Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.

Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT.

Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19.

Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is needed for understanding skewed immune responses and defining predictors of outcome. Here, we performed a longitudinal multi-omics study using a two-center cohort of 14 patients. We analyzed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of interferon-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signaling. Megakaryocyte- and erythroid-cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond adaptive immune cells and provides an entry point toward developing biomarkers and targeted treatments of patients with COVID-19.

Impaired left ventricular deformation and ventricular-arterial coupling in post-COVID-19: association with autonomic dysregulation.

Coronavirus disease-19 (COVID-19) has extended implications namely the long COVID-19 syndrome. We assessed over-time changes in left ventricular (LV) function, aortic stiffness, autonomic function, and ventricular-arterial coupling (VAC) in post-COVID-19 patients. We followed 34 post-COVID-19 subjects, up to 6 months post-hospital discharge. Subjects without COVID-19 served as control. We evaluated LV global longitudinal strain (LV-GLS), arterial stiffness [carotid-femoral pulse wave velocity (cf-PWV)], and heart rate variability -standard deviation of normal RR intervals (SDNN). VAC was estimated as the ratio of cf-PWV to LV-GLS. Post-COVID-19 individuals (1-month post-hospital discharge) presented with impaired LV-GLS [-18.4%(3.1) vs. -22.0%(2.7), P < 0.001], cf-PWV [12.1 m/s (3.2) vs. 9.6 m/s (1.9), P < 0.001], SDNN [111.3 ms (22.6) vs. 147.2 ms (14.0), P < 0.001], and VAC [-0.68 (0.22) vs. -0.44 (0.10), P < 0.001] compared to control. LV-GLS, SDNN, and VAC improved at the 6-month follow-up however they did not reach control levels. In post-COVID-19 subjects, SDNN and VAC were correlated at the 1-month (R = 0.499, P = 0.003) and 6-month (R = 0.372, P = 0.04) follow-up. Long COVID-19 syndrome was associated with impaired LV-GLS, SDNN, and VAC. Post-COVID-19 subjects presented with autonomic dysregulation associated with aortic stiffness, ventricular-arterial impairment, and LV dysfunction, even 6-months post-hospital discharge. These abnormalities may be related to the presence of long COVID-19 syndrome.

FDA-Approved Monoclonal Antibodies for Unresectable Hepatocellular Carcinoma: What Do We Know So Far?

Unresectable hepatocellular carcinoma (HCC) is an advanced primary liver malignancy with a poor prognosis. The Food and Drug Administration (FDA) has, to date, approved nivolumab, pembrolizumab, ramucirumab, nivolumab/ipilimumab, atezolizumab/bevacizumab, as well as tremelimumab/durvalumab, as first- or second-line monoclonal antibodies (mAbs) for unresectable HCC. The present review examines the current state of knowledge, and provides a useful update on the safety and efficacy of these therapeutic agents, thus attempting to define the suitability of each mAb for different patient subgroups.

Molecular Mechanisms and Therapeutic Implications of Endothelial Dysfunction in Patients with Heart Failure.

Heart failure is a complex medical syndrome that is attributed to a number of risk factors; nevertheless, its clinical presentation is quite similar among the different etiologies. Heart failure displays a rapidly increasing prevalence due to the aging of the population and the success of medical treatment and devices. The pathophysiology of heart failure comprises several mechanisms, such as activation of neurohormonal systems, oxidative stress, dysfunctional calcium handling, impaired energy utilization, mitochondrial dysfunction, and inflammation, which are also implicated in the development of endothelial dysfunction. Heart failure with reduced ejection fraction is usually the result of myocardial loss, which progressively ends in myocardial remodeling. On the other hand, heart failure with preserved ejection fraction is common in patients with comorbidities such as diabetes mellitus, obesity, and hypertension, which trigger the creation of a micro-environment of chronic, ongoing inflammation. Interestingly, endothelial dysfunction of both peripheral vessels and coronary epicardial vessels and microcirculation is a common characteristic of both categories of heart failure and has been associated with worse cardiovascular outcomes. Indeed, exercise training and several heart failure drug categories display favorable effects against endothelial dysfunction apart from their established direct myocardial benefit.

The Impact of Nutritional and Functional Status on Postoperative Outcomes following Esophageal Cancer Surgery.

Malnourished patients undergoing esophagectomy have increased risk of postoperative complications. The aim of the current study was to identify nutritional and functional risk factors for postoperative complications in patients with esophageal and gastroesophageal junction cancer who underwent esophagectomy. Seventy patients who were admitted at the First Department of Surgery, Laikon General Hospital, Athens, Greece, were included in this study. Laboratory data and data regarding nutritional and functional status were recorded preoperatively. Postoperative complications were graded according to Clavien-Dindo classification. Thirty-seven patients (52.9%) developed postoperative complications. Albumin and Geriatric Nutritional Risk Index (GNRI) levels were lower in patients who developed major complications compared to patients who did not develop postoperative complications (3.90 ± 0.44 vs 4.18 ± 0.37 g/dL, p = 0.014 and 107.40 ± 15.76 vs 114.98 ± 12.26, p = 0.050 respectively). Major complications were associated with higher percentage of weight loss (12.1 ± 11.1 vs 6.2 ± 7.5%, p = 0.019) and with low handgrip strength (80 vs 16.9%, p = 0.006). Albumin (3.93 ± 0.18 vs 4.15 ± 0.41 g/dL, p = 0.019) and low muscle mass (22.6 vs 2.8%, p = 0.016) were significantly associated with anastomotic leakage occurence. The incorporation of patients' nutritional and functional status in the preoperative risk assessment might increase prognostic ability concerning postoperative complications of patients undergoing esophagectomy.

The association of diabetes mellitus with carotid atherosclerosis and arterial stiffness in the Corinthia study.

BACKGROUND AND AIMS: Evaluation of arterial stiffness and carotid atherosclerotic burden can provide important prognostic information regarding the risk of future cardiovascular events. The aim of this study was to assess these vascular properties in patients with diabetes mellitus (DM). METHODS AND RESULTS: In the context of the observational "Corinthia" study, we analyzed 1757 participants with determined DM status. Carotid ultrasonography was performed to evaluate intima-media thickness (cIMT) and carotid plaque burden. Arterial stiffness was estimated via assessment of carotid-to-femoral pulse wave velocity (cfPWV). Individuals with DM had increased mean cIMT, maximum cIMT, carotid plaque burden, and cfPWV compared to those without DM. After multivariable regression analysis, the presence of DM was still associated with significantly increased mean cIMT (by 0.074 mm, p = .004), maximum cIMT (by 0.134 mm, p = .007), cfPWV (by 0.929 m/s, p < .001), and a higher prevalence of carotid plaques (odds ratio 1.52, 95% confidence intervals 1.11, 2.10, p = .01). In a propensity score-matched cohort, mean cIMT, maximum cIMT, and carotid plaque burden were significantly higher in individuals with DM. Analysis according to territory of cIMT measurement displayed substantial differences in left (DM: 1.32 ± 0.78 mm vs. no DM: 1.20 ± 0.66 mm, p = .04) and right carotid bulbs (DM: 1.33 ± 0.82 mm vs. no DM: 1.18 ± 0.69 mm, p = .02) with respect to DM status while non-significant variations were observed in left (DM: 0.98 ± 0.49 mm vs. no DM: 0.91 ± 0.35 mm, p = .06) and right common carotid artery (DM: 0.95 ± 0.50 mm vs. no DM: 0.92 ± 0.40 mm, p = .36). CONCLUSIONS: Diabetes mellitus is associated with increased cfPWV and cIMT, with more pronounced lesions in the carotid bulb.

Medical education challenges and innovations during COVID-19 pandemic.

COVID-19 pandemic has undoubtedly disrupted the well-established, traditional structure of medical education. Τhe new limitations of physical presence have accelerated the development of an online learning environment, comprising both of asynchronous and synchronous distance education, and the introduction of novel ways of student assessment. At the same time, this prolonged crisis had serious implications on the lives of medical students including their psychological well-being and the impact on their academic trajectories. The new reality has, on many occasions, triggered the 'acting up' of medical students as frontline healthcare staff, which has been perceived by many of them as a positive learning and contributing experience, and has led to a variety of responses from the educational institutions. All things considered, the urgency for rapid and novel adaptations to the new circumstances has functioned as a springboard for remarkable innovations in medical education,including the promotion of a more "evidence-based" approach.

Targeted Therapies for Hepatocellular Carcinoma Treatment: A New Era Ahead-A Systematic Review.

Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.

High-Intensity Endurance and Strength Training in Water Polo Olympic Team Players: Impact on Arterial Wall Properties.

INTRODUCTION: Regular physical activity is recommended to minimize health risk. However, the upper intensity threshold associated with the best health outcomes is difficult to be determined. Water polo (WP) Olympic athletes present unique characteristics such as high-intensity exercise, long training sessions, and a combination of endurance and strength training. Therefore, we examined in which way the long-term, intense, mixed endurance and strength training affects the peripheral and central hemodynamics. METHODS: The study population consisted of 20 WP Olympic team players, 20 matched recreationally active (RA) subjects, and 20 sedentary control subjects (Cl). Reflected waves were assessed with the augmentation index (AIx), central aortic stiffness with pulse wave velocity (PWV), and endothelial function with flow-mediated dilation (FMD). RESULTS: Amongst Cl subjects, RA subjects, and WP players, there was no difference in age (p = 0.33) as well as in brachial systolic pressure (p = 0.52), while there was a stepwise decrease in aortic systolic pressure (116 ± 16 mm Hg vs. 107 ± 14 mm Hg vs. 106 ± 6 mm Hg, p = 0.03). There was also a stepwise improvement in AIx (-4.22 ± 9.97% vs. -6.97 ± 11.28% vs. -12.14 ± 6.62%, p = 0.03) and FMD (6.61 ± 1.78% vs. 7.78 ± 1.98% vs. 8.3 ± 2.05%, p = 0.04) according to the intensity of exercise, with WP players having lower AIx and higher FMD compared to RA subjects and Cl subjects. No difference was found in PWV (Cl: 5.88 ± 0.72 m/s vs. RA: 6.04 ± 0.75 m/s vs. WP: 5.97 ± 1.09 m/s, p = 0.82) among the three studied groups. CONCLUSIONS: Young WP Olympic team players depict improved arterial wall properties and endothelial function compared to RA and Cl subjects.

Endothelial dysfunction and impaired arterial wall properties in patients with retinal vein occlusion.

Retinal vein occlusion (RVO) is a common retinal vascular lesion, and a leading cause of visual impairment. Patients with RVO have an increased risk for cardiovascular disease and share multiple common risk factors. In this study, we investigated the endothelial function and arterial stiffness of patients with RVO compared to healthy-control (CL) subjects. We enrolled 40 consecutive patients with RVO and 40 CL subjects. RVO was diagnosed by an ophthalmologist, endothelial function was evaluated by flow mediated dilation (FMD) in the brachial artery, and carotid-femoral pulse wave velocity (PWV) and augmentation index (AIx) of the radial artery were measured to evaluate arterial stiffness and reflected waves, respectively. No significant differences were detected between the studied groups in sex, age, presence of hypertension or dyslipidemia, body mass index, systolic and diastolic blood pressure levels, total cholesterol levels, and smoking habits (p > 0.05 for all). However, patients with RVO had impaired FMD (p = 0.002) and increased PWV (p = 0.004), even after adjustment for several confounders. Both FMD and PWV were also significantly and independently associated with the development of RVO. Furthermore, a significant and positive correlation between PWV and systolic blood pressure existed only in the CL group. Therefore, we have shown that RVO is associated with significant endothelial dysfunction and increased arterial stiffness. Our results strengthen the vascular theory, according to which, systemic endothelial dysfunction and arteriosclerosis play a significant role in the pathogenesis of RVO.

Markers of Vascular Dysfunction in Hypertension.

Hypertension is a modifiable cardiovascular risk factor and displays a rapidly growing incidence due to aging and the acquisition of an unhealthy lifestyle. Hypertension is linked to the development of target organ damage in several vascular beds such as coronary arteries, peripheral, cerebral, and renal arteries. Besides, along with the presence of other cardiovascular risk factors, it aggravates vascular dysfunction due to the aging process. The mechanisms of vascular dysfunction in hypertension are complex and involve excessive salt intake and water retention, activation of neurohormonal systems, induction of endothelial dysfunction of large arteries and microcirculation, development of arterial stiffness, and complex interactions with cellular pathways of inflammation, oxidative stress, and thrombosis. The extent of vascular dysfunction in patients with hypertension can be assessed by evaluating endothelial function, measuring arterial stiffness, and testing the levels of circulating biomarkers of oxidative stress, pro-inflammatory cytokines, and thrombosis. Assessing these markers in subjects with and without hypertension could aid in identifying those at risk of vascular damage and improving risk prediction for future cardiovascular events. While several lifestyle and pharmacological therapies have shown promise in addressing vascular dysfunction in hypertension, none of these biomarkers have been established as an independent risk factor or treatment target. Therefore, in this article, we review the literature on the evidence that exists regarding the role of vascular dysfunction in the pathophysiology, diagnosis, progression, and treatment of hypertension, highlighting the lack of conclusive evidence in this field.

The Impact of the COVID-19 Pandemic on Elite Swimmers and Water Polo Players: Lessons for the Future.

BACKGROUND: The COVID-19 pandemic has disrupted global daily life, including the world of elite athletes. This paper examines the multifaceted impact the COVID-19 pandemic had on elite swimmers and water polo athletes, specifically their mental health, their concerns over the virus, their intentions of getting vaccinated, and sleep disturbances that they may have faced. METHODS: We conducted a cross-sectional study on elite swimmers and water polo players, using an anonymous questionnaire. RESULTS: A total of 200 elite athletes participated. The majority of the participants reported a negative impact on their mental health, screened positive for insomnia (n = 107 (53.5%), with females (n = 101; 57.7%), swimmers (n = 100, 66.7%), and university students (n = 71, 71.7%) being more vulnerable (p < 0.001). Concerns about contracting the disease especially during important training or tournament periods and potential career disruption also affected their psychological well-being. While the majority (75%) had the intention of getting vaccinated, an alarming percentage was yet uncertain over its decision. CONCLUSIONS: This study highlights the significant psychological distress faced by elite aquatic athletes during the pandemic. It emphasizes the difficulties faced by elite swimmers and water polo athletes and determines not only the importance of addressing the vaccination intentions of athletes, but also how critical it is to confront the challenges they face both for their personal health and for the restoration of world sports to their pre-pandemic state. More large-scale studies are required to inform policies targeted at minimizing disruption to the athletes' career, provision of information on preventive measures and vaccination, and improvement in psychological well-being in case of similar major public health issues in the future. Additionally, this study calls for further research to explore the unique challenges faced by aquatic athletes, such as those related to their training environments and fear of contagion, to better support them in future public health crises.

Evaluation of the Histone Deacetylase 2 (HDAC-2) Expression in Human Breast Cancer.

BACKGROUND/AIM: Triple negative breast cancer belongs to the most aggressive breast cancer forms. Histone deacetylases (HDACs) constitute a class of enzymes that exhibit a significant role in breast cancer genesis and progression. In this study, we aimed at assessing the clinical importance of HDAC-2 in triple negative breast cancer. MATERIALS AND METHODS: A total of 138 breast cancer specimens were examined on an immunohistochemical basis. A statistical analysis was performed in order to examine the association between HDAC-2 and the survival and clinicopathological features of the patients. RESULTS: Increased HDAC-2 expression was observed in every fourth case of triple negative breast cancer with positive HDAC-2 staining, whereas only 12 out of 98 non-triple negative breast cancer samples showed high HDAC-2 expression. HDAC-2 overexpression correlated with prolonged overall survival (OS) and disease-free survival (DFS) in triple negative breast cancer. CONCLUSIONS: High HDAC-2 levels in triple negative breast cancer seem to positively influence patient survival, disease stage and recurrence.

Metabolic model predictions enable targeted microbiome manipulation through precision prebiotics.

While numerous health-beneficial interactions between host and microbiota have been identified, there is still a lack of targeted approaches for modulating these interactions. Thus, we here identify precision prebiotics that specifically modulate the abundance of a microbiome member species of interest. In the first step, we show that defining precision prebiotics by compounds that are only taken up by the target species but no other species in a community is usually not possible due to overlapping metabolic niches. Subsequently, we use metabolic modeling to identify precision prebiotics for a two-member Caenorhabditis elegans microbiome community comprising the immune-protective target species Pseudomonas lurida MYb11 and the persistent colonizer Ochrobactrum vermis MYb71. We experimentally confirm four of the predicted precision prebiotics, L-serine, L-threonine, D-mannitol, and γ-aminobutyric acid, to specifically increase the abundance of MYb11. L-serine was further assessed in vivo, leading to an increase in MYb11 abundance also in the worm host. Overall, our findings demonstrate that metabolic modeling is an effective tool for the design of precision prebiotics as an important cornerstone for future microbiome-targeted therapies.IMPORTANCEWhile various mechanisms through which the microbiome influences disease processes in the host have been identified, there are still only few approaches that allow for targeted manipulation of microbiome composition as a first step toward microbiome-based therapies. Here, we propose the concept of precision prebiotics that allow to boost the abundance of already resident health-beneficial microbial species in a microbiome. We present a constraint-based modeling pipeline to predict precision prebiotics for a minimal microbial community in the worm Caenorhabditis elegans comprising the host-beneficial Pseudomonas lurida MYb11 and the persistent colonizer Ochrobactrum vermis MYb71 with the aim to boost the growth of MYb11. Experimentally testing four of the predicted precision prebiotics, we confirm that they are specifically able to increase the abundance of MYb11 in vitro and in vivo. These results demonstrate that constraint-based modeling could be an important tool for the development of targeted microbiome-based therapies against human diseases.

Diphtheria and Tetanus Immunity Status among Greek Adults: Results from a Nationwide Seroprevalence Study.

Diphtheria and tetanus could lead to serious morbidity. We aimed to evaluate immunity levels by measuring specific IgG antibodies for diphtheria and tetanus in serum samples from a nationally expanded sample of the Greek population. A geographically stratified sampling approach based on regional units (NUTS level 2) was applied by considering variables such as age group (30-80+) and sex. In total, 1201 persons (47.7% males and 52.3% females) participated in the survey. Bivariate analysis revealed a negative relationship between diphtheria and tetanus median antibody titers and age. The overall seropositivity rate for diphtheria IgG antibodies (≥0.10 IU/mL) was estimated at 31.5%. Regarding tetanus, the total seropositivity rate was estimated at 59.5% (tetanus IgG antibodies ≥0.10 IU/mL). Logistic regression analysis indicated that age groups <40 years and 40-59 years were independently associated with tetanus seropositivity. Logistic regression also revealed that male sex and being aged 60-69 years were independent risk factors for diphtheria-related seropositivity. Lastly, being resident of some regions was an independent risk factor for both diphtheria- and tetanus-related seropositivity. The present study shows that Greek adults are still not completely immune to diphtheria and tetanus. It is likely possible to achieve optimal immunization coverage by implementing serviceable public health initiatives after comprehending real community needs.

Consumption of a boiled Greek type of coffee is associated with improved endothelial function: the Ikaria study.

OBJECTIVE: The association of coffee consumption with cardiovascular disease remains controversial. Endothelial function is associated with cardiovascular risk. We examined the association between chronic coffee consumption and endothelium function in elderly inhabitants of the island of Ikaria. METHODS: The analysis was conducted on 142 elderly subjects (aged 66-91 years) of the Ikaria Study. Endothelial function was evaluated by ultrasound measurement of flow-mediated dilation (FMD). Coffee consumption was evaluated based on a food frequency questionnaire and was categorized as 'low' (< 200 ml/day), 'moderate' (200-450 ml/day), or 'high' (> 450 ml/day). RESULTS: From the subjects included in the study, 87% consumed a boiled Greek type of coffee. Moreover, 40% had a 'low', 48% a 'moderate' and 13% a 'high' daily coffee consumption. There was a linear increase in FMD according to coffee consumption ('low': 4.33 ± 2.51% vs 'moderate': 5.39 ± 3.09% vs 'high': 6.47 ± 2.72%; p = 0.032). Moreover, subjects consuming mainly a boiled Greek type of coffee had a significantly higher FMD compared with those consuming other types of coffee beverages (p = 0.035). CONCLUSIONS: Chronic coffee consumption is associated with improved endothelial function in elderly subjects, providing a new connection between nutrition and vascular health.

Combining STAT3-Targeting Agents with Immune Checkpoint Inhibitors in NSCLC.

Despite recent therapeutic advances, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor (TF) with multiple tumor-promoting effects in NSCLC, including proliferation, anti-apoptosis, angiogenesis, invasion, metastasis, immunosuppression, and drug resistance. Recent studies suggest that STAT3 activation contributes to resistance to immune checkpoint inhibitors. Thus, STAT3 represents an attractive target whose pharmacological modulation in NSCLC may assist in enhancing the efficacy of or overcoming resistance to immune checkpoint inhibitors. In this review, we discuss the biological mechanisms through which STAT3 inhibition synergizes with or overcomes resistance to immune checkpoint inhibitors and highlight the therapeutic strategy of using drugs that target STAT3 as potential combination partners for immune checkpoint inhibitors in the management of NSCLC patients.

Targeting YAP/TAZ in Combination with PD-L1 Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC).

The survival of non-small cell lung cancer (NSCLC) patients has improved in the last decade as a result of introducing new therapeutics, such as immune checkpoint inhibitors, in the clinic. Still, some NSCLC patients do not benefit from these therapies due to intrinsic resistance or the development of acquired resistance and their malignant disease progresses. Further research on the molecular underpinnings of NSCLC pathobiology is required in order to discover clinically relevant molecular targets that regulate tumor immunity and to develop reasonable therapeutic combinations that will promote the efficacy of immune checkpoint inhibitors. Yes-associated Protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), the final effectors of the Hippo signaling transduction pathway, are emerging as key players in NSCLC development and progression. Herein, we overview studies that have investigated the oncogenic role of YAP/TAZ in NSCLC, focusing on immune evasion, and highlight the therapeutic potential of combining YAP/TAZ inhibitory agents with immune checkpoint inhibitors for the management of NSCLC patients.