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Here we show that FTO as an N 6 -methyladenosine (m 6 A) RNA demethylase is degraded by selective autophagy, which is impaired by low-level arsenic exposure to promote tumorigenesis. We found that in arsenic-associated human skin lesions, FTO is upregulated, while m 6 A RNA methylation is downregulated. In keratinocytes, chronic relevant low-level arsenic exposure upregulated FTO, downregulated m 6 A RNA methylation, and induced malignant transformation and tumorigenesis. FTO deletion inhibited arsenic-induced tumorigenesis. Moreover, in mice, epidermis-specific FTO deletion prevented skin tumorigenesis induced by arsenic and UVB irradiation. Targeting FTO genetically or pharmacologically inhibits the tumorigenicity of arsenic-transformed tumor cells. We identified NEDD4L as the m 6 A-modified gene target of FTO. Finally, arsenic stabilizes FTO protein through inhibiting p62-mediated selective autophagy. FTO upregulation can in turn inhibit autophagy, leading to a positive feedback loop to maintain FTO accumulation. Our study reveals FTO-mediated dysregulation of mRNA m 6 A methylation as an epitranscriptomic mechanism to promote arsenic tumorigenicity. RNA m6A demethylase FTO has oncogenic roles in cancers. Here the authors show that chronic low-level exposure of arsenic inhibits autophagic degradation of FTO, leading to FTO stabilisation and reduced m6A RNA methylation in keratinocytes and its subsequent malignant transformation.

Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N 6 -methyladenosine (m 6 A) mRNA demethylation by fat mass and obesity-associated protein (FTO) increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy. FTO level is increased in human melanoma and enhances melanoma tumorigenesis in mice. FTO is induced by metabolic starvation stress through the autophagy and NF-κB pathway. Knockdown of FTO increases m 6 A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m 6 A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFNγ) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity. Our findings demonstrate a crucial role of FTO as an m 6 A demethylase in promoting melanoma tumorigenesis and anti-PD-1 resistance, and suggest that the combination of FTO inhibition with anti-PD-1 blockade may reduce the resistance to immunotherapy in melanoma. FTO is an m6A demethylase. Here, the authors show that FTO promotes melanoma tumorigenicity and contributes to resistance to anti-PD1 blockade, while FTO inhibition sensitizes melanoma to anti-PD1 blockade.

Purpose of Review The heterogeneity of heart failure with preserved ejection fraction (HFpEF) is responsible for the limited success of broad management strategies. The role of biomarkers has been evolving helping to provide insight into the diversity of pathophysiology, prognosis, and potential targets for treatments. We will review the role of traditional and novel biomarkers in diagnosing, prognosticating, and evolving the management of patients with HFpEF. As circulating biomarker discovery rapidly evolves, we will explore technology for new biomarker discovery with examples of successful implementation. Recent Findings Besides cardiac-specific biomarkers (natriuretic peptides and troponin), other novel nonspecific biomarkers increasingly identify the diversity of pathophysiological mechanisms of HFpEF including inflammation, fibrosis, and renal dysfunction. Newer approaches have provided increasing granularity providing opportunities to integrate large amounts of information from proteomics and genomics as biomarkers of interest in HFpEF. Summary HFpEF has been marked with failure of many medications to show benefit, whether measuring single targeted biomarkers or broader targeted discovery proteomics or genomic circulating biomarkers are providing increasing opportunities to better understand and manage HFpEF patients.

Mice deficient in the IL-10 pathway are the most widely used models of intestinal immunopathology. IL-17A is strongly implicated in gut disease in mice and humans, but conflicting evidence has drawn IL-17's role in the gut into question. IL-22 regulates antimicrobial and repair activities of intestinal epithelial cells (IECs) and is closely associated with IL-17A responses but it's role in chronic disease is uncertain. We report that IL-22, like IL-17A, is aberrantly expressed in colitic Il10−/− mice. While IL-22+ Th17 cells were elevated in the colon, IL-22-producing ILC3s were highly enriched in the small intestines of Il10−/− mice. Remarkably, Il10−/−Il22−/− mice did not develop colitis despite retaining high levels of Th17 cells and remaining colonized with colitogenic Helicobacter spp. Accordant with IL-22-induced IEC proliferation, the epithelia hyperplasia observed in Il10−/− animals was reversed in Il10−/−Il22−/− mice. Also, the high levels of antimicrobial IL-22-target genes, including Reg3g, were normalized in Il10−/−Il22−/− mice. Consistent with a heightened antimicrobial environment, Il10−/− mice had reduced diversity of the fecal microbiome that was reestablished in Il10−/−Il22−/− animals. These data suggest that spontaneous colitis in Il10−/− mice is driven by IL-22 and implicates an underappreciated IL-10/IL-22 axis in regulating intestinal homeostasis.

Antigen encounter directs CD4 + T cells to differentiate into T helper or regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern T helper cell versus T regulatory cell fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4 + T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells develop Th2 and Th9 inflammation and show pathophysiological features of atopic asthma. Following T cell activation, Cul5 forms a complex with CIS and pJak1. Cul5 deletion reduces ubiquitination and subsequent degradation of pJak1, leading to an increase in pJak1 and pSTAT6 levels and reducing the threshold of IL-4 receptor signaling. As a consequence, Cul5 deficient CD4 + T cells deviate from Treg to Th9 differentiation in low IL-4 conditions. These data support the notion that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma. Cytokine signaling influences the differentiation of CD4 + T cells into varying functional subsets. Here the authors show that an E3 ubiquitin ligase Cul5 alters T H 2 and T H 9 development and absence of Cul5 in T cells results in higher levels of allergy-associated IL-4 and IL-9 secreting T cells.

Standardized instruments for measuring patients' activity limitations and participation restrictions have been advocated for use by rehabilitation professionals for many years. The available literature provides few recent reports of the use of these measures by physical therapists in the United States. The primary purpose of this study was to determine: (1) the extent of the use of standardized outcome measures and (2) perceptions regarding their benefits and barriers to their use. A secondary purpose was to examine factors associated with their use among physical therapists in clinical practice. The study used an observational design. A survey questionnaire comprising items regarding the use and perceived benefits and barriers of standardized outcome measures was sent to 1,000 randomly selected members of the American Physical Therapy Association (APTA). Forty-eight percent of participants used standardized outcome measures. The majority of participants (>90%) who used such measures believed that they enhanced communication with patients and helped direct the plan of care. The most frequently reported reasons for not using such measures included length of time for patients to complete them, length of time for clinicians to analyze the data, and difficulty for patients in completing them independently. Use of standardized outcome measures was related to specialty certification status, practice setting, and the age of the majority of patients treated. The limitations included an unvalidated survey for data collection and a sample limited to APTA members. Despite more than a decade of development and testing of standardized outcome measures appropriate for various conditions and practice settings, physical therapists have some distance to go in implementing their use routinely in most clinical settings. Based on the perceived barriers, alterations in practice management strategies and the instruments themselves may be necessary to increase their use.

The role of systemic corticosteroid as a therapeutic agent for patients with COVID-19 pneumonia is controversial. The purpose of this study was to evaluate the effect of corticosteroids in non-intensive care unit (ICU) patients with COVID-19 pneumonia complicated by acute hypoxemic respiratory failure (AHRF). This was a single-center retrospective cohort study, from 16th March, 2020 to 30th April, 2020; final follow-up on 10th May, 2020. 265 patients consecutively admitted to the non-ICU wards with laboratory-confirmed COVID-19 pneumonia were screened for inclusion. 205 patients who developed AHRF (SpO2/FiO2 ≤ 440 or PaO2/FiO2 ≤ 300) were only included in the final study. Direct admission to the Intensive care unit (ICU), patients developing composite primary outcome within 24 hours of admission, and patients who never became hypoxic during their stay in the hospital were excluded. Patients were divided into two cohorts based on corticosteroid. The primary outcome was a composite of ICU transfer, intubation, or in-hospital mortality. Secondary outcomes were ICU transfer, intubation, in-hospital mortality, discharge, length of stay, and daily trend of SpO2/FiO2 (SF) ratio from the index date. Cox-proportional hazard regression was implemented to analyze the time to event outcomes. Among 205 patients, 60 (29.27%) were treated with corticosteroid. The mean age was ~57 years, and ~75% were men. Thirteen patients (22.41%) developed a primary composite outcome in the corticosteroid cohort vs. 54 (37.5%) patients in the non-corticosteroid cohort (P = 0.039). The adjusted hazard ratio (HR) for the development of the composite primary outcome was 0.15 (95% CI, 0.07-0.33; P <0.001). The adjusted hazard ratio for ICU transfer was 0.16 (95% CI, 0.07 to 0.34; P < 0.001), intubation was 0.31 (95% CI, 0.14 to 0.70; P- 0.005), death was 0.53 (95% CI, 0.22 to 1.31; P- 0.172), composite of death or intubation was 0.31 (95% CI, 0.15 to 0.66; P- 0.002) and discharge was 3.65 (95% CI, 2.20 to 6.06; P<0.001). The corticosteroid cohort had increasing SpO2/FiO2 over time compared to the non-corticosteroid cohort who experience decreasing SpO2/FiO2 over time. Among non-ICU patients hospitalized with COVID-19 pneumonia complicated by AHRF, treatment with corticosteroid was associated with a significantly lower risk of the primary composite outcome of ICU transfer, intubation, or in-hospital death, composite of intubation or death and individual components of the primary outcome.

Although transplantation remains the gold-standard treatment for patients with end-organ failure, lifelong adherence to immunosuppressant medication is required to prevent rejection, graft failure, and mortality. Given the increase in thoracic organ transplantation, it is crucial to better understand the associated barriers to treatment. Examining sociodemographic, transplant, healthcare access, post-transplant treatment, and patient-related psychosocial factors may help to elucidate treatment barriers that have not been previously considered in the existing literature. This single-site cross-sectional study surveyed 65 thoracic (heart and lung) transplant recipients (mean age: 62 years; 76.2% male; 72.3% White, and 21.5% Black) via phone interviews. Immunosuppressant nonadherence was found in 49.2% of participants (46.9% heart, 51.5% lung). In a four-week period, 20% of participants missed at least one dose, 40% did not take their medications on time, and 1% stopped completely. Significant correlates of nonadherence included poorer diet quality, fewer comorbidities, and maladaptive coping responses to perceived discrimination. This preliminary study highlights the importance of considering the social determinants of health—particularly post-transplant treatment and psychosocial patient-related factors—to inform post-transplant care. Addressing such variables may improve medication adherence and, subsequently, overall health outcomes. Further research with larger samples is needed to better understand the associated correlates and inform effective interventions for enhanced medication adherence.

Neisseria gonorrhoeae is one of the most common bacterial sexually transmitted infections. The emergence of antimicrobial-resistant N. gonorrhoeae is an urgent public health threat. Currently, the diagnosis of N. gonorrhoeae infection requires expensive laboratory infrastructure, while antimicrobial susceptibility determination requires bacterial culture, both of which are infeasible in low-resource areas where the prevalence of infection is highest. Recent advances in molecular diagnostics, such as s pecific h igh-sensitivity e nzymatic r eporter un lock ing (SHERLOCK) using CRISPR-Cas13a and isothermal amplification, have the potential to provide low-cost detection of pathogen and antimicrobial resistance. We designed and optimized RNA guides and primer sets for SHERLOCK assays capable of detecting N. gonorrhoeae via the por A gene and of predicting ciprofloxacin susceptibility via a single mutation in the gyrase A ( gyr A) gene. We evaluated their performance using both synthetic DNA and purified N. gonorrhoeae isolates. For por A , we created both a fluorescence-based assay and lateral flow assay using a biotinylated fluorescein reporter. Both methods demonstrated sensitive detection of 14 N . gonorrhoeae isolates and no cross-reactivity with 3 non-gonococcal Neisseria isolates. For gyr A, we created a fluorescence-based assay that correctly distinguished between 20 purified N. gonorrhoeae isolates with phenotypic ciprofloxacin resistance and 3 with phenotypic susceptibility. We confirmed the gyr A genotype predictions from the fluorescence-based assay with DNA sequencing, which showed 100% concordance for the isolates studied. We report the development of Cas13a-based SHERLOCK assays that detect N. gonorrhoeae and differentiate ciprofloxacin-resistant isolates from ciprofloxacin-susceptible isolates. Neisseria gonorrhoeae, the cause of gonorrhea, disproportionately affects resource-limited settings. Such areas, however, lack the technical capabilities for diagnosing the infection. The consequences of poor or absent diagnostics include increased disease morbidity, which, for gonorrhea, includes an increased risk for HIV infection, infertility, and neonatal blindness, as well as an overuse of antibiotics that contributes to the emergence of antibiotic resistance. We used a novel CRISPR-based technology to develop a rapid test that does not require laboratory infrastructure for both diagnosing gonorrhea and predicting whether ciprofloxacin can be used in its treatment, a one-time oral pill. With further development, that diagnostic test may be of use in low-resource settings.

Purpose of Review Heart failure is increasing in prevalence with a lack of recently developed therapies that produce major beneficial effects on its associated mortality. MicroRNAs are small non-coding RNA molecules that regulate gene expression, are differentially regulated in heart failure, and are found in the circulation serving as a biomarker of heart failure. Recent Findings Data suggests that microRNAs may be used to detect allograft rejection in cardiac transplantation and may predict the degree of myocardial recovery in patients with a left ventricular assist device or treated with beta-blocker therapy. Given their role in regulating cellular function, microRNAs are an intriguing target for oligonucleotide therapeutics, designed to mimic or antagonize (antagomir) their biological effects. Summary We review the current state of microRNAs as biomarkers of heart failure and associated conditions, the mechanisms by which microRNAs control cellular function, and how specific microRNAs may be targeted with novel therapeutics designed to treat heart failure.