Exercise training decreases lactylation and prevents myocardial ischemia-reperfusion injury by inhibiting YTHDF2.

Exercise improves cardiac function and metabolism. Although long-term exercise leads to circulating and micro-environmental metabolic changes, the effect of exercise on protein post-translational lactylation modifications as well as its functional relevance is unclear. Here, we report that lactate can regulate cardiomyocyte changes by improving protein lactylation levels and elevating intracellular N6-methyladenosine RNA-binding protein YTHDF2. The intrinsic disorder region of YTHDF2 but not the RNA m6A-binding activity is indispensable for its regulatory function in influencing cardiomyocyte cell size changes and oxygen glucose deprivation/re-oxygenation (OGD/R)-stimulated apoptosis via upregulating Ras GTPase-activating protein-binding protein 1 (G3BP1). Downregulation of YTHDF2 is required for exercise-induced physiological cardiac hypertrophy. Moreover, myocardial YTHDF2 inhibition alleviated ischemia/reperfusion-induced acute injury and pathological remodeling. Our results here link lactate and lactylation modifications with RNA m6A reader YTHDF2 and highlight the physiological importance of this innovative post-transcriptional intrinsic regulation mechanism of cardiomyocyte responses to exercise. Decreasing lactylation or inhibiting YTHDF2/G3BP1 might represent a promising therapeutic strategy for cardiac diseases.

Primitive neuroectodermal tumors of the ovary: a multidecade review of the scientific literature.

Primitive neuroectodermal tumor (PNET) is a general term used in scientific literature for a heterogeneous group of small round-cell malignant tumors primarily arising from neural crest cells. These are extremely aggressive neoplasms which usually occur within soft tissue or bone of young adults. Ovarian tumors composed of primitive neuroectodermal elements are extremely rare, with only few case reports in scientific literature. Due to being so exceedingly rare, PNETs are frequently misdiagnosed and there are no standard therapeutic guidelines. Young patients seem to have better prognoses and individualized strategy is recommended. Limited data suggests that various gene deletions as well as amplifications may be crucial factors for tumorigenesis and the aggressive behavior of PNET. In this paper, we performed a brief review of all cases of primary ovarian PNETs published in the scientific literature to date, in regard to their clinical, histopathological, and therapeutic aspects, with the aim to provide a more comprehensive understanding of this exceedingly rare pathology.

Exercise-Induced miR-210 Promotes Cardiomyocyte Proliferation and Survival and Mediates Exercise-Induced Cardiac Protection against Ischemia/Reperfusion Injury.

Exercise can stimulate physiological cardiac growth and provide cardioprotection effect in ischemia/reperfusion (I/R) injury. MiR-210 is regulated in the adaptation process induced by exercise; however, its impact on exercise-induced physiological cardiac growth and its contribution to exercise-driven cardioprotection remain unclear. We investigated the role and mechanism of miR-210 in exercise-induced physiological cardiac growth and explored whether miR-210 contributes to exercise-induced protection in alleviating I/R injury. Here, we first observed that regular swimming exercise can markedly increase miR-210 levels in the heart and blood samples of rats and mice. Circulating miR-210 levels were also elevated after a programmed cardiac rehabilitation in patients that were diagnosed of coronary heart diseases. In 8-week swimming model in wild-type (WT) and miR-210 knockout (KO) rats, we demonstrated that miR-210 was not integral for exercise-induced cardiac hypertrophy but it did influence cardiomyocyte proliferative activity. In neonatal rat cardiomyocytes, miR-210 promoted cell proliferation and suppressed apoptosis while not altering cell size. Additionally, miR-210 promoted cardiomyocyte proliferation and survival in human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and AC16 cell line, indicating its functional roles in human cardiomyocytes. We further identified miR-210 target genes, cyclin-dependent kinase 10 (CDK10) and ephrin-A3 (EFNA3), that regulate cardiomyocyte proliferation and apoptosis. Finally, miR-210 KO and WT rats were subjected to swimming exercise followed by I/R injury. We demonstrated that miR-210 crucially contributed to exercise-driven cardioprotection against I/R injury. In summary, this study elucidates the role of miR-210, an exercise-responsive miRNA, in promoting the proliferative activity of cardiomyocytes during physiological cardiac growth. Furthermore, miR-210 plays an essential role in mediating the protective effects of exercise against cardiac I/R injury. Our findings suggest exercise as a potent nonpharmaceutical intervention for inducing miR-210, which can alleviate I/R injury and promote cardioprotection.

A Catastrophic Biodiversity Loss in the Environment Is Being Replicated on the Skin Microbiome: Is This a Major Contributor to the Chronic Disease Epidemic?

There has been a catastrophic loss of biodiversity in ecosystems across the world. A similar crisis has been observed in the human gut microbiome, which has been linked to "all human diseases affecting westernized countries". This is of great importance because chronic diseases are the leading cause of death worldwide and make up 90% of America's healthcare costs. Disease development is complex and multifactorial, but there is one part of the body's interlinked ecosystem that is often overlooked in discussions about whole-body health, and that is the skin microbiome. This is despite it being a crucial part of the immune, endocrine, and nervous systems and being continuously exposed to environmental stressors. Here we show that a parallel biodiversity loss of 30-84% has occurred on the skin of people in the developed world compared to our ancestors. Research has shown that dysbiosis of the skin microbiome has been linked to many common skin diseases and, more recently, that it could even play an active role in the development of a growing number of whole-body health problems, such as food allergies, asthma, cardiovascular diseases, and Parkinson's, traditionally thought unrelated to the skin. Damaged skin is now known to induce systemic inflammation, which is involved in many chronic diseases. We highlight that biodiversity loss is not only a common finding in dysbiotic ecosystems but also a type of dysbiosis. As a result, we make the case that biodiversity loss in the skin microbiome is a major contributor to the chronic disease epidemic. The link between biodiversity loss and dysbiosis forms the basis of this paper's focus on the subject. The key to understanding why biodiversity loss creates an unhealthy system could be highlighted by complex physics. We introduce entropy to help understand why biodiversity has been linked with ecosystem health and stability. Meanwhile, we also introduce ecosystems as being governed by "non-linear physics" principles-including chaos theory-which suggests that every individual part of any system is intrinsically linked and implies any disruption to a small part of the system (skin) could have a significant and unknown effect on overall system health (whole-body health). Recognizing the link between ecosystem health and human health allows us to understand how crucial it could be to maintain biodiversity across systems everywhere, from the macro-environment we inhabit right down to our body's microbiome. Further, in-depth research is needed so we can aid in the treatment of chronic diseases and potentially change how we think about our health. With millions of people currently suffering, research to help mitigate the crisis is of vital importance.

Exercise and microbiome: From big data to therapy.

Exercise is a vital component in maintaining optimal health and serves as a prospective therapeutic intervention for various diseases. The human microbiome, comprised of trillions of microorganisms, plays a crucial role in overall health. Given the advancements in microbiome research, substantial databases have been created to decipher the functionality and mechanisms of the microbiome in health and disease contexts. This review presents an initial overview of microbiomics development and related databases, followed by an in-depth description of the multi-omics technologies for microbiome. It subsequently synthesizes the research pertaining to exercise-induced modifications of the microbiome and diseases that impact the microbiome. Finally, it highlights the potential therapeutic implications of an exercise-modulated microbiome in intestinal disease, obesity and diabetes, cardiovascular disease, and immune/inflammation-related diseases.

Pancreaticogastrostomy versus Pancreaticojejunostomy and the Proposal of a New Postoperative Pancreatic Fistula Risk Score.

Despite the substantial decrease in mortality rates following a pancreaticoduodenectomy to less than 5%, morbidity rates remain significant, reaching even 73%. Postoperative pancreatic fistula is one of the most frequent major complications and is significantly associated with other complications, including patient death. Currently, there is no consensus regarding the ideal type of pancreatic anastomosis, as the question of the choice between a pancreaticogastrostomy and pancreaticojejunostomy is still open. Furthermore, worldwide implementation of an ideal pancreatic fistula risk prediction score is missing. Our study found several significant predictive factors for the postoperative occurrence of fistulas, such as the soft consistency of the pancreas, non-dilated Wirsung duct, important intraoperative blood loss, other perioperative complications, preoperative patient hypoalbuminemia, and patient weight loss. Our study also revealed that for patients who exhibit fistula risk factors, pancreaticogastrostomy demonstrates a significantly lower pancreatic fistula rate than pancreaticojejunostomy. The occurrence of pancreatic fistulas has been significantly associated with the development of other postoperative major complications, and patient death. As the current pancreatic fistula risk scores proposed by various authors have not been consensually validated, we propose a simple, easy-to-use, and sensitive score for the risk prediction of postoperative pancreatic fistula occurrence based on important predictors from statistical analyses that have also been found to be significant by most of the reported studies. The new pancreatic fistula risk score proposed by us could be extremely useful for improved therapeutic management of cephalic pancreaticoduodenectomy patients.

Unraveling Immunological Dynamics: HPV Infection in Women-Insights from Pregnancy.

During pregnancy, hormonal and immune adaptations are vital for supporting the genetically distinct fetus during elevated infection risks. The global prevalence of HPV necessitates its consideration during pregnancy. Despite a seemingly mild immune response, historical gestational viral infections underscore its significance. Acknowledging the established HPV infection risks during pregnancy, our review explores the unfolding immunological changes in pregnant women with HPV. Our analysis aims to uncover strategies for safely modulating the immune system, mitigating adverse pregnancy consequences, and enhancing maternal and child health. This comprehensive narrative review delves into the existing knowledge and studies on this topic.

Chronic Wound Management: From Gauze to Homologous Cellular Matrix.

BACKGROUND: Chronic wounds are a significant health problem with devastating consequences for patients' physical, social, and mental health, increasing healthcare systems' costs. Their prolonged healing times, economic burden, diminished quality of life, increased infection risk, and impact on patients' mobility and functionality make them a major concern for healthcare professionals. PURPOSE: This review offers a multi-perspective analysis of the medical literature focusing on chronic wound management. METHODS USED: We evaluated 48 articles from the last 21 years registered in the MEDLINE and Global Health databases. The articles included in our study had a minimum of 20 citations, patients > 18 years old, and focused on chronic, complex, and hard-to-heal wounds. Extracted data were summarized into a narrative synthesis using the same health-related quality of life instrument. RESULTS: We evaluated the efficacy of existing wound care therapies from classical methods to modern concepts, and wound care products to regenerative medicine that uses a patient's pluripotent stem cells and growth factors. Regenerative medicine and stem cell therapies, biologic dressings and scaffolds, negative pressure wound therapy (NPWT), electrical stimulation, topical growth factors and cytokines, hyperbaric oxygen therapy (HBOT), advanced wound dressings, artificial intelligence (AI), and digital wound management are all part of the new arsenal of wound healing. CONCLUSION: Periodic medical evaluation and proper use of modern wound care therapies, including the use of plasma-derived products [such as platelet-rich plasma (PRP) and platelet-rich fibrin (PRF)] combined with proper systemic support (adequate protein levels, blood sugar, vitamins involved in tissue regeneration, etc.) are the key to a faster wound healing, and, with the help of AI, can reach the fastest healing rate possible.

Particular aspects of treating rectal cancer: The watch and wait approach.

Background: Rectal cancer is one of the most common malignant pathologies worldwide. Currently, the standard treatment of this pathology consists of radio-chemotherapy followed by low anterior resection with total mesorectal excision or abdominoperineal proctectomy for medium/low rectal cancer. Objectives: In recent years, another treatment strategy has been proposed, stemming from the finding that up to 40% of patients receiving neoadjuvant treatment had a complete pathological response. This method, also referred to as the watch and wait approach, implies delaying surgery and following a rigorous protocol for patients who have developed a complete response to neoadjuvant treatment with a good oncologic outcome. The objective of this study was to highlight the merits of this approach in selected patients. Case Reports: In this study, we present two patients with low-rectal tumors who developed complete response post neoadjuvant therapy and for whom the watch and wait protocol has been applied over the past 4 years. Conclusion: Although the watch and wait protocol appears to be a feasible option in the management of patients with a complete clinical and pathological response post neoadjuvant therapy, more prospective studies and randomized trials comparing this approach with standard surgical treatment are required before establishing it as the standard of care for distal rectal cancer. Therefore, establishing universal criteria for the selection and assessment of the patients with a complete clinical response following neoadjuvant treatment is required.

Study of the Thyroid Profile of Patients with Alopecia.

Thyroid hormones are required for the physiological growth and maintenance of hair follicles. We aim to study the thyroid profile of patients with alopecia. This is a narrative review. PubMed literature was searched from 2013 to 2022. We followed different types of alopecia: alopecia areata (AA), androgenic alopecia in males and females, telogen effluvium (TE), frontal fibrosing alopecia (FFA), lichen planopilaris, and alopecia neoplastica (AN). AA shares a common autoimmune background with autoimmune thyroid diseases, either sporadic or belonging to autoimmune polyglandular syndromes. Some data suggested that AA is more severe if thyroid anomalies are confirmed, including subclinical dysfunction or positive antithyroid antibodies with normal hormone values. However, routine thyroid screening for patients with AA, if the patients are asymptomatic from a thyroid point of view and they have negative personal and family history of autoimmunity, remains controversial. TE, apart from the autoimmune type, associates thyroid anomalies of a hormonal assay (between 5.7% and 17%). FFA, mostly a postmenopausal entity (however, not exclusive), associates a higher prevalence of thyroid conditions (up to 50%) than the general population. However, these might have an age-dependent pattern, thus the association may be incidental since there are a limited number of studies. Overall, alopecia remains a very challenging condition for patients and physicians; a multidisciplinary team is required to improve the outcome and quality of life. The common autoimmune background is suggestive of some types of alopecia and thyroid disorders, yet, the underlying mechanisms are still a matter of debate. AA, TE, FFA, LPP, and, potentially, female pattern hair loss have been found to be connected with thyroid entities, thus a state of awareness from a dual perspective, of trichology and endocrinology, is helpful.

The Interplay Between Gut Microbiota and miRNAs in Cardiovascular Diseases.

The human microbiota contains microorganisms found on the skin, mucosal surfaces and in other tissues. The major component, the gut microbiota, can be influenced by diet, genetics, and environmental factors. Any change in its composition results in pathophysiological changes that can further influence the evolution of different conditions, including cardiovascular diseases (CVDs). The microbiome is a complex ecosystem and can be considered the metagenome of the microbiota. MicroRNAs (miRNAs) are speculated to interact with the intestinal microbiota for modulating gene expressions of the host. miRNAs represent a category of small non-coding RNAs, consisting of approximately 22 nucleotides, which can regulate gene expression at post-transcriptional level, by influencing the degradation of mRNA and modifying protein amounts. miRNAs display a multitude of roles, being able to influence the pathogenesis and progression of various diseases. Circulating miRNAs are stable against degradation, due to their enclosure into extracellular vesicles (EVs). This review aims to assess the current knowledge of the possible interactions between gut microbiota, miRNAs, and CVDs. As more scientific research is conducted, it can be speculated that personalized patient care in the future may include the management of gut microbiota composition and the targeted treatment against certain expression of miRNAs.

Maternal HPV Infection: Effects on Pregnancy Outcome.

The human papilloma virus (HPV) infection, caused by a ubiquitous virus typically transmitted through the direct contact of infected organs, either through the skin or mucosa, is the most common sexually transmitted infection, placing young women at a high risk of contracting it. Although the vast majority of cases spontaneously clear within 1-2 years, persistent HPV infection remains a serious concern, as it has repeatedly been linked to the development of multiple malignancies, including cervical, anogenital, and oropharyngeal cancers. Additionally, more recent data suggest a harmful effect of HPV infection on pregnancy. As the maternal hormonal environment and immune system undergo significant changes during pregnancy, the persistence of HPV is arguably favored. Various studies have reported an increased risk of adverse pregnancy outcomes among HPV-positive women, with the clinical impact encompassing a range of conditions, including preterm birth, miscarriage, pregnancy-induced hypertensive disorders (PIHD), intrauterine growth restriction (IUGR), low birth weight, the premature rupture of membranes (PROM), and fetal death. Therefore, understanding the mechanisms employed by HPV that negatively impact pregnancy and assessing potential approaches to counteract them would be of interest in the quest to optimize pregnancy outcomes and improve child survival and health.

Fatal Association of Mirror and Eisenmenger Syndrome during the COVID-19 Pandemic.

Mirror syndrome (MS) or Ballantyne's syndrome is a rare maternal condition that can be life-threatening for both mother and fetus. The condition is characterized by maternal signs and symptoms similar to those seen in preeclampsia in the setting of fetal hydrops. Despite recent advances in the field of maternal-fetal medicine, the etiopathogenesis of MS remains elusive. For patients and doctors, the COVID-19 pandemic has become an extra hurdle to overcome. The following case illustrates how patients' non-compliance associated with mirror syndrome and SARS-CoV-2 infection led to the tragic end of a 19-year-old patient. Therefore, knowledge of the signs and symptoms of mirror syndrome should always be part of the armamentarium of every obstetrician.

Determination of whether HIPEC is beneficial in patients with synchronous peritoneal and liver metastases from colorectal cancer (Review).

Peritoneal carcinomatosis, as well as the presence of liver metastases from colorectal cancer, has been long considered as the sign of a systemic disease, transforming the patient into a candidate for palliation and best supportive care. However, in recent decades, progress in the field of medical and surgical oncology has allowed scientists worldwide to produce curative therapeutic strategies for these cases such as hyperthermic intraperitoneal chemotherapy (HIPEC) or extended liver resection. In addition, the association of these two therapies has also been performed with encouraging results. The aim of the current study was to review articles published thus far in regard to the association of these two therapeutic strategies, in order to identify which cases can benefit the most, which is the most efficient agent or combination of agents, and whether these types of therapy should be performed as monotherapy or as a two-stage procedure.

Gut Microbiome, Functional Food, Atherosclerosis, and Vascular Calcifications-Is There a Missing Link?

The gut microbiome is represented by the genome of all microorganisms (symbiotic, potential pathogens, or pathogens) residing in the intestine. These ecological communities are involved in almost all metabolic diseases and cardiovascular diseases are not excluded. Atherosclerosis, with a continuously increasing incidence in recent years, is the leading cause of coronary heart disease and stroke by plaque rupture and intraplaque hemorrhage. Vascular calcification, a process very much alike with osteogenesis, is considered to be a marker of advanced atherosclerosis. New evidence, suggesting the role of dietary intake influence on the diversity of the gut microbiome in the development of vascular calcifications, is highly debated. Gut microbiota can metabolize choline, phosphatidylcholine, and L-carnitine and produce vasculotoxic metabolites, such as trimethylamine-N-oxide (TMAO), a proatherogenic metabolite. This review article aims to discuss the latest research about how probiotics and the correction of diet is impacting the gut microbiota and its metabolites in the atherosclerotic process and vascular calcification. Further studies could create the premises for interventions in the microbiome as future primary tools in the prevention of atherosclerotic plaque and vascular calcifications.

Monaldi cavernostomy for lung aspergillosis: A case report.

Pulmonary aspergillosis in patients with respiratory failure can severely affect the pulmonary functional status and may aggravate it through pulmonary suppuration, by recruitment of new parenchyma and hemoptysis, which can sometimes be massive, with lethal risk by flooding the bronchus. The treatment consists of a combination of medical therapy, surgery and interventional radiology. In small lesions, less than 2-3 cm, medical therapy methods may be sufficient; however, in invasive forms (larger than 3 cm) surgical resection is necessary. Surgical resection is the ideal treatment; nevertheless, when lung function does not allow it, action must be taken to eliminate the favorable conditions of the infection. In such cases, whenever the lung cavity is peripheral, a cavernostomy may be performed. Four cases of lung cavernous lesions colonized with aspergillus, in which the need for a therapeutic gesture was imposed by repeated small to medium hemoptysis and by the progression of respiratory failure, were evaluated, one of which is presented in the current study. Cavernostomy closure can be realized either surgically with muscle flap or spontaneously by scarring, after closure of the bronchial fistulas by epithelization and granulation. There were no recurrences of hemoptysis or suppurative phenomena. There was one death, a patient with severe respiratory failure caused by superinfection with nonspecific germs. However, in the case presented in this study, the patient recovered following cavernostomy, which seems to be an effective and safe method for cases in which lung resection is not feasible.

Hyperthyroidism in Pregnancy: The Delicate Balance between Too Much or Too Little Antithyroid Drug.

Overt hyperthyroidism (HT) during pregnancy is associated with a risk of maternal-fetal complications. Antithyroid drugs (ATD) have a potential risk for teratogenic effects and fetal-neonatal hypothyroidism. This study evaluated ATD treatment and thyroid function control during pregnancy, and pregnancy outcome in women with HT. PATIENTS AND METHODS: A retrospective analysis of 36 single fetus pregnancies in 29 consecutive women (median age 30.3 ± 4.7 years) with HT diagnosed before or during pregnancy; a control group of 39 healthy euthyroid pregnant women was used. RESULTS: Twenty-six women had Graves' disease (GD, 33 pregnancies), 1 had a hyperfunctioning autonomous nodule, and 2 had gestational transient thyrotoxicosis (GTT). Methimazole (MMI) was administered in 22 pregnancies (78.5%), Propylthiouracil (PTU) in 2 (7.1%), switch from MMI to PTU in 4 (14.2%), no treatment in 8 pregnancies (3 with subclinical HT, 5 euthyroid with previous GD remission before conception). In the 8 pregnancies of GD patients diagnosed during gestation or shortly before (<6 weeks), i.e., with fetal exposure to uncontrolled HT, there was 1 spontaneous abortion at 5 weeks (3.4% of all ATD-treated pregnancies), and 1 premature delivery at 32 weeks with neonatal death in 24 h (3.4%); 1 child had neonatal hyperthyroidism (3.3% of live children in GD women) and a small atrial sept defect (4% of live children in ATD treated women). In women treated more than 6 months until conception (20 pregnancies): (a) median ATD doses were lower than those in women diagnosed shortly before or during pregnancy; (b) ATD was withdrawn in 40% of pregnancies in trimester (T)1, all on MMI < 10 mg/day (relapse in 14.2%), and in up to 55% in T3; (c) TSH level was below normal in 37%, 35% and 22% of pregnancies in T1, T2 and T3 respectively; FT4 was increased in 5.8% (T1) and subnormal in 11.75% in T2 and T3; (d) no fetal birth defects were recorded; one fetal death due to a true umbilical cord knot was registered. Mean birth weight was similar in both ATD-treated and control groups. Hyperthyroidism relapsed postpartum in 83% of GD patients (at median 3 ± 2.6 months). CONCLUSION: In hyperthyroid women with long-term ATD treatment before conception, drugs could be withdrawn in T1 in 40% of them, the thyroid function control was better, and pregnancy and fetal complications were rarer, compared to women diagnosed during pregnancy. Frequent serum TSH and FT4 monitoring is needed to maintain optimal thyroid function during pregnancy.

Ovarian Cancer: Biomarkers and Targeted Therapy.

Ovarian cancer is one of the most common causes of death in women as survival is highly dependent on the stage of the disease. Ovarian cancer is typically diagnosed in the late stage due to the fact that in the early phases is mostly asymptomatic. Genomic instability is one of the hallmarks of ovarian cancer. While ovarian cancer is stratified into different clinical subtypes, there still exists extensive genetic and progressive diversity within each subtype. Early detection of the disorder is one of the most important steps that facilitate a favorable prognosis and a good response to medical therapy for the patients. In targeted therapies, individual patients are treated by agents targeting the changes in tumor cells that help them grow, divide and spread. Currently, in gynecological malignancies, potential therapeutic targets include tumor-intrinsic signaling pathways, angiogenesis, homologous-recombination deficiency, hormone receptors, and immunologic factors. Ovarian cancer is usually diagnosed in the final stages, partially due to the absence of an effective screening strategy, although, over the times, numerous biomarkers have been studied and used to assess the status, progression, and efficacy of the drug therapy in this type of disorder.

Erratum: Crucial Role of miR-433 in Regulating Cardiac Fibrosis: Erratum.

[This corrects the article DOI: 10.7150/thno.15007.].