Background/Objectives: Vancomycin remains a cornerstone antibiotic for Gram-positive infections, but its narrow therapeutic window and marked pharmacokinetic variability in critical patients complicate dosing. This study aimed to analyze survival and identify factors associated with mortality in intensive care unit (ICU) patients receiving vancomycin under therapeutic drug monitoring (TDM). Methods: A single-center, retrospective cohort study was conducted at City Clinical Hospital named after I.V. Davydovsky (Moscow, Russia) between December 2021 and January 2026 (IRB protocol VANCO-2021). A total of 190 adult patients from surgical, therapeutic, and cardiac ICUs receiving vancomycin for at least 3–5 days were analyzed; trough concentrations were determined by HPLC-MS/MS. Cox proportional hazards, spline Cox, and segmented (piecewise) Cox models were applied to identify mortality predictors, with bootstrap subsampling assessing threshold robustness. Results: Three independent predictors of mortality were identified: ln(minimum vancomycin concentration) (HR = 1.644, p = 0.028), age (HR = 1.019, p = 0.037), and serum creatinine (HR = 1.004, p < 0.001). A data-driven threshold trough concentration (Ctrough) of 25.5 µg/mL was identified, above which mortality increased substantially (63.0% vs. 26.4%; p < 0.05). The adjusted hazard ratio for Ctrough ≥ 25.5 µg/mL was approximately 1.88 (p = 0.054); bootstrap subsampling yielded an uncertainty interval of 23.2–33.6 µg/mL. Conclusions: Elevated minimum vancomycin concentrations exceeding 25.5 µg/mL are independently and statistically associated with increased mortality in ICU patients, likely reflecting altered drug exposure and illness severity rather than a direct causal effect. Systematic TDM is essential for maintaining vancomycin within the therapeutic range.

Local drug delivery increasingly relies on injectable hydrogels that form directly at the x‘administration site, among which light-cured systems are of particular interest: irradiation converts a liquid precursor into a depot and can trigger drug release with high spatiotemporal resolution. The aim of this critical narrative review is to systematize the key design elements of such systems and to assess their path toward the clinic. We analyze the mechanisms of photoactivation, the role of wavelength, the natural, synthetic, and hybrid polymer matrices together with their tuning parameters, and the photoinitiators. The clinical and preclinical experience in dentistry, ophthalmology, regenerative medicine, and oncology is then considered separately. Finally, we address standardization through the Quality by Design concept. We show that, despite an extensive preclinical base, no photocrosslinkable injectable depot for drug delivery has yet been approved, whereas photopolymerization itself and the photoinitiators employed are already accepted in the clinic in adjacent fields. We conclude that clinical translation is defined by three tractable tasks: qualifying photoinitiators for the injectable route of administration, overcoming the limited depth of light activation, and standardizing characterization on the basis of Quality by Design.

IntroductionThis study investigates the metacognitive awareness of pharmacy students and pharmacists at various educational stages.MethodsWe compare metacognitive indicators among 2nd and 5th-year students from Sechenov University Institute of Pharmacy and pharmacists undergoing additional professional education at Sechenov University Institute of Postgraduate Education. Metacognitive awareness was assessed using the Metacognitive Awareness Inventory, Evaluation of Metacognitive Knowledge and Activity, and a self-reflection scale.ResultsSignificant differences were found between 2nd and 5th-year students’ metacognitive awareness, with 5th-year students showing higher levels of metacognitive knowledge. Pharmacists undergoing additional education displayed higher metacognitive awareness than undergraduate students, with differences observed in declarative and procedural knowledge, error control, and evaluation.ConclusionCognitive and regulatory metacognitive indicators develop throughout the educational continuum, emphasizing the need to cultivate reflexive qualities in future pharmacists. Tailored approaches for improving metacognitive abilities among pharmaceutical specialists are essential. Further exploration of the motivational aspect of metacognitive awareness in pharmacy education is warranted.

Introduction. Search for new plant species containing biologically active substances (hereinafter – BAS) is one of the leading tasks of pharmacognosy as a science. The search for flavonoid glycosides in plant raw materials is especially relevant, since they have anti-inflammatory, antioxidant, immunostimulating, as well as weak fungicidal and bacteriostatic action. Staphylea pinnata L. is an endemic plant of the Caucasus, cultivated not only in Georgia, but also in the Russian Federation in the Northern and Northwestern Caucasus. In foreign literature there are studies of antioxidant, antiproliferative and cytotoxic activity of leaf extracts of several species of S. pinnata L., as well as inhibitory activity of COX-1, COX-2 and LTB4 formation. Meanwhile, no serious Russian-language scientific studies on either the chemical composition or pharmacological action of generative organs of S. pinnata were found in the literature. This work is part of a comprehensive phytochemical study of S. pinnata . The aim of the work is to study the qualitative and quantitative composition of flavonoids in the studied object. Aim. To isolate, identify and quantify flavonoids in flowers and buds of Staphylea pinnata L. Materials and methods. Alcohol-water extracts from dried generative organs of the studied plant were used as analyzed solutions. Solutions were analyzed on a spectrophotometer SF-2000 (LLC "OKB Spectr", Russia) after sample preparation with aluminum chloride and on an HPLC Nexera-i LC-2040 (Shimadzu Corporation, Japan) equipped with a column and sample thermostat, degasser and autosampler using an individually selected elution gradient of the mobile phase (0.1 % orthophosphoric acid/acetonitrile solution). The primary data were processed using LabSolutions Single LC software (Shimadzu Corporation, Japan). Compounds from the flavonoid group were identified by retention times. Detection was carried out using a UV detector with an absorption wavelength of 365 ± 2 nm. Result and discussion. Alcohol-water extracts from flowers and buds of S. pinnata L. were obtained. Quantitative evaluation by spectrophotometry for flavonoid content was carried out. A gradient elution mode for HPLC was selected for simultaneous determination of 7 flavonoid glycosides. These chromatographic conditions allowed the identification and quantification of astragaline, cynaroside, cosmosiin, narcissin and rutin in flowers and buds of Staphylea pinnata L. Flavonoid glycosides: raponticin and kaempferol were not detected. Conclusion. Flavonoid glycosides were isolated from the generative organs of S. pinnata L., a technique for quantitative determination of flavonoid glycosides in alcohol-water extracts was developed, astragalin, cynaroside, cosmosiin, narcissin and rutin were detected and quantified.

Autophagy is the process by which damaged regions of the cytoplasm and intracellular pathogens are degraded. This mechanism often serves an adaptive role in cells, enhancing their survival. It plays a direct or indirect role in the development of various pathological conditions within the body. This phenomenon is common in various malignant diseases, where autophagy is associated with the resistance of transformed cells to chemotherapy. Conversely, abnormal activation of autophagy can trigger cell death, a process often seen in neurodegenerative conditions. Given that dysregulation of autophagy is associated with the progression of numerous pathological conditions, this is of significant interest to the developers of drugs that can effectively modulate autophagy for both basic research and clinical applications. Here, we provide a brief description of the mechanism of macroautophagy, the most prevalent form of autophagy identified in humans. We also discuss the clinical potential of drugs that can modulate autophagy, highlighting their use in combating diseases associated with direct or indirect dysregulation of this essential process.

(1) Background: Impacted third molar extraction with a scalpel and rotary instruments is one of the most traumatic surgeries in dentistry. Therefore, it is necessary to discover less traumatic methods and instruments to reduce the risk of postoperative complications. (2) Methods: This study is reported in accordance with the CONSORT guidelines. The study aim is to assess the effectiveness of an Er:YAG laser with a wavelength of 2.94 μm, cutting and rotating instruments in the extraction of lower third molars in comparison with the traditional instruments using clinical and radiology parameters. In the control group, the impacted third molars were extracted with the traditional instruments, like scalpel and rotary instruments; in the test group, the impacted third molars were extracted with an Er:YAG laser. As per the inclusion and exclusion criteria, we enrolled 60 patients who were randomly assigned into two groups (Er:YAG laser group and control group). The efficacy of the Er:YAG laser was assessed by postoperative pain, collateral swelling, mouth opening, and radiology parameters such as radiographic infrabony defects and radiographic bone height after tooth extraction. (3) Results: The results showed that the clinical postoperative parameters like pain, collateral swelling, and mouth opening were less pronounced in the Er:YAG laser group than those in the control group (p < 0.001). According to the data of the radiology parameters (RBH and RID), the regeneration of the socket after extraction was better in the laser group than in the control group (p < 0.001). (4) Conclusions: Based on the obtained results of clinical and radiology parameters assessment, it was shown that third molar extraction using an Er:YAG laser is a less traumatic method than extraction using a scalpel and rotary instruments.

The off-label use of drugs is a common practice worldwide. The legal basis for off-label medical use varies from country to country. Regulatory control of the pharmaceutical market in the off-label preventive and therapeutic practice at the international and national levels has become a breakthrough with the emergence of the coronavirus pandemic. The prospects for off-label use in the context of innovations in the legislation of public health in the Russian Federation are crucial. Professionally significant aspects of the use of medicinal products outside the Summary of Product Characteristics and the off-label use have been introduced by supranational regulatory authorities for the common market of medicinal products of the Eurasian Economic Union. Special attention should be paid to the regulatory control of the use of extemporaneous medicines as part of improving the government regulation of drug compounding in pharmacies. The active development of pharmacy activities in drug compounding within the framework of improving regulatory practice determines the relevance of actual off-label prescriptions and the use of extemporaneous formulations. Aim – to perform a systematic analysis of national, transnational legislative and regulatory documents regulating off-label use of medicinal products, determine the main conceptual components of the current regulatory pool and directions for future development in this area. Systematic analysis of the national legislative and regulatory pool of documents and the regulatory framework of the common market of medicinal products of the Eurasian Economic Union on the regulation of various aspects of the off-label use of medicinal products. Study of the components and identification of the main trends in the regulatory practice of prescriptions outside the Summary of Product Characteristics and the off-label use. An analytical search was carried out in the reference legal systems "ConsultantPlus" and "Garant" on the official websites of the Ministry of Health of Russia, the Eurasian Economic Union, the RusMed information resource of the National Library resource of Russia in medicine and pharmacy "Central Scientific Medical Library" was used. A logical generalization of the results on the current state of the legal framework and the development of conceptual proposals on the key directions of the prospective development of regulation, control, and supervisory activities of the pharmaceutical off-label use of medicinal products was made.

The vast majority of human transcriptome is represented by various types of small RNAs with little or no protein-coding capability referred to as non-coding RNAs (ncRNAs). Functional ncRNAs include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which are expressed at very low, but stable and reproducible levels in a variety of cell types. ncRNAs regulate gene expression due to miRNA capability of complementary base pairing with mRNAs, whereas lncRNAs and circRNAs can sponge miRNAs off their target mRNAs to act as competitive endogenous RNAs (ceRNAs). Each miRNA can target multiple mRNAs and a single mRNA can interact with several miRNAs, thereby creating miRNA-mRNA, lncRNA-miRNA-mRNA, and circRNA-miRNA-mRNA regulatory networks. Over the past few years, a variety of differentially expressed miRNAs, lncRNAs, and circRNAs (DEMs, DELs, and DECs, respectively) have been linked to cancer pathogenesis. They can exert both oncogenic and tumor suppressor roles. In this review, we discuss the recent advancements in uncovering the roles of DEMs, DELs, and DECs and their networks in aberrant cell signaling, cell cycle, transcription, angiogenesis, and apoptosis, as well as tumor microenvironment remodeling and metabolic reprogramming during hepatocarcinogenesis. We highlight the potential and challenges in the use of differentially expressed ncRNAs as biomarkers for liver cancer diagnosis and prognosis.

Short linear motifs (SLiMs) are evolutionarily conserved functional modules of proteins composed of 3 to 10 residues and involved in multiple cellular functions. Here, we performed a search for SLiMs that exert sequence similarity to two segments of alpha-fetoprotein (AFP), a major mammalian embryonic and cancer-associated protein. Biological activities of the peptides, LDSYQCT (AFP14–20) and EMTPVNPGV (GIP-9), have been previously confirmed under in vitro and in vivo conditions. In our study, we retrieved a vast array of proteins that contain SLiMs of interest from both prokaryotic and eukaryotic species, including viruses, bacteria, archaea, invertebrates, and vertebrates. Comprehensive Gene Ontology enrichment analysis showed that proteins from multiple functional classes, including enzymes, transcription factors, as well as those involved in signaling, cell cycle, and quality control, and ribosomal proteins were implicated in cellular adaptation to environmental stress conditions. These include response to oxidative and metabolic stress, hypoxia, DNA and RNA damage, protein degradation, as well as antimicrobial, antiviral, and immune response. Thus, our data enabled insights into the common functions of SLiMs evolutionary conserved across all taxonomic categories. These SLiMs can serve as important players in cellular adaptation to stress, which is crucial for cell functioning.

Short linear motifs (SLiMs) are evolutionarily conserved functional modules of proteins that represent amino acid stretches composed of 3 to 10 residues. The biological activities of two short peptide segments of human alpha-fetoprotein (AFP), a major embryo-specific and cancer-related protein, have been confirmed experimentally. This is a heptapeptide segment LDSYQCT in domain I designated as AFP14–20 and a nonapeptide segment EMTPVNPGV in domain III designated as GIP-9. In our work, we searched the UniprotKB database for human proteins that contain SLiMs with sequence similarity to the both segments of human AFP and undertook gene ontology (GO)-based functional categorization of retrieved proteins. Gene set enrichment analysis included GO terms for biological process, molecular function, metabolic pathway, KEGG pathway, and protein–protein interaction (PPI) categories. We identified the SLiMs of interest in a variety of non-homologous proteins involved in multiple cellular processes underlying embryonic development, cancer progression, and, unexpectedly, the regulation of redox homeostasis. These included transcription factors, cell adhesion proteins, ubiquitin-activating and conjugating enzymes, cell signaling proteins, and oxidoreductase enzymes. They function by regulating cell proliferation and differentiation, cell cycle, DNA replication/repair/recombination, metabolism, immune/inflammatory response, and apoptosis. In addition to the retrieved genes, new interacting genes were identified. Our data support the hypothesis that conserved SLiMs are incorporated into non-homologous proteins to serve as functional blocks for their orchestrated functioning.

The world's older population is growing dramatically. At the same time, ensuring an appropriate high standard of living for the elderly by reducing of morbidity and disability of geriatric patients is one of the main objectives of the modern healthcare system. However, changes associated with body aging necessitate application of novel approaches to the correction of pharmacotherapy and usage of specialized dosage forms. Such medicinal products provide both an appropriate therapeutic effect and facilitate their use. Presented review considers several features of pharmacotherapy of geriatric patients.

Purpose of the study: to determine and analyze the possibility of potentiation of virotherapy by combination with autophagy inducers.

(1) Background: Antibiotics are used in every medical field including dentistry, where they are used for the prevention of postoperative complications in routine clinical practice during the third molar extraction. (2) Methods: This study is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The present systematic review aimed to evaluate and systematize the use of antibacterial drugs in order to prevent postoperative complications in outpatient oral surgery for wisdom teeth extraction. We conducted a systematic review using electronic databases such as Medline PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. Considering inclusion and exclusion criteria, we included randomized clinical trials published up to 2021 investigating the antibiotic prescription for third molar extraction. (3) Results: We selected 10 studies after the application of inclusion and exclusion criteria. The results showed that the most widely used antibiotic was amoxicillin both with and without clavulanic acid, in different dosages and duration. There were no statistically significant differences between treatment groups for development of postoperative complications. (4) Conclusions: Based on the analysis of the included studies, penicillin is currently the most widely prescribed group of antibiotics. The widespread use of this antibiotic group can lead to antimicrobial resistance (AMR). Due to increasing prevalence of bacteria resistance to penicillins, clinicians should carefully prescribe these antibiotics and be aware that the widespread use of amoxicillin may do more harm than good for the population.

The most common primary malignant brain tumors in adults are gliomas. Glioblastoma is the most prevalent and aggressive tumor subtype of glioma. Current standards for the treatment of glioblastoma include a combination of surgical, radiation, and drug therapy methods. The drug therapy currently includes temozolomide (TMZ), an alkylating agent, and bevacizumab, a recombinant monoclonal IgG1 antibody that selectively binds to and inhibits the biological activity of vascular endothelial growth factor. Supplementation of glioblastoma radiation therapy with TMZ increased patient survival from 12.1 to 14.6 months. The specificity of TMZ effect on brain tumors is largely determined by special aspects of its pharmacokinetics. TMZ is an orally bioavailable prodrug, which is well absorbed from the gastrointestinal tract and is converted to its active alkylating metabolite 5-(3-methyl triazen-1-yl)imidazole-4-carbozamide (MTIC) spontaneously in physiological condition that does not require hepatic involvement. MTIC produced in the plasma is not able to cross the BBB and is formed locally in the brain. A promising way to increase the effectiveness of TMZ chemotherapy for glioblastoma is to prevent its hydrolysis in peripheral tissues and thereby increase the drug concentration in the brain that nanoscale delivery systems can provide. The review discusses possible ways to increase the efficacy of TMZ using nanocarriers.

Takotsubo cardiomyopathy (TTS) has become a recognised clinical entity since the Japanese scientist Sato first described it in 1990. Despite an increasing number of confirmed cases, especially during the COVID-19 pandemic, its pathophysiology remains incompletely understood, and decision-making differs in the diagnosis and treatment. In addition, it is not evident whether a significant increase in TTS is due to better understanding among practitioners and widespread access to coronary angiography, or if it is a reflection of an actual increase in incidence. We analysed a series of international research studies from 1990 to 2021. Beyond epidemiology and clinical presentation, we evaluated and summarised fundamental knowledge about various predisposing factors, with particular attention to the iatrogenic impact of certain drugs, namely antidepressants, chemotherapy, and antiarrhythmics. Furthermore, we highlighted the main pathophysiological theories to date. In addition, based on published studies and clinical cases, we investigated the role of numerous diagnostic approaches in the differential diagnosis of TTS and identified predictors of TTS complications, such as cardiogenic shock, ventricular fibrillation, and left ventricular thrombi. Accordingly, we sought to propose a diagnostic algorithm and further treatment management of TTS under the presence of possible complications to help practitioners make more informed decisions, as the initial presentation continues to pose a challenge due to its close similarity to acute coronary syndrome with ST-elevation. In conclusion, this article examines Takotsubo cardiomyopathy from different perspectives and, along with future systematic reviews and meta-analyses, can be of particular interest to practising cardiologists and researchers in developing clinical guidelines.

The concept of oxidative distress had arisen from the assessment of cellular response to high concentrations of reactive species that result from an imbalance between oxidants and antioxidants and cause biomolecular damage. The intracellular distribution and flux of reactive species dramatically change in time and space contributing to the remodeling of the redox landscape and sensitivity of protein residues to oxidants. Here, we hypothesize that compromised spatiotemporal control of generation, conversions, and removal of reactive species underlies protein damage and dysfunction of protein degradation machineries. This leads to the accumulation of oxidatively damaged proteins resulted in an age-dependent decline in the organismal adaptability to oxidative stress. We highlight recent data obtained with the use of various cell cultures, animal models, and patients on irreversible and non-repairable oxidation of key redox-sensitive residues. Multiple reaction products include peptidyl hydroperoxides, alcohols, carbonyls, and carbamoyl moieties as well as Tyr-Tyr, Trp-Tyr, Trp-Trp, Tyr-Cys, His-Lys, His-Arg, and Tyr-Lys cross-links. These lead to protein fragmentation, misfolding, covalent cross-linking, oligomerization, aggregation, and ultimately, causing impaired protein function and turnover. 20S proteasome and autophagy-lysosome pathways are two major types of machinery for the degradation and elimination of oxidatively damaged proteins. Spatiotemporal dysregulation of these pathways under oxidative distress conditions is implicated in aging and age-related disorders such as neurodegenerative and cardiovascular diseases and diabetes. Future investigations in this field allow the discovery of new drugs to target components of dysregulated cell signaling and protein degradation machinery to combat aging and age-related chronic diseases.

The forced massive transition of universities to distance learning due to the pandemic has raised questions about the effectiveness of online education in general and video lectures in particular. Research shows that video lectures are either comparable or less effective than face-to-face lectures. In this work, based on the data collected as part of the experiment, we compare two lecture formats (videolecture and face-to-face lecture) based on the educational results of students, and also evaluate the combined lecture format. The experiment involved 151 second-year students in the direction of training “Pharmacy” of Sechenov University. The field experiment was carried out in the spring semester of the 2020-2021 academic year in three stages. At the first stage, some of the students listened to a face-to-face lecture, and some - a video lecture. At the second stage, both groups were swapped. At the final stage, both groups listened to a combined lecture. Our research has shown that a video lecture and a face-to-face lecture are the same in their effectiveness: on average, students received the same educational results as a result of mastering the lecture material. At the same time, the combined lecture led to an increase in the educational results of students - after the combined lecture format, students received a higher score for the post-test, and also showed a greater increase in the level of knowledge. The results of the study will be especially relevant for the administration of universities responsible for the implementation of online learning, and teachers who conduct lectures.

Background: Modern medicine has provided considerable knowledge of the pathophysiology of mental disorders at the body, systemic, organ and neurochemical levels of the biological organization of the body. Modern clinical diagnostics of depression have some problems, that is why psychiatric society makes use of diagnostics and taxonomy of different types of depression by implemention of modern molecular biomarkers in diagnostic procedures. But up to now, there are no reliable biomarkers of major depressive disorder (MDD) and other types of depression. Objective: The purpose of this review is to find fundamentals in pathological mechanisms of depression, which could be a basis for development of molecular and genetic biomarkers, being the most feasible for clinical use. Method: This review summarizes the published data using PubMed, Science Direct, Google Scholar and Scopus. Results: In this review, we summarized and discussed findings in molecular biology, genetics, neuroplasticity, neurotransmitters, and neuroimaging that could increase our understanding of the biological foundations of depression and show new directions for the development of reliable biomarkers. We did not find any molecular and genetic biomarker approved for the clinic. But the Genome-Wide Association Study method promises some progress in the development of biomarkers based on SNP in the future. Epigenetic factors also are a promising target for biomarkers. We have found some differences in the etiology of different types of atypical and melancholic depression. This knowledge could be the basis for development of biomarkers for clinical practice in diagnosis, prognosis and selection of treatment. Conclusion: Depression is not a monoetiological disease. Many pathological mechanisms are involved in depression, thus up to now, there is no approved and reliable biomarker for diagnosis, prognosis and correction of treatment of depression. The structural and functional complexity of the brain, the lack of invasive technology, poor correlations between genetic and clinical manifestation of depression, imperfect psychiatric classification and taxonomy of subtypes of disease are the main causes of this situation. One of the possible ways to come over this situation can be to pay attention to the trigger mechanism of disease and its subtypes. Researchers and clinicians should focus their efforts on searching the trigger mechanism of depression and different types of it . HPA axis can be a candidate for such trigger in depression caused by stress, because it influences the main branches of disease: neuroinflammation, activity of biogenic amines, oxidative and nitrosative stress, epigenetic factors, metabolomics, etc. But before we shall find any trigger mechanism, we need to create complex biomarkers reflecting genetic, epigenetic, metabolomics and other pathological changes in different types of depression. Recently the most encouraging results have been obtained from genetics and neuroimaging. Continuing research in these areas should be forced by using computational, statistical and systems biology approaches, which can allow to obtain more knowledge about the neurobiology of depression. In order to obtain clinically useful tests, search for biomarkers should use appropriate research methodologies with increasing samples and identifying more homogeneous groups of depressed patients.

Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third cancer-related cause of death worldwide. In recent years, several systemic therapy drugs including sorafenib, lenvatinib, regorafenib, cabozantinib, ramucicurab, nivilumab, and pembrolizumab have been approved by FDA for advanced HCC. However, their insufficient efficacy, toxicity, and drug resistance require clinically applicable and validated predictive biomarkers.Areas covered: Our review covers the recent advancements in the identification of proteomic/genomic/epigenomic/transcriptomic biomarkers for predicting HCC treatment efficacy with the use of multi-kinase inhibitors (MKIs), CDK4/6 inhibitors, and immune checkpoint inhibitors (ICIs). Alpha-fetoprotein, des-carboxyprothrombin, vascular endothelial growth factor, angiopoietin-2, and dysregulated MTOR, VEGFR2, c-KIT, RAF1, PDGFRβ have the potential of proteomic/genomic biomarkers for sorafenib treatment. Alanine aminotransferase, aspartate aminotransferase, and albumin-bilirubin grade can predict the efficacy of other MKIs. Rb, p16, and Ki-67, and genes involved in cell cycle regulation, CDK1-4, CCND1, CDKN1A, and CDKN2A have been proposed for CD4/6 inhibitors, while dysregulated TERT, CTNNB1, TP53 FGF19, and TP53 are found to be predictors for ICI efficacy.Expert opinion: There are still limited clinically applicable and validated predictive biomarkers to identify HCC patients who benefit from systemic therapy. Further prospective biomarker validation studies for HCC personalized systemic therapy are required.

Pain is an important signal of almost all pathological processes. At the same time, in the presence of painful sensations, a person tried to eliminate them to improve the quality of life. Therefore, at all times, painkillers are played a very important role in the pharmaceutical market. The search for new molecules with analgesic properties and the development of dosage forms for already acting drugs are still important tasks in the pharmaceutical environment. In this review, we tried to show development path of the search for a new painkillers.