025

Optimizing genetic ancestry adjustment in DNA methylation studies: a comparative analysis of approaches.

BACKGROUND: Genetic ancestry is an important factor to account for in DNA methylation studies because genetic variation influences DNA methylation patterns. One approach uses principal components (PCs) calculated from CpG sites that overlap with common SNPs to adjust for ancestry when genotyping data is not available. However, this method does not remove technical and biological variations, such as sex and age, prior to calculating the PCs. The first PC is therefore often associated with factors other than ancestry. METHODS: We developed and adapted the adapted EpiAnceR+ approach, which includes (1) residualizing the CpG data overlapping with common SNPs for control probe PCs, sex, age, and cell type proportions to remove the effects of technical and biological factors, and (2) integrating the residualized data with genotype calls from the SNP probes (commonly referred to as rs probes) present on the arrays, before calculating PCs and evaluated the clustering ability and relationship to genetic ancestry. RESULTS: The PCs generated by EpiAnceR+ led to improved clustering for repeated samples from the same individual and stronger associations with genetic ancestry groups predicted from genotype information compared to the original approach. EpiAnceR+ also outperformed the use of DNA methylation PCs or surrogate variables for ancestry adjustment. CONCLUSIONS: We show that the EpiAnceR+ approach improves the adjustment for genetic ancestry in DNA methylation studies. EpiAnceR+ can be integrated into existing R pipelines for commercial methylation arrays, such as 450 K, EPIC v1, and EPIC v2. The code is available on GitHub ( https://github.com/KiraHoeffler/EpiAnceR ).

DNA Methylation↗

PubMed2024

Advancing responsible genomic analyses of ancient mollusc shells.

The analysis of the DNA entrapped in ancient shells of molluscs has the potential to shed light on the evolution and ecology of this very diverse phylum. Ancient genomics could help reconstruct the responses of molluscs to past climate change, pollution, and human subsistence practices at unprecedented temporal resolutions. Applications are however still in their infancy, partly due to our limited knowledge of DNA preservation in calcium carbonate shells and the need for optimized methods for responsible genomic data generation. To improve ancient shell genomic analyses, we applied high-throughput DNA sequencing to 27 Mytilus mussel shells dated to ~111-6500 years Before Present, and investigated the impact, on DNA recovery, of shell imaging, DNA extraction protocols and shell sub-sampling strategies. First, we detected no quantitative or qualitative deleterious effect of micro-computed tomography for recording shell 3D morphological information prior to sub-sampling. Then, we showed that double-digestion and bleach treatment of shell powder prior to silica-based DNA extraction improves shell DNA recovery, also suggesting that DNA is protected in preservation niches within ancient shells. Finally, all layers that compose Mytilus shells, i.e., the nacreous (aragonite) and prismatic (calcite) carbonate layers, with or without the outer organic layer (periostracum) proved to be valuable DNA reservoirs, with aragonite appearing as the best substrate for genomic analyses. Our work contributes to the understanding of long-term molecular preservation in biominerals and we anticipate that resulting recommendations will be helpful for future efficient and responsible genomic analyses of ancient mollusc shells.

Animals↗