Obesity and main urologic cancers: Current systematic evidence, novel biological mechanisms, perspectives and challenges.

Urologic cancers (UC) account for 13.1% of all new cancer cases and 7.9% of all cancer-related deaths. A growing body of evidence has indicated a potential causal link between obesity and UC. The aim of the present review is to appraise in a critical and integrative manner evidence from meta-analyses and mechanistic studies on the role of obesity in four prevalent UC (kidney-KC, prostate-PC, urinary bladder-UBC, and testicular cancer-TC). Special emphasis is given on Mendelian Randomization Studies (MRS) corroborating a genetic causal association between obesity and UC, as well as on the role of classical and novel adipocytokines. Furthermore, the molecular pathways that link obesity to the development and progression of these cancers are reviewed. Available evidence indicates that obesity confers increased risk for KC, UBC, and advanced PC (20-82%, 10-19%, and 6-14%, respectively), whereas for TC adult height (5-cm increase) may increase the risk by 13%. Obese females tend to be more susceptible to UBC and KC than obese males. MRS have shown that a higher genetic-predicted BMI may be causally linked to KC and UBC but not PC and TC. Biological mechanisms that are involved in the association between excess body weight and UC include the Insulin-like Growth Factor axis, altered availability of sex hormones, chronic inflammation and oxidative stress, abnormal secretion of adipocytokines, ectopic fat deposition, dysbiosis of the gastrointestinal and urinary tract microbiomes and circadian rhythm dysregulation. Anti-hyperglycemic and non-steroidal anti-inflammatory drugs, statins, and adipokine receptor agonists/antagonists show potential as adjuvant cancer therapies. Identifying obesity as a modifiable risk factor for UC may have significant public health implications, allowing clinicians to tailor individualized prevention strategies for patients with excess body weight.

The Role of Endocrine Disruptors Bisphenols and Phthalates in Obesity: Current Evidence, Perspectives and Controversies.

Excess body weight constitutes one of the major health challenges for societies and healthcare systems worldwide. Besides the type of diet, calorie intake and the lack of physical exercise, recent data have highlighted a possible association between endocrine-disrupting chemicals (EDCs), such as bisphenol A, phthalates and their analogs, and obesity. EDCs represent a heterogeneous group of chemicals that may influence the hormonal regulation of body mass and adipose tissue morphology. Based on the available data from mechanistic, animal and epidemiological studies including meta-analyses, the weight of evidence points towards the contribution of EDCs to the development of obesity, associated disorders and obesity-related adipose tissue dysfunction by (1) impacting adipogenesis; (2) modulating epigenetic pathways during development, enhancing susceptibility to obesity; (3) influencing neuroendocrine signals responsible for appetite and satiety; (4) promoting a proinflammatory milieu in adipose tissue and inducing a state of chronic subclinical inflammation; (5) dysregulating gut microbiome and immune homeostasis; and (6) inducing dysfunction in thermogenic adipose tissue. Critical periods of exposure to obesogenic EDCs are the prenatal, neonatal, pubertal and reproductive periods. Interestingly, EDCs even at low doses may promote epigenetic transgenerational inheritance of adult obesity in subsequent generations. The aim of this review is to summarize the available evidence on the role of obesogenic EDCs, specifically BPA and phthalate plasticizers, in the development of obesity, taking into account in vitro, animal and epidemiologic studies; discuss mechanisms linking EDCs to obesity; analyze the effects of EDCs on obesity in critical chronic periods of exposure; and present interesting perspectives, challenges and preventive measures in this research area.

Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Where Do We Stand?

Lipoprotein(a) [Lp(a)] consists of a low-density lipoprotein-like molecule and an apolipoprotein(a) [apo(a)] particle. Lp(a) has been suggested to be an independent risk factor of atherosclerotic cardiovascular disease (ASCVD). Lp(a) plasma levels are considered to be 70-90% genetically determined through the codominant expression of the LPA gene. Therefore, Lp(a) levels are almost stable during an individual's lifetime. This lifelong stability, together with the difficulties in measuring Lp(a) levels in a standardized manner, may account for the scarcity of available drugs targeting Lp(a). In this review, we synopsize the latest data regarding the structure, metabolism, and factors affecting circulating levels of Lp(a), as well as the laboratory determination measurement of Lp(a), its role in the pathogenesis of ASCVD and thrombosis, and the potential use of various therapeutic agents targeting Lp(a). In particular, we discuss novel agents, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) that are currently being developed and target Lp(a). The promising role of muvalaplin, an oral inhibitor of Lp(a) formation, is then further analyzed.

Sepsis-Associated Acute Kidney Injury: Where Are We Now?

Worldwide, sepsis is a well-recognized cause of death. Acute kidney injury (AKI) may be related to sepsis in up to 70% of AKI cases. Sepsis-associated AKI (SA-AKI) is defined as the presence of AKI according to the Kidney Disease: Improving Global Outcomes criteria in the context of sepsis. SA-AKI is categorized into early, which presents during the first 48 h of sepsis, and late, presenting between 48 h and 7 days of sepsis. SA-AKI is associated with a worse prognosis among patients with sepsis. However, there are different SA-AKI phenotypes as well as different pathophysiological pathways of SA-AKI. The aim of this review is to provide an updated synopsis of the pathogenetic mechanisms underlying the development of SA-AKI as well as to analyze its different phenotypes and prognosis. In addition, potential novel diagnostic and prognostic biomarkers as well as therapeutic approaches are discussed. A plethora of mechanisms are implicated in the pathogenesis of SA-AKI, including inflammation and metabolic reprogramming during sepsis; various types of cell death such as apoptosis, necroptosis, pyroptosis and ferroptosis; autophagy and efferocytosis; and hemodynamic changes (macrovascular and microvascular dysfunction). Apart from urine output and serum creatinine levels, which have been incorporated in the definition of AKI, several serum and urinary diagnostic and prognostic biomarkers have also been developed, comprising, among others, interleukins 6, 8 and 18, osteoprotegerin, galectin-3, presepsin, cystatin C, NGAL, proenkephalin A, CCL-14, TIMP-2 and L-FABP as well as biomarkers stemming from multi-omics technologies and machine learning algorithms. Interestingly, the presence of long non-coding RNAs (lncRNAs) as well as microRNAs (miRNAs), such as PlncRNA-1, miR-22-3p, miR-526b, LncRNA NKILA, miR-140-5p and miR-214, which are implicated in the pathogenesis of SA-AKI, may also serve as potential therapeutic targets. The combination of omics technologies represents an innovative holistic approach toward providing a more integrated view of the molecular and physiological events underlying SA-AKI as well as for deciphering unique and specific phenotypes. Although more evidence is still necessary, it is expected that the incorporation of integrative omics may be useful not only for the early diagnosis and risk prognosis of SA-AKI, but also for the development of potential therapeutic targets that could revolutionize the management of SA-AKI in a personalized manner.

Gut Microbiota and Its Role in the Brain-Gut-Kidney Axis in Hypertension.

PURPOSE OF REVIEW: The role of the gut microbiota in modulating blood pressure is increasingly being recognized, currently. The purpose of this review is to summarize recent findings about the mechanisms involved in hypertension with regard to the phenomenon of "gut dysbiosis." RECENT FINDINGS: Gut dysbiosis, i.e., the imbalance between the gut microbiota and the host, is characterized by a disruption of the tight junction proteins, such as occludins, claudins, and JAMs (junctional adhesion molecules), resulting in increased gut permeability or the so called "leaky gut." Due to the influence of genetic as well as environmental factors, various metabolites produced by the gut microbiota, such as indole and p-cresol, are increased. Thereby, uremic toxins, such as indoxyl sulfates and p-cresol sulfates, accumulate in the blood and the urine, causing damage in the podocytes and the tubular cells. In addition, immunological mechanisms are implicated as well. In particular, a switch from M2 macrophages to M1 macrophages, which produce pro-inflammatory cytokines, occurs. Moreover, a higher level of Th17 cells, releasing large amounts of interleukin-17 (IL-17), has been reported, when a diet rich in salt is consumed. Therefore, apart from the aggravation of uremic toxins, which may account for direct harmful effects on the kidney, there is inflammation not only in the gut, but in the kidneys as well. This crosstalk between the gut and the kidney is suggested to play a crucial role in hypertension. Notably, the brain is also implicated, with an increasing sympathetic output. The brain-gut-kidney axis seems to be deeply involved in the development of hypertension and chronic kidney disease (CKD). The notion that, by modulating the gut microbiota, we could regulate blood pressure is strongly supported by the current evidence. A healthy diet, low in animal protein and fat, and low in salt, together with the utilization of probiotics, prebiotics, synbiotics, or postbiotics, may contribute to our fight against hypertension.

Immunotherapy in Head and Neck Cancer: Where Do We Stand?

PURPOSEOF REVIEW: Head and neck cancer (HNC) comprises a group of malignancies, amongst which squamous cell carcinoma accounts for more than 90% of the cases. HNC has been related to tobacco use, alcohol consumption, human papillomavirus, Epstein-Barr virus, air pollution, and previous local radiotherapy. HNC has been associated with substantial morbidity and mortality. This review aims to summarize the recent findings regarding immunotherapy in HNC. RECENT FINDINGS: The recent introduction of immunotherapy, with the use of programmed death 1 (PD-1) inhibitors pembrolizumab and nivolumab, which have been FDA approved for the treatment of metastatic or recurrent head and neck squamous cell carcinoma, has changed the field in metastatic or recurrent disease. There are many ongoing trials regarding the use of novel immunotherapeutic agents, such as durvalumab, atezolizumab, avelumab, tremelimumab, and monalizumab. In this review, we focus on the therapeutic potential of novel immunotherapy treatment modalities, such as combinations of newer immune-checkpoint inhibitors; the use of tumor vaccines such as human papillomavirus-targeted vaccines; the potential use of oncolytic viruses; as well as the latest advances regarding adoptive cellular immunotherapy. As novel treatment options are still emerging, a more personalized approach to metastatic or recurrent HNC therapy should be followed. Moreover, the role of the microbiome in immunotherapy, the limitations of immunotherapy, and the various diagnostic, prognostic, and predictive biomarkers based on genetics and the tumor microenvironment are synopsized.

Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges.

Long COVID (LC) encompasses a constellation of long-term symptoms experienced by at least 10% of people after the initial SARS-CoV-2 infection, and so far it has affected about 65 million people. The etiology of LC remains unclear; however, many pathophysiological pathways may be involved, including viral persistence; a chronic, low-grade inflammatory response; immune dysregulation and a defective immune response; the reactivation of latent viruses; autoimmunity; persistent endothelial dysfunction and coagulopathy; gut dysbiosis; hormonal and metabolic dysregulation; mitochondrial dysfunction; and autonomic nervous system dysfunction. There are no specific tests for the diagnosis of LC, and clinical features including laboratory findings and biomarkers may not specifically relate to LC. Therefore, it is of paramount importance to develop and validate biomarkers that can be employed for the prediction, diagnosis and prognosis of LC and its therapeutic response, although this effort may be hampered by challenges pertaining to the non-specific nature of the majority of clinical manifestations in the LC spectrum, small sample sizes of relevant studies and other methodological issues. Promising candidate biomarkers that are found in some patients are markers of systemic inflammation, including acute phase proteins, cytokines and chemokines; biomarkers reflecting SARS-CoV-2 persistence, the reactivation of herpesviruses and immune dysregulation; biomarkers of endotheliopathy, coagulation and fibrinolysis; microbiota alterations; diverse proteins and metabolites; hormonal and metabolic biomarkers; and cerebrospinal fluid biomarkers. At present, there are only two reviews summarizing relevant biomarkers; however, they do not cover the entire umbrella of current biomarkers, their link to etiopathogenetic mechanisms or the diagnostic work-up in a comprehensive manner. Herein, we aim to appraise and synopsize the available evidence on the typical laboratory manifestations and candidate biomarkers of LC, their classification based on pathogenetic mechanisms and the main LC symptomatology in the frame of the epidemiological and clinical aspects of the syndrome and furthermore assess limitations and challenges as well as potential implications in candidate therapeutic interventions.

The Role of Next-Generation Probiotics in Obesity and Obesity-Associated Disorders: Current Knowledge and Future Perspectives.

Obesity and obesity-associated disorders pose a major public health issue worldwide. Apart from conventional weight loss drugs, next-generation probiotics (NGPs) seem to be very promising as potential preventive and therapeutic agents against obesity. Candidate NGPs such as Akkermansia muciniphila, Faecalibacterium prausnitzii, Anaerobutyricum hallii, Bacteroides uniformis, Bacteroides coprocola, Parabacteroides distasonis, Parabacteroides goldsteinii, Hafnia alvei, Odoribacter laneus and Christensenella minuta have shown promise in preclinical models of obesity and obesity-associated disorders. Proposed mechanisms include the modulation of gut flora and amelioration of intestinal dysbiosis, improvement of intestinal barrier function, reduction in chronic low-grade inflammation and modulation of gut peptide secretion. Akkermansia muciniphila and Hafnia alvei have already been administered in overweight/obese patients with encouraging results. However, safety issues and strict regulations should be constantly implemented and updated. In this review, we aim to explore (1) current knowledge regarding NGPs; (2) their utility in obesity and obesity-associated disorders; (3) their safety profile; and (4) their therapeutic potential in individuals with overweight/obesity. More large-scale, multicentric and longitudinal studies are mandatory to explore their preventive and therapeutic potential against obesity and its related disorders.

Diagnostic and Prognostic Value of Serum Omentin-1 in Sepsis: A Prospective Study in Critically Ill Patients.

Background and Objectives: Omentin-1, also known as intelectin-1, is a novel adipokine with anti-inflammatory activities implicated in inflammatory diseases and sepsis. We aimed to explore serum omentin-1 and its kinetics in critically ill patients early in sepsis and its association with severity and prognosis. Materials and Methods: Serum omentin-1 was determined in 102 critically ill patients with sepsis during the first 48 h from sepsis onset and 1 week later, and in 102 age- and gender-matched healthy controls. The outcome of sepsis at 28 days after enrollment was recorded. Results: Serum omentin-1 at enrollment was significantly higher in patients compared to controls (763.3 ± 249.3 vs. 451.7 ± 122.3 µg/L, p < 0.001) and it further increased 1 week after (950.6 ± 215.5 vs. 763.3 ± 249.3 µg/L, p < 0.001). Patients with septic shock (n = 42) had higher omentin-1 compared to those with sepsis (n = 60) at enrollment (877.9 ± 241.2 vs. 683.1 ± 223.7 µg/L, p < 0.001) and 1 week after (1020.4 ± 224.7 vs. 901.7 ± 196.3 µg/L, p = 0.007). Furthermore, nonsurvivors (n = 30) had higher omentin-1 at sepsis onset (952.1 ± 248.2 vs. 684.6 ± 204.7 µg/L, p < 0.001) and 1 week after (1051.8 ± 242 vs. 908.4 ± 189.8 µg/L, p < 0.01). Patients with sepsis and survivors presented higher kinetics than those with septic shock and nonsurvivors (Δ(omentin-1)% 39.8 ± 35.9% vs. 20.2 ± 23.3%, p = 0.01, and 39.4 ± 34.3% vs. 13.3 ± 18.1%, p < 0.001, respectively). Higher omentin-1 at sepsis onset and 1 week after was an independent predictor of 28-day mortality (HR 2.26, 95% C.I. 1.21-4.19, p = 0.01 and HR: 2.15, 95% C.I. 1.43-3.22, p < 0.001, respectively). Finally, omentin-1 was significantly correlated with the severity scores, the white blood cells, coagulation biomarkers, and CRP, but not procalcitonin and other inflammatory biomarkers. Conclusions: Serum omentin-1 is increased in sepsis, while higher levels and lower kinetics during the first week of sepsis are associated with the severity and 28-day mortality of sepsis. Omentin-1 may be a promising biomarker of sepsis. However, more studies are needed to explore its role in sepsis.

Diabetes type 1: Can it be treated as an autoimmune disorder?

Type 1 Diabetes Mellitus (T1DM) is characterized by progressive autoimmune-mediated destruction of the pancreatic beta-cells leading to insulin deficiency and hyperglycemia. It is associated with significant treatment burden and necessitates life-long insulin therapy. The role of immunotherapy in the prevention and management of T1DM is an evolving area of interest which has the potential to alter the natural history of this disease.In this review, we give insight into recent clinical trials related to the use of immunotherapeutic approaches for T1DM, such as proinflammatory cytokine inhibition, cell-depletion and cell-therapy approaches, autoantigen-specific treatments and stem cell therapies. We highlight the timing of intervention, aspects of therapy including adverse effects and the emergence of a novel lymphocyte crucial in T1DM autoimmunity. We also discuss the role of cardiac autoimmunity and its link to excess CVD risk in T1DM.We conclude that significant advances have been made in development of immunotherapeutic targets and agents for the treatment and prevention of T1DM. These immune-based therapies promise preservation of beta-cells and decreasing insulin dependency. In their current state, immunotherapeutic approaches cannot yet halt the progression from a preclinical state to overt T1DM nor can they replace standard insulin therapy in existing T1DM. It remains to be seen whether immunotherapy will ultimately play a key role in the prevention of progression to overt T1DM and whether it may find a place in our therapeutic armamentarium to improve clinical outcomes and quality of life in established T1DM.

Clostridioides difficile infection in a patient with immunoglobulin A vasculitis: a triggering factor or a rare complication of the disease? A case-based review.

IgA vasculitis, formerly known as Henoch-Schonlein purpura (HSP), is the most common form of systemic vasculitis in children and is characterized by inflammation of the small vessels with typical deposition of IgA immune complexes. It is a leukocytoclastic type of vasculitis and is characterized by a tetrad of clinical manifestations: non-thrombocytopenia or coagulopathy-induced palpable purpura, arthritis, or arthralgia, gastrointestinal, and renal involvement. The exact cause of IgA vasculitis is not known yet, although infections, vaccinations and insect bites have been implicated in the appearance of the disease. The main risk factors for Clostridioides difficile infection (CDI) are previous CDI, age > 65 years old, pharmacologic agents (antibiotics, PPIs, histamine-2 receptor antagonists, glucocorticoids, and chemotherapy), prior hospitalization, the presence of co-morbidities, especially inflammatory bowel diseases and chronic kidney disease (CKD) and immunosuppression. Oral vancomycin or fidaxomicin are the gold standard of the therapy, with metronidazole being an alternative choice. The purpose of this study was to describe a case of IgA vasculitis and Clostridioides difficile infection to see whether there is any association between the two distinct clinical entities. Herein, we describe a 17-year old patient with IgA vasculitis and bloody diarrhea due to Clostridioides difficile infection and we discuss the co-existence of these two pathological conditions. The patient presented to the hospital with diffuse abdominal pain, nausea, vomiting, and two episodes of bloody diarrhea. Stools tested positive for Clostridioides difficile toxins, while he remained afebrile with hs-CRP = 1.5 mg/dL (normal range < 0.5 mg/dL). Direct immunofluorescence from the extremities' purplish eruption showed leukocytoclastic vasculitis with IgA deposition. Whether co-existence of the two above-mentioned distinct clinical entities is just a co-incidence or CDI is a triggering factor for IgA vasculitis remains to be elucidated in future large-scale studies.

ANGPTL3 Inhibitors　- Their Role in Cardiovascular Disease Through Regulation of Lipid Metabolism.

Elevated plasma lipid levels are linked to atherosclerosis, a hallmark for coronary artery disease (CAD), documented by animal studies as well as angiographic and clinical studies. The ability to treat hyperlipidemia through lifestyle changes and lipid-lowering agents has been related to the slow progression of atherosclerosis and decreased incidence of major coronary events. Angiopoietin-like proteins (ANGPTLs) are a family of secreted glycoproteins expressed in the liver that share common domain characteristics with angiopoietins, the main regulators of angiogenesis. Although ANGPTLs cannot bind the angiopoietin receptors expressed on endothelial cells, 2 ANGPTL family members (ANGPTL3 and ANGPTL4) have clinical importance because of their unambiguous effects on lipoprotein metabolism in mice and humans. The regulation of plasma lipid levels by ANGPTL3 is controlled via affecting lipoprotein lipase and endothelial lipase-mediated hydrolysis of triglycerides (TGs) and phospholipids. ANGPTL 3, along with the other 2 members, 4 and 8, is a key to balancing the distribution of circulating TGs between white adipose tissue (WAT) and oxidative tissues. Thus, ongoing trials with newly discovered medications in the form of monoclonal antibodies or antisense oligonucleotides with novel targets are under analysis and may represent a fresh frontier in the treatment of hyperlipidemia and CAD.

Sodium glucose co-transporter 2 inhibitors and their nephroprotective potential
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Chronic kidney disease among patients with diabetes is on the rise. The sodium glucose co-transporters 2 inhibitors are a new class of glucose-lowering agents, which act through a novel mechanism by producing a decline in glucose reabsorption in the kidney, thereby increasing glucosuria and decreasing serum glucose levels. Data suggest that they possess nephroprotective properties. It is noteworthy that the efferent glomerular arteriole is 10 - 100 times more sensitive to the vasoconstrictive properties of angiotensin II than the afferent one and this might account for the consequently higher intra-glomerular capillary pressure, which is believed to be the cornerstone of diabetic nephropathy. These drugs are demonstrated to restore intra-glomerular pressure by increasing angiotensin (1 - 7), which exerts vasodilatory and anti-inflammatory effects. In this review, the nephroprotective potential of this novel class of glucose-lowering drugs will be further discussed.
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Inverse Relationship between Adherence to the Mediterranean Diet and Serum Cystatin C Levels.

OBJECTIVE: The aim of the present study was to examine serum cystatin C levels in association with the Mediterranean diet in a healthy Greek population. METHODS: Cystatin C together with basic clinical chemistry tests was measured in a total of 490 adults (46±16 years, 40% of males), who underwent an annual health check. Demographic, anthropometric and lifestyle characteristics were recorded, while adherence to the Mediterranean diet was evaluated through the MedDietScore (0-55). RESULTS: The mean level of serum cystatin C was 0.84 mg/L, while men had increased serum cystatin C levels compared to women (0.86 mg/L vs. 0.83 mg/L, respectively, 0.017). After adjusting for age, gender, body mass index, smoking status, hypertension, diabetes, hypercholesterolemia, estimated glomerular filtration rate (eGFR), albumin and ferritin levels, each unit increase in MedDietScore led to 0.002 mg/dL drop off in cystatin C serum levels. CONCLUSIONS: We have demonstrated an inverse relationship between the MedDietScore and serum cystatin C levels. Our finding that increases in MedDietScore are associated with decreases in serum cystatin C levels could imply that adherence to the Mediterranean diet may reduce the cardiovascular risk, as assessed by cystatin C, a prognostic marker of the cardiometabolic risk. This notion could have a great impact on public health.

25-hydroxyvitamin D and parathyroid hormone in new onset sepsis: A prospective study in critically ill patients.

Hypovitaminosis D is highly prevalent in critically ill patients, and it has been suggested to be a risk factor for infections, sepsis and higher mortality. We sought to investigate whether serum 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) in critically ill patients with new onset sepsis are associated with severity and outcome. We prospectively included 50 consecutive critically ill adult cases with new onset sepsis and 50 healthy controls matched for age and sex. PTH and 25(OH)D were determined in serum via electrochemiluminescence immunoassays at inclusion in the study in all cases and controls, and one week after sepsis onset in cases. Patients had reduced 25(OH)D compared to controls at sepsis onset (7.9 ± 3 vs 24.6 ± 6.7 ng/mL, p < 0.001), whilst PTH was similar (median (range): 34.5 (5.7-218.5) vs 44.2 (14.2-98.1) pg/mL, p = 0.35). In patients, 25(OH)D upon enrollment and one week after did not differ significantly (7.9 ± 3 vs 7 ± 4.3 ng/mL, p = 0.19). All patients presented with hypovitaminosis D (25(OH)D < 20 ng/mL), while 40 patients (80 %) had vitamin D deficiency (25(OH)D < 12 ng/mL) at sepsis onset, including all ten (20 %) nonsurvivors, who died within 28 days from sepsis onset. Patients with sepsis (N = 28) and septic shock (N = 22) as well as survivors (N = 40) and nonsurvivors (N = 10) had similar 25(OH)D at enrollment (p > 0.05). 25(OH)D was positively correlated with ionized calcium (r = 0.46, p < 0.001) and negatively with PTH (p < 0.05), while inflammatory biomarkers or the severity scores exhibited no correlation with 25(OH)D. Patients with septic shock and nonsurvivors had lower PTH than patients with sepsis and survivors respectively (42.2 ± 42.9 vs 73.4 ± 61.9 pg/mL, p = 0.04, and 18.3 ± 10.7 vs 69.9 ± 58.8 pg/mL, p = 0.001, respectively). C-reactive protein was negatively associated with PTH (r = -0.44, p = 0.001). In conclusion, vitamin D deficiency was present in 80 % of critically ill patients at sepsis onset, while nonsurvivors exhibited lower PTH than survivors. Additional, larger and multicenter studies are warranted to elucidate the contribution of vitamin D and PTH to the pathogenesis of sepsis and its outcomes.

Obesity and Leukemia: Biological Mechanisms, Perspectives, and Challenges.

PURPOSE OF REVIEW: To examine the epidemiological data on obesity and leukemia; evaluate the effect of obesity on leukemia outcomes in childhood acute lymphoblastic leukemia (ALL) survivors; assess the potential mechanisms through which obesity may increase the risk of leukemia; and provide the effects of obesity management on leukemia. Preventive (diet, physical exercise, obesity pharmacotherapy, bariatric surgery) measures, repurposing drugs, candidate therapeutic agents targeting oncogenic pathways of obesity and insulin resistance in leukemia as well as challenges of the COVID-19 pandemic are also discussed. RECENT FINDINGS: Obesity has been implicated in the development of 13 cancers, such as breast, endometrial, colon, renal, esophageal cancers, and multiple myeloma. Leukemia is estimated to account for approximately 2.5% and 3.1% of all new cancer incidence and mortality, respectively, while it represents the most frequent cancer in children younger than 5 years. Current evidence indicates that obesity may have an impact on the risk of leukemia. Increased birthweight may be associated with the development of childhood leukemia. Obesity is also associated with worse outcomes and increased mortality in leukemic patients. However, there are several limitations and challenges in meta-analyses and epidemiological studies. In addition, weight gain may occur in a substantial number of childhood ALL survivors while the majority of studies have documented an increased risk of relapse and mortality among patients with childhood ALL and obesity. The main pathophysiological pathways linking obesity to leukemia include bone marrow adipose tissue; hormones such as insulin and the insulin-like growth factor system as well as sex hormones; pro-inflammatory cytokines, such as IL-6 and TNF-α; adipocytokines, such as adiponectin, leptin, resistin, and visfatin; dyslipidemia and lipid signaling; chronic low-grade inflammation and oxidative stress; and other emerging mechanisms. Obesity represents a risk factor for leukemia, being among the only known risk factors that could be prevented or modified through weight loss, healthy diet, and physical exercise. Pharmacological interventions, repurposing drugs used for cardiometabolic comorbidities, and bariatric surgery may be recommended for leukemia and obesity-related cancer prevention.

NAFLD in the 21st Century: Current Knowledge Regarding Its Pathogenesis, Diagnosis and Therapeutics.

Non-alcoholic fatty liver disease (NAFLD) is a major public health issue worldwide. It is the most common liver disease in Western countries, andits global prevalence is estimated to be up to 35%. However, its diagnosis may be elusive, because liver biopsy is relatively rarely performed and usually only in advanced stages of the disease. Therefore, several non-invasive scores may be applied to more easily diagnose and monitor NAFLD. In this review, we discuss the various biomarkers and imaging scores that could be useful in diagnosing and managing NAFLD. Despite the fact that general measures, such as abstinence from alcohol and modulation of other cardiovascular disease risk factors, should be applied, the mainstay of prevention and management is weight loss. Bariatric surgery may be suggested as a means to confront NAFLD. In addition, pharmacological treatment with GLP-1 analogues or the GIP agonist tirzepatide may be advisable. In this review, we focus on the utility of GLP-1 analogues and GIP agonists in lowering body weight, their pharmaceutical potential, and their safety profile, as already evidenced inanimal and human studies. We also elaborate on other options, such as the use of vitamin E, probiotics, especially next-generation probiotics, and prebiotics in this context. Finally, we explore future perspectives regarding the administration of GLP-1 analogues, GIP agonists, and probiotics/prebiotics as a means to prevent and combat NAFLD. The newest drugs pegozafermin and resmetiron, which seem to be very promising, arealso discussed.

NAFLD/MASLD and the Gut-Liver Axis: From Pathogenesis to Treatment Options.

Nonalcoholic fatty liver disease (NAFLD) poses an emerging threat topublic health. Nonalcoholic steatohepatitis (NASH) is reported to be the most rapidly rising cause of hepatocellular carcinoma in the western world. Recently, a new term has been proposed: metabolic dysfunction-associated steatotic liver disease (MASLD). The introduction of this new terminology has sparked a debate about the interchangeability of these terms. The pathogenesis of NAFLD/MASLD is thought to be multifactorial, involving both genetic and environmental factors. Among these factors, alterations in gut microbiota and gut dysbiosis have recently garnered significant attention. In this context, this review will further discuss the gut-liver axis, which refers to the bidirectional interaction between the human gut microbiota and the liver. Additionally, the therapeutic potential of probiotics, particularly next-generation probiotics and genetically engineered bacteria, will be explored. Moreover, the role of prebiotics, synbiotics, postbiotics, and phages as well as fecal microbiota transplantation will be analyzed. Particularly for lean patients with NAFLD/MASLD, who have limited treatment options, approaches that modify the diversity and composition of the gut microbiota may hold promise. However, due to ongoing safety concerns with approaches that modulate gut microbiota, further large-scale studies are necessary to better assess their efficacy and safety in treating NAFLD/MASLD.

The Pleiotropic Effects of Lipid-Modifying Interventions: Exploring Traditional and Emerging Hypolipidemic Therapies.

Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as a major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, with statins emerging as the cornerstone treatment. These interventions play a crucial role in both primary and secondary prevention by effectively reducing cardiovascular risk through lipid profile enhancements. Beyond their primary lipid-lowering effects, extensive research indicates that these therapies exhibit pleiotropic actions, offering additional health benefits. These include anti-inflammatory properties, improvements in vascular health and glucose metabolism, and potential implications in cancer management. While statins and ezetimibe have been extensively studied, newer lipid-lowering agents also demonstrate similar pleiotropic effects, even in the absence of direct cardiovascular benefits. This narrative review explores the diverse pleiotropic properties of lipid-modifying therapies, emphasizing their non-lipid effects that contribute to reducing cardiovascular burden and exploring emerging benefits for non-cardiovascular conditions. Mechanistic insights into these actions are discussed alongside their potential therapeutic implications.

Alterations of the Adipo-Myokine Irisin in Sepsis and Septic Shock: Diagnostic and Prognostic Implications.

Irisin, a novel adipo-myokine with metabolic regulatory functions, exerts anti-inflammatory, antioxidant, and anti-apoptotic actions that may confer protection against sepsis-induced organ injury in experimental studies. Until now, only one human study has explored circulating irisin at sepsis onset. We aimed to examine serum irisin and its kinetics in critically ill patients with sepsis and septic shock with regard to sepsis severity and outcome. We enrolled 102 critically ill patients with sepsis or septic shock within 48 h of diagnosis and 102 age- and gender-matched healthy controls. Irisin was determined in serum upon enrollment in all participants and one week later in patients using an immunoenzymatic method. The outcome of sepsis was recorded 28 days after enrollment. At enrollment, circulating irisin was significantly lower in patients than controls (22.3 ± 6.8 µg/L vs. 28.1 ± 6.7 µg/L, p < 0.001), and increased significantly one week later (22.3 ± 6.8 µg/L vs. 26.6 ± 9.5 µg/L, p < 0.001). Irisin was significantly lower in patients who presented with septic shock than those with sepsis, and in non-survivors than survivors both at enrollment and one week later. However, kinetics of irisin did not differ between the groups (p > 0.05). Patients with higher circulating irisin during the first week of sepsis had a better outcome (p < 0.001). Lower irisin was independently associated with 28-day mortality (sepsis onset: HR 0.44, 95% C.I. 0.26-0.77, p = 0.004 and one week after: HR 0.37, 95% C.I. 0.23-0.58, p < 0.001). Irisin was negatively correlated with severity scores, metabolic, and inflammatory biomarkers. Circulating irisin decreases early in sepsis and is an independent predictor of 28-day mortality. Irisin may be a promising diagnostic and prognostic sepsis biomarker; nevertheless, larger studies are needed to explore its role in sepsis.