Beta-Catenin In Stress And Depression

The beta-catenin protein, integrally involved in Wnt signaling, influences stress and depression.  Abstract:

Beta-catenin is a protein with dual functions in the cell, playing a role in both adhesion between cells as well as gene transcription via the canonical Wnt signalling pathway. In the canonical Wnt signalling pathway, beta-catenin again plays multiple roles. In the embryonic stage, the regulation of beta-catenin levels activates genes that govern cell proliferation and differentiation. In an adult organism, beta-catenin continues to regulate the cell cycle - as a result over-expression of beta-catenin may lead to cancer. In the brain, dysfunctions in Wnt signalling related to beta-catenin levels may also cause various pathological conditions like Alzheimer's disease, Parkinson's disease, and depression. Beta-catenin can be influenced by stressful conditions and increases in glucocorticoid levels. In addition, beta-catenin can be regulated by neurotransmitters such as serotonin and dopamine. Fluctuations in beta-catenin in brain regions under duress have been associated with depressive-like behaviours. It is theorized that the change in behaviour can be attributed to the regulation of Dicer by beta-catenin. Dicer, a protein that produces micro-RNAs in the cell, is a target gene for beta-catenin. Amongst the micro-RNA that it produces are those involved in stress resilience. In this way, beta-catenin has taken its place in the well-studied biochemistry of stress and depression, and future research into this interesting protein may yet yield fruitful results in that field.

On a side note, the picture accompanying this post is a typical snapshot of the depressed attitudes of people at my workplace (including me).

Mice, The Immune System, And The Microbiota

The immune response, naturally, shapes the content of the gut microbiota, maintaining tissue homeostasis (normal stable equilibrium), and influencing lipid metabolism.  How the body’s lymphocytes can control the content of the gut microbiota to affect these various bodily processes has been demonstrated in mice.  Abstract:

The mammalian gut is colonized by numerous microorganisms collectively termed the microbiota, which have a mutually beneficial relationship with their host. Normally, the gut microbiota matures during ontogeny to a state of balanced commensalism marked by the absence of adverse inflammation. Subsets of innate lymphoid cells (ILCs) and conventional T cells are considered to have redundant functions in containment and clearance of microbial pathogens, but how these two major lymphoid-cell populations each contribute to shaping the mature commensal microbiome and help to maintain tissue homeostasis has not been determined. Here we identify, using advanced multiplex quantitative imaging methods, an extensive and persistent phosphorylated-STAT3 signature in group 3 ILCs and intestinal epithelial cells that is induced by interleukin (IL)-23 and IL-22 in mice that lack CD4+ T cells. By contrast, in immune-competent mice, phosphorylated-STAT3 activation is induced only transiently by microbial colonization at weaning. This early signature is extinguished as CD4+ T cell immunity develops in response to the expanding commensal burden. Physiologically, the persistent IL-22 production from group 3 ILCs that occurs in the absence of adaptive CD4+ T-cell activity results in impaired host lipid metabolism by decreasing lipid transporter expression in the small bowel. These findings provide new insights into how innate and adaptive lymphocytes operate sequentially and in distinct ways during normal development to establish steady-state commensalism and tissue metabolic homeostasis

Circulating Tumor DNA Fail?

Some bad news: not much evidence to support the current use of circulating tumor DNA assays; more work is required.  Abstract:

Purpose Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. Methods An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. Results The literature search identified 1,338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion. Conclusion The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity and clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, re-evaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice

Salbutamol And Power Production

The drug salbutamol has been shown to increase power production in the Wingate test. The point here is to investigate mechanism, NOT that people should take this drug for athletic purposes (as opposed to taking it for legitimate medical reasons; potential side effects are one concern among other things.  Abstract:

The effects of a chronic salbutamol intake (SAL, 12 mg/d during 3 weeks) on changes in body composition, metabolic indices and performance during a 30-second Wingate test were determined in 8 strength-trained male athletes (T) and 7 sedentary male (UT) subjects, according to a double-blind, randomized, cross-over protocol. Blood samples were collected both at rest, at the end of the test, and during passive recovery (5 min, 10 min, 15 min) for leptin (at rest), and blood lactate measurements. No significant changes in lean body mass, fat mass, and leptin were observed with SAL treatment in either group during the trial. Peak power was significantly increased (p < 0.05) after SAL intake in all subjects (T: 11.9 %; UT: 8.3 %) with a decrease in time to peak power with SAL compared to placebo (PLA) (p < 0.05). There was no change in total work performed and in fatigue indices with SAL compared to PLA. Blood lactate was significantly increased after SAL vs. PLA during the recovery (p < 0.05) in all subjects. The data demonstrate that the chronic administration of therapeutic levels of salbutamol increases maximal anaerobic power in man, irrespective of the subjects' training status. This study also rules out any implication of an anabolic effect in this improvement in performance during supramaximal exercise. Further studies are necessary to clarify the mechanisms involved.

Expanding The Immunotherapy Arsenal

A review on cancer immunotherapy is here, including the interesting approach of viruses that target and destroy tumor cells. Abstract:

Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized. Immunotherapy, however, extends beyond immune checkpoint therapy by using new molecules such as chimeric monoclonal antibodies and antibody drug conjugates that target malignant cells and promote their destruction. Genetically modified T cells expressing chimeric antigen receptors are able to recognize specific antigens on cancer cells and subsequently activate the immune system. Native or genetically modified viruses with oncolytic activity are of great interest as, besides destroying malignant cells, they can increase anti-tumor activity in response to the release of new antigens and danger signals as a result of infection and tumor cell lysis. Vaccines are also being explored, either in the form of autologous or allogenic tumor peptide antigens, genetically modified dendritic cells that express tumor peptides, or even in the use of RNA, DNA, bacteria, or virus as vectors of specific tumor markers. Most of these agents are yet under development, but they promise to be important options to boost the host immune system to control and eliminate malignancy. In this review, we have provided detailed discussion of different forms of immunotherapy agents other than checkpoint-modifying drugs. The specific focus of this manuscript is to include first-in-human phase I and phase I/II clinical trials intended to allow the identification of those drugs that most likely will continue to develop and possibly join the immunotherapeutic arsenal in a near future.

Home Alone: Why People Believe Others' Social Lives Are Richer Than Their Own

Do others in general really have a richer social life than you?  Probably not, and the bias that makes you believe otherwise is based on over-focusing on a relatively small set of “trendsetters and socialites …extremely social people.”  Abstract:

Although decades of research show that people tend to see themselves in the best possible light, we present evidence that people have a surprisingly grim outlook on their social lives. In 11 studies (N = 3,293; including 3 preregistered), we find that most people think that others lead richer and more active social lives than they do themselves. We show that this bias holds across multiple populations (college students, MTurk respondents, shoppers at a local mall, and participants from a large, income-stratified online panel), correlates strongly with well-being, and is particularly acute for social activities (e.g., the number of parties one attends or proximity to the "inner circle" of one's social sphere). We argue that this pessimistic bias stems from the fact that trendsetters and socialites come most easily to mind as a standard of comparison and show that reducing the availability of extremely social people eliminates this bias. We conclude by discussing implications for research on social comparison and self-enhancement. (PsycINFO Database Record.

Localized Immunotherapy

Localized immunotherapy – injecting the agents directly into the tumor – has shown promise in studies.  Remarkably, if two tumors of the same origin are in different parts of the body – presumably in a mouse model – injecting in one of the tumors is sufficient to target the other one as well.  This would seem to have considerable therapeutic potential.  Abstract:

It has recently become apparent that the immune system can cure cancer. In some of these strategies, the antigen targets are preidentified and therapies are custom-made against these targets. In others, antibodies are used to remove the brakes of the immune system, allowing preexisting T cells to attack cancer cells. We have used another noncustomized approach called in situ vaccination. Immunoenhancing agents are injected locally into one site of tumor, thereby triggering a T cell immune response locally that then attacks cancer throughout the body. We have used a screening strategy in which the same syngeneic tumor is implanted at two separate sites in the body. One tumor is then injected with the test agents, and the resulting immune response is detected by the regression of the distant, untreated tumor. Using this assay, the combination of unmethylated CG-enriched oligodeoxynucleotide (CpG)-a Toll-like receptor 9 (TLR9) ligand-and anti-OX40 antibody provided the most impressive results. TLRs are components of the innate immune system that recognize molecular patterns on pathogens. Low doses of CpG injected into a tumor induce the expression of OX40 on CD4+ T cells in the microenvironment in mouse or human tumors. An agonistic anti-OX40 antibody can then trigger a T cell immune response, which is specific to the antigens of the injected tumor. Remarkably, this combination of a TLR ligand and an anti-OX40 antibody can cure multiple types of cancer and prevent spontaneous genetically driven cancers.

Shared Gene Expression For Mental Illness?

There seems to be a shared pattern of gene expression among various neuropsychiatric diseases, although there are of course distinct patterns as well.  The shared patterns are related to SNP variation (single base pair differences in DNA) and are hence likely genetic and heritable. Abstract:

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.

Cartilage Repair, Cell Signaling, And Osteoarthritis

Cartilage repair, aging, and osteoarthritis; new findings described here.  Cell signaling pathways are involved; modulating these pathways may be part of new, optimized treatments for this disease.  

Ageing processes play a major contributing role for the development of Osteoarthritis (OA). This prototypic degenerative condition of ageing is the most common form of arthritis and is accompanied by a general decline, chronic pain and mobility deficits. The disease is primarily characterized by articular cartilage degradation, followed by subchondral bone thickening, osteophyte formation, synovial inflammation and joint degeneration. In the early stages, osteoarthritic chondrocytes undergo phenotypic changes that increase cell proliferation and cluster formation and enhance the production of matrix-remodelling enzymes. In fact, chondrocytes exhibit differentiation plasticity and undergo phenotypic changes during the healing process. Current studies are focusing on unravelling whether OA is a consequence of an abnormal wound healing response. Recent investigations suggest that alterations in different proteins, such as TGF-ß/BMPs, NF-Kß, Wnt, and Cx43, or SASP factors involved in signalling pathways in wound healing response, could be directly implicated in the initiation of OA. Several findings suggest that osteoarthritic chondrocytes remain in an immature state expressing stemness-associated cell surface markers. In fact, the efficacy of new disease-modifying OA drugs that promote chondrogenic differentiation in animal models indicates that this may be a drug-sensible state. In this review, we highlight the current knowledge regarding cellular plasticity in chondrocytes and OA. A better comprehension of the mechanisms involved in these processes may enable us to understand the molecular pathways that promote abnormal repair and cartilage degradation in OA. This understanding would be advantageous in identifying novel targets and designing therapies to promote effective cartilage repair and successful joint ageing by preventing functional limitations and disability.

Against Fibrosis

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8674830

Fibrosis, a disorder characterized by formation of excess connective fibrous tissue, is common in various disease states, including cardiovascular and kidney disease, negative affecting the function of these organs.  A new study suggests that inhibition of interleukin 11 signaling can repress fibrosis formation and can serve as a possible therapy for fibrotic disease.  Abstract:

Fibrosis is a final common pathology in cardiovascular disease1. In the heart, fibrosis causes mechanical and electrical dysfunction1,2 and in the kidney, it predicts the onset of renal failure3. Transforming growth factor β1 (TGFB1) is the principal pro-fibrotic factor4,5 but its inhibition is associated with side effects due to its pleiotropic roles6,7. We hypothesised that downstream effectors of TGFB1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicities. Using integrated imaging-genomics analyses of primary human fibroblasts, we found that Interleukin 11 (IL11) upregulation is the dominant transcriptional response to TGFB1 exposure and required for its profibrotic effect. IL11 and its receptor (IL11RA) are expressed specifically in fibroblasts where they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il11 injection causes heart and kidney fibrosis and organ failure whereas genetic deletion of Il11ra1 is protective against disease. Thus, inhibition of IL11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These data reveal a central role of IL11 in fibrosis and we propose inhibition of IL11 as a new therapeutic strategy to treat fibrotic diseases.