Gene Therapy for Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome that leads to acute respiratory failure and accounts for over 70,000 deaths per year in the United States alone, even prior to the COVID-19 pandemic. While its molecular details have been teased apart and its pathophysiology largely established over the past 30 years, relatively few pharmacological advances in treatment have been made based on this knowledge. Indeed, mortality remains very close to what it was 30 years ago. As an alternative to traditional pharmacological approaches, gene therapy offers a highly controlled and targeted strategy to treat the disease at the molecular level. Although there is no single gene or combination of genes responsible for ARDS, there are a number of genes that can be targeted for upregulation or downregulation that could alleviate many of the symptoms and address the underlying mechanisms of this syndrome. This review will focus on the pathophysiology of ARDS and how gene therapy has been used for prevention and treatment. Strategies for gene delivery to the lung, such as barriers encountered during gene transfer, specific classes of genes that have been targeted, and the outcomes of these approaches on ARDS pathogenesis and resolution will be discussed.

Minimally invasive endoscopic approach to perform complete coccygectomy in patients with chronic refractory coccydynia: illustrative case

BACKGROUND Coccydynia refers to debilitating pain in the coccygeal region of the spine. Treatment strategies range from conservative measures (e.g., ergonomic adaptations, physical therapy, nerve block injections) to partial or complete removal of the coccyx (coccygectomy). Because the surgical intervention is situated in a high-pressure location close to the anus, a possible complication is the formation of sacral pressure ulcers and infection at the incision site. OBSERVATIONS In this case report, the authors presented a minimally invasive, fully endoscopic approach to safely perform complete coccygectomy for treatment of refractory posttraumatic coccydynia. LESSONS Although this is a single case report, the authors hope that this novel endoscopic approach may achieve improved wound healing, reduced infection rates, and lower risk of penetration injury to retroperitoneal organs in patients requiring coccygectomy.

Immunological Classification of Pancreatic Carcinomas to Identify Immune Index and Provide a Strategy for Patient Stratification

BackgroundCancer immunotherapy has produced significant positive clinical effects in a variety of tumor types. However, pancreatic ductal adenocarcinoma (PDAC) is widely considered to be a “cold” cancer with poor immunogenicity. Our aim is to determine the detailed immune features of PDAC to seek new treatment strategies.MethodsThe immune cell abundance of PDAC patients was evaluated with the single-sample gene set enrichment analysis (ssGSEA) using 119 immune gene signatures. Based on these data, patients were classified into different immune subtypes (ISs) according to immune gene signatures. We analyzed their response patterns to immunotherapy in the datasets, then established an immune index to reflect the different degrees of immune infiltration through linear discriminant analysis (LDA). Finally, potential prognostic markers associated with the immune index were identified based on weighted correlation network analysis (WGCNA) that was functionally validated in vitro.ResultsThree ISs were identified in PDAC, of which IS3 had the best prognosis across all three cohorts. The different expressions of immune profiles among the three ISs indicated a distinct responsiveness to immunotherapies in PDAC subtypes. By calculating the immune index, we found that the IS3 represented higher immune infiltration, while IS1 represented lower immune infiltration. Among the investigated signatures, we identified ZNF185, FANCG, and CSTF2 as risk factors associated with immune index that could potentially facilitate diagnosis and could be therapeutic target markers in PDAC patients.ConclusionsOur findings identified immunologic subtypes of PDAC with distinct prognostic implications, which allowed us to establish an immune index to represent the immune infiltration in each subtype. These results show the importance of continuing investigation of immunotherapy and will allow clinical workers to personalized treatment more effectively in PDAC patients.

AB5 Enterotoxin-Mediated Pathogenesis: Perspectives Gleaned from Shiga Toxins

Foodborne diseases affect an estimated 600 million people worldwide annually, with the majority of these illnesses caused by Norovirus, Vibrio, Listeria, Campylobacter, Salmonella, and Escherichia coli. To elicit infections in humans, bacterial pathogens express a combination of virulence factors and toxins. AB5 toxins are an example of such toxins that can cause various clinical manifestations, including dehydration, diarrhea, kidney damage, hemorrhagic colitis, and hemolytic uremic syndrome (HUS). Treatment of most bacterial foodborne illnesses consists of fluid replacement and antibiotics. However, antibiotics are not recommended for infections caused by Shiga toxin-producing E. coli (STEC) because of the increased risk of HUS development, although there are conflicting views and results in this regard. Lack of effective treatment strategies for STEC infections pose a public health threat during outbreaks; therefore, the debate on antibiotic use for STEC infections could be further explored, along with investigations into antibiotic alternatives. The overall goal of this review is to provide a succinct summary on the mechanisms of action and the pathogenesis of AB5 and related toxins, as expressed by bacterial foodborne pathogens, with a primary focus on Shiga toxins (Stx). The role of Stx in human STEC disease, detection methodologies, and available treatment options are also briefly discussed.

“It’s called overamping”: experiences of overdose among people who use methamphetamine

Background The USA is experiencing increases in methamphetamine use and methamphetamine-related or attributed deaths. In the current study, we explore qualitative narratives of methamphetamine overdose and strategies used by people who use drugs to reduce the undesirable effects associated with methamphetamine use. Methods We conducted 21 qualitative interviews with people over the age of 18 who reported using methamphetamine in the previous 3 months in Nevada and New Mexico. Interviews were recorded, transcribed, and analyzed using qualitative thematic analysis. Results Respondents described a constellation of psychological and physical symptoms that they characterized as “overamping,” experienced on a continuum from less to more severe. Reports of acute, fatal methamphetamine overdose were rare. Few reported seeking medical attention for undesirable effects (usually related to psychological effects). General self-care strategies such as sleeping and staying hydrated were discussed. Conclusions When asked directly, our respondents claimed that acute, fatal methamphetamine overdose is rare or even impossible. However, they described a number of undesirable symptoms associated with overconsumption of methamphetamine and had few clinical or harm reduction strategies at their disposal. Addressing this current wave of drug-related deaths will require attention to the multiple factors that structure experiences of methamphetamine “overdose,” and a collaborative effort with PWUDs to devise effective harm reduction and treatment strategies.

Bioactivities and mechanisms of natural medicines in the management of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive and rare disease without obvious clinical symptoms that shares characteristics with pulmonary vascular remodeling. Right heart failure in the terminal phase of PAH seriously threatens the lives of patients. This review attempts to comprehensively outline the current state of knowledge on PAH its pathology, pathogenesis, natural medicines therapy, mechanisms and clinical studies to provide potential treatment strategies. Although PAH and pulmonary hypertension have similar pathological features, PAH exhibits significantly elevated pulmonary vascular resistance caused by vascular stenosis and occlusion. Currently, the pathogenesis of PAH is thought to involve multiple factors, primarily including genetic/epigenetic factors, vascular cellular dysregulation, metabolic dysfunction, even inflammation and immunization. Yet many issues regarding PAH need to be clarified, such as the “oestrogen paradox”. About 25 kinds monomers derived from natural medicine have been verified to protect against to PAH via modulating BMPR2/Smad, HIF-1α, PI3K/Akt/mTOR and eNOS/NO/cGMP signalling pathways. Yet limited and single PAH animal models may not corroborate the efficacy of natural medicines, and those natural compounds how to regulate crucial genes, proteins and even microRNA and lncRNA still need to put great attention. Additionally, pharmacokinetic studies and safety evaluation of natural medicines for the treatment of PAH should be undertaken in future studies. Meanwhile, methods for validating the efficacy of natural drugs in multiple PAH animal models and precise clinical design are also urgently needed to promote advances in PAH. Graphical Abstract

Cellular and Molecular Alterations Underlying Abnormal Bone Growth in X-Linked Hypophosphatemia

X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets, is caused by inactivating mutations of the phosphate-regulating endopeptidase gene (PHEX). XLH is mainly characterized by short stature, bone deformities and rickets, while in hypophosphatemia, normal or low vitamin D levels and low renal phosphate reabsorption are the principal biochemical aspects. The cause of growth impairment in patients with XLH is not completely understood yet, thus making the study of the growth plate (GP) alterations necessary. New treatment strategies targeting FGF23 have shown promising results in normalizing the growth velocity and improving the skeletal effects of XLH patients. However, further studies are necessary to evaluate how this treatment affects the GP as well as its long-term effects and the impact on adult height.