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Cancer and cardiovascular diseases are the two major causes of mortality, morbidity, and disability worldwide. The improvement in effective therapeutic options for the management of breast cancer (BC) has led to an increased number of BC survivors, who can experience longterm toxicities from cancer treatments. Adverse events including cardiovascular toxicities must be considered in light of effectiveness of recently approved drugs for BC treatment, including elacestrant, tucatinib, neratinib, olaparib, the immune checkpoint inhibitors, trastuzumab deruxtecan, or sacituzumab govitecan. Many cancer drugs affect the cardiovascular system with a range of clinical manifestations. Prompt diagnosis and treatment as well as a multidisciplinary approach involving a cardio-oncologist is optimal for management of these cardiovascular events. [ABSTRACT FROM AUTHOR]

Aims Non-invasive left ventricular (LV) pressure–strain loops provide a novel method for quantifying myocardial work by incorporating LV pressure in measurements of myocardial deformation. Early studies suggest that myocardial work parameters such as global constructive work (GCW) could be useful and reliable in arrhythmia prediction, particularly in patients undergoing cardiac resynchronization therapy (CRT). The aim of this study was to evaluate whether the magnitude of GCW was associated with the occurrence of ventricular arrhythmias in patients after CRT. Methods and results Patients on guideline-recommended treatment with a CRT defibrillator (CRT-D) were evaluated by 2D speckle-tracking echocardiography including measurements of GCW at least 6 months after implantation. The primary outcome was a composite of appropriate defibrillator therapy and sustained ventricular arrhythmia under the monitor zone. A total of 162 patients [mean age 66 years (±10), 122 males (75%)] were included. Sixteen (10%) patients experienced the primary outcome during a median follow-up of 18 months (interquartile range: 12–25) after the performance of index echocardiography. Patients with a below-median GCW (<1473 mmHg%) had a hazard ratio (HR) for the outcome of 8.14 [95% confidence interval (CI): 1.83–36.08], P = 0.006 compared with patients above the median in a univariate model and remained an independent predictor after multivariate adjustment for the estimated glomerular filtration rate and QRS duration [HR 4.75 (95% CI: 1.01–22.28), P < 0.05]. Conclusion In patients treated with CRT-D, a GCW below median level was associated with a five-fold increase in the risk of ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

Doxorubicin (Dox) may induce loss of follicles, resulting in the depletion of ovarian reserve and consequent premature ovarian failure. Selenium (Se) is an oligoelement with fundamental biological features and is among the most common chemical inhibitor compounds. The present study describes the curative effects of dietary supplementation with different Se doses on Dox‐induced ovarian damage in rats. In this study, 64 adult female Wistar rats were randomly separated into eight groups: Control group, Dox group (5 mg/kg intraperitoneal [i.p.]), low‐dose Se (0.5 mg/kg i.p.), middle dose Se (1 mg/kg i.p.), high dose (Se 2 mg/kg i.p.), Dox + low‐dose Se group (0.5 mg/kg i.p.), Dox + middle dose Se (1 mg/kg i.p.), and Dox + high‐dose Se group (2 mg/kg i.p.). After the experiment, ovarian follicles were counted, and Antimüllerian hormone, interleukin 1 beta, tumor necrosis factor alpha, and caspase‐3 expression were determined. Levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase were biochemically measured in ovarian tissue. Dox caused ovarian injury, as evidenced by significant changes in ovarian markers, histological abnormalities, and the debilitation of antioxidant defense mechanisms. Furthermore, Dox therapy significantly changed the expression of inflammatory and apoptotic markers. Dox + 1 mg Se with various saturations was studied, and this study demonstrated both histopathological and follicular reserve and more protective features. 1 mg Se pretreatment improved Dox‐induced ovarian toxicity through alleviating the antioxidant mechanism, decreasing inflammation and apoptosis, and restoring ovarian architecture. As a result, our findings indicate that 1 mg Se is a promising therapeutic agent for the prevention of ovarian damage associated with Dox. [ABSTRACT FROM AUTHOR]

Background Cancers with non-V600 BRAF-activating alterations have no matched therapy. Preclinical data suggest that these tumors depend on ERK signaling; however, clinical response to MEK/ERK inhibitors has overall been low. We hypothesized that a narrow therapeutic index, driven by ERK inhibition in healthy (wild-type) tissues, limits the efficacy of these inhibitors. As these mutants signal as activated dimers, we further hypothesized that RAF inhibitors given concurrently would improve the therapeutic index by opposing ERK inhibition in normal tissues and not activate ERK in the already activated tumor. Materials and Methods Using cell lines and patient-derived xenografts, we evaluated the effect of RAF inhibition, alone and in combination with MEK/ERK inhibitors. We then undertook a phase I/II clinical trial of a higher dose of the MEK inhibitor binimetinib combined with the RAF inhibitor encorafenib in patients with advanced cancer with activating non-V600 BRAF alterations. Results RAF inhibition led to modest inhibition of signaling and growth in activated non-V600 BRAF preclinical models and allowed higher dose of MEK/ERK inhibitors in vivo for more profound tumor regression. Fifteen patients received binimetinib 60 mg twice daily plus encorafenib 450 mg daily (6 gastrointestinal primaries, 6 genitourinary primaries, 3 melanoma, and 2 lung cancer; 7 BRAF mutations and 8 BRAF fusions). Treatment was well tolerated without dose-limiting toxicities. One patient had a confirmed partial response, 8 had stable disease, and 6 had radiographic or clinical progression as best response. On-treatment biopsies revealed incomplete ERK pathway inhibition. Conclusion Combined RAF and MEK inhibition does not sufficiently inhibit activated non-V600 BRAF-mutant tumors in patients. [ABSTRACT FROM AUTHOR]

The article provides information on bimekizumab-bkzx, a humanized interleukin-17A and F antagonist. Bimekizumab-bkzx is used to treat moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Also mentioned are its dosage and administration, drug interactions, and advice to patients.

The article describes the case of a 19-year-old female patient who was initially assessed at 16 years of age with complaint of recurrent fever episodes for six months. Topics discussed include differential diagnosis, a timeline showing the patient's clinical findings from admission and treatment over time, and observation of haemophagocytosis in the bone marrow aspiration.

Background. Anti-vascular endothelial growth factor (anti-VEGF) therapy via intravitreal injection is an effective treatment for patients with abnormal ocular neovascularization, such as age-related macular degeneration (AMD) and diabetic macular edema (DME). However, prolonged and frequent anti-VEGF treatment is associated with a risk of local and systemic adverse events, including geographic atrophy, cerebrovascular disease, and death. Furthermore, some patients do not adequately respond to anti-VEGF therapy. Hypoxia-inducible factor (HIF) is a transcription factor that controls the expression of hypoxia-responsive genes involved in angiogenesis, inflammation, and metabolism. The HIF/VEGF pathway plays an important role in neovascularization, and the inhibition of HIF activation could be an effective biomolecular target for neovascular diseases. The demand for disease prevention or treatment using functional foods such as superfoods has increased in recent years. Few reports to date have focused on the antineovascular effects of superfoods in the retinal pigment epithelium (RPE). In light of the growing demand for functional foods, we aimed to find novel HIF inhibitors from superfoods worked in RPE cells, which could be an adjuvant for anti-VEGF therapy. Methods. Seven superfoods were examined to identify novel HIF inhibitor candidates using luciferase assay screening. We used the human RPE cell line ARPE-19 and fetal human RPE (fhRPE) to investigate the biomolecular actions of novel HIF inhibitors using quantitative PCR and western blotting. Results. Under CoCl2-induced pseudohypoxic condition and 1% oxygen hypoxic incubation, camu-camu (Myrciaria dubia) showed HIF inhibitory effects determined by luciferase assays. Camu-camu downregulated HIF-1α and VEGFA mRNA expressions in a concentration-dependent manner. Camu-camu also inhibited HIF-1α protein expressions, and its inhibitory effect was greater than that of vitamin C, which is present at high levels in camu-camu. Conclusion. The camu-camu extract suppressed the activation of HIF and VEGF in RPE cells. This could assist anti-VEGF therapy in patients with abnormal ocular neovascularization. [ABSTRACT FROM AUTHOR]

Lung cancer is the most prevalent cancer in the world, and the main treatment for advanced non-small cell lung cancer is immunotherapy combined with chemotherapy. In recent years, bTMB has received increasing attention as an emerging metric for monitoring the efficacy of tumour immunotherapy in terms of its operability, accessibility and real-time nature. We envisaged whether immunotherapy alone could be used to reduce the side effects of chemotherapy in patients with high bTMB lung cancer. We thus did a meta-analysis in order to show that immunotherapy alone is feasible in patients with high bTMB NSCLC. Methods This study aims to compare the efficacy of PD- 1/PD-L1 inhibitors (namely, atezolizumab, pembrolizumab, nivolumab, or tislelizumab) versus chemotherapy in NSCLC patients. The search for relevant studies was conducted in three major databases (i.e., PubMed, Embase, and Medline) up until January 2023. Specifically, we identified studies that reported risk ratios (HRs) for reporting progression-free survival (PFS) or overall survival (OS), or objective remission rates (ORs) for immunotherapy alone versus chemotherapy in high bTMB and low bTMB patient groups. Given that NSCLC represents the predominant type of lung cancer, we exclusively focused on this subtype. Our analysis encompassed a meta-analysis of the identified literature, incorporating heterogeneity analysis and sensitivity analysis. The quality of the evidence is evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to ascertain the reliability and robustness of the findings. Result-We conducted a meta-analysis of seven randomised controlled trials including 4,755 patients with advanced non-small cell lung cancer (NSCLC) evaluated the efficacy of PD- 1 or PD-L1 monotherapy compared to chemotherapy alone. All patients were randomized to receive either PD- 1/PD-L1 treatment alone or chemotherapy alone as a control. In the high bTMB patient group, PD- 1/PD-L1 monotherapy resulted in significant improvements in overall survival (HR = 0.55, 95% CI 0.49–0.61, p = 0.77) and progression-free survival (HR = 0.74, 95% CI 0.68–0.81, p = 0.78) compared to chemotherapy alone. Conversely, in the low bTMB patient group, PD- 1 monotherapy or PD-L1 monotherapy failed to demonstrate significant improvements in overall survival (HR = 0.82, 95% CI 0.73–0.92, p = 0. 13) and progression-free survival (HR = 1.22, 95% CI 1.22- 1.45, p = 0.003) in advanced NSCLC. Conclusion Our analysis suggests that monotherapy with immunotherapy is a feasible option for patients with advanced NSCLC and high bTMB. However, the results have to be construed with caution because of the small sample size and the potential bias in the studies included. Therefore, further research with larger sample sizes and rigorous study designs is necessary to confirm the observed benefits of immunotherapy in this patient population. [ABSTRACT FROM AUTHOR]

Co-firing hydrogen (H 2) with hydrocarbon fuels is widely seen as an effective pathway to reduce soot emissions. Nevertheless, the soot-reducing potential of H 2 can be strongly dependent on the type of the co-fired hydrocarbon and the combustion conditions. In extreme cases H 2 enrichment could even promote soot production in hydrocarbon flames, thus highlighting the necessity of an in-depth understanding on the roles of H 2 addition. The present study aims to clarify the effects of H 2 addition on soot formation in non-premixed flames of propane. The effects of He and N 2 addition are included for a cross-comparison to identify the different effects of H 2 (i.e. , direct chemical roles, dilution or transport effects associated with fuel stream's physical properties). The technique of laser-induced incandescence (LII) was used for soot volume fraction measurement, and accompanying soot modeling analysis was performed for additional kinetic insights into the experimental results. The measurements and modeling results consistently show that H 2 is a more effective soot inhibitor than the chemical inert additive of He. Considering the comparative transport properties between H 2 and He, we concluded that H 2 has additional chemically-inhibiting effects on soot formation; kinetic analysis indicates that the chemical roles of H 2 mainly occur in the stages of soot precursor formation and soot nucleation process. Another interesting finding is that while both He and N 2 are chemically inert, He has notably stronger soot-reducing ability than N 2 , suggesting the favorable physical properties of He (i.e. , the high diffusivity) in reducing soot formation. The major contributions of this work include: 1) experimentally identify the different effects of H 2 (chemical, dilution and physical) on soot formation in counterflow flames of propane, 2) unravel the chemical roles of H 2 in the different sooting stages including soot precursors formation, soot inception and surface growth process, 3) provide new datasets for mechanism validation and refinement related to sooting characteristics of H 2 /hydrocarbon mixture fuels. • H 2 more effective in inhibiting soot than He and N 2 in propane flames. • The high diffusivity of H 2 /He contributes notably to soot inhibition. • The chemical roles of H 2 in different sooting stages discussed. • New soot data provided for mechanism validation in H 2 -enriched flame. [ABSTRACT FROM AUTHOR]

The uncontrolled spread of drug-resistant tuberculosis (DR-TB) clinical cases necessitates the urgent discovery of newer chemotypes with novel mechanisms of action. Here, we report the chemical synthesis of rationally designed novel transition-state analogues (TSAs) by targeting the cyclization (Cy) domain of phenyloxazoline synthase (MbtB), a key enzyme of the conditionally essential siderophore biosynthesis pathway. Following bio-assay-guided evaluation of TSA analogues preferentially in iron-deprived and iron-rich media to understand target preferentiality against a panel of pathogenic and non-pathogenic mycobacteria strains, we identified a hit, i.e., TSA-5. Molecular docking, dynamics, and MMPBSA calculations enabled us to comprehend TSA-5's stable binding at the active site pocket of MbtB_Cy and the results imply that the MbtB_Cy binding pocket has a strong affinity for electron-withdrawing functional groups and contributes to stable polar interactions between enzyme and ligand. Furthermore, enhanced intracellular killing efficacy (8 μg/mL) of TSA-5 against Mycobacterium aurum in infected macrophages is noted in comparison to moderate in vitro antimycobacterial efficacy (64 μg/mL) against M. aurum. TSA-5 also demonstrates whole-cell efflux pump inhibitory activity against Mycobacterium smegmatis. Identification of TSA-5 by focusing on the modular MbtB_Cy domain paves the way for accelerating novel anti-TB antibiotic discoveries. [ABSTRACT FROM AUTHOR]

Simple Summary: Low molecular weight heparin (LMWH) has been the standard of care for venous thromboembolism (VTE) but new guidelines approved using non-vitamin K antagonist oral anticoagulants (NOAC). By conducting an individual patient data meta-analysis of randomised controlled trials (RCTs) comparing the outcomes of NOAC versus LMWH in cancer patients, we aim to determine an ideal strategy for the prophylaxis of VTE and prevention of VTE recurrence. Our study further addresses the conflicting evidence in the literature with an individual patient data meta-analysis. However, other studies are required to balance the risk of recurrent VTE and bleeding among different cancer subgroups. Emerging data highlight the need for individualised antithrombotic strategies to achieve optimal management of cancer patients. Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in cancer patients. Low molecular weight heparin (LMWH) has been the standard of care but new guidelines have approved the use of non-vitamin K antagonist oral anticoagulants (NOAC). By conducting an individual patient data (IPD) meta-analysis of randomised controlled trials (RCTs) comparing the outcomes of NOAC versus LMWH in cancer patients, we aim to determine an ideal strategy for the prophylaxis of VTE and prevention of VTE recurrence. Three databases were searched from inception until 19 October 2022. IPD was reconstructed from Kaplan–Meier curves. Shared frailty, stratified Cox and Royston–Parmar models were fit to compare the outcomes of venous thromboembolism recurrence and major bleeding. For studies without Kaplan–Meier curves, aggregate data meta-analysis was conducted using random-effects models. Eleven RCTs involving 4844 patients were included. Aggregate data meta-analysis showed that administering NOACs led to a significantly lower risk of recurrent VTE (RR = 0.65; 95%CI: 0.50–0.84) and deep vein thrombosis (DVT) (RR = 0.60; 95%CI: 0.40–0.90). In the IPD meta-analysis, NOAC when compared with LMWH has an HR of 0.65 (95%CI: 0.49–0.86) for VTE recurrence. Stratified Cox and Royston–Parmar models demonstrated similar results. In reducing risks of recurrent VTE and DVT among cancer patients, NOACs are superior to LMWHs without increased major bleeding. [ABSTRACT FROM AUTHOR]

Simple Summary: The lysosomal lipid hydrolase acid ceramidase is upregulated in acute myeloid leukemia and promotes leukemic blast survival, underscoring its potential for therapeutic targeting. B-13 is an established ceramidase inhibitor with demonstrated efficacy in multiple solid cancers. Next-generation lysosome-localizing prodrugs of B-13 have been developed but have not been evaluated in AML. This study characterizes the in vitro anti-leukemic efficacy and cell death mechanisms of the B-13 analog and acid ceramidase inhibitor LCL-805 in acute myeloid leukemia. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 μM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 μM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide. [ABSTRACT FROM AUTHOR]

Simple Summary: The presence of t(11;14) in MM is a significant genetic abnormality and plays an essential role in tailoring treatment decisions. t(11;14) is present in 15% to 20% of MM and is associated with an upregulation of cyclin D1, leading to tumor cell proliferation. Patients harboring t(11;14) often exhibit clinical characteristics that position them between standard- and high-risk categories. Moreover, t(11;14) is associated with higher levels of BCL2, and published data demonstrate that t(11;14) is predictive of the BCL2 dependency. A better understanding of this genetic abnormality influences the choice of therapeutic approaches. In recent studies, the impact of t(11;14) on treatment responses was evident, which emphasize its role in shaping therapeutic strategies. In this review, we highlight the association of t(11;14) with other molecular abnormalities, raise questions about the predictive and prognostic value of t(11;14) in MM and summarize current clinical studies of BCL2 inhibitors in terms of efficacy and safety. Multiple myeloma (MM) represents a hematological neoplasia with an uncontrolled proliferation of malignant plasma cells and complex cytogenetic abnormalities. t(11;14) has emerged as a crucial genetic aberration and is one of the most common primary translocations in MM. Patients harboring t(11;14) represent a distinctive subgroup with a clinical profile that differs from t(11;14)-negative MM risk categories. One of the key features linked with t(11;14) is the BCL2 dependency, indicating vulnerability to BCL2 inhibition. BCL2 inhibitors, such as venetoclax, demonstrated impressive efficacy alone or in combination with other anti-myeloma drugs in patients with RRMM accompanied by t(11;14) and BCL2 overexpression. Therefore, t(11;14) plays a key role in both risk stratification and informed decision making towards a tailored therapy. In this review, we highlight the biology of t(11;14) in MM cells, summarize the current evolving role of t(11;14) in the era of novel agents and novel targeted therapies, illuminate current efficacy and safety data of BCL2-based treatment options and explore the future prospects of individualized precision medicine for this special subgroup of patients with MM. [ABSTRACT FROM AUTHOR]

Simple Summary: In Europe, seven out of eight patients with lung cancer die within 5 years after diagnosis. DDR1, a tyrosine kinase receptor, has emerged as a potential new therapeutic target for non-small cell lung cancer given its association with poor prognosis among affected patients. This study investigates the impact of DDR1 on tumor burden and immune cell infiltration into the tumor microenvironment. We found that pharmacological inhibition and knockout of DDR1 increased the tumor burden in an immunocompetent mouse model of lung adenocarcinoma. The absence of DDR1 reduced CD8+ cytotoxic T-cell infiltration but increased CD4+ helper and regulatory T-cell infiltration. Regulatory T cells, which promote tumorigenesis by suppressing the immune system, were also more common among The Cancer Genome Atlas (TCGA) lung adenocarcinoma patients with low DDR1 expression. These findings suggest that therapeutic inhibition of DDR1, in certain circumstances, might even have negative effects, although further studies are needed to confirm these findings. Lung cancer is the leading cause of cancer-related death worldwide. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, has been associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). However, its role in tumorigenesis remains poorly understood. This work aimed to explore the impact of DDR1 expression on immune cell infiltration in lung adenocarcinoma. Pharmacological inhibition and knockout of DDR1 were used in an immunocompetent mouse model of KRAS/p53-driven lung adenocarcinoma (LUAD). Tumor cells were engrafted subcutaneously, after which tumors were harvested for investigation of immune cell composition via flow cytometry. The Cancer Genome Atlas (TCGA) cohort was used to perform gene expression analysis of 509 patients with LUAD. Pharmacological inhibition and knockout of DDR1 increased the tumor burden, with DDR1 knockout tumors showing a decrease in CD8+ cytotoxic T cells and an increase in CD4+ helper T cells and regulatory T cells. TCGA analysis revealed that low-DDR1-expressing tumors showed higher FoxP3 (regulatory T-cell marker) expression than high-DDR1-expressing tumors. Our study showed that under certain conditions, the inhibition of DDR1, a potential therapeutic target in cancer treatment, might have negative effects, such as inducing a pro-tumorigenic tumor microenvironment. As such, further investigations are necessary. [ABSTRACT FROM AUTHOR]

Simple Summary: Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Approximately 30% of patients treated with conventional chemotherapy experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL, such as the morphological pattern of the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL requires salvage therapy. Recently, targeted therapies such as ALK inhibitors and brentuximab vedotin have demonstrated dramatic responses in chemoresistant ALK-positive ALCL. Hematopoietic stem cell transplantation has also been reported to be an effective therapy. This article reviews pediatric ALK-positive ALCL, focusing on the risk factors associated with poor prognosis and treatment strategies for relapsed or refractory disease. Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Although conventional chemotherapy is effective in most patients, approximately 30% experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL. These include morphological patterns with the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL is often resistant to conventional chemotherapy; therefore, salvage therapy is required. In recent years, targeted therapies such as ALK inhibitors and brentuximab vedotin (BV) have been developed. ALK inhibitors block the continuous activation of ALK kinase, a driver mutation that leads to cell proliferation in ALK-positive ALCL. Additionally, BV is an antibody–drug conjugate that targets CD30-positive cells. Both ALK inhibitors and BV have displayed dramatic effects in chemoresistant ALK-positive ALCL. Weekly vinblastine treatment and hematopoietic stem cell transplantation have also been reported to be effective therapies. This article reviews pediatric ALK-positive ALCL, focusing on risk factors and treatment strategies for pediatric patients with relapsed or refractory ALK-positive ALCL. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancer is the most common type of cancer that affects the female reproductive organs. Over 50% of women with EC present with early-stage, low-risk disease, and are treated with surgery alone. However, women diagnosed with advanced or recurrent disease have a poor prognosis and they have poor response to current therapies. However, the molecular mechanisms and the prognostic prediction for EC patients remain unclear. In this work, we identified that cancer cells utilize dysregulated nucleotide metabolism to enhance proliferation and progression. We targeted one of the dysregulated genes (DHODH) that is critical for metabolism of nucleotide biosynthesis in endometrial cancer cell. Our results provide potential clinical application to select endometrial cancer patient using "overexpression of dysregulated genes (DHODH) as the genetic markers for tailored therapeutic intervention using repurposed FDA approved drugs (Teriflunomide). Furthermore, it revealed a potential combination therapeutic strategy (Teriflunomide+ Olaparib) for the treatment of "DHODH overexpressing" endometrial cancer. Overall, this result provides preclinical data to establish future clinical therapeutic intervention to increase the efficacy of treatment response that improves overall survival of endometrial cancer patients. Endometrial carcinoma (EC) is the most common gynecological malignancy in the United States. De novo pyrimidine synthesis pathways generate nucleotides that are required for DNA synthesis. Approximately 38% of human endometrial tumors present with an overexpression of human dihydroorotate dehydrogenase (DHODH). However, the role of DHODH in cancer cell DNA replication and its impact on modulating a treatment response is currently unknown. Here, we report that endometrial tumors with overexpression of DHODH are associated with a high mutation count and chromosomal instability. Furthermore, tumors with an overexpression of DHODH show significant co-occurrence with mutations in DNA replication polymerases, which result in a histologically high-grade endometrial tumor. An in vitro experiment demonstrated that the inhibition of DHODH in endometrial cancer cell lines significantly induced replication-associated DNA damage and hindered replication fork progression. Furthermore, endometrial cancer cells were sensitive to the DHODH inhibitor either alone or in combination with the Poly (ADP-ribose) polymerase 1 inhibitor. Our findings may have important clinical implications for utilizing DHODH as a potential target to enhance cytotoxicity in high-grade endometrial tumors. [ABSTRACT FROM AUTHOR]

Objective. The bromodomain-containing 4 (BRD4) is a member of the bromodomain and extra terminal domain (BET) family, which is an important epigenetic reader. It is currently a promising oncology target. In some tumors, BET bromodomain inhibitors have demonstrated promising results. Proteolysis-targeting methods (PROTAC), which rapidly and effectively degrade BRD4, have displayed considerable potential in the treatment of tumors in recent years. The purpose of this study is to examine the potential impact of BRD4 PROTAC compounds ARV-825 on oncogene BRD4-NUT fused protein in NUT carcinoma. Methods. The effectiveness of ARV-825 was evaluated at the cellular level using the cell counting kit 8 test, wound healing, cell transfection, western blotting analysis, and RNA sequencing. The effectiveness of ARV-825 was also examined in vivo using a xenograft model. Results. The BRD4-NUT fusion gene was overexpressed in 3T3 cells, and the pathogenic fusion gene was simulated. The results showed that the overexpression of BRD4-NUT could promote the proliferation and migration of 3T3 cells, but the expression of BRD4 protein was degraded after the addition of the novel cereblon-based PROTAC compound ARV-825 against BRD4, resulting in inhibition of BRD4-NUT 3T3 cell proliferation and migration. Further RNA-seq analysis showed that overexpression of BRD4-NUT was accompanied by increased expression of gene (e.g., Myc, E2F, TRAFs, Wnt, Gadd45g, and Sox6) with significantly enriched pathway (e.g., small cell lung cancer, NF-kappa B signaling pathway, and breast cancer), promoted cell cycle from G 1 phase to S phase, and increased cell proliferation and migration, activated the antiapoptosisi signal, led to abnormal cell growth, and ultimately led to tumorigenesis. The addition of ARV-825 effectively rescued this process and effectively inhibited cell vitality, proliferation, and migration. In vivo studies demonstrated that treatment with ARV-825 greatly suppressed tumor growth without causing harmful side effects and downregulated the BRD4-NUT expression level. Conclusion. Through the induction of BRD4 protein degradation, ARV-825 can successfully limit BRD4-NUT 3T3 cell proliferation in vitro and in vivo. These findings suggested that the BRD4 inhibitor ARV-825 would be an effective therapeutic strategy for treating NUT carcinoma that with the genetic feature of BRD4-NUT fusion event. [ABSTRACT FROM AUTHOR]

The precise control of free auxin (indole-3-acetic acid, IAA) gradient, which is orchestrated by biosynthesis, conjugation, degradation, hydrolyzation, and transport, is critical for all aspects of plant growth and development. Of these, the GRETCHEN HAGEN 3 (GH3) acyl acid amido synthetase family, pivotal in conjugating IAA with amino acids, has garnered significant interest. Recent advances in understanding GH3-dependent IAA conjugation have positioned GH3 functional elucidation as a hot topic of research. This review aims to consolidate and discuss recent findings on (i) the enzymatic mechanisms driving GH3 activity, (ii) the influence of chemical inhibitor on GH3 function, and (iii) the transcriptional regulation of GH3 and its impact on plant development and stress response. Additionally, we explore the distinct biological functions attributed to IAA-amino acid conjugates. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study was to investigate the therapeutic effect of ammidin on hypoxia/reoxygenation (H/R) injury in primary neonatal rat cardiomyocytes by observing the role of ferroptosis in the process of H/R injury, and to verify its target and regulatory signaling pathways. Methods: The network pharmacology analysis was used to predict the biological processes, core targets and related signaling pathways of Angelica dahurica in the treatment of ferroptosis. Cell viability was assessed using live cell imaging and cell counting kit-8. Lactate dehydrogenase (LDH), reactive oxygen species (ROS) production, and malondialdehyde (MDA), superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) content were determined to assess the level of ferroptosis. Western blotting was performed to measure protein expression. Results: Network pharmacology predicted that Acyl-CoA synthetase long chain family member 4 (ACSL4) was highly associated with myocardial H/R injury in the intersection of Angelica dahurica and ferroptosis. The top three active components of Angelica dahurica were found to be mandenol, alloisoimperatorin and ammidin, among which ammidin was found to have the strongest binding to the target proteins of the ACSL4/AMPK/mTOR pathway. H/R reduced the viability of cardiomyocytes, while the inhibition of ferroptosis by ferrostatin-1 alleviated the H/R-induced inhibition of cardiomyocyte viability. This was evidenced by the increased cell viability, SOD release, MMP level and glutathione peroxidase 4 (GPX4) protein expression, as well as the decreased LDH and MDA release and ROS production and ACSL4 protein expression (P < 0.05). To verify the existence of ferroptosis in myocardial hypoxia/reoxygenation injury. In addition, ammidin increased cell viability and GPX4 protein expression (P < 0.05), decreased ROS generation, and MDA and MTT expression (P < 0.05), then inhibited ferroptosis, and finally alleviated myocardial H/R injury by regulating the ACSL4/AMPK signaling pathway. Conclusions: Network pharmacology was used to predict the correlation between ammidin and ferroptosis following myocardial H/R injury. It was demonstrated that ammidin may regulate ferroptosis by inhibiting the ACSL4/AMPK/mTOR signaling pathway and reduce H/R injury in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Background: Migraine is a disabling neurological disorder, characterized by recurrent headaches. During migraine attacks, individuals often experience sensory symptoms such as cutaneous allodynia which indicates the presence of central sensitization. This sensitization is prevented by oral administration of propranolol, a common first-line medication for migraine prophylaxis, that also normalized the activation of the locus coeruleus (LC), considered as the main origin of descending noradrenergic pain controls. We hypothesized that the basal modulation of trigeminal sensory processing by the locus coeruleus is shifted towards more facilitation in migraineurs and that prophylactic action of propranolol may be attributed to a direct action in LC through beta-adrenergic receptors. Methods: We used simultaneous in vivo extracellular recordings from the trigeminocervical complex (TCC) and LC of male Sprague–Dawley rats to characterize the relationship between these two areas following repeated meningeal inflammatory soup infusions. Von Frey Hairs and air-puff were used to test periorbital mechanical allodynia. RNAscope and patch-clamp recordings allowed us to examine the action mechanism of propranolol. Results: We found a strong synchronization between TCC and LC spontaneous activities, with a precession of the LC, suggesting the LC drives TCC excitability. Following repeated dural-evoked trigeminal activations, we observed a disruption in coupling of activity within LC and TCC. This suggested an involvement of the two regions' interactions in the development of sensitization. Furthermore, we showed the co-expression of alpha-2A and beta-2 adrenergic receptors within LC neurons. Finally propranolol microinjections into the LC prevented trigeminal sensitization by desynchronizing and decreasing LC neuronal activity. Conclusions: Altogether these results suggest that trigemino-coerulean coupling plays a pivotal role in migraine progression, and that propranolol's prophylactic effects involve, to some extent, the modulation of LC activity through beta-2 adrenergic receptors. This insight reveals new mechanistic aspects of LC control over sensory processing. [ABSTRACT FROM AUTHOR]

Transglutaminase 1 (TGM1) plays an essential role in skin barrier formation by cross-linking proteins in differentiated keratinocytes. Here, we established a protocol for the antibody-dependent detection of TGM1 protein and the parallel detection of TGM activity. TGM1 immunoreactivity initially increased and co-localized with membrane-associated TGM activity during keratinocyte differentiation. TGM activity persisted upon further differentiation of keratinocytes, whereas TGM1 immunoreactivity was lost under standard assay conditions. Pretreatment of tissue sections with the proteases trypsin or proteinase K enabled immunodetection of TGM1 in cornified keratinocytes, indicating that removal of other proteins was a prerequisite for TGM1 immunolabeling after cornification. The increase of TGM activity and subsequent loss of TGM1 immunoreactivity could be replicated in HEK293T cells transfected with TGM1, suggesting that protein cross-linking mediated by TGM1 itself may lead to reduced recognition of TGM1 by antibodies. To screen for proteins potentially regulating TGM1, we performed Virotrap experiments and identified the CAPNS1 subunit of calpain as an interaction partner of TGM1. Treatment of keratinocytes and TGM1-transfected HEK293T cells with chemical inhibitors of calpain suppressed transglutamination. Our findings suggest that calpain contributes to the control of TGM1-mediated transglutamination and proteins cross-linked by transglutamination mask epitopes of TGM1. [ABSTRACT FROM AUTHOR]

In this editorial we aim to provide potential therapeutic options in patients who do not benefit from treatment with CGRP(r) monoclonal antibodies. Based on current real-life studies and analysis of practical and economic aspects, we will analyze the potential benefits of changing CGRP-targeted treatment. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is an age-related common bone disorder characterized by low bone mineral density and increased fragility fracture risk. Various Antiresorptive medications are being used to target osteoclast mediated bone resorption to prevent bone loss and reduce fracture risk. About Denosumab: Denosumab is a novel biological antiresorptive drug that belongs to the class of monoclonal antibodies. It binds to and inhibits the cytokine receptor activator of nuclear factor kappa-B ligand (RANKL), which is requisite for osteoclast differentiation, function and survival. Effectiveness: Denosumab has been shown to be a potent and effective therapy for osteoporosis, with clinical trial data demonstrating significant improvement in bone mineral density (BMD) and reductions in fracture risk at various skeletal sites for more than 10 years of treatment. Safety Profile: Denosumab has a favourable benefit/risk profile, with low rates of complications such as infection, atypical femoral fracture and osteonecrosis of the jawbone. Challenges: However, denosumab treatment requires continuous administration, as discontinuation leads to rapid bone mineral loss and increased risk of multiple vertebral fractures due to rebound of bone turnover. Therefore, modification to another anti-osteoporosis drug therapy after denosumab discontinuation is required to maintain bone health. Conclusion: Denosumab is a promising biological antiresorptive therapy for osteoporosis that offers high efficacy and safety, but also poses challenges for long-term management. [ABSTRACT FROM AUTHOR]

Background: Carbapenem-resistant enterobacteriaceae (CRE) is associated with high mortality in critically ill patients, with limited treatment options. This study aims to compare clinical response, microbiological response, and mortality in patients treated with ceftazidime--avibactam with or without aztreonam (CAZ-AVI + AZT) and colistin or polymyxin B (polymyxins) in CRE infections. Materials and methods: This single-center prospective observational study included adult patients with CRE infections treated with CAZ-AVI+AZT or polymyxins between January 2022 and December 2022 at a Tertiary Care Medical Center in India. The clinical response, microbiological response, and mortality were compared between the two groups using a Cox multivariate regression model adjusted for the baseline SOFA score and comorbidities. Results: A total of 89 patients were enrolled, with 59 (66%) patients receiving CAZ-AVI + AZT and 30 receiving polymyxins. Baseline demographics and clinical characteristics were similar between the two groups. The Cox multivariate regression analysis showed a statistically significant difference in clinical failure on day 14 with the CAZ-AVI + AZT group vs polymyxins (HR = 0.78, 95% CI 0.63-0.95, p = 0.018). There was no difference in microbiological failure (HR = 1.08, 95% CI 0.66-1.77, p = 0.76), microbiological relapse (HR = 0.75, 95% CI 0.36-3.02, p = 0.62), and hospital mortality (HR = 1.04, 95% CI 0.75-1.43, p = 0.796) between the two groups. Conclusion: Treatment with ceftazidime--avibactam with or without aztreonam for CRE infections associated with a better clinical response compared with polymyxins monotherapy but without any difference in microbiological response or mortality. [ABSTRACT FROM AUTHOR]

Background: Anamorelin is the first drug approved for the treatment of cancer cachexia, a debilitating condition characterized by weight loss, anorexia, and muscle mass depletion. Cachexia negatively affects a patient's quality of life, survival, and response to chemotherapy. Studies describing anamorelin use are currently limited to a small number of pancreatic cancer cases. Objectives: We aimed to examine the incidence and risk factors of adverse metabolic effects on glucose levels in cachexia patients with various carcinomas treated with anamorelin. Method: We used real-world data of patients who received anamorelin between August 2021 and July 2022 and were registered in the JMDC claims database. We investigated the impact of metabolic adverse effects on glucose in patients receiving anamorelin with respect to the following factors: sex (male), age (>75 years), types of carcinoma, history of diabetes mellitus (DM), and concomitant use of steroids. Results: The incidence of adverse metabolic effects on glucose was 12.3%, and pancreatic cancer and history of DM were associated with adverse metabolic effects on glucose. The median onset of adverse metabolic effects on glucose was 17 days after anamorelin treatment. Conclusions: This study highlights the need to monitor and manage hyperglycemia in cachexia patients receiving anamorelin, especially in those with pancreatic cancer and a history of DM. [ABSTRACT FROM AUTHOR]

Targeting metalloproteinases has been in the focus of drug design for a long time. However, meprin α and β emerged as potential drug targets just recently and are linked to several diseases with different pathological background. Nevertheless, the validation of meprins as suitable drug targets still requires highly potent and selective inhibitors as chemical probes to elucidate their role in pathophysiology. Albeit highly selective inhibitors of meprin β have already been reported, only inhibitors of meprin α with modest activity or selectivity are known. Starting from recently reported heteroaromatic scaffolds, the aim of this study was the optimisation of meprin α and/or meprin β inhibition while keeping the favourable off-target inhibition profile over other metalloproteases. We report potent pan-meprin inhibitors as well as highly active inhibitors of meprin α with superior selectivity over meprin β. The latter are suitable to serve as chemical probes and enable further target validation. [ABSTRACT FROM AUTHOR]

SGK1 is a serine/threonine kinase involved in several neurodegenerative-related pathways such as apoptosis, neuroinflammation, ionic channel regulation, and autophagy, among others. Despite its potential role as a pharmacological target against this kind of diseases, there are no reported inhibitors able to cross the BBB so far, being a field yet to be explored. In this context, a structure-based virtual screening against this kinase was performed, pointing out the deazapurine moiety as an interesting and easy-to-derivatize scaffold. Moreover, these inhibitors are able to i) exert neuroprotection in an in vitro model of AD and ii) block mitophagy in a PRKN-independent manner, reinforcing the hypothesis of SGK1 inhibitors as neuroprotective chemical tools. [ABSTRACT FROM AUTHOR]

Introduction: Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses. Materials and methods: A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors. Results: We identified eight cases, most of them at stages 0–1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug's half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific. Conclusion: We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ. [ABSTRACT FROM AUTHOR]

Introduction: CDK4/6 inhibitors (ribociclib, palbociclib and abemaciclib) are 1st line therapy in metastatic breast cancer (MBC). No comparative data exists between agents regarding toxicity or efficacy. Methods: A retrospective study was performed at our tertiary referral centre evaluating patients on a CDK4/6 inhibitor for MBC between July 2017 and December 2021. Toxicity was evaluated along with variability in full blood counts and liver function over the first 12 weeks of therapy. Results: Two hundred and seventeen patients were treated (palbociclib 59%, abemaciclib 25% and ribociclib 16%). 86% received the agent as 1st line therapy. Most patients were white women with a median age of 61 years (32–95) and ECOG 0/1. Twelve patients were switched to an alternative CDK4/6 inhibitor due to toxicity and two did not tolerate this. Toxicity profiles of agents were consistent with published trials. However, there was greater overlap in hepatitis, diarrhoea and bone marrow suppression. Blood results indicated a minimum of four weeks treatment before development of neutropenia. Forty percent of patients went onto have subsequent lines of therapy. The progression-free survival per agent was palbociclib 27.9 months (95% CI 23–32.5), ribociclib 29 months (95% CI 21.5–37.0) and abemaciclib 20.6 months (95% CI 15.0–26.0). The overall survival was palbociclib 38.0 months (95% CI 33.5–42.5), ribociclib 33.9 months (95% CI 26.7–41.1) and abemaciclib 27.3 months (95% CI 22.5–32.1). Conclusions: Toxicity across CDK4/6 inhibitors overlaps. The optimal sequence of therapies post CDK4/6 inhibitors remains unknown but rechallenge with an alternative agent is possible. [ABSTRACT FROM AUTHOR]

The aims of the research were (i) to compare the clinical outcome of IVF using follicular-phase depot gonadotropin-releasing hormone (GnRH) agonist (depot agonist) protocol and GnRH antagonist protocol in patients with repeated IVF failure (RIF), (ii) to discover the optimal ovarian stimulation protocol for this group of low prognosis patients. 801 RIF patients with normal ovarian reserve receiving in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) were included in this retrospective study. Among them, 492 patients were treated with the depot agonist protocol, and the remaining 309 patients with the antagonist protocol. Multivariable logistic regression analysis was used to find the predictor(s) of the chance of live birth. Higher live birth rate (LBR) and clinical pregnancy rate (CPR) in fresh embryo transfer (ET) cycles were associated with the use of depot agonist compared with the antagonist protocols (44.81% vs. 27.27%, 54.64% vs. 34.93%, respectively; both p < 0.01) and depot agonist protocol was a strong predictor of live birth (OR = 2.182, 95% CI 1.355–3.514, p < 0.01). The CPR in thawed ET cycles was not significantly different between the two groups (38.12% vs. 45.26%, p > 0.05). A higher cumulative live birth rate (CLBR) was achieved in the depot agonist group (46.59% vs. 35.21%, p < 0.01). Beneficial endometrial receptivity in the depot agonist protocol contributed to a higher LBR in fresh ET cycles, rendering this protocol the preferred option in the treatment of RIF patients. [ABSTRACT FROM AUTHOR]

A 21-year-old woman with multiple sclerosis (taking regular fingolimod) developed sudden-onset severe headache with nausea and malaise. Neurological examination was normal and she was afebrile. Blood results showed lymphocytes 0.53 x 109/L and C reactive protein 19 mg/L. CT scan of head and venogram were normal. CSF showed an opening pressure of 33 cm H2O and an incidental light growth of Cryptococcus neoformans, confirmed with positive India Ink stain and a positive cryptococcal antigen (1:100). She was treated for cryptococcal meningoencephalitis with amphotericin and flucytosine. Her presenting symptoms had closely mimicked subarachnoid haemorrhage. This atypical presentation of cryptococcal CNS infection highlights the need for vigilance in immunosuppressed patients. [ABSTRACT FROM AUTHOR]

Background Several studies have shown that the TGF-β signaling pathway plays a critical role in colorectal cancer (CRC) pathogenesis. The aim of the current study is to investigate the therapeutic potential of Vactosertib (EW-7197), a selective inhibitor of TGF-β receptor type I, either alone or in combination with the standard first-line chemotherapeutic treatment, 5-Fluorouracil (5-FU), in CRC progression in both cellular and animal models. Methods Real-Time PCR, Zymography, enzyme-linked immunosorbent assay (ELISA), Hematoxylin and Eosin (H&E) tissue staining, and Flow cytometry techniques were applied to determine the anti-tumor properties of this novel TGF-β inhibitor in in vitro (CT-26 cell line) and in vivo (inbred BALB/C mice) samples. Results Our findings showed that Vactosertib decreased cell proliferation and induced spheroid shrinkage. Moreover, this inhibitor suppressed the cell cycle and its administration either alone or in combination with 5-FU induced apoptosis by regulating the expression of p53 and BAX proteins. It also improved 5-FU anti-cancer effects by decreasing the tumor volume and weight, increasing tumor necrosis, and regulating tumor fibrosis and inflammation in an animal model. Vactosertib also enhanced the inhibitory effect of 5-FU on invasive behavior of CRC cells by upregulating the expression of E-cadherin and inhibiting MMP-9 enzymatic activity. Conclusion This study demonstrating the potent anti-tumor effects of Vactosertib against CRC progression. Our results clearly suggest that this inhibitor could be a promising agent reducing CRC tumor progression when administered either alone or in combination with standard treatment in CRC patients. [ABSTRACT FROM AUTHOR]

Owing to their potential to cause serious adverse health effects, significant efforts have been made to develop antidotes for organophosphate (OP) anticholinesterases, such as nerve agents. To be optimally effective, antidotes must not only reactivate inhibited target enzymes, but also have the ability to cross the blood–brain barrier (BBB). Progress has been made toward brain-penetrating acetylcholinesterase reactivators through the development of a new group of substituted phenoxyalkyl pyridinium oximes. To help in the selection and prioritization of compounds for future synthesis and testing within this class of chemicals, and to identify candidate broad-spectrum molecules, an in silico framework was developed to systematically generate structures and screen them for reactivation efficacy and BBB penetration potential. [ABSTRACT FROM AUTHOR]

The family of calcium-activated chloride channels, TMEM16, plays a significant role in contributing to the pathogenesis of airway inflammatory diseases. Targeting these ion channels and aiming to modulate them may provide an interesting new approach to the therapy of these potentially fatal diseases. We tested this hypothesis in both healthy and ovalbumin (OVA)-sensitized male Dunkin-Hartley guinea pigs. The ion channel activity was modulated by TMEM16A-nonselective (benzbromarone) and TMEM16A-selective blockers (CaCCinh-A01). In vivo airway reactivity, induced by histamine and methacholine, was expressed as specific airway resistance (sRaw) values. The number of citric acid-induced coughs was counted using a double-chambered body plethysmograph, and the frequency of ciliary beating (CBF) was assessed in vitro by brushing method. For comparison, salbutamol and codeine were tested under the same conditions. The results showed significant differences in the responses of unsensitized and sensitized airways to both TMEM16 blockers administered. CaCCinh-A01 and benzbromarone significantly reduced the number of cough efforts in the group of OVA-sensitized guinea pigs. Significant improvement in sRaw values could be observed in OVA-sensitized TMEM16 blocker–treated animals compared to salbutamol when challenged with inhalational histamine, and the outcome was similar to salbutamol when challenged with methacholine. CBF was significantly inhibited in animals sensitized to OVA treated with selective inhibition of TMEM16A. The results demonstrated that treatment with blockers of TMEM16 can reduce both cough effort and sRaw, and the difference between TMEM16A-selective and TMEM16A-nonselective blocking is only negligibly in favor of CaCCinh-A01. It is also worthwhile to note the impairment of CBF in OVA-sensitized animals treated with CaCCinh-A01. [ABSTRACT FROM AUTHOR]

Iruplinalkib (Trade name: 启欣可®; Code name: WX-0593), a highly selective oral anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI), is being developed by Qilu Pharmaceutical Co., Ltd. for the treatment of ALK-positive (ALK+) or ROS1-positive (ROS1+) non-small cell lung cancer (NSCLC). In June 2023, iruplinalkib was approved in China for the treatment of patients with locally advanced or metastatic ALK+ NSCLC who have progressed after prior crizotinib therapy or are intolerant to crizotinib. This article summarizes the milestones in the development of iruplinalkib leading to this first approval for the treatment of patients with locally advanced or metastatic ALK+ NSCLC. [ABSTRACT FROM AUTHOR]

Background: Limited evidence regarding the use of guideline directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF) undergoing coronary artery bypass grafting (CABG) is available. Objective: The purpose of this study was to characterize prescription of HFrEF GDMT use before and after CABG. Methods: A retrospective analysis of adult patients with an ejection fraction ≤40% undergoing CABG was performed. The primary objective was to evaluate patients receiving HFrEF GDMT, defined as a heart failure beta-blocker (HFBB) and a renin-angiotensin inhibitor preoperatively and postoperatively. Secondary outcomes included dosing, percent of patients on each individual therapy, mineralocorticoid receptor antagonist (MRA) use, and the combination thereof. The follow up period was 1 year. Results: Thirty-eight patients met criteria for inclusion. Prior to CABG, 52.6% of patients were receiving HFrEF GDMT. The prescribing rate of HFrEF GDMT was not significantly higher at any point within 1 year postoperatively (P =.299). The rate of renin-angiotensin inhibitors, HFBB, and aldosterone antagonists use significantly increased from 13.2% preoperatively to 36.8% at 1 year after CABG (P =.022). Doses of individual therapies were not significantly different across all time points preoperatively and postoperatively. Conclusion: HFrEF GDMT use and doses of individual therapies after CABG were not maximized. Collaborative efforts between cardiac surgeons, heart failure cardiologists, and pharmacists could be used to optimize HFrEF GDMT use and dose titration. [ABSTRACT FROM AUTHOR]

Simple Summary: Neutrophilic infiltration into the tumor microenvironment (TME) in response to radiation therapy (RT) is an early innate inflammatory immune response that occurs within 24–48 h where the neutrophils exhibit an anti-tumor phenotype. It is postulated that RT-induced DNA damage leads to innate sensing of DNA activating the cGAS-STING pathway, which is responsible for the immune modulatory effects of RT. We report that the CXCLs/CXCR2 axis translates the downstream effect of RT-induced innate DNA sensing resulting in an early innate neutrophilic response in the TME. This study identifies CXCLs/CXCR2 as a potential therapeutic target to improve RT-induced innate immune response. The early events that lead to the inflammatory and immune-modulatory effects of radiation therapy (RT) in the tumor microenvironment (TME) after its DNA damage response activating the innate DNA-sensing pathways are largely unknown. Neutrophilic infiltration into the TME in response to RT is an early innate inflammatory response that occurs within 24–48 h. Using two different syngeneic murine tumor models (RM-9 and MC-38), we demonstrated that CXCR2 blockade significantly reduced RT-induced neutrophilic infiltration. CXCR2 blockade showed the same effects on RT-induced tumor inhibition and host survival as direct neutrophil depletion. Neutrophils highly and preferentially expressed CXCR2 compared to other immune cells. Importantly, RT induced both gene and protein expression of CXCLs in the TME within 24 h, attracting neutrophils into the tumor. Expectedly, RT also upregulated the gene expression of both cGAS and AIM2 DNA-sensing pathways in cGAS-positive MC-38 tumors but not in cGAS-negative RM-9 tumors. Activation of these pathways resulted in increased IL-1β, which is known to activate the CXCLs/CXCR2 axis. Gene ontology analysis of mRNA-Seq supported these findings. Taken together, the findings suggest that the CXCLs/CXCR2 axis mediates the RT-induced innate inflammatory response in the TME, likely translating the effects of innate DNA-sensing pathways that are activated in response to RT-induced DNA damage. [ABSTRACT FROM AUTHOR]

Simple Summary: Exploring the impact of heat shock protein (HSP) inhibition in cancer may give new insights into the cellular processes that these molecules sustain to promote cancer survival and may accelerate the discovery of more HSP inhibitors to be introduced in clinical trials. In this study, we explored the expression and role of high-molecular-weight HSP110 in the survival of Primary Effusion Lymphoma (PEL) cells. We found that the proper expression of this HSP is required to prevent lysosomal permeabilization, DNA damage, c-Myc downregulation and STAT3 de-phosphorylation. Indeed, HSP silencing strongly reduces PEL cell survival through the dysregulation of these processes that have been found to be interconnected. Heat shock proteins (HSPs) are highly expressed in cancer cells and represent a promising target in anti-cancer therapy. In this study, we investigated for the first time the expression of high-molecular-weight HSP110, belonging to the HSP70 family of proteins, in Primary Effusion Lymphoma (PEL) and explored its role in their survival. This is a rare lymphoma associated with KSHV, for which an effective therapy remains to be discovered. The results obtained from this study suggest that targeting HSP110 could be a very promising strategy against PEL, as its silencing induced lysosomal membrane permeabilization, the cleavage of BID, caspase 8 activation, downregulated c-Myc, and strongly impaired the HR and NHEJ DNA repair pathways, leading to apoptotic cell death. Since chemical inhibitors of this HSP are not commercially available yet, this study encourages a more intense search in this direction in order to discover a new potential treatment that is effective against this and likely other B cell lymphomas that are known to overexpress HSP110. [ABSTRACT FROM AUTHOR]

Simple Summary: Activated STAT3 is an essential factor in cancer development; therefore, blocking STAT3 may be of therapeutic benefit in multiple cancer types. Thanks to recent developments in the regulatory function of non-coding nucleic acids, a new branch of nucleic acid-based molecules with significant therapeutic potential has emerged. Therapeutics such as siRNA, shRNA, ASO, and ODN-decoy that target STAT3 found an application in cancer therapies. The main advantage of using nucleic acid-based therapeutics is their high specificity based on the complementarity of the therapeutic sequence with the target. Conversely, oligonucleotide therapeutics struggle with stability, toxicity, sensitivity to nucleases, specificity toward cell type, and cellular uptake, which hamper their applicability. Among the various solutions proposed to overcome these problems, embedding the oligonucleotide in the carrier is an interesting strategy. The review combines the knowledge about STAT3 biology in cancer, the application of anti-STAT3 oligonucleotide therapeutics in cancer therapy, and carriers for their delivery. High expression and phosphorylation of signal transducer and transcription activator 3 (STAT3) are correlated with progression and poor prognosis in various types of cancer. The constitutive activation of STAT3 in cancer affects processes such as cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. The importance of STAT3 in cancer makes it a potential therapeutic target. Various methods of directly and indirectly blocking STAT3 activity at different steps of the STAT3 pathway have been investigated. However, the outcome has been limited, mainly by the number of upstream proteins that can reactivate STAT3 or the relatively low specificity of the inhibitors. A new branch of molecules with significant therapeutic potential has emerged thanks to recent developments in the regulatory function of non-coding nucleic acids. Oligonucleotide-based therapeutics can silence target transcripts or edit genes, leading to the modification of gene expression profiles, causing cell death or restoring cell function. Moreover, they can reach untreatable targets, such as transcription factors. This review briefly describes oligonucleotide-based therapeutics that found application to target STAT3 activity in cancer. Additionally, this review comprehensively summarizes how the inhibition of STAT3 activity by nucleic acid-based therapeutics such as siRNA, shRNA, ASO, and ODN-decoy affected the therapy of different types of cancer in preclinical and clinical studies. Moreover, due to some limitations of oligonucleotide-based therapeutics, the importance of carriers that can deliver nucleic acid molecules to affect the STAT3 in cancer cells and cells of the tumor microenvironment (TME) was pointed out. Combining a high specificity of oligonucleotide-based therapeutics toward their targets and functionalized nanoparticles toward cell type can generate very efficient formulations. [ABSTRACT FROM AUTHOR]

Simple Summary: Anti-PD-1/PD-L1 treatments still face the problem of resistant diseases in non-small cell lung cancer. This resistance can be classified as primary or secondary (acquired). The existing literature suggests different outcomes and mechanisms in both situations, yet they need to be comparatively characterized. This unique comparative study reveals diverging survival and progression patterns: initial durable clinical benefit (minimum of 6 months of controlled disease) prior to progression associated with longer post-progression survival. In this situation, progression most often occurs in pre-existing lesions and rarely spreads to other sites. The radiological measure of the tumor growth rate also appears as a useful tool to help decide anti-PD-1/PD-L1 continuation. Altogether, these results benefit our understanding and management of resistance to anti-PD-1/PD-L1. Background and aim: A better understanding of resistance to checkpoint inhibitors is essential to define subsequent treatments in advanced non-small cell lung cancer. By characterizing clinical and radiological features of progression after anti-programmed death-1/programmed death ligand-1 (anti-PD-1/PD-L1), we aimed to define therapeutic strategies in patients with initial durable clinical benefit. Patients and methods: This monocentric, retrospective study included patients who presented progressive disease (PD) according to RECIST 1.1 criteria after anti-PD-1/PD-L1 monotherapy. Patients were classified into two groups, "primary resistance" and "Progressive Disease (PD) after Durable Clinical Benefit (DCB)", according to the Society of Immunotherapy of Cancer classification. We compared the post-progression survival (PPS) of both groups and analyzed the patterns of progression. An exploratory analysis was performed using the tumor growth rate (TGR) to assess the global growth kinetics of cancer and the persistent benefit of immunotherapy beyond PD after DCB. Results: A total of 148 patients were included; 105 of them presented "primary resistance" and 43 "PD after DCB". The median PPS was 5.2 months (95% CI: 2.6–6.5) for primary resistance (p < 0.0001) vs. 21.3 months (95% CI: 18.5–36.3) for "PD after DCB", and the multivariable hazard ratio was 0.14 (95% CI: 0.07–0.30). The oligoprogression pattern was frequent in the "PD after DCB" group (76.7%) and occurred mostly in pre-existing lesions (72.1%). TGR deceleration suggested a persistent benefit of PD-1/PD-L1 blockade in 44.2% of cases. Conclusions: PD after DCB is an independent factor of longer post-progression survival with specific patterns that prompt to contemplate loco-regional treatments. TGR is a promising tool to assess the residual benefit of immunotherapy and justify the continuation of immunotherapy in addition to radiotherapy or surgery. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to understand how the oncogenic transcription factor MYC affects cellular processes contributing to cancer. Therefore, we used cell lines derived from multiple myeloma (MM), a malignant plasma cell disorder that is highly dependent on MYC expression. Through quantitative mass spectrometry analysis, we examined how MYC depletion affects the proteome of MM cells. We observed that upon MYC depletion, the levels of the two RNA-binding proteins hnRNPC and LARP1 decreased, suggesting a direct regulation by MYC. Notably, a reanalysis of publicly available data demonstrated that high expression of hnRNPC and LARP1 was linked to poor survival and disease progression in MM patients, suggesting their potential as prognostic markers and therapeutic MYC target proteins. Our findings demonstrate the efficacy of our approach in identifying MYC-regulated target proteins that could potentially serve as predictors of both patient survival and disease progression in MM. Multiple myeloma (MM) is a malignant plasma cell disorder in which the MYC oncogene is frequently dysregulated. Due to its central role, MYC has been proposed as a drug target; however, the development of a clinically applicable molecule modulating MYC activity remains an unmet challenge. Consequently, an alternative is the development of therapeutic options targeting proteins located downstream of MYC. Therefore, we aimed to identify undescribed MYC-target proteins in MM cells using Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) and mass spectrometry. We revealed a cluster of proteins associated with the regulation of translation initiation. Herein, the RNA-binding proteins Heterogeneous Nuclear Ribonucleoprotein C (hnRNPC) and La Ribonucleoprotein 1 (LARP1) were predominantly downregulated upon MYC depletion. CRISPR-mediated knockout of either hnRNPC or LARP1 in conjunction with redundant LARP family proteins resulted in a proliferative disadvantage for MM cells. Moreover, high expression levels of these proteins correlate with high MYC expression and with poor survival and disease progression in MM patients. In conclusion, our study provides valuable insights into MYC's role in translation initiation by identifying hnRNPC and LARP1 as proliferation drivers of MM cells and as both predictive factors for survival and disease progression in MM patients. [ABSTRACT FROM AUTHOR]

Background: Recent studies have established cefepime as an effective treatment option for AmpC beta-lactamase (AmpC) Enterobacterales; however, the efficacy of beta-lactam/beta-lactamase inhibitors is unclear. Objective: The objective of this study was to determine if piperacillintazobactamis an appropriate alternative to cefepime for the treatment of intra-abdominal infections (IAIs) secondary to AmpC-producing organisms. Methods: This multicenter, retrospective cohort study was conducted in hospitalized adults with an IAI caused by an AmpC-producing organism and received either cefepime or piperacillin-tazobactam for definitive treatment after a source control procedure. The primary outcome was a composite of surgical site infections, recurrent IAIs, or in-hospital mortality. Secondary outcomes included the individual components of the composite outcome, hospital length of stay (LOS), microbiologic failure, study antibiotic duration, time to clinical resolution, and incidence of Clostridioides difficile infection (CDI). Results: This study included 119 patients. There was no difference in the primary outcome between the cefepime and piperacillin-tazobactam groups (35% vs 27%, P = 0.14). Microbiological failure was the only secondary outcome with an observed difference between groups (17% vs 0%, P = 0.01): hospital LOS (15 vs 13 days, P = 0.09), days of therapy (7 vs 7 days, P = 0.87), time to clinical resolution (7 vs 4 days, P = 0.30), and CDI (1% vs 2%, P = 0.58) were all similar. [ABSTRACT FROM AUTHOR]

β‐eudesmol is a major bioactive component of Atractylodes lancea (AL). AL has been developed as the capsule formulation of standardized AL extract for treating cholangiocarcinoma (CCA). However, the complex constituents of herbal products increase the risk of adverse drug interactions. β‐eudesmol has demonstrated inhibitory effects on rCYP2C19 and rCYP3A4 in the previous research. This study aimed to identify the cytochrome P450 (CYP) isoforms responsible for the metabolism of β‐eudesmol and determine the enzyme kinetic parameters and the metabolic stability of β‐eudesmol metabolism in the microsomal system. Reaction phenotyping using human recombinant CYPs (rCYPs) and selective chemical inhibitors of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 was performed, and enzyme kinetics and metabolic stability were investigated using human liver microsome (HLM). The results suggest that CYP2C19 and CYP3A4 play significant roles in β‐eudesmol metabolism. The disappearance half‐life (t1/2) and intrinsic clearance (CLint) of β‐eudesmol were 17.09 min and 0.20 mL/min·mg protein, respectively. Enzyme kinetic analysis revealed the Michaelis–Menten constant (Km) and maximum velocity (Vmax) of 16.76 μM and 3.35 nmol/min·mg protein, respectively. As a component of AL, β‐eudesmol, as a substrate and inhibitor of CYP2C19 and CYP3A4, has a high potential for drug–drug interactions when AL is co‐administered with other herbs or conventional medicines. [ABSTRACT FROM AUTHOR]

Purpose This review provides an overview of the management of chronic kidney disease (CKD) associated with type 2 diabetes (T2D), how the novel treatment class of nonsteroidal mineralocorticoid receptor antagonists (MRAs) fits within the treatment landscape, and how pharmacists can contribute to the multidisciplinary care of patients with CKD associated with T2D. Summary Optimizing pharmacotherapy for patients with CKD associated with T2D is critical to prevent or slow progression to end-stage kidney disease and reduce the incidence of cardiovascular events. However, many patients with CKD receive suboptimal treatment, in part because of the high complexity of care required, a lack of disease recognition among providers and patients, and a failure to utilize new kidney-protective therapies. Finerenone is the first nonsteroidal, selective MRA to be approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of adult patients with CKD associated with T2D. Clinical trials have demonstrated that finerenone significantly reduces the risk of cardiorenal disease progression vs placebo and has a reduced risk of hyperkalemia compared to traditional steroidal MRAs. Initiation of finerenone should follow evaluation of baseline estimated glomerular filtration rate and serum potassium levels. Consideration of potential drug-drug interactions, follow-up monitoring of potassium levels, and coordination of changes in pharmacotherapy across the patient care team are also important. Conclusion Finerenone is a valuable addition to the treatment landscape for CKD associated with T2D. Through their expertise in -medication -management, transitions of care, and patient education, clinical pharmacists are well positioned to ensure patients receive safe and effective -treatment. [ABSTRACT FROM AUTHOR]

Four new phloroglucinol derivatives (1 − 4) were isolated from the leaves of Syzygium fluviatile. Their structures were elucidated by means of extensive spectroscopic data. Among them, compounds 1 and 3 showed significant inhibitory activity against α-glucosidase with IC50 values of 10.60 and 5.07 µM, respectively. The structure-activity relationship was also discussed briefly. [ABSTRACT FROM AUTHOR]