Abnormal Profile Research Articles

Blood serum lipid profiling may improve the management of recurrent miscarriage: a combination of machine learning of mid-infrared spectra and biochemical assays.

The present article is focused on developing and validating an efficient, credible, minimally invasive technique based on spectral signatures of blood samples of women with recurrent miscarriage vs. those of healthy individuals who were followed in the Department of Obstetrics and Gynecology for 2 years. For this purpose, blood samples from a total of 120 participants, including healthy women (n=60) and women with diagnosed recurrent miscarriage (n=60), were obtained. The lipid profile (high-density lipoprotein, low-density lipoprotein, triglyceride, and total cholesterol levels) and lipid peroxidation (malondialdehyde and glutathione levels) were evaluated with a Beckman Coulter analyzer system for chemical analysis. Biomolecular structure and composition were determined using an attenuated total reflectance sampling methodology with Fourier transform infrared spectroscopy alongside machine learning technology to advance toward clinical translation. Here, we developed and validated instrumentation for the analysis of recurrent miscarriage patient serum that was able to differentiate recurrent miscarriage and control patients with an accuracy of 100% using a Fourier transform infrared region corresponding to lipids. We found that predictors of lipid profile abnormalities in maternal serum could significantly improve this patient pathway. The study also presents preliminary results from the first prospective clinical validation study of its kind.

P.76 Gene variant and neuromuscular findings from a long-chain fatty acid oxidation disorder gene panel program

Long-chain fatty acid oxidation disorders (LC-FAOD) are rare, life-threatening, autosomal recessive conditions that can be diagnosed clinically with plasma acylcarnitine analysis and molecular testing. Undiagnosed LC-FAOD may present with hypoglycemia, cardiomyopathy, cardiac arrhythmias, and neuromuscular symptoms. Patients with a clinical diagnosis or suspicion of LC-FAOD are eligible for this no-charge, next-generation sequencing gene panel which includes 6 genes associated with LC-FAOD plus 18 genes associated with disorders that cause abnormal acylcarnitine profiles. As of 28 October 2021, LC-FAOD gene variants were identified in 153 (37%) of 417 patients tested, including 83 variants of uncertain significance (VUS), 8 likely pathogenic (LP), and 102 pathogenic (P) variants. Twenty-three patients had positive (2 P/LP) LC-FAOD results and 19 had potential positive (2 variants, at least 1 VUS) results. VUS resolution analysis led to the reclassification of 6 variants from VUS to LP or P. Five patients had variants in two or more LC-FAOD genes and 22 had variants in one LC-FAOD gene and one or more non-LC-FAOD genes. Fifty-one patients had only one LC-FAOD gene variant identified. The most common neuromuscular symptoms among patients ages ≥13 (76 reported) were myopathy (42), elevated creatine kinase (36), and rhabdomyolysis (30), and among patients <13 years (83 reported) were elevated creatine kinase (22), and myopathy (12). Program results demonstrate the diverse composition of gene variants in patients referred for LC-FAOD genetic testing. Approaches to resolve VUS and identify previously undetected variants in patients with suspected LC-FAOD are important and necessary.

Case Report

Snakebite envenomation is a potentially life-threatening event which results due to the toxins present in the bite of venomous snakes. Snake bites commonly present with complications such as erythema, edema, bleeding, blistering, and tenderness at the bite site and autonomic symptoms such as nausea, vomiting, diarrhea, and increased salivation and sweating. Labored breathing and coagulopathy are among others. However, cardiac complications are not known to be a prominent feature of snakebites, although a few rare manifestations such as myocardial infarction and arrhythmias have been found in the literature. The case report that follows describes a patient of Snakebite who came with chief complaints of drowsiness, palpitation, nausea and vomiting. Blood investigation showed an abnormal coagulation profile. Electrocardiography revealed atrial fibrillation after which the patient was shifted to the intensive care unit and was treated with anti-snake venom. It eventually got resolved. Therefore, the case of snakebite warrants attentive cardiac monitoring.

Melatonin in Endometriosis: Mechanistic Understanding and Clinical Insight.

Endometriosis is defined as the development of endometrial glands and stroma outside the uterine cavity. Pathophysiology of this disease includes abnormal hormone profiles, cell survival, migration, invasion, angiogenesis, oxidative stress, immunology, and inflammation. Melatonin is a neuroendocrine hormone that is synthesized and released primarily at night from the mammalian pineal gland. Increasing evidence has revealed that melatonin can be synthesized and secreted from multiple extra-pineal tissues where it regulates immune response, inflammation, and angiogenesis locally. Melatonin receptors are expressed in the uterus, and the therapeutic effects of melatonin on endometriosis and other reproductive disorders have been reported. In this review, key information related to the metabolism of melatonin and its biological effects is summarized. Furthermore, the latest in vitro and in vivo findings are highlighted to evaluate the pleiotropic functions of melatonin, as well as to summarize its physiological and pathological effects and treatment potential in endometriosis. Moreover, the pharmacological and therapeutic benefits derived from the administration of exogenous melatonin on reproductive system-related disease are discussed to support the potential of melatonin supplements toward the development of endometriosis. More clinical trials are needed to confirm its therapeutic effects and safety.

Rare Cause of Arrhythmia and Seizures in a Late-Preterm Newborn

Rare Cause of Arrhythmia and Seizures in a Late-Preterm Newborn

Cost-effective methylome sequencing of cell-free DNA for accurately detecting and locating cancer

Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our approach to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, allowing us to learn new features and expand to other cancer types as training cohorts grow.

Tartary Buckwheat (Fagopyrum tataricum) Ameliorates Lipid Metabolism Disorders and Gut Microbiota Dysbiosis in High-Fat Diet-Fed Mice.

Jinqiao II, a newly cultivated variety of tartary buckwheat (Fagopyrum tataricum), has been reported to exhibit a higher yield and elevated levels of functional compounds compared to traditional native breeds. We aimed to investigate the potential of Jinqiao II tartary buckwheat to alleviate lipid metabolism disorders by detecting serum biochemistry, pathological symptoms, gene expression profiling, and gut microbial diversity. C57BL/6J mice were provided with either a normal diet; a high-fat diet (HFD); or HFD containing 5%, 10%, and 20% buckwheat for 8 weeks. Our results indicate that Jinqiao II tartary buckwheat attenuated HFD-induced hyperlipidemia, fat accumulation, hepatic damage, endotoxemia, inflammation, abnormal hormonal profiles, and differential lipid-metabolism-related gene expression at mRNA and protein levels in response to the dosages, and high-dose tartary buckwheat exerted optimal outcomes. Gut microbiota sequencing also revealed that the Jinqiao II tartary buckwheat elevated the level of microbial diversity and the abundance of advantageous microbes (Alistipes and Alloprevotella), lowered the abundance of opportunistic pathogens (Ruminococcaceae, Blautia, Ruminiclostridium, Bilophila, and Oscillibacter), and altered the intestinal microbiota structure in mice fed with HFD. These findings suggest that Jinqiao II tartary buckwheat might serve as a competitive candidate in the development of functional food to prevent lipid metabolic abnormalities.

Early Sensory Profile in Autism Spectrum Disorders Predicts Emotional and Behavioral Issues.

Background: Abnormal sensory reactivity is considered one of the diagnostic criteria for autism spectrum disorders (ASD) and has been associated with autism severity, poorer functional outcomes, and behavioral difficulties across the lifespan. Its early characterization could provide valuable insights into the processes favoring the instantiation of maladaptive behaviors. Objectives: The present study has two aims: (1) to describe the sensory profile of preschool children with ASD compared with an age-matched population of children with a diagnosis of language disorder (DLD) and typically developing (TD) control peers; (2) to explore within each group whether the sensory alterations play a predictive role in the instantiation of emotional and behavioral issues. Methods: The parents of 42 ASD, 18 DLD, and 56 TD filled out the Sensory Processing Measure—Preschool (SPM-P). To gather information on competencies, behaviors, and emotional problems of children, the Child Behavior Checklist 1½-5 (CBCL 1½-5) was also administered. Results: On the SPM-P, ASD and DLD samples generally had scores more compromised than control peers. The contrast between ASD and DLD was reflected in a higher (and highly significant) impairment on the social participation and hearing subscales, suggesting a greater sensitivity and a possible specificity of these scores for ASD. More importantly, linear regression analyses revealed a strong and predictive association for ASD children with SPM total scores explaining more than 50% of the variance of the CBCL 1½-5 total scores (p < 0.001). Conclusions: Our findings reinforce the need to detect the abnormal sensory profiles of ASD already at an early stage and during clinical evaluations. Due to the impact on the emotional and behavioral manifestations, such a procedure has significant clinical and social implications, potentially guiding the development of new interventions relying on multisensory strategies.

Blood profile abnormalities among Indonesian police exposed to lead: a cross-sectional study

Blood profile abnormalities among Indonesian police exposed to lead: a cross-sectional study

Abnormal circadian blood pressure regulation and cognitive impairment in α-synucleinopathies.

Circadian blood pressure (BP) rhythm is important for the maintenance of healthy daily life, and its disruption is associated with poor outcomes. Cardiovascular autonomic failure is often observed in older populations but has a greater impact on neurodegenerative disorders such as α-synucleinopathies. These BP abnormalities include orthostatic hypotension (OH), supine hypertension (SH), and a loss of nocturnal BP fall. OH not only causes falls or syncope but is also related to cognitive impairment in α-synucleinopathies. For example, OH doubles or triples the risk for the development of cognitive impairment in Parkinson's disease (PD). The diffuse central and peripheral neuropathology of α-synuclein may contribute to both OH and cognitive impairment. Moreover, repeated cerebral hypoperfusion in OH is thought to be related to cerebrovascular and neuronal damage, which may cause cognitive impairment. SH, which often coexists with OH, is also associated with cognitive impairment through cerebrovascular damage, such as white matter lesions and cerebral microbleeds. The reverse-dipping (riser) pattern on ambulatory BP monitoring is commonly observed in PD (∼56%), regardless of disease duration and severity. It is also related to cognitive impairment and more pronounced when coexisting with OH. These abnormal circadian BP profiles may be synergistically associated with cognitive impairment and poor outcomes in α-synucleinopathies. Although evidence for aggressive control of BP dysregulation improving cognitive impairment and outcomes is limited, regular BP monitoring appears to be important for total management of α-synucleinopathies.

Alteration of Fatty Acid Profile in Fragile X Syndrome.

Fragile X Syndrome (FXS) is the most prevalent monogenic cause of Autism Spectrum Disorders (ASDs). Despite a common genetic etiology, the affected individuals display heterogenous metabolic abnormalities including hypocholesterolemia. Although changes in the metabolism of fatty acids (FAs) have been reported in various neuropsychiatric disorders, it has not been explored in humans with FXS. In this study, we investigated the FA profiles of two different groups: (1) an Argentinian group, including FXS individuals and age- and sex-matched controls, and (2) a French-Canadian group, including FXS individuals and their age- and sex-matched controls. Since phospholipid FAs are an indicator of medium-term diet and endogenous metabolism, we quantified the FA profile in plasma phospholipids using gas chromatography. Our results showed significantly lower levels in various plasma FAs including saturated, monosaturated, ω-6 polyunsaturated, and ω-3 polyunsaturated FAs in FXS individuals compared to the controls. A decrease in the EPA/ALA (eicosapentaenoic acid/alpha linoleic acid) ratio and an increase in the DPA/EPA (docosapentaenoic acid/eicosapentaenoic acid) ratio suggest an alteration associated with desaturase and elongase activity, respectively. We conclude that FXS individuals present an abnormal profile of FAs, specifically FAs belonging to the ω-3 family, that might open new avenues of treatment to improve core symptoms of the disorder.

Acute kidney injury in snake bite patients

Background: In India, large proportion of snake bites occur when people are working barefoot in fields or while walking at night. Objectives: To study i) clinical profile of renal involvement in snake bite patients. ii) in-hospital outcome of acute kidney injury in snake bite patients Methodology: Patients are classified into three stages of acute kidney injury proposed by Acute Kidney Injury Network which defines AKI as an abrupt increase in serum creatinine concentration of ≥0.3 mg/dl from baseline, a percentage increase in the serum creatinine concentration ≥50% or oliguria of 0.5 ml/kg/hr &gt;6 hours. Results: Mean age of patients was 43.8±12.63 years. Male to female ratio was 1.63:1 with male preponderance. Mean interval between snakebite and presentation to hospital was 15.37 hours. All snake bites were inflicted to lower limbs and 48% of snake bites were due to Viper as identified by patients. 98% patients presented with local signs of inflammation. 52% patients presented with coagulation abnormality and 60% with decreased urine output which were associated with increase severity of AKI and need for haemodialysis in 12% of patients.Conclusion: Common manifestations of poisonous snake bite include cellulitis, abnormal Coagulation profile and decreased urine output.

The utility of glucose area under the curve from the oral glucose tolerance test as a screening tool for cystic fibrosis-related diabetes.

Consistently abnormal glucose levels on oral glucose tolerance test (OGTT) are the most effective screening tool for cystic fibrosis-related diabetes (CFRD). However, some cystic fibrosis (CF) patients demonstrate abnormal glucose profiles not reaching levels required for CFRD diagnosis and are, therefore, left untreated. Since CFRD is associated with disease deterioration, early diagnosis and treatment are desirable. To explore the association between the area under the curve of glucose (G-AUC) obtained during a five-point2-hstandard OGTT and CF disease severity parameters. All CF patients referred for an annual routine OGTT at the Hadassah CF Center between 2002 and 2018, were included. Disease severity parameters were correlated with the G-AUC. Two hundred forty-twoOGTTs were performed in 81 patients (mean age 19.7 ± 9.0 years); 54% were normal, 14% showed impaired glucose tolerance (IGT), 5% had values in the indeterminate range (INDET), 11% had both IGT and INDET and 16% were diagnosed with CFRD. A gradual increase in mean G-AUC was observed among the groups. In multivariate regression models, G-AUC ≥ 295 mg h/dl was independently associated with an increased number of pulmonary exacerbations (PEx). Not all the patients having this value met the CFRD definition. Patients who do not fulfill the criteria for CFRD may have abnormal glucose metabolism identifiable by abnormally high G-AUC values, which may be associated with more PEx. The potential advantage of treating these patients with insulin and the subsequent reduction in PEx needs further investigation.

Toward a new taxonomy of obstetrical disease: improved performance of maternal blood biomarkers for the great obstetrical syndromes when classified according to placental pathology

The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known. To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion. This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion. 1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions. Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders.

Effect of ozone versus naringin on testicular injury in experimentally induced ulcerative colitis in adult male albino rats

ABSTRACT Testicular dysfunction is caused by the continuous inflammation and oxidative stress that are present at the local site in ulcerative colitis (UC) spreading to the testes via systemic circulation. The influence of ozone and naringine on colitis-mediated testicular dysfunction was investigated in this study. Forty-eight adult male rats were divided into four groups: I control group, II dextran sodium sulfate (DSS) UC-induced group, III DSS+naringine, and IV DSS+ozone groups. UC was induced in groups II, III, and IV using 0.1 ml of 4% DSS in their drinking water per day for 6 days by gastric gavage. All animals were sacrificed 45 days from the start. Blood samples were obtained to estimate serum testosterone hormone. Testicular tissues were processed for measurement of tissue malondialdehyde (MDA) and examined by light and electron microscopes. Ultrastructurally, group II revealed a relatively thick basement membrane enveloping the seminiferous tubule. Sertoli cell cytoplasm appears rarified with wide intracellular spaces, vacuoles, and multiple lysosomes; distorted spermatogonia with electron dense nuclei and cytoplasm; and primary spermatocytes with small nuclei and electron dense cytoplasm. Abnormal sperm profiles were visible in middle pieces, mid, principle, and end pieces that were markedly affected with disorganization of axoneme and outer dense fibers. Leydig cells revealed dilated cisternae of smooth endoplasmic reticulum. Morphometric and statistical analyses were performed. Group III showed some improvement; however, group IV showed more improvement. The results indicated that ozone caused marked improvement than naringine against UC-induced testicular damage via their antioxidant and anti-inflammatory properties.

Evaluation of individual-based morphological brain network alterations in children with attention-deficit/hyperactivity disorder: a multi-method investigation.

To investigate the topological organization of individual-based morphological brain networks (MBNs) in attention-deficit/hyperactivity disorder (ADHD) children with different methods. A total of 60 ADHD children and 60 typically developing (TD) controls matched for age and gender were enrolled. Each participant underwent a structural 3D T1-weighted scan. Based on the inter-regional morphological similarity of GM regions, Kullback-Leibler-based similarity (KLS), Multivariate Euclidean Distance (MED), and Tijms's method were used to construct individual-based MBNs, respectively. The between-group difference of global and nodal network topological profiles was estimated, and partial correlation analysis was used for further analysis. According to KLS and MED-based network, ADHD showed a decreased global efficiency (Eglob) and increased characteristic path length (Lp) compared to the TD group, while Tijms's method-based network showed no between-group difference in global and nodal profiles. Nodal profiles were significantly decreased in the bilateral caudate, and nodal efficiency of the bilateral caudate was negatively correlated with clinical symptom severity of ADHD (P < 0.05, FDR-corrected) by the KLS-based network. Nodal betweenness was significantly decreased in the left inferior occipital gyrus and correlated with clinical symptom severity of ADHD (P < 0.05, FDR-corrected) by the MED-based network. ADHD was found to have a significantly less integrated organization and a shift to a "weaker small-worldness" pattern, while abnormal nodal profiles were mainly in the corpus striatum and default-mode networks. Our study highlights the crucial role of abnormal morphological connectivity patterns in understanding the brain maturational effects in ADHD and enriching the insights into MBNs at an individual level.

Application Value of Serum Metabolic Markers for Cognitive Prediction in Elderly Epilepsy.

Background and Study AimsElderly epilepsy is the third most common chronic disease that affects metabolism either alone or through antiepileptic drugs (AEDs). Here, we focus on whether neurocognitive profiles in elderly epilepsy and its treatment are linked to metabolic conditions.Patients and MethodsElderly patients with epilepsy without cognitive impairment (n = 78) and with cognitive impairment (n = 75) were enrolled. C-reactive protein (CRP) and metabolic markers (triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c), albumin, fasting glucose (Glu) and glycosylated hemoglobin (HbA1c)) were measured. Serum markers were modeled using logistic regression analysis.ResultsTG, TC, fasting glucose, HbA1c and CRP were significantly increased (p < 0.05, 0.05, 0.001, 0.001, 0.01, respectively) in elderly epilepsy, whereas HDL-c, LDL-c and serum albumin were decreased (p < 0.001, 0.001, 0.001) in elderly epilepsy. TG, TC, fasting Glu, HbA1c and CRP were significantly elevated (p < 0.05, 0.001, 0.001, 0.001, 0.001, respectively) in epilepsy with cognitive impairment, whereas HDL-c, LDL-c and serum albumin were decreased (p < 0.001, 0.001, 0.001). The abnormal glycolipid profile was predominated in AED-treated patients. The regression model combined with TG, LDL-c, HDL-c and albumin performed better (area under the ROC curve was 0.824) in AED-treated patients.ConclusionThe relevant relationship between glycolipid profile and cognitive impairment with epilepsy was described, and the logistic regression model based on serum TG, LDL-c, HDL-c and albumin is reported and may serve as promising diagnostic markers for elderly epilepsy with cognitive impairment. Additionally, a specific emphasis on the complex role of altered lipid metabolism and AEDs is made.

Abnormal profiles of cathepsin C secreted in urine of Papillon Lefevre syndrome patients

BackgroundPapillon Lefevre syndrome (PLS) is an autosomal recessive disorder that results from a mutated gene that encodes a lysosomal peptidase known as cathepsin C (CTSC). The clinical presentation of PLS involves mainly palmoplantar keratosis and periodontitis with a variable degree of severity. Subjectsand methods: Our study included ten patients with a broad spectrum of palmoplantar keratosis and periodontitis severity. CTSC variants were detected by Sanger sequencing. CTSC protein secreted in urine was detected by western blotting. ResultsFive patients have missense variants, Four have nonsense variants, and one has splice variants in CTSC. The activation products of cathepsin C protein (Heavy and light chains) were absent in all patients’ urine samples except one with a significantly reduced level compared to the controls. The dimeric form of CTSC protein was found in all the studied cases. The monomeric form was found in five cases. The products of proteolytic activation of CTSC by other cathepsins (L and S) were found in the urine samples of five of the patients. Each patient had a characteristic pattern of accumulated CTSC protein maturation/activation substrates, intermediates, and products. 40% of the patients had the activation products of other lysosomal cathepsins. ConclusionUrinary CTSC in PLS patients could be used as a diagnostic biomarker for the biochemical screening of the disease. Different variants in CTSC result in different profiles of CTSC secreted in the urine of PLS patients. The profiles of secreted CTSC in urine could be correlated to the severity of palmoplantar keratosis.

Differential progression of unhealthy diet-induced hepatocellular carcinoma in obese and non-obese mice.

BackgroundNon-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25–30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood.MethodsIn this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice.ResultsObese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice.ConclusionsUnhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis.

Multi-omics analysis reveals RNA splicing alterations and their biological and clinical implications in lung adenocarcinoma

Alternative RNA splicing is one of the most important mechanisms of posttranscriptional gene regulation, which contributes to protein diversity in eukaryotes. It is well known that RNA splicing dysregulation is a critical mechanism in tumor pathogenesis and the rationale for the promising splice-switching therapeutics for cancer treatment. Although we have a comprehensive understanding of DNA mutations, abnormal gene expression profiles, epigenomics, and proteomics in lung adenocarcinoma (LUAD), little is known about its aberrant alternative splicing profiles. Here, based on the multi-omics data generated from over 1000 samples, we systematically studied the RNA splicing alterations in LUAD and revealed their biological and clinical implications. We identified 3688 aberrant alternative splicing events (AASEs) in LUAD, most of which were alternative promoter and exon skip. The specific regulatory roles of RNA binding proteins, somatic mutations, and DNA methylations on AASEs were comprehensively interrogated. We dissected the functional implications of AASEs and concluded that AASEs mainly affected biological processes related to tumor proliferation and metastasis. We also found that one subtype of LUAD with a particular AASEs pattern was immunogenic and had a better prognosis and response rate to immunotherapy. These findings revealed novel events related to tumorigenesis and tumor immune microenvironment and laid the foundation for the development of splice-switching therapies for LUAD.