AI and pharmacophore-based screening, molecular docking, and dynamic simulation for identification of CDK6 inhibitors to combat NSCLC.

The emergence of anti-vascular endothelial growth factor (anti-VEGF) therapy has marked a paradigm shift in the treatment of retinal and choroidal vascular diseases. Following the identification of VEGF as a central mediator of pathological angiogenesis and vascular permeability, anti-VEGF molecules have undergone significant evolution with increasing molecular sophistication and efficacy. Landmark clinical trials have defined contemporary treatment paradigms, along with established and emerging therapeutic indications related to anti-VEGF injections. This comprehensive review outlines the progression of anti-VEGF agents across successive generations, highlighting their mechanisms of action, pharmacokinetic and pharmacodynamic properties, and complications associated with and challenges related to anti-VEGF therapy, including the financial implications of long-term treatment in routine clinical practice. Recent advances in injection techniques, sustained drug-delivery systems, alternative delivery routes, growing availability of biosimilars, and gene-based therapies offer promising strategies to reduce treatment burden and improve cost-effectiveness. In addition to the conventional intravitreal route, alternate routes of anti-VEGF injections, like subretinal, supra-choroidal, and topical therapies, are being explored in various phases of the ongoing clinical trials. However, safety issues are vital for the clinical adaptability of the newer injection regimens, especially sustained drug deliveries and gene therapies. Furthermore, emerging technologies such as artificial intelligence-assisted home optical coherence tomography monitoring are poised to transform disease surveillance and personalized care. Collectively, these developments are expected to reshape the future landscape of anti-VEGF therapy and improve global retinal disease outcomes.

Poly(ADP-ribose) polymerase (PARP) inhibition has emerged as a prominent approach in cancer treatment, leading to the development of several poly(ADP-ribose) polymerase inhibitors (PARPi), which have demonstrated substantial progress in clinical trials and efficacy in the management of ovarian cancer (OC), breast cancer (BC), and solid tumors (STs). These PARPi are approved for several cancers, including BC and OC. Among PARPi, Talazoparib (Talzenna®) is a potent therapy for patients with locally advanced or metastatic BC (mBC) with germline BRCA mutations (gBRCAm) and HER2-negative status, demonstrating the highest potency (IC50 = 0.57 nM), which is 4-10 times lower than that of other PARP inhibitors; olaparib (2.0 nM), rucaparib (1.9 nM), and veliparib (4.7 nM), indicating superior efficacy. This review describes the role of BRCA1/2 in BC and OC, highlighting key discovery milestones and providing an overview of available PARP inhibitors (PARPi) at various stages of development. Additionally, it details the discovery and development of talazoparib, one of the key PARPis, its current clinical status, and therapeutic implications. The latest advancements in talazoparib research, including all related clinical trials (Phase 1-3) for the treatment of BC, OC, and other solid tumors (STs), are also summarized. A comprehensive analysis of all clinical trials involving talazoparib, whether as monotherapy or in combination with other drugs, elucidates its potential to improve clinical outcomes, address drug resistance, and explore synergistic combinations with other PARPi or novel agents, thereby providing insights into the clinical utility of talazoparib.

Trial run-in phases are sometimes used to select participants into clinical trials who are most likely to remain adherent to study medications. The study designs and data analysis methods employed lack clear regulatory guidance while reporting is not consistent or transparent. This study aims to develop a consensus guideline for the Measurement, Analysis, and Reporting of Medication Adherence during the Run-in phase (MARMAR) of clinical trials. Initial "items" (specific statements relating to the measurement, analysis, and reporting of medication adherence during trial run-in phases) were generated following a systematic review of trial run-in phases. Items were split into 2 domains (methods and reporting), refined through a pilot exercise and subsequently evaluated using a two-round modified Delphi survey of international experts in medication adherence and clinical trials. Participants were recruited via e-mailing lists. In survey round one, respondents rated the importance of items across a scale labelled strongly agree to strongly disagree and provided free-text comments. In survey round two, respondents categorised items as essential or desirable and suggested alternative wording. A final consensus meeting of the research team was held to finalise the guideline. Guideline development was endorsed by the International Society for Medication Adherence (ESPACOMP) and registered with EQUATOR. In round one, 49 respondents rated 29 items, with 64-100% (mean 86.5%) of experts scoring an item 4 or 5. Consensus was reached for 28 items, and 226 free-text comments led to merging overlapping items. In round two, 27 respondents rated 20 revised items, with 33-100% (mean 78.7%) of experts judging them essential and providing 66 free-text comments. The final MARMAR guideline comprises 20 items: 9 methodological and 11 reporting considerations for medication adherence during trial run-in phases. The MARMAR guideline provides the first structured, consensus-based guideline specifically focused on medication adherence during trial run-in phases. By supporting more transparent and rigorous measurement, analysis and reporting, it should serve to improve the quality of future trial run-in phases.

Emerging incretin- and multi-agonist-based treatments - the continued refinement and continuous expansion of a potent therapeutic armamentarium for cardio-kidney-liver-metabolic diseases and beyond.

Adjusting for intercurrent events using Bayesian joint models for longitudinal outcomes in clinical trials.

Today, pharmaceutical companies aim to speed up the time it takes for drugs to reach the market at minimal cost, increasingly collaborating with contract research organizations (CROs) in all areas, from study design and patient recruitment to regulatory submissions and data management. The aim of this article is to summarize and systematize the stages of development of clinical outsourcing models based on a study of the characteristics of the global CRO market. The article explains the essence of CROs and clinical research sites (CRSs). The factors driving the growth of the global CRO market have been identified: increased research and development funding, a rise in the number of clinical trials, and the expiration of patents for well-known drugs. The phases of clinical trials are analyzed in terms of content, number of participants, duration, cost, and success rate. The risks of clinical trials have been identified, including: significant cost, high dropout rate, considerable duration, and complexity of regulatory acts. Regional features of conducting clinical trials have been considered. The top 10 leaders in the global CRO market in 2024 have been characterized. Models of cooperation between CROs and sponsors have been summarized. The advantages, disadvantages, and examples of applying existing clinical outsourcing models have been determined. The stages of development of clinical outsourcing models have been systematized: from targeted outsourcing to strategic partnership and transformational outsourcing. Current directions for improving CRO activities have been determined. The goal of further research in this direction should be to explore ways to expand cooperation between CROs and leading IT companies regarding the implementation of digital health technologies in working with clinical trial participants and artificial intelligence for managing data during its course.

Brain-computer interface (BCI) medical devices represent a category of innovative medical devices. They assist in treating neurological disorders by leveraging human-machine interaction to improve patients' quality of life. Simultaneously, ultrasound is a non-invasive and effective medical physics technology. It enables imaging of cerebral hemodynamic changes and neuromodulation, specifically for acquiring brain activity information and stimulating deep brain tissues. Notably, ultrasound BCI medical devices targeting deep brain stimulation remain in the research and clinical trial phases. Consequently, ultrasound BCI technology has significant research prospects. In this paper, different types of ultrasound BCI medical device technologies are firstly summarized and organized, followed by a review of their current research status. Then, the regulatory laws and regulations for ultrasound-based BCI devices are briefly discussed, and finally the future regulatory requirements for related products are prospected.

Background: Clinical trials contribute to the generation of new knowledge and can lead to the discovery of novel treatments. By introducing more effective therapies, they can improve patients' quality of life and reduce the complications of diseases. For searching scientific resources in this context, one should focus on appropriate keywords, identify synonyms, related phrases, and academic terms in this field to expand the scope of the search. The first phase of clinical trials is the initial step in evaluating an investigational drug product in humans. Conclusion: In this review, given the importance of Phase I clinical trials, we first address the different and common names of Phase I clinical trials and then provide examples of synonyms for "study participants." It is hoped that researchers can, by identifying synonyms and related academic phrases, more quickly and accurately find relevant scientific resources and produce more precise and clear scientific writing

Advancing Alzheimer's therapeutics via in silico strategies: Tideglusib based multi-target analogues.

Cancer development is linked to dysregulated immune surveillance, chronic inflammation, and immunosuppressive signaling within the tumor microenvironment. Emerging evidence suggests that the anticancer effects of naturally occurring phytochemicals are not directly mediated by cytotoxicity but rather by altering key components of both innate and adaptive immunity. Over the last few years, significant progress has been made in understanding the interactions of specific classes of phytochemicals, including polyphenols, flavonoids, alkaloids, and terpenoids, with immune-linked signal transduction mechanisms involved in carcinogenesis. These include the suppression of pro- and anti-inflammatory mediators, the control of immune checkpoint-related pathways, the polarization of tumor-associated macrophages, the enhancement of cytotoxic T-cell and natural killer cell functions, and the suppression of angiogenic and metastatic signaling. Notably, many phytochemicals have demonstrated translational relevance, and some have advanced to later clinical trial phases. This narrative review highlights the recent preclinical, translational, and clinical evidence on the immunomodulatory effects of phytochemicals in cancer prevention and treatment. There is an accentuated focus on mechanistic convergence, the strength of the evidence, and translational potential, and the most frequently targeted immune pathways by phytochemicals are identified, with a highlight of the major challenges of integrating them into contemporary anticancer approaches.

Respiratory diseases pose a severe threat to global health, with notable limitations in current diagnosis and treatment, such as insufficient sensitivity of diagnostic tools and a lack of effective targeted therapies. Due to their highly efficient information transmission capabilities and excellent safety profile, exosomes carrying non-coding RNA, particularly microRNA (miRNA), are increasingly attracting attention. Compared with free miRNAs, exosomes can protect miRNAs from nuclease degradation, prolong their circulation time in the body, thereby improving the stability and bioavailability of miRNAs. At the same time, they can also address the major bottleneck in the clinical application of miRNAs, including low in vivo delivery efficiency, poor stability, lack of targeting specificity, and off-target effects. Increasing evidence indicate that miRNAs play a significant role in respiratory diseases, including targeting multiple signaling pathways, regulating inflammation and oxidative stress, influencing tumor growth and apoptosis, and participating in tissue damage and repair, thus holding promising prospects for diagnosis and treatment in respiratory diseases. MSC-derived exosomes exhibit low tumorigenic risk because they originate from adult stem cells with limited differentiation ability, have low immunogenicity, and do not highly express major histocompatibility complex class II (MHC-II) molecules, making them suitable for allogeneic use. To enhance the therapeutic efficacy and specificity of exosomes in respiratory diseases, engineering modifications of MSC-exosomes (MSC-exos) are crucial. Current methods for engineering MSC-exos primarily include cargo loading and surface modification to improve therapeutic efficacy and targeting specificity. Through these engineering methods, more precise miRNA delivery can be achieved, reducing the side effects of traditional treatments and improving treatment efficacy. Although MSC-exos demonstrate significant potential in treating respiratory diseases, their clinical translation is hindered by critical hurdles, including individual differences in therapeutic efficacy, insufficient miRNA targeting specificity, challenges in large-scale production, and potential immunogenicity risks. To accelerate clinical application, future research should prioritize optimizing engineered targeting strategies (eg, precision surface modification), enhancing large-scale preparation efficiency of functional MSC-exos, and validating their long-term safety and efficacy in multi-center studies. At present, the good manufacturing practice (GMP) production process of MSC-exos has been established. Early clinical trials (Phase I/II) have shown its potential in respiratory diseases such as pulmonary fibrosis without serious adverse reactions. However, it has not yet been approved for clinical transformation and still faces challenges such as large-scale targeting and safety. Overall, MSC-exos carrying miRNAs show great promise in the treatment of respiratory diseases, but their true clinical application still requires more systematic research and validation.

The discovery and development of HIV-1 integrase strand transfer inhibitors (INSTIs) represent one of the remarkable success stories in antiviral drug discovery, transforming fundamental insights of retroviral enzymology into highly effective first-line therapies for HIV-1/AIDS patients. Currently there are five INSTIs approved for clinical use. Among these, second generation drugs Dolutegravir, Bictegravir and Cabotegravir offer excellent virologic suppression, favorable tolerability and a high genetic barrier to resistance. The long-acting formulation of the most recent INSTI Cabotegravir has also been approved for pre-exposure prophylaxis in high-risk populations. Apart from inhibiting the active site of integrase, a new class of allosteric integrase inhibitors (ALLINIs), which target integrase multimerization affecting multiple steps in viral life cycle, are in the advanced phases of clinical trials. The mechanisms of HIV-1 integration, development of integrase inhibitors, structural biology breakthroughs that guided inhibitor optimization and clinical use of INSTIs, their successes and challenges for HIV/1AIDS management are reviewed here.

Targeted precision Strike in Extensive-Stage small cell lung Cancer: Current advances and future Perspectives for Antibody-Drug conjugates.

Overuse and misuse of antibiotics used for treating bacterial infections has resulted in ineffectiveness of the drugs and hence increase in the cases of antimicrobial resistance. This has precipitated to the need for research and development of novel strategies to target pathogenic microbes. ESKAPE pathogens include high priority pathogens such as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae (sometimes K. aerogenes), Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species (e.g., E. cloacae) which are responsible for causing healthcare associated infections whereas non ESKAPE pathogens such as Escherichia coli and Mycobacterium tuberculosis contribute to community acquired infections. Hence, targeting enzymes involved in amino acid and protein biosynthesis pathways is one such strategy for growth inhibition of these pathogens. Amino acids and their products are essential for various functions such as bacterial survivability, pathogenicity, cell wall integrity, essential mineral acquisition from surrounding or inside pathogen and activation of transporters. This review details the amino acid and protein biosynthetic pathways in pathogenic bacteria along with efficacy and translational potential of various natural and synthetic antimicrobial molecules discovered and synthesized against enzymes of these pathways for combating bacterial growth. This review also highlights promising antibacterial molecules such as quercetin, pyrazinoic acid, mupirocin and enrofloxacin etc. which are at various phases of clinical trials and hold promise for treatment of bacterial infections. Lastly, the review also lists risks such as cytotoxicity, redundancy and metabolic bypass associated with these inhibitors and also proposes future strategies such as trojan horse and combination therapy to deal with the above issues.

Lyme disease is a vector-borne disease transmitted by ticks of the Ixodes genus, caused by a heterogeneous group of Borrelia burgdorferi sensu lato. Human infection occurs through a tick bite and its feeding on the skin. Due to the diverse symptoms, diagnosing Lyme disease is challenging and usually involves a two-step serological approach. Currently, there is still no vaccine against Lyme disease, but in 2024, data on the immunogenicity and safety of the VLA15-221 vaccine, which is in the second phase of clinical trials, was announced. The aim of the study is to discuss the epidemiological situation of Lyme disease in Poland in 2023 compared to previous years. To assess the epidemiological situation of Lyme disease in Poland, data sent to NIPH NIH - NRI by the district Sanitary-Epidemiological Stations and published in the annual bulletin: "Infectious diseases and poisonings in Poland in 2023" were used. In 2023, there were 25 285 reported cases of Lyme disease and 1 155 hospitalizations. This represents a significant increase in cases by 45.58% compared to the previous year. Seasonal variations in case occurrences are evident in distinct quarters, with the number rising from 2 466 in Q1 to 11 626 in Q3, and then declining in Q4 to 5 945. The highest incidence was recorded in the Małopolskie voivodeship (122.9 per 100,000), Podlaskie voivodeship (96 per 100,000), and Warmińsko-Mazurskie voivodeship (95.2 per 100,000). The number of borreliosis cases returned to pre-pandemic levels but also increased by 22.57% compared to 2019 (20 630 cases), and doubled (95.49%) compared to 2020 (12 934 cases). Seasonality has remained unchanged for years. Usually, eastern Poland (most often the Podlaskie voivodeship) is characterised by the highest incidence, however, in 2023, the highest incidence was recorded in the Małopolskie voivodeship at 122.9 per 100,000.

Background. Transplantation models, including allografts and xenografts are crucial in oncology research because they help study the mechanisms of carcinogenesis and assess the activity of promising antitumor agents. Objectives : 1) to conduct a traditional analysis of scientific literature devoted to orthotopic transplantation in laboratory animals using various sources of tumor material, 2) to describe the main advantages and limitations of orthotopic models, 3) to provide practical recommendations for researchers dealing with orthotopic transplantation models. Material and Methods . A search was conducted in PubMed and Google Scholar bibliographic databases. The review included relevant publications available for search until April 30, 2025. Results . Compared to transplantation of tumor cell suspensions cultured in vitro, transplantation of solid tumor fragments ensures preservation of the clonal heterogeneity of the tumor, components of its microenvironment and extracellular matrix, which support engraftment and tumor growth. Compared to subcutaneous transplantation, orthotopic models offer a more realistic depiction of the complex interactions in the tumor-host system and the pathological characteristics of human cancers, particularly those involving metastasis. Because orthotopic tumors exist within their natural environment, the evaluation of their response during preclinical research is more likely to be translatable in the initial phases of clinical trials. Conclusion. Incorporating orthotopic models into non-clinical in vivo pharmacodynamic research programs improve the predicitve value and dependability of preclinical results and offer a chance to gain a more thorough understanding of the antitumor activity of the experimental treatment.

ABSTRACT The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), established in April 1990, has released an updated version of its ICH E6 guidelines for Good Clinical Practice (GCP). This new version, ICH E6 (R3), replaces ICH E6 (R2) and introduces major changes promoting innovation across all stages of clinical trials, from planning to reporting. These updates enhance flexibility, inclusivity, risk management, and integration of modern technologies, ensuring ethical conduct and data integrity. Released in January 2025, E6 (R3) focuses on patient safety, advanced data management, transparency through public trial registration and result sharing, and more efficient, adaptable trial designs. At the same time, it presents challenges such as the need for comprehensive staff training and integration of digital health tools. We conducted a literature search using ScienceDirect, PubMed, and Google, along with ICH resources, to identify relevant publications. This narrative review, written in accordance with ICH GCP E6 (R3), emphasizes the key updates, including a risk-based approach that prioritizes patient safety and data quality, the use of electronic systems, decentralized and remote monitoring methods, and strengthened roles for investigators, sponsors, ethics committees, and regulators. Overall, ICH GCP E6 (R3) brings transformative changes that foster innovation at every phase of clinical trials. By promoting patient-centered approaches, fostering innovation, and reinforcing accountability, the guideline offers a framework for safer, faster, and more reliable trials. Effective implementation will depend on training, technological adaptation, and sustained collaboration among stakeholders.

Describe and compare the clinical evidence, post-marketing requirements, and regulatory outcomes of all anticancer drugs that have obtained conditional or accelerated approval based on single-arm trial data in China and the United States. This paper took all the anticancer drugs that had received accelerated or conditional approval based on single-arm trials in the United States and China as of August 31, 2025, as a research sample, and conducted a comparative analysis of the approval status based on single-arm trials in the United States and China from three aspects: the clinical evidence for the accelerated or conditional approval, the conditions attached to the marketing, and the regulatory outcomes. Regarding clinical evidence, the phase and number of pivotal clinical trials and sample size in China and the United States were similar, with significant differences in geographic distribution and supporting evidence. In terms of the conditions attached to marketing, there were significant differences between the United States and China in the purpose and confirmatory trial design requirements. In terms of regulatory outcomes, significant differences existed in the time taken to convert to regular approval (RA) and the response rate (RR) of anticancer drugs converted to regular approval in China and the United States. Among these drugs, those simultaneously granted accelerated or conditional approval in both countries based on single-arm trials experienced a significant approval lag in China. Only two conditional approvals were withdrawn in China. At the same time, there was a statistically significant difference between the RR values of anticancer drugs withdrawn in the United States due to unproven clinical benefits and those withdrawn for other reasons. There are substantial differences between the United States and China across multiple aspects. Compared with the experience of the United States for more than 30years, China is still in the initial stage, and it is advisable for China to thoroughly learn from the experiences and lessons of the United States to optimize its conditional approval pathway for anticancer drugs supported by single-arm trials.

This study aimed to evaluate the immediate three-dimensional (3D) transfer accuracy of three virtually designed CAD/CAM lingual retainers fabricated from nickel–titanium (NiTi), titanium grade 5 (Ti5), and cobalt–chromium (CoCr). The investigation represents the baseline (T = 0) phase of a registered randomized clinical trial (DRKS00028974). Sixty patients (32 females, 28 males; mean age 19.2 ± 6.9 years) were randomly allocated to receive one of the three CAD/CAM retainers. Immediately after bonding (T0–T1), intraoral scans were superimposed with the digital design to determine deviations at predefined interproximal contact points. Non-parametric Kruskal–Wallis tests with Dunn’s post-hoc comparisons were applied (p ≤ 0.05). All 60 patients completed the baseline assessment. Transfer deviations were lowest in the NiTi group (0.17 mm, IQR 0.16–0.21), followed by Ti5 (0.37 mm, IQR 0.32–0.41) and CoCr (0.35 mm, IQR 0.30–0.40). NiTi showed significantly higher transfer accuracy compared with Ti5 (p < 0.001) and CoCr (p < 0.001). No significant difference was observed between Ti5 and CoCr (p > 0.999). No adverse events occurred. Laser-cut NiTi CAD/CAM retainers demonstrated significantly higher immediate transfer precision than milled Ti5 and CoCr retainers. These findings represent the baseline phase of the ongoing randomized clinical trial; subsequent analyses will determine whether such accuracy differences translate into clinically relevant stability outcomes. Accurate passive fit of CAD/CAM retainers is essential to prevent unwanted forces on teeth. Understanding material-dependent transfer deviations may improve digital bonding workflows and guide material selection in clinical orthodontics. DRKS00028974 (registered May 2022)