Review of the Different Outcomes Produced by Genetic Knock Out of the Long Non-coding microRNA-host-gene MIR22HG versus Pharmacologic Antagonism of its Intragenic microRNA product miR-22-3p.

BACKGROUND: Publications reveal different outcomes achieved by genetically knocking out a long non-coding microRNA-host-gene (lncMIRHG) versus the administration of pharma-cologic antagomirs specifically targeting the guide strand of such intragenic microRNA. This suggests that lncMIRHGs may perform diverse functions unrelated to their role as intragenic miRNA precursors. OBJECTIVE: This review synthesizes in silico, in vitro, and in vivo findings from our lab and others to compare the effects of knocking out the long non-coding RNA MIR22HG, which hosts miR-22, versus administering pharmacological antagomirs targeting miR-22-3p. METHODS: In silico analyses at the gene, pathway, and network levels reveal both distinct and overlapping targets of hsa-miR-22-3p and its host gene, MIR22HG. While pharmacological an-tagomirs targeting miR-22-3p consistently improve various metabolic parameters in cell culture and animal models across multiple studies, genetic knockout of MIR22HG yields inconsistent results among different research groups. RESULTS: Additionally, MIR22HG functions as a circulating endogenous RNA (ceRNA) or "sponge" that simultaneously modulates multiple miRNA-mRNA interactions by competing for binding to several miRNAs. CONCLUSIONS: From a therapeutic viewpoint, genetic inactivation of a lncMIRHG and pharmaco-logic antagonism of the guide strand of its related intragenic miRNA produce different results. This should be expected as lncMIRHGs play dual roles, both as lncRNA and as a source for primary miRNA transcripts.

Sustainable Synthesis of Guanidine Derivatives and Computational Assessment of their Antidiabetic Efficacy.

BACKGROUND: Type 2 Diabetes Mellitus (T2DM) represents a significant and pressing worldwide health concern, necessitating the quest for enhanced antidiabetic pharmaceuticals. Guanidine derivatives, notably metformin and buformin, have emerged as pivotal therapeutic agents for T2DM management. AIMS: The present study introduces an efficient one-pot synthesis method for the production of symmetrical guanidine compounds. METHODS: This synthesis involves the reaction of isothiocyanates with secondary amines, employing an environmentally friendly and recyclable reagent, tetrabutylphosphonium tribromide (TBPTB). RESULTS: A comprehensive assessment of the biological activity of the synthesized guanidine compounds, specifically in the context of T2DM, has been rigorously conducted. CONCLUSION: Additionally, computational analyses have unveiled their substantial potential as promising antidiabetic agents. Results highlight the relevance of these compounds in the ongoing pursuit of novel therapeutic solutions for T2DM.

Deletion of miR-146a enhances therapeutic protein restoration in model of dystrophin exon skipping.

Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the absence of dystrophin protein. One current DMD therapeutic strategy, exon skipping, produces a truncated dystrophin isoform using phosphorodiamidate morpholino oligomers (PMOs). However, the potential of exon skipping therapeutics has not been fully realized as increases in dystrophin protein have been minimal in clinical trials. Here, we investigate how miR-146a-5p, which is highly elevated in dystrophic muscle, impacts dystrophin protein levels. We find inflammation strongly induces miR-146a in dystrophic, but not wild-type myotubes. Bioinformatics analysis reveals that the dystrophin 3' UTR harbors a miR-146a binding site, and subsequent luciferase assays demonstrate miR-146a binding inhibits dystrophin translation. In dystrophin-null mdx52 mice, co-injection of miR-146a reduces dystrophin restoration by an exon 51 skipping PMO. To directly investigate how miR-146a impacts therapeutic dystrophin rescue, we generated mdx52 with body-wide miR-146a deletion (146aX). Administration of an exon skipping PMO via intramuscular or intravenous injection markedly increases dystrophin protein levels in 146aX vs. mdx52 muscles while skipped dystrophin transcript levels are unchanged supporting a post-transcriptional mechanism of action. Together, these data show that miR-146a expression opposes therapeutic dystrophin restoration, suggesting miR-146a inhibition warrants further research as a potential DMD exon skipping co-therapy.

Extracellular vesicle transfer of lncRNA H19 splice variants to cardiac cells.

The delivery of therapeutic long non-coding RNAs (lncRNA) to the heart by extracellular vesicles (EVs) is promising for heart repair. H19, a lncRNA acting as a major regulator of gene expression within the cardiovascular system, is alternatively spliced, but the loading of its different splice variants into EVs and their subsequent uptake by recipient cardiac cells remain elusive. Here, we dissected the cellular expression of H19 splice variants and their loading into EVs secreted by Wharton-Jelly mesenchymal stromal/stem cells (WJ-MSCs). We demonstrated that overexpression of the mouse H19 gene in WJ-MSCs induces the expression of H19 splice variants at different levels. Interestingly, EVs isolated from the H19-transfected WJ-MSCs (EV-H19) showed similar expression levels for all tested splice variant sets. In vitro, we further demonstrated that EV-H19 was taken up by cardiomyocytes, fibroblasts, and endothelial cells (ECs). Finally, analysis of EV tropism in living rat myocardial slices indicated that EVs were internalized mostly by cardiomyocytes and ECs. Collectively, our results indicated that EVs can be loaded with different lncRNA splice variants and successfully internalized by cardiac cells.

Long-Term Culture of Human Pluripotent Stem Cells in Xeno-Free Condition Using Functional Polymer Films.

Human pluripotent stem cells (hPSCs), encompassing human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), hold immense potential in regenerative medicine, offering new opportunities for personalized cell therapies. However, their clinical translation is hindered by the inevitable reliance on xenogeneic components in culture environments. This study addresses this challenge by engineering a fully synthetic, xeno-free culture substrate, whose surface composition is tailored systematically for xeno-free culture of hPSCs. A functional polymer surface, pGC2 (poly(glycidyl methacrylate-grafting-guanidine-co-carboxylic acrylate)), offers excellent cell-adhesive properties as well as non-cytotoxicity, enabling robust hESCs and hiPSCs growth while presenting cost-competitiveness and scalability over Matrigel. This investigation includes comprehensive evaluations of pGC2 across diverse experimental conditions, demonstrating its wide adaptability with various pluripotent stem cell lines, culture media, and substrates. Crucially, pGC2 supports long-term hESCs and hiPSCs expansion, up to ten passages without compromising their stemness and pluripotency. Notably, this study is the first to confirm an identical proteomic profile after ten passages of xeno-free cultivation of hiPSCs on a polymeric substrate compared to Matrigel. The innovative substrate bridges the gap between laboratory research and clinical translation, offering a new promising avenue for advancing stem cell-based therapies.

Exploring the Therapeutic Potential of C-Type Natriuretic Peptide for Preeclampsia.

BACKGROUND: Preeclampsia is a serious condition of pregnancy, complicated by aberrant maternal vascular dysfunction. CNP (C-type natriuretic peptide) contributes to vascular homeostasis, acting through NPR-B (natriuretic peptide receptor-B) and NPR-C (natriuretic peptide receptor-C). CNP mitigates vascular dysfunction of arteries in nonpregnant cohorts; this study investigates whether CNP can dilate maternal arteries in ex vivo preeclampsia models. METHODS: Human omental arteries were dissected from fat biopsies collected during cesarean section. CNP, NPR-B, and NPR-C mRNA expression was assessed in arteries collected from pregnancies complicated by preeclampsia (n=6) and normotensive controls (n=11). Using wire myography, we investigated the effects of CNP on dilation of arteries from normotensive pregnancies. Arteries were preconstricted with either serum from patients with preeclampsia (n=6) or recombinant ET-1 (endothelin-1; vasoconstrictor elevated in preeclampsia; n=6) to model vasoconstriction associated with preeclampsia. Preconstricted arteries were treated with recombinant CNP (0.001-100 µmol/L) or vehicle and vascular relaxation assessed. In further studies, arteries were preincubated with NPR-B (5 µmol/L) and NPR-C (10 µmol/L) antagonists before serum-induced constriction (n=4-5) to explore mechanistic signaling. RESULTS: CNP, NPR-B, and NPR-C mRNAs were not differentially expressed in omental arteries from preeclamptic pregnancies. CNP potently stimulated maternal artery vasorelaxation in our model of preeclampsia (using preeclamptic serum). Its vasodilatory actions were driven through the activation of NPR-B predominantly; antagonism of this receptor alone dampened CNP vasorelaxation. Interestingly, CNP did not reduce ET-1-driven omental artery constriction. CONCLUSIONS: Collectively, these data suggest that enhancing CNP signaling through NPR-B offers a potential therapeutic strategy to reduce systemic vascular constriction in preeclampsia.

Evaluation of Romosozumab's Effects on Bone Marrow Adiposity in Postmenopausal Osteoporotic Women: Results from the FRAME Bone Biopsy Sub-Study.

Romosozumab, a humanized monoclonal antibody that binds and inhibits sclerostin produces a marked increase in bone formation with a concomitant decreased bone resorption. This transient rise in bone formation in the first two months of treatment is mainly due to an increased modeling-based bone formation. This requires the recruitment and differentiation of osteoblasts, one possibility being a preferential switch in commitment of precursors to osteoblasts over adipocytes. The purpose of this study was to analyze the marrow adiposity in transiliac bone biopsies at months 2 or 12 from the FRAME biopsy sub-study in patients receiving romosozumab or placebo. The total adipocyte area, number and density were measured on the total cancellous bone area. The size and shape at the individual adipocyte level were assessed including the mean adipocyte area, perimeter, min and max diameters and aspect ratio. No significant difference in total adipocyte area, number or density between placebo and romosozumab groups was observed at months 2 and 12, and no difference was observed between 2 and 12 months. After 2 or 12 months, romosozumab did not modify the size or shape of the adipocytes. No relationship between the adipocyte parameters and the dynamic parameters of bone formation could be evidenced. In conclusion, based on the analysis of a small number of biopsies, no effect of romosozumab on bone marrow adiposity of iliac crest was identified after 2 and 12 months suggesting that the modeling-based formation observed at month 2 was not due to a preferential commitment of the precursor to osteoblast over adipocyte cell lines but may result from a reactivation of bone lining cells and from a progenitor pool independent of the marrow adipocyte population.

Osteoporosis is characterized by bone loss resulting from an imbalance between the bone resorption and the bone formation in favor of the resorption. Romosozumab, a new medication to treat osteoporosis, has been shown to induce an early transient increase in bone formation that requires the differentiation of new bone forming cells called osteoblasts. Osteoblasts and fat-containing cells known as adipocytes present in the bone marrow originate from a common precursor cell. Thus, a preferential switch of this precursor to osteoblast over adipocyte is thought to be a possible cause for the increase in bone formation. The purpose of this study was to analyze the bone marrow adipocytes on bone biopsies from the pelvis in osteoporotic patients treated with romosozumab in order to evaluate that possibility. After treatment, the proportion of adipocytes, their size and shape, did not change when compared to untreated patients. In conclusion, no effect of romosozumab on bone marrow adipocytes was identified suggesting that the increased bone formation induced by romosozumab was not due to a preferential differentiation of precursor cells to osteoblasts over adipocytes.

Dual-Engineered Macrophage-Microbe Encapsulation for Metastasis Immunotherapy.

Lung metastases are the leading cause of death among cancer patients. The challenges of inefficient drug delivery, compounded by a robust immunosuppressive microenvironment, make effective treatment difficult. Here, an innovative dual-engineered macrophage-microbe encapsulation (Du-EMME) therapy is developed that integrates modified macrophages and engineered antitumor bacteria. These engineered macrophages, termed R-GEM cells, are designed to express RGD peptides on extracellular membranes, enhancing their tumor cell binding and intratumor enrichment. R-GEM cells are cocultured with attenuated Salmonella typhimurium VNP20009, producing macrophage-microbe encapsulation (R-GEM/VNP cells). The intracellular bacteria maintain bioactivity for more than 24 h, and the bacteria released from R-GEM/VNP cells within the tumor continue to exert bacteria-mediated antitumor effects. This is further supported by macrophage-based chemotaxis and camouflage, which enhance the intratumoral enrichment and biocompatibility of the bacteria. Additionally, R-GEM cells loaded with IFNγ-secreting strains (VNP-IFNγ) form R-GEM/VNP-IFNγ cells. Treatment with these cells effectively halts lung metastatic tumor progression in three mouse models (breast cancer, melanoma, and colorectal cancer). R-GEM/VNP-IFNγ cells vigorously activate the tumor microenvironment, suppressing tumor-promoting M2-type macrophages, MDSCs, and Tregs, and enhancing tumor-antagonizing M1-type macrophages, mature DCs, and Teffs. Du-EMME therapy offers a promising strategy for targeted and enhanced antitumor immunity in treating cancer metastases.

Genetic cholestasis: classification according to the cellular defect. / Colestasis genéticas: clasificación según el defecto celular.

Advances in molecular biology achieved during the last years have allowed us to know the genes involved in biliary secretion and the mutations capable of generating cholestasis. The mechanisms involved in forming bile and its circulation have been clarified. According to the biology of biliary secretion, we classify the genetic causes of cholestasis as follows: 1) transport abnormalities in canalicular or basolateral membranes, 2) alterations in intracellular vesicle transit, 3) increased paracellular permeability, 4) mutations in nuclear receptors, 5) cholangiopathies, and 6) hepatocellular diseases, due to disturbance of the function of intracellular organelles or errors of metabolism. This physiopathological classification of chronic cholestasis in childhood will facilitate pediatricians' diagnostic guidance and timely specialized referrals, as patients should receive early and appropriate treatment for its complications.

Los avances en biología molecular alcanzados durante los últimos años nos han permitido conocer los genes que intervienen en la secreción biliar y las mutaciones capaces de generar un cuadro de colestasis. Los mecanismos involucrados en la formación de la bilis y su circulación han sido precisados. De acuerdo a la biología de la secreción biliar, clasificamos las causas genéticas de colestasis en 1) anomalías del transporte en las membranas canalicular o basolateral, 2) alteraciones del tránsito de vesículas intracelulares, 3) aumento de la permeabilidad paracelular, 4) mutaciones en los receptores nucleares, 5) colangiopatías, 6) enfermedades hepatocelulares, por perturbación de la función de orgánulos intracelulares o errores del metabolismo. Esta clasificación fisiopatológica de las colestasis crónicas de la infancia facilitará la orientación diagnóstica de los pediatras y la derivación especializada oportuna, ya que los pacientes deben recibir tempranamente un tratamiento adecuado a las complicaciones de la colestasis.

Recent advances in methods for quantifying the cell penetration of macromolecules.

As the landscape of macromolecule therapeutics advances, drug developers are continuing to aim at intracellular targets. To activate, inhibit, or degrade these targets, the macromolecule must be delivered efficiently to intracellular compartments. Quite often, there is a discrepancy between binding affinity in biochemical assays and activity in cell-based assays. Identifying the bottleneck for cell-based activity requires robust assays that quantify total cellular uptake and/or cytosolic delivery. Recognizing this need, chemical biologists have designed a plethora of assays to make this measurement, each with distinct advantages and disadvantages. In this review, we describe the latest and most promising developments in the last 3 to 4 years.

A smartphone app-based intervention combined with face-to-face sessions for alcohol dependence at internal medicine clinics: A randomized controlled trial.

BACKGROUND: Addressing the limited access to treatments for alcohol dependence, we developed ALM-002, a therapeutic application to be "prescribed" for non-abstinence-oriented treatment in internal medicine settings. Our objective was to preliminarily assess the efficacy and safety of ALM-002. METHODS: In a multicenter, open-label randomized controlled trial, participants aged ≥20 with alcohol dependence and daily alcohol consumption exceeding 60 g for men and 40 g for women, without severe complications, were randomly assigned to either the intervention group using ALM-002 or the treatment-as-usual control group. Participant in both groups received individual face-to-face sessions by physicians at weeks 0, 4, 8, and 12. The primary endpoint was the change in heavy drinking days (HDDs) from week 0 to week 12. A mixed model for repeated measures was employed. RESULTS: We enrolled 43 participants: 22 in the intervention group and 21 in the control group. A significant reduction in HDDs every 4 weeks from week 0 to week 12 was observed, with a between-group difference of -6.99 days (95% CI: -12.4 to -1.6 days, standardized mean difference: -0.80). CONCLUSIONS: These results indicate the potential of ALM-002 as a viable treatment for alcohol dependence. Further studies are needed to evaluate the clinical potential of ALM-002.

Irreversible Electroporation for the Focal Treatment of Prostate Cancer: A Systematic Review.

PURPOSE: Irreversible electroporation (IRE) is a promising alternative treatment for low-intermediate-risk localized prostate cancer. In this systematic review we aim to evaluate the safety profile and functional and oncological outcomes of this new technique. MATERIALS AND METHODS: A systematic review of the literature was performed on PubMed, EMBASE, and Scopus up to 24 August 2023. Nineteen studies were analyzed, including 12 prospective studies and 7 retrospective studies. A total of 1,452 patients underwent IRE as the sole primary treatment modality. RESULTS: The in-field clinically significant prostate cancer rate was reported between 0%-15.6% in the repeat biopsy. The retreatment rate was reported from 8% to 36.6%. The 3 years failure-free survival was presented between 90%-96.8%. The post-operative pad-free rate ranged between 96.7%-100%. Greater heterogeneity exists considering the change in erectile function. The most common reported complications were urinary tract infection and hematuria. Major complications were rare. CONCLUSIONS: These results underline that IRE achieves favorable oncological control with an excellent safety profile, in the meantime preserving patients' urinary and erectile function.

Incidence, initial management and survival of high-risk non-muscle invasive bladder cancer in Northern France.

OBJECTIVE: Information on bladder cancer (BC) according to the risk scoring for recurrence or progression in a general population is scarce despite its clinical relevance. The objective was to describe the characteristics of incident BC in a general population, with a focus on the initial management of high-risk non-muscle invasive BC (HR-NMIBC). MATERIALS: BC incident in 2011-2012 recorded in a population-based cancer registry were studied. Data was extracted from medical files. NMIBC were classified according to potential risk for recurrence/progression. Individual and tumor characteristics of incident BC were described. Incidence, initial management and survival (12/31/2021) of HR-NMIBC were assessed. RESULTS: Among 538 BC cases, 380 were NMIBC [119 low (22.1%), 163 intermediate (30.3%), 98 high (18.2%) risk] and 147 (27.3%) were MIBC. HR-NMIBC diagnostic and therapeutic management [imaging, re-TUR, multidisciplinary team meetings (MDT) assessment, specific treatment] revealed discrepancies with guidelines recommendations. Seventy-two out of 98 cases were assessed in an MDT with a median time from diagnosis of 18days [first quartile: 12-third quartile: 32]. Globally, treatment agreed with MDT decisions. Intravesical instillation was the most common treatment (n=56) but 27 HR-NMIBC did not receive specific treatment after TUR. Five and 10years overall survival was 52% [42-63] and 41% [31-51], respectively. Five years net survival was 63% [47-75]. CONCLUSIONS: Despite National cancer plans aiming to improve care giving and despite the severity of HR-NMIBC, guideline-recommended patterns of care were underused in this region. This may deserve attention to identify obstacles to guideline adoption to try to improve BC patient care and survival.

Potentiation of BKCa channels by cystic fibrosis transmembrane conductance regulator (CFTR) correctors VX-445 and VX-121.

Cystic fibrosis (CF) results from mutations in the CFTR anion channel, ultimately leading to diminished transepithelial anion secretion and mucociliary clearance. CFTR correctors are therapeutics that restore the folding/trafficking of mutated CFTR to the plasma membrane. The BKCa potassium channel is also critical for maintaining lung ASL volume. Here, we show the CFTR corrector, VX-445 (Elexacaftor), a component of Trikafta, induces K+ secretion across WT and F508del CFTR primary human bronchial epithelial cells (HBEs), which was entirely inhibited by the BKCa antagonist paxilline. Similar results were observed with VX-121 - a corrector under clinical evaluation. Whole-cell patch-clamp recordings confirmed potentiated channel activity from CFTR correctors on the BKCa α-subunit, and excised patch-clamp recordings demonstrated a significant increase in open probability. In mesenteric artery, VX-445 induced a paxilline-sensitive vasorelaxation of preconstricted arteries. VX-445 also reduced action potential firing frequency in primary hippocampal and cortical neurons. VX-445 effects were observed at low micomolar concentrations (1-10 µM) - within the range reported in plasma and tissues from CF patients. We raise the possibilities that CFTR correctors gain additional clinical benefit by activation of BKCa in the lung, yet may lead to adverse events through BKCa activation, elsewhere.

Harnessing the ocean's pharmacy: marine bioactive compounds as next-generation therapeutics.

The ocean's vast and diverse ecosystem offers a rich reservoir of bioactive compounds with immense clinical potential. Marine organisms produce structurally unique and biologically active compounds, leading to breakthroughs in therapeutic development. Notable examples include anticancer agents like trabectedin and cytarabine, and the analgesic ziconotide. Marine compounds also exhibit potent antimicrobial and antiviral properties, addressing critical challenges like antibiotic resistance and emerging viral infections. Despite the promise, challenges such as sustainable harvesting and complex extraction processes persist. Advances in synthetic biology and metabolic engineering provide solutions for sustainable production, ensuring a stable supply of these valuable compounds. The integration of marine bioactives into modern medicine could revolutionize treatments for cancer, chronic pain, and infectious diseases, underscoring the need for continued investment in marine bioprospecting and biotechnological innovation.

Intracellular delivery of antisense oligonucleotides by tri-branched cyclic disulfide units.

Therapeutic oligonucleotides, such as antisense DNA, show promise in treating previously untreatable diseases. However, their applications are still hindered by the poor membrane permeability of naked oligonucleotides. Therefore, it is necessary to develop efficient methods for intracellular oligonucleotide delivery. Previously, our group successfully developed disulfide-based Membrane Permeable Oligonucleotides (MPON), which achieved enhanced cellular uptake and gene silencing effects through an endocytosis-free uptake mechanism.  Herein, we report a new molecular design for the next generation of MPON, called trimer MPON. The trimer MPON consists of a tri-branched backbone, three α-lipoic acid units, and a spacer linker between the oligonucleotides and tri-branched cyclic disulfide unit. We describe the design, synthesis, and functional evaluation of the trimer MPON, offering new insights into the molecular design for efficient oligonucleotide delivery.

Impact of elexacaftor/tezacaftor/ivacaftor CFTR modulator therapy on rates of endoscopic sinus surgery in cystic fibrosis.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI), a combination cystic fibrosis transmembrane receptor (CFTR) modulator, has demonstrated improved pulmonary outcomes in individuals with cystic fibrosis (CF). However, ETI's impact on functional endoscopic sinus surgery (FESS) remains unclear. METHODS: The TriNetX Analytics Research Network, consisting of 120 million global de-identified electronic medical records, was queried from 2012 to 2023 for subjects with CF who underwent sinus surgery.1 Patients on ETI prior to FESS (n = 6,056) were propensity score matched to control individuals with CF not on CFTR modulators (n = 37,906) and those on other FDA-approved CFTR modulators (tezacaftor/ivacaftor, lumacaftor/ivacaftor, and ivacaftor) (n = 2437) based on relevant factors. The primary outcome was the absolute risk reduction (ARR) of undergoing FESS. Secondary outcomes included ARR of CF-related pulmonary exacerbations and hospital admission from 0 to 6, 6 to 12, and 12 to 24 months following FESS. RESULTS: ETI use demonstrated a significant ARR for FESS when compared to CF patients not on CFTR modulators (2.12%; 95% confidence interval [CI] 1.5-2.75; p-value < 0.0001) and those on other CFTR modulators (4.7%; 95% CI 3.54-5.85; p-value < 0.0001). No significant differences occurred in secondary outcomes between ETI and non-CFTR modulator groups, except for reduced CF-related pulmonary exacerbations from 0 to 6 months post-FESS. Additionally, a significant reduction in pulmonary exacerbations was observed at all time points and hospital admissions within 6 months following FESS compared to those using other CFTR modulators. CONCLUSIONS: In a large dataset, CF patients on ETI demonstrated significantly reduced risk of FESS, pulmonary exacerbations, and hospital admission compared to patients not on CFTR modulators or those on other CFTR modulators, suggesting improved sinonasal disease and overall health status in CF.

Overcoming cancer drug-resistance calls for novel strategies targeting abnormal alternative splicing.

Abnormal gene alternative splicing (AS) events are strongly associated with cancer progression. Here, we summarize AS events that contribute to the development of drug resistance and classify them into three categories: alternative cis-splicing (ACS), alternative trans-splicing (ATS), and alternative back-splicing (ABS). The regulatory mechanisms underlying AS processes through cis-acting regulatory elements and trans-acting factors are comprehensively described, and the distinct functions of spliced variants, including linear spliced variants derived from ACS, chimeric spliced variants arising from ATS, and circRNAs generated through ABS, are discussed. The identification of dysregulated spliced variants, which contribute to drug resistance and hinder effective cancer treatment, suggests that abnormal AS processes may together serve as a precise regulatory mechanism enabling drug-resistant cancer cell survival or, alternatively, represent an evolutionary pathway for cancer cells to adapt to changes in the external environment. Moreover, this review summarizes recent advancements in treatment approaches targeting AS-associated drug resistance, focusing on cis-acting regulatory elements, trans-acting factors, and specific spliced variants. Collectively, gaining an in-depth understanding of the mechanisms underlying aberrant alternative splicing events and developing strategies to target this process hold great promise for overcoming cancer drug resistance.

Impact of healthcare interventions on distress following acute musculoskeletal/orthopaedic injury: a scoping review of systematic reviews.

BACKGROUND: Musculoskeletal injuries can cause distress, and distress is associated with delayed recovery. Numerous interventions have been developed to facilitate recovery from injury, and several systematic reviews evaluate the efficacy of these interventions for reducing psychological distress. OBJECTIVES: This scoping review aims to map the synthesised evidence for the relationship between treatment interventions and distress-related outcomes following acute injury. The objectives were (1) to describe the types of interventions that have been evaluated in relation to distress-related outcomes following accidental injury, (2) to examine the scope of distress-related outcomes that have been measured in relation to these interventions and (3) to explore the range of clinical professions that deliver these interventions. DESIGN: We searched nine electronic databases and grey literature (to 21 April 2022). We included any systematic review reporting on the relationship between interventions delivered in the time following injury and distress-related outcomes. Data relevant to the specific objectives of this scoping review were extracted and described using narrative synthesis. RESULTS: From 8412 systematic reviews imported for screening, 8266 unique records were screened. 179 were selected for full-text review. 84 systematic reviews were included in the study. Interventional types were pharmacological, psychological, exercise based, physical/manual therapies, virtual reality based, multimodal and workplace based. Interventions were delivered digitally, face to face and using virtual reality by a variety of healthcare professionals, including doctors, nurses, psychologists and physiotherapists. The most frequently reported distress-related variables included anxiety, depression, post-traumatic stress disorder diagnosis. CONCLUSION: A wide range of interventions may help to mitigate distress following acute accidental musculoskeletal or orthopaedic injury. Even interventions that were not designed to reduce distress were found to improve distress-related outcomes. In view of the important role of distress in recovery from injury, it is recommended that distress-related variables are measured as core outcomes in the evaluation of treatments for acute injuries.