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The Phosphatidylinositol-3-kinase (PI3K) family is well-known to comprise three classes of intracellular enzymes. Class I PI3Ks primarily function in signaling by responding to cell surface receptor stimulation, while class II and III are more involved in membrane transport. Under normal physiological conditions, the PI3K signaling network orchestrates cell growth, division, migration and survival. Aberrant activation of the PI3K signaling pathway disrupts cellular activity and metabolism, often marking the onset of cancer. Currently, the Food and Drug Administration (FDA) has approved the clinical use of five class I PI3K inhibitors. These small-molecule inhibitors, which exhibit varying selectivity for different class I PI3K family members, are primarily used in the treatment of breast cancer and hematologic malignancies. Therefore, the development of novel class I PI3K inhibitors has been a prominent research focus in the field of oncology, aiming to enhance potential therapeutic selectivity and effectiveness. In this review, we summarize the specific structures of PI3Ks and their functional roles in cancer progression. Additionally, we critically evaluate small molecule inhibitors that target class I PI3K, with a particular focus on their clinical applications in cancer treatment. Moreover, we aim to analyze therapeutic approaches for different types of cancers marked by aberrant PI3K activation and to identify potential molecular targets amenable to intervention with small-molecule inhibitors. Ultimately, we propose future directions for the development of therapeutic strategies that optimize cancer treatment outcomes by modulating the PI3K family. [ABSTRACT FROM AUTHOR]

Stroke is a leading cause of mortality and long-term disability globally, with acute ischemic stroke (AIS) being the most common subtype. Despite significant advances in reperfusion therapies, their limited time window and associated risks underscore the necessity for novel treatment strategies. Stem cell-derived extracellular vesicles (EVs) have emerged as a promising therapeutic approach due to their ability to modulate the post-stroke microenvironment and facilitate neuroprotection and neurorestoration. This review synthesizes current research on the therapeutic potential of stem cell-derived EVs in AIS, focusing on their origin, biogenesis, mechanisms of action, and strategies for enhancing their targeting capacity and therapeutic efficacy. Additionally, we explore innovative combination therapies and discuss both the challenges and prospects of EV-based treatments. Our findings reveal that stem cell-derived EVs exhibit diverse therapeutic effects in AIS, such as promoting neuronal survival, diminishing neuroinflammation, protecting the blood-brain barrier, and enhancing angiogenesis and neurogenesis. Various strategies, including targeting modifications and cargo modifications, have been developed to improve the efficacy of EVs. Combining EVs with other treatments, such as reperfusion therapy, stem cell transplantation, nanomedicine, and gut microbiome modulation, holds great promise for improving stroke outcomes. However, challenges such as the heterogeneity of EVs and the need for standardized protocols for EV production and quality control remain to be addressed. Stem cell-derived EVs represent a novel therapeutic avenue for AIS, offering the potential to address the limitations of current treatments. Further research is needed to optimize EV-based therapies and translate their benefits to clinical practice, with an emphasis on ensuring safety, overcoming regulatory hurdles, and enhancing the specificity and efficacy of EV delivery to target tissues. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to highlight the feasibility of an olfactory training program entirely monitored through online media in COVID-19 patients. Methods: Classic olfactory training was performed with a sample with olfactory loss due COVID-19 (n = 11). Participants were engaged on a weekly video call in order to improve adherence and collect information regarding the number of correct answers and the individuals' perception of olfactory function. The olfactory status after training was compared to two groups, one composed of participants who contracted COVID-19 but did not report olfactory loss (n = 11) and a sample composed of healthy participants (n = 11). Results: The experimental group showed improvements throughout the training period (TDI score on week 0 was 20.3 (5.6) and 24.6 (4.3) for week 12, and on week 24 was 25.4 (6.2) (F = 5.115, df = 2, 20, p = 0.016), and post hoc tests showed that participants significantly improved their TDI score in W12 compared to W0 (SMD = 0.869, p = 0.041) and in W24 compared to W0 (SMD = 0.859, p = 0.041). The experimental group showed lower scores when compared with both groups, and the no OT COVID-19 group showed lower scores than the healthy control group, even though they did not report olfactory alterations. Conclusions: Findings suggest that the strategies applied to improve adherence were successful since 100% of the sample completed the training adherence, offering a valuable framework for future olfactory training studies. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of this study was to evaluate the usefulness and relevance of projective techniques such as house‐tree‐person (HTP) and family in individuals with Prader‐Willi syndrome (PWS), who have a limited ability to identify and verbalize emotions and express them often using behaviors. Methods: We included individuals with genetic confirmation of PWS immersed in a regular transdisciplinary treatment in an institution dedicated to rare diseases. All individuals were evaluated using the HTP and family projective techniques. These instruments are commonly administered to the general population and, in this case, to people with mild to moderate intellectual disabilities, including difficulties in their communication abilities. Results: A total of 25 individuals with PWS between 10 and 41 years old (15 men and 10 women) were included. We identified the presence of graphic indicators corresponding to the behavioral phenotype of individuals with PWS, such as anxiety, stubbornness, emotional lability, difficulty in achieving adequate externalization and identification of emotions, impulsivity, aggressive traits, poor social skills, need for support and interaction, low self‐concept, and compulsive behaviors. Conclusions: In the present study, we demonstrated the usefulness of graphic techniques to elucidate aspects of behavior, emotions, and thoughts that individuals with PWS cannot formulate due to expression and communication difficulties. [ABSTRACT FROM AUTHOR]

NREM parasomnias, also known as non-rapid eye movement sleep parasomnias, are a group of sleep disorders that occur during the deeper stages of NREM sleep. These parasomnias can lead to a range of behaviors, including sleepwalking, sleep talking, and night terrors. NREM parasomnias usually occur during the first third of the night and can last from a few seconds to 30 minutes or more. The person may appear to be awake and alert, but is actually in a state of deep sleep. People with NREM parasomnias may also engage in activities that are dangerous, such as leaving the house or driving a car. The causes are not well-understood, but it is believed that NREM parasomnias are related to disturbances in the normal sleep cycle. They can be caused by stress, sleep deprivation, or the use of certain medications or substances. Their treatment may include a combination of behavioral therapy and medication. Behavioral therapy can help the person to understand better their sleep patterns and develop strategies to reduce the occurrence of parasomnias. Medication can help regulate sleep cycles or manage any underlying medical conditions. A sleep specialist can help diagnose and treat NREM parasomnias and provide guidance on how to manage these disorders effectively. In conclusion, NREM parasomnias are a group of sleep disorders that can lead to a range of behaviors during deep NREM sleep. These disorders can disrupt daily life and can be dangerous if left untreated. Treatment for NREM parasomnias may include a combination of behavioral therapy and medication, and it is important to seek medical help if these disorders are suspected. [ABSTRACT FROM AUTHOR]

Purpose: Study the efficacy of olfactory training in smell recovery. Methods: An extensive search was performed through different databases in order to find articles analyzing the efficacy of olfactory training as a treatment for olfactory dysfunction. Methodological quality of primary studies within the final sample was assessed following PRISMA guidelines. Standardized mean differences in pre–post olfactory training groups, and also in experimental-control and pre-follow up if possible, were computed by Hedges' g effect size statistic. Each effect size was weighted by its inverse variance. Results: Final sample was composed of 36 articles (45 pre–post effect sizes). Contrasts were performed separately for odor identification, odor discrimination, odor threshold and general olfactory function. Moderate to large and heterogeneous effect was obtained for olfactory function (g = 0.755, k = 45, SE = 0.093, CI 95% = [0.572, 0.937]), different moderators had a significant effects, such as, training duration, age and anosmia diagnosis. Conclusion: Olfactory training was found to have a positive and significant effect on rehabilitating the olfactory function. [ABSTRACT FROM AUTHOR]

• Computer simulations and the Lipinski rule evaluate the pharmacokinetic and toxicological aspects of methyl eugenol as a drug candidate. • Treatment with methyl eugenol (ME) during and after the initiation of acute respiratory distress syndrome (ARDS) can prevent the progression of acute inflammation. • In vivo and in silico tests indicate that ME oil is an orally bioavailable drug that exerts multifunctional cytoprotective activities. • ME oil can treat and prevent intestinal I/R-induced ARDS in rats. Acute respiratory distress syndrome (ARDS) is an inflammatory disease that affects the lungs with rupture of the alveolar-capillary barrier and loss of lung compliance, orchestrated by an intense inflammatory process mediated by neutrophils that culminates in diffuse alveolar data and tissue hypoxia. In this context, no specific drug has yet been applied to treat the syndrome. Therefore, finding new therapeutic targets that can treat the syndrome has become a research study. In view of this, methyl-eugenol (ME) has become the target of this study. The aim of this work was to carry out an in silico pharmacological and toxicological analysis with ADMET, as well as to determine, by means of molecular docking, the interaction affinity of the 5-LOX and COX-2 enzymes with ME and then the in vivo tests; in which male rats were distributed into five groups with five rats each, in which some groups were subjected to the process of ischemia and reperfusion (I/R). Groups G4 and G5 were treated by inhalation with ME (10 %). After completing these procedures, statistical analysis and lung histology were carried out. In the ADMET prediction, ME showed high intestinal absorption and a medium-permeability blood-brain barrier. ME had no violations of Lipinski's rule, demonstrating high potential as a drug candidate. Molecular docking showed that ME had the highest binding affinity with the 5-LOX enzyme. Finally, the statistical and histological analyses of the in vivo test showed acute and accentuated lung damage in the G1 group, while in the G4 and G5 groups, ME showed pharmacological efficacy, reducing the number of inflammatory cells, free macrophages and free radicals. The results indicate that ME oil is a favorable therapeutic approach in the treatment of ARDS. [ABSTRACT FROM AUTHOR]

• Tenascin-C is highly expressed in cancer generating immune suppressive niches. • Tenascin-C is used as tumor biomarker and as zip code for delivery of therapeutic agents. • Tenascin-C is targeted by a huge arsenal of versatile molecular tools. • Numerous clinical trials are supporting tenascin-C targeting as clinical option. • Targeting tenascin-C immune suppression offer novel targeting opportunities. Tenascin-C (TNC) is a matricellular and multimodular glycoprotein highly expressed under pathological conditions, especially in cancer and chronic inflammatory diseases. Since a long time TNC is considered as a promising target for diagnostic and therapeutic approaches in anti-cancer treatments and was already extensively targeted in clinical trials on cancer patients. This review provides an overview of the current most advanced strategies used for TNC detection and anti-TNC theranostic approaches including some advanced clinical strategies. We also discuss novel treatment protocols, where targeting immune modulating functions of TNC could be center stage. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis, a process characterized by excessive extracellular matrix (ECM) deposition, is a common pathological consequence of many cardiovascular diseases (CVDs) normally resulting in organ failure and death. Cardiac fibroblasts (CFs) play an essential role in deleterious cardiac remodeling and dysfunction. In response to injury, quiescent CFs become activated and adopt a collagen-secreting phenotype highly contributing to cardiac fibrosis. In recent years, studies have been focused on the exploration of molecular and cellular mechanisms implicated in the activation process of CFs, which allow the development of novel therapeutic approaches for the treatment of cardiac fibrosis. Transcriptomic analyses using single-cell RNA sequencing (RNA-seq) have helped to elucidate the high cellular diversity and complex intercellular communication networks that CFs establish in the mammalian heart. Furthermore, a significant body of work supports the critical role of epigenetic regulation on the expression of genes involved in the pathogenesis of cardiac fibrosis. The study of epigenetic mechanisms, including DNA methylation, histone modification, and chromatin remodeling, has provided more insights into CF activation and fibrotic processes. Targeting epigenetic regulators, especially DNA methyltransferases (DNMT), histone acetylases (HAT), or histone deacetylases (HDAC), has emerged as a promising approach for the development of novel anti-fibrotic therapies. This review focuses on recent transcriptomic advances regarding CF diversity and molecular and epigenetic mechanisms that modulate the activation process of CFs and their possible clinical applications for the treatment of cardiac fibrosis. [ABSTRACT FROM AUTHOR]

REM parasomnias, or rapid eye movement sleep parasomnias, are a group of sleep disorders that occur during the REM stage of sleep. These parasomnias can lead to a range of behaviors including vivid and intense dreams, nightmares, sleep paralysis and REM behavior disorder (RBD). RBD is a particularly dangerous form of REM parasomnias, in which the person physically acts out their dreams during REM sleep. This can lead to injuries to themselves or a sleeping partner. REM parasomnias can be caused by a variety of factors, including medications, substance use, and underlying medical conditions. They may also be associated with sleep deprivation and high stress levels. Their treatment may include a combination of behavioral therapy and medication. Behavioral therapy can help the person develop strategies to reduce the occurrence of parasomnias. Medication can help regulate sleep cycles or manage any underlying medical conditions. These disorders can disrupt daily life and can be dangerous if left untreated. In conclusion, REM parasomnias are a group of sleep disorders that can lead to a range of behaviors during REM sleep, including vivid and intense dreams, nightmares, sleep paralysis, and RBD. RBD is a dangerous form of REM parasomnias. Treatment for REM parasomnias may involve a combination of behavioral therapy and medication, and it is important to seek medical help if these disorders are suspected. [ABSTRACT FROM AUTHOR]

Glaucoma is a neurodegenerative disease that causes blindness. In this study, we aimed to evaluate the protective role of cilastatin (CIL), generally used in the treatment of nephropathologies associated with inflammation, in an experimental mouse model based on unilateral (left) laser-induced ocular hypertension (OHT). Male Swiss mice were administered CIL daily (300 mg/kg, i.p.) two days before OHT surgery until sacrifice 3 or 7 days later. Intraocular Pressure (IOP), as well as retinal ganglion cell (RGC) survival, was registered, and the inflammatory responses of macroglial and microglial cells were studied via immunohistochemical techniques. Results from OHT eyes were compared to normotensive contralateral (CONTRA) and naïve control eyes considering nine retinal areas and all retinal layers. OHT successfully increased IOP values in OHT eyes but not in CONTRA eyes; CIL did not affect IOP values. Surgery induced a higher loss of RGCs in OHT eyes than in CONTRA eyes, while CIL attenuated this loss. Similarly, surgery increased macroglial and microglial activation in OHT eyes and to a lesser extent in CONTRA eyes; CIL prevented both macroglial and microglial activation in OHT and CONTRA eyes. Therefore, CIL arises as a potential effective strategy to reduce OHT-associated damage in the retina of experimental mice. [ABSTRACT FROM AUTHOR]

Obesity or excessive weight gain is identified as the most important and significant risk factor in the development and progression of type 2 diabetes mellitus (DM) in all age groups. It has reached pandemic dimensions, making the treatment of obesity crucial in the prevention and management of type 2 DM worldwide. Multiple clinical studies have demonstrated that moderate and sustained weight loss can improve blood glucose levels, insulin action and reduce the need for diabetic medications. A combined approach of diet, exercise and lifestyle modifications can successfully reduce obesity and subsequently ameliorate the ill effects and deadly complications of DM. This approach also helps largely in the prevention, control and remission of DM. Obesity and DM are chronic diseases that are increasing globally, requiring new approaches to manage and prevent diabetes in obese individuals. Therefore, it is essential to understand the mechanistic link between the two and design a comprehensive approach to increase life expectancy and improve the quality of life in patients with type 2 DM and obesity. This literature review provides explicit information on the clinical definitions of obesity and type 2 DM, the incidence and prevalence of type 2 DM in obese individuals, the indispensable role of obesity in the pathophysiology of type 2 DM and their mechanistic link. It also discusses clinical studies and outlines the recent management approaches for the treatment of these associated conditions. Additionally, in vivo studies on obesity and type 2 DM are discussed here as they pave the way for more rigorous development of therapeutic approaches. [ABSTRACT FROM AUTHOR]

Immature sacrococcygeal teratoma represents a histological form with rapid tumor growth, a risk of premature birth, an enhanced rate of complications, an increased risk of recurrence, and a higher mortality rate than the mature type. Thus, prenatal diagnosis of immature forms would significantly improve the prognosis of these cases. To this end, we performed an extensive literature review on the diagnosis, therapeutic management, and follow-up of immature teratomas. Regarding this medical conduct, we also presented our case. In conclusion, the early identification of immature sacrococcygeal teratomas with or without other associated structural abnormalities and their correct therapeutic approach are basic principles for a favorable evolution of these cases. [ABSTRACT FROM AUTHOR]

Urinary retention due to the impossibility of evacuation of bladder contents and the secondary pathophysiologic processes, which it entails, as well as by inducing mental discomfort or a perpetual state of restlessness, represents a medical emergency in pets. The etiology of urinary retention is represented by: mechanical urinary retention, retention caused by obstruction or occlusion, urethral but also extraurethral; paralytic urinary retention, which occurs secondary to spinal cord lesions, or in geriatric patients due to proliferative processes or degeneration of the spinal column. Retention of spastic origin is characterized by the occurrence of sphincter spasm which is frequently produced by sympathetic irritation resulting in increased tonicity of the bladder sphincter, consequence of pelvic plexus irritation or the presence of diseases such as colic or peritonitis. A good therapeutic management influences both the evolution and the well-being of the patient, therefore an early identification of the specific clinical signs of urinary retention is essential in all types of urinary retention. [ABSTRACT FROM AUTHOR]

Deubiquitylating enzymes (DUBs) maintain relative homeostasis of the cellular ubiquitome by removing the post‐translational modification ubiquitin moiety from substrates. Numerous DUBs have been demonstrated specificity for cleaving a certain type of ubiquitin linkage or positions within ubiquitin chains. Moreover, several DUBs perform functions through specific protein–protein interactions in a catalytically independent manner, which further expands the versatility and complexity of DUBs' functions. Dysregulation of DUBs disrupts the dynamic equilibrium of ubiquitome and causes various diseases, especially cancer and immune disorders. This review summarizes the Janus‐faced roles of DUBs in cancer including proteasomal degradation, DNA repair, apoptosis, and tumor metastasis, as well as in immunity involving innate immune receptor signaling and inflammatory and autoimmune disorders. The prospects and challenges for the clinical development of DUB inhibitors are further discussed. The review provides a comprehensive understanding of the multi‐faced roles of DUBs in cancer and immunity. [ABSTRACT FROM AUTHOR]

• The ethanolic extract was prepared from the leaves of P. insignis. • GC-MS analysis performed on the ethanolic extract of P. insignis leaves revealed the presence of 60 phytocompounds. • HPLC analysis identified the flavonoid catechin which justifies the anti-inflammatory effect of P. insignis in the treatment of acute respiratory distress syndrome. Platonia insignis Mart., popularly known as bacuri, is a plant in which all its parts are indicated for use in folk medicine. The decoction of the seeds, for example, is used to treat diarrhea, while the oil from the seeds is used to treat skin diseases, otitis, rheumatism, arthritis, and cicatrization. The objective of this work was to perform a phytochemical analysis of the ethanolic extract of P. insignis leaves and to evaluate the pharmacological action of the extract on acute respiratory distress syndrome (ARDS) by intestinal ischemia and reperfusion in rats. For the induction of ARDS, male rats were distributed into seven groups. The negative control group was submitted to ischemia and reperfusion but was not treated. The test groups were treated by inhalation with ethanolic extract of freeze-dried P. insignis leaves (500 mg/kg) and associations. Lung structural and inflammatory changes were evaluated by histological examination. The preliminary phytochemical screening found that the leaf extract contained alkaloids, saponins, and triterpenes. The GCMS– analysis verified that the extract presented 60 compounds, in which phytol (10.54%), gamma-sitosterol (9.88%), and hexadecanoic acid (9.84%) were the major compounds identified. Analysis by CLAE revealed the secondary metabolite catechin in the extract. Finally, the extract was able to stagnate the marked dilation of terminal and respiratory bronchioles and alveoli. The results suggest that the ethanolic extract of P. insignis leaves is a promising therapeutic option to treat ARDS. [ABSTRACT FROM AUTHOR]

Background: Viral warts, induced by infection by different HPV genotypes, are highly frequent in the general population, particularly during infancy and among adolescents. The effectiveness of the 595 nm Pulse dye‐laser in treating viral warts on the hands and feet in both adults and children was investigated in this study. Materials and Methods: A selection of 203 patients with multiple viral warts was made. All patients underwent 4–5 treatment sessions with a 595 nm pulse Dye Laser (PDL). Treatment outcome was assessed by a quartile scale: 1 indicates no or low results (0%–25% of the lesion area cleared), 2 indicates slight clearance (25%–50% of the lesion area cleared), 3 indicates moderate‐good clearance (50%–75%), and 4 indicates excellent clearance (75%–100%). Patients were asked for a subjective evaluation of the perceived overall results by means of the following score: unsatisfied (1), not very satisfied (2), satisfied (3), and very satisfied (4). Possible side effects were monitored. Results obtained were judged with a photographic evaluation, immediately and at the control visit (6 months after the last laser session). Results: All patients observed global improvements. Most of the lesions were completely removed after laser therapy. A total of 95% of patients achieved excellent clearance and they were very satisfied following the laser treatment. Relevant side effects were absent in all patients. Conclusion: PDL treatment with the study device using a wavelength of 595 nm has proven to be a tolerable and safe therapy for viral warts management. [ABSTRACT FROM AUTHOR]

Objective: This research was carried out to reduce the fear, anxiety and pain of 4–6 age circumcised children with therapeutic play and video animation interventions. Methods: This research was conducted as a randomized controlled study between November 2019 and April 2021. Using block randomization, 30 (n = 30) children were assigned to the control group, 30 (n = 30) to the therapeutic puppet group and 30 (n = 30) to the video animation group. Before the circumcision surgery, therapeutic puppet and video animation interventions were applied to children with scenario prepared with psychodrama technique. Fear, anxiety, and pain findings of children before and after surgery were determined. Results: The fear and anxiety scores of the children were similar before the nursing intervention in all groups, and that the fear and anxiety scores of therapeutic puppet play and video animation intervention groups had statistically lower than the control group after nursing intervention. The pain scores of the children from the therapeutic puppet play and video animation groups had lower pain scores than the control group after surgery (F = 5.24, p = 0.007). Conclusions: Therapeutic play and video animation intervention can be effective in reducing fear and anxiety of children aged 4–6 before and after circumcision surgery. [ABSTRACT FROM AUTHOR]

1) Background: Temporomandibular joint (TMJ) is responsible for vital functions like mastication, swallowing, and suction reflex and other relational functions, like talking and phonation. The etiology of temporomandibular joint disorders is multifactorial and involves subjective and objective clinical symptomatology. (2) Methods: The therapy is complex and encompasses a series of methods that interconnects various medical specialties. Bad habits and parafunction are risk factors that may initiate and exacerbate a temporomandibular joint pathology. This prospective study aimed to show the positive impact of correct multidisciplinary therapy on the complex of TMJ disorders - pain and bad oral behaviors. The therapy methods used in this study were: medical, prosthetic, orthodontic, surgical, and physiotherapy (PKT). (3) Results: The data obtained showed good results if the oral habits and TMJ disorders are treated correctly and simultaneously. (4) Conclusions: All therapeutical approaches addressed in this study had beneficial effects on the recovery of the temporomandibular joint. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are lipid bilayer nanovesicles generated by almost all living cells which possess various size ranges depending on producer cells and biogenesis mechanisms. Several EV markers were determined including tetraspanins (e.g., CD9, CD63 and CD81), heat shock proteins (HSP70 and HSP90), some 14–3–3 proteins (a family of conserved regulatory molecules), major histocompatibility complex molecules (MHC-I/-II), and enzymes (Glyceraldehyde 3-phosphate dehydrogenase and enolase-1). EVs are known as an abundant source of antigens and immune molecules that can be used for vaccine development in human and animals. EV-based immunization could significantly activate immune responses in different infections such as Porcine reproductive and respiratory syndrome virus (PRRSV), Lymphocytic choriomeningitis virus (LCMV), Marek's disease virus (MDV), and SARS-CoV-2 infections. The engineered and modified EVs showed a promising potential in development of anti-tumor vaccines and therapeutics, protection against parasitic diseases (e.g., Eimeria, and Plasmodium yoelii) and viral diseases (e.g., COVID-19), and improvement of biomarkers. Also, EVs possess a crucial role in antigen presentation in vivo. In this review, we describe the roles of EVs in vaccine development and therapeutic approaches for viral diseases. [Display omitted] • Extracellular vesicles (EVs) provide abundant source of antigens and immune molecules for vaccine development. • Encapsulating cargo into EVs is performed through cell- and non-cell-based loading methods. • EVs harboring biomolecules contribute to cellular communication and tissue repair. • Antiviral drug-loaded exosomes combat respiratory viruses through various strategies. • Safety of different cargos-loaded EVs should be determined for any clinical intervention. [ABSTRACT FROM AUTHOR]

To describe MDD patients starting antidepressant (AD) treatment by pharmacological approach and identify factors associated with a longer sick leave (SL) duration. Retrospective study on IQVIA German Disease Analyser (specialists) and Spanish Longitudinal Patient Database (general practitioners and specialists). MDD patients initiating AD treatment between July 2016–June 2018 were grouped by therapeutic approach (AD monotherapy vs. combination/switch/add-on) and their characteristics were analysed descriptively. Multiple logistic regression models were run to evaluate factors affecting SL duration (i.e., >30 days). One thousand six hundred and eighty-five patients (monotherapy: 58%; combination/switch/add-on: 42%) met inclusion criteria for Germany, and 1817 for Spain (monotherapy: 83%; combination/switch/add-on: 17%). AD treatment influenced SL duration: combination/switch/add-on patients had a 2-fold and a 4-fold risk of having >30 days of SL than monotherapy patients, respectively in Germany and Spain. Patients with a gap of time between MDD diagnosis and AD treatment initiation had a higher likelihood of experiencing a longer SL both in Germany and Spain (38% higher likelihood and 6-fold risk of having >30 days of SL, respectively). A careful and timely selection of AD treatment approach at the time of MDD diagnosis may improve functional recovery and help to reduce SL, minimising the socio-economic burden of the disease. The major depressive disorder has a substantial impact on work absenteeism. The present study aimed to describe MDD patients starting antidepressant (AD) treatment depending on the pharmacological approach and to identify factors associated with longer sick leave (SL) duration. Patients receiving AD monotherapy had a lower likelihood of having more than 30 days of sick leave than those receiving AD combination/switch/add-on. Patients for whom a gap of time between MDD diagnosis and initiation of AD treatment was observed, showed a higher likelihood of having more than 30 days of sick leave. Because findings from this analysis relied on secondary data, the authors would like to claim the urgency of conducting prospective observational studies that further investigate the effect that different AD therapeutic approaches and timely initiation of treatment might exert on patients' recovery. [ABSTRACT FROM AUTHOR]

Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically "cold" tumor microenvironment (TME). However, we have shown that STING is silenced in many human cancers, including pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC). In this study, we demonstrated that mRNA-lipid nanoparticle (LNP) technology could be used to efficiently deliver naturally occurring constitutively active STING mutant STINGR284S into these cancer cells to reactivate STING antitumor immunity and trigger robust killing of tumor cells. STING agonists are being actively pursued as cancer immunotherapies. However, traditional STING agonists can induce T cell cytotoxicity, counteracting the desired antitumor immune response. In addition, the antitumor efficacy of traditional STING agonists obligatorily depends on STING expression and does not work in STING-silenced cancers. Importantly, we found that STINGR284S mRNA-LNP does not introduce T cell cytotoxicity. Our studies demonstrated that mRNA-LNP delivery of STINGR284S can reactivate the antitumor response without introducing antiproliferative effects in lymphocytic immune cells, overcoming the toxicity and limitations of conventional STING agonists. Our work therefore identifies a novel therapeutic tool for reactivating antitumor immunity in an array of STING-silenced immunologically "cold" tumors that are refractory to current therapies. [ABSTRACT FROM AUTHOR]

Introduction: CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental condition, primarily affecting girls for which no cure currently exists. Neuronal morphogenesis and plasticity impairments as well as metabolic dysfunctions occur in CDD patients. The present study explored the potential therapeutic value for CDD of FRAX486, a brain‐penetrant molecule that was reported to selectively inhibit group I p21‐activated kinases (PAKs), serine/threonine kinases critically involved in the regulation of neuronal morphology and glucose homeostasis. Methods: The effects of treatment with FRAX486 on CDD‐related alterations were assessed in vitro (100 nM for 48 h) on primary hippocampal cultures from Cdkl5‐knockout male mice (Cdkl5‐KO) and in vivo (20 mg/Kg, s.c. for 5 days) on Cdkl5‐KO heterozygous females (Cdkl5‐Het). Results: The in vitro treatment with FRAX486 completely rescued the abnormal neuronal maturation and the number of PSD95‐positive puncta in Cdkl5‐KO mouse neurons. In vivo, FRAX486 normalized the general health status, the hyperactive profile and the fear learning defects of fully symptomatic Cdkl5‐Het mice. Systemically, FRAX486 treatment normalized the levels of reactive oxidizing species in the whole blood and the fasting‐induced hypoglycemia displayed by Cdkl5‐Het mice. In the hippocampus of Cdkl5‐Het mice, treatment with FRAX486 rescued spine maturation and PSD95 expression and restored the abnormal PAKs phosphorylation at sites which are critical for their activation (P‐PAK‐Ser144/141/139) or for the control cytoskeleton remodeling (P‐PAK1‐Thr212). Conclusions: Present results provide evidence that PAKs may represent innovative therapeutic targets for CDD. [ABSTRACT FROM AUTHOR]

The Omicron variant (B.529) of COVID-19 caused disease outbreaks worldwide because of its contagious and diverse mutations. To reduce these outbreaks, therapeutic drugs and adjuvant vaccines have been applied for the treatment of the disease. However, these drugs have not shown high efficacy in reducing COVID-19 severity, and even antiviral drugs have not shown to be effective. Researchers thus continue to search for an effective adjuvant therapy with a combination of drugs or vaccines to treat COVID-19 disease. We were motivated to consider melatonin as a defensive agent against SARS-CoV-2 because of its various unique properties. Over 200 scientific publications have shown the significant effects of melatonin in treating diseases, with strong antioxidant, anti-inflammatory, and immunomodulatory effects. Melatonin has a high safety profile, but it needs further clinical trials and experiments for use as a therapeutic agent against the Omicron variant of COVID-19. It might immediately be able to prevent the development of severe symptoms caused by the coronavirus and can reduce the severity of the infection by improving immunity. [ABSTRACT FROM AUTHOR]

• The most important and controversial areas in PAH are the definition and correct classification of pulmonary hypertension and its impact on the clinical ground, the limitations of the current risk stratification tools and the therapeutic approach. • A mild increase in mPAP may be caused by different factors such as left heart diseases and lung diseases, thus clinicians have to recognize the underlying disease and optimize its treatment. • Risk stratification models in PAH need to be improved, including individual genetic profile and evaluation of right ventricular function. • PAH patients treated with oral combination therapies need a strict follow-up to avoid the delay of parenteral prostanoids that could have a detrimental effect on prognosis. [ABSTRACT FROM AUTHOR]

Borderline personality disorder is the most severe and frequently studied personological diagnosis. There is a significant increase in the frequency and severity of manifestations in this spectrum. It is important to have early detection of risk factors and comorbid conditions, in order to determine the most efficient therapeutic and rehabilitative approach. Affective symptoms, suicide risk and self-control are particularly targeted. Studies in recent years have confirmed the complexity of the phenomenon by offering new ways of understanding the therapeutic efficiency. [ABSTRACT FROM AUTHOR]

• Tumor-associated macrophages (TAMs) exert profound influences on cancer progression. • The review delves into the impact of TAM-derived exosomes on fundamental cancer hallmarks, elucidating their involvement in promoting cancer. • miRNAs, such as miR-155, miR-196a-5p, and miR-221-3p, are highlighted for their pivotal roles in mediating TAM-derived exosomal communication. Tumor-associated macrophages (TAMs) exert profound influences on cancer progression, orchestrating a dynamic interplay within the tumor microenvironment. Recent attention has focused on the role of TAM-derived exosomes, small extracellular vesicles containing bioactive molecules, in mediating this intricate communication. This review comprehensively synthesizes current knowledge, emphasizing the diverse functions of TAM-derived exosomes across various cancer types. The review delves into the impact of TAM-derived exosomes on fundamental cancer hallmarks, elucidating their involvement in promoting cancer cell proliferation, migration, invasion, and apoptosis evasion. By dissecting the molecular cargo encapsulated within these exosomes, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and proteins, the review uncovers key regulatory mechanisms governing these effects. Noteworthy miRNAs, such as miR-155, miR-196a-5p, and miR-221-3p, are highlighted for their pivotal roles in mediating TAM-derived exosomal communication and influencing downstream targets. Moreover, the review explores the impact of TAM-derived exosomes on the immune microenvironment, particularly their ability to modulate immune cell function and foster immune evasion. The discussion encompasses the regulation of programmed cell death ligand 1 (PD-L1) expression and subsequent impairment of CD8 + T cell activity, unraveling the immunosuppressive effects of TAM-derived exosomes. With an eye toward clinical implications, the review underscores the potential of TAM-derived exosomes as diagnostic markers and therapeutic targets. Their involvement in cancer progression, metastasis, and therapy resistance positions TAM-derived exosomes as key players in reshaping treatment strategies. Finally, the review outlines future directions, proposing avenues for targeted therapies aimed at disrupting TAM-derived exosomal functions and redefining the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Despite advances in understanding of corticospinal motor control and stroke pathophysiology, current rehabilitation therapies for poststroke upper limb paresis have limited efficacy at the level of impairment. To address this problem, we make the conceptual case for a new treatment approach. We first summarize current understanding of motor control deficits in the arm and hand after stroke and their shared physiological mechanisms with spinal cord injury (SCI). We then review studies of spinal cord stimulation (SCS) for recovery of locomotion after SCI, which provide convincing evidence for enhancement of residual corticospinal function. By extrapolation, we argue for using cervical SCS to restore upper limb motor control after stroke. Permanent motor deficits after stroke, such as loss of dexterity, loss of strength, and aberrant muscle synergies, are the result of damage to the corticospinal tract (CST). In patients with spinal cord injury, electrical stimulation of the lumbosacral spinal cord has an assistive effect (i.e., it enables voluntary control over previously paralyzed limbs). These assistive effects appear immediately upon turning on the stimulation and disappear as soon as it is turned off. Recent data show that spinal cord stimulation (SCS) combined with extensive training can also have a therapeutic effect (i.e., recovery of voluntary motor control in the absence of stimulation). Data from animals and humans show that SCS increases the efficacy of the residual CST. Thus, SCS combined with intense training focused on impairment may be an effective restorative approach for the poststroke arm and hand. [ABSTRACT FROM AUTHOR]

Vesicants are compounds that cause severe toxic effects on various tissues. Such chemical action causes tissue necrosis, with clinical expression of skin lesions with a burning character and characteristic blisters. Clinical toxic effects of cutaneous vesicles are correlated with the absorbed dose and exposure time. The goals of the study are to evaluate in vitro the skin toxicity produced by the vesicant chemical compound 2-chloroethyl-ethyl sulfide (CEES), to develop a complex antidote formula, and to optimize the therapeutic efficacy by inclusion in controlled release systems. The experimental protocol aims at the in vitro evaluation of the cytotoxicity of the vesicant compound CEES and of the optimized complex antidote, using the MTT cell viability test. Optimization of the complex antidote formula was achieved by developing and in vitro and in vivo testing of a fixed combination of active substances with anti-inflammatory and antioxidant effects, formulated as a solution with cutaneous administration. In vitro cytotoxicity tests on fibroblast cultures revealed the protective effect of the newly developed antidote solution, specifically a dose-related effect in the case of vesicant exposure. [ABSTRACT FROM AUTHOR]

• ApoE4 provokes neuroinflammation and exacerbates amyloid and tau pathologies. • Genetic knock-down or depletion of apoE alleviates amyloid and tau pathologies. • ApoE reduction via its receptor LDLR attenuates AD pathologies. • ApoE4 reduction by apoE specific ASOs and siRNAs alleviates AD pathologies. APOE4 is the first identified genetic risk factor and remains as the strongest predictor for late-onset Alzheimer's disease (AD). Studies of AD patients, AD patient-specific induced pluripotent stem cell-derived neurons and cerebral organoids, and human apoE4-expressing and apoE-deficient mouse models clearly demonstrate that apoE4 provokes neuroinflammation, impairs cerebrovasculature, and exacerbates amyloid and tau pathologies. ApoE expression is greatly up-regulated in disease-associated microglia in mouse models of amyloidosis and in human microglia from AD brains. Importantly, genetic knock-down or depletion of apoE in mice greatly attenuates neuroinflammation and alleviates amyloid and tau pathologies. Similar beneficial effects can be achieved when apoE reduction is induced by the overexpression of apoE metabolic receptor LDLR. Toward therapeutic implications, administration of apoE antisense oligonucleotides or apoE siRNAs leads to significant pharmacologic effects, i.e., significant alleviation of AD pathologies in mouse models. Therefore, apoE reduction represents a promising therapeutic strategy for the treatment of AD patients carrying the APOE ε4 allele. In this review, we summarize evidence and rationale on why and how we target apoE4 reduction for AD therapy. [ABSTRACT FROM AUTHOR]

This study evaluated the association between nurse spirituality and frequency of spiritual care among 560 nurses working at Dicle University Hospital in Turkey. The Spirituality Scale and the Nurse Spiritual Care Therapeutic Scale were administered. Results indicated that scores on the Spirituality Scale were positively correlated with frequency of provision of spiritual care (Nurse Spiritual Care Therapeutic Scale). It was found that the spirituality levels of the nurses had a positive effect (R2 = 0.245, B = 0.391, p < 0.0001) on the frequency of providing spiritual curative care. It was determined that the frequency of providing spiritual care of nurses with high spirituality level increased. No significant associations were found between Nurse Spiritual Care Therapeutic Scale means of point and gender, marital status, education level, unit work, or duration of professional experience. [ABSTRACT FROM AUTHOR]

Hypertensive emergencies (HE) represent high cardiovascular risk situations defined by a severe increase in blood pressure (BP) associated with acute, hypertension mediated organ damage (A-HMOD) to the heart, brain, retina, kidneys, and large arteries. Blood pressure values alone do not accurately predict the presence of HE; therefore, the search for A-HMOD should be the first step in the management of acute severe hypertension. A rapid therapeutic intervention is mandatory in order to limit and promote regression of end-organ damage, minimize the risk of complications, and improve patient outcomes. Drug therapy for HE, target BP, and the speed of BP decrease are all dictated by the type of A-HMOD, specific drug pharmacokinetics, adverse drug effects, and comorbidities. Therefore, a tailored approach is warranted. However, there is currently a lack of solid evidence for the appropriate treatment strategies for most HE. This article reviews current pharmacological strategies while providing a stepwise, evidence based approach for the management of HE. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease is a group of conditions of unknown etiology, represented by Crohn's disease and ulcerative colitis and characterized by the presence of intestinal wall inflammation. From the first cases described to date, several studies have been performed to elucidate the cause of inflammatory bowel disease. Generally, the genetic factors predispose to their occurrence while epigenetic and environmental factors trigger them. Genetic factors are mutations of the genes involved in the response and recognition of immune cells to different pathogens. The most studied epigenetic and environmental factors are smoking (which predisposes to Crohn's disease and can be protective for ulcerative colitis), lack of vitamin D, a diet rich in sugars and low in flavonoids and fibers. The diagnosis is usually established by endoscopy and biopsy. Recent technologies can perform live biopsies such as endocytoscopy or confocal laser endomicroscopy, with an accuracy of 100% compared to classical methods. Therapy involves several classes of drugs, preferably in association with diet and lifestyle changes. In case of complications or in non-responsive diseases, surgery must be considered, as documented for ulcerative colitis that can be cured by removing the entire colon. The purpose of this review is to present recent findings on pathology, as well as modern diagnosis and treatment methods for IBD. [ABSTRACT FROM AUTHOR]

Pneumonia is an infection of the lung parenchyma caused by a bacterial, viral, or fungal infection. In some cases of bacterial pneumonia, the infection progresses and causes necrosis and destruction of the lungs, and finally parapneumonic effusion occurs. This effusion arise from the spread of pleural inflammation and infection, or infection in other areas adjacent to the pleura, such as the retropharynx, vertebrae, abdomen, and retroperitoneal spaces. In the beginning, parapneumonic effusion, the pleura becomes inflamed, and then, due to inflammation and damage to the vascular endothelium, proteins, fluids, and leukocytes leak into the pleural space, and the fluid inside the chest gradually increases. At the time of formation, the effusion is usually sterile with a low leukocyte count .Over time, bacteria invade the fluid and lead to empyema. The presence of severe purulent fluid in the pleural cavity is called empyema. The aim of this study is etiology, diagnosis and treatment of empyema in children. [ABSTRACT FROM AUTHOR]

To identify sick leave days (SLD) predictors after starting antidepressant (AD) treatment in patients affected by major depressive disorder (MDD), managed by general practitioners, with a focus on different AD therapeutic approaches. Retrospective study on German IQVIA® Disease Analyser database. 19–64 year old MDD patients initiating AD treatment between July-2016 and June-2018 were grouped by therapeutic approach (AD monotherapy versus combination/switch/add-on). Data were analysed descriptively by AD therapeutic approach, while a zero-inflated Poisson (ZIP) multiple regression model was run to evaluate SLD predictors. 8,891 patients met inclusion criteria (monotherapy: 66%; combination/switch/add-on: 34%). All covariates had an influence on SLD after AD treatment initiation. Focussing on variables that physicians may more easily intervene to improve outcomes, it was found that the expected SLD number of combination/switch/add-on patients was 1.6 times that of monotherapy patients, and the expected SLD number of patients diagnosed with MDD before the decision to start AD treatment was 1.2 times that of patients not diagnosed with MDD. A patient tailored approach in the selection of AD treatment at the time of MDD diagnosis may improve functional recovery and help to reduce the socio-economic burden of the disease. Few studies previously investigated the effect of antidepressant treatment approaches on sick leave days in major depressive disorder. To the authors' knowledge, this is the first study evaluating the effect of different antidepressant treatment approaches on sick leave days in major depressive disorder in German patients. Patients receiving antidepressant monotherapy treatment seemed to lose fewer working days than patients receiving antidepressants combination/switch/add-on therapy, both before and after starting treatment, even if differences were more pronounced after treatment has started. The use of antidepressant monotherapy or combination/switch/add-on therapy was the strongest predictor of sick leave days after starting antidepressant treatment: the expected number of sick leave days for the combination/switch/add-on group was 1.6 times that of the monotherapy group. Among factors associated with increased sick leave days, antidepressant therapeutic approach and the promptness of starting the antidepressant treatment when major depressive disorder is diagnosed, are those on which physicians may more easily intervene to improve outcomes. Findings from the present study suggest that a patient tailored approach may improve functional recovery and help reducing the socio-economic burden of the disease. [ABSTRACT FROM AUTHOR]

Evidence‐based practice (EBP) has been proposed as a solution to the growing need for mental health treatment in the United States. We surveyed 205 college counselors regarding their attitudes toward EBP, institutional support, theoretical orientation, and job satisfaction. Our findings support the idea that counselors' attitudes toward EBP is predicted by institutional support and percentage of time spent engaged in training. The implications of these findings for practitioners and researchers are explored. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to analyze a Chinese institution's experience with managing cervical necrotizing fasciitis (CNF) and observe the effects of a new therapeutic approach for postoperative drainage system. Methods: A retrospective study was established including a total of 46 CNF patients who underwent surgical debridement between April 2006 and April 2018. Analyses of demographic data, etiology, comorbidity, microbiology, complications, treatment methods, duration of treatment, and treatment outcomes were obtained. Results: There were 16 kinds of microbes cultured in 29 patients. Diabetic patients were more commonly infected by microbes (P < 0.05). There was a significant reduction in the number of operative time (P < 0.05) and length of hospitalization (P < 0.01) with postoperative therapy of double-cannula irrigation–drainage (DCID) system. Conclusion: CNF management includes controlling for comorbidities especially glycemic control and reasonable utilization of antibiotics and aggressive postoperative therapy. DCID system can effectively reduce operative frequency and duration of hospitalization. [ABSTRACT FROM AUTHOR]

Bipolar affective disorder (BAD) is a psychiatric pathology defined by changes in mood and voluntary activity with a marked resonance on functionality. Although relatively common, BAD is still an underdiagnosed disorder, mainly due to the misdiagnosis as unipolar depression. The diagnosis and treatment of BAD are two aspects of real importance due to the high morbidity and mortality of this pathology, therefore an early identification of symptoms and an individualized therapeutic approach improve the prognosis of the disease and, thus, the quality of life. Although the attitude of the general population towards psychiatric pathologies has registered a positive evolution in recent years, towards the acceptance of these patients, stigma is still present in society. In addition to stigma, fluctuating disease awareness, low adherence to treatment, predisposition to get involved in activities with potentially negative consequences and the use of psychoactive substances are factors that contribute to a decreased quality of life of patients with bipolar disorder. [ABSTRACT FROM AUTHOR]

Microorganisms that inhabits human digestive tract affect global health and enteric disorders. Previous studies have documented the effectiveness and mode of action of probiotics and classified as human-friendly biota and a competitor to enteric pathogens. Statistical studies reported more than 1.5 billion cases of gastrointestinal infections caused by enteric pathogens and their long-term exposure can lead to mental retardation, temporary or permanent physical weakness, and leaving the patient susceptible for opportunistic pathogens, which can cause fatality. We reviewed previous literature providing evidence about therapeutic approaches regarding probiotics to cure enteric infections efficiently by producing inhibitory substances, immune system modulation, improved barrier function. The therapeutic effects of probiotics have shown success against many foodborne pathogens and their therapeutic effectiveness has been exponentially increased using genetically engineered probiotics. The bioengineered probiotic strains are expected to provide a better and alternative approach than traditional antibiotic therapy against enteric pathogens, but the novelty of these strains also raise doubts about the possible untapped side effects, for which there is a need for further studies to eliminate the concerns relating to the use and safety of probiotics. Many such developments and optimization of the classical techniques will revolutionize the treatments for enteric infections. [ABSTRACT FROM AUTHOR]

• Conventional youth justice facilities are typically highly restrictive, complicating the relationships between staff and young people. • Relational security recognises the importance of collaborative relationships between staff and young people. • This research puts forward key considerations for establishing relational security in conventional youth justice detention. • Staff workloads, high turnover, and procedural inflexibility form some of the main challenges. • Trust and respect, being adaptable to young people's needs, and maintaining professional boundaries are key. Constructive relationships between staff and young people in youth justice detention are a vital component of a therapeutic youth justice approach, which extends to the maintenance of a safe environment (i.e. relational security). However, there is a dearth of research on relational security and how it can be implemented and operationalized in conventional youth justice settings. Our aim was to understand custodial officers' views on, and approaches to, establishing a relational approach with young people, while maintaining safety and security. We conducted semi-structured interviews with 26 staff at a youth justice detention facility in Victoria, Australia. Thematic analysis using a framework analysis approach. Four main themes were derived: Staff roles, maintaining a safe environment, establishing a constructive relationship, and staffing challenges. These findings shed light on how relational security principles can provide a way to balance the care and support of young people with a need for safety and security in a conventional youth justice detention setting in Australia, as well as challenges of current procedures and arrangements. We argue that a relational security approach should inform staff recruitment, training, support, and management strategies, as well as decisions about the design and use of space in youth justice detention settings. [ABSTRACT FROM AUTHOR]

It seems that 2020 would be always remembered by the name of novel coronavirus (designated as SARS-CoV-2), which exerted its deteriorating effects on the health care, economy, education, and political relationships. In August 2020 more than eight hundred thousand patients lost their lives due to acute respiratory syndrome. In the limited list of therapeutic approaches, the effectiveness of low-dose radiation therapy (LD-RT) for curing inflammatory-related diseases have sparkled a light that probably this approach would bring promising advantages for COVID-19 patients. LD-RT owns its reputation from its ability to modulate the host inflammatory responses by blocking the production of pro-inflammatory cytokines and hampering the activity of leukocytes. Moreover, the cost-effective and availability of this method allow it to be applied to a large number of patients, especially those who could not receive anti-IL-6 treatments in low-income countries. But enthusiasm for applying LD-RT for the treatment of COVID-19 patients has been muted yet. In this review, we take a look at LD-RT mechanisms of action in the treatment of nonmalignant diseases, and then through studying both the dark and bright sides of this approach, we provide a thorough discussion if LD-RT might be a promising therapeutic approach in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Innate antiviral immunity is the first line of host defense against invading viral pathogens. Immunity activation primarily relies on the recognition of pathogen‐associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). Viral proteins or nucleic acids mainly engage three classes of PRRs: Toll‐like receptors (TLRs), retinoic acid‐inducible gene I (RIG‐I)‐like receptors (RLRs), and DNA sensor cyclic GMP‐AMP (cGAMP) synthase (cGAS). These receptors initiate a series of signaling cascades that lead to the production of proinflammatory cytokines and type I interferon (IFN‐I) in response to viral infection. This system requires precise regulation to avoid aberrant activation. Emerging evidence has unveiled the crucial roles that the ubiquitin system, especially deubiquitinating enzymes (DUBs), play in controlling immune responses. In this review, an overview of the most current findings on the function of DUBs in the innate antiviral immune pathways is provided. Insights into the role of viral DUBs in counteracting host immune responses are also provided. Furthermore, the prospects and challenges of utilizing DUBs as therapeutic targets for infectious diseases are discussed. [ABSTRACT FROM AUTHOR]

Atypical fibroxanthoma (AFX) is a rare, low‐grade dermal sarcoma. We analyzed our files from January 2001 to January 2020 for AFX. Clinical parameters, histopathology, treatment and outcome have been investigated. We identified 87 patients (mean age of 80.0 ± 8.4 years) with 105 confirmed tumors. Of these patients 86.2% were males. The most common clinical presentation was nodular (93.3%). The majority of AFX was located on the head with a mean tumor diameter of 15.0 mm ± 3.5 mm. All tumors showed a dermal localization, in 46.4% with a focal infiltration of the deeper layers. Second skin cancer was reported in 62.1% of patients. Collision tumors were seen in six patients. Treatment was surgical with three‐dimensional margin control. Relapses were noted in 11.4% of tumors with a mean delay of 11.7 ± 17.3 months. Focally deeper infiltration of AFX was a risk factor (P =.014). None of the purely dermal AFX relapsed. No metastasis was observed. AFX is a rare mesenchymal tumor of elderly patients. Treatment of choice is the complete surgical excision. Due to the high rate of other skin malignancies among patients with AFX, a regular follow‐up is recommended. [ABSTRACT FROM AUTHOR]

Complex regional pain syndrome is the modern name of the disease previously known as the Sudeck's disease. If not found and treated early, CRPS can have long term negative consequences. The pathophysiological and clinical characteristics of the syndrome are described in the article. The importance of physical factors in treating the condition has been thoroughly explored. Timely diagnosis and the right therapeutic approach in patients with CRS are crucial to maintaining the health of the affected individuals and shortening the recovery time. Employing an interdisciplinary approach is the contemporary solution to the problem. Physical factors relevant to the stage of the disease occupy the first place in the treatment. The physical factors, relevant to the stage of the disease, are the most important thing to consider when it comes to treatment. The aim is to achieve maximum physical, psychological and behavioral recovery of the patient. [ABSTRACT FROM AUTHOR]

Background: Eukaryotic histone methyltransferases 2 (EHMT2 or G9A) has been regarded as a potential target for non-small cell lung cancer (NSCLC) therapy. This study investigated the regulatory roles of G9A in tumorigenesis and stemness in NSCLC. We isolated and enriched tumor-initiating cells (TIC) from surgically resected NSCLC tissues by FACS and sphere formation assays. We then knocked down G9A using shRNA and carried out genome-wide 850K methylation array and RNA sequencing analyses. We carried out in vivo tumorigenecity asssay using mice xenografts and examined G9A interactions with its novel target using chromatin Immunoprecipitation (ChIP). Results: We identified 67 genes hypomethylated and 143 genes upregulated following G9A knockdown of which 43 genes were both hypomethylated and upregulated. We selected six genes (CDYL2, DPP4, SP5, FOXP1, STAMBPL1, and ROBO1) for validation. In addition, G9A expression was higher in TICs and targeting G9a by shRNA knockdown or by selective inhibitor UNC0642 significantly inhibited the expression of cancer stem cell markers and sphere forming capacity, in vitro proliferation, and in vivo growth. Further, transient overexpression of FOXP1, a protein may promote normal stem cell differentiation, in TICs resulted in downregulation of stem cell markers and sphere forming capacity and cell proliferation in vitro indicating that the genes we identified are directly regulated by G9A through aberrant DNA methylation and subsequent expression. Similarly, ChIP assay has shown that G9a interacts with its target genes through H3K9me2 and downregulation of H3K9me2 following G9a knockdown disrupts its interaction with its target genes. Conclusions: These data suggest that G9A is involved in lung cancer stemness through epigenetic mechanisms of maintaining DNA methylation of multiple lung cancer stem cell genes and their expression. Further, targeting G9A or its downstream genes could be a novel therapeutic approach in treating NSCLC patients. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the cancers with the highest mortality and morbidity. The causes of poor prognosis of PDAC underline the dysregulation of the molecular mechanisms including cell cycle, resistance of apoptosis and chemotherapy, deterioration of cell structure as a result of interaction with the tumor microenvironment, hypoxia formation and change of the stromal structure. Due to the impairment of balance between production and degradation of extracellular matrix proteins, the fibrotic stroma is concentrated and accelerated the invasion, migration and metastasis mechanisms. Once cancer cells are secreted exosomes containing cytokines, peptides, mRNA and protein inhibitors, cancer associated fibroblasts and irregular collagen weave are formed as a result of the disruption of the natural structure of fibroblasts and collagen. Followed by this, the increase in hyaluronan synthase enzyme activity and also accumulation of hyaluronan in extracellular matrix cause to enhance the concentration of stroma. The generation of immunosuppressive tumor microenvironment resulting in impairment of matrix morphology lead to decrease to treat PDAC patients having immunotherapy and chemotherapy. Therefore, the novel therapeutic approaches targeted extracellular matrix degradation are needed to develop to increase the efficiency of chemotherapeutic drugs gemcitabine and paclitaxel. For this purpose, phase studies are ongoing to develop therapeutic approaches targeted the prevention of migration using matrix metalloproteinase inhibitors, the blocking of fibrotic stroma mediated antagonistic monoclonal antibodies and small peptides to Hedgehog receptors, the usage of CD40 agonists to increase macrophage filtration into the tumor microenvironment. In this review, it was aimed to understand pancreatic tumor microenvironment and explain the molecular mechanisms affecting extracellular matrix degradation. Given the reports in literature, our review will help to light on future investigations related to extracellular matrix degradation targeted novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Folliculotropic mycosis fungoides is a variant of cutaneous T-cell lymphoma characterized as having a folliculocentric infiltrate of malignant T cells along with a worse prognosis in comparison to the epidermotropic variants. Patients with advanced forms of folliculotropic mycosis fungoides are often poorly responsive to both skin-directed as well as to systemic therapies. We report here a high response rate using a novel therapeutic regimen combining interferon gamma, isotretinoin in low dose and topical carmustine, and in some cases concomitant skin-directed therapies, among 6 consecutive patients with refractory folliculotropic mycosis fungoides with stages IB through IIIB who had previously failed both topical and systemic therapies. The potential mechanisms of this multimodality approach are discussed. [ABSTRACT FROM AUTHOR]

The present study is an attempt to evaluate the in vitro anti‐inflammatory and in silico anticancer potentials of the plant Cassia auriculata (CA). The aerial parts of CA were subjected to solvent extraction, and the extracts were fractionised by gas chromatography and mass spectrometry analysis for its phytochemical content. The antiinflammatory activity of the extracts were confirmed by the IC50 value of 125.02 µg/ml for red blood cell membrane stabilisation and 195.7 µg/ml for inhibition of protein denaturation activity. The interaction of bioactive compounds of CA ethanol extract with target protein was predicted through molecular docking studies, serine/threonine–protein kinase B (AKT1), responsible for development and progression of lung cancer using AutoDock tools. Extensive studies have been carried out on a range of kinase inhibitors targeting Akt, but obtaining promising results is a challenge yet due to its toxicity and resistance issues. Yohimbine, undecanoic acid 10‐methyl‐ethyl ester and chrysin significantly bind to the target protein with least binding energy. Hence, the present paper establishes the anti‐inflammatory and anticancer capacities of CA ethanol extract as an alternative to the existing therapeutic approach to inflammation and cancer through a systematic in vitro and in silico approaches supplementing the findings. [ABSTRACT FROM AUTHOR]

In this article, the author sought to raise awareness of and discuss ways to effectively address contextual challenges faced by mental health workers who provide therapeutic services to child rape survivors in war-affected regions, in general, and in the cultural context of the eastern region of the Democratic Republic of Congo, in particular, where rape is considered a sexual taboo, causing or amplifying attachment issues for survivors. A qualitative analysis of current literature review and therapeutic practice has been conducted in this article. Two cases are presented to illustrate contextual challenges. The analysis of case one focuses on ethical dilemmas between asserting professional boundaries and addressing clients' needs in situations wherein there are no alternative resources beyond the therapist's scope of practice, whereas the analysis of case two focuses on relationship and attachment challenges for survivors because of the interpretation of rape as sexual taboo. It was observed that, given extraordinary contextual challenges, therapists who assist child survivors in war-affected zones interact with their clients beyond their offices. Connecting at an empathy level alone is not enough. It also takes the therapists' ability to demonstrate compassion and creativity in their effort to facilitate the healing journey of their clients. [ABSTRACT FROM AUTHOR]

This article aims to understand the perception of Parengi Porja's ways of illness treatments and health management. The Parengi Porja is a Particularly Vulnerable Tribal Population (PVTG), inhabiting the hilly regions of Visakhapatnam district, Andhra Pradesh, India. They strongly believe in supernatural agents as being the cause of illness. For this study, the Parengi Porja tribal mothers were purposively selected from five villages situated in the study district. We used participant observation, in-depth interviews, focus group discussions, case studies, and semistructured interview schedules. We conducted five focus group discussions (FGDs) to understand the reasons for illness, and its diagnostic and therapeutic approaches. Data types include demographic variables, incidences of illnesses, and their management. The study shows that this tribal population has its own understanding about the illness etiology and management strategy to regain healthy life. [ABSTRACT FROM AUTHOR]