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Purpose: To evaluate the effect of interleukin-6 (IL-6) inhibitor (tocilizumab) on bacterial infection-associated bone resorption around implants during osseointegration in rabbits. Materials and Methods: At total of 24 male, 9-monthold New Zealand white rabbits were included, and their two mandibular anterior teeth were extracted. Three months after extraction, 24 one-piece Dentium implants (Ø 2.5 mm, intraosseous length of 12 mm) were inserted in the anterior mandible, and the rabbits were divided into four groups (n = 6 per group). Different treatment methods were used in each group: blank control group (BC); only silk ligation (negative control [NC]); silk ligation and injection with minocycline hydrochloride ointment (positive control [PC]); and silk ligation and injection with tocilizumab at 8 mg/kg via the auricle vein (experimental [EP]). Eight weeks later, the animals were sacrificed, and samples were collected and then analyzed using microcomputed tomography (microCT) scanning, immunohistochemical analysis, and histologic analysis. Results: From the microCT measurement, the ratio of the bone volume to the total volume (BV/TV) in the EP group was 67.00% ± 2.72%, which was higher than that in the other three groups (58.85% ± 2.43% in the BC group, 55.72% ± 2.48% in the PC group, and 36.52% ± 3.02% in the NC group). From immunohistochemical analysis, the expression of IL-6 was found to be higher in the NC group than in the BC, PC, and EP groups, but there was no statistical difference between these three groups. Furthermore, the RANKL (receptor activator of nuclear factor-κB ligand) expression was the lowest in the EP group, followed by the BC group, the PC group, and the NC group, which had the highest expression; there was no difference between the NC and PC groups. Upon histologic analysis, significant new bone was found on the implant surfaces in the EP group, sparse and less new bone could be seen in the BC and PC groups, and the most serious bone resorption occurred in the NC group. Conclusions: Tocilizumab, an inhibitor of IL-6, has a certain effect in preventing bone loss around implants caused by bacterial infection during the osseointegration period. [ABSTRACT FROM AUTHOR]

Laccase is a multicopper enzyme that plays a unique role in bioremediation of environmental pollutants. Bacteria were isolated from hospital wastewater and screened for laccase production. The laccase production process condition was optimised, and the laccase obtained was characterised. The 16S rRNA molecular analysis conducted on the best laccase producer revealed a Bacillus sp. NU2 identified. The process conditions: pH5, 45°C, 100 rpm, 5% inoculum, and growth constituents viz: tangerine peel and wheat bran agro-wastes, beef extract, ammonium persulfate, glucose, galactose, xylose, sorbitol, fructose carbon sources; and 4-aminophenol inducer optimally stimulated laccase production. The Bacillus sp. NU2 laccase was optimal at pH and temperature conditions of 8.0°C and 60°C, with a noteworthy pH and thermal stability observed. Furthermore, NU2 laccase showed a moderate/high tolerance and relative activity effect on various chemical inhibitors, halides and surfactant of triton x-100 (105 ± 0.92%), PMSF (107 ± 0.81%), and NaCl (94 ± 0.81%) at 1, 3, and 6 (mM) concentration. Additionally, NU2 laccase maintained a relative activity of 101%, 104%, and 102% for Mg2+, Zn2+, and Fe3+ at 1, 3, and 6 mM respectively. Acetone and propanol significantly upregulated laccase activity at 114 ± 0.0008% and 118.24 ± 0.35 and also at 30 and 20 (%) concentrations. Conclusively, the tolerant effect of Bacillus sp. NU2 laccase in pH, temperature, inhibitors and organic solvents suggests its potential for biotechnological application and promotion of a greener environment. [ABSTRACT FROM AUTHOR]

This review article provides an in-depth examination of various aspects related to tirzepatide, a synthetic peptide given the positive signal by the "United States Food and Drug Administration" for managing type 2 diabetes. Beginning with an overview of diabetes introduction, epidemiology, and issues related to β-cell dysfunction, is explored in the narrative. It further delves into the significance of incretins in the context of diabetes and introduces tirzepatide as a novel "twincretin" owing to its dual agonistic activity on the glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptors. The document delves into the chemistry and structure of tirzepatide, providing insights into its unique composition of 39 amino acids derived from native GLP-1, GIP, and semaglutide sequences. Tirzepatide's pharmacology, with a focus on its pharmacokinetic characteristics, and its mechanism of action (MOA) are extensively discussed. Notably, tirzepatide exhibits a preference for GIP receptors, leading to effective reduction of hyperglycemia and positive effects on pancreatic β-cells. Clinical trials examining tirzepatide's impact on glycemic and obesity control are detailed, demonstrating its efficacy in reducing body weight and appetite. Furthermore, the review article explores tirzepatide's effects on cardiovascular and kidney function, highlighting potential renal benefits for diabetic and elevated cardiovascular risk individuals. The narrative also addresses the association between tirzepatide and NAFLD, emphasizing potential benefits in mitigating NAFLD outcomes. Additionally, a comprehensive overview of tirzepatide's side effects, supported by scientific trials, is presented in this article. In conclusion, this review article provides a thorough examination of tirzepatide's multifaceted impact on diabetes management, shedding light on its pharmacological properties, clinical implications, and potential side effects. The information presented contributes to a comprehensive understanding of tirzepatide's role in the evolving landscape of T2D therapeutics. [ABSTRACT FROM AUTHOR]

Objectives Fibrodysplasia ossificans progressiva (FOP) is one of the most catastrophic forms of genetic heterotopic ossification (HO). FOP is characterized by severe, progressive inflammatory flare-ups, that often lead to HO. The flare-ups are associated with increased inflammatory cytokine production, suggesting auto-inflammatory features driven by IL-1β. This study describes the short- and long-term responses of FOP patients to anti-IL-1 therapy. Methods Previously, we reported that a patient with FOP treated with anti-IL-1 agents showed dramatically lower rates of flare-ups, improved flare-up symptoms, decreased use of glucocorticoids and apparently decreased size of residual lesions. Plasma analyses also showed marked elevation in IL-1β levels during a FOP flare, further supporting a role of IL-1β in the pathogenesis of FOP flares. Here, we report results from long-term therapy with IL-1 inhibitors in that patient and describe 3 additional patients, from two medical centres. Results All 4 patients showed persistent improvement in flare activity during treatment with IL-1 inhibitors, with minimal formation of new HO sites. Two patients who stopped therapy experienced a resurgence of flare activity that was re-suppressed upon re-initiation. These patients had IL-1β levels comparable to those in IL-1β-driven diseases. Child Health Assessment Questionnaires confirmed extensive subjective improvements in the pain and general health visual analogue scales. Conclusion This case series demonstrates significant benefits from IL-1 inhibitors for reducing flare activity and improving the general health of patients with FOP. These data provide strong support for additional studies to better understand the function of IL-1 inhibition, primarily in reducing the formation of new HO. Funding RH received support from the International FOP Association ACT grant; ECH received support from NIH/NIAMS R01AR073015 and the UCSF Robert Kroc Chair in Connective Tissue and Rheumatic Diseases III. [ABSTRACT FROM AUTHOR]

Despite extensive works have been devoted to study the scale inhibition behavior, the performance of inhibitors is still not fully understood. In this paper, we present a laboratory study to elucidate the impact of water composition on the performance of some commonly used phosphonate and polymeric calcium carbonate scale inhibitors, in highly supersaturated brines at high temperature. Calcium tolerance inhibitor chemicals with various molecular structures are studied using dynamic scale loop test method at 150 °C. Brine composition is varied by changing the non-stoichiometry of scaling lattice ions, e.g., ( Ca 2 + ) / ( CO 3 2 − ) ratio, over a wide range. Test results indicate that the effectiveness of inhibitors can be significantly changed by the scaling ion ratio. In general, the efficacy of inhibitors decreases significantly with calcium concentration in the test brine even at constant supersaturation state and temperature, and also the performance ranking of the different inhibitor chemistries can be changed with brine composition. This could be caused by the alternations of interactions between inhibitor molecules and the surface of calcium carbonate scale crystals. Findings from this study suggest that the effect of scaling ion ratio must be considered in scaling risk assessment and for the optimization of inhibitor treatment programs. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to quantitatively compare the efficacy and safety of CDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors for ER+/HER2− metastatic breast cancer. Methods: A parametric survival function was used to analyze the time course of overall survival (OS) and progression-free survival (PFS). The objective response rate (ORR) and the incidence of any grade and grade 3–4 adverse events were summarized using the random-effects model of a single-arm meta-analysis. Results: This study included 44 arms from 48 publications, with a total sample size of 7881 patients. Our study revealed that CDK4/6 inhibitors had a median OS of 40.7 months, a median PFS of 14.8 months, and an ORR of 40%, whereas PI3K/AKT/mTOR inhibitors had a median OS of 29.8 months, a median PFS of 8.3 months, and an ORR of 20%. Additionally, this study also found that the proportion of patients with visceral metastases and specific endocrine therapy used in combination significantly impact OS and PFS. In terms of adverse events, CDK4/6 inhibitors exhibited a relatively high incidence of hematological adverse events. Conclusion: Our study provides solid quantitative evidence for the first-line recommendation of CDK4/6 inhibitors combined with endocrine therapy for ER+/HER2− metastatic breast cancer in clinical guidelines. [ABSTRACT FROM AUTHOR]

Obicetrapib is a selective inhibitor of cholesteryl ester transfer protein that is currently in phase 3 of development for the treatment of dyslipidemia as adjunct therapy. The purpose of this study was to comprehensively characterize the pharmacokinetic (PK) and pharmacodynamic (PD) disposition of obicetrapib. Data from 7 clinical trials conducted in healthy adults and those with varying degrees of dyslipidemia were included for model development. The structural model that best described obicetrapib PK was a 3‐compartment model with 4‐compartment transit absorption and first‐order elimination. Body weight was the only covariate found to significantly explain observed variability and was therefore included using allometric scaling on all disposition parameters. For a typical patient weighing 75 kg, the estimated apparent total body clearance and apparent volume of distribution of the central compartment was 0.81 L/h and 36.1 L, respectively. The final PK model parameters were estimated with good precision and were ultimately leveraged to sequentially inform 2 turnover models that describe obicetrapib's effect on low‐density lipoprotein cholesterol (LDL‐C) and high‐density lipoprotein cholesterol (HDL‐C) concentrations. The maximum stimulatory effect of obicetrapib on LDL‐C loss was estimated to be 1.046, while the maximum inhibitory effect of obicetrapib on HDL‐C loss was 0.691. This corresponds to a predicted typical maximum percent change from baseline LDL‐C and HDL‐C of 51.1% and 224%, respectively. The final sequential model described obicetrapib PKPD well and was ultimately able to both demonstrate evidence of internal consistency and support decision‐making throughout the development lifecycle. [ABSTRACT FROM AUTHOR]

Cancer remains a significant global health challenge, and despite remarkable advancements in therapeutic strategies, poor tolerability of drugs (causing dose reduction/interruptions) and/or the emergence of drug resistance are major obstacles to successful treatment outcomes. Metastatic renal cell carcinoma (mRCC) accounts for 2% of global cancer diagnoses and deaths. Despite the initial success of targeted therapies in mRCC, challenges remain to overcome drug resistance that limits the long‐term efficacy of these treatments. Our analysis aim was to develop a semi‐mechanistic longitudinal exposure‐tumor growth inhibition model for patients with mRCC to characterize and compare everolimus (mTORC1) and apitolisib's (dual PI3K/mTORC1/2) ability to inhibit tumor growth, and quantitate each drug's efficacy decay caused by emergence of tumor resistance over time. Model‐estimated on‐treatment tumor growth rate constant was 1.7‐fold higher for apitolisib compared to everolimus. Estimated half‐life for loss of treatment effect over time for everolimus was 16.1 weeks compared to 7.72 weeks for apitolisib, suggesting a faster rate of tumor re‐growth for apitolisib patients likely due to the emergence of resistance. Goodness‐of‐fit plots including visual predictive check indicated a good model fit and the model was able to capture individual tumor size–time profiles. Based on our knowledge, this is the first clinical report to quantitatively assess everolimus (mTORC1) and apitolisib (PI3K/mTORC1/2) efficacy decay in patients with mRCC. These results highlight the difference in overall efficacy of 2 drugs due to the quantified efficacy decay caused by emergence of resistance, and emphasize the importance of model‐informed drug development for targeted cancer therapy. [ABSTRACT FROM AUTHOR]

With the continued development of biologics for the treatment of psoriasis, some patients have achieved optimal control, but a recommended biologic sequence if a biologic fails to initially improve the skin, termed primary nonresponse, or loses efficacy after initial improvement, termed secondary nonresponse, is still lacking. Primary and secondary nonresponse can occur with any class of biologics, and the type of nonresponse can drive the choice of whether to switch within a biologic class or to a different biologic class. The choice of biologic can also be challenging when managing psoriasis and concomitant psoriatic arthritis, as treatment differs on the basis of the severity of both diseases and further classification of axial and peripheral joint involvement. When choosing a biologic, each patient's comorbidities and preferences are also taken into account to provide the optimal therapy. With this lack of an established biologic sequence after biologic failure, the objective of our review is to define a therapy sequence for the tumor necrosis factor (TNF), interleukin-17 (IL-17), and interleukin-23 (IL-23) inhibitor classes in the treatment of psoriasis and psoriatic arthritis. Our proposed biologic sequence was derived through an analysis of the efficacy of each biologic class, primary and secondary nonresponse rates from clinical trials, and clinical experience with expert opinion. [ABSTRACT FROM AUTHOR]

Hedgehog pathway inhibitors (HHIs) have broadened the treatment options available for patients with advanced basal cell carcinoma (BCC) for whom traditional therapeutic approaches are not feasible or effective. Sonidegib and vismodegib are oral HHIs that were approved for treatment of patients with advanced BCC after demonstrating promising efficacy in the pivotal Phase II BOLT (NCT01327053) and ERIVANCE (NCT00833417) trials, respectively. However, the incidence and types of treatment-emergent adverse events (AEs) observed with these agents may limit continuous use of HHIs and ultimately impact clinical outcomes. In this review, we summarize the safety and tolerability profiles of sonidegib and vismodegib and discuss potential management strategies for HHI class-effect AEs, including muscle spasms, creatine phosphokinase increase, alopecia, and dysgeusia. These AEs primarily occur early in treatment and can lead to treatment discontinuation. Differences in the pharmacokinetic profiles of sonidegib and vismodegib may contribute to the variability noted in times to onset and resolution of these and other AEs. Evidence suggests that protocol modifications, such as treatment interruptions and dose reductions, are effective ways to manage AEs while maintaining disease control. Nonpharmacologic and pharmacologic interventions may also be considered as part of an AE management strategy. Overall, healthcare providers and patients with advanced BCC should be aware of the HHI class-effect AEs and plan effective management strategies to avoid treatment discontinuation and optimize therapeutic response. [ABSTRACT FROM AUTHOR]

The article focuses on examining the progression of tau pathology relative to the duration of amyloid-beta positivity in Alzheimer's disease and the correlation between the length of amyloid-beta positivity and the spread of tau pathology, the impact of tau pathology on cognitive decline.

Summary: In this large population-based matched cohort study, patients with primary aldosteronism were at increased risk of hip fracture, particularly subgroups traditionally considered at higher risk of osteoporosis such as women, patients older than 56 years at diagnosis, patients with established cardiovascular disease at diagnosis, and patients treated with MRA. Purpose: Previous studies suggest that primary aldosteronism (PA) is associated with dysregulated bone homeostasis. The aim of this study was to evaluate the incidence of hip fractures in patients with PA. Methods: We studied a nationwide cohort of 2419 patients with PA (1997–2019) and 24 187 age and sex matched controls from the general population. Hip fractures were identified by ICD codes in the Swedish National Patient Register. We estimated hazard ratios (HRs) for incident hip fractures, adjusted for prior fractures, socioeconomic factors, diabetes, osteoporosis, hyperparathyroidism, and cardiovascular disease (CVD). Pairwise subgroup comparisons were performed by age (18–56 and > 56 years), sex, CVD at baseline, and treatment for PA. Results: During a mean follow up of 8 ± 5 years, 64 (2.6%) patients had a hip fracture after being diagnosed with PA, compared to 401 (1.7%) controls. After adjustments, PA was associated with a 55% increased risk of hip fracture compared to controls (HR 1.55 [1.18–2.03]). HRs were increased in women (HR 1.76 [95% CI 1.24–2.52]), patients aged > 56 years (HR 1.62 [95% CI 1.21–2.17]), and patients with CVD at diagnosis (HR 2.15 [95% CI 1.37–3.37]). PA patients treated with adrenalectomy did not have higher risk than controls (HR 0.84 [95% CI 0.35–2.0]), while patients treated with mineralocorticoid receptor antagonists (MRA) retained a greater risk (HR 1.84 [95% CI 1.20–2.83]). Conclusion: PA is associated with increased hip fracture risk, especially in women, patients diagnosed after the age of 56 years and patients with established CVD at diagnosis. Also, patients treated with MRA seem to have an increased risk of hip fractures, while adrenalectomy may be protective. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) affects as many as 1 in 200 people in the adult population globally. Patients may present with exertional dyspnea, presyncope or syncope, atrial and ventricular arrhythmias, heart failure, and even sudden cardiac death. Current guideline-based therapy involves medical therapy for treatment of symptoms in milder forms of the disease and surgical or catheter-based septal reduction therapies in obstructive HCM. Until recently, there has existed a gap between these two approaches that is now being filled by a new class of drugs, cardiac myosin inhibitors, which directly target the underlying disease process in HCM. Current investigations examine the effects of two cardiac myosin inhibitors on reported symptoms, echocardiographic evidence of disease, and the associated need for septal reduction. This paper reviews the contemporary evidence for the use of cardiac myosin inhibitors in HCM in adults and highlights future directions for this exciting field of cardiovascular medicine. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a severe complication of acute respiratory distress syndrome (ARDS). Emerging studies have revealed the effects of pyrrolidine dithiocarbamate (PDTC) on improving surgery-induced cognitive impairment. The major aim of the study was to investigate whether PDTC protected against ARDS-induced cognitive dysfunction and to identify the underlying mechanisms involved. The rat model of ARDS was established by intratracheal instillation of lipopolysaccharide (LPS), followed by treatment with PDTC. The cognitive function of rats was analyzed by the Morris Water Maze, and pro-inflammatory cytokines were assessed by quantitative real-time PCR, enzyme-linked immunosorbent assay, and western blot assays. A dual-luciferase reporter gene assay was performed to identify the relationship between miR-181c and its target gene, TAK1 binding protein 2 (TAB2). The results showed that PDTC improved cognitive impairment and alleviated neuroinflammation in the hippocampus in LPS-induced ARDS model. Furthermore, we demonstrated that miR-181c expression was downregulated in the hippocampus of the ARDS rats, which was restored by PDTC treatment. In vitro studies showed that miR-181c alleviated LPS-induced pro-inflammatory response by inhibiting TAB2, a critical molecule in the nuclear factor (NF)-κB signaling pathway. PDTC improves cognitive impairment in LPS-induced ARDS by regulating miR-181c/NF-κB axis-mediated neuroinflammation, providing a potential opportunity for the treatment of this disease. [ABSTRACT FROM AUTHOR]

Considering the established pharmacokinetics and toxicity profiles, drug repurposing has emerged as an alternative therapeutic approach for treating cancer. Mefloquine has previously demonstrated inhibitory effects on multiple cancer types. This study aims to explore the impact of mefloquine on nasopharyngeal carcinoma (NPC). We found that mefloquine, at pharmacologically achievable concentrations, displayed anti-NPC activity while sparing normal counterparts. Mefloquine inhibits proliferation and induces death by reducing the levels of Cyclin A2, Bcl-2, and Bcl-xL. Intriguingly, we observed an increase in the levels of the anti-apoptotic protein Mcl-1. Mefloquine exerts its effects on NPC cells by inducing lysosomal-mediated ROS production, and the heightened expression of Mcl-1 is a consequence of ROS generation in mefloquine-treated NPC cells. The combination of an Mcl-1 inhibitor with mefloquine synergistically inhibits NPC growth in mice without causing substantial toxicity. These findings demonstrate the effectiveness and limited toxicity of mefloquine as a monotherapy and in combination with an Mcl-1 inhibitor. Our research underscores the promise of the mefloquine and Mcl-1 inhibitor combination as a potential treatment for NPC. Additionally, the elevation of Mcl-1 is a compensatory response in cells exposed to oxidative stress, offering a potential target to overcome resistance induced by pro-oxidant therapies. [ABSTRACT FROM AUTHOR]

The article examines the safety of using mineralocorticoid receptor antagonists (MRAs) in heart failure patients with renal dysfunction, based on a post hoc analysis of the RALES and EMPHASIS HF trials. Topics discussed include the potential for MRAs to worsen renal function, the overall benefits of continuing MRA therapy despite renal impairment, and the increased risk of hyperkalemia associated with MRAs in patients with reduced glomerular filtration rate (GFR).

Introduction: Limited awareness exists regarding real-world data (RWD) for palbociclib in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced/metastatic breast cancer in populations from certain countries outside of Western regions. Methods: A systematic scoping review was conducted using PubMed and Embase to evaluate RWD for palbociclib from countries outside of Western regions that are underrepresented in clinical trials. Search criteria were aligned with our research question for relevant English-language publications, without restrictions on publication date, followed by Phase 1 (title and abstract) and Phase 2 (full-text) screening of retrieved citations as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data analyses of eligible studies were done separately for abstracts and full-text publications to enhance the precision and reliability of the results. Results: Database search yielded 1485 non-duplicate records, 46 qualified for inclusion, of which 47.8% were published as full text. The analysis of outcomes, based exclusively on full-text publications that collectively included 2048 patients treated with palbociclib, revealed the median progression-free survival (PFS) of 20.2–36.7 months, overall survival (OS) of 39.9 months (reported in one publication) and objective response rate (ORR) of 45.3–80.0% with first-line treatment. In ≥ second line, the median PFS, OS and ORR ranged from 7.0 to 24.2 months, 11 to 19.6 months, and 13.9% to 47.9%, respectively. The safety profile of palbociclib was similar to that reported in pivotal clinical studies, and no new safety concerns were identified. Conclusions: A comprehensive volume of evidence demonstrates that palbociclib's effectiveness and safety profile in real-world settings align with those observed in clinical trials, offering valuable insights for clinical decision-making in countries outside of Western regions underrepresented in clinical trials. [ABSTRACT FROM AUTHOR]

Summary Interleukin‐18 (IL‐18), a potent and multifunctional pro‐inflammatory cytokine, plays a critical role in regulating β‐cell failure, β‐cell death, insulin resistance, and various complications of diabetes mellitus (DM). It exerts its effects by triggering various signaling pathways, enhancing the production of pro‐inflammatory cytokines and nitric oxide (NO), as well as promoting immune cells infiltration and β‐cells death. Abnormal alterations in IL‐18 levels have been revealed to be strongly associated with the onset and development of DM and its complications. Targeting IL‐18 may present a novel and promising approach for DM therapy. An increasing number of IL‐18 inhibitors, including chemical and natural inhibitors, have been developed and have been shown to protect against DM and diabetic complications. This review provides a comprehensive understanding of the production, biological functions, action mode, and activated signaling pathways of IL‐18. Next, we shed light on how IL‐18 contributes to the pathogenesis of DM and its associated complications with links to its roles in the modulation of β‐cell failure and death, insulin resistance in various tissues, and pancreatitis. Furthermore, the therapeutic potential of targeting IL‐18 for the diagnosis and treatment of DM is also highlighted. We hope that this review will help us better understand the functions of IL‐18 in the pathogenesis of DM and its complications, providing novel strategies for DM diagnosis and treatment. [ABSTRACT FROM AUTHOR]

The ATR kinase responds to elevated levels of single-stranded DNA (ssDNA) to activate the G2/M checkpoint, regulate origin utilization, preserve fork stability, and allow DNA repair to ensure genome integrity. The intrinsic replication stress in cancer cells makes this pathway an attractive therapeutic target. The ssDNA that drives ATR signaling is sensed by the ssDNA-binding protein replication protein A (RPA), which acts as a platform for ATRIP recruitment and subsequent ATR activation by TopBP1. We have developed chemical RPA inhibitors (RPAi) that block RPA-ssDNA interactions (RPA-DBi) and RPA protein–protein interactions (RPA-PPIi); both activities are required for ATR activation. Here, we biochemically reconstitute the ATR kinase signaling pathway and demonstrate that RPA-DBi and RPA-PPIi abrogate ATR-dependent phosphorylation of target proteins with selectivity advantages over active site ATR inhibitors. We demonstrate that RPA post-translational modifications (PTMs) impact ATR kinase activation but do not alter sensitivity to RPAi. Specifically, phosphorylation of RPA32 and TopBP1 stimulate, while RPA70 acetylation does not affect ATR phosphorylation of target proteins. Collectively, this work reveals the RPAi mechanism of action to inhibit ATR signaling that can be regulated by RPA PTMs and offers insight into the anti-cancer activity of ATR pathway-targeted cancer therapeutics. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the long-term cost-effectiveness of conventional care (CC) and seven first-line targeted therapies marketed in China for the treatment of patients with ankylosing spondylitis (AS)–namely secukinumab, ixekizumab, infliximab, etanercept, adalimumab and golimumab and tofacitinib–from the perspective of the Chinese health care system. Methods: The York model was structured as a 12-week decision tree leading into two Markov models. This study set 1 year as a recurring cycle and a lifetime timeframe for the model. Primary model outcomes included the costs in Chinese yuan (CNY), health outcomes in quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) under a willingness-to-pay threshold of ¥89,358 (equal to the per capita gross domestic product in China in 2023) per QALY. Parameters in the York model were captured from network meta-analyses and literature including treatment response, short-term disease progression, patient functioning and long-term structural disease progression. Utilities are dependent on indicators such as the BASDAI score, the BASFI score, gender and age. Drug prices were analysed using the median price of the Chinese market from YAOZH net in the basic analysis. Costs and outcomes were discounted at 5.0%. We performed deterministic and probabilistic sensitivity analyses to investigate the robustness of the results. The prices of original drugs and generic drugs were used in the scenario analysis. Results: Compared with CC, the ICER of golimumab was ¥104,217.4/QALY, which is between 1 and 3 times the GDP per capita, while the ICERs of the other six targeted therapies were less than ¥89,358/QALY. The specific economic rank of the targeted therapy was as follows: secukinumab > ixekizumab > tofacitinib > infliximab > etanercept > adalimumab > golimumab. Treatment response rates such as the BASDAI50, changes in the BASDAI/BASFI scores and the discounting rate were key model drivers. According to the scenario analysis, IL-17 inhibitors were still the most economical intervention when original drugs and generic drugs were used. Conclusion: Targeted therapies are cost-effective treatments for AS. Overall, IL-17 inhibitors were the dominant treatment. The choice of the brand-new prices or generic drug prices can greatly affect economics. [ABSTRACT FROM AUTHOR]

Tunlametinib (科露平®) is an oral, selective, mitogen-activated protein kinase kinase 1 and 2 (MEK 1/2) inhibitor being developed by Shanghai KeChow Pharma, Inc. for the treatment of solid tumours with RAS and RAF mutations, including melanoma, non-small cell cancer (NSCLC), colorectal cancer (CRC) and neurofibromatosis type 1 (NF1) plexiform neurofibromas. In March 2024, tunlametinib was granted conditional approval in China (based on surrogate endpoints) for use in patients with NRAS-mutated advanced melanoma who have failed anti-PD-1/PD-L1 treatment. This article summarizes the milestones in the development of tunlametinib leading to this first approval for the treatment of solid tumours with RAS and RAF mutations. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment options for lung cancer have greatly expanded in the last decade. Immune checkpoint inhibitors for patients without driver mutations have become the standard of care in widespread disease and, more recently, localized disease. However, resistance can develop, and new treatments are needed. We discussed current combination treatments with radiation and chemotherapy, as well as newer agents. Lung cancer continues to contribute to the highest percentage of cancer-related deaths worldwide. Advancements in the treatment of non-small cell lung cancer like immune checkpoint inhibitors have dramatically improved survival and long-term disease response, even in curative and perioperative settings. Unfortunately, resistance develops either as an initial response to treatment or more commonly as a progression after the initial response. Several modalities have been utilized to combat this. This review will focus on the various combination treatments with immune checkpoint inhibitors including the addition of chemotherapy, various immunotherapies, radiation, antibody–drug conjugates, bispecific antibodies, neoantigen vaccines, and tumor-infiltrating lymphocytes. We discuss the status of these agents when used in combination with immune checkpoint inhibitors with an emphasis on lung cancer. The early toxicity signals, tolerability, and feasibility of implementation are also reviewed. We conclude with a discussion of the next steps in treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Glutamine (Gln) plays a critical role in the development and progression of prostate cancer (PCa). Non-malignant prostate cells are not addicted to Gln, but PCa cells become Gln-dependent due to the low levels of the Gln-producing enzyme glutamine synthetase. Gln metabolism in PCa is controlled by oncogenes such as MYC, AR, and mTOR, which contribute to therapy resistance and more aggressive forms of the disease. Studies have shown that depriving PCa cells of Gln can inhibit their growth and survival and make them more sensitive to radiotherapy. Targeting Gln metabolism is, therefore, a promising approach for PCa treatment. Clinical trials are currently testing the safety and efficacy of drugs that inhibit Gln metabolism in combination with other therapies for different types of cancer, including PCa. Understanding of how tumor cells metabolically interact with their environment may help improve these treatments and patient outcomes. In this review, we present the latest advances in Gln research in PCa and insights into the current clinical trials. Glutamine (Gln) is a non-essential amino acid that is involved in the development and progression of several malignancies, including prostate cancer (PCa). While Gln is non-essential for non-malignant prostate epithelial cells, PCa cells become highly dependent on an exogenous source of Gln. The Gln metabolism in PCa is tightly controlled by well-described oncogenes such as MYC, AR, and mTOR. These oncogenes contribute to therapy resistance and progression to the aggressive castration-resistant PCa. Inhibition of Gln catabolism impedes PCa growth, survival, and tumor-initiating potential while sensitizing the cells to radiotherapy. Therefore, given its significant role in tumor growth, targeting Gln metabolism is a promising approach for developing new therapeutic strategies. Ongoing clinical trials evaluate the safety and efficacy of Gln catabolism inhibitors in combination with conventional and targeted therapies in patients with various solid tumors, including PCa. Further understanding of how PCa cells metabolically interact with their microenvironment will facilitate the clinical translation of Gln inhibitors and help improve therapeutic outcomes. This review focuses on the role of Gln in PCa progression and therapy resistance and provides insights into current clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Regorafenib offers longer survival for patients with refractory metastatic colorectal cancer (mCRC). We aimed to identify biomarkers for regorafenib through preclinical and translational studies. In silico analysis identified matrix metalloproteinase (MMP)-14 and MMP-9 as key biomarkers. Validation in patients receiving regorafenib or FTD/TPI showed that high MMP-14 levels were correlated with a better response to regorafenib. Additionally, lower MMP-9 levels before the second cycle were linked to improved disease control and survival. These findings suggest that MMP-14 and MMP-9 could serve as prognostic markers for regorafenib efficacy. In identifying biomarkers for anticancer drugs, the lack of objectivity in selecting candidate factors makes interpretation difficult. We performed preclinical analysis and a translational validation study to identify candidate biomarkers for regorafenib efficacy in metastatic colorectal cancer (mCRC). Using in silico COMPARE analysis with a human cancer cell line panel, JFCR39, we selected candidate biomarkers whose expression correlates with regorafenib sensitivity. We validated predictive values in mCRC patients receiving regorafenib (discovery, n = 53) and FTD/TPI (control, n = 16). Blood samples were obtained at baseline (BL), before the second cycle (2nd), and at progressive disease (PD), and biomarker levels were measured using ELISA. Our analysis showed that high matrix metalloproteinase (MMP)-14 expression was associated with a high sensitivity to regorafenib. In the discovery cohort, high MMP-14 levels at BL and PD were correlated with tumor shrinkage and longer progression-free survival (PFS). A subsequent analysis of other related factors further indicated that the patients with decreased MMP-9 levels at the 2nd had higher disease control rates, tumor shrinkage, longer PFS, and overall survival than those with increased changes. These findings were not observed in the control cohort. Our study suggests MMP-14 and MMP-9 may serve as prognostic markers for regorafenib and provide insights into novel combination therapies with anti-MMP-9 agents or FTD/TPI. [ABSTRACT FROM AUTHOR]

Simple Summary: Angiogenesis is a crucial process in the progression and metastasis of melanoma. Recent research has highlighted the significant role of epigenetic modifications in regulating angiogenesis. This review comprehensively examines the current understanding of how epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, influence angiogenic pathways in melanoma, with some important therapeutic approaches. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial process in the progression and metastasis of melanoma. Recent research has highlighted the significant role of epigenetic modifications in regulating angiogenesis. This review comprehensively examines the current understanding of how epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, influence angiogenic pathways in melanoma. DNA methylation, a key epigenetic modification, can silence angiogenesis inhibitors such as thrombospondin-1 and TIMP3 while promoting pro-angiogenic factors like vascular endothelial growth factor (VEGF). Histone modifications, including methylation and acetylation, also play a pivotal role in regulating the expression of angiogenesis-related genes. For instance, the acetylation of histones H3 and H4 is associated with the upregulation of pro-angiogenic genes, whereas histone methylation patterns can either enhance or repress angiogenic signals, depending on the specific histone mark and context. Non-coding RNAs, particularly microRNAs (miRNAs) further modulate angiogenesis. miRNAs, such as miR-210, have been identified as key regulators, with miR-9 promoting angiogenesis by targeting E-cadherin and enhancing the expression of VEGF. This review also discusses the therapeutic potential of targeting epigenetic modifications to inhibit angiogenesis in melanoma. Epigenetic drugs, such as DNA methyltransferase inhibitors (e.g., 5-azacytidine) and histone deacetylase inhibitors (e.g., Vorinostat), have shown promise in preclinical models by reactivating angiogenesis inhibitors and downregulating pro-angiogenic factors. Moreover, the modulation of miRNAs and lncRNAs presents a novel approach for anti-angiogenic therapy. [ABSTRACT FROM AUTHOR]

The article provides information on danicopan, a small molecule complement factor D inhibitor indicated as add-on therapy to ravulizumab or eculizumab for the treatment of extravascular hemolysis (EVH) in adults with paroxysmal nocturnal hemoglobinuria (PNH). Topics discussed include dosage and administration, drug interactions, and advice to patients.

Background: Clinically, most patients with lung cancer (LC) die from tumor spread and metastasis. Specific metastasis‐related molecules can provide reference for clinical prediction of efficacy, evaluation of prognosis, and search for the best treatment plan. Troponin T1 (TNNT1) is highly expressed in various cancer tissues, which affects malignant behavior of tumor cells and is related to patients' survival and prognosis. However, the role and molecular mechanism of TNNT1 in LC invasion and metastasis have not yet been investigated. Methods: Gene expression profiling interactive analysis (GEPIA) online analysis was used to analyze TNNT1 expression in LC tissues. Quantitative real‐time‐polymerase chain reaction (qRT‐PCR) or western blot were performed to measure TNNT1 or epithelial‐to‐mesenchymal transition (EMT)‐related and Wnt/β‐catenin pathway‐related protein expression in LC cells. After TNNT1 knockdown, cell scratch healing and transwell assays were introduced to assess cell migration and invasion, respectively. Results: TNNT1 expression in LC tissues and cells was increased. TNNT1 knockdown notably impaired LC cell migration, invasion and EMT. TNNT1 knockdown inhibited Wnt/β‐catenin pathway of LC cells. Lithium chloride (LiCl) addition partially restored the inhibition of TNNT1 knockdown on migration, invasion, EMT and Wnt/β‐catenin of LC cells. Conclusion: TNNT1 knockdown attenuated LC migration, invasion and EMT, possibly through Wnt/β‐catenin signaling. [ABSTRACT FROM AUTHOR]

Background: Peganum harmala L. is used in traditional medicine to treat several health ailments. Hence, the present work aimed to investigate the DPPH free radical scavenging, α-amylase, cytotoxic, and antifibrotic effects of the hydrophilic extract and fixed oil obtained from P. harmala seeds. Methods: The hydrophilic extract and fixed oil of P. harmala were assessed for their abilities to scavenge DPPH free radicals and inhibit α-amylase using reference bioassays. The cytotoxicity was assessed on several cancer and normal cell lines, including B16F1, Caco-2, COLO205, HeLa, Hep 3B and Hep G2, MCF-7, and HEK-293 T cells. The MTS assay was used to evaluate the antifibrotic capabilities utilizing the human hepatic stellate (LX-2) cell line. Results: P. harmala plant fixed oil has potent DPPH free radical scavenging activity with an IC50 dose of 79.43 ± 0.08 µg/ml. Besides, the hydrophilic extract has a poor anti-α-amylase effect compared with the antidiabetic drug Acarbose, with IC50 doses of 398 ± 0.59 and 25.11 ± 1.22 µg/ml, respectively. In addition, the growth of MCF-7, Hep3B, HepG2, HeLa, COLO205, CaCo2, B16F1, and HeK293t was inhibited by P. harmala hydrophilic extract with IC50 doses of 121.34 ± 1.71, 268.3 ± 0.75, 297.20 ± 1.00, 155.60 ± 1.14, 150.01 ± 0.51, 308.35 ± 0.53, 597.93 ± 1.36, and 5.38 ± 0.99 µg/ml, respectively. In addition, at 1000 µg/ml, 5-Fluorouracil reduced fibrosis cells by 0.089%, while the hydrophilic extract decreased the number of LX-2 cells by 5.81%. Conclusion: P. harmala plant-fixed oil exhibits potential antioxidant properties. While the hydrophilic extract showed limited effectiveness as an anti-α-amylase agent and demonstrated notable cytotoxic effects against various tested cancer cell lines. Furthermore, this extract significantly reduces the number of LX-2 fibrotic cells. These findings emphasize the therapeutic potential of these products in managing various health disorders and warrant further investigation into their mechanisms of action and clinical applications. [ABSTRACT FROM AUTHOR]

Introduction: Venous thromboembolism (VTE) is a major concern following total knee arthroplasty (TKA). The optimal pharmacological prophylaxis remains, however, controversial. The present investigation compared several non-vitamin K antagonist oral anticoagulants commonly employed as VTE prophylaxis following TKA. A Bayesian network meta-analysis was conducted to compare apixaban, aspirin, dabigatran, edoxaban, enoxaparin, fondaparinux, and rivaroxaban. The outcomes of interest were to compare the rate of deep venous thrombosis (DVT), pulmonary embolism (PE), and major and minor haemorrhages. Methods: This study was conducted according to the PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-Analyses of Health Care Interventions. In March 2024, PubMed, Web of Science, and Google Scholar were accessed with no time constraints. All randomised controlled trials (RCTs) comparing two or more drugs for the prevention of VTE following TKA were considered for inclusion. Results: Data from 29,678 patients were collected. Of them, 67% (19,884 of 29,678 patients) were women. The mean age of the patients was 66.8 ± 2.8 years, and the mean BMI was 29.2 ± 1.5 kg/m2. There was comparability in age, sex, and BMI at baseline. Apixaban 5 mg, dabigatran 220 mg, and rivaroxaban 10 mg were the most effective in reducing the rate of DVT. Apixaban 5 mg, enoxaparin 60 mg, and rivaroxaban 40 mg were the most effective in reducing the rate of PE. Apixaban 5 mg, rivaroxaban 10 mg, and apixaban 10 mg were associated with the lowest rate of major haemorrhages. Apixaban 5 mg and 20 mg, and dabigatran 220 mg were associated with the lowest rate of minor haemorrhages. Conclusion: Administration of apixaban 5 mg demonstrated the best balance between VTE prevention and haemorrhage control following TKA. Level of evidence: Level I, network meta-analysis of RCTs. [ABSTRACT FROM AUTHOR]

Objective: This systematic review and network meta-analysis aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) in adults aged 75 and over undergoing acute venous thromboembolism (VTE) treatment. Methods: PubMed, Embase and the CENTRAL were searched up to 25 December 2023. The incidence of VTE recurrence and bleeding events was assessed. Employing a frequentist network meta-analysis approach, interventions not directly compared could be indirectly assessed through the 95% confidence interval (CI), enhancing the interpretability of the search results. The surface under the cumulative ranking curves (SUCRA) was utilized to generate the relative ranking probabilities for each group. Results: Our study, analysing 6 randomised controlled trials with 3665 patients, compares direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in adults aged 75 and over with acute venous thromboembolism. Edoxaban reduces VTE recurrence risk compared with VKAs (risk ratio [RR].50, 95% CI 0.27 –.95), while apixaban significantly decreases bleeding risk compared with VKAs (RR.23, 95% CI 0.08 –.69), edoxaban (RR.28, 95% CI 0.09 –.86) and rivaroxaban (RR.28, 95% CI 0.09 –.86). Despite low overall evidence quality, apixaban consistently ranks highest for both efficacy and safety. Findings underscore the nuanced efficacy-safety balance in this population, emphasizing cautious interpretation due to evidence limitations. Conclusion: Apixaban emerges as a favourable choice for acute VTE treatment in the elderly, displaying reduced bleeding risk compared to other treatments while maintaining comparable efficacy. Future studies should explore diverse anticoagulants efficacy and safety in older populations. Additionally, clinical prediction models tailored to geriatric cohorts are crucial for guiding treatment duration decisions. [ABSTRACT FROM AUTHOR]

Background: Device‐related thrombosis (DRT) is a common finding after left atrial appendage closure (LAAC) and is associated with worse outcomes. As women are underrepresented in clinical studies, further understanding of sex differences in DRT patients is warranted. Methods and Results: This sub‐analysis from the EUROC‐DRT‐registry compromises 176 patients with diagnosis of DRT after LAAC. Women, who accounted for 34.7% (61/176) of patients, were older (78.0 ± 6.7 vs. 74.9 ± 9.1 years, p =.06) with lower rates of comorbidities. While DRT was detected significantly later in women (173 ± 267 vs. 127 ± 192 days, p =.01), anticoagulation therapy was escalated similarly, mainly with initiation of novel oral anticoagulant (NOAC), vitamin K antagonist (VKA) or heparin. DRT resolution was achieved in 67.5% (27/40) of women and in 75.0% (54/72) of men (p =.40). In the remaining cases, an intensification/switch of anticoagulation was conducted in 50.% (9/18) of men and in 41.7% (5/12) of women. Final resolution was achieved in 72.5% (29/40) cases in women, and in 81.9% (59/72) cases in men (p =.24). Women were followed‐up for a similar time as men (779 ± 520 vs. 908 ± 687 days, p =.51). Kaplan–Meier analysis revealed no difference in mortality rates in women (Hazard Ratio [HR]: 1.73, 95%‐Confidence interval [95%‐CI]:.68–4.37, p =.25) and no differences in stroke (HR:.83, 95%‐CI:.30–2.32, p =.72) within 2 years after LAAC. Conclusion: Evaluation of risk factors and outcome revealed no differences between men and women, with DRT in women being diagnosed significantly later. Women should be monitored closely to assess for DRT formation/resolution. Treatment strategies appear to be equally effective. [ABSTRACT FROM AUTHOR]

Background: A recent Phase 2/3 study in Japanese patients showed that caplacizumab was effective in treating immune-mediated thrombotic thrombocytopenic purpura (iTTP), with a low rate of iTTP recurrence. ADAMTS13 activity is monitored weekly during caplacizumab treatment to guide discontinuation of caplacizumab and consequently avoid exacerbations or relapse. The aim of this study was to assess changes in ADAMTS13 activity/inhibitor levels during caplacizumab treatment in this patient population. Methods: A post hoc analysis of the Phase 2/3 study in Japanese patients was conducted. Patients ≥ 18 years old with confirmed iTTP received 10 mg of caplacizumab daily in conjunction with therapeutic plasma exchange (TPE) and immunosuppression for 30 days post-TPE. Outcomes included time to recovery of ADAMTS13 activity, ADAMTS13 activity level at treatment end, incidence of ADAMTS13 inhibitor re-elevation (ie, inhibitor boosting) during treatment, time to platelet count recovery, number of days of TPE, and safety. Outcomes according to presence of inhibitor boosting were also assessed. Results: Nineteen patients had confirmed iTTP and were included in this analysis. Median (95% confidence interval) time to recovery of ADAMTS13 activity to ≥ 10%, ≥ 20%, and ≥ 60% was 14.6 (5.9–24.8), 18.5 (5.9–31.8), and 47.5 (18.5–60.9) days, respectively. Median (range) ADAMTS13 activity level at caplacizumab treatment end was 62.0% (29.0–101.0). Nine patients had ADAMTS13 inhibitor boosting. Delayed response of ADAMTS13 activity was observed in patients with inhibitor boosting. The median time to platelet count response and median number of TPE days were shorter in patients with inhibitor boosting compared with patients without inhibitor boosting. Rituximab was administered to almost all patients with inhibitor boosting (88.9%), after completion of TPE. Patients without inhibitor boosting who were treated with rituximab received it prior to completion of TPE. Only one patient experienced a recurrence, which occurred shortly after caplacizumab discontinuation due to an adverse event. Conclusions: In patients with iTTP, caplacizumab with TPE and immunosuppression may reduce the risk of ADAMTS13 inhibitor boosting if rituximab is administered early in the iTTP treatment period. Early administration of rituximab in addition to caplacizumab may prevent iTTP recurrence with inhibitor boosting. Trial registration: NCT04074187. [ABSTRACT FROM AUTHOR]

Objective: Spinal radiographic progression is an important outcome in radiographic axial spondyloarthritis (SpA). The objective of the phase IIIb SURPASS study was to compare spinal radiographic progression in patients with radiographic axial SpA treated with secukinumab (interleukin‐17A inhibitor) versus adalimumab biosimilar (Sandoz adalimumab [SDZ‐ADL]; tumor necrosis factor inhibitor). Methods: Biologic‐naive patients with active radiographic axial SpA, at high risk of radiographic progression (high‐sensitivity C‐reactive protein [hsCRP] ≥5 mg/L and/or ≥1 syndesmophyte[s] on spinal radiographs), were randomized (1:1:1) to secukinumab (150/300 mg) or SDZ‐ADL (40 mg). The proportion of patients with no radiographic progression (change from baseline [CFB] in modified Stoke Ankylosing Spondylitis Spinal Score [mSASSS] ≤0.5) on secukinumab versus SDZ‐ADL at week 104 (primary endpoint), mean CFB‐mSASSS, proportion of patients with ≥1 syndesmophyte(s) at baseline with no new syndesmophyte(s), and safety were evaluated. Results: Overall, 859 patients (78.5% male, mSASSS 16.6, Bath Ankylosing Spondylitis Disease Activity Index 7.1, hsCRP 20.4 mg/L, and 73.0% with ≥1 syndesmophyte[s]) received secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or SDZ‐ADL (n = 286). At week 104, the proportion of patients with no radiographic progression was 66.1%, 66.9%, and 65.6% (P = not significant, both secukinumab doses) and mean CFB‐mSASSS was 0.54, 0.55, and 0.72 in secukinumab 150 mg, secukinumab 300 mg, and SDZ‐ADL arms, respectively. Overall, 56.9%, 53.8%, and 53.3% of patients on secukinumab 150 mg, secukinumab 300 mg, and SDZ‐ADL, respectively, with ≥1 syndesmophyte(s) at baseline did not develop new syndesmophyte(s) by week 104. There were no unexpected safety findings. Conclusion: Spinal radiographic progression over two years was low with no significant difference between secukinumab and SDZ‐ADL arms. The safety of both treatments was consistent with previous reports. [ABSTRACT FROM AUTHOR]

BI 187004, a selective small‐molecule inhibitor of 11β‐hydroxysteroid dehydrogenase‐1 (11β‐HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β‐HSD1 inhibition (50%) was detected in a very low‐dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose‐dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target‐mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high‐affinity and low‐capacity target 11β‐HSD1. The non‐intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small‐molecule compound. Among the various models explored, the best model was a two‐compartment TMDD model with three transit absorption components. The final model provides insights into 11β‐HSD1 binding‐related parameters for BI 187004, including the total amount of 11β‐HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM−1h−1), and the first‐order dissociation rate constant (estimated to be 0.11 h−1). Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004's future clinical trials. [ABSTRACT FROM AUTHOR]

Objectives: Ixekizumab, an interleukin (IL)-17A inhibitor, exerts its therapeutic effects in psoriasis by inhibiting the interleukin (IL)-17 signaling pathway. Common adverse reactions to ixekizumab include injection site reactions and upper respiratory tract infections (URIs), while occurrences of inflammatory bowel disease (IBD) and multiple mucosal ulcers are infrequent. We present a case of a 51-year-old man who developed multiple mucosal ulcers after ixekizumab treatment. Methods: A 51-year-old man presented to our hospital with a 1-month history of pharyngalgia. The flexible laryngoscope displayed mild hyperemia in the pharyngeal mucosa and tonsils, redness and swelling of the epiglottis, as well as multiple ulcers in the oral cavity, uvula, and epiglottis. These ulcers did not improve with conventional treatment. Results: Upon evaluation, the ulcers were an immune-related adverse event induced by ixekizumab. Consequently, a decision was made to discontinue the drug and initiate a therapeutic regimen including corticosteroids and thalidomide. Eventually, the patient's symptoms abated. Conclusions: Biologics are now becoming increasingly popular in psoriasis. It is vital for clinicians to be aware of this potential adverse event and to identify and intervene early to alleviate patients' suffering. [ABSTRACT FROM AUTHOR]

Background: The growing incidence of lower gastrointestinal bleeding (LGIB) is leading to a rise in-hospital admissions even though most LGIB episodes are self-limiting. The Oakland and SHA2PE scores were designed to identify patients best suited to outpatient care. Our aim is explore the validity of the SHA2PE score and compare both of these scores in terms of predictiveness of safe discharge. Methods: Retrospective observational study of LGIB patients admitted to a tertiary hospital between June 2014 and June 2019. Safe discharge was defined as the absence of all the following: blood transfusion, haemostatic intervention, re-bleeding, in-hospital death, and re-admission due to LGIB within 28 days after discharge. Results: From 595 hospital admissions for LGIB, 398 episodes were included. Fifty-four per cent met safe discharge criteria, with these cases being younger, with a lower score in the Charlson's index and significantly higher haemoglobin concentration upon arrival. The performance of both scores was good, with an AUC for the Oakland score of 0.85 (95% CI 0.82–0.89) and of 0.797 (95% CI 0.75–0.84) for the SHA2PE score. The Oakland score performed better in terms of prediction of safe discharge, with a positive predictive value and specificity of 100% when a cut-off value of ≤ 8 points was used; however, only a minority of patients might benefit from its implementation given its low sensitivity. Conclusions: Almost half of the patients admitted for LGIB met criteria for safe discharge. However, the available indexes only allow for the identification of a small proportion of those patients candidates for outpatient care. [ABSTRACT FROM AUTHOR]

Over the past 50 years there have been great strides made in the discovery of the composition and relevance of the total stratum corneum (SC) ceramide matrix. However, the focus of this review is on the free intercellular class of ω‐linoleoyloxyacylceramides, corneocyte‐bound ceramides and associated lipids known as the corneocyte lipid envelope (CLE) together with their processing enzymes involved in aiding ceramide attachment the corneocyte protein envelope (CPE). Two structural models and partially shared biosynthetic pathways have been proposed for the attachment of CPE‐bound O‐ceramides (ω‐hydroxyceramides attached to glutamate residues of proteins in the (CPE) using the 12R‐lipoxygenase (12R‐LOX)/epidermal lipoxygenase‐3 (eLOX3)/epoxide hydrolase‐3 (EPHX3)/unknown esterase/ transglutaminase‐1 (TG1) attachment pathway) and CPE‐bound EO‐ceramides (epoxy‐enone ceramides attached to cysteine residues of proteins in the CPE using the 12R‐LOX/eLOX3/short chain dehydrogenase/reductase family 9C member 7 (SDR9C7)/non‐enzymatic attachment pathway), i.e. there is a bifurcation step beyond epidermal eLOX3. Their formation and structures will be discussed as well as their relevance in compromised skin barrier conditions together with our own work on SC maturation examined by proteomics, lipidomics, enzyme immunolocalization studies, mechanical fragility assays and Nile red staining of corneocyte envelopes (CE). Reduced levels of 12R‐LOX, eLOX3, SDR9C7 and TG1 were observed in photodamaged skin of the cheeks that were associated with reduced SC maturation as evidenced by Nile red staining and increased CE fragility. In the severely photodamaged cheeks of Albino African SC we also observed increased levels of acylceramides. Concomitantly by reducing the activity of 12R‐LOX by antibody inhibition and TG1 inhibition with a known chemical inhibitor, we demonstrated in a humidity‐based ex vivo SC maturation model that these enzymes contributed to increased CE hydrophobicity and mechanical integrity. We hypothesize that at least the CPE‐bound O‐ceramide pathway is operational in the SC. Nevertheless, our understanding of the full complexity of ω‐linoleoyloxyacylceramides and the composition of the CLE is limited particularly on cosmetically relevant body sites such as the face. [ABSTRACT FROM AUTHOR]

Simple Summary: Aquaporins (AQPs) have emerged as potential predictors of response to cancer therapy and as targets for increasing sensitivity to treatment. However, systemic therapeutic inhibition using pan-AQP or AQP-specific inhibitors has not been characterized for efficacy in treating breast cancer or as a component of combination treatment. We evaluated AQP inhibition using established AQP inhibitors in cytotoxicity and pharmacologic assays. This study identified AQPs as a targetable vulnerability in breast cancer. AQP inhibitors can increase therapeutic efficacy, both as single agents and in a combination therapy strategy, in treating breast cancer progression and metastasis. These results provide significant insights that support the future development of improved AQP inhibitors. AQPs contribute to breast cancer progression and metastasis. We previously found that genetic inhibition of Aqp7 reduces primary tumor burden and metastasis in breast cancer. In this study, we utilized two AQP inhibitors, Auphen and Z433927330, to evaluate the efficacy of therapeutic inhibition of AQPs in breast cancer treatment. The inhibitors were evaluated in breast cancer for both cytotoxicity and metabolic stability assays across both murine and human breast cancer cell lines. Both AQP inhibitors also affected the expression of other AQP transcripts and proteins, which demonstrates compensatory regulation between AQP family members. As a single agent, Auphen treatment in vivo extended overall survival but did not impact primary or metastatic tumor burden. However, Auphen treatment made cells more responsive to chemotherapy (doxorubicin) or endocrine treatment (tamoxifen, fulvestrant). In fact, treatment with Tamoxifen reduced overall AQP7 protein expression. RNA-seq of breast cancer cells treated with Auphen identified mitochondrial metabolism genes as impacted by Auphen and may contribute to reducing mammary tumor progression, lung metastasis, and increased therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we found that Auphen and tamoxifen cooperate to reduce breast cancer cell viability, which suggests that Auphen treatment makes the cells more susceptible to Tamoxifen. Together, this study highlights AQPs as therapeutic vulnerabilities of breast cancer metastasis that are promising and should be exploited. However, the pharmacologic results suggest additional chemical refinements and optimization of AQP inhibition are needed to make these AQP inhibitors appropriate to use for therapeutic benefit in overcoming endocrine therapy resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute myeloid leukemia (AML) arises from a stepwise acquisition of multiple genetic alterations in the hematopoietic stem and progenitor cell and is characterized by an accumulation of immature leukemic cells, called blasts, in the bone marrow and tissues. How the single gene alterations mediate the underlying processes is unclear in the majority of cases. IDH1/2 mutations are among the most frequent mutations in AML, accounting for about 15–20%, and are targets of specific small molecule inhibitors. Experimental evidence suggests that they occur early in leukemogenesis. Mostly, murine models of IDH1/2 mutations have been studied. Our study is the first to highlight that—in the human system—IDH1/2 mutants drive a complete block of hematopoietic cell differentiation in vitro, which is completely unleashed by the specific inhibitor, providing a model for early leukemogenesis studies in this setting. How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we study isocitrate dehydrogenase (IDH) gene mutations in the human model of HSPC and discuss the available literature on this topic. IDH1/2 mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on HSPCs, we expressed IDH1-R132H or IDH2-R140Q mutants into human CD34+ healthy donor cells via lentiviral transduction and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by specific inhibitors, confirming that it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed progressive and marked improvements in their fitness over time, in terms of CFU ability and propensity to differentiate. They attained clonal trilinear reconstitution of hematopoiesis and complete hematological remission. [ABSTRACT FROM AUTHOR]

Objective: Andexanet alfa is approved for the reversal of life-threatening or uncontrolled bleeding due to factor-Xa inhibitors. Data are limited on outcomes for patients who receive both andexanet alfa and 4-factor prothrombin complex concentrate (4F-PCC). The aim of this case series is to evaluate the safety and efficacy outcomes in patients receiving the two agents in combination. Methods: Electronic medical records of patients who received both 4F-PCC and andexanet alfa for nontraumatic intracranial hemorrhage from January 2019 to March 2022 were retrospectively reviewed. Hemostatic efficacy and complications related to concurrent use of 4F-PCC with andexanet alfa were documented. Results: Nine patients received 4F-PCC and andexanet alfa for reversal of factor Xa inhibitor-associated intracranial bleeding, eight of whom required reversal of apixaban. Of these nine patients, five patients died within 28 days for a 56% incidence of mortality. The average time from 4F-PCC administration to andexanet alfa administration was 3 hours and 9 minutes. Most doses of andexanet alfa were given for concern for bleed expansion after 4F-PCC administration. Hemostatic efficacy based on stability of repeat computed tomography scans post-administration of both agents was found in six patients (66.67%), with a 55.56% n incidence of thromboembolism, including two pulmonary embolisms, two deep vein thromboses, and one renal artery thrombosis. Conclusion : Risks and benefits should be weighed to determine if there is benefit to adding andexanet alfa to 4F-PCC in patients with incomplete hemostasis and life-threatening hemorrhage. The combination of andexanet alfa and 4F-PCC may increase the risk of thrombotic complications without improving mortality. [ABSTRACT FROM AUTHOR]

The author comments on banning puberty-pausing medications and how such endangers transgender adolescents. Topics covered include the prescribed treatment of gender-dysphoria in adolescents, how such types of medications are also used in a variety of other medical contexts and implication of legislation attacking the provision of puberty-pausing medications.

Phenolics produced during xylooligosaccharide production might inhibit xylanases and enhance the antioxidant and antimicrobial activities of XOS. The effects of phenolic compounds on xylanases may depend on the type and concentration of the compound, the plant biomass used, and the enzyme used. Understanding the effects of phenolic compounds on xylanases and their impact on XOS is critical for developing viable bioconversion of lignocellulosic biomass to XOS. Understanding the complex relationship between phenolic compounds and xylanases can lead to the development of strategies that improve the efficiency and cost-effectiveness of XOS manufacturing processes and optimise enzyme performance. [ABSTRACT FROM AUTHOR]

Introduction: Rheumatic heart disease with persistent atrial fibrillation (RHD‐AF) is associated with increased morbidity. However, there is no standardized approach for the maintenance of sinus rhythm (SR) in them. We aimed to determine the utility of a stepwise approach to achieve SR in RHD‐AF. Methods: Consecutive patients with RHD‐AF from July 2021 to August 2023 formed the study cohort. The stepwise approach included pharmacological rhythm control and/or electrical cardioversion (Central illustration). In patients with recurrence, additional options included AF ablation or pace and ablate strategy with conduction system pacing or biventricular pacing. Clinical improvement, NT‐proBNP, 6‐Minute Walk Test (6MWT), heart failure (HF) hospitalizations, and thromboembolic complications were documented during follow‐up. Results: Eighty‐three patients with RHD‐AF (mean age 56.13 ± 9.51 years, women 72.28%) were included. Utilizing this approach, 43 (51.81%) achieved and maintained SR during the study period of 11.04 ± 7.14 months. These patients had improved functional class, lower NT‐proBNP, better distance covered for 6MWT, and reduced HF hospitalizations. The duration of AF was shorter in patients who achieved SR, compared to those who remained in AF (3.15 ± 1.29 vs 6.93 ± 5.23, p = 0.041). Thirty‐five percent (29) maintained SR after a single cardioversion over the study period. Only one underwent AF ablation. Of the 24 who underwent pace and ablate strategy, atrial lead was implanted in 22 (hybrid approach), and 50% of these achieved and maintained SR. Among these 24, none had HF hospitalizations, but patients who maintained SR had further improvement in clinical and functional parameters. Conclusions: RHD‐AF patients who could achieve SR with a stepwise approach, had better clinical outcomes and lower HF hospitalizations. [ABSTRACT FROM AUTHOR]

mTORC1/2 dual inhibitors may be more effective than mTORC1 inhibitor rapamycin. However, their metabolic impacts on colon cancer cells remain unexplored. We conducted a comparative analysis of the anti-proliferative effects of rapamycin and the novel OSI-027 in colon cancer cells HCT-116, evaluating their metabolic influences through ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Our results demonstrate that OSI-027 more effectively inhibits colon cancer cell proliferation than rapamycin. Additionally, we identified nearly 600 metabolites from the spectra, revealing significant differences in metabolic patterns between cells treated with OSI-027 and rapamycin. Through VIP value screening, we pinpointed crucial metabolites contributing to these distinctions. For inhibiting glycolysis and reducing glucose consumption, OSI-027 was likely to be more potent than rapamycin. For amino acids metabolism, although OSI-027 has a broad effect as rapamycin, their effects in degrees were not exactly the same. These findings address the knowledge gap regarding mTORC1/2 dual inhibitors and lay a foundation for their further development and research. [ABSTRACT FROM AUTHOR]

Worldwide, pancreatic cancer (PC) is a major health problem and almost 0.5 million people were diagnosed with PC in 2020. In the United States, more than 64,000 adults will be diagnosed with PC in 2023. PC is highly resistant to currently available treatments and standard of care chemotherapies cause serious side effects. Most PC patients are resistant to clinical therapies. Combination therapy has showed superior efficacy over single-agent treatment. However, most therapy has failed to show a significant improvement in overall survival due to treatment-related toxicity. Developing efficacious clinically useful PC therapies remains a challenge. Herein, we show the efficacy of an innovative pathway modulator, p53-Activator Wnt Inhibitor-2 (PAWI-2) against tumors arising from human pancreatic cancer stem cells (i.e., hPCSCs, FGβ3 cells). PAWI-2 is a potent inhibitor of tumor growth. In the present study, we showed PAWI-2 potently inhibited growth of tumors from hPCSCs in orthopic xenograft models of both male and female mice. PAWI-2 worked in a non-toxic manner to inhibit tumors. Compared to vehicle-treated animals, PAWI-2 modulated molecular regulators of tumors. Anti-cancer results showed PAWI-2 in vivo efficacy could be correlated to in vitro potency to inhibit FGβ3 cells. PAWI-2 represents a safe, new approach to combat PC. [ABSTRACT FROM AUTHOR]

Mobocertinib (TAK-788) is a first-in-class oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that received accelerated approval for the treatment of patients with non-small cell lung cancer with EGFR exon 20 insertion mutations previously treated with platinum-based chemotherapy. This phase 1, 2-period, study was conducted to assess the absolute bioavailability of mobocertinib (Period 1), as well as mass balance, pharmacokinetics, metabolism, and excretion of [14C]-mobocertinib (Period 2) in healthy adult males. In Period 1, participants received a single oral capsule dose of 160 mg mobocertinib, followed by a 15-minute intravenous infusion of 50 µg (~ 2 µCi) [14C]-mobocertinib administered from 3.75 to 4 h after the capsule dose. In Period 2, a single oral dose of 160 mg (~ 100 µCi) [14C]-mobocertinib was administered as an oral solution. The geometric mean absolute bioavailability of mobocertinib was determined to be 36.7%. After oral administration of [14C]-mobocertinib, mobocertinib and its active metabolites, AP32960 and AP32914, were minor components in plasma, accounting for only 0.275% of total plasma radioactivity as the majority of mobocertinib-related material was covalently bound to plasma proteins. The geometric mean percentage of the administered radioactive dose recovered in the urine and feces was 3.57% and 76.0%, respectively. Only 0.39% of the oral dose of [14C]-mobocertinib was recovered in the urine as mobocertinib; thus, indicating that renal excretion of unchanged drug was a very minor pathway of elimination. In both treatment periods, mobocertinib was generally safe and well-tolerated as all adverse events were Grade 1 in severity. (Trial registration number ClinicalTrials.gov NCT03811834. Registration date January 22, 2019). [ABSTRACT FROM AUTHOR]

Background: Anticoagulant drugs are a valuable tool for minimizing thrombotic risks in at-risk patients. The purpose of this study is to conduct a literature review highlighting the management of these drugs during daily clinical dental practice. Materials and Methods: We limited our search to English-language papers published between 1 January 1989, and 7 March 2024, in PubMed, Scopus and Web of Science that were relevant to our topic. In the search approach, the Boolean keywords "anticoagulant AND dentistry" were used. Results: Twenty-five clinical trials were included for final review from 623 articles obtained from the databases Web of Science (83), PubMed (382), and Scopus (158), eliminating duplicates and 79 off-topic items, resulting in 419 articles after removing 315 entries and confirming eligibility. Overall, these studies support the use of local hemostatic measures to manage the risk of bleeding in patients on anticoagulant therapy undergoing dental procedures and highlight the importance of greater education and collaboration among healthcare professionals. Conclusions: Research and clinical investigation have improved understanding and management of dental procedures in patients undergoing anticoagulant or antiplatelet therapy. Hemostatic agents, clinical protocols, risk factors, and continuous education are essential for navigating the complexities of anticoagulant therapy, ensuring optimal outcomes and enhancing patient well-being. [ABSTRACT FROM AUTHOR]

Demodex blepharitis, a chronic lid margin disease, is caused by an infestation of Demodex mites, the most common ectoparasites in human skin and eyelids. Lotilaner ophthalmic solution, 0.25% (Xdemvy, Tarsus Pharmaceuticals), is the first therapy approved to treat Demodex blepharitis. This narrative review characterizes lotilaner ophthalmic solution, 0.25%, and describes its efficacy, safety, and tolerability. The safety and efficacy of lotilaner ophthalmic solution, 0.25%, for treating Demodex blepharitis was evaluated in four phase 2 and two phase 3 trials. The data of 980 patients included in these phase 2 and 3 clinical trials revealed that the proportion of eyes with a clinically meaningful reduction to 10 or fewer collarettes (the cylindrical, waxy debris found at the base of the eyelashes) ranged from 81 to 93%. The mite eradication rate confirmed by a microscopy of epilated lashes ranged from 52 to 78%. No serious treatment-related adverse events were reported in any of these clinical studies. As high as 92% of the patients receiving lotilaner eyedrops in the phase 3 trials found it to be neutral to very comfortable. Given the positive safety and efficacy outcomes, the drug is likely to become the standard of care in the treatment of Demodex blepharitis. [ABSTRACT FROM AUTHOR]

Background and Objective: Periodontitis is intimately associated with the development of various systemic diseases, among which type 2 diabetes mellitus (T2DM) has a bidirectional relationship with the pathogenesis of periodontitis. The objective of the present work was to investigate the role of berberine (BBR) in periodontitis with T2DM and related mechanisms. Methods: The mRNA expression of macrophage polarization‐related factors in the microenvironment of periodontal inflammation was detected using real‐time quantitative PCR (RT‐qPCR). The experimental periodontitis model was constructed in wild‐type (WT) and T2DM (db/db) mice, which were administered BBR after 7 days of modeling. Alveolar bone loss (ABL) in each group of mice was measured utilizing micro‐computed tomography images. RT‐qPCR was performed to analyze the levels of macrophage polarization‐related factors in mouse gingiva. Lastly, using western blotting and RT‐qPCR, the signaling pathway of BBR affecting macrophage polarization in the microenvironment of periodontitis was explored. Results: BBR inhibited M1 polarization and stimulated M2 polarization in the periodontitis microenvironment. BBR decreased ABL in the WT and T2DM periodontitis models. And BBR reduced the production of proinflammatory cytokines and increased anti‐inflammatory cytokine expression in the gingiva of WT and T2DM model mice. Ultimately, BBR mediates its anti‐inflammatory effects on periodontitis through inhibition of the NF‐κB pathway. Conclusions: BBR had a therapeutic effect on T2DM‐associated periodontitis via inhibiting the NF‐κB pathway to affect macrophage polarization, which may have implications for the new pharmacological treatment of T2DM‐associated periodontitis. [ABSTRACT FROM AUTHOR]