Application of model-informed drug development (MIDD) for dose selection in regulatory submissions for drug approval in Japan.

Model-informed drug development (MIDD) is an approach to improve the efficiency of drug development. To promote awareness and application of MIDD in Japan, the Data Science Expert Committee of the Drug Evaluation Committee in the Japan Pharmaceutical Manufacturers Association established a task force, which surveyed MIDD applications for approved products in Japan. This study aimed to reveal the trends and challenges in the use of MIDD by analyzing the survey results.

Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial.

Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors.

Outcomes and predictive factors for fluid resolution following three loading injections of faricimab for treatment-naïve neovascular age-related macular degeneration.

To evaluate the outcomes and predictive factors for fluid resolution following three loading injections of faricimab for neovascular age-related macular degeneration(AMD). This retrospective study included patients diagnosed with treatment-naïve neovascular AMD who received three monthly injections of faricimab. Changes in best-corrected visual acuity(BCVA) and central retinal thickness(CRT) following treatment were evaluated.

Rapidly spreading with OXA-48-like carbapenemases.

(mostly , ) with OXA-48-like carbapenemases (e.g., OXA-48, -181, -232, -244) are undermining the global efficiency of carbapenem therapy.

Epidermal Growth Factor Receptors Unveiled: A Comprehensive Survey on Mutations, Clinical Insights of Global Inhibitors, and Emergence of Heterocyclic Derivatives as EGFR Inhibitors.

Mutations that overexpress the epidermal growth factor receptor (EGFR) are linked to cancers like breast (15-20%), head and neck (10-15%), colorectal (5-8%), and non-small cell lung cancer (10-50%), especially in East Asian populations. EGFR activation stimulates "RAS/RAF/MEK/ERK, PI3K/Akt, and MAPK" pathways, which enhance cell division, survival, angiogenesis, and tumor growth while inhibiting apoptosis and metastasis. Secondary mutations (e.

Extracellular phospholipase, protease and hemolysin production by strains of opportunistic yeasts from the excreta of Mew Gulls breeding in natural and urban habitats.

Extracellular hydrolytic activity (phospholipase, protease and hemolysin production) was evaluated in 178 strains of potentially pathogenic ascomycetous (Candida parapsilosis, Candida tropicalis) and basidiomycetous (Rhodotorula mucilaginosa) yeasts isolated from the excreta of Mew Gulls. Two bird colonies, one nesting in a natural habitat and the other in an urban habitat at the landfill, were studied simultaneously during their 7-month breeding season. Significant differences in phospholipase and protease production were found between natural and anthropophized strains.

Next generation thiazolyl ketone inhibitors of cytosolic phospholipase A α for targeted cancer therapy.

Eicosanoids are key players in inflammatory diseases and cancer. Targeting their production by inhibiting Group IVA cytosolic phospholipase A (cPLAα) offers a promising approach for cancer therapy. In this study, we synthesize a second generation of thiazolyl ketone inhibitors of cPLAα starting with compound GK470 (AVX235) and test their in vitro and cellular activities.

Mid- to Long-Term Clinical Outcomes and Failure Rates After ALPSA Lesion Repair.

Background: Anterior labroligamentous periosteal sleeve avulsion (ALPSA) lesions are associated with recurrent shoulder instability and higher rates of failure after capsulolabral repair compared with similarly treated Bankart lesions. Although these lesions can portend poor outcomes, there are limited data on the associated conditions and postoperative course in a young, active population.

Purpose: To evaluate the mid- to long-term clinical course and failure rates after ALPSA repairs and assess features associated with these outcomes.

Novel thermosensitive small multilamellar lipid nanoparticles with promising release characteristics made by dual centrifugation.

Thermosensitive liposomes (TSLs) have great potential for the selective delivery of cytostatic drugs to the tumor site with greatly reduced side effects. Here we report the discovery and characterization of new thermosensitive small multilamellar lipid nanoparticles (tSMLPs) with unusually high temperature selectivity. Furthermore, the temperature-dependent release of the fluorescent marker calcein from tSMLPs is enhanced by human serum albumin.

Deep dive into the diversity and properties of rhodopsins in actinomycetes of the family Geodermatophilaceae.

In recent decades, most studies of microbial rhodopsins have focused on their identification and characterization in aquatic bacteria. In 2021, actinomycetes of the family Geodermatophilaceae, commonly inhabiting terrestrial ecosystems in hot and arid regions, have been reported to contain rhodopsins with DTEW, DTEF and NDQ amino acid motifs. An advanced bioinformatics analysis performed in this work additionally revealed NTQ rhodopsin and heliorhodopsins.

Boldenone and Testosterone Production from Phytosterol via One-Pot Cascade Biotransformations.

Testosterone (TS) and its 1(2)-dehydrogenated derivative boldenone (BD) are widely used in medicine, veterinary science and as precursors in organic synthesis of many therapeutic steroids. Green production of these compounds is possible from androstenedione (AD) enzymatically, or from phytosterol (PS) using fermentation stages. In this study, the ascomycete sp.

Aortitis Increases the Risk of Surgical Complications and Re-Operations After Major Aortic Surgery.

Aortitis, defined as inflammation of the aorta, can lead to aneurysms and dissections. Intra-operative sampling is essential for diagnosis, with many cases presenting asymptomatically as clinically isolated aortitis. Previous studies investigating aortitis in major aortic surgery have been limited by low intra-operative sampling.

Impact of Bifurcation Lesions on Outcomes After FFR-Guided PCI or CABG.

Background: In the era of first-generation drug-eluting stents and angiography-guided percutaneous coronary intervention (PCI), the presence of a bifurcation lesion was associated with adverse outcomes after PCI. In contrast, the presence of a bifurcation lesion had no impact on outcomes following coronary artery bypass grafting (CABG). Therefore, the presence of a coronary bifurcation lesion requires special attention when choosing between CABG and PCI.

Cardiovascular-Liver-Metabolic Health: Recommendations in Screening, Diagnosis, and Management of Metabolic Dysfunction-Associated Steatotic Liver Disease in Cardiovascular Disease via Modified Delphi Approach.

There is a new awareness of the widespread nature of metabolic dysfunction-associated steatotic liver disease (MASLD) and its connection to cardiovascular disease (CVD). This has catalyzed collaboration between cardiologists, hepatologists, endocrinologists, and the wider multidisciplinary team to address the need for earlier identification of those with MASLD who are at increased risk for CVD. The overlap in the pathophysiologic processes and parallel prevalence of CVD, metabolic syndrome, and MASLD highlight the multisystem consequences of poor cardiovascular-liver-metabolic health.

Data-driven CSF biomarker profiling: imaging and clinical outcomes in a cohort at risk of Alzheimer's disease.

Background: Cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction, neuroinflammation, and glial response, complementing Alzheimer's disease (AD) core biomarkers, have improved the pathophysiological characterization of the disease. Here, we tested the hypothesis that the co-expression of multiple CSF biomarkers will help the identification of AD-like phenotypes when biomarker positivity thresholds are not met yet.

Methods: Two hundred and seventy cognitively unimpaired adults with family history (FH) of sporadic AD (mean age = 60.

Outcomes and management of invasive procedures in participants with hemophilia A post gene therapy: a post hoc analysis of the GENEr8-1 phase III trial.

Background: Hemophilia A is caused by coagulation factor VIII (FVIII) deficiency and increases bleeding risk during invasive procedures.

Objectives: To investigate FVIII concentrate use and bleeding outcomes for invasive procedures after valoctocogene roxaparvovec gene transfer.

Design: This manuscript presents post hoc analysis of the phase III GENEr8-1 trial.

Carbon Monoxide in Healthcare Monitoring Balancing Potential and Challenges in Public Health Perspective: A Narrative Review.

Carbon monoxide (CO) has medicinal potential and harmful qualities. However, excessive exposure to CO can lead to severe organ failure. CO is exogenously and endogenously generated within the human body.

Evaluating the need for standardised disease manifestation categories in patients infected with the tick-borne encephalitis virus: A Delphi panel.

Categorization systems for tick-borne encephalitis virus (TBEV) infection lack consistency in classifying disease severity. To evaluate the need for a standard, consensus-based categorisation system for TBEV infection across subtypes, we gathered an expert panel of clinicians and scientists with diverse expertise in TBEV infection. Consensus was sought using the Delphi technique, which consisted of 2 web-based survey questionnaires and a final, virtual, consensus-building exercise.

Inclisiran as a siRNA Inhibitor of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9); Past, Present, and Future.

Reducing low-density lipoprotein cholesterol (LDL-C) levels has been shown to reduce the risk of developing atherosclerotic cardiovascular disease (ASCVD). Statins are the foundation of LDL-C lowering therapy with other non-statin agents used in circumstances where goal LDL-C levels are not reached or owing to intolerance to adverse effects of statins. In 2003, the discovery of the role of the proprotein convertase subtilisin/kexin type 9 (PCSK9) system in promoting elevated LDL-C levels led to new avenues of drug development to achieve target LDL-C.

The efficacy of plasma exosomal miRNAs as predictive biomarkers for PD-1 blockade plus chemotherapy in gastric cancer.

Background: The response of gastric cancer (GC) patients to first-line programmed cell death 1 (PD-1) blockade and S-1 plus oxaliplatin (SOX) chemotherapy varies considerably, and the underlying mechanisms driving this variability remain elusive. Exosomal microRNAs (miRNAs or miRs) have emerged as potential biomarkers for efficacy prediction due to their roles in GC biology and stable expression in serum. In this study, we aimed to identify biomarkers to predict patients' response to anti-PD-1 therapy and further elucidate the potential mechanisms by which these exosomal miRNAs modulate the immune response in GC.

Pushing the boundaries of radiotherapy-immunotherapy combinations: highlights from the 7 immunorad conference.

Over the last decade, the annual Immunorad Conference, held under the joint auspicies of Gustave Roussy (Villejuif, France) and the Weill Cornell Medical College (New-York, USA) has aimed at exploring the latest advancements in the fields of tumor immunology and radiotherapy-immunotherapy combinations for the treatment of cancer. Gathering medical oncologists, radiation oncologists, physicians and researchers with esteemed expertise in these fields, the Immunorad Conference bridges the gap between preclinical outcomes and clinical opportunities. Thus, it paves a promising way toward optimizing radiotherapy-immunotherapy combinations and, from a broader perspective, improving therapeutic strategies for patients with cancer.

Evaluation of immune checkpoint inhibitor efficacy for solid tumors with (PD-L1 gene) amplification identified by comprehensive genomic profiling: retrospective study based on a nationwide database.

Background: Amplification of the programmed cell death-ligand 1 gene () is highly prevalent and associated with a high response rate to immune checkpoint inhibitors (ICIs) in lymphomas, and is also a potential biomarker for ICI treatment of solid tumors. However, the efficacy of ICIs for solid tumors with amplification identified by comprehensive genomic profiling (CGP) has been unclear. We here examined ICI efficacy for solid tumors with amplification identified by CGP in a national database.

Longitudinal changes in consonant production in infant-directed speech and infants' early speech production from 6 to 12 months.

Previous research suggests that acoustic features of infant-directed speech (IDS) might be beneficial for infants' language development. However, consonants have gained less attention than prosodic and vowel-based features. In the current study, we examined voice onset time (VOT) - a distinguishing cue for stop consonant contrasts - in IDS and adult-directed speech (ADS), and its relation to infants' speech production.