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Tirbanibulin 1% ointment is a synthetic antiproliferative agent approved in 2021 by the European Union for treating actinic keratoses (AK). Topical tirbanibulin has clinically resolved HPV-57 (+) squamous cell carcinoma (SCC), HPV-16 (+) vulvar high-grade squamous intraepithelial lesion, epidermodysplasia verruciformis, and condyloma. We examined how tirbanibulin might affect HPV oncoprotein expression and affect other cellular pathways involved in cell proliferation and transformation. We treated the HeLa cell line, containing integrated HPV-18, with increasing doses of tirbanibulin to determine the effects on cell proliferation. Immunoblotting was performed with antibodies against the Src canonical pathway, HPV 18 E6 and E7 transcription regulation, apoptosis, and invasion and metastasis pathways. Cell proliferation assays with tirbanibulin determined the half‐maximal inhibitory concentration (IC50) of HeLa cells to be 31.49 nmol/L. Increasing concentrations of tirbanibulin downregulates the protein expression of Src (p < 0.001), phospho-Src (p < 0.001), Ras (p < 0.01), c-Raf (p < 0.001), ERK1 (p < 0.001), phospho-ERK1 (p < 0.001), phospho-ERK2 (p < 0.01), phospho-Mnk1 (p < 0.001), eIF4E (p < 0.01), phospho-eIF4E (p < 0.001), E6 (p < 0.01), E7 (p < 0.01), Rb (p < 0.01), phospho-Rb (p < 0.001), MDM2 (p < 0.01), E2F1 (p < 0.001), phospho-FAK (p < 0.001), phospho-p130 Cas (p < 0.001), Mcl-1 (p < 0.01), and Bcl-2 (p < 0.001), but upregulates cPARP (p < 0.001), and cPARP/fPARP (p < 0.001). These results demonstrate that tirbanibulin may impact expression of HPV oncoproteins via the Src- MEK- pathway. Tirbanibulin significantly downregulates oncogenic proteins related to cell cycle regulation and cell proliferation while upregulating apoptosis pathways.Plain Language Summary: Tirbanibulin is Promising Novel Therapy for Human Papillomavirus (HPV)-associated Diseases. Tirbanibulin 1% ointment is an approved synthetic topical ointment for treating actinic keratoses (AK), a precancer of skin cancer. Topical tirbanibulin has previously been reported to clinically resolve human papillomavirus (HPV)-(+) diseases. In this study, we examine how tirbanibulin may affect the HPV and pathways associated with cancer. We treated the HeLa cell line to determine the effects on HPV cell proliferation. Increasing the concentration of tirbanibulin statistically significantly affected numerous cellular pathways often associated with cancer. These results demonstrate that tirbanibulin may impact expression of HPV oncoproteins and thereby kill cancer cells. [ABSTRACT FROM AUTHOR]

Abstract Type II D‐2‐Hydroxyglutaric aciduria (T2D2HGA) is caused by a gain‐of‐function pathogenic variant in Isocitrate Dehydrogenase 2 (IDH2). Patients with T2D2HGA commonly present with developmental delay, seizures, cardiomyopathy, and arrhythmias. The recently approved IDH2‐inhibitor Enasidenib targets the p.Arg140Gln pathogenic IDH2 variant and decreases production of D2HGA. We present a 7‐year‐old female with T2D2HGA due to the p.Arg140Gln variant. She was diagnosed at 3‐years‐old after presenting with global developmental delay, leukoencephalopathy, communicating hydrocephalus, seizures, and dilated cardiomyopathy. At age 3 years 11 months, 50 mg Enasidenib daily was initiated. Primary outcomes included seizure frequency, hospital admissions, development, and cardiac structure. Laboratories were monitored biweekly for common Enasidenib side effects. Our patient tolerated Enasidenib well. Urine 2‐HGA decreased significantly from 244 mg/g creatinine to undetectable within 2 weeks of treatment. Inpatient admissions decreased from 8 during the 2 years preceding treatment to 1 during treatment. She has been seizure‐free since Enasidenib initiation. Echocardiography showed improvement in dilated cardiomyopathy with normal left ventricular systolic function. Developmental assessment demonstrated improvements in gross motor, fine motor, language, and socialization domains. Treatment was complicated by mild elevations in alanine transaminase (118 IU/L, range 0–28) and creatine kinase (334 U/L, range 45–198) that resolved by decreasing Enasidenib dosing frequency to three times weekly. Enasidenib is a viable treatment for Type II D2HGA with benefits including developmental gains, fewer acute medical interventions, and cardiomyopathy improvement. While drug‐induced hepatitis is a novel adverse effect of Enasidenib, it can be ameliorated by decreasing dose frequency.

As it appears that we are currently at the cusp of an era in which drugs that are new, re-purposed, or "supplements" will be introduced to the management of celiac disease, we need to reflect on whether the framework is set for celiac disease to be treated increasingly with pharmaceuticals as well as diet. This refers to reflecting on the rigor of current diagnostic practices; the limitations of the current standard of care, which is a gluten-free diet; and that we lack objective markers of disease severity. Investigating these issues will help us to identify gaps in technology and practices that could be critical for selecting patients with a well-defined need for an improved or alternative treatment. Both aspects, circumscribed limitations of the gluten-free diet and diagnostics helping to define celiac disease target groups, together with the guiding requirements by the responsible regulatory authorities, will contribute to defining the subgroups of patients with confirmed celiac disease eligible for distinct pharmacologic strategies. Because many patients with celiac disease are diagnosed in childhood, these aspects need to be differentially discussed for the pediatric setting. In this perspective, we aimed to describe these contextual issues and then looked ahead to the future. What might be the major challenges in celiac disease clinics in the coming years once drugs are an option alongside diet? And what will be the future objectives for researchers who further decipher the mucosal immunology of celiac disease? Speculating on the answers to these questions is as stimulating as it is fascinating to be part of this turning point. [ABSTRACT FROM AUTHOR]

As a nutrient rich emulsion extracted from plant materials, plant-based milk (PBM) has been the latest trend and hot topic in the food industry due to the growing awareness of consumers toward plant-based products in managing the environmental (carbon footprint and land utility), ethical (animal well-fare) and societal (health-conscious) issues. There have been extensive studies and reviews done to discuss the distinct perspective of PBM including its production, health effects and market acceptance. However, not much has been emphasized on the valuable antioxidants present in PBM which is one of the attributes making them stand apart from dairy milk. The amounts of antioxidants in PBM are important. They offered tremendous health benefits in maintaining optimum health and reducing the risk of various health disorders. Therefore, enhancing the extraction of antioxidants and preserving their activity during production and storage is important. However, there is a lack of a comprehensive review of how these antioxidants changes in response to different processing steps involved in PBM production. Presumably, antioxidants in PBM could be potentially lost due to thermal degradation, oxidation or leaching into processing water. Hence, this paper aims to fill the gaps by addressing an extensive review of how different production steps (germination, roasting, soaking, blanching, grinding and filtration, and microbial inactivation) affect the antioxidant content in PBM. In addition, the effect of different microbial inactivation treatments (thermal or non-thermal processing) on the alteration of antioxidant in PBM was also highlighted. This paper can provide useful insight for the industry that aims in selecting suitable processing steps to produce PBM products that carry with them a health declaration. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease (ASCVD) stands as the leading cause of mortality worldwide. At its core lies a progressive process of atherosclerosis, influenced by multiple factors. Among them, lifestyle-related factors are highlighted, with inadequate diet being one of the foremost, alongside factors such as cigarette smoking, low physical activity, and sleep deprivation. Another substantial group of risk factors comprises comorbidities. Amongst others, conditions such as hypertension, diabetes mellitus (DM), chronic kidney disease (CKD), or familial hypercholesterolemia (FH) are included here. Extremely significant in the context of halting progression is counteracting the mentioned risk factors, including through treatment of the underlying disease. What is more, in recent years, there has been increasing attention paid to perceiving atherosclerosis as an inflammation-related disease. Consequently, efforts are directed towards exploring new anti-inflammatory medications to limit ASCVD progression. Simultaneously, research is underway to identify biomarkers capable of providing insights into the ongoing process of atherosclerotic plaque formation. The aim of this study is to provide a broader perspective on ASCVD, particularly focusing on its characteristics, traditional and novel treatment methods, and biomarkers that can facilitate its early detection. [ABSTRACT FROM AUTHOR]

Wet age-related macular degeneration (w-AMD) is a leading cause of visual impairment globally, with its prevalence expected to rise alongside increasing life expectancy. The current standard treatment involves frequent intravitreal injections of anti-VEGF agents, which although revolutionary, pose significant burdens on both patients and healthcare services. This review explores current and emerging pharmaceutical treatments for w-AMD, focusing on their pharmacokinetics, pharmacodynamics, efficacy, and safety. Promising developments include extending treatment intervals with newer anti-VEGF agents like brolucizumab and faricimab, biosimilars offering cost-effective options, and exploring innovative drug delivery methods such as subretinal gene therapy. Combination therapies, gene therapies, and novel agents like KSI-301 and OPT-302 show potential for improving treatment outcomes and reducing treatment burden. While current treatments for w-AMD have significantly advanced with the advent of anti-VEGF therapies, their limitations in terms of treatment burden and incomplete responses have spurred research into diverse alternative approaches. These innovative strategies offer hope for improving patient outcomes and reducing healthcare burdens, suggesting a promising future for w-AMD management. [ABSTRACT FROM AUTHOR]

Introduction: Radiation treatment has replaced enucleation as an organ-preservation treatment for patients with uveal melanoma (UM). We developed a novel non-invasive, frameless LINAC based solution for fractionated stereotactic radiosurgery (fSRS) treatment. Methods: We designed and constructed the a stereotactic ocular localization box that can be attached and indexed to a stereotactic LINAC tabletop. It contains adjustable LED lights as a gaze focus point and CCD camera for monitoring of the patient's eye position. The device also has 6 infrared spheres compatible with the ExacTRAC IGRT system. Treatment plans were developed using iPLAN Dose version 4.5, with conformal dynamic arcs and 6MV photon beam in flattening filter free mode, dosed to 50Gy in 5 fractions. During treatment, patients were instructed to stare at the light when a radiation beam is prepared and ready for delivery. Eye movement was tracked throughout treatment. Residual setup errors were recorded for evaluation. Results: The stereotactic ocular localization box was 3D-printed with polylactic acid material and attached to the stereotactic LINAC tabletop. 10 patients were treated to evaluate the feasibility, tolerability and setup accuracy. Median treatment time for each arc is 17.3 ± 2.4 seconds (range: 13.8-23.4). After ExacTRAC setup, the residual setup errors are -0.1 ± 0.3 mm laterally, -0.1 ± 0.3 mm longitudinally, and 0 ± 0.2 mm vertically. The residue rotational errors are -0.1 ± 0.3 degree pitch, 0.1 ± 0.2 degree roll, and 0 ± 0.2 degree couch rotation. All patients received treatment successfully. Conclusion: We successfully developed a novel non-invasive frameless mask-based LINAC solution for SRS for uveal melanoma, or other ocular tumors. It is well tolerated with high set up accuracy. Future directions for this localization box would include a multi-center trial to assess the efficacy and reproducibility in the fabrication and execution of such a solution for UM therapy. [ABSTRACT FROM AUTHOR]

Abstract Background Rhabdomyolysis is characterized by the destruction and necrosis of skeletal muscle tissue, resulting in acute kidney injury (AKI). Recombinant antithrombin (rAT) has DNA repair and vascular endothelial-protection properties. Herein, we investigated whether rAT therapy has beneficial effects against rhabdomyolysis-induced AKI. Ten-week-old male B6 mice were injected with 5 mL/kg of 50% glycerol intramuscularly in the left thigh after 24 h of fasting to create a rhabdomyolysis mouse model. Further, 750 IU/kg rAT was injected intraperitoneally at 24 and 72 h after the rhabdomyolysis model was established. The mice were euthanized after 96 h for histological analysis. Saline was administered to mice in the control group. Results Blood tests show elevated serum creatinine, urea nitrogen, and neutrophil gelatinase-associated lipocalin levels in rhabdomyolysis. Loss of tubular epithelial cell nuclei and destruction of the tubular luminal surface structure was observed in the untreated group, which improved with rAT treatment. Immunostaining for Ki-67 showed increased Ki-67-positive nuclei in the tubular epithelial cells in the rAT group, suggesting that rAT may promote tubular epithelial cell regeneration. The microvilli of the brush border of the renal tubules were shed during rhabdomyolysis, and rAT treatment reduced this injury. The vascular endothelial glycocalyx, which is usually impaired by rhabdomyolysis, became functional following rAT treatment. Conclusions Treatment with rAT suppressed rhabdomyolysis-induced AKI, suggesting that rAT therapy may be a novel therapeutic approach.

Key Clinical Message: Innovative mixed treatment offers hope for persistent mixed urinary incontinence (MUI): PRP‐Fibrin Glue‐Stem Cell injection, Botox, and TVT in a single session. Successful case study reveals promising outcomes, emphasizing the need for further research. Mixed urinary incontinence is a complaint of stress and urge incontinence which affects patients' quality of life and dramatic changes in patients' physical, mental, and socioeconomic status. The treatment is challenging and depends on the dominance of one of the complaints to the other. The progress in the method of treatment is still under discussion. This study reports treatment of a MUI case in a 56‐year‐old, with a history of MUI of 7‐year duration, which was persistent to pharmacological treatment, pelvic muscle training, biofeedback, and anti‐incontinence surgery (Burch Colposuspension). PRP‐Fibrin Glue‐Stem Cell injection, Botox injection, and TVT were performed in a one surgery session. Patient was discharged with ability to urinate with acceptable amount of post void residue. After 3‐month follow‐up, patient was completely satisfied and happy. Further research is needed to substantiate the efficacy of these mixed treatments for MUI. [ABSTRACT FROM AUTHOR]

We employed a structural bioinformatics approach to develop novel peptides with predicted affinity to the binding site for negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5). Primary screening in zebrafish (Danio rerio) revealed a stimulatory effect of two peptides, LCGM-10 and LCGM-15. Target validation studies using calcium ion flux imaging and a luciferase reporter assay confirmed mGluR5 as the target. LCGM-10 showed greater potency than LCGM-15; it was comparable to that of the mGluR5 NAM 2-methyl-6-(phenylethynyl) pyridine (MPEP). Rodent behavioral screening in the open field and elevated plus maze revealed increased locomotor activity in both tests after acute LCGM-10 treatment, supported by further analysis of home cage spontaneous locomotor activity (SLA). The stimulating effect of a single LCGM-10 administration on SLA was evident up to 60 min after administration and was not accompanied by hypokinetic rebound observed for caffeine. According to our results, LCGM-10 has therapeutic potential to treat hypoand dyskinesias of various etiologies. Further investigation of LCGM-10 effects in the delay discounting model of impulsive choice in rats revealed reduced trait impulsivity after single and chronic administrations, suggesting potential implication for attention deficit hyperactivity disorder, obsessive compulsive disorder, and addictions. [ABSTRACT FROM AUTHOR]

In physiological concentrations, reactive oxygen species play a vital role in regulating cell signaling and gene expression. Nevertheless, oxidative stress is implicated in the pathogenesis of numerous diseases and can inflict damage on diverse cell types and tissues. Thus, understanding the factors that mitigate the deleterious effects of oxidative stress is imperative for identifying new therapeutic targets. In light of the absence of direct treatment recommendations for reducing oxidative stress, there is a continuing need for fundamental research that utilizes innovative therapeutic approaches. Metformin, known for its multifaceted beneficial properties, is acknowledged for its ability to counteract the adverse effects of increased oxidative stress at both molecular and cellular levels. In this review, we delve into recent insights regarding metformin's antioxidant attributes, aiming to expand its clinical applicability. Our review proposes that metformin holds promise as a potential adjunctive therapy for various diseases, given its modulation of oxidative stress characteristics and regulation of diverse metabolic pathways. These pathways include lipid metabolism, hormone synthesis, and immunological responses, all of which may experience dysregulation in disease states, contributing to increased oxidative stress. Furthermore, our review introduces potential novel metformin-based interventions that may merit consideration in future research. Nevertheless, the necessity for clinical trials involving this drug remains imperative, as they are essential for establishing therapeutic dosages and addressing challenges associated with dosedependent effects. [ABSTRACT FROM AUTHOR]

Simple Summary: In the complex world of cancer, iron and copper play essential roles as trace metal ions that are crucial for cancer cell survival. Disruption in their metabolic functions can be lethal to cancer cells, triggering ferroptosis and cuproptosis, respectively. Given an accelerated proliferation rate, cancer cells exhibit a heightened dependence on iron and copper, exposing vulnerabilities that could potentially be exploited to reverse drug resistance. Notably, mitochondria, the cellular powerhouses, play a crucial role in regulating both ferroptosis and cuproptosis. This review focuses on elucidating the key mechanisms behind ferroptosis and cuproptosis and summarizes recent clinical applications targeting dysfunctional iron and copper metabolic pathways. Drug resistance is a hallmark of cancer development that underscores a critical need to address it, underscoring the critical need to explore novel approaches. Understanding and targeting these metal-related processes offers promising approaches for developing innovative cancer therapies, making use of vulnerabilities specific to cancer cells. Iron (Fe) and copper (Cu), essential transition metals, play pivotal roles in various cellular processes critical to cancer biology, including cell proliferation, mitochondrial respiration, distant metastases, and oxidative stress. The emergence of ferroptosis and cuproptosis as distinct forms of non-apoptotic cell death has heightened their significance, particularly in connection with these metal ions. While initially studied separately, recent evidence underscores the interdependence of ferroptosis and cuproptosis. Studies reveal a link between mitochondrial copper accumulation and ferroptosis induction. This interconnected relationship presents a promising strategy, especially for addressing refractory cancers marked by drug tolerance. Harnessing the toxicity of iron and copper in clinical settings becomes crucial. Simultaneous targeting of ferroptosis and cuproptosis, exemplified by the combination of sorafenib and elesclomol-Cu, represents an intriguing approach. Strategies targeting mitochondria further enhance the precision of these approaches, providing hope for improving treatment outcomes of drug-resistant cancers. Moreover, the combination of iron chelators and copper-lowering agents with established therapeutic modalities exhibits a synergy that holds promise for the augmentation of anti-tumor efficacy in various malignancies. This review elaborates on the complex interplay between ferroptosis and cuproptosis, including their underlying mechanisms, and explores their potential as druggable targets in both cancer research and clinical settings. [ABSTRACT FROM AUTHOR]

Background: Rhabdomyolysis is characterized by the destruction and necrosis of skeletal muscle tissue, resulting in acute kidney injury (AKI). Recombinant antithrombin (rAT) has DNA repair and vascular endothelial-protection properties. Herein, we investigated whether rAT therapy has beneficial effects against rhabdomyolysis-induced AKI. Ten-week-old male B6 mice were injected with 5 mL/kg of 50% glycerol intramuscularly in the left thigh after 24 h of fasting to create a rhabdomyolysis mouse model. Further, 750 IU/kg rAT was injected intraperitoneally at 24 and 72 h after the rhabdomyolysis model was established. The mice were euthanized after 96 h for histological analysis. Saline was administered to mice in the control group. Results: Blood tests show elevated serum creatinine, urea nitrogen, and neutrophil gelatinase-associated lipocalin levels in rhabdomyolysis. Loss of tubular epithelial cell nuclei and destruction of the tubular luminal surface structure was observed in the untreated group, which improved with rAT treatment. Immunostaining for Ki-67 showed increased Ki-67-positive nuclei in the tubular epithelial cells in the rAT group, suggesting that rAT may promote tubular epithelial cell regeneration. The microvilli of the brush border of the renal tubules were shed during rhabdomyolysis, and rAT treatment reduced this injury. The vascular endothelial glycocalyx, which is usually impaired by rhabdomyolysis, became functional following rAT treatment. Conclusions: Treatment with rAT suppressed rhabdomyolysis-induced AKI, suggesting that rAT therapy may be a novel therapeutic approach. [ABSTRACT FROM AUTHOR]

Celiac disease (CeD) is a chronic autoimmune disorder triggered by the ingestion of gluten, affecting around 1% of the global population. It is a multifactorial disease involving both genetics and environmental factors. Nowadays, the only available treatment for CeD is a life-long gluten-free diet (GFD), which can cause a significant burden for patients, since symptoms and mucosal injury can persist despite apparent compliance with a GFD. This could also lead to psychological consequences and affect the quality of life of these patients. Thankfully, recent advances in understanding the pathogenesis of CeD and the availability of various targets have made it feasible to explore pharmaceutical treatments specific to CeD. Recently, the FDA has highlighted the unmet needs of adult patients on a GFD who experience ongoing symptoms attributed to CeD and also show persistent duodenal villous atrophy. This review will outline the limitations of a GFD, describe the targets of potential novel treatment of CeD and provide an overview of the primary clinical trials involving oral and injectable agents for a non-dietary treatment of CeD. [ABSTRACT FROM AUTHOR]

Breast cancer is a prevalent disease that primarily affects women, with significant implications for public health. Early detection improves survival rates, and technological advancements can enhance early diagnosis. Protein structure prediction methods can provide valuable insights into the structure of proteins involved in breast cancer, including human epidermal growth factor receptor-2 (HER2). HER2 is a known protein receptor that plays a critical role in breast cancer development and is a target for therapy. Predicting the binding affinity between HER2 and potential ligands can help identify novel treatment options. This study aimed to predict the structure of HER2 using I-TASSER and determine potential ligands using empirical graph neural network-based scoring functions. Molecular docking simulations were performed to evaluate the binding conformation and stability of the HER2-ligand complexes. The results showed the potential ligands identified by I-TASSER: AEE, UUU, and Mg2+. Afterward, their binding affinity with HER2 was assessed, yielding AEE as the best binding with the lowest vina score. [ABSTRACT FROM AUTHOR]

Key Clinical Message Innovative mixed treatment offers hope for persistent mixed urinary incontinence (MUI): PRP‐Fibrin Glue‐Stem Cell injection, Botox, and TVT in a single session. Successful case study reveals promising outcomes, emphasizing the need for further research. Abstract Mixed urinary incontinence is a complaint of stress and urge incontinence which affects patients' quality of life and dramatic changes in patients' physical, mental, and socioeconomic status. The treatment is challenging and depends on the dominance of one of the complaints to the other. The progress in the method of treatment is still under discussion. This study reports treatment of a MUI case in a 56‐year‐old, with a history of MUI of 7‐year duration, which was persistent to pharmacological treatment, pelvic muscle training, biofeedback, and anti‐incontinence surgery (Burch Colposuspension). PRP‐Fibrin Glue‐Stem Cell injection, Botox injection, and TVT were performed in a one surgery session. Patient was discharged with ability to urinate with acceptable amount of post void residue. After 3‐month follow‐up, patient was completely satisfied and happy. Further research is needed to substantiate the efficacy of these mixed treatments for MUI.

IntroductionRadiation treatment has replaced enucleation as an organ-preservation treatment for patients with uveal melanoma (UM). We developed a novel non-invasive, frameless LINAC based solution for fractionated stereotactic radiosurgery (fSRS) treatment.MethodsWe designed and constructed the a stereotactic ocular localization box that can be attached and indexed to a stereotactic LINAC tabletop. It contains adjustable LED lights as a gaze focus point and CCD camera for monitoring of the patient’s eye position. The device also has 6 infrared spheres compatible with the ExacTRAC IGRT system. Treatment plans were developed using iPLAN Dose version 4.5, with conformal dynamic arcs and 6MV photon beam in flattening filter free mode, dosed to 50Gy in 5 fractions. During treatment, patients were instructed to stare at the light when a radiation beam is prepared and ready for delivery. Eye movement was tracked throughout treatment. Residual setup errors were recorded for evaluation.ResultsThe stereotactic ocular localization box was 3D-printed with polylactic acid material and attached to the stereotactic LINAC tabletop. 10 patients were treated to evaluate the feasibility, tolerability and setup accuracy. Median treatment time for each arc is 17.3 ± 2.4 seconds (range: 13.8-23.4). After ExacTRAC setup, the residual setup errors are -0.1 ± 0.3 mm laterally, -0.1 ± 0.3 mm longitudinally, and 0 ± 0.2 mm vertically. The residue rotational errors are -0.1 ± 0.3 degree pitch, 0.1 ± 0.2 degree roll, and 0 ± 0.2 degree couch rotation. All patients received treatment successfully.ConclusionWe successfully developed a novel non-invasive frameless mask-based LINAC solution for SRS for uveal melanoma, or other ocular tumors. It is well tolerated with high set up accuracy. Future directions for this localization box would include a multi-center trial to assess the efficacy and reproducibility in the fabrication and execution of such a solution for UM therapy.

We employed a structural bioinformatics approach to develop novel peptides with predicted affinity to the binding site for negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5). Primary screening in zebrafish (Danio rerio) revealed a stimulatory effect of two peptides, LCGM-10 and LCGM-15. Target validation studies using calcium ion flux imaging and a luciferase reporter assay confirmed mGluR5 as the target. LCGM-10 showed greater potency than LCGM-15; it was comparable to that of the mGluR5 NAM 2-methyl-6-(phenylethynyl) pyridine (MPEP). Rodent behavioral screening in the open field and elevated plus maze revealed increased locomotor activity in both tests after acute LCGM-10 treatment, supported by further analysis of home cage spontaneous locomotor activity (SLA). The stimulating effect of a single LCGM-10 administration on SLA was evident up to 60 min after administration and was not accompanied by hypokinetic rebound observed for caffeine. According to our results, LCGM-10 has therapeutic potential to treat hypo- and dyskinesias of various etiologies. Further investigation of LCGM-10 effects in the delay discounting model of impulsive choice in rats revealed reduced trait impulsivity after single and chronic administrations, suggesting potential implication for attention deficit hyperactivity disorder, obsessive compulsive disorder, and addictions.

In physiological concentrations, reactive oxygen species play a vital role in regulating cell signaling and gene expression. Nevertheless, oxidative stress is implicated in the pathogenesis of numerous diseases and can inflict damage on diverse cell types and tissues. Thus, understanding the factors that mitigate the deleterious effects of oxidative stress is imperative for identifying new therapeutic targets. In light of the absence of direct treatment recommendations for reducing oxidative stress, there is a continuing need for fundamental research that utilizes innovative therapeutic approaches. Metformin, known for its multifaceted beneficial properties, is acknowledged for its ability to counteract the adverse effects of increased oxidative stress at both molecular and cellular levels. In this review, we delve into recent insights regarding metformin’s antioxidant attributes, aiming to expand its clinical applicability. Our review proposes that metformin holds promise as a potential adjunctive therapy for various diseases, given its modulation of oxidative stress characteristics and regulation of diverse metabolic pathways. These pathways include lipid metabolism, hormone synthesis, and immunological responses, all of which may experience dysregulation in disease states, contributing to increased oxidative stress. Furthermore, our review introduces potential novel metformin-based interventions that may merit consideration in future research. Nevertheless, the necessity for clinical trials involving this drug remains imperative, as they are essential for establishing therapeutic dosages and addressing challenges associated with dose-dependent effects.

Atherosclerotic cardiovascular disease (ASCVD) stands as the leading cause of mortality worldwide. At its core lies a progressive process of atherosclerosis, influenced by multiple factors. Among them, lifestyle-related factors are highlighted, with inadequate diet being one of the foremost, alongside factors such as cigarette smoking, low physical activity, and sleep deprivation. Another substantial group of risk factors comprises comorbidities. Amongst others, conditions such as hypertension, diabetes mellitus (DM), chronic kidney disease (CKD), or familial hypercholesterolemia (FH) are included here. Extremely significant in the context of halting progression is counteracting the mentioned risk factors, including through treatment of the underlying disease. What is more, in recent years, there has been increasing attention paid to perceiving atherosclerosis as an inflammation-related disease. Consequently, efforts are directed towards exploring new anti-inflammatory medications to limit ASCVD progression. Simultaneously, research is underway to identify biomarkers capable of providing insights into the ongoing process of atherosclerotic plaque formation. The aim of this study is to provide a broader perspective on ASCVD, particularly focusing on its characteristics, traditional and novel treatment methods, and biomarkers that can facilitate its early detection.

• Although there is no drug treatment available for CMT, great advances are being made. • Promising approaches are under investigation and clinical trials ongoing/planned. • Different approaches are under study for CMT1A including PMP22 gene silencing. • Gene therapy and several compounds for different pathways are being evaluated. • Active trials include PXT3003 in CMT1A, aldose reductase inhibitor for defective SORD. There is still no effective drug treatment available for Charcot-Marie-Tooth disease (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment. The challenge is to find disease-modifying therapies. Several approaches, including gene silencing (by means of ASO, siRNA, shRNA, miRNA, CRISPR-Cas9 editing), to counteract the PMP22 gene overexpression in the most frequent CMT1A type are under investigation. PXT3003 is the compound in the most advanced phase for CMT1A, as a second phase-III trial is ongoing. Gene therapy to substitute defective genes (particularly in recessive forms associated with loss-of-function mutations) or insert novel ones (e.g., NT3 gene) are being developed and tested in animal models and in still exceptional cases have reached the clinical trial phase in humans. Novel treatment approaches are also aimed at developing compounds acting on pathways important for different CMT types. Modulation of the neuregulin pathway determining myelin thickness is promising for both hypo-demyelinating and hypermyelinating neuropathies; intervention on Unfolded Protein Response seems effective for rescuing misfolded myelin proteins such as MPZ in CMT1B. HDAC6 inhibitors improved axonal transport and ameliorated phenotypes in different CMT models. Other potential therapeutic strategies include targeting macrophages, lipid metabolism, and Nav1.8 sodium channel in demyelinating CMT and the P2×7 receptor, which regulates calcium influx into Schwann cells, in CMT1A. Further approaches are aimed at correcting metabolic abnormalities, including the accumulation of sorbitol caused by biallelic mutations in the sorbitol dehydrogenase (SORD) gene and of neurotoxic glycosphingolipids in HSN1. [ABSTRACT FROM AUTHOR]

Iron (Fe) and copper (Cu), essential transition metals, play pivotal roles in various cellular processes critical to cancer biology, including cell proliferation, mitochondrial respiration, distant metastases, and oxidative stress. The emergence of ferroptosis and cuproptosis as distinct forms of non-apoptotic cell death has heightened their significance, particularly in connection with these metal ions. While initially studied separately, recent evidence underscores the interdependence of ferroptosis and cuproptosis. Studies reveal a link between mitochondrial copper accumulation and ferroptosis induction. This interconnected relationship presents a promising strategy, especially for addressing refractory cancers marked by drug tolerance. Harnessing the toxicity of iron and copper in clinical settings becomes crucial. Simultaneous targeting of ferroptosis and cuproptosis, exemplified by the combination of sorafenib and elesclomol-Cu, represents an intriguing approach. Strategies targeting mitochondria further enhance the precision of these approaches, providing hope for improving treatment outcomes of drug-resistant cancers. Moreover, the combination of iron chelators and copper-lowering agents with established therapeutic modalities exhibits a synergy that holds promise for the augmentation of anti-tumor efficacy in various malignancies. This review elaborates on the complex interplay between ferroptosis and cuproptosis, including their underlying mechanisms, and explores their potential as druggable targets in both cancer research and clinical settings.

Here we discuss the case of a patient with treatment-resistant pyoderma gangrenosum. We explore the difficulties in managing this condition and reveal the approaches tested in order to bring about clinical improvements. [ABSTRACT FROM AUTHOR]

T-cell large granular lymphocyte (T-LGL) leukemia is a rare and indolent clonal disorder of LGLs, associated with rheumatoid arthritis and neutropenia. The authors present a case of a 62-year-old male with rheumatoid arthritis (RA) who was diagnosed with T-LGL leukemia, with predominant neutropenia, and a poor response to conventional treatment. Subsequently, tofacitinib (a Janus Kinase 1 and 3 inhibitor, [JAK1/3 inhibitor]) resulted in improvement of the patient’s RA symptoms and temporary improvement of the neutropenia. Ultimately, upadacitinib (a specific JAK1 inhibitor) resulted in further improvement of the neutropenia and control of his RA. To the best of our knowledge, this is the first case report of coexisting RA and LGL leukemia that was treated with upadacitinib and showed clinical improvement.

Celiac disease (CeD) is a chronic autoimmune disorder triggered by the ingestion of gluten, affecting around 1% of the global population. It is a multifactorial disease involving both genetics and environmental factors. Nowadays, the only available treatment for CeD is a life-long gluten-free diet (GFD), which can cause a significant burden for patients, since symptoms and mucosal injury can persist despite apparent compliance with a GFD. This could also lead to psychological consequences and affect the quality of life of these patients. Thankfully, recent advances in understanding the pathogenesis of CeD and the availability of various targets have made it feasible to explore pharmaceutical treatments specific to CeD. Recently, the FDA has highlighted the unmet needs of adult patients on a GFD who experience ongoing symptoms attributed to CeD and also show persistent duodenal villous atrophy. This review will outline the limitations of a GFD, describe the targets of potential novel treatment of CeD and provide an overview of the primary clinical trials involving oral and injectable agents for a non-dietary treatment of CeD.

The purpose of this research was to investigate the efficacy of ZB-06 vaginal biofilm as a novel treatment for recurrent bacterial vaginosis (BV). BV is a prevalent vaginal infection that primarily affects women of reproductive age and is linked to adverse health outcomes. Biofilm production allows bacteria to cling to the vaginal epithelium, making antibiotics harder to penetrate and treat the illness efficiently. ZB-06 is a vaginal biofilm inhibitor that may dissolve the biofilm generated by the bacteria causing BV, enhancing antibiotic therapy efficacy and lowering the risk of recurrence. The current literature on BV, biofilm formation, and the possible function of ZB-06 as a therapy option for recurrent BV is reviewed in this article. More research is needed to determine ZB-06's safety and efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: Epithelial cancers, such as lung, breast, and colon cancers, have high mortality rates because of their ability to spread across multiple organs in the body. Besides the standard of care which includes chemotherapy and radiotherapy, approaches directed to use patient's own immune responses against the disease called immunotherapies have emerged as a powerful treatment option. In the past 10 years, immune checkpoint blockade, a form of immunotherapy which either stimulates or removes the breaks of the immune response against cancer, is having the largest impact in the clinic. However epithelial cancers are commonly either naturally resistant or develop resistance to these types of treatments. Hence, there is an urgent need to boost the effectiveness of immune checkpoint blockers. Small molecule inhibitors are chemical molecules which are specifically designed to target important cancer proteins and unlike chemotherapy, typically have manageable toxicity. These inhibitors have shown good efficacy in reducing tumour growth but more recently, they have been shown to enhance the performance of immune cells in eliminating cancers. In this review, we have focused on tactical usage of small molecule inhibitors to boost the efficacy of immune checkpoint blockers. We believe our review will pave the way for novel research combining the two therapeutic modalities. Immune checkpoint blockade (ICB) is now standard of care for several metastatic epithelial cancers and prolongs life expectancy for a significant fraction of patients. A hostile tumor microenvironment (TME) induced by intrinsic oncogenic signaling induces an immunosuppressive niche that protects the tumor cells, limiting the durability and efficacy of ICB therapies. Addition of receptor tyrosine kinase inhibitors (RTKi) as potential modulators of an unfavorable local immune environment has resulted in moderate life expectancy improvement. Though the combination strategy of ICB and RTKi has shown significantly better results compared to individual treatment, the benefits and adverse events are additive whereas synergy of benefit would be preferable. There is therefore a need to investigate the potential of inhibitors other than RTKs to reduce malignant cell survival while enhancing anti-tumor immunity. In the last five years, preclinical studies have focused on using small molecule inhibitors targeting cell cycle and DNA damage regulators such as CDK4/6, CHK1 and poly ADP ribosyl polymerase (PARP) to selectively kill tumor cells and enhance cytotoxic immune responses. This review provides a comprehensive overview of the available drugs that attenuate immunosuppression and overcome hostile TME that could be used to boost FDA-approved ICB efficacy in the near future. [ABSTRACT FROM AUTHOR]

Real-world patterns of care and attrition of la/mUC patients eligible for systemic therapy following PD-1/L1 inhibitors are not well understood. In an ambispective chart review of patients with la/mUC after PD-1/L1 discontinuation, only one third received subsequent treatment. Prior to the introduction of novel therapies, real-world outcomes following treatment with PD-1/L1 inhibitor therapy were poor. Introduction: The patterns of care and attrition of locally advanced or metastatic urothelial carcinoma (la/mUC) patients eligible for systemic therapy following PD-1/L1 inhibitors are unclear. The objective of this study was to evaluate the clinical characteristics and treatment patterns among patients with la/mUC following discontinuation of first-line (1L) or second-line (2L) PD-1/L1 inhibitor therapy. Methods: An ambispective, multisite, chart review study was conducted in the United States, including patients with la/mUC. Eligible patients had initiated and subsequently discontinued PD-1/L1 therapy in the 1L or 2L setting for la/mUC between May 2016 and July 2018; with follow-up through October 2019. Patient characteristics, treatments, and overall survival (OS) were described. Patients had the option to complete a 1-time patient reported outcomes (PRO) survey. Results: Among 300 patients included in the chart review, 198 (66%) received 1L PD- 1/L1 inhibitor and 102 (34%) received 2L PD-1/L1 inhibitor. Following discontinuation of PD-1/L1 inhibitor therapy, 34% (n = 68) received subsequent therapy in 2L and 29% (n = 30) in third-line (3L). The median OS post-1L PD-1/L1 inhibitor was 9.4 (95% CI 8.6-NA) and 2.5 months (95% CI 2.24-3.50) for those who received and did not receive subsequent therapy, respectively. Following 2L PD-1/L1 inhibitor discontinuation, the median OS was 5.7 (95% CI 5.1-7.8) and 3.98 (95% CI 3.29-4.87) months for those who received and did not receive subsequent therapy, respectively. Among those with PRO data, 64% reported experiencing cancer-related pain and 29.6% received an opioid. Only 12.7% reported having a caregiver, requiring approximately 13 h/d of service. Conclusion: The symptom and caregiver burden are high among real-world patients with la/mUC who discontinued 1L or 2L PD-1/L1 inhibitors and outcomes are dismal, with a minority receiving subsequent therapy. Patterns of care in the setting of 1L maintenance avelumab and novel agents require further investigation. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) is a steroid hormone receptor widely detected in breast cancer. Evidence suggests that the AR might be a tumor suppressor in estrogen receptor alpha-positive (ERα+ve) breast cancer but a tumor promoter in estrogen receptor alpha-negative (ERα-ve) breast cancer. Modulating AR activity could be a potential strategy for treating breast cancer. For ERα+ve breast cancer, activation of the AR had been demonstrated to suppress the disease. In contrast, for ERα-ve breast cancer, blocking the AR could confer better prognosis to patients. These studies support the feasibility of utilizing AR modulators as anti-cancer drugs for different subtypes of breast cancer patients. Nevertheless, several issues still need to be addressed, such as the lack of standardization in the determination of AR positivity and the presence of AR splice variants. In future, the inclusion of the AR status in the breast cancer report at the time of diagnosis might help improve disease classification and treatment decision, thereby providing additional treatment strategies for breast cancer. [ABSTRACT FROM AUTHOR]

We present 4 consecutive cases of CCH that were treated with half dose and full fluence PDT, all of them exhibiting good anatomical and functional outcomes comparable with standardized PDT (full dose-full fluence). Due to the vascular characteristics of the hemangioma, photodynamic therapy (PDT) provides an effective treatment and is considered the gold standard therapeutic approach for this condition [[1], [3]]. Keywords: choroidal hemangioma; choroidal tumor; photodynamic therapy; novel treatment EN choroidal hemangioma choroidal tumor photodynamic therapy novel treatment 1748 7 11/17/22 20221101 NES 221101 1. Modified approaches using half-dose and/or half-fluence modalities have been evaluated in treating CSCR and polypoidal choroidal vasculopathy, with non-inferior anatomical and functional outcomes vs. standard PDT treatment protocols [[12], [18]]. [Extracted from the article]

The aim of this study was to develop a novel peptide potentially applicable for the treatment of metabolic conditions, such as obesity and type 2 diabetes (T2D). We identified CHM-273S from the list of peptides from milk hydrolysate obtained by HPLC/MS-MS. In vitro analysis of primary murine fibroblasts indicated the potential of CHM-273S to upregulate IRS2 mRNA expression. CHM-273S showed a prominent anorexigenic effect in mice with the induction of a key mechanism of leptin signaling via STAT3 in the hypothalamus as a possible effector. In the animal model of metabolic disease, CHM-273S alleviated glucose intolerance and insulin resistance, and induced phosphorylation of Akt at Ser473 and Thr308 in the hepatocytes of high-sucrose diet-fed rats. In a murine model of T2D, CHM-273S mitigated high-fat diet-induced hyperglycemia and insulin resistance and improved low-grade inflammation by diminishing serum TNFα. Mice treated with chronic CHM-273S had a significant reduction in body weight, with a lower visceral fat pad weight and narrow adipocytes. The effects of the peptide administration were comparable to those of metformin. We show the potential of CHM-273S to alleviate diet-induced metabolic alterations in rodents, substantiating its further development as a therapeutic for obesity, T2D, and other metabolic conditions. [ABSTRACT FROM AUTHOR]

Abstract Background Alcohol use increases risk for morbidity and mortality and is associated with over 3 million annual deaths worldwide. Contingency Management (CM) is one of the most effective interventions for substance use disorders, and has recently been coupled with technologies to promote novel treatments for alcohol use disorders (AUD). Leveraging these technological advances, we are developing the Automated Reinforcement Management System (ARMS), an integrated CM system designed to enable CM treatment as a component of a digital therapeutic or adjunct therapy remotely to anyone with a smartphone. Objective To collect detailed provider feedback on ARMS and determine the need for modifications to make the system most feasible, acceptable, and useful to providers. Methods Seven providers completed one-hour structured interviews/focus groups wherein we described the ARMS system and its application to clinical care. Providers viewed screen shots of the ARMS provider facing and patient facing systems. Providers gave feedback on their current AUD treatment practices, preferences for the functionality and appearance of the system, preferences for receipt of information on their patients, why they and their patients would or would not use the system, suggestions for improvement, and the proposed intervention overall. To analyze the qualitative data gathered, we used a qualitative descriptive approach with content analysis methods. Results The overarching theme of Individualized Treatment emerged throughout the interviews. This sentiment supports use of ARMS, as it is intended to supplement provider communication and intervention as an adjunctive and customizable tool with the ability to reach rural patients, not a stand-alone option. Themes of Accountability and Objective Assessment arose during discussions of why people would use the system. Themes within provider obstacles included, Information Overload and Clinical Relevance, and in patient obstacles, Sustained Engagement and Security Concerns. Two themes emerged regarding suggestions for improvement: Increasing Accessibility and Bi-directional Communication. Discussion Themes from provider input are being used to modify ARMS to make it more user friendly, time saving, and relevant to treatment of AUD. If successful, ARMS will provide effective, individualized-digital therapeutic for those needing adjunctive treatment or those living in rural remote areas needing better connected care.

Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing the most common tumors in women worldwide. To date, no long-term or noninvasive treatment option exists for hormone-dependent uterine fibroids, due to the limited knowledge about the molecular mechanisms underlying the initiation and development of uterine fibroids. This paper comprehensively summarizes the recent research advances on uterine fibroids, focusing on risk factors, development origin, pathogenetic mechanisms, and treatment options. Additionally, we describe the current treatment interventions for uterine fibroids. Finally, future perspectives on uterine fibroids studies are summarized. Deeper mechanistic insights into tumor etiology and the complexity of uterine fibroids can contribute to the progress of newer targeted therapies. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation has improved survival for patients with acute myeloid leukemia (AML), especially for patients with disease at high risk of relapse. However, relapse remains the most common cause of treatment failure and death in the posttransplant period. Maintenance therapy, an extended course of treatment after achieving remission to reduce the rate of relapse, is an important component of the treatment of various hematologic malignancies; however, its role in the treatment of AML is far less welldefined. Recently, there has been significant interest in the use of novel therapeutic agents as maintenance therapy after allogeneic stem cell transplant, utilizing new mechanisms of treatment and more favorable toxicity profiles. In this review, we will discuss the mechanistic and clinical data for post-transplant maintenance therapies in AML. Then, we will review several emergent and current clinical trials which aim to incorporate novel agents into maintenance therapy regimens. [ABSTRACT FROM AUTHOR]

Inclusion body myositis (IBM) is a late onset sporadic myopathy with a characteristic clinical presentation, but as yet unknown aetiology or effective treatment. Typical clinical features are early predominant asymmetric weakness of finger flexor and knee extensor muscles. Muscle biopsy shows endomysial inflammatory infiltrate, mitochondrial changes, and protein aggregation. Proteostasis (protein turnover) appears to be impaired, linked to potentially dysregulated chaperone-mediated autophagy and mitophagy (mitochondrial quality control). In this review, we bring together the most recent clinical and biological data describing IBM. We then address the question of diagnosing this pathology and the relevance of the current biological markers that characterize IBM. In these descriptions, we put a particular emphasis on data related to the deregulation of autophagic processes and to the mitochondria-lysosome crosstalk. Finally, after a short description of current treatments, an overview is provided pointing towards novel therapeutic targets and upcoming regulating molecules tested for treating IBM. Special attention is paid to autophagy inhibitors that may offer innovative breakthrough therapies for patients with IBM., Competing Interests: Declaration of competing interest SM is named as co-inventor on CNRS-ImmuPharma patents relating to the P140 peptide. She declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Pyoderma gangrenosum (PG) is a rare, chronic, ulcerative disease characterized by non-healing wounds that worsen with debridement, a phenomenon called pathergy. No consensus regarding pathogenesis, diagnosis, or treatment exists for PG. A previous pilot study using dehydrated human amniotic/chorionic membrane (dHACM), following excisional debridement, augmented PG wound healing and allowed for subsequent wound closure through split-thickness skin grafting (STSG). In this clinical trial (NCT05120726), four patients with an established PG diagnosis were enrolled to undergo treatment with dHACM and characterize the pre- and post-treatment transcriptome profiles. RNA sequencing was used to isolate the total RNA from specimens. Genes of particular interest were quantified through real-time quantitative reverse transcription polymerase chain reaction. We observed varied changes to the local expression of inflammatory response, positive regulators of cellular proliferation, and extracellular matrix disassembly cytokines. All PG wounds produced granulation tissue following treatment and were closed using split-thickness skin grafts., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The corresponding author serves as a paid consultant for Aroa Biosurgery and is on the advisory board for Prytime Medical. Otherwise, the authors have no relevant conflicts of interest to disclose.

Chronic urticaria (CU) is a common and long-lasting mast cell-mediated skin disease associated with psychiatric and autoimmune comorbidities, high economic costs, and considerable impact on quality of life. Available therapies show limited efficacy in many CU patients, which may be related to distinct underlying pathophysiology. Targeted and disease-modifying treatments with higher and broader efficacy are needed and are under development for CU. These novel drugs, small molecules, and monoclonal antibodies target mast cells and their receptors, signaling pathways, or mediators and other immune cells. In this article, the authors focus on the most promising emerging therapeutics in advanced development and discuss their potential place in future management of CU., Competing Interests: Disclosure MMu: is or recently was a speaker and/or advisor for and/or has received research funding from AstraZeneca, Blueprint, Takeda and Roche. E. Kocatürk is or recently was a speaker and/or advisor for and/or has received research funding from Novartis, Menarini, LaRoche Posey, Sanofi, Bayer, Germany. M. Maurer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Allerdia, Amgen, United States, Aralez, Argenx, Netherlands, AstraZeneca, United Kingdom, Celldex, United States, Centogene, CSL Behring, United States, FAES, United States, Genentech, United States, GIInnovation, Innate Pharma, France, Kyowa Kirin, LEO Pharma, Denmark, Lilly, Menarini, Moxie, Novartis, Switzerland, Pfizer, United States, Roche, Switzerland, Sanofi, United States/Regeneron, United States, Third Harmonic Bio, UCB, Belgium, and Uriach. P. Kolkhir was a speaker/consultant and/or advisor for and/or has received research funding from Novartis, ValenzaBio and Roche outside of submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: This review looks at novel combinations of topical agents (i.e., zinc gluconate, zinc oxide, dexpanthenol, and taurine) that target a combination of mechanisms in diaper dermatitis. Methods: A literature search of published studies was conducted using the search terms “diaper dermatitis”, “treatment of diaper dermatitis in infants”, “treatment of diaper dermatitis in adults”, “nonsteroidal”, “nonantibiotic”, “antiinflammatory”, “moisturizer”, and “treatment for irritation”. A total of 207 related articles were screened, and those categorized as clinical trials and reviews were studied and compared. Articles with common themes were categorized, summarized, and presented herein. Results: Diaper dermatitis, also referred to as diaper rash, napkin dermatitis, and nappy rash, is the most common skin eruption in infants and toddlers. In the last several years, there have been several technologic advances in diaper design to lessen the severity of diaper dermatitis symptoms. However, due to the unique environment of the diaper area, children and adults continue to have recurring symptoms of diaper dermatitis. Both commercially available products and certain home remedies are considered effective for managing sensitive and delicate skin in the diaper area. These topical agents create a protective barrier over the skin and reduce the impact of external irritants, which cause the reddening and burning sensation often associated with diaper dermatitis. Conclusion: A range of therapeutic strategies for preventing and controlling diaper dermatitis are summarized in this manuscript.

Allogeneic stem cell transplantation has improved survival for patients with acute myeloid leukemia (AML), especially for patients with disease at high risk of relapse. However, relapse remains the most common cause of treatment failure and death in the post-transplant period. Maintenance therapy, an extended course of treatment after achieving remission to reduce the rate of relapse, is an important component of the treatment of various hematologic malignancies; however, its role in the treatment of AML is far less well-defined. Recently, there has been significant interest in the use of novel therapeutic agents as maintenance therapy after allogeneic stem cell transplant, utilizing new mechanisms of treatment and more favorable toxicity profiles. In this review, we will discuss the mechanistic and clinical data for post-transplant maintenance therapies in AML. Then, we will review several emergent and current clinical trials which aim to incorporate novel agents into maintenance therapy regimens.

The study and use of resilience is of the utmost importance to psychodynamic psychiatry. It is deeply ingrained in ideas about well-being and the treatment and care of patients. However, its neurobiology is incompletely understood, its terminology and relation to trauma and coping not well defined, and its efficacy underutilized in clinical practice. This article reviews the scientific literature on resilience, especially as it relates to trauma and coping. It also attempts to point the way for its greater application in psychiatry and mental health by utilizing resilience in more informed and individualized approaches. [ABSTRACT FROM AUTHOR]

Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Therefore, additional novel approaches are needed to improve outcomes for MM patients. The oncogenic transcription factor MYC drives cell growth, differentiation and tumor development in many cancers. MYC protein levels are tightly regulated by the proteasome and an increase in MYC protein expression is found in more than 70% of all human cancers, including MM. In addition to the ubiquitin-dependent degradation of MYC by the 26S proteasome, MYC levels are also regulated in a ubiquitin-independent manner through the REGγ activation of the 20S proteasome. Here, we demonstrate that a small molecule activator of the 20S proteasome, TCH-165, decreases MYC protein levels, in a manner that parallels REGγ protein-mediated MYC degradation. TCH-165 enhances MYC degradation and reduces cancer cell growth in vitro and in vivo models of multiple myeloma by enhancing apoptotic signaling, as assessed by targeted gene expression analysis of cancer pathways. Furthermore, 20S proteasome enhancement is well tolerated in mice and dogs. These data support the therapeutic potential of small molecule-driven 20S proteasome activation for the treatments of MYC-driven cancers, especially MM. [ABSTRACT FROM AUTHOR]

We have previously described the LCGA-17 peptide as a novel anxiolytic and antidepressant candidate that acts through the α2δ VGCC (voltage-gated calcium channel) subunit with putative synergism with GABA-A receptors. The current study tested the potential efficacy of acute and chronic intranasal (i.n.) LCGA-17 (0.05 mg/kg and 0.5 mg/kg) in rats on predator odor-induced conditioned place aversion (POCPA), a model of post-traumatic stress disorder (PTSD), and chronic unpredictable stress (CUS) that produce a range of behavioral and physiological changes that parallel symptoms of depression in humans. CUS and LCGA-17 treatment effects were tested in the sucrose preference (SPT) social interaction (SI), female urine sniffing (FUST), novelty-suppressed feeding (NSFT), and forced swim (FST) tests. Analysis of the catecholamines content in brain structures after CUS was carried out using HPLC. The efficacy of i.n. LCGA-17 was also assessed using the Elevated plus-maze (EPM) and FST. Acute LCGA-17 administration showed anxiolytic and antidepressant effects in EPM and FST, similar to diazepam and ketamine, respectively. In the POCPA study, LCGA-17 significantly reduced place aversion, with efficacy greater than doxazosin. After CUS, chronic LCGA-17 administration reversed stress-induced alterations in numerous behavioral tests (SI, FUST, SPT, and FST), producing significant anxiolytic and antidepressant effects. Finally, LCGA-17 restored the norepinephrine levels in the hippocampus following stress. Together, these results support the further development of the LCGA-17 peptide as a rapid-acting anxiolytic and antidepressant. [ABSTRACT FROM AUTHOR]

Abstract Until recently, acute myeloid leukemia (AML) patients used to have limited treatment options, depending solely on cytarabine + anthracycline (7 + 3) intensive chemotherapy and hypomethylating agents. Allogeneic stem cell transplantation (Allo-SCT) played an important role to improve the survival of eligible AML patients in the past several decades. The exploration of the genomic and molecular landscape of AML, identification of mutations associated with the pathogenesis of AML, and the understanding of the mechanisms of resistance to treatment from excellent translational research helped to expand the treatment options of AML quickly in the past few years, resulting in noteworthy breakthroughs and FDA approvals of new therapeutic treatments in AML patients. Targeted therapies and combinations of different classes of therapeutic agents to overcome treatment resistance further expanded the treatment options and improved survival. Immunotherapy, including antibody-based treatment, inhibition of immune negative regulators, and possible CAR T cells might further expand the therapeutic armamentarium for AML. This review is intended to summarize the recent developments in the treatment of AML.

Background: Alcohol use increases risk for morbidity and mortality and is associated with over 3 million annual deaths worldwide. Contingency Management (CM) is one of the most effective interventions for substance use disorders, and has recently been coupled with technologies to promote novel treatments for alcohol use disorders (AUD). Leveraging these technological advances, we are developing the Automated Reinforcement Management System (ARMS), an integrated CM system designed to enable CM treatment as a component of a digital therapeutic or adjunct therapy remotely to anyone with a smartphone. Objective: To collect detailed provider feedback on ARMS and determine the need for modifications to make the system most feasible, acceptable, and useful to providers. Methods: Seven providers completed one-hour structured interviews/focus groups wherein we described the ARMS system and its application to clinical care. Providers viewed screen shots of the ARMS provider facing and patient facing systems. Providers gave feedback on their current AUD treatment practices, preferences for the functionality and appearance of the system, preferences for receipt of information on their patients, why they and their patients would or would not use the system, suggestions for improvement, and the proposed intervention overall. To analyze the qualitative data gathered, we used a qualitative descriptive approach with content analysis methods. Results: The overarching theme of Individualized Treatment emerged throughout the interviews. This sentiment supports use of ARMS, as it is intended to supplement provider communication and intervention as an adjunctive and customizable tool with the ability to reach rural patients, not a stand-alone option. Themes of Accountability and Objective Assessment arose during discussions of why people would use the system. Themes within provider obstacles included, Information Overload and Clinical Relevance, and in patient obstacles, Sustained Engagement and Security Concerns. Two themes emerged regarding suggestions for improvement: Increasing Accessibility and Bi-directional Communication. Discussion: Themes from provider input are being used to modify ARMS to make it more user friendly, time saving, and relevant to treatment of AUD. If successful, ARMS will provide effective, individualized-digital therapeutic for those needing adjunctive treatment or those living in rural remote areas needing better connected care. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a common inflammatory disease with several implications on health, disability and economy. Conventional treatment for RA centers on anti-inflammatory drugs and specific targeting of tumor necrosis factor  (TNF-) and interleukin 6 (IL-6). Baricitinib is a novel, Food and Drug Administration (FDA) approved, once daily oral drug that is effective in combination with current treatment and results in significantly reduced symptoms with good safety profile. Further studies are required to find rare side effects and evaluate the long term efficacy in disease modulation and patient symptom reduction. This is a comprehensive review of the literature on baricitinib for the treatment of RA. This review provides an update on the pathophysiology, diagnosis and conventional treatment of RA, then proceeds to introduce baricitinib and the data that exists to support or refute its use in RA. The presented study also indicated clinical trials confirming the effectiveness of baricitinib in this indication.