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Cytochrome c oxidase (CcO) is a large membrane-bound hemeprotein that catalyzes the reduction of dioxygen to water. Unlike classical dioxygen binding hemeproteins with a heme b group in their active sites, CcO has a unique binuclear center (BNC) composed of a copper atom (CuB) and a heme a3 iron, where O2 binds and is reduced to water. CO is a versatile O2 surrogate in ligand binding and escape reactions. Previous time-resolved spectroscopic studies of the CO complexes of bovine CcO (bCcO) revealed that photolyzing CO from the heme a3 iron leads to a metastable intermediate (CuB-CO), where CO is bound to CuB, before it escapes out of the BNC. Here, with a pump-probe based time-resolved serial femtosecond X-ray crystallography, we detected a geminate photoproduct of the bCcO-CO complex, where CO is dissociated from the heme a3 iron and moved to a temporary binding site midway between the CuB and the heme a3 iron, while the locations of the two metal centers and the conformation of Helix-X, housing the proximal histidine ligand of the heme a3 iron, remain in the CO complex state. This new structure, combined with other reported structures of bCcO, allows for a clearer definition of the ligand dissociation trajectory as well as the associated protein dynamics.

BACKGROUND: Anastomotic leak is the most serious complication in rectal surgery. Predicting and preventing anastomotic leak remains an urgent task. AIM: The purpose of the study is to analyze the 17-year-long experience of the Federal Research Clinical Center of Specialized Medical Care and Medical Technologies of FMBA of Russia in performing an anterior resection of the rectum in patients with cancer of the rectum and rectosigmoid junction and to establish the risk factors for the development of an anastomotic leak. METHODS: The results of the treatment of 492 patients who underwent an anterior resection of the rectum in 2006–2022 have been studied. 21 patients developed an anastomotic leak. A retrospective comparison of the characteristics of two groups of patients was carried out: those with a smooth course of the postoperative period and those with the development of an anastomotic leak. RESULTS: The reliable risk factors for the development of an anastomotic leak were identified and, based on the statistical analysis, a prognostic scoring model was proposed: smoking — 1 point, type 2 diabetes mellitus — 1 point, preoperative chemotherapy — 1 point, blood loss over 50 ml — 2 points, preoperative radiation therapy — 3 points, and the location of the colorectal anastomosis at a distance of up to 5 cm from the anus — 4 points. The sensitivity of the model was 85.6%, with the specificity above 97.4% when using a training set with 8 points or more. CONCLUSION: The following tactics are proposed: in the case of 4 points and above by the developed scale, one should form a preventive intestinal stoma; in the case of 1–3 points, one should install a transanal drainage. The complete abandonment of these two preventive measures is possible only if the patient does not have any of the listed risk factors for the development of an anastomotic leak.

Background: To date, there is no single standard for conducting HAL-RAR operations. The constant discussion raises the question of the number of terminal branches of the superior rectal artery, which must be ligated in the submucosal layer of the rectum in order to provide the adequate dearterialization of hemorrhoids. Aim: To study the anatomy of the branches of the superior rectal artery and to develop recommendations for the optimal ligation of the terminal branches of the superior rectal artery. Methods: 150 protocols of the previous operations have been studied. In order to further objectify our results, the results of radiation diagnostics (CT and MRI) were revised for 100 patients without pathological changes of the rectum and anal canal to study the variant anatomy of the superior rectal artery and its terminal branches in the rectal wall. Results: In 148 patients, 6 terminal branches were identified, in 2 (1.333%) patients, 5 branches were found. 100 cases without pathological changes were also analyzed (60 MRI and 40 CT scans). In all the cases, 6 terminal branches of the superior rectal artery were determined, located at 1, 3, 5, 7, 9 and 11 o'clock positions of the conventional dial. At the same time, a large number of identified anatomical options for the branching of the VPA and the method for reaching the rectal wall should be noted, which we used as a basis to propose a classification. Conclusion: In the vast majority of cases, there are 6 terminal branches of the superior rectal artery, located in the lower ampulla of the rectum at approximately 1, 3, 5, 7, 9 and 11 hours of the conventional dial. A number of variants of the vascular anatomy of the proximal branches are possible, but 6 distal branches are involved in the direct blood supply of the hemorrhoids. When performing selective Doppler-controlled dearterialization of hemorrhoids, it is expedient to ligate 6 arterial vessels.

Ribosomal RNAs are decorated by numerous post-transcriptional modifications whose exact roles in ribosome biogenesis, function, and human pathophysiology remain largely unknown. Here, we report a targeted direct rRNA sequencing approach involving a substrate selection step and demonstrate its suitability to identify differential modification sites in combination with the JACUSA2 software. We compared JACUSA2 to other tools designed for RNA modification detection and show that JACUSA2 outperforms other software with regard to detection of base modifications such as methylation, acetylation and aminocarboxypropylation. To illustrate its widespread usability, we applied our method to a collection of CRISPR-Cas9 engineered colon carcinoma cells lacking specific enzymatic activities responsible for particular rRNA modifications and systematically compared them to isogenic wild-type RNAs. Besides the numerous 2′-O methylated riboses and pseudouridylated residues, our approach was suitable to reliably identify differential base methylation and acetylation events. Importantly, our method does not require any prior knowledge of modification sites or the need to train complex models. We further report for the first time detection of human rRNA modifications by direct RNA-sequencing on Flongle flow cells, the smallest-scale nanopore flow cell available to date. The use of these smaller flow cells reduces RNA input requirements, making our workflow suitable for the analysis of samples with limited availability and clinical work.

Abstract Cytochrome c oxidase (CcO) is an essential enzyme in mitochondrial and bacterial respiration. It catalyzes the four-electron reduction of molecular oxygen to water and harnesses the chemical energy to translocate four protons across biological membranes. The turnover of the CcO reaction involves an oxidative phase, in which the reduced enzyme (R) is oxidized to the metastable OH state, and a reductive phase, in which OH is reduced back to the R state. During each phase, two protons are translocated across the membrane. However, if OH is allowed to relax to the resting oxidized state (O), a redox equivalent to OH, its subsequent reduction to R is incapable of driving proton translocation. Here, with resonance Raman spectroscopy and serial femtosecond X-ray crystallography (SFX), we show that the heme a 3 iron and CuB in the active site of the O state, like those in the OH state, are coordinated by a hydroxide ion and a water molecule, respectively. However, Y244, critical for the oxygen reduction chemistry, is in the neutral protonated form, which distinguishes O from OH, where Y244 is in the deprotonated tyrosinate form. These structural characteristics of O provide insights into the proton translocation mechanism of CcO.

Abstract The system of oceanic flows constituting the Atlantic Meridional Overturning Circulation (AMOC) moves heat and other properties to the subpolar North Atlantic, controlling regional climate, weather, sea levels, and ecosystems. Climate models suggest a potential AMOC slowdown towards the end of this century due to anthropogenic forcing, accelerating coastal sea level rise along the western boundary and dramatically increasing flood risk. While direct observations of the AMOC are still too short to infer long-term trends, we show here that the AMOC-induced changes in gyre-scale heat content, superimposed on the global mean sea level rise, are already influencing the frequency of floods along the United States southeastern seaboard. We find that ocean heat convergence, being the primary driver for interannual sea level changes in the subtropical North Atlantic, has led to an exceptional gyre-scale warming and associated dynamic sea level rise since 2010, accounting for 30-50% of flood days in 2015-2020.

Abstract Background Patients with advanced hepatocellular carcinoma (HCC) and poor liver function lack effective systemic therapies. Low‐energy electromagnetic fields (EMFs) can influence cell biological processes via non‐thermal effects and may represent a new treatment option. Methods This single‐site feasibility trial enrolled patients with advanced HCC, Child‐Pugh A and B, Eastern Cooperative Oncology Group 0–2. Patients underwent 90‐min amplitude‐modulated EMF exposure procedures every 2–4 weeks, using the AutEMdev (Autem Therapeutics). Patients could also receive standard care. The primary endpoints were safety and the identification of hemodynamic variability patterns. Exploratory endpoints included health‐related quality of life (HRQoL), overall survival (OS). and objective response rate (ORR) using RECIST v1.1. Results Sixty‐six patients with advanced HCC received 539 AutEMdev procedures (median follow‐up, 30 months). No serious adverse events occurred during procedures. Self‐limiting grade 1 somnolence occurred in 78.7% of patients. Hemodynamic variability during EMF exposure was associated with specific amplitude‐modulation frequencies. HRQoL was maintained or improved among patients remaining on treatment. Median OS was 11.3 months (95% confidence interval [CI]: 6.0, 16.6) overall (16.0 months [95% CI: 4.4, 27.6] and 12.0 months [6.4, 17.6] for combination therapy and monotherapy, respectively). ORR was 24.3% (32% and 17% for combination therapy and monotherapy, respectively). Conclusion AutEMdev EMF exposure has an excellent safety profile in patients with advanced HCC. Hemodynamic alterations at personalized frequencies may represent a surrogate of anti‐tumor efficacy. NCT01686412.

Abstract Formation of extracellular vesicles (EVs) has emerged as a novel paradigm in cell‐to‐cell communication in health and disease. EVs are notably produced during cell death but it had remained unclear whether different modalities of regulated cell death (RCD) influence the biogenesis and composition of EVs. To this end, we performed a comparative analysis of steady‐state (ssEVs) and cell death‐associated EVs (cdEVs) following TNF‐induced necroptosis (necEVs), anti‐Fas‐induced apoptosis (apoEVs), and ML162‐induced ferroptosis (ferEVs) using the same cell line. For each RCD condition, we determined the biophysical and biochemical characteristics of the cell death‐associated EVs (cdEVs), the protein cargo, and the presence of methylated ribosomal RNA. We found that the global protein content of all cdEVs was increased compared to steady‐state EVs. Qualitatively, the isolated exosomal ssEVs and cdEVs, contained a largely overlapping protein cargo including some quantitative differences in particular proteins. All cdEVs were enriched for proteins involved in RNA splicing and nuclear export, and showed distinctive rRNA methylation patterns compared to ssEVs. Interestingly, necEVs and apoEVs, but strikingly not ferEVs, showed enrichment of proteins involved in ribosome biogenesis. Altogether, our work documents quantitative and qualitative differences between ssEVs and cdEVs.

Detailed descriptions of microbial communities have lagged far behind physical and chemical measurements in the marine environment. Here, we present 971 globally distributed surface ocean metagenomes collected at high spatio-temporal resolution. Our low-cost metagenomic sequencing protocol produced 3.65 terabases of data, where the median number of base pairs per sample was 3.41 billion. The median distance between sampling stations was 26 km. The metagenomic libraries described here were collected as a part of a biological initiative for the Global Ocean Ship-based Hydrographic Investigations Program, or "Bio-GO-SHIP." One of the primary aims of GO-SHIP is to produce high spatial and vertical resolution measurements of key state variables to directly quantify climate change impacts on ocean environments. By similarly collecting marine metagenomes at high spatiotemporal resolution, we expect that this dataset will help answer questions about the link between microbial communities and biogeochemical fluxes in a changing ocean.

The cyclin pathway may confer resistance to standard treatments but also offer novel therapeutic opportunities in prostate cancer. Herein, we analyzed prostate cancer samples (majority metastatic) using comprehensive genomic profiling performed by next-generation sequencing (315 genes, >500× coverage) for alterations in activating and sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), androgen receptor (AR) gene, and coalterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1). Overall, cyclin sensitizing pathway genomic abnormalities were found in 9.7% of the 5,356 tumors. Frequent alterations included CCND1 amplification (4.2%) and CDKN2A and B loss (2.4% each). Alterations in possible resistance genes, RB1 and CCNE1, were detected in 9.7% (up to 54.6% in neuroendocrine) and 1.2% of cases, respectively, whereas AR alterations were seen in 20.9% of tumors (~27.3% in anaplastic). Cyclin sensitizing alterations were also more frequently associated with concomitant AR alterations.

The article is devoted to the peculiarities of the formation and systematization of the phonogram archive of the Udmurt Institute of History, Language and Literature of the Udmurt Federal Research Center of the Ural Branch of the Russian Academy of Sciences. The purpose of the article is to analyze the history of the formation of funds, the features of digitization of sound media on compact cassettes and reel-to-reel tapes, to identify the current state of the sound laboratory of the Institute as the main academic storage of materials on the spiritual culture of the region. The article analysis condition of the magnetic carriers, the work of the sound laboratory. Importance of timely digitization of magnetic tapes in accordance with international standards is marked. The examples from personal experience are given. Much attention is paid to the results of the British project «Vanishing voices from the Uralic world». Due to the project, modern standards of work have been implemented in laboratory. In conclusion, the author emphasis the necessity of formation of a unified music library of Udmurt records at the Institute as the main base for the preservation of the cultural heritage of the Udmurt Republic.

Recombinant protein expression in Escherichia coli is a fundamental technique in molecular biology and biotechnology. This review provides a comprehensive overview of various additivities to enhance the expression levels of soluble recombinant proteins in E. coli. The discussion encompasses five key aspects. Inducer Optimization: strategies for optimizing the inducer concentration to enhance protein expression. Autoinduction system optimization: the examination of glucose, lactose, and glycerol optimization within autoinduction systems to improve protein production. Osmolytes and osmoprotectants: an analysis of the use of osmolytes and osmoprotectants, such as sorbitol and glycine-betaine, to overcome with ease osmotic stress and enhance protein solubility. Ethanol additives: the impact of ethanol on E. coli physiology and its potential to improve recombinant protein expression. Cofactors and metabolic precursors: insights into the addition of cofactors, such as pyridoxal phosphate, riboflavin, thiamine, and pyridoxine, and the utilization of metabolic precursors to enhance the corresponding protein expression. This review highlights both the successful strategies and challenges in recombinant protein expression and provides insights into potential future research directions. Understanding and optimizing these factors is crucial for the efficient production of recombinant proteins for various applications in biotechnology. Furthermore, based on the analyzed data, we propose a straightforward scheme to optimize the additives in the cultivation medium.

Ribonucleoside hydrolase C (RihC, EC 3.2.2.1, 3.2.2.2, 3.2.2.3, 3.2.2.7, 3.2.2.8) belongs to the family of ribonucleoside hydrolases Rih and catalyzes the cleavage of ribonucleosides to nitrogenous bases and ribose. RihC is one of the enzymes that are synthesized by lactobacilli in response to the presence of Klebsiella. To characterize this protein from Limosilactobacillus reuteri LR1, we cloned and expressed it. The activity of the enzyme was studied towards a wide range of substrates, including ribonucleosides, deoxyribonucleosides as well as an arabinoside. It was shown that the enzyme is active only with ribonucleosides and arabinoside, with the best substrate being uridine. The thermal stability of this enzyme was studied, and its crystal structure was obtained, which demonstrated the tetrameric architecture of the enzyme and allowed to shed light on a correlation between its structure and enzymatic activity. Comprehensive comparisons of all known RihC structures, both existing crystal structures and computed model structures from various species, were made, allowing for the identification of structural motifs important for enzyme functioning.

Link for citation: Yankovsky S.A., Lavrinenko S.V., Tsibulskiy S.A., Yankovskaya N.S., Gamov D.L. Cycle diagram of geothermal energy. Bulletin of the Tomsk Polytechnic University. Geo Аssets Engineering, 2023, vol. 334, no. 7, рр. 122-136. In Rus. The relevance of the research is caused by the need to develop alternative and environmentally friendly energy sources in conditions of global warming. The development of geothermal energy will make it possible to produce thermal and electric energy without emissions of CO2 into the environment and reduce the dependence of the energy sector on hydrocarbon raw materials. The main aim of this study is a comprehensive analysis of the features of geothermal power plants, including the existing technologies for converting geothermal energy to provide consumers of electric and thermal energy. Objects: diagrams of geothermal power plants operating in different geographical and climatic conditions, as well as their working fluids. Methods: analytical review of thematic publications using the materials of the databases of the RSCI, Scopus and Web of Science, a comparative analysis of the effectiveness of geothermal power plants for various indicators. Results. Currently, there are about 400 geothermal power plants in the world. The active development of geothermal energy is caused by environmental friendliness, low cost of energy produced, minimal operating costs, lack of dependence on atmospheric influences, and the absence of the need to burn fuel, etc. At the same time, most of the world's geothermal power plants use the energy of a geothermal source with a water temperature of 100–200 °C. Among the main thermodynamic cycles and thermal schemes implemented, it is possible to single out direct cycle geothermal power plants with one-stage and two-stage separation of a geothermal source, with direct supply of dry steam to the turbine, binary and combined versions. The analysis shows that direct cycle geothermal power plants have the lowest cost of installed electrical power due to the relative simplicity and high thermal efficiency, but require high parameters of a geothermal source. On the other hand, binary geothermal power plants have the highest unit cost, but can be implemented on geothermal sources with relatively low water parameters, which was the main reason for their greatest spread in the world. At the same time, the implementation of a binary geothermal power plant with a Organic Rankine сycle has a number of advantages compared to the thermodynamic cycles of Kalina, Stirling and Brighton, among which the main ones are relative ease of adaptation and application, as well as low maintenance costs.

Chemotherapy can often cause a variety of side effects including bone marrow (BM) suppression, termed as myelosuppression. Accordingly, facile and effective management of chemotherapy-induced myelosuppression is currently a pivotal task for experimental pathologists and oncologists. Here, we chose to use activated carbon (AC) with an extensive surface area for studying its possible protective effectiveness with respect to BM in doxorubicin (DOX)-treated rats. Spherical AC with an extended surface area up to 4490 m2/g was prepared for per os (p/o) delivery, whereas for intraperitoneal (i/p) delivery we used the powdered form of AC that was derived from the aforementioned spherical AC. During the monthly treatment of animals with AC and DOX these two components were delivered alternately (not in the same day). After treatment, BM cells were isolated from femurs of sacrificed animals, stained with acridine orange (AO) and analyzed by flow cytometry. Regardless of the route of AC delivery (p/o or i/p), apparent myeloprotection with a possible regenerative effect was observed in animals that received DOX, as evidenced by recovery of the populations of total nucleated cells (TNC) and polychromatic (immature) erythrocytes accompanied by a considerable reduction of the number of apoptotic/dead cells among TNC (≤2.0%). Moreover, as a result of AC administrations, there was a significant increase of AO green and far-red fluorescence intensities in the population of TNC, which is suggestive of the ongoing quantitative and conformational changes in DNA and RNA associated with cell recovery and proliferation. Thus, AC preparations under the present experimental conditions can effectively tackle DOX-induced myelosuppression via mechanisms not necessarily associated with adsorptive detoxification.

Hundreds of trials are being conducted to evaluate combination of newer targeted drugs as well as immunotherapy. Our aim was to compare efficacy and safety of combination versus single non-cytotoxic anticancer agents. We searched PubMed (01/01/2001 to 03/06/2018) (and, for immunotherapy, ASCO and ESMO abstracts (2016 through March 2018)) for randomized clinical trials that compared a single non-cytotoxic agent (targeted, hormonal, or immunotherapy) versus a combination with another non-cytotoxic partner. Efficacy and safety endpoints were evaluated in a meta-analysis using a linear mixed-effects model (guidelines per PRISMA Report).We included 95 randomized comparisons (single vs. combination non-cytotoxic therapies) (59.4%, phase II; 41.6%, phase III trials) (29,175 patients (solid tumors)). Combinations most frequently included a hormonal agent and a targeted small molecule (23%). Compared to single non-cytotoxic agents, adding another non-cytotoxic drug increased response rate (odds ratio [OR]=1.61, 95%CI 1.40-1.84)and prolonged progression-free survival (hazard ratio [HR]=0.75, 95%CI 0.69-0.81)and overall survival (HR=0.87, 95%CI 0.81-0.94) (all p

BackgroundASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways.ObjectivesThe objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate-to-severe AD. Methods A total of 36 patients with moderate-to-severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28-day period (20 mg, 40 mg and 80 mg once daily).ResultsASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg -1·3 ± 2·1, P = 0·81; 40 mg -3·1 ± 2·7, P = 0·27; 80 mg -4·7 ± 2·1, P = 0·01; placebo -1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose-dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis-associated biomarker E selectin/SELE.ConclusionsIn patients with moderate-to-severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.

Background: The article presents the stages and results of treating a patient with a life-threatening condition caused by acute paraproctitis complicated by necrotizing fasciitis of the perineum and scrotum (Fournier's gangrene). The patient underwent a radical surgical treatment with the removal of the affected tissues, and, in the delayed period, a plastic surgery of the perineum and scrotum with a pedicled flap. Clinical case description: Patient Sh., 62 years old, was hospitalized at the Federal Research and Clinical Center of the Federal Medical and Biological Agency of Russia on an emergency basis with the following diagnosis: acute horseshoe-shaped posterior paraproctitis; non-clostridial phlegmon of the perineum and scrotum; sepsis. The patient was operated on urgently: a total necrectomy was performed with a wide excision of the affected tissues, excision of the anterior fistula, and a leak along the left inguinal cord into the abdominal cavity was identified and drained. The patient's condition in a few hours after the operation was characterized by pronounced positive dynamics, the effects of intoxication were stopped. 7 hours after the operation, the patient was transferred from the ICU to the department of coloproctology. A repeated surgical treatment with the revision of wounds was not required. 16 weeks after the first operation, a planned operation was performed with an excision of the fistula of the rectum and plasty of the perineum and scrotum with a rotary flap. The wounds healed by first intention. The patient recovered with all the pelvic functions completely restored. Conclusion: This clinical example can be used as a guide for the step-by-step treatment in this category of patients.

Small molecules that target RNA Polymerase I inhibit ribosome biogenesis to activate p53 through the nucleolar surveillance response pathway. Here, the authors show that p53 induction by ribosome stress is dependent on extracellular glutamine availability.

Relevance Traumatic spinal cord injury is a complex, urgent and multidisciplinary problem with a high percentage of disability and subsequent social exclusion. Treatment of neuroorthopedic pathologies is often associated with the need to use technical means of rehabilitation. The objective was to develop a successful orthosis for a patient with severe spinal cord injury. Material and methods The article describes a clinical case of a 16-year-old female patient with the outcome of a severe concomitant injury: lower paraplegia, sensory disturbances in the lower extremities and pelvic organ function. MRI of the spinal cord revealed cystic-glial changes and atrophy of the spinal cord at the Th10-12 level. Results and discussion With clinical signs of paraplegia and a complete spinal cord injury according to the instrumentation findings, the patient had poor prognosis for the recovery of motor functions in the lower limbs. One of the main tasks of medical rehabilitation of patients with spinal cord injury is the activation of movements and restoration of locomotion. The Hip-Knee-Ankle-Foot Orthosis (HKAFO) manufactured at the Center was intended for unloading, replacement and fixation. The device was light and strong due to greater use of carbon layers, equipped with functional hinges to prevent development of contractures, had a high corset for external stabilization of the body and double knee splint for safe standing. Conclusion For the paraplegic patient, the opportunity to stand and walk with the support using successful orthosis was important from both physical and psychosocial perspectives and allowed correction of contractures in the catamnesis.

Background: The plant Viscum album (Mistletoe) is a known source of biologically active substances, used in traditional medicine in Europe and Asia. Aim: The goal was to study cytotoxic/cytostatic effect of mistletoe extract on tumour and normal cells and its influences on certain proteins of the blood coagulation system. Setting: Mistletoe was collected in Ukraine in November 2020. Methods: Water extract of V. album, both leaves and stems, was obtained and fractionated; it was characterised using high-performance liquid chromatography (HPLC) and mass spectrometry and tested on cancer cells and blood plasma. Results: Extract demonstrated the presence of viscotoxins and carbohydrates and thermolabile compounds that enhance the activity of thrombin and factor X in plasma in the presence of calcium ions and increased the activated partial thromboplastin time (APTT) by 2.7 times. The cytotoxic/cytostatic action of the mistletoe fractions, the total extract and the fraction 10 000 Da were higher in relation to Lewis lung carcinoma (LLC) cells than with Vero cells. The IC50 of total extract for LLC cells was 35% (p 0.05) lower than that for Vero cells (1.12 ± 0.2 and 1.71 ± 0.15 mg/ml). Thus, the IC50 of the fraction 10 000 Da for LLC cells was more than by 44% (p 0.05) lower than that for Vero cells (2.07 ± 0.26 and 3.67 ± 0.41 mg/ml). Conclusion: It was shown that both extracts exhibited a cytotoxic/cytostatic effect, more pronounced against tumour cells than normal cells and enhanced the clotting of blood plasma by thermolabile compounds by facilitating plasma coagulation. Contribution: This research makes it possible to study mistletoe as a light and cheap anticancer therapy plant and cure blood coagulopathy or construct antibleeding bandages.

In southern and southeastern Brazil, the TP53 founder variant c.1010G>A (R337H) has been previously documented with a prevalence of 0.3% within the general population and linked to a heightened incidence of lung adenocarcinomas (LUADs). In the present investigation, we cover clinical and molecular characterizations of lung cancer patients from the Brazilian Li-Fraumeni Syndrome Study (BLISS) database. Among the 175 diagnosed malignant neoplasms, 28 (16%) were classified as LUADs, predominantly occurring in females (68%), aged above 50 years, and never-smokers (78.6%). Significantly, LUADs manifested as the initial clinical presentation of Li-Fraumeni Syndrome in 78.6% of cases. Molecular profiling was available for 20 patients, with 14 (70%) revealing EGFR family alterations. In total, 23 alterations in cancer driver genes were identified, comprising 7 actionable mutations and 4 linked to resistance against systemic treatments. In conclusion, the carriers of TP53 R337H demonstrate a predisposition to LUAD development. Furthermore, our results indicate that environmental pollution potentially impacts the carcinogenesis of lung tumors in the carriers of TP53 R337H.