Targeting PI3K/AKT/mTOR and MAPK Signaling Pathways in Gastric Cancer.

Gastric cancer (GC) is the fourth leading cause of death worldwide, with more than 1 million cases diagnosed every year. Helicobacter pylori represents the main risk factor, being responsible for 78% of the cases. Increased amounts of salt, pickled food, red meat, alcohol, smoked food, and refined sugars negatively affect the stomach wall, contributing to GC development. Several gene mutations, including PIK3CA, TP53, ARID1A, CDH1, Ras, Raf, and ERBB3 are encountered in GC pathogenesis, leading to phosphatidylinositol 3-kinase (PI3K) protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-PI3K/AKT/mTOR-and mitogen-activated protein kinase (MAPK) signaling pathway activation and promoting tumoral activity. Helicobacter pylori, growth factors, cytokines, hormones, and oxidative stress also activate both pathways, enhancing GC development. In clinical trials, promising results have come from monoclonal antibodies such as trastuzumab and ramucirumab. Dual inhibitors targeting the PI3K/AKT/mTOR and MAPK signaling pathways were used in vitro studies, also with promising results. The main aim of this review is to present GC incidence and risk factors and the dysregulations of the two protein kinase complexes together with their specific inhibitors.

Growth Factors, PI3K/AKT/mTOR and MAPK Signaling Pathways in Colorectal Cancer Pathogenesis: Where Are We Now?

Colorectal cancer (CRC) is a predominant malignancy worldwide, being the fourth most common cause of mortality and morbidity. The CRC incidence in adolescents, young adults, and adult populations is increasing every year. In the pathogenesis of CRC, various factors are involved including diet, sedentary life, smoking, excessive alcohol consumption, obesity, gut microbiota, diabetes, and genetic mutations. The CRC tumor microenvironment (TME) involves the complex cooperation between tumoral cells with stroma, immune, and endothelial cells. Cytokines and several growth factors (GFs) will sustain CRC cell proliferation, survival, motility, and invasion. Epidermal growth factor receptor (EGFR), Insulin-like growth factor -1 receptor (IGF-1R), and Vascular Endothelial Growth Factor -A (VEGF-A) are overexpressed in various human cancers including CRC. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and all the three major subfamilies of the mitogen-activated protein kinase (MAPK) signaling pathways may be activated by GFs and will further play key roles in CRC development. The main aim of this review is to present the CRC incidence, risk factors, pathogenesis, and the impact of GFs during its development. Moreover, the article describes the relationship between EGF, IGF, VEGF, GFs inhibitors, PI3K/AKT/mTOR-MAPK signaling pathways, and CRC.

Using the ClinFIT COVID-19 Instrument to Assess the Functional Impairments Specific to Post-COVID-19 Patients in Romania.

INTRODUCTION: The COVID-19 pandemic has led to approximately 3.5 million cases in Romania, causing systemic inflammation and over 200 symptoms affecting various body systems. This complexity has challenged rehabilitation systems, necessitating personalized plans tailored to each patient's illness stage and impairment level. The ISPRM-developed ClinFIT COVID-19 instrument, aligned with the ICF categories, assists in assessing patients during acute, post-acute, and long-term phases. OBJECTIVE: This study aimed to evaluate and assess functional impairments in post-COVID-19 patients in Romania, with a secondary goal of generating rehabilitation directions. METHODS: Data were collected from patients at two Bucharest medical centers, including those with persistent symptoms post-acute phase. Participants were assessed using the adapted ClinFIT COVID-19 instrument, and descriptive statistics were applied. CONCLUSIONS: Findings revealed diverse functional impairments in physical, psychological, and social domains among post-COVID-19 patients, with severe impairments more common in those with long-term COVID-19. Complete impairment in complex movement and paid work was noted, affecting one-third of salaried employees and forcing some to retire. In the acute phase, the most frequent functional impairments were sleep, attention, pain sensation, and exercise tolerance functions. In contrast, the most severely affected functions were exercise tolerance and mobility joint functions. Age did not positively correlate with any of the analyzed functions. In the post-acute phase, sleep, energy, and drive functions remained the most frequently affected functions, while the most severely affected was, by far, the moving around function. In the post-acute period, respiratory and respiratory muscle functions strongly correlated with all tasks related to physical activity. In the long COVID-19 phase, remunerative employment was the most severely affected function, while attention functions remained the most frequently affected, similar to the acute phase. The ClinFIT COVID-19 instrument effectively captured these impairments, underscoring the need for comprehensive rehabilitation strategies.

mTOR Dysregulation, Insulin Resistance, and Hypertension.

Worldwide, diabetes mellitus (DM) and cardiovascular diseases (CVDs) represent serious health problems associated with unhealthy diet and sedentarism. Metabolic syndrome (MetS) is characterized by obesity, dyslipidemia, hyperglycemia, insulin resistance (IR) and hypertension. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase with key roles in glucose and lipid metabolism, cell growth, survival and proliferation. mTOR hyperactivation disturbs glucose metabolism, leading to hyperglycemia and further to IR, with a higher incidence in the Western population. Metformin is one of the most used hypoglycemic drugs, with anti-inflammatory, antioxidant and antitumoral properties, having also the capacity to inhibit mTOR. mTOR inhibitors such as rapamycin and its analogs everolimus and temsirolimus block mTOR activity, decrease the levels of glucose and triglycerides, and reduce body weight. The link between mTOR dysregulation, IR, hypertension and mTOR inhibitors has not been fully described. Therefore, the main aim of this narrative review is to present the mechanism by which nutrients, proinflammatory cytokines, increased salt intake and renin-angiotensin-aldosterone system (RAAS) dysregulation induce mTOR overactivation, associated further with IR and hypertension development, and also mTOR inhibitors with higher potential to block the activity of this protein kinase.

Characteristics of Patients with Persistent COVID-19 Symptoms and Unscheduled Return Visits to a Centre for COVID-19 Evaluation.

Background: This retrospective study aimed to evaluate the characteristics of patients with long COVID syndrome. Methods: This study included 457 adults who had at least one persistent symptom after COVID-19 infection. Results: The median time interval between the last SARS-CoV-2 infection and emergency room presentation was 3 months. Older patients had comorbidities (61.7 vs. 44.9 years, p < 0.0001), moderate or severe forms of COVID-19 (61.2 vs. 50.9 years, p < 0.0001), and respiratory symptoms (56.1 vs. 52.0 years, p = 0.0027). Non-vaccinated patients were older than vaccinated patients (56.0 vs. 51.5 years, p = 0.0008) and had residual lung abnormalities following COVID-19 infection (51.5% vs. 36.8%, p < 0.003). The time interval between the last SARS-CoV-2 infection and the hospital evaluation was shorter for vaccinated patients (3.2 vs. 3.9 months, p < 0.0001) and those with mild forms (3.3 vs. 4.12 months, p = 0.0001) versus non-vaccinated individuals. After the last SARS-CoV-2 infection, 107 patients developed impaired fasting glucose, impaired glucose tolerance, or diabetes mellitus, being patients with already known chronic diseases (p = 0.0002), or hypertension (p = 0.001). Conclusions: Our study pointed out the heterogeneity of symptoms following COVID-19, and they are associated with age, vaccination status, or severity of SARS-CoV-2 infection.