Antibodies toward Na+,HCO3--cotransporter NBCn1/SLC4A7 block net acid extrusion and cause pH-dependent growth inhibition and apoptosis in breast cancer.

BACKGROUND: Na+,HCO3--cotransporter NBCn1/Slc4a7 accelerates murine breast carcinogenesis. Lack of specific pharmacological tools previously restricted therapeutic targeting of NBCn1 and identification of NBCn1-dependent functions in human breast cancer. METHODS: We develop extracellularly-targeted anti-NBCn1 antibodies, screen for functional activity on cells, and evaluate (a) mechanisms of intracellular pH regulation in human primary breast carcinomas, (b) proliferation, cell death, and tumor growth consequences of NBCn1 in triple-negative breast cancer, and (c) association of NBCn1-mediated Na+,HCO3--cotransport with human breast cancer metastasis. RESULTS: We identify high-affinity (KD ≈ 0.14 nM) anti-NBCn1 antibodies that block human NBCn1-mediated Na+,HCO3--cotransport in cells, without cross-reactivity towards human NBCe1 or murine NBCn1. These anti-NBCn1 antibodies abolish Na+,HCO3--cotransport activity in freshly isolated primary organoids from human breast carcinomas and lower net acid extrusion effectively in primary breast cancer tissue from patients with macrometastases in axillary lymph nodes. Inhibitory anti-NBCn1 antibodies decelerate tumor growth in vivo by ~50% in a patient-derived xenograft model of triple-negative breast cancer and pH-dependently reduce colony formation, cause G2/M-phase cell cycle accumulation, and increase apoptosis of metastatic triple-negative breast cancer cells in vitro. CONCLUSIONS: Inhibitory anti-NBCn1 antibodies block net acid extrusion in human breast cancer tissue, particularly from patients with disseminated disease, and pH-dependently limit triple-negative breast cancer growth.

Multidisciplinary approach in cardiomyopathies: From genetics to advanced imaging.

Cardiomyopathies are myocardial diseases characterized by mechanical and electrical dysfunction of the heart muscle which could lead to heart failure and life-threatening arrhythmias. Certainly, an accurate anamnesis, a meticulous physical examination, and an ECG are cornerstones in raising the diagnostic suspicion. However, cardiovascular imaging techniques are indispensable to diagnose a specific cardiomyopathy, to stratify the risk related to the disease and even to track the response to the therapy. Echocardiography is often the first exam that the patient undergoes, because of its non-invasiveness, wide availability, and cost-effectiveness. Cardiac magnetic resonance imaging allows to integrate and implement the information obtained with the echography. Furthermore, cardiomyopathies' genetic basis has been investigated over the years and the list of genetic mutations deemed potentially pathogenic is expected to grow further. The aim of this review is to show echocardiographic, cardiac magnetic resonance imaging, and genetic features of several cardiomyopathies: dilated cardiomyopathy (DMC), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), left ventricular noncompaction cardiomyopathy (LVNC), myocarditis, and takotsubo cardiomyopathy.

Meta-regression analysis on the impact of medical therapy on long-term outcome in spontaneous coronary artery dissection.

Background: Spontaneous coronary artery dissection (SCAD) is a relatively rare condition affecting predominantly young adults, with a prevalence of female sex. The best management of SCAD is still unclear and not adequately evidence-based both in the acute phase but especially over the long-term. We therefore aimed to evaluate the impact of medical therapy usually adopted for coronary artery disease on long-term outcome in SCAD patients. Methods: We performed a meta-regression analysis including all the studies evaluating the long-term outcome of patients affected by SCAD. We used long-term mortality, recurrent SCAD, admission for angina and major adverse cardio-vascular events (MACE) as dependent variables and the rates of discharge drug rates (beta-blockers, statins, renin-angiotensin-aldosterone system inhibitors, aspirin, dual antiplatelet therapy (DAPT)) as independent variables. Results: Fourteen observational studies were included with a long-term follow-up of 3.5 ± 1.7 years. No statistically significant correlations between drug therapy (beta-blockers, statins, calcium channel blockers, nitrates, renin-angiotensin-aldosterone inhibitors) and mortality, MACE, admission for angina, and SCAD recurrence were found. Higher aspirin use rates were significantly correlated with lower admission rates for angina (p < 0.05); DAPT, however, showed a borderline correlation with higher rates of SCAD recurrence (p = 0.068). Conclusions: In a meta-regression analysis including observational studies aspirin use rates correlated with lower long-term rates of admission for angina, while a borderline correlation between DAPT and rates of SCAD recurrence was found. Other drugs usually used for the treatment of coronary artery disease do not seem to impact long-term outcome of SCAD patients.

Brugada Syndrome: More than a Monogenic Channelopathy.

Brugada syndrome (BrS) is an inherited cardiac channelopathy first diagnosed in 1992 but still considered a challenging disease in terms of diagnosis, arrhythmia risk prediction, pathophysiology and management. Despite about 20% of individuals carrying pathogenic variants in the SCN5A gene, the identification of a polygenic origin for BrS and the potential role of common genetic variants provide the basis for applying polygenic risk scores for individual risk prediction. The pathophysiological mechanisms are still unclear, and the initial thinking of this syndrome as a primary electrical disease is evolving towards a partly structural disease. This review focuses on the main scientific advancements in the identification of biomarkers for diagnosis, risk stratification, pathophysiology and therapy of BrS. A comprehensive model that integrates clinical and genetic factors, comorbidities, age and gender, and perhaps environmental influences may provide the opportunity to enhance patients' quality of life and improve the therapeutic approach.

Short-term anti-remodeling effects of gliflozins in diabetic patients with heart failure and reduced ejection fraction: an explainable artificial intelligence approach.

Introduction: Sodium-glucose cotransporter type 2 inhibitors (SGLT2i), gliflozins, play an emerging role for the treatment of heart failure with reduced left ventricular ejection fraction (HFrEF). Nevertheless, the effects of SGLT2i on ventricular remodeling and function have not been completely understood yet. Explainable artificial intelligence represents an unprecedented explorative option to clinical research in this field. Based on echocardiographic evaluations, we identified some key clinical responses to gliflozins by employing a machine learning approach. Methods: Seventy-eight consecutive diabetic outpatients followed for HFrEF were enrolled in the study. Using a random forests classification, a single subject analysis was performed to define the profile of patients treated with gliflozins. An explainability analysis using Shapley values was used to outline clinical parameters that mostly improved after gliflozin therapy and machine learning runs highlighted specific variables predictive of gliflozin response. Results: The five-fold cross-validation analyses showed that gliflozins patients can be identified with a 0.70 ± 0.03% accuracy. The most relevant parameters distinguishing gliflozins patients were Right Ventricular S'-Velocity, Left Ventricular End Systolic Diameter and E/e' ratio. In addition, low Tricuspid Annular Plane Systolic Excursion values along with high Left Ventricular End Systolic Diameter and End Diastolic Volume values were associated to lower gliflozin efficacy in terms of anti-remodeling effects. Discussion: In conclusion, a machine learning analysis on a population of diabetic patients with HFrEF showed that SGLT2i treatment improved left ventricular remodeling, left ventricular diastolic and biventricular systolic function. This cardiovascular response may be predicted by routine echocardiographic parameters, with an explainable artificial intelligence approach, suggesting a lower efficacy in case of advanced stages of cardiac remodeling.

The trilemma among CO2 emissions, energy use, and economic growth in Russia.

This paper examines the relationship among CO2 emissions, energy use, and GDP in Russia using annual data ranging from 1990 to 2020. We first conduct time-series analyses (stationarity, structural breaks, cointegration, and causality tests). Then, we performed some Machine Learning experiments as robustness checks. Both approaches underline a bidirectional causal flow between energy use and CO2 emissions; a unidirectional link running from CO2 emissions to real GDP; and the predominance of the "neutrality hypothesis" for energy use-GDP nexus. Therefore, energy conservation measures should not adversely affect the economic growth path of the country. In the current geopolitical scenario, relevant policy implications may be derived.

Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer.

BACKGROUND: Carbonic anhydrases catalyze CO2/HCO3- buffer reactions with implications for effective H+ mobility, pH dynamics, and cellular acid-base sensing. Yet, the integrated consequences of carbonic anhydrases for cancer and stromal cell functions, their interactions, and patient prognosis are not yet clear. METHODS: We combine (a) bioinformatic analyses of human proteomic data and bulk and single-cell transcriptomic data coupled to clinicopathologic and prognostic information; (b) ex vivo experimental studies of gene expression in breast tissue based on quantitative reverse transcription and polymerase chain reactions, intracellular and extracellular pH recordings based on fluorescence confocal microscopy, and immunohistochemical protein identification in human and murine breast cancer biopsies; and (c) in vivo tumor size measurements, pH-sensitive microelectrode recordings, and microdialysis-based metabolite analyses in mice with experimentally induced breast carcinomas. RESULTS: Carbonic anhydrases-particularly the extracellular isoforms CA4, CA6, CA9, CA12, and CA14-undergo potent expression changes during human and murine breast carcinogenesis. In patients with basal-like/triple-negative breast cancer, elevated expression of the extracellular carbonic anhydrases negatively predicts survival, whereas, surprisingly, the extracellular carbonic anhydrases positively predict patient survival in HER2/ErbB2-enriched breast cancer. Carbonic anhydrase inhibition attenuates cellular net acid extrusion and extracellular H+ elimination from diffusion-restricted to peripheral and well-perfused regions of human and murine breast cancer tissue. Supplied in vivo, the carbonic anhydrase inhibitor acetazolamide acidifies the microenvironment of ErbB2-induced murine breast carcinomas, limits tumor immune infiltration (CD3+ T cells, CD19+ B cells, F4/80+ macrophages), lowers inflammatory cytokine (Il1a, Il1b, Il6) and transcription factor (Nfkb1) expression, and accelerates tumor growth. Supporting the immunomodulatory influences of carbonic anhydrases, patient survival benefits associated with high extracellular carbonic anhydrase expression in HER2-enriched breast carcinomas depend on the tumor inflammatory profile. Acetazolamide lowers lactate levels in breast tissue and blood without influencing breast tumor perfusion, suggesting that carbonic anhydrase inhibition lowers fermentative glycolysis. CONCLUSIONS: We conclude that carbonic anhydrases (a) elevate pH in breast carcinomas by accelerating net H+ elimination from cancer cells and across the interstitial space and (b) raise immune infiltration and inflammation in ErbB2/HER2-driven breast carcinomas, restricting tumor growth and improving patient survival.

Impact of vaccination on electrocardiograms of hospitalized patients for Covid-19.

Introduction: We sought to assess the impact of SarsCov-2 vaccination on admission12-lead electrocardiogram of hospitalized patients. Methods: We retrospectively analyzed and compared admission 12-lead electrocardiograms of all patients hospitalized in dedicated Internal Medicine Unit for Covid-19 both in pre-vaccination period (PV) and after vaccination (V). Results: 667 consecutive Covid-19 in-patients were enrolled in the study: PV hospitalized patients were older (68vs57 years, p < 0.01), had higher rates of atrial fibrillation/flutter (13%vs2.5%, p < 0.01), any arrhythmia (26%vs8%, p < 0.01), and ST-T abnormalities (22%vs7.4%, p < 0.01). Mortality rates in hospitalized Covid-19 patients were higher before vaccination period (20%vs4%, p < 0.01). Minimal vaccination coverage of population (V period) was inversely and independently associated with in-hospital mortality (odds ratio 0.09, 95%CI 0.01-0.68, p < 0.05). Conclusions: SarsCov-2 vaccination campaign and even partial coverage of local population was associated with less frequent abnormalities at admission ECG in hospitalized non-critically hill Covid-19 patients and lower mortality.

Dapagliflozin protects the kidney in a non-diabetic model of cardiorenal syndrome.

Cardiorenal syndrome encompasses a spectrum of disorders involving heart and kidney dysfunction, and sharing common risk factors, such as hypertension and diabetes. Clinical studies have shown that patients with and without diabetes may benefit from using sodium-glucose cotransporter 2 inhibitors to reduce the risk of heart failure and ameliorate renal endpoints. Because the underlying mechanisms remain elusive, we investigated the effects of dapagliflozin on the progression of renal damage, using a model of non-diabetic cardiorenal disease. Dahl salt-sensitive rats were fed a high-salt diet for five weeks and then randomized to dapagliflozin or vehicle for the following six weeks. After treatment with dapagliflozin, renal function resulted ameliorated as shown by decrease of albuminuria and urine albumin-to-creatinine ratio. Functional benefit was accompanied by a decreased accumulation of extracellular matrix and a reduced number of sclerotic glomeruli. Dapagliflozin significantly reduced expression of inflammatory and endothelial activation markers such as NF-κB and e-selectin. Upregulation of pro-oxidant-releasing NADPH oxidases 2 and 4 as well as downregulation of antioxidant enzymes were also counteracted by drug treatment. Our findings also evidenced the modulation of both classic and non-classic renin-angiotensin-aldosterone system (RAAS), and effects of dapagliflozin on gene expression of ion channels/transporters involved in renal homeostasis. Thus, in a non-diabetic model of cardiorenal syndrome, dapagliflozin provides renal protection by modulating inflammatory response, endothelial activation, fibrosis, oxidative stress, local RAAS and ion channels.

How brachial access compares to femoral access for invasive cardiac angiography when radial access is not feasible: A meta-analysis.

BACKGROUND: Trans-radial access is considered the best approach for cardiac catheterization. The choice of an alternative access route may be complex and trans-femoral access (TFA) is generally preferred. However, trans-brachial approach (TBA) may represent another feasible alternative. We therefore aimed to compare TBA and TFA in terms of access site bleeding and complications in a meta-analysis study. METHODS: We systematically searched principal databases for studies comparing femoral and brachial approach in terms of in-hospital vascular complications in patients undergoing cardiac catheterization (coronary angiography or percutaneous coronary intervention). RESULTS: Five retrospective studies and one randomized study were identified for the meta-analysis; 2756 patients undergoing a TBA and 331.208 patients undergoing a TFA for cardiac catheterization were included in the final study. No significant differences between access routes were found in terms of risk of any vascular complications (relative risk 1.18; 95% CI: 0.91-1.53; p n.s.). Brachial access was associated with a significantly lower risk of access site bleeding (relative risk 0.46; 95% CI 0.24-0.88, p = 0.02). CONCLUSIONS: TBA for cardiac catheterization was associated with a lower risk of access site bleeding and a comparable risk of any vascular complications compared with TFA. TBA may be considered a reasonable alternative access route for cardiac catheterization, at least as femoral approach.

A machine learning algorithm to analyse the effects of vaccination on COVID-19 mortality.

The coronavirus disease 2019 (COVID-19), with new variants, continues to be a constant pandemic threat that is generating socio-economic and health issues in manifold countries. The principal goal of this study is to develop a machine learning experiment to assess the effects of vaccination on the fatality rate of the COVID-19 pandemic. Data from 192 countries are analysed to explain the phenomena under study. This new algorithm selected two targets: the number of deaths and the fatality rate. Results suggest that, based on the respective vaccination plan, the turnout in the participation in the vaccination campaign, and the doses administered, countries under study suddenly have a reduction in the fatality rate of COVID-19 precisely at the point where the cut effect is generated in the neural network. This result is significant for the international scientific community. It would demonstrate the effective impact of the vaccination campaign on the fatality rate of COVID-19, whatever the country considered. In fact, once the vaccination has started (for vaccines that require a booster, we refer to at least the first dose), the antibody response of people seems to prevent the probability of death related to COVID-19. In short, at a certain point, the fatality rate collapses with increasing doses administered. All these results here can help decisions of policymakers to prepare optimal strategies, based on effective vaccination plans, to lessen the negative effects of the COVID-19 pandemic crisis in socioeconomic and health systems.

Diagnostic challenges of adenomyoepithelioma: A case report.

INTRODUCTION: Breast adenomyoepithelioma is a very uncommon tumor, which is generally considered to be benign, however malignant transformation has been reported. PRESENTATION OF CASE: We report two cases of two women with breast adenomyoepithelioma. CONCLUSION: Diagnosis of adenomyoepithelioma is challenging because tumor may mimic other breast diseases. It has neither specific clinical signs nor radiological features, and the diagnosis is based on histopathological examination of the lesion. The treatment of choice is surgery. The type of surgery depends on the tumor factors and breast size. In malignant cases treatment such as radiotherapy, chemotherapy, immunotherapy may be used as well. It is very important to give an adequate treatment, otherwise the risk of tumor recurrence, growth or even metastatic spread, when tumor has malignant potential, increases.

Amplified Ca2+ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation.

Intracellular Ca2+ dynamics shape malignant behaviors of cancer cells. Whereas previous studies focused on cultured cancer cells, we here used breast organoids and colonic crypts freshly isolated from human and murine surgical biopsies. We performed fluorescence microscopy to evaluate intracellular Ca2+ concentrations in breast and colon cancer tissue with preferential focus on intracellular Ca2+ release in response to purinergic and cholinergic stimuli. Inhibition of the sarco-/endoplasmic reticulum Ca2+ ATPase with cyclopiazonic acid elicited larger Ca2+ responses in breast cancer tissue, but not in colon cancer tissue, relative to respective normal tissue. The resting intracellular Ca2+ concentration was elevated, and ATP, UTP and acetylcholine induced strongly augmented intracellular Ca2+ responses in breast cancer tissue compared with normal breast tissue. In contrast, resting intracellular Ca2+ levels and acetylcholine-induced increases in intracellular Ca2+ concentrations were unaffected and ATP- and UTP-induced Ca2+ responses were smaller in colon cancer tissue compared with normal colon tissue. In accordance with the amplified Ca2+ responses, ATP and UTP substantially increased proliferative activity-evaluated by bromodeoxyuridine incorporation-in breast cancer tissue, whereas the effect was minimal in normal breast tissue. ATP caused cell death-identified with ethidium homodimer-1 staining-in breast cancer tissue only at concentrations above the expected pathophysiological range. We conclude that intracellular Ca2+ responses are amplified in breast cancer tissue, but not in colon cancer tissue, and that nucleotide signaling stimulates breast cancer cell proliferation within the extracellular concentration range typical for solid cancer tissue.

Pharmacological Anti-Remodelling Effects of Disease-Modifying Drugs in Heart Failure with Reduced Ejection Fraction.

Cardiac remodelling is an adverse phenomenon linked to heart failure progression and an important contributor to heart failure severity. Cardiac remodelling could represent the real therapeutic goal in the treatment of patients with heart failure with reduced ejection fraction, being potentially reversed through different pharmacotherapies. Currently, there are well-established drugs such as angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and ß-blockers with anti-remodelling effects; recently, angiotensin receptor neprilysin inhibitor effects on inhibiting cardiac remodelling (improving N-terminal pro-B-type natriuretic peptide levels, echocardiographic parameters of reverse cardiac remodelling and right ventricular function in patients with heart failure with reduced ejection fraction) were demonstrated. More recently, hemodynamic consequences of gliflozins, reduced cardiac hydrostatic pressure as a possible cause of ventricular remodelling and hypertrophy were proposed to explain potential anti-remodelling effects of gliflozins. Gliflozins exert their cardioprotective effects by attenuating myofibroblast activity and collagen-mediated remodelling. Another postulated mechanism is represented by the reduction in sympathetic activity, through the reduction in renal afferent nervous activity and the suppression of central reflex mechanisms. Benefits of gliflozins on left ventricular hypertrophy, dilation, and systolic and diastolic function were also described. In this review, we aimed to provide a wide overview on cardiac remodelling with a particular focus on possible anti-remodelling effects of angiotensin receptor neprilysin inhibitors and gliflozins.

Electrocardiographic findings and mortality in covid-19 patients hospitalized in different clinical settings.

BACKGROUND: Twelve-lead electrocardiogram (ECG) represents the first-line approach for cardiovascular assessment in patients with Covid-19. OBJECTIVES: We sought to describe and compare admission ECG findings in 3 different hospital settings: intensive-care unit (ICU) (invasive ventilatory support), respiratory care unit (RCU) (non-invasive ventilatory support) and Covid-19 dedicated internal-medicine unit (IMU) (oxygen supplement with or without high flow). We also aimed to assess the prognostic impact of admission ECG variables in Covid-19 patients. METHODS: We retrospectively analyzed the admission 12-lead ECGs of 1124 consecutive patients hospitalized for respiratory distress and Covid-19 in a single III-level hospital. Age, gender, main clinical data and in-hospital survival were recorded. RESULTS: 548 patients were hospitalized in IMU, 361 in RCU, 215 in ICU. Arrhythmias in general were less frequently found in RCU (16% vs 26%, p<0.001). Deaths occurred more frequently in ICU patients (43% vs 20-21%, p<0.001). After pooling predictors of mortality (age, intensity of care setting, heart rate, ST-elevation, QTc prolongation, Q-waves, right bundle branch block, and atrial fibrillation), the risk of in-hospital death can be estimated by using a derived score. Three zones of mortality risk can be identified: <5%, score <5 points; 5-50%, score 5-10, and >50%, score >10 points. The accuracy of the score assessed at ROC curve analysis was 0.791. CONCLUSIONS: ECG differences at admission can be found in Covid-19 patients according to different clinical settings and intensity of care. A simplified score derived from few clinical and ECG variables may be helpful in stratifying the risk of in-hospital mortality.

Arrhythmic myocarditis in an adolescent male: A unique presentation of multi-organ inflammatory syndrome (MIS-C).

Although children with Covid-19 generally present with mild symptoms or are often asymptomatic, there is increasing recognition of a delayed multi-organ inflammatory syndrome (MIS-C) following SARS-CoV-2 infection. We report the case of MIS-C associated arrhythmic myocarditis which recovered after anti-inflammatory therapy and immunoglobulin infusion.

Breast-Conserving Surgery or Mastectomy?: Impact on Survival.

The early randomized controlled trials revealed no differences in survival between breast-conserving surgery (BCS) and mastectomy. However, breast cancer treatment has undergone changes, and the results of recent population-based registry studies suggest superior long-term survival after BCS. To explore the current evidence, a systematic review and meta-ana lysis of population-based observational studies from 2010 and onward was conducted. Methods: A literature search was conducted in the PubMed, Embase, and Cochrane databases to identify relevant literature. Keywords included "mastectomy," "breast conserving surgery," and "survival." The identified studies were narratively reviewed and effect sizes (hazard ratios [HRs]) for overall (OS) and breast cancer-specific survival (BCSS) were combined with random-effects models. Results: A total of 30 reports were included in the review, and results from 25 studies were included in the meta-analyses. Compared with mastectomy, BCS was associated with better OS (HR = 1.34 [1.20-1.51]; N = 1,311,600) and BCSS (HR = 1.38 [1.29-1.47]; N = 494,267). Selected subgroups of patients, based on lymph node status, age (<50 years/≥50 years), and radiation therapy after mastectomy (±), all showed better overall survival after BCS. The number (range 4-12) and type of prognostic variables adjusted for in the survival analyses of the studies did not statistically significantly moderate the differences in survival between BCS and mastectomy. Conclusions: The combined findings from large population-based studies indicate that BCS is associated with survival benefit compared with mastectomy, suggesting that BCS be the recommended treatment of early breast cancer (T1-2N0-1M0) if a radical lumpectomy can be performed.

Meta-Regression Analysis of the Impact of Medical Therapy on Long-Term Mortality in Type 2 Myocardial Infarction.

The first approach for Type-2 myocardial infarction (T2MI) consists of the elimination of the condition determining the oxygen supply/demand mismatch. However, the long-term impact of medical therapy with beta blockers, statins, aspirin, and P2Y12 inhibitors, used in the case of Type-1 myocardial infarction has been poorly investigated and remains unclear. We, therefore, sought to assess the impact of medical therapy on 1-year mortality in patients with T2MI using a meta-regression analysis. A meta-regression analysis was performed with studies involving in patients with T2MI: 1-year all-cause mortality, rates of beta blockers, statins, aspirin, and P2Y12 inhibitors use were recorded and analyzed. After careful study selection, 8 observational studies were pooled in the analysis, including 3,756 in patients. During meta-regression analysis, a borderline correlation between rates of aspirin, P2Y12 inhibitors, and statins use and 1-year mortality (p = 0.087, p = 0.05, and p = 0.067, respectively) was found; no significant correlation was found at multivariable analysis. In conclusion, in a meta-regression analysis, no significant correlation was found between rates of use of usual drug therapy indicated for Type-1 myocardial infarction (statins, aspirin, P2Y12 inhibitors, ß-blockers) and 1-year mortality in T2MI patients.

Assessing a fossil fuels externality with a new neural networks and image optimisation algorithm: the case of atmospheric pollutants as confounders to COVID-19 lethality.

This paper demonstrates how the combustion of fossil fuels for transport purpose might cause health implications. Based on an original case study [i.e. the Hubei province in China, the epicentre of the coronavirus disease-2019 (COVID-19) pandemic], we collected data on atmospheric pollutants (PM2.5, PM10 and CO2) and economic growth (GDP), along with daily series on COVID-19 indicators (cases, resuscitations and deaths). Then, we adopted an innovative Machine Learning approach, applying a new image Neural Networks model to investigate the causal relationships among economic, atmospheric and COVID-19 indicators. Empirical findings emphasise that any change in economic activity is found to substantially affect the dynamic levels of PM2.5, PM10 and CO2 which, in turn, generates significant variations in the spread of the COVID-19 epidemic and its associated lethality. As a robustness check, the conduction of an optimisation algorithm further corroborates previous results.

Acid-base transporters and pH dynamics in human breast carcinomas predict proliferative activity, metastasis, and survival.

Breast cancer heterogeneity in histology and molecular subtype influences metabolic and proliferative activity and hence the acid load on cancer cells. We hypothesized that acid-base transporters and intracellular pH (pHi) dynamics contribute inter-individual variability in breast cancer aggressiveness and prognosis. We show that Na+,HCO3- cotransport and Na+/H+ exchange dominate cellular net acid extrusion in human breast carcinomas. Na+/H+ exchange elevates pHi preferentially in estrogen receptor-negative breast carcinomas, whereas Na+,HCO3- cotransport raises pHi more in invasive lobular than ductal breast carcinomas and in higher malignancy grade breast cancer. HER2-positive breast carcinomas have elevated protein expression of Na+/H+ exchanger NHE1/SLC9A1 and Na+,HCO3- cotransporter NBCn1/SLC4A7. Increased dependency on Na+,HCO3- cotransport associates with severe breast cancer: enlarged CO2/HCO3--dependent rises in pHi predict accelerated cell proliferation, whereas enhanced CO2/HCO3--dependent net acid extrusion, elevated NBCn1 protein expression, and reduced NHE1 protein expression predict lymph node metastasis. Accordingly, we observe reduced survival for patients suffering from luminal A or basal-like/triple-negative breast cancer with high SLC4A7 and/or low SLC9A1 mRNA expression. We conclude that the molecular mechanisms of acid-base regulation depend on clinicopathological characteristics of breast cancer patients. NBCn1 expression and dependency on Na+,HCO3- cotransport for pHi regulation, measured in biopsies of human primary breast carcinomas, independently predict proliferative activity, lymph node metastasis, and patient survival.