Reverse Shoulder Arthroplasty for Acute Proximal Humerus Fractures Treated With Trabecular Metal Prosthesis: Medium-Term Results.

Introduction Reverse shoulder arthroplasty (RSA) is becoming increasingly popular as a primary procedure for complex proximal humeral fractures (PHF) in acute trauma due to more emerging evidence and better patient outcomes. Methods This study is a retrospective case series of 51 patients who underwent a trabecular metal RSA for non-reconstructable, acute three or four-part PHF performed by a single surgeon between 2013 and 2019 with a minimum follow-up of three years. This included 44 females and seven males. Mean age was 76 years (range: 61-91 years). Oxford shoulder score (OSS) along with relevant patient information relating to demographics and functional outcomes were collected at regular intervals in outpatient clinic follow-ups. Complications were addressed accordingly during treatment and follow-up. Results The mean follow-up duration was 5.08 years. Two patients were lost to follow-up and nine patients died due to other causes. Four of them had developed severe dementia and were excluded as an outcome score from them could not be acquired. Two patients who had surgery beyond four weeks post-injury were excluded. Thirty-four patients in total were followed up. Patients had good range of motion and mean OSS of 40.28 post-operatively. The overall complication rate was 11.7%, and none of the patients had deep infections, scapular notching, or acromial fractures. Revision rate was 5.8% at mean follow-up of five years and one month (range: three years to nine years two months). Greater tuberosity union following intra-operative repair was evident on radiographs in 61.7% of the patients. Conclusion RSA is certainly a rewarding surgery in patients with complex PHF and was associated with good post-operative OSS along with patient satisfaction, and positive radiological outcomes at minimum three-year follow-up.

WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma.

Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1 family-mediated Lys4 methylation of histone H3 (H3K4me), associated with positive regulation of transcription. In GBM CSCs, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. Use of a SOX2/OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.

Investigating the Effectiveness of Very Low-Calorie Diets and Low-Fat Vegan Diets on Weight and Glycemic Markers in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Caloric restriction and vegan diets have demonstrated protective effects for diabetes, however their role in improving clinically relevant outcomes has not been summarized. Our aim was to evaluate the evidence for low-calorie diets (VLCD) and vegan diets on weight and glycemic control in the management of patients with Type 2 Diabetes. Database searches were conducted using Cochrane Library, MEDLINE (Ovid) and Embase. Systematic Review Registration: CRD42022310299. Methodological quality of studies was assessed using Cochrane RoB Tool for RCTs, Cochrane ROBINS-I RoB Tool for non-RCTs and NIH Quality Assessment tool for other studies. Sixteen studies with a total of 834 individuals were included and assessed to have a moderate to high risk of bias. Statistically significant changes in weight, BMI, and HbA1c were not observed in vegan diet cohorts. However, LDL cholesterol was significantly decreased by vegan diet. VLCDs significantly improved glycaemic control, with reductions in fasting glucose, pooled mean difference (MD) -1.51 mmol/L (95% CI -2.89, -0.13; p = 0.03; 2 studies) and HbA1c, pooled MD -0.66% (95% CI -1.28, -0.03; p = 0.04; 3 studies) compared to non-dietary therapy. Both diets suggested a trend towards improved weight loss and anthropometric markers vs. control. VLCD diet intervention is associated with improvement in glycaemia control in patients with Type 2 Diabetes.

RNA splicing: a dual-edged sword for hepatocellular carcinoma.

RNA splicing is the fundamental process that brings diversity at the transcriptome and proteome levels. The spliceosome complex regulates minor and major processes of RNA splicing. Aberrant regulation is often associated with different diseases, including diabetes, stroke, hypertension, and cancer. In the majority of cancers, dysregulated alternative RNA splicing (ARS) events directly affect tumor progression, invasiveness, and often lead to poor survival of the patients. Alike the rest of the gastrointestinal malignancies, in hepatocellular carcinoma (HCC), which alone contributes to ~ 75% of the liver cancers, a large number of ARS events have been observed, including intron retention, exon skipping, presence of alternative 3'-splice site (3'SS), and alternative 5'-splice site (5'SS). These events are reported in spliceosome and non-spliceosome complexes genes. Molecules such as MCL1, Bcl-X, and BCL2 in different isoforms can behave as anti-apoptotic or pro-apoptotic, making the spliceosome complex a dual-edged sword. The anti-apoptotic isoforms of such molecules bring in resistance to chemotherapy or cornerstone drugs. However, in contrast, multiple malignant tumors, including HCC that target the pro-apoptotic favoring isoforms/variants favor apoptotic induction and make chemotherapy effective. Herein, we discuss different splicing events, aberrations, and antisense oligonucleotides (ASOs) in modulating RNA splicing in HCC tumorigenesis with a possible therapeutic outcome.

PLP2 drives collective cell migration via ZO-1-mediated cytoskeletal remodeling at the leading edge in human colorectal cancer cells.

Collective cell migration (CCM), in which cell-cell integrity remains preserved during movement, plays an important role in the progression of cancer. However, studies describing CCM in cancer progression are majorly focused on the effects of extracellular tissue components on moving cell plasticity. The molecular and cellular mechanisms of CCM during cancer progression remain poorly explored. Here, we report that proteolipid protein 2 (PLP2), a colonic epithelium-enriched transmembrane protein, plays a vital role in the CCM of invasive human colorectal cancer (CRC) epithelium by modulating leading-edge cell dynamics in 2D. The extracellular pool of PLP2, secreted via exosomes, was also found to contribute to the event. During CCM, the protein was found to exist in association with ZO-1 (also known as TJP1) and to be involved in the positioning of the latter at the migrating edge. PLP2-mediated positioning of ZO-1 at the leading edge further alters actin cytoskeletal organization that involves Rac1 activation. Taken together, our findings demonstrate that PLP2, via its association with ZO-1, drives CCM in CRC epithelium by modulating the leading-edge actin cytoskeleton, thereby opening up new avenues of cancer research. This article has an associated First Person interview with the first author of the paper.

Tumor reversion: a dream or a reality.

Reversion of tumor to a normal differentiated cell once considered a dream is now at the brink of becoming a reality. Different layers of molecules/events such as microRNAs, transcription factors, alternative RNA splicing, post-transcriptional, post-translational modifications, availability of proteomics, genomics editing tools, and chemical biology approaches gave hope to manipulation of cancer cells reversion to a normal cell phenotype as evidences are subtle but definitive. Regardless of the advancement, there is a long way to go, as customized techniques are required to be fine-tuned with precision to attain more insights into tumor reversion. Tumor regression models using available genome-editing methods, followed by in vitro and in vivo proteomics profiling techniques show early evidence. This review summarizes tumor reversion developments, present issues, and unaddressed challenges that remained in the uncharted territory to modulate cellular machinery for tumor reversion towards therapeutic purposes successfully. Ongoing research reaffirms the potential promises of understanding the mechanism of tumor reversion and required refinement that is warranted in vitro and in vivo models of tumor reversion, and the potential translation of these into cancer therapy. Furthermore, therapeutic compounds were reported to induce phenotypic changes in cancer cells into normal cells, which will contribute in understanding the mechanism of tumor reversion. Altogether, the efforts collectively suggest that tumor reversion will likely reveal a new wave of therapeutic discoveries that will significantly impact clinical practice in cancer therapy.

Role of ACE2 receptor and the landscape of treatment options from convalescent plasma therapy to the drug repurposing in COVID-19.

Since the first case reports in Wuhan, China, the SARS-CoV-2 has caused a pandemic and took lives of > 8,35,000 people globally. This single-stranded RNA virus uses Angiotensin-converting enzyme 2 (ACE2) as a receptor for entry into the host cell. Overexpression of ACE2 is mainly observed in hypertensive, diabetic and heart patients that make them prone to SARS-CoV-2 infection. Mitigations strategies were opted globally by the governments to minimize transmission of SARS-CoV-2 via the implementation of social distancing norms, wearing the facemasks, and spreading awareness using digital platforms. The lack of an approved drug treatment regimen, and non-availability of a vaccine, collectively posed a challenge for mankind to fight against the SARS-CoV-2 pandemic. In this scenario, repurposing of existing drugs and old treatment options like convalescent plasma therapy can be one of the potential alternatives to treat the disease. The drug repurposing provides a selection of drugs based on the scientific rationale and with a shorter cycle of clinical trials, while plasma isolated from COVID-19 recovered patients can be a good source of neutralizing antibody to provide passive immunity. In this review, we provide in-depth analysis on these two approaches currently opted all around the world to treat COVID-19 patients. For this, we used "Boolean Operators" such as AND, OR & NOT to search relevant research articles/reviews from the PUBMED for the repurposed drugs and the convalescent plasma in the COVID-19 treatment. The repurposed drugs like Chloroquine and Hydroxychloroquine, Tenofovir, Remdesivir, Ribavirin, Darunavir, Oseltamivir, Arbidol (Umifenovir), Favipiravir, Anakinra, and Baricitinib are already being used in clinical trials to treat the COVID-19 patients. These drugs have been approved for a different indication and belong to a diverse category such as anti-malarial/anti-parasitic, anti-retroviral/anti-viral, anti-cancer, or against rheumatoid arthritis. Although, the vaccine would be an ideal option for providing active immunity against the SARS-CoV-2, but considering the current situation, drug repurposing and convalescent plasma therapy and repurposed drugs are the most viable option against SARS-CoV-2.