Metabolic liver cancer: associations of rare and common germline variants in one-carbon metabolism and DNA methylation genes.

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in the overall sample and among non-Hispanic whites. The results show that among non-Hispanic whites, presence of rare functional variants in ABCC2 was associated with 7-fold higher risk of metabolic HCC (OR = 6.92, 95% CI: 2.38-20.15, P = 0.0004), and this association remained significant when analyses were restricted to functional rare variants observed in ≥2 participants (cases 3.2% versus controls 0.0%, P = 1.02 × 10-5). In the overall multiethnic sample, presence of rare functional variants in ABCC2 was nominally associated with metabolic HCC (OR = 3.60, 95% CI: 1.52-8.58, P = 0.004), with similar nominal association when analyses were restricted to functional rare variants observed in ≥2 participants (cases 2.9% versus controls 0.2%, P = 0.006). A common variant in PNPLA3 (rs738409[G]) was associated with higher HCC risk in the overall sample (P = 6.36 × 10-6) and in non-Hispanic whites (P = 0.0002). Our findings indicate that rare functional variants in ABCC2 are associated with susceptibility to metabolic HCC in non-Hispanic whites. PNPLA3-rs738409 is also associated with metabolic HCC risk.

Gut-brain axis: altered microbiome and depression - review.

The concept of a 'gut-brain axis' was recently developed when the complex communications between the brain and the gut became evident. The interaction may affect emotions, motivation, mood, and higher cognitive functions as well as gut homeostasis. Human microbe symbiosis's merits are now acknowledged to transcend human mental health. Research has recently indicated that the gut-brain axis plays a vital role in brain health maintenance. The term 'gut-brain axis' can only partially capture the intricacy of these interactions. Dysbiosis of the gut commensals has been seen in patients with psychiatric diseases, such as depression. Major depressive disorder is caused by complicated interactions between the individual gene and the environment. In a forced swimming test, P. Zheng et al. discovered that germ-free mice with no gut microbiota had a shorter immobility duration than healthy mice. More radical effects were expressed on the use of probiotics rather than prebiotics and postbiotics in reducing the symptoms of depression in patients with major depressive disorder. One of prime importance can be given to exploring more microbiota to investigate the better therapeutic effects of probiotics, prebiotics, and postbiotics.

A Rare Case of Refractory Catastrophic Antiphospholipid Syndrome Successfully Treated With Rituximab and Plasma Exchange.

A small subset of patients with antiphospholipid syndrome (APS) may develop widespread thrombotic disease with organ damage, referred to as catastrophic APS (CAPS) that is associated with a high mortality. Medical therapy typically involves a combination of anticoagulation, systemic glucocorticoids, plasmapheresis, and intravenous immune globulin (IVIG). There is currently no consensus for the management of refractory cases of CAPS. However, monoclonal antibodies such as rituximab and eculizumab have shown some benefits. Herein, we present a 29-year-old female with previous pulmonary embolism who presented with necrotic left toes and was eventually diagnosed with refractory CAPS, successfully treated with Plasmapheresis and Rituximab. With this case report, we hope to encourage the usage of Rituximab in the management of CAPS.

Primary Cardiac Sarcoma: Clinical Characteristics and Prognostic Factors over the Past 2 Decades.

BACKGROUND: Primary cardiac sarcomas (PCS) are extremely rare malignant tumors involving the heart. Only isolated case reports have been described in the literature over different periods of time. This pathology has been associated with a dismal prognosis and given its rarity; treatment options are very limited. Furthermore, there are contrasting data about the effectiveness of current treatment modalities in improving the survival of patients with PCS, including surgical resection which is the mainstay of therapy. There is a paucity of data on the epidemiological characteristics of PCS. This study has the objective of investigating the epidemiologic characteristics, survival outcomes, and independent prognostic factors of PCS. METHODS: A total of 362 patients were ultimately registered in our study from the Surveillance, Epidemiology, and End Results (SEER) database. The study period was from 2000 to 2017. Demographics such as clinical characteristics, overall mortality (OM), and PCS-specific mortality (CSM) were taken into account. A p value of <0.1 in the univariate analysis leads to the incorporation of the variable into multivariate analysis adjusting for covariates. Adverse prognostic factors were represented by a Hazard Ratio (HR) greater than one. The five-year survival analysis was carried out using the Kaplan-Meier method and the log-rank test was used to compare survival curves. RESULTS: Crude analysis revealed a high OM in age 80+ (HR = 5.958, 95% CI 3.357-10.575, p < 0.001), followed by age 60-79 (HR = 1.429, 95% CI 1.028-1.986, p = 0.033); and PCS with distant metastases (HR = 1.888, 95% CI 1.389-2.566, p < 0.001). Patients that underwent surgical resection of the primary tumor and patients with malignant fibrous histiocytomas (HR = 0.657, 95% CI 0.455-0.95, p = 0.025) had a better OM (HR = 0.606, 95% CI 0.465-0.791, p < 0.001). The highest cancer-specific mortality was observed in age 80+ (HR = 5.037, 95% CI 2.606-9.736, p < 0.001) and patients with distant metastases (HR = 1.953, 95% CI 1.396-2.733, p < 0.001). Patients with malignant fibrous histiocytomas (HR = 0.572, 95% CI 0.378-0.865, p = 0.008) and those who underwent surgery (HR = 0.581, 95% CI 0.436-0.774, p < 0.001) had a lower CSM. Patients in the age range 80+ (HR = 13.261, 95% CI 5.839-30.119, p < 0.001) and advanced disease with distant metastases (HR = 2.013, 95% CI 1.355-2.99, p = 0.001) were found to have a higher OM in the multivariate analyses adjusting for covariates). Lower OM was found in patients with rhabdomyosarcoma (HR = 0.364, 95% CI 0.154-0.86, p = 0.021) and widowed patients (HR = 0.506, 95% CI 0.263-0.977, p = 0.042). Multivariate cox proportional hazard regression analyses of CSM also revealed higher mortality of the same groups, and lower mortality in patients with Rhabdomyosarcoma. CONCLUSION: In this United States population-based retrospective cohort study using the SEER database, we found that cardiac rhabdomyosarcoma was associated with the lowest CSM and OM. Furthermore, as expected, age and advanced disease at diagnosis were independent factors predicting poor prognosis. Surgical resection of the primary tumor showed lower CSM and OM in the crude analysis but when adjusted for covariates in the multivariate analysis, it did not significantly impact the overall mortality or the cancer-specific mortality. These findings allow for treating clinicians to recognize patients that should be referred to palliative/hospice care at the time of diagnosis and avoid any surgical interventions as they did not show any differences in mortality. Surgical resection, adjuvant chemotherapy, and/or radiation in patients with poor prognoses should be reserved as palliative measures rather than an attempt to cure the disease.

Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization.

BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. METHODS: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. RESULTS: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. CONCLUSIONS: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

Can Nutritional Adequacy Help Evade Neurodegeneration in Older Age? A Review.

There is an increase in susceptibility to chronic and debilitating diseases with aging. The reason for the underlying neuronal degeneration and normal aging of the brain remains elusive. Different research studies have been conducted to discover how the brain degenerates and the importance of vitamins' role in the neurocognitive decline. Comprehensive literature research was conducted using all relevant data available from PubMed and Google scholar for this article. There has been evidence linking the consumption of essential nutrients to preventing the disease conditions that result in cognitive decline. This article provides the latest scientific advances specific to how dietary nutrients and non-nutrient may affect cognitive aging. An adequate supply of nutrients like vitamin B2 (riboflavin), vitamin B12, vitamin E, essential fatty acid (omega-3 fatty acid), and flavonoids play a vital role in ensuring healthy aging, enhancing memory, and strengthening neuroprotection. These nutrients help in neurodegenerative diseases like Alzheimer's disease and Parkinson's. We recommend more research studies to determine the underlying mechanism of how these essential nutrients work in the prevention of cognitive decline. These studies will help provide the evidence needed for new dietary recommendations for combating these diseases that often affect aging patients.

The Role of the Gut Microbiota and the Immune System in the Development of Autism.

Autism| |spectrum| |disorders| |(ASDs)| |are| |neurodevelopmental| |disorders| |that| |present| |with| |social| skills| |and| |communication| |challenges,| |restricted| |interest,| |and| |repetitive| |behavior.| |The| |specific| cause |of| |autism| |is| |not| |well| |understood| |yet.| |However,| |numerous| |studies| |indicated| |that| |environmental| |and| |genetic| |factors,| |dysregulated| |immune| |response,| |and| |alterations| |to| |the| |balance| |and| |content| |of| |the| |gut| |microbiota| |are| |implemented| |in| |the| |development| |of| |autism.| |Many| |non-pharmacological| |interventions| |are| |nominated| |to| |manage |autism,| |including| |family| |support| |services| |and| |psychoeducational| |methods|. Moreover,| |different| |pharmacological| |therapy| |modalities| |are| |recommended| |for| |children| |with| |ASD.| |Learning| |more| |about| |the| |brain,| |immune| |system, |and| |gut| |connections| |could| |assist| |in early| |diagnosis| |and| |treatment| |of| |this| |devastating| |neurodevelopmental| |disorders| |as| |an| |early| |intervention| |in| |ASD| |could| |improve| |a| |child's| |overall| |development.| We| |gathered| |data| |from| |relevant| |previously| |published| |articles| |on| |PubMed| |to| |evaluate |the| |role| |of| |the| |gut| |microbiota| |and| |the| |immune| |system| |on| |the| |development| |of| |autism.|.

Minerals: An Untapped Remedy for Autoimmune Hypothyroidism?

For decades, the focus of managing autoimmune hypothyroidism has been on thyroxine replacement. Correcting lab parameters such as thyroid stimulating hormone (TSH) has been a primary goal. The increasing prevalence of Hashimoto's thyroiditis (HT) continues to impact the quality of life in patients. We believe a holistic approach to this disease entity, considering its underlying complex etiopathogenesis, would benefit patients. Nutraceuticals are combinations of essential nutrients and are becoming a part of novel medical treatments despite the lack of regulation. This review aims to present a concise summary of recent developments regarding minerals such as zinc, selenium, magnesium, iron, and their potential clinical benefit as nutraceuticals in patients with HT. We have explored the potential benefits and associations of these minerals in HT and thyroid function. We reviewed relevant articles, metanalyses, and clinical trials in literature platforms such as PubMed, PubMed Central, and Google Scholar. Significant data found in the literature suggesting a potential health benefit of these minerals in HT though there were many studies to the contrary. Many trials demonstrated the restoration of residual symptoms, reversal of HT-associated thyroid morphological changes, and improvement in thyroid functions. Many of these trials lack statistical power due to the small sample sizes, and their external validity may be questionable due to unaccounted confounding factors. In our opinion, to support an evidence-based holistic clinical approach, further scientific evidence is needed. The association of these elements in thyroid function necessitates more large scale pragmatic trials to elucidate the benefits of nutraceuticals in HT.