Cancer cachexia as a blueprint for treating obesity

Effective pharmacological treatments to achieve significant and sustained weight loss in obese individuals remain limited. Here, we apply a ‘reverse engineering’ approach to cancer cachexia, an extreme form of dysregulated energy balance resulting in net catabolism. We discuss three phenotypic features of the disease, summarize the underlying molecular checkpoints, and explore their translation to obesity research. We then provide examples for established pharmaceuticals, which follow a reverse engineering logic, and propose additional targets that may be of relevance for future studies. Finally, we argue that approaching diseases from this perspective may prove useful as a generic strategy to fuel the development of innovative therapies.     

Inference of recent admixture using genotype data

The inference of biogeographic ancestry (BGA) has become a focus of forensic genetics. Misinference of BGA can have profound unwanted consequences for investigations and society. We show that recent admixture can lead to misclassification and erroneous inference of ancestry proportions, using state of the art analysis tools with (i) simulations, (ii) 1000 genomes project data, and (iii) two individuals analyzed using the ForenSeq DNA Signature Prep Kit. Subsequently, we extend existing tools for estimation of individual ancestry (IA) by allowing for different IA in both parents, leading to estimates of parental individual ancestry (PIA), and a statistical test for recent admixture. Estimation of PIA outperforms IA in most scenarios of recent admixture. Furthermore, additional information about parental ancestry can be acquired with PIA that may guide casework.     

Genetic link between rheumatoid arthritis and autoimmune liver diseases: A two-sample Mendelian randomization study

BackgroundAn association between rheumatoid arthritis (RA) and autoimmune liver diseases (AILDs) was found in observational studies. However, neither the direction nor the cause-effect chain was clear. This study aimed to assess the causal associations between AILDs and RA.MethodsWe performed a two-sample Mendelian randomization (MR) analysis. Following a strict assessment, genome-wide association study (GWAS) datasets were used to select potential candidate single-nucleotide polymorphisms. The inverse-variance weighted (IVW) was used as the primary analysis approach, supplemented with four sensitive analysis methods applied to assess the robustness of the results.ResultsWe discovered that a genetically increased primary biliary cholangitis (PBC) risk had a positive causal effect on RA (IVW OR=1.149, 95% CI=1.063–1.241, P<0.001). According to the MR-Egger regression, horizontal pleiotropy was unlikely to impact causality (intercept = -0.028, P = 0.263). Using the leave-one-out strategy, sensitivity studies revealed that the MR analysis results were robust and reliable. Genetically determined primary sclerosing cholangitis (PSC) was not linked with the risk of RA (IVW OR=1.071, 95%CI=0.984–1.166, P = 0.111). The results of the MR analysis were further validated by sensitivity analyses utilizing the leave-one-out approach. In the other direction, there was no causal relationship between RA and PBC (OR=1.132, 95% CI=0.881–1.454, P = 0.333) or PSC (OR=1.067, 95% CI=0.891–1.279, P = 0.088).ConclusionsUsing a two-sample MR analysis, we investigated the relationship between AILDs and RA and revealed first that PBC increases the risk of RA. Large-scale cross-disease GWAS are required to further illuminate the genomic landscape of AILDs and RA.     

Alterations in pain during adolescence and puberty

During adolescence and puberty, alterations in pain, both experimental and clinical, are observed. In addition, adolescents undergo extensive biopsychosocial changes as they transition from childhood to adulthood. However, a better understanding of how the biopsychosocial changes during adolescence impact pain is needed to improve pain management and develop targeted pain interventions for adolescents. This review synthesizes the literature on alterations in pain during adolescence in humans, describes the potential biopsychosocial factors impacting pain during adolescence, and suggests future research directions to advance the understanding of the impact of adolescent development on pain.     

A review of patent literature on the regulation of glucose metabolism by six phytocompounds in the management of diabetes mellitus and its complications

Diabetes mellitus is a chronic disease, typified by hyperglycemia resulting from failures in complex multifactorial metabolic functions, that requires life-long medication. Prolonged uncontrolled hyperglycemia leads to micro- and macro-vascular complications. Although antidiabetic drugs are prescribed as the first-line treatment, many of them lose efficacy over time or have severe side effects. There is a lack of in-depth study on the patents filed concerning the use of natural compounds to manage diabetes. Thus, this patent analysis provides a comprehensive report on the antidiabetic therapeutic activity of 6 phytocompounds when taken alone or in combinations. Four patent databases were searched, and 17,649 patents filed between 2001 and 2021 were retrieved. Of these, 139 patents for antidiabetic therapeutic aids that included berberine, curcumin, gingerol, gymnemic acid, gymnemagenin and mangiferin were analyzed. The results showed that these compounds alone or in combinations, targeting acetyl-coenzyme A carboxylase 2, serine/threonine protein kinase, α-amylase, α-glucosidase, lipooxygenase, phosphorylase, peroxisome proliferator-activated receptor-γ (PPARγ), protein tyrosine phosphatase 1B, PPARγ co-activator-1α, phosphoinositide 3-kinase and protein phosphatase 1 regulatory subunit 3C, could regulate glucose metabolism which are validated by pharmacological rationale. Synergism, or combination therapy, including different phytocompounds and plant extracts, has been studied extensively and found effective, whereas the efficacy of commercial drugs in combination with phytocompounds has not been studied in detail. Curcumin, gymnemic acid and mangiferin were found to be effective against diabetes-related complications.Please cite this article as: DasNandy A, Virge R, Hegde HV, Chattopadhyay D. A review of patent literature on the regulation of glucose metabolism by six phytocompounds in the management of diabetes mellitus and its complications. J Integr Med. 2023; 21(3): 226–235     

Generalized pancreatic cancer diagnosis via multiple instance learning and anatomically-guided shape normalization

Pancreatic cancer is a highly malignant cancer type with a high mortality rate. As no obvious symptoms are associated with this cancer type, most of the diagnoses are made when the patients are already in a late stage. In this work, we propose an automated method for effective early diagnosis of pancreatic cancer based on multiple instance learning with contrast-enhanced CT images. In this method, diagnosis stability and generalizability were improved through shape normalization based on anatomical structures as well as instance-level contrastive learning. Specifically, anatomically-guided shape normalization were developed to reconstruct the pancreatic regions of interest by spatial transformations, account for larger tumor parts in these regions, and hence enhance the extraction of pancreatic features. Moreover, instance-level contrastive learning was employed to aggregate different types of tumor features within the multiple instance learning framework. This learning approach can maintain the tumor feature integrity and enhance the diagnosis stability. Finally, a balance-adjustment strategy was designed to alleviate the class imbalance problem caused by the scarcity of tumor samples. Extensive experimental results demonstrated remarkable performance of our method when conducted cross-validation on an in-house dataset with 310 patients and independent test on two unseen datasets (a private test set with 316 and a publicly-available test set with 281). The proposed strategies also led to significant improvements in generalizability. Besides, the clinical significance of the proposed method was further verified through two independent test results in which tumors smaller than 2 cm in diameter were identified at accuracies of 80.9% and 90.1%, respectively. Overall, our method provides a potentially successful tool for early diagnosis of pancreatic cancer. Our source codes will be released at https://github.com/SJTUBME-QianLab/MIL_PAdiagnosis.     

Modeling human mutations to understand TRIO GEF function during development

In a recent study, Bonnet and colleagues leveraged in silico structure prediction and human genetic data to understand the molecular regulation of the Rac1-activating guanie nucleotide exchange factor (Rac1-GEF) domain of Trio. Their work sheds new light on the role of Trio during axon guidance and explores the mechanism by which Trio GEF function is regulated in health and dysregulated in disease.