Citations

Introduction: Previously, miR-425 have been implicated in the inhibition of the cardiac natriuretic peptide (NP) ANP gene expression with their role on BNP undefined. The mechanism by which miR-425 modulates NP expression remains to be explored. In heart failure (HF), adrenergic and neurohormone pathways are aberrantly activated. Our goal was to investigate the role of miR-425 and its downstream target Cofilin 2 (CFL2) on ANP and BNP expression in human CV disease (CVD). Hypothesis: We hypothesized miR-425, via CFL2, supresses NPs expression in vitro. MiR-425, CFL2 and NP levels were also determined in CVD patients. Methods: In vitro, human cardiomyocytes (HCM) were treated with vehicle (Veh), catecholamine isoproterenol (ISO) and cytokine endothelin (ET), miR-425 mimic. Cells were transfected with CFL2 plasmid or CFL2 siRNA. Normal (NM, n=100), Hypertension (HTN, n=30) and Acute HF (AHF, n=74) cohorts were studied. A confirmatory cohort was recruited. Plasma NT-proBNP, miR-425 were measured. In left ventricles (LV) from NM or HF (n=5 each), NP, CFL2 and miR-425 expression were assessed. Data expressed as means±SEM. * p<0.05 vs NM or Veh. Results: In vitro in HCM, treatment with ISO or ET in HCM reduced miR-425 and elevated NP mRNA levels. Furthermore, miR-425 mimic reduced Nppa (Veh: 1.0±0.03, mimic: 0.7±0.02*) and Nppb levels (Veh: 1.0±0.03, mimic: 0.5±0.01*). We showed that a top predicted target of miR-425, CFL2, was also reduced by the mimic. Further, NP mRNA was elevated by CFL2 overexpression and reduced by the knockdown of CFL2. In humans, MiR-425 was lower in HTN and AHF patients (NM: 0.15±0.03, HTN: 0.03±0.005*, HF: 0.01±0.003*) than NM. MiR-425 negatively correlates with NT-proBNP in NM and AHF cohorts. Downregulation of miR-425 was validated in a second AHF cohort. Similarly, in HF LV tissues, miR-425 (NM: 2.5±0.5, HF: 1.0±0.5*) was lower than NM group, while CFL2 and NP gene and protein expression were increased. Conclusion: In vitro, cardiac stress hormones downregulate miR-425 and increase NP gene expression, potentially through a novel target, CFL2. In CVD patients, miR-425 is lower, accompanied by an elevation of CFL2 and NP. Our findings implicate the pathway of stress hormones/miR-425/CFL2/NP production in CVD.

Respiratory disorders, being one of the leading causes of disability worldwide, account for constant evolution in management technologies, resulting in the incorporation of artificial intelligence (AI) in the recording and analysis of lung sounds to aid diagnosis in clinical pulmonology practice. Although lung sound auscultation is a common clinical practice, its use in diagnosis is limited due to its high variability and subjectivity. We review the origin of lung sounds, various auscultation and processing methods over the years and their clinical applications to understand the potential for a lung sound auscultation and analysis device. Respiratory sounds result from the intra-pulmonary collision of molecules contained in the air, leading to turbulent flow and subsequent sound production. These sounds have been recorded via an electronic stethoscope and analyzed using back-propagation neural networks, wavelet transform models, Gaussian mixture models and recently with machine learning and deep learning models with possible use in asthma, COVID-19, asbestosis and interstitial lung disease. The purpose of this review was to summarize lung sound physiology, recording technologies and diagnostics methods using AI for digital pulmonology practice. Future research and development in recording and analyzing respiratory sounds in real time could revolutionize clinical practice for both the patients and the healthcare personnel.

Abstract Chronic cough is not only one of the leading causes of seeking healthcare all over the world but also a huge emotional drain on the affected patient population. In this study, we used 24-hour cough recordings to analyze the intervening conversations for sentiment analyses to better diagnose, guide, and manage treatment in such patients. We surveyed a cough clinic and selected four subjects with active cough complaints using relevant ICD-10 codes. Subjects were given and instructed to wear a device to record cough for 24 hours and the recordings were collected at weeks 0, 4, 8, and 12 of the treatment. The collected data was preprocessed to eliminate sections with no data (sleep, silence) and the number of coughs was counted. Google search API calls were used to transcribe the audio files and NLTK’s VADER analyzer was used to classify sentiments on a scale of 0 to 1. Finally, average scores were calculated and plotted over a graph to interpret any trends. 12 weeks of cough treatment had varied results on the four subjects. We categorized the exhibited sentiments into negative, neutral, positive, and compound and noted that they also showed no general trends. Among these, the compound sentiment displayed the most erratic patterns, and the obtained results could not generate a steady trend. Further studies are required with a large cohort to collect data over a longer duration to accurately analyze the sentiments associated with chronic cough.

Gastrointestinal (GI) cancers, including esophageal, gastroesophageal junction, gastric, duodenal and distal small bowel, biliary tract, pancreatic, colon, rectal, and anal cancer, comprise a heterogeneous group of malignancies that impose a significant global burden. Immunotherapy has transformed the treatment landscape for several GI cancers, offering some patients durable responses and prolonged survival. Specifically, immune checkpoint inhibitors (ICIs) directed against programmed cell death protein 1 (PD-1), either as monotherapies or in combination regimens, have gained tissue site-specific regulatory approvals for the treatment of metastatic disease and in the resectable setting. Indications for ICIs in GI cancer, however, have differing biomarker and histology requirements depending on the anatomic site of origin. Furthermore, ICIs are associated with unique toxicity profiles compared with other systemic treatments that have long been the mainstay for GI cancer, such as chemotherapy. With the goal of improving patient care by providing guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of GI cancer. Drawing from published data and clinical experience, the expert panel developed evidence- and consensus-based recommendations for healthcare professionals using ICIs to treat GI cancers, with topics including biomarker testing, therapy selection, and patient education and quality of life considerations, among others.

The natriuretic peptide system (NPS) and renin-angiotensin-aldosterone system (RAAS) function oppositely at multiple levels. While it has long been suspected that angiotensin II (ANGII) may directly suppress NPS activity, no clear evidence to date supports this notion. This study was designed to systematically investigate ANGII–NPS interaction in humans, in vivo, and in vitro. Circulating atrial, b-type, and c-type natriuretic peptides (ANP, BNP, CNP), cyclic guanosine monophosphate (cGMP), and ANGII were simultaneously investigated in 128 human subjects. Prompted hypothesis was validated in vivo to determine the influence of ANGII on ANP actions. The underlying mechanisms were further explored via in vitro approaches. In humans, ANGII demonstrated an inverse relationship with ANP, BNP, and cGMP. In regression models predicting cGMP, adding ANGII levels and the interaction term between ANGII and natriuretic peptides increased the predictive accuracy of the base models constructed with either ANP or BNP, but not CNP. Importantly, stratified correlation analysis further revealed a positive association between cGMP and ANP or BNP only in subjects with low, but not high, ANGII levels. In rats, co-infusion of ANGII even at a physiological dose attenuated cGMP generation mediated by ANP infusion. In vitro, we found the suppressive effect of ANGII on ANP-stimulated cGMP requires the presence of ANGII type-1 (AT1) receptor and mechanistically involves protein kinase C (PKC), as this suppression can be substantially rescued by either valsartan (AT1 blocker) or Go6983 (PKC inhibitor). Using surface plasmon resonance (SPR), we showed ANGII has low binding affinity to the guanylyl cyclase A (GC-A) receptor compared to ANP or BNP. Our study reveals ANGII is a natural suppressor for the cGMP-generating action of GC-A via AT1/PKC dependent manner and highlights the importance of dual-targeting RAAS and NPS in maximizing beneficial properties of natriuretic peptides in cardiovascular protection.