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Introduction: Direct oral anticoagulants (DOACs) become the recommended treatment over vitamin K antagonists (VKA) in patients with non‐valvular atrial fibrillation (AF). However, their effectiveness in reducing cognitive impairment and dementia compared to VKA remains unclear. Methods: A systematic literature search was conducted on Ovid MEDLINE, EMBASE, and Cochrane Database. Randomized controlled trials, cohort, or case–control study that assessed incident dementia between AF patients who received DOAC compared to VKA were selected. Relevant study characteristics and the number of incident dementia diagnosis or hazard ratios (HRs) for incident dementia and each dementia subtypes were extracted. Random‐effects model was used to perform meta‐analysis. Standardized mean differences (SMDs) were used to estimate effect sizes for continuous data. Results: Twelve cohort studies comprising 1 451 069 individuals were included. The incidence of dementia was lower in AF patients prescribed DOACs compared to VKA (HR 0.88, 95% CI 0.83–0.93, I2 = 61.2%). A lower incident dementia in DOACs group relative to VKA was significantly observed in those less than 75 years of age (< 65 years, HR 0.83 (95% CI 0.72–0.97, I2 = 0%); 65–74 years, HR 0.86 (95% CI 0.81–0.92, I2 = 55.4%); and ≥ 75 years, HR 1.07 (95% CI 0.74–1.55, I2 = 92.5%)) and for the subgroup of patients with vascular dementia (HR 0.91, 95% CI 0.824–0.997, I2 = 0%). Conclusions: This meta‐analysis reveals a reduction in incidence of dementia in AF patients prescribed DOACs compared to VKA, particularly in those less than 75 years old and in the vascular dementia subtype. [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).

Tumor necrosis factor- α (TNF- α) is a promising target for inflammatory and autoimmune diseases. Spirohypertones A (1) and B (2), two unprecedented polycyclic polyprenylated acylphloroglucinols with highly rearranged skeletons, were isolated from Hypericum patulum. The structures of 1 and 2 were confirmed through comprehensive spectroscopic analysis, single-crystal X-ray diffraction and electronic circular dichroism calculations. Importantly, 2 showed remarkable TNF- α inhibitory activity, which could protect L929 cells from death induced by co-incubation with TNF- α and actinomycin D. It also demonstrated the ability to suppress the inflammatory response in HaCaT cells stimulated with TNF- α. Notably, in an imiquimod-induced psoriasis murine model, 2 restrained symptoms of epidermal hyperplasia associated with psoriasis, presenting anti-inflammatory and antiproliferative effects. This discovery positions 2 as a potent TNF- α inhibitor, providing a promising lead compound for developing an antipsoriatic agent. Spirohypertones A and B, two new compounds with rearranged skeletons were isolated from Hypericum patulum and spirohypertone B was found to be a potential antipsoriatic via inhibit TNF- α. [Display omitted] [ABSTRACT FROM AUTHOR]

MdDOX-Co, the ectopic expression of which is considered to cause the apple columnar tree shape, belongs to the 2-oxoglutaratedependent dioxygenase (2ODD) family. It adds a hydroxyl group to position 12 of gibberellins (GAs). However, the 2ODD enzymes related to GA biosynthesis and catabolism are phylogenetically distinct from MdDOX-Co. Thus, it is possible that substrates other than GAs exist in MdDOX-Co. To identify the previously unidentified substrate(s) of MdDOX-Co, we searched for MdDOX-Co-specific inhibitors. Chemical screening using gas chromatography-mass spectrometry was performed to investigate the effects of 2400 compounds that inhibited the catalytic reaction of MdDOX-Co, but not the catabolic reaction of GA 2-oxidase, an enzyme involved in GA catabolism. By applying two positive compounds in Arabidopsis, a chemical 3-((2-chloro-6-fluorobenzyl)thio)-5,7-dimethyl-5Hpyrazolo [3,4-e][1,4,2]dithiazine-1,1-dioxide designated as TPDD that did not inhibit GA biosynthesis was selected. The structureactivity relationships among the TPDD analogs were also obtained. [ABSTRACT FROM AUTHOR]

An editorial focuses on the potential of small molecule GLP-1 agonists, specifically orforglipron and danuglipron, to become the next first-line drugs in the management of type-2 diabetes mellitus due to their enhanced efficacy and affordability compared to existing peptide GLP-1 agonists.

The emergence of antimicrobial resistance raises the fear of untreatable diseases. Antimicrobial resistance is a multifaceted and dynamic phenomenon that is the cumulative result of different factors. While Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus and Clostridium difficile, were previously the most concerning issues in the field of public health, Gram-negative pathogens are now of prime importance. The World Health Organization's priority list of pathogens mostly includes multidrug-resistant Gram-negative organisms particularly carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and extensively drug-resistant Acinetobacter baumannii. The spread of Gram-negative bacterial resistance is a global issue, involving a variety of mechanisms. Several strategies have been proposed to control resistant Gram-negative bacteria, such as the development of antimicrobial auxiliary agents and research into chemical compounds with new modes of action. Another emerging trend is the development of naturally derived antibacterial compounds that aim for targets novel areas, including engineered bacteriophages, probiotics, metal-based antibacterial agents, odilorhabdins, quorum sensing inhibitors, and microbiome-modifying agents. This review focuses on the current status of alternative treatment regimens against multidrugresistant Gram-negative bacteria, aiming to provide a snapshot of the situation and some information on the broader context. [ABSTRACT FROM AUTHOR]

Angiotensin receptor/neprilysin inhibitors (ARNI) have become a pillar of heart failure (HF) management. Clinicians gain practical insight into the use of sacubitril/valsartan in patients with HF with reduced ejection fraction (EF) from a comprehensive overview based on clinical experience with ARNI therapy. The objective was to develop a consensus document addressing common concerns regarding the use of ARNI in patients with HF in clinical settings in India. Subject matter experts (SMEs) from India with decision-making expertise in the management of HF were identified to address experiences of ARNI use in Indian patients, its function in reversing myocardial remodeling, improvement in health status, and its safety. In regional meetings, five SMEs from India who consented to participate discussed data from practical experiences and current evidence. ARNI has been shown to substantially enhance EF 5%–10% in a majority of HF patients, although the range of improvement could vary widely in a few patients. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blocker antagonists have been eclipsed by ARNI. Patients who have diminished or declining estimated glomerular filtration rates are more likely than those with normal renal function to experience hyperkalemia. It is prudent to consistently monitor potassium levels in patients with borderline chronic kidney disease. In India, potassium binders may be used to temporarily control hyperkalemia caused by ARNI. Patients with a systolic blood pressure of <100 mmHg may initiate taking ARNI while being tracked for clinical symptoms. In clinical practice, symptomatic improvement with ARNI is observed soon after initiating, even before alterations noted in echocardiography. [ABSTRACT FROM AUTHOR]

Background and objective Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic, progressive interstitial lung disease with a diagnosed median survival of 3-5 years. IPF is associated with an increased risk of lung cancer. Therefore, exploring the shared pathogenic genes and molecular pathways between IPF and lung adenocarcinoma (LUAD) holds significant importance for the development of novel therapeutic approaches and personalized precision treatment strategies for IPF combined with lung cancer. Methods Bioinformatics analysis was conducted using publicly available gene expression datasets of IPF and LUAD from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis was employed to identify common genes involved in the progression of both diseases, followed by functional enrichment analysis. Subsequently, additional datasets were used to pinpoint the core shared genes between the two diseases. The relationship between core shared genes and prognosis, as well as their expression patterns, clinical relevance, genetic characteristics, and immune-related functions in LUAD, were analyzed using The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing datasets. Finally, potential therapeutic drugs related to the identified genes were screened through drug databases. Results A total of 529 shared genes between IPF and LUAD were identified. Among them, SULF1 emerged as a core shared gene associated with poor prognosis. It exhibited significantly elevated expression levels in LUAD tissues, concomitant with high mutation rates, genomic heterogeneity, and an immunosuppressive microen-vironment. Subsequent single-cell RNA-seq analysis revealed that the high expression of SULF1 primarily originated from tumor-associated fibroblasts. This study further demonstrated an association between SULF1 expression and tumor drug sensitivity, and it identified potential small-molecule drugs targeting SULF1 highly expressed fibroblasts. Conclusions This study identified a set of shared molecular pathways and core genes between IPF and LUAD. Notably, SULF1 may serve as a potential immune-related biomarker and therapeutic target for both diseases. [ABSTRACT FROM AUTHOR]

• Obicetrapib is a selective CETP inhibitor for reducing LDL-C and ASCVD. • Obicetrapib plus ezetimibe on top of high-intensity statin lowers LDL-C by 63%. • Obicetrapib monotherapy and with ezetimibe are both safe and well tolerated. Obicetrapib, a selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein particles, and apolipoproteins, when added to high-intensity statin in patients with dyslipidemia. To evaluate the safety and lipid-altering efficacy of obicetrapib plus ezetimibe combination therapy as an adjunct to high-intensity statin therapy. This double-blind, randomized, phase 2 trial administered 10 mg obicetrapib plus 10 mg ezetimibe (n = 40), 10 mg obicetrapib (n = 39), or placebo (n = 40) for 12 weeks to patients with LDL-C >70 mg/dL and triglycerides (TG) <400 mg/dL, on stable high-intensity statin. Endpoints included concentrations of lipids, apolipoproteins, lipoprotein particles, and proprotein convertase subtilisin kexin type 9 (PCSK9), safety, and tolerability. Ninety-seven patients were included in the primary analysis (mean age 62.6 years, 63.9% male, 84.5% white, average body mass index of 30.9 kg/m2). LDL-C decreased from baseline to week 12 by 63.4%, 43.5%, and 6.35% in combination, monotherapy, and placebo groups, respectively (p <0.0001 vs. placebo). LDL-C levels of <100, <70, and <55 mg/dL were achieved by 100%, 93.5%, and 87.1%, respectively, of patients taking the combination. Both active treatments also significantly reduced concentrations of non-HDL-C, apolipoprotein B, and total and small LDL particles. Obicetrapib was well tolerated and no safety issues were identified. The combination of obicetrapib plus ezetimibe significantly lowered atherogenic lipid and lipoprotein parameters, and was safe and well tolerated when administered on top of high-intensity statin to patients with elevated LDL-C. [ABSTRACT FROM AUTHOR]

Background: The balance of stroke risk reduction and potential bleeding risk associated with antithrombotic treatment (ATT) remains unclear in atrial fibrillation (AF) at non‐gender CHA2DS2‐VASc scores 0–1. A net clinical benefit (NCB) analysis of ATT may guide stroke prevention strategies in AF with non‐gender CHA2DS2‐VASc scores 0–1. Methods: This multi‐center cohort study evaluated the clinical outcomes of treatment with a single antiplatelet (SAPT), vitamin K antagonist (VKA), and non‐VKA oral anticoagulant (NOAC) in non‐gender CHA2DS2‐VASc score 0–1 and further stratified by biomarker‐based ABCD score (Age [≥60 years], B‐type natriuretic peptide [BNP] or N‐terminal pro‐BNP [≥300 pg/mL], creatinine clearance [<50 mL/min], and dimension of the left atrium [≥45 mm]). The primary outcome was the NCB of ATT, including composite thrombotic events (ischemic stroke, systemic embolism, and myocardial infarction) and major bleeding events. Results: We included 2465 patients (age 56.2 ± 9.5 years; female 27.0%) followed‐up for 4.0 ± 2.8 years, of whom 661 (26.8%) were treated with SAPT; 423 (17.2%) with VKA; and 1040 (42.2%) with NOAC. With detailed risk stratification using the ABCD score, NOAC showed a significant positive NCB compared with the other ATTs (SAPT vs. NOAC, NCB 2.01, 95% confidence interval [CI] 0.37–4.66; VKA vs. NOAC, NCB 2.38, 95% CI 0.56–5.40) in ABCD score ≥1. ATT failed to show a positive NCB in patients with truly low stroke risk (ABCD score = 0). Conclusions: In the Korean AF cohort at non‐gender CHA2DS2‐VASc scores 0–1, NOAC showed significant NCB advantages over VKA or SAPT with ABCD score ≥1. [ABSTRACT FROM AUTHOR]

The mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation is mainly caused by the loss of c-Cbl tyrosine binding site. This mutation could result in a decrease in the degradation rate of proteasome-mediated MET proteins, trigger continuous activation of downstream pathways, and ultimately lead to tumorigenesis. The incidence of MET exon 14 skipping mutation in patients with non-small cell lung cancer (NSCLC) is 0.9% to 4.0%. Patients with advanced NSCLC are recommended to test MET exon 14 skipping mutations who may benefit from MET inhibitors-targeted therapy. MET inhibitors have a high objective response rate and good safety profiles, which could prolong the survival of NSCLC patients with MET exon 14 skipping mutations. The Lung Cancer Specialty Committee of Chinese Elderly Health Care Association organized multidisciplinary experts to give suggestions on the important issues of clinical aspects for targeted therapy of MET exon 14 skipping mutation in NSCLC according to the clinical practice experiences and evidences based medicine. "Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation" is proposed, aiming to provide standardized guidances for the clinical practice of Chinese physicians. [ABSTRACT FROM AUTHOR]

The management of patients who are receiving an anticoagulant or antiplatelet drug and require surgery or an invasive procedure is a common clinical problem encountered by a broad spectrum of health care professionals. This review provides an evidence-based but practical approach to common clinical scenarios involving patients who require an elective surgery/procedure and are receiving either a vitamin K antagonist, a direct oral anticoagulant, or single or dual antiplatelet therapy. This review also addresses the role of perioperative heparin bridging and the management of patients who are receiving an anticoagulant drug and need urgent surgery. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most lethal malignancies in the world, with non-small cell lung cancer (NSCLC) accounting for approximately 80%-85% of all pathological types. Approximately 30%-55% of NSCLC patients develop brain metastases. It has been reported that 5%-6% of patients with brain metastases harbor anaplastic lymphoma kinase (ALK) fusion. ALK-positive NSCLC patients have shown significant therapeutic benefits after treatment with ALK inhibitors. Over the past decade, ALK inhibitors have rapidly evolved and now exist in three generations: first-generation drugs such as Crizotinib; second-generation drugs including Alectinib, Brigatinib, Ceritinib, and Ensartinib; and third-generation drugs like Lorlatinib. These drugs have exhibited varying efficacy in treating brain metastases in ALK-positive NSCLC patients. However, the numerous options available for ALK inhibition present a challenge for clinical decision-making. Therefore, this review aims to provide clinical guidance by summarizing the efficacy and safety of ALK inhibitors in treating NSCLC brain metastases. [ABSTRACT FROM AUTHOR]

The article focuses on an orally effective version of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor as a potential alternative to injection therapy. Topics include the oral agent MK-0616 demonstrated significant and dose-dependent reductions in low-density lipoprotein (LDL) cholesterol levels of as compared to placebo over an eight-week period; and the drug offer a potent alternative for patients reluctant to take statins or receive injections for LDL cholesterol reduction.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase and its rearrangements occur in non- small cell lung cancer (NSCLC), resulting in signal dysregulation in kinase domain. As a new generation of potent ALK tyrosine kinase inhibitors (TKIs), Brigatinib was approved in China in March 2022 as a treatment for locally advanced or metastatic NSCLC patients with ALK rearrangement positive. Brigatinib significantly improved the survival, cranial efficacy and quality of life compared to Crizotinib in clinical trials. Brigatinib is generally well tolerated. Brigatinib has been one of the preferred treatments and an addition of options in ALK-rearranged NSCLC. Pulmonary toxicity is one of the adverse effects observed during the treatment of TKIs and deserves the intense attention of clinicians, despite of its low incidence rate. Pulmonary toxicity reported during the treatment of Brigatinib has shown distinct clinical presentations, such as early-onset (median time to onset, 2 days) and rapid tolerance and reversibility of symptoms. In view of this, the concept of early-onset pulmonary events (EOPEs) was proposed and established during the submission for regulatory review and approval. We focused on clinical characteristics, potential mechanism of etiology, and management strategies of EOPEs to provide clinicians evidence for better clinical decision support. [ABSTRACT FROM AUTHOR]

Scleroderma is a rare, female predominant clinically heterogenous, autoimmune condition characterized by the presence of autoantibodies, vascular abnormalities, and fibrosis. Skin thickening as a result of fibrosis is a hallmark clinical finding, and the extent of this skin thickening further classifies clinical subsets of scleroderma. Organ systems affected may include pulmonary (interstitial lung disease, pulmonary arterial hypertension), renal (scleroderma renal crisis), gastrointestinal (dysmotility, reflux esophagitis, gastric antral vascular ectasia), cardiac (arrhythmias, cardiac fibrosis), and musculoskeletal (arthritis, contractures). Raynaud phenomenon and telangiectasis occur as a result of vascular involvement. Diagnostic workup requires a thorough history and physical examination, supplemented by autoantibody testing. No single therapeutic agent is indicated to treat all manifestations of scleroderma. Rather, system- or organ-based treatment is indicated. Not only are skin manifestations often the presenting feature of scleroderma, progressive skin changes carry prognostic implications, underscoring the value of dermatology insight for early diagnosis suspicion, referral to rheumatology, and timely management. [ABSTRACT FROM AUTHOR]

Background and objective Small cell lung cancer (SCLC) with high c-Myc expression is prone to relapse and metastasis, leading to extremely low survival rate. Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor Abemaci-clib plays a key role in the treatment of tumors, but the effects and mechanisms on SCLC remain unclear. This study was to analyze the effect and molecular mechanism of Abemaciclib in inhibiting proliferation, migration and invasion of SCLC with high c-Myc expression, with a view to expanding a new direction for reducing the recurrence and metastasis. Methods Proteins interacting with CDK4/6 were predicted using the STRING database. The expressions of CDK4/6 and c-Myc in 31 cases of SCLC cancer tissues and paired adjacent normal tissues were analyzed by immunohistochemistry. The effects of Abemaciclib on the proliferation, invasion and migration of SCLC were detected by CCK-8, colony formation assay, Transwell and migration assay. Western blot was used to detect the expressions of CDK4/6 and related transcription factors. Flow cytometry was used to analyze the effects of Abemaciclib on the cell cycle and checkpoint of SCLC. Results The expression of CDK4/6 was associated with c-Myc by STRING protein interaction network. c-Myc can directly modalize achaete-scute complex homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1) and Yes-associated protein 1 (YAP1). Moreover, CDK4 and c-Myc regulate the expression of programmed cell death ligand 1 (PD-L1). Immunohistochemistry showed that the expressions of CDK4/6 and c-Myc in cancer tissues were higher than those in adjacent tissues(P<0.0001). CCK-8, colony formation assay, Transwell and migration assay verified that Abemaciclib could effectively inhibit the proliferation, invasion and migration of SBC-2 and H446OE(P<0.0001). Western blot analysis further showed that Abemaciclib not only inhibited CDK4 (P<0.05) and CDK6 (P<0.05), but also affected c-Myc (P<0.05), ASCL1 (P<0.05), NEUROD1 (P<0.05) and YAP1 (P<0.05), which are related to SCLC invasion and metastasis. Flow cytometry showed that Abemaciclib not only inhibited the cell cycle progression of SCLC cells (P<0.0001), but also significantly increased PD-L1 expression on SBC-2 (P<0.01) and H446OE (P<0.001). Conclusion Abemaciclib significantly inhibits the proliferation, invasion, migration and cell cycle progression of SCLC by inhibiting the expressions of CDK4/6, c-Myc, ASCL1, YAP1 and NEUROD1. Abemaciclib can also increase the expression of PD-L1 in SCLC. [ABSTRACT FROM AUTHOR]

Background: Many studies suggest that early rejection episodes and chronic changes in the allograft kidneys were often subclinical without a concomitant rise in the serum creatinine or proteinuria. Early identification of subclinical pathology by doing protocol biopsy and appropriate intervention is likely to improve long-term graft outcomes. However, it is often not done, out of concern about the procedure-related complications. Methods: All patients who underwent live donor kidney transplantation at Aster Medcity from September 2019 to August 2021 with stable graft function were included in the study. Stable graft function is defined as variation in the creatinine values of <25% from the nadir creatinine. Protocol biopsies were taken at 3 months after transplant surgery. Biopsies were done using spring-loaded biopsy guns percutaneously under ultrasound guidance, and patients were observed for 24 h in the hospital for any complication. Biopsies were analyzed by light microscopy and C4d staining and scored based on the Banff classification 2017 update. Results: Seventy patients underwent protocol kidney biopsy at a prespecified time of 3 months. Majority of our patients (74.3%) received a kidney from the first-degree blood relatives, and the rest (25.7%) of the patients received kidneys from spouses. Induction therapy was given in 57% of the patients, and the rest (43%) were transplanted without an induction agent. Of 70 specimens studied, 44 (62.9%) had normal histology and 26 (37.1%) had varying degrees of histological abnormalities. Thirteen (18.6%) had evidence of subclinical rejection, of which 12 (17.2%) showed borderline rejection and 1 (1.4%) had acute T-cell-mediated rejection (acute TCMR). Other histological findings include chronic active TCMR in 1 (1.4%), varying degrees of interstitial fibrosis and tubular atrophy in 5 (7.1%), evidence of BK virus nephropathy in 2 (2.8%), features of tacrolimus toxicity in 2 (2.8%), and acute interstitial nephritis in one patient. None of the patients developed any complication after the procedure. With appropriate treatment interventions, all patients had stable graft functions at 6-month follow-up. Conclusions: Protocol graft biopsy under real-time ultrasound guidance has a very good safety profile and can help the clinician optimize the immunosuppression with more precision, and on a long term, it might prove cost effective to the patient. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LSCC) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases and is the second most common histological type of lung cancer. Anaplastic lymphoma kinase (ALK)-positive NSCLC accounts for only 2%-5% of all NSCLC cases, and is almost exclusively detected in patients with lung adenocarcinoma. Tus, ALK testing is not routinely performed in the LSCC population, and the efficacy of such treatment for ALK-rearranged LSCC remains unknown. Echinoderm microtubule associated protein like 4 (EML4)-ALK (V ) and TP53 co-mutations were identified by next generation sequencing (NGS) in this patient with advanced LSCC. On December 3, 2020, Ensatinib was taken orally and the efficacy was evaluated as partial response (PR). The progression-free survival (PFS) was 9 months. When the disease progressed, the medication was changed to Loratinib. To our knowledge, Enshatinib created the longest PFS of ALK-mutant LSCC patients treated with targeted therapy since literature review. Herein, we described one case treated by Enshatinib involving a patient with both EML4-ALK and TP53 positive LSCC, and the relevant literatures were reviewed for discussing the treatment of this rare disease. [ABSTRACT FROM AUTHOR]

Background: Despite anticoagulant therapy, patients with atrial fibrillation are still at high risk of ischemic stroke. This study aimed to determine the effect of known pre-stroke atrial fibrillation on the pre-stroke prescription rate of oral anticoagulants, as well as the factors affecting the prescription. Methods: This registry-based prospective cohort study included patients with known atrial fibrillation before stroke who were hospitalized between December 1, 2012, to December 31, 2016. We analyzed the use of oral anticoagulants before the onset of index-stroke and stratified patients according to their therapeutic and non-therapeutic anticoagulant status. Results: Of the 511 acute ischemic stroke patients with atrial fibrillation, 243 (47.6%) were known to have atrial fibrillation before stroke. Only 40 (16.5%) of 243 patients received therapeutic anticoagulation therapy. Patients therapeutic on anticoagulation were more likely to have a lower NIHSS score (7.4 ± 6.6 vs. 10.8 ± 8.4, p = 0.01), shorter length of hospital stay (13.1 ± 9.7 vs. 18.8 ± 13.6, p = 0.01), and higher rates of good functional outcomes at discharge (40% vs. 25.1%, p = 0.01) and at 90 days (60% vs. 39.4%, p = 0.02). Lower CHA2DS2VASc score (3.5 ± 2 vs. 4 ± 1.5, p = 0.01), younger age and male gender were associated with the use of therapeutic anticoagulants before stroke. Conclusion: In patients with atrial fibrillation, oral anticoagulant therapy after the era of non-vitamin K antagonist oral anticoagulants was still underutilized before the onset of stroke. This underused is associated with increased stroke severity and disability. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a prevalent pruritic chronic relapsing inflammatory skin condition that predominantly manifests before the age of 5 years. Physical, mental, and financial burdens of AD are substantial and can adversely reflect on patients, carers, and society. Objective: This article purpose is to review available systemic treatments for moderate-severe AD in children and adolescents and present the evidence behind it. Methods: A thorough search was performed on PubMed. Keywords used were systemic treatment, atopic dermatitis, moderate-severe, and children and adolescents, in addition to search for individual systemic agents. English-published data were utilized exclusively. Results and recommendations drawn from elected studies and guidelines are displayed in this review. Results: Treating patients with moderate-severe AD has proved to be challenging. Not long ago, the available systemic treatments were restricted to conventional immunosuppressants including ciclosporin and methotrexate among others. However, recent years have witnessed impressive advancement in the understanding of AD pathogenesis at the molecular level that resulted in the emergence of multiple promising targeted biologic therapy options including interleukin (IL)-4 and IL-13 inhibitors, IL-13 inhibitors, and JAK inhibitors. Conclusion: Although the new biologic agents have been proposed to be more effective and possibly safer than the traditionally used conventional wide-spectrum immunosuppressive agents for moderate-severe AD, head-to-head comparative studies are limited and long-term data to ascertain the safety of these biologic agents are lacking. Moreover, the cost of biologic agents is far greater than conventional immunosuppressant agents which could contribute to its limited availability in some institutions. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) eliminates tumor cells by high doses of radiation causing DNA damage. However, some tumor cells are reported with radiation resistance that can compromise the efficacy of RT. Cyclin Dependent Kinase Inhibitor 1A (CDKN1A or p21) is a gene associated with the regulation of cell cycle, including DNA damage repair mechanism. The resistance can be a result brought by the suppression of CDKN1A expression. Preliminarily, a stress-responsive protein, Musashi-1, was found to inhibit CDKN1A through direct 3'UTR binding. Therefore, this study aims to develop a radiosensitizer screening platform utilizing the Musashi-1-CDKN1A regulatory circuit to speed up the discovery of novel anti-cancer therapy. Glioblastoma (GBM) cells with wild-type and loss-of-phosphorylation Musashi-1 were established by lentiviral infection. The radiosensitivity was assessed by clonogenic assays. Comet Assay was performed to quantitatively compare DNA damage levels. Western blots were used for the assessment of protein levels in different conditions. A renilla luciferase-based CDKN1A 3'UTR reporter system was obtained from Dr. Gorospe and was subjected to molecular cloning to magnify the bioluminescent signal. Musashi-1 is proved to be oncogenic in clonogenic assays and the subsequent radiation resistance. However, most oncogenic behaviors were eliminated when the phosphorylation site is mutant. The protein level of CDKN1A was enhanced with Musashi-1 loss-of-phosphorylation. However, mRNA and Musashi-1-bound RNA remain unchanged, suggesting a translational regulation may occur. The tail moment in the comet assay suggested the enhancement of radiosensitivity when Musashi-1 phosphorylation is deprived. Our study indicated that the phosphorylation of Musashi-1 can be a therapeutic target due to its ability to hinder the DNA repair mechanisms of GBM cells. To further exploit this mechanism, a luciferase reporter system can be established to screen for potential radiosensitizers, such as kinase inhibitors that can prevent the phosphorylation of Musashi-1 to increase the efficacy of RT treatment. [ABSTRACT FROM AUTHOR]

Angiogenesis is a key factor in determining tumor progression and antitumor response. The integration of angiogenesis imaging into treatment response monitoring has shown promising results and brought significant advancements in managing head and neck cancer (HNC). Despite vigorous development of angiogenesis imaging for the prediction of therapeutic outcomes, there is a lack of reliable analytical methodologies for accurate interpretation and classification of angiogenesis images from the HNC models. This study aims to develop a multi-level ensemble classifier that can distinguish normal, cancerous, and post-treatment samples, enhancing the comprehension of the effects exerted by Cetuximab and anti-CD47 therapy on HNC We developed an ensemble model combining predictions from CNNs (DenseNet121, Vgg16, ResNet50) and machine learning classifiers (SVM, KNN, Naive Bayes). Predictions from both models were firstly averaged and then unified through Bootstrap Aggregating. A total of 784 samples containing images and vascular records were selected and analyzed. This ensemble model was critically evaluated against models solely based on either imaging or vascular data The ensemble model demonstrates a superior performance, achieving 94.28% accuracy (ACC), 0.96 area under the curve (AUC), 89.32% sensitivity (SEN), and 90.17% specificity (SPE). In comparison, the image-based model records an ACC of 91.42%, AUC of 0.93, SEN of 85.40%, and SPE of 88.76%, while the vascular record-based model records an ACC of 85.71%, AUC of 0.90, SEN of 86.33%, and SPE of 82.57% This research highlights the advanced capabilities of the multi-level ensemble model in classifying various treatment responses. To this end, we provide, for the first time, a personalized analytical tool for monitoring tumor angiogenesis, thus verifying targeted and immunotherapeutic responses on HNC models. [ABSTRACT FROM AUTHOR]

Background and objective Acquired and primary resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is still the bottleneck of clinical treatment of advanced non-small cell lung cancer (NSCLC). STE029 is a novel anticancer drug which consists of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) inhibitor and novel cancer cell membrane targeting molecular. This study aimed to investigate the reversal mechanism of EGFR-TKI resistance by STE029 in lung adenocarcinoma. Methods CCK8 test was used to test the cell viability and survival rate of EGFR mutated PC9 cell (Gefitinib sensitive), PC9/BB4 cell (acquired Gefitinib resistant), and EGFR wild type A549 cell after treatment of STE029, Gefitinib or combination of both. EdU test was applied to detect changes in cell cycle and Hoechst 33258 was applied to detect apoptosis rate in overcoming the EGFR-TKI resistance. The activity of EGFR/PI3K/Akt, cell cycle and apoptosis signal pathways were examined. In vivo, nude mice were exposed to STE029, Gefitinib and STE029+Gefitinib for 5 wk. And the the tumor volume was measured and tumor weight was obtained on the last day. Results (1) PC9 cells was highly sensitive to Gefitinib, while PC9/BB4 and A549 cell showed significant resistance to Gefitinib treatment; (2) STE029+Gefitinib treatment could significantly decrease the 50% inhibitory concentrarion (IC50) of Gefitinib in PC9, PC9/BB4 and A549 cells (P<0.05, respectively); (3) In PC9 and PC9/BB4 cells, STE029+Gefitinib can block cell cycle and inhibit cell proliferation (P<0.001), while there was no significant difference in apoptosis rate among three drug intervention groups (P>0.05); However, apoptosis rate was increased in STE029+Gefitinib group in A549 cell (P<0.01), while no significance detected in cell proliferation (P>0.05). (4) In PC9 and PC9/BB4 cells, the combination of STE029 and Gefitinib could downregulate p-EGFR, p-Akt, p-Cyclin D1 and Cyclin D1 (P<0.001), and upregulate the expression of GSK-3β (P<0.001), and the expression of cleaved caspase-8, caspase-8 cleaved caspase-9, caspase-9 showed no difference among groups (P>0.05). In A549 cells, the combination of STE029 and Gefitinib could downregulate p-Akt (P<0.001) and upregulate cleaved caspase-8 and cleaved caspase-9 (P<0.001); (5)In vivo, the combination of STE029 and Gefitinib effectively inhibited tumor development and progression compared to STE029 alone or Gefitinib alone, with significant difference (P<0.05) in PC9 and PC9/BB4 xenografted tumor. Conclusion STE029 could sensitize Gefitinib by inhibiting EGFR/PI3K/Akt pathway, blocking the tumor cell cycle and proliferation and inducing apoptosis through caspase-8 and caspase-9 dependent pathway. STE029 deserves further investigations in overcoming EGFR-TKI resistance in lung cancer. [ABSTRACT FROM AUTHOR]

Thrombotic complications appear to be a major predictor of death in COVID-19 patients, and multiple studies have shown that anticoagulants can help to improve the outcome. The Food and Drug Administration's acceptance of non-vitamin K antagonist oral anticoagulants (NOACs) has sparked much excitement about their potential as a replacement for existing oral anticoagulants. NOACs target a single clotting factor, often activated factor X or thrombin, and involve the coagulation factor Xa inhibitors including apixaban, edoxaban, and rivaroxaban, and the thrombin inhibitor dabigatran. COVID-19 is an infectious disease that causes thrombotic events by inducing a pro-inflammatory and prothrombotic condition. This article provides a comprehensive overview of the mechanism behind enhanced thrombogenicity accompanying COVID-19, the clinical range of NOACs, and the role of NOACs in treatment of COVID-19 based on recent investigations and clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Clinically significant pocket hematoma (CSH) is a common complication to cardiac implantable electronic device (CIED) surgery. We aimed to evaluate predictors of CSH after CIED surgery. Methods: We performed a nationwide population‐based prospective cohort study with systematic patient chart review of all Danish patients undergoing CIED surgery during a 12‐month period. Multiple logistic regression analysis was used to estimate adjusted odds ratios (aOR) with 95% confidence intervals for association between predictors and CSH. Results: We included 5918 consecutive patients, 63% males, mean age 72.6 years. A total of 148 (2.5%) patients experienced CSH, including 10 patients (0.2%) requiring re‐operation with hematoma evacuation. The risk of CSH was significantly increased in patients treated with aspirin (aOR 1.8; 1.2–2.7), aspirin and clopidogrel (aOR 3.9; 2.3–6.5), or heparin (aOR 2.1; 1.1–4.1), and in patients with INR≥2.0 (aOR 2.0; 1.2–3.2). Patients operated by low‐volume operators (aOR 2.7; 1.6–4.6) or undergoing more complex CIED surgery such as cardiac resynchronization therapy (aOR 2.0; 1.1–3.5) or dual‐chamber defibrillator (aOR 2.1; 1.2–3.8) also had significantly increased CSH risk. Conclusion: In a large nationwide cohort of consecutive patients undergoing CIED surgery, the risk of CSH was 2.5%, with 0.2% necessitating evacuation. CSH risk was increased both in patients receiving aspirin, dual antiplatelet therapy or continued vitamin K‐antagonist therapy. Dual antiplatelet therapy had the highest risk (aOR) of CSH. Both low operator volume and more complex CIED surgery were independently associated with higher CSH risk. These data should be considered when planning CIED surgery. [ABSTRACT FROM AUTHOR]

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• Black subjects are under-reported in lipid-lowering ASCVD outcomes trials. • Black subjects are under-represented in lipid-lowering ASCVD outcomes trials. • Inclusion of Black persons will help to address disparities in preventive care. Non-Hispanic (NH) Black participants have been under-represented in studies of cardiovascular disease. We sought to determine the trends of reporting and representation of NH Black subjects in randomized controlled trials (RCTs) of lipid-lowering therapies demonstrating atherosclerotic cardiovascular disease (ASCVD) risk reduction benefit. The electronic databases of MEDLINE, EMBASE and ClinicalTrials.gov were searched from 1990-2020. Studies of lipid-lowering therapies (i.e., statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9], and icosapent ethyl) with proven ASCVD benefit, sample sizes of at least 1000 subjects and follow-up of at least 1 year were included (40 RCTs, N=306 747 total participants). We examined articles and supplementary material for participant-level race data. Using United States disease prevalence data, the participation-to-prevalence ratio (PPR) metric was used to estimate the representation of NH Black subjects compared with their reported disease burden (i.e., < 0.8 indicated under-representation; > 1.2, over-representation; and 0.8 to <1.2, adequate representation). The median (interquartile range) number of participants per trial was 4871 (2434-10077). NH Black enrollees comprised 7.3% (95% CI, 0.9%-15.4%) of the total number of subjects reported. During the time intervals 1990-1995, 1996-2000, 2001-2005, 2006-2010, 2011-2015 and 2016-2020, NH Black participation was 0%, 1.1%, 4.4%, 4.8%, 0.2% and 0.7% respectively (P for trend <0.001). For statin trials, the participation of NH Black subjects was reported in 0 studies between 1990-1995 and in 9 of 28 trials from 1996-2020. For ezetimibe and icosapent ethyl, NH Black participants were reported in 0 of 3 and 0 of 1 studies, respectively. For trials of PCSK9 inhibitors, NH Black subjects were reported in 2 of 5 (40%). NH Black participants were under-represented compared with their disease burden in studies evaluating subjects with diabetes, hypercholesterolemia, stable coronary artery disease, and acute coronary syndrome (PPR < 0.8 for all). NH Black participants are markedly under-represented, and results are under-reported. The inclusion of population and disease specific representation of NH Black persons and their related social determinants of health will help to address the disparity in preventive care for this historically undertreated population. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Preclinical data support investigation of selective CDK4/6 inhibition as a therapeutic strategy for human papillomavirus (HPV)-unrelated head and neck squamous cell carcinoma (HNSCC). Phase 1 clinical trials established the feasibility of combining palbociclib with cetuximab in patients with recurrent or metastatic HNSCC. Nonrandomized phase II trials showed that palbociclib plus cetuximab resulted in efficacy outcomes better than cetuximab in biomarker-unselected, platinum-resistant or cetuximab-resistant, HPV-unrelated HNSCC. A double-blind, randomized phase II trial (PALATINUS) evaluated the efficacy of palbociclib or placebo and cetuximab in patients with biomarker-unselected, platinum-resistant, cetuximab-naive, HPV-unrelated HNSCC. Palbociclib and cetuximab did not significantly prolong overall survival compared with placebo and cetuximab. However, correlative biomarker analyses identified that trends for better overall survival with palbociclib and cetuximab were observed in certain prespecified subsets; the largest reduction in risk of death with palbociclib versus placebo and cetuximab occurred in the subset with CDKN2A mutations. Several phase II-III trials are underway investigating palbociclib in biomarker-selected patients with HPV-unrelated locally advanced or recurrent or metastatic HNSCC. [ABSTRACT FROM AUTHOR]

Adenosine is a metabolite produced abundantly in the tumor microenvironment, dampening immune response in inflamed tissues via adenosine A2A receptor (A2AR) which is widely expressed on immune cells, inhibiting anti-tumor immune response accordingly. Therefore, blocking adenosine signaling pathway is of potential to promote anti-tumor immunity. This review briefly introduces adenosine signaling pathway, describes its role in regulating tumor immunity and highlights A2AR blockade in cancer therapy. Prospective anti-tumor activity of adenosine/A2AR inhibition has been revealed by preclinical data, and a number of clinical trials of A2AR antagonists are under way. Primary results from clinical trials suggest that A2AR antagonists are well tolerated in cancer patients and are effective both as monotherapy and in combination with other therapies. In the future, finding predictive biomarkers are critical to identify patients most likely to benefit from adenosine pathway blockade, and further researches are needed to rationally combine A2AR antagonists with other anti-tumor therapies. [ABSTRACT FROM AUTHOR]

Rationale: Thrombosis of the internal jugular vein is an infrequent and underdiagnosed pathology due to the absence of symptoms. If present, the symptoms are frequently manifested as a sensation of pain and cervical tension. Its etiology is variable, including trauma, central catheterization, and hypercoagulable states, among others. Patient's Concern: A 41-year-old female, previously healthy, was admitted to the emergency room for worsening pain in the left cervical area of 5 d. Previously, she was treated for suspected acute pharyngotonsillitis yet without improvement. Diagnosis: Physical examination revealed a 2 cm in length cervical mass of hard consistency that was painful on palpation and nonfluctuating. Ultrasound study showed thrombosis of the left internal jugular vein. A computed tomography scan revealed that the thrombosis occurred at the cervical portion of the left internal jugular vein as well as the left transverse sinus. Interventions: Hospital admission and treatment with low molecular weight heparin at a dose of 1.5 mg/kg every 24 h. Outcomes: The patient was discharged after 3 d of treatment with vitamin K antagonists. Lessons: Venous thrombosis at the level of the internal jugular vein is an infrequent entity. Clinical suspicion is necessary for the diagnosis given the possibility of absence of symptoms. [ABSTRACT FROM AUTHOR]

NewAmsterdam Pharma. The oral selective cholesteryl ester transfer protein (CETP) inhibitor, obicetrapib, is in development for dyslipidemia in patients unable to achieve sufficient low-density lipoprotein cholesterol (LDL-C) lowering with other lipid-lowering medications. Previous Phase 1 and 2 trials evaluated obicetrapib as monotherapy, in combination with statins and on top of high-intensity statins (HIS). In this study we tested the efficacy and safety of obicetrapib in combination with ezetimibe on top of HIS. ROSE2 enrolled men and women without current clinically manifest cardiovascular disease who had LDL-C >70 mg/dL and triglycerides <400 mg/dL, while taking HIS. Participants continued their HIS and were randomized to obicetrapib 10 mg + ezetimibe 10 mg (n=40), obicetrapib 10 mg (n=39), or placebo (n=40) for 12 weeks. Endpoints included the LDL-C response to combination therapy vs. placebo (primary), and non-high-density lipoprotein cholesterol (non-HDL-C), nuclear magnetic resonance-assessed lipoprotein particles (-P), apolipoprotein B (ApoB), lipoprotein (a) [Lp(a)], small dense (sd)LDL-C, other lipid biomarkers and safety. Obicetrapib monotherapy and with ezetimibe, respectively, significantly (all P<0.05) reduced LDL-C (43.5 and 63.4%), non-HDL-C (37.5 and 55.6%), ApoB (24.2 and 34.4%), total LDL-P (54.8 and 72.1%), small LDL-P (92.7 and 95.4%), sdLDL-C (30.9 and 44.4%), and Lp(a) (47.2 and 40.2%), and increased HDL-C (142 and 136%). Obicetrapib was well tolerated, with no dose-related adverse events or clinically significant changes in vital signs, electrocardiograms, hematology or biochemistry. The tremendous lowering of LDL particles with obicetrapib + ezetimibe suggests a synergistic effect perhaps due to an additional mechanism of action (MoA) for CETP inhibition; it upregulates LDL receptors (as previous studies have indicated), but also increases cholesterol removal through transintestinal cholesterol excretion (TICE). Ezetimibe meanwhile prevents reuptake of the excreted cholesterol removed via the inhibition of Niemann-Pick C1-like 1 (Figure). Obicetrapib monotherapy, in combination with HIS, and with HIS plus ezetimibe is safe, well-tolerated and produces robust reductions in LDL-C, LDL particles, sdLDL-C, and Lp(a). ROSE2 obicetrapib monotherapy results concur with findings across the phase 1/2 development program, while combination therapy results support a synergistic effect of obicetrapib + ezetimibe on circulating LDL particles, consistent with the drugs' known and hypothesized MoAs. [ABSTRACT FROM AUTHOR]

NewAmsterdam Pharma. Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor currently in clinical development for the treatment of hypercholesterolemia and reduction of cardiovascular risk that strongly reduces apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) and concomitantly increases plasma high-density lipoprotein cholesterol (HDL-C). Ezetimibe reduces absorption of biliary and dietary cholesterol from the small intestine, thereby reducing LDL-C levels. The current study was carried out to elucidate the mechanism of action responsible for the observed decrease in non-HDL-C by obicetrapib monotherapy and in combination with ezetimibe in a translational mouse model for hyperlipidemia and atherosclerosis. Female ApoE*3-Leiden.CETP transgenic mice were fed a Western diet with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing obicetrapib alone (2 mg/kg/day), ezetimibe alone (1 mg/kg/day) or the combination of obicetrapib and ezetimibe. Obicetrapib, ezetimibe and the combination thereof reduced total plasma cholesterol levels (-42%, -23% and -62%), mainly attributed to a decrease in non-HDL-C levels (-61%, -24% and -80%). Obicetrapib alone and in combination with ezetimibe nearly completely blocked CETP activity (-99% and -100%) resulting in increased HDL-C (+260% and +245%) and ApoA1 levels (98% and 81%). Obicetrapib, ezetimibe and to a larger extent the combination thereof enhanced clearance of VLDL-like particles (half-life: -44%, -23% and -57%) and enhanced hepatic LDL receptor expression (+63% and +74%). Fecal analysis demonstrated increased bile acid excretion in obicetrapib-treated mice (+41%) and increased neutral sterol excretion in ezetimibe-treated mice, which was even more pronounced in combination with obicetrapib (+68% and +100%), resulting in a net fecal sterol loss. Obicetrapib alone and the combination with ezetimibe reduce non-HDL-C levels by increased VLDL lipolysis, increased VLDL clearance and elevated LDL receptor levels accompanied by an enhanced fecal bile acid and neutral sterol excretion. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 is an emerging viral pathogen and a major global public health challenge since December of 2019, with limited effective treatments throughout the pandemic. As part of the innate immune response to viral infection, type I interferons (IFN-I) trigger a signaling cascade that culminates in the activation of hundreds of genes, known as interferon stimulated genes (ISGs), that collectively foster an antiviral state. We report here the identification of a group of type I interferon suppressed genes, including fatty acid synthase (FASN), which are involved in lipid metabolism. Overexpression of FASN or the addition of its downstream product, palmitate, increased viral infection while knockout or knockdown of FASN reduced infection. More importantly, pharmacological inhibitors of FASN effectively blocked infections with a broad range of viruses, including SARS-CoV-2 and its variants of concern. Thus, our studies not only suggest that downregulation of metabolic genes may present an antiviral strategy by type I interferon, but they also introduce the potential for FASN inhibitors to have a therapeutic application in combating emerging infectious diseases such as COVID-19. Type I interferon-mediated downregulation of fatty acid synthase (FASN) results in decreased viral infection. Pharmacological inhibitors of FASN could be a novel antiviral therapy against enveloped viruses including SARS-CoV-2. [Display omitted] [ABSTRACT FROM AUTHOR]

Programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors and PD-1 inhibitors plus chemotherapy combination regimens have been widely used in the first-line treatment of advanced non- small cell lung cancer(NSCLC), but patients with low PD-L1 expression have limited objective response and survival benefits. Existing treatment regimens are still difficult to fully meet the clinical needs of patients in the real world. Therefore, researchers are still exploring novel superactive treatment options to further improve the efficacy and survival prognosis of different subgroups in NSCLC. Dual immunotherapy [such as the combination of PD-1 and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitors] has shown considerable long-term survival benefits in a variety of tumors and has also shown broad clinical prospects in NSCLC. In addition to exploring different emerging combination options, how to accurately identify the optimal-benefit groups through predictive biomarkers and how to effectively manage the safety of combination immunotherapy through multidisciplinary collaboration are also the focus of dual immunotherapy. This article reviews the mechanism of action, research progress, predictive biomarkers and future exploration directions of dual immunotherapy. [ABSTRACT FROM AUTHOR]

The first rate-limiting enzyme of the serine synthesis pathway (SSP), phosphoglycerate dehydrogenase (PHGDH), is hyperactive in multiple tumors, which leads to the activation of SSP and promotes tumorigenesis. However, only a few inhibitors of PHGDH have been discovered to date, especially the covalent inhibitors of PHGDH. Here, we identified withangulatin A (WA), a natural small molecule, as a novel covalent inhibitor of PHGDH. Affinity-based protein profiling identified that WA could directly bind to PHGDH and inactivate the enzyme activity of PHGDH. Biolayer interferometry and LC–MS/MS analysis further demonstrated the selective covalent binding of WA to the cysteine 295 residue (Cys295) of PHGDH. With the covalent modification of Cys295, WA blocked the substrate-binding domain (SBD) of PHGDH and exerted an allosteric effect to induce PHGDH inactivation. Further studies revealed that with the inhibition of PHGDH mediated by WA, the glutathione synthesis was decreased and intracellular levels of reactive oxygen species (ROS) were elevated, leading to the inhibition of tumor proliferation. This study indicates WA as a novel PHGDH covalent inhibitor, which identifies Cys295 as a novel allosteric regulatory site of PHGDH and holds great potential in developing anti-tumor agents for targeting PHGDH. WA is a novel covalent-allosteric inhibitor of phosphoglycerate dehydrogenase (PHGDH), and inhibits the serine synthesis pathway and proliferation of colon cancer cells with overexpression of PHGDH. [Display omitted] [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) fusion gene, as a tumor driver gene, was crucial for the occurrence and development of non-small cell lung cancer (NSCLC). Recently, targeted ALK fusion gene has become the main treatment method for ALK-positive NSCLC. The first and second generation ALK inhibitors (ALKi), such as crizotinib, ceritinib, alectinib and ensartinib have been approved in China. However, there was no guidance for the management of ALKi adverse reactions. Therefore, this "Recommendations from experts in the management of adverse reactions to ALK inhibitors (2021 version)" has been summarized, led by Lung Cancer Professional Committee of Sichuan Cancer Society and Sichuan Medical Quality Control Center for Tumor Diseases, to provide practical and feasible strategies for clinical ALKi management specification of adverse reactions. [ABSTRACT FROM AUTHOR]

Rare events can sometime arise in clinical development of treatments. For example, CYPIDES was a single-arm study of the CYP11A1 inhibitor ODM-208 to treat metastatic prostate cancer. Preclinical testing of the compound identified elevated thyroid-stimulating hormone (TSH) and bilirubin in rats and dogs. Unusual findings in preclinical testing focus attention and magnify evidence if similar results occur in humans. By analogy, imagine a murder trial in which the only evidence against the defendant arose from a database search of DNA matching the partial profile found at the crime scene. Multiple people could match, so without other evidence, the perpetrator could be any of them. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase-13 (MMP-13) has been reported to be involved in different biological processes such as degradation of extracellular matrix proteins, activating or degrading some significant regulatory proteins, wound healing, tissue remodeling, cartilage degradation, bone development, bone mineralization, ossification, cell migration, and tumor cell invasion. Further, MMP-13 participates in many oral diseases such as tooth decay, gingivitis, and degradation of enamel and tissue around the implant. In addition, inhibition of MMP-13 has shown therapeutic properties for Alzheimer's disease (AD). We performed molecular docking to assess the binding affinity of 29 flavonoid compounds with the MMP-13. Additionally, pharmacokinetic and toxicity characteristics of the top-ranked flavonoids were studied. The current study also intended to identify the most important amino acids involved in the inhibition of MMP-13 based on topological feature (degree) in the ligand-amino acid network for MMP-13. Molecular docking and network analysis were studied using AutoDock and Cytoscape software, respectively. Pharmacokinetic and toxicity characteristics of compounds were predicted using bioinformatics web tools. The results revealed that nine of the studied flavonoids had considerable estimated free energy of binding and inhibition constant: Rutin, nicotiflorin, orientin, vitexin, apigenin-7-glucoside, quercitrin, isoquercitrin, quercitrin-3-rhamnoside, and vicenin-2. Proline-242 was found to be the most important amino acid inhibiting the enzyme. The results of the current study may be helpful in the prevention and therapeutic procedures of many disorders such as cancer, tooth caries, and AD. Nevertheless, validation tests are required in the future. [ABSTRACT FROM AUTHOR]

Background and objective Anaplastic lymphoma kinase (ALK) is an important therapeutic target for advanced non-small cell lung cancer (NSCLC). In recent years, with the emergence of several ALK tyrosine kinase inhibitors (TKI), the overall survival (OS) of ALK fusion positive patients is gradually extended. This paper reports the treatment of a late stage non-small cell lung cancer (NSCLC) patient with ALK fusion positive for more than 5 years, and analyzes the treatment process and effect evaluation, so as to provide experience for the follow-up treatment of patients. Methods The diagnosis and treatment process of a patient with advanced ALK fusion mutation positive lung cancer admitted to the third ward of Department of oncology, Chifeng hospital, Inner Mongolia on July 3, 2015 was retrospectively analyzed. Results A 42 years old male patient was admitted to our department on July 3, 2015 for "intermittent cough, chest tightness for 2 months, diagnosed with lung adenocarcinoma for 1 day". Imaging examination showed a space occupying lesion in the left lower lobe of the lung, accompanied by mediastinal lymphadenopathy and left encapsulated pleural effusion. Bronchoscopic pathology showed non-small cell carcinoma, and adenocarcinoma was tentatively suggested. Diagnosis: left lower lobe adenocarcinoma T1bN2M1a stage IV. Fluorescence in situ hybridization (FISH) indicated the translocation of ALK (2p23) chromosome. After 2 cycles of docetaxel+cisplatin (DP) regimens chemotherapy, disease progression occurred, so we used 6 cycles of pemetrexed+carboplatin to apply combination chemotherapy, 4 cycles of pemetrexed monotherapy were used after that. The efficacy evaluation: PR. On April 9, 2016, the patient was treated with crizotinib. In August 2019, multiple intracranial metastases were found and whole brain radiotherapy was given. Since September 4, 2019, oral administration of nsatinib has been carried out. As of March 1, 2021, the patients were followed up well. Conclusion The advanced ALK fusion positive lung ad-enocarcinoma patients, though the first-line and the second-line chemotherapy, and the follwing application of ALK-TKI treatment, has procured a total OS has reached 68 months, and the current follow-up is good. [ABSTRACT FROM AUTHOR]

The development of immune checkpoint inhibitors (iCis) has significantly improved the prognosis of cancer patients, but a large population of patients are still ineffective to iCis treatment or develop aquired drug resistance. in order to improve the clinical benefits, a number of studies on iCis based combination therapy have been actively explored, and have achieved satisfactory results. With the application of iCis based combination therapy in clinical practice, increasing attention has been paid to the safety of combination therapy and the management of treatment-related adverse events. in this review, the characteristics of adverse events related to iCis based combination therapies, especially programmed cell death protein 1/protein ligand 1 (PD-1/PD-L1) inhibitors are discussed, in order to provide profound thoughts for toxicity evaluation and individualized treatment decision in future clinical practice. [ABSTRACT FROM AUTHOR]

Phyllanthus niruri has been known as an immunomodulator and also reported to possess an antiviral activity against several RNA viruses, such as hepatitis B virus and hepatitis C virus by inhibiting viral entry and replication. Since the current situation of Coronavirus Disease 2019 (COVID-19) which infected among the world and caused severe disease and high morbidity, it urgently needed to find new agents against COVID-19. Therefore, in silico screening against COVID-19 receptors is carried out as an initial stage of drug discovery by evaluating the activity of phyllanthin and hypophyllanthin, an isolated from Phyllanthus niruri, in inhibiting spike glycoprotein (6LZG) and main protease (5R7Y) which play as target receptors of COVID-19. Molegro Virtual Docker 6.0 used to determine the best binding energy through the rerank score which shows the total energy bonds calculation. Phyllanthin and hypophyllanthin demonstrated to possess greater binding affinity toward the COVID-19 inhibition sites than their native ligand. The rerank score of phyllanthin and hypophyllanthin are lower than the native ligands 6LZG and 5R7Y. This result indicated that phyllanthin and hypophyllanthin have a stronger interaction than the native ligands both in spike glycoprotein (entry inhibitor) and main protease (translation and replication inhibitor). In conclusion, phyllanthin and hypophyllanthin are predicted to have strong activity against COVID-19 through inhibiting spike glycoprotein and main protease under in silico study. Further research is needed to support the development of P. niruri as inhibitor agents of COVID-19 through bioassay studies. [ABSTRACT FROM AUTHOR]

In food ingestion, alpha-glucosidase (α-glucosidase) and alpha-amylase (α-amylase) are enzymes that are responsible to convert a carbohydrate into glucose. Inhibition of both enzyme activities can prolong absorption of glucose in intestine and reduce post-prandial increase of blood glucose concentration, thus, it is beneficial for type-2 diabetes treatment. Traditionally, Urena lobata (U. lobata) has been used to manage diabetes, but the scientific proof of this claim remains scarce. Therefore, the objective of this study to examine the anti-diabetic potential of U. lobata leaf extract through inhibition of α-amylase and α-glucosidase. U. lobata leaf extract was obtained through extraction process using ethanol and the chemical compounds in the extract were analyzed by liquid chromatography–mass spectra (LC–MS). The inhibitory activity of U. lobata on α-glucosidase and α-amylase was evaluated by in silico using docking server, whereas in vitro enzymatic assays were using para-nitrophenyl-α-d-glucopyranoside (α-NPG) and starch as substrates. The data were presented as mean ± SD and the IC50 value was calculated using SPSS. U. lobata leaf extract showed inhibitory activity on α-glucosidase and α-amylase with the IC50 value was 43.73 and 83.73 μg/mL, respectively, meanwhile, acarbose as standard has IC50 value at 1.14 and 0.08 μg/mL. Molecular docking study indicated β-sitosterol and stigmasterol from U. lobata extract have a huge inhibitory activity both on α-amylase and α-glucosidase based on inhibition constant (Ki) value. Ethanolic extract of U. lobata showed inhibition activity on α-glucosidase stronger than on α-amylase as antidiabetic. [ABSTRACT FROM AUTHOR]

Background and objective Immune checkpoint inhibitors (ICIs) such as antibodies against programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), have shown remarkable efficacies in many subtypes of cancers. However, ICIs may also cause severe immune-related adverse events in the recipient patients. Recently, ICI-associated myocarditis have been reported in hundreds of patients worldwide, with a mortality rate of approximately 50% in these cases. This study aims to recapitulate the cardiotoxicity and explore the detoxicifying approaches to attenuate mortality caused by PD-1/PD-L1 inhibitors in healthy mice. Methods Six to eight-week-old C57BL/6 mice were inoculated with anti-PD-1 antibody (12.5 µg/g every 5 days for 6 injections), anti-PD-L1 antibody (10 µg/g once a week for 6 weeks), anti-PD-L1 antibody (with the same dosage described above) in combination with levothyroxine (0.25 µg/g, intraperitoneally injected half an hour before anti-PD-L1 antibody injection), or isotype control immunoglobulin IgG (10 µg/g once a week for 6 weeks). The ejection function of the hearts was detected by echocardiography, body temperature and blood pressure were detected by Mouse Monitor™ and non-invasive blood pressure mniotor, and serum free thyroxine concentration was detected by The enzyme linked immunosorbent assay (ELISA). Results PD-L1 was expressed at different levels by the cardiomyocytes of the mice. The isotype control immunoglobulin and anti-PD-1 antibody did not cause death of the mice. The 12 mice receiving 3-6 injections of anti-PD-L1 antibody showed a significant increase in the heart-to-tibial ratio and cardiomyoctye degeneration, hyalinization and extravascular inflammatory cell infiltration. In addition, the serum thyroxine was mardedly decreased to 1/3 of that in the control group mice, and the blood pressure and body temperature were abnormally decreased in mice upon treatment with PD-L1 blockade. Eight of the 12 (66.7%) mice died from multiple intravenous injection of anti-PD-L1 antibody. Intraperitoneal injection of levothyroxine 30 min before the injection of anti-PD-L1 antibody significantly attenuated the mortality rate of the anti-PD-L1 antibody-treated mice. Conclusion The anti-PD-L1 antibody is cardiotoxic and lethal, and levothyroxine is able to rescue the mice from this immune checkpoint inhibitor-caused mortality. [ABSTRACT FROM AUTHOR]

Hyperkinetic movement disorders are a common group of movement abnormalities in children, characterized with repetitive unintended involuntary movements. Major hyperkinetic movements include tremor, tic, dystonia, myoclonus, and chorea. Although a number of drugs have been proven to be beneficial for these abnormalities, some patients may become resistant to conventional treatments. Vesicular monoamine transporter2 (VMAT2) inhibitors (Tetrabenazine, Deutetrabenazine, and Valbenazine) are new agents introduced in the last decade for treating some of movement disorders, in particular tardive dyskinesia, Huntington chorea, and Tourette syndrome. In this brief review, we discussed the role of these drugs in managing hyperkinetic movement disorders. [ABSTRACT FROM AUTHOR]

The echinoderm microtubule associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) were fractured and fused to become EML4-ALK. Most of these EML4-ALK-positive non-small cell lung cancer patients respond well to the ALK inhibitor. Many patients can benefit from drug target therapy for a long time, and some patients can achieve long-term survival of more than 7 years under the optimized treatment mode. This patient has lung adenocarcinoma positive for EML4-ALK fusion gene, but the treatment outcome is obviously different from that of other patients with lung cancer positive for EML4-ALK fusion gene. After the first to third generations of ALK inhibitor targeted therapy and chemotherapy, the disease progresses rapidly, the drug resistance time is short, the survival time is short, and the benefit is limited. The patient received targeted therapy of Crizotinib, Ceritinib and Lorlatinib successively from July 15, 2019, followed by two chemotherapy courses of Bevacizumab combined with Pemetrexed and Carboplatin. The patient died on September 10, 2020, with a survival of 15 months. At the same time, the treatment showed common adverse reactions of ALK inhibitors. This paper analyzed the therapeutic effect and treatment dilemma of this patient, and provided an exploration direction for the treatment of patients with EML4-ALK fusion gene positive lung cancer. [ABSTRACT FROM AUTHOR]

Background and objective Immune checkpoint inhibitor monotherapy is reported to have little effect in advanced non-small cell lung cancer (NSCLC) patients with driver oncogenes. However, recent studies have shown that some patients with driver genes are still benefit from combination immunotherapy after tyrosine kinase inhibitors (TKIs) drug resistance. The purpose of this study was to analyze the efficacy of posterior line immunotherapy in NSCLC patients with epidermal growth factor (EGFR) sensitive mutation, and to evaluate the value of immunotherapy in posterior line therapy in patients with advanced EGFR mutation. Methods A total of 27 patients with EGFR mutation diagnosed in Beijing Chest Hospital, Capital Medical University from June 2018 to November 2020 were collected. After the progress of targeted therapy, they had received programmed cell death protein 1 (PD-1) checkpoint inhibitor combined with chemotherapy and anti-angiogenic drug therapy. Results Of the 27 advanced NSCLC patients, 19 cases (70.4%) did not have T790M mutation. There were 8 cases (29.6%) with T790M point mutation. The total objective response rate (ORR) was 40.7%. Kaplan-Meier survival analysis showed that there was no statistically significant difference among different EGFR mutations (χ²=4.15, P=0.230). But progression-free survival (PFS) was significantly longer in patients without T790M mutation than in patients with T790M mutation (9.2 mon vs 3.3 mon, χ²=2.808, P=0.041), and the same trend was observed in patients with overall survival treated with the PD-1 inhibitor (12.2 mon vs 7.3 mon, χ²=3.22, P=0.062). ORR of patients without T790M was significantly better than that with T790M (52.63% vs 12.5%, P=0.045). Conclusion Patients with EGFR mutation can benefit from later-line combined immunotherapy. The patients with T790M mutation in the population of EGFR mutation had the worst effect of immunotherapy in the later line. Therefore, the follow-up treatment and whole-course management of these patients need to explore better treatment strategies to improve the benefit. [ABSTRACT FROM AUTHOR]

Background and objective Lung cancer is one of the leading causes of cancer-related morbidity and mortality. Oncolytic virotherapy is an emerging therapeutic modality that utilizes replication-competent viruses to destroy cancers. As a powerful tool to kill tumor cells with excellent safety profile, attenuated measles virus of the Edmonston strain (MV-Edm) has been widely applied in the development of tumor therapy and preclinical trials. The aim of this study was to investigate the synergistic effect of nuclear factor kappa B (NF-κB) signaling pathway inhibitor and oncolytic measles virus vaccine against lung cancer and the involved mechanisms. Methods Using Western blot to detect MV-Edm infection of A549 and H1299 were infected by MV-Edm alone or used the NF-κB pathway inhibitor PS1145/cell autophagy related siRNA, expression level of p-IκBα, IκBα, PARP and BAX were determined by western blot. Using flow cytometry to analysis the rate of apoptosis, and using MTT [3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide] method to detect the cell survival rate. Results Inhibition of cell autophagy could obviously inhibit the MV-Edm infection induced the NF-κB pathway activation in A549 and H1299. In MV-Edm infected A549 and H1299, p-IκBα level increased and IκBα level decreased over infection time, compared with control group. Inhibition of the NF-κB pathway by PS1145 could promote the apoptosis of MV-Edm infected A549 and H1299 and amplify the tumor killing effect. Conclusion The combination of NF-κB signaling pathway inhibitor pS 1145 and oncolytic measles virus vaccine strains can promote the apoptosis of human lung cancer cells A549 and H1299 and enhance their oncolytic effect. [ABSTRACT FROM AUTHOR]

Immunotherapy is one of the main strategies of anti-tumor therapy at present, in which immune checkpoint inhibitors (ICIs) are the most widely used drug. ICIs resistance is mediated by a variety of cytokines and immune cells, and the mechanism is complex, which is the main reason for the failure of immunotherapy in cancer patients. Histone deacetylase inhibitor (HDACi), as a class of epigenetic regulatory drugs, plays an important role in regulating cell cycle, proliferation, differentiation, and activity. In recent years, Studies have found that HDACi can not only regulate cell biological characteristics, but also closely related to the improvement of tumor ICIs drug resistance. Therefore, the study on how HDACi enhances the efficacy of ICIs is of great significance to tumor immunotherapy. This article will review the research progress of HDACi combined with ICIs in treating malignant tumors and their related mechanism. [ABSTRACT FROM AUTHOR]