Mobocertinib in Patients with EGFR Exon 20 Insertion-Positive Non-Small Cell Lung Cancer (MOON): An International Real-World Safety and Efficacy Analysis.

EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.

Measurement of the retinal venous pressure with a new instrument in patients with primary open angle glaucoma.

PURPOSE: To compare the results of retinal venous pressure (RVP) measurement performed with contact lens dynamometry (CLD) and with the new IOPstim. METHODS: In this cross-sectional study, we included 36 patients with primary open angle glaucoma with a median age (Q25; Q75) of 74 (64; 77) years (m/f = 18/18), baseline intraocular pressure (IOP): 13.9 (12.2; 15.1) mmHg. Median mean defect: - 5.8 (- 11.9; - 2.6) db. Principle of the IOPstim: an empty balloon with a diameter of 8 mm is positioned on the eye, laterally of the limbus. Under observation of the central retinal vein (CRV), the examiner inflates the balloon. As soon as the CRV starts pulsation, the inflation is stopped and the IOP is measured, equaling the RVP at this moment. In the CLD, the pulsation of the CRV is observed with a contact lens. The RVP is calculated from the attachment force applied when pulsation appears. COURSE OF EXAMINATIONS: Three single measurements of RVP in quick succession with both methods. The sequence of the two methods was randomized. The means of the three RVP measurements were compared. RESULTS: Pressures in mmHg. RVP: IOPstim: 19.4 ± 5.4 (mean ± SD), CLD: 20.3 ± 5.9. Range of three single measurements: IOPstim: 2.9 ± 1.5, CLD: 2.2 ± 1.1. The differences were RVPIOPstim - RVPCLD = - 0.94 ± 1.15, and approximately normally distributed. Bland-Altman analysis: only one data point was 0.5 mmHg higher than the upper line of agreement. The confidence interval of this line was 0.65 mmHg. Concordance correlation coefficient according to Lin (CCC): 0.96. Intraclass correlation coefficient: both methods, 0.94. CONCLUSION: In both methods, the range of the single measurements may be taken as a sign of good reliability, the CCC of 0.96 as a sign of a very good agreement. At the mean, the IOPstim RVP values were 1 mmHg lower than those obtained with the CLD. This difference may be due to the different directions of the prevailing force vectors induced by the instruments. The IOPstim seems applicable in glaucoma diagnostics.

Stratifying esophago-gastric cancer treatment using a patient-derived organoid-based threshold.

BACKGROUND AND AIMS: This study sought to determine the value of patient-derived organoids (PDOs) from esophago-gastric adenocarcinoma (EGC) for response prediction to neoadjuvant chemotherapy (neoCTx). METHODS: Endoscopic biopsies of patients with locally advanced EGC (n = 120) were taken into culture and PDOs expanded. PDOs' response towards the single substances of the FLOT regimen and the combination treatment were correlated to patients' pathological response using tumor regression grading. A classifier based on FLOT response of PDOs was established in an exploratory cohort (n = 13) and subsequently confirmed in an independent validation cohort (n = 13). RESULTS: EGC PDOs reflected patients' diverse responses to single chemotherapeutics and the combination regimen FLOT. In the exploratory cohort, PDOs response to single 5-FU and FLOT combination treatment correlated with the patients' pathological response (5-FU: Kendall's τ = 0.411, P = 0.001; FLOT: Kendall's τ = 0.694, P = 2.541e-08). For FLOT testing, a high diagnostic precision in receiver operating characteristic (ROC) analysis was reached with an AUCROC of 0.994 (CI 0.980 to 1.000). The discriminative ability of PDO-based FLOT testing allowed the definition of a threshold, which classified in an independent validation cohort FLOT responders from non-responders with high sensitivity (90%), specificity (100%) and accuracy (92%). CONCLUSION: In vitro drug testing of EGC PDOs has a high predictive accuracy in classifying patients' histological response to neoadjuvant FLOT treatment. Taking into account the high rate of successful PDO expansion from biopsies, the definition of a threshold that allows treatment stratification paves the way for an interventional trial exploring PDO-guided treatment of EGC patients.

Assisted reproduction after SARS-CoV-2-infection: results of a single-center cohort-study.

PURPOSE: The effects of SARS-CoV-2 infections on the outcome of assisted reproduction techniques (ART) were studied in a retrospective cohort study. METHODS: The outcome of 1581 treatment cycles with embryo transfer at a university fertility center in Germany was compared in years before and during the COVID-19 pandemic. For 335 treatment cycles in 2022 a detailed analysis was carried out depending on infection and immunization status of both partners. RESULTS: ART cycles did not differ in most of the parameters examined between 2018-2022. In spite of comparable clinical pregnancy rates, there was a significantly higher miscarriage rate at 34.6% (27/78) in 2022, compared to 19.7% (29/147) in the pre-pandemic years of 2018-2019 (p = 0.014). In 37.0% of the treatment cycles (124/335) 2022 at least one partner reported a SARS-CoV-2-Infection 6 months before ART, mostly with the virus variant Omicron. Clinical pregnancy rates were lower in cycles without infection. Comparing women with confirmed infection to no infection, a significantly higher risk of miscarriage was seen (62.5% vs. 26.2%, p = 0.009). In treatment cycles of partners with basic immunization against SARS-CoV-2 a statistically significant increase of pregnancy rates was seen comparing to cycles with both unvaccinated partners (p = 0.011). CONCLUSION: The results indicate a negative impact of SARS-CoV-2-infections up to 6 months on ART treatment, in particular an increased risk of miscarriage. Vaccination was associated with a better outcome of ART treatment.

[Gender-specific results of the Dresden children and adolescents headache program DreKiP]. / Geschlechtsspezifische Ergebnisse des Dresdner Kinder- und Jugendkopfschmerzprogrammes DreKiP.

BACKGROUND: Girls and women are more frequently affected by headache than boys and men. The influence of gender on the effectiveness of headache therapies has so far been hardly investigated. We examined gender differences in the outpatient multimodal Dresden Child and Adolescent Headache Program DreKiP. METHODS: We treated 140 patients with primary headache in a 15-hour structured group program. At baseline (T0) and six (T1) and twelve months (T2) after the end of the program, data on headache-related limitation of daily activities (PedMIDAS) as well as headache frequency, intensity, and pain-related disability (P-PDI) were collected. Retrospectively, these data were analyzed separately for girls and boys. RESULTS: For 91 patients (9-19 years, median = 15; 71.4 % female) data were available for at least two measurement time points. Girls showed significantly higher headache frequency than boys at all time points (median headache days/last three months at T0: ♀ 43, ♂ 20; T1: ♀ 32, ♂ 12; T2: ♀ 28, ♂ 9) as well as numerically higher headache-related limitation of daily life. There were significant effects over time with a decrease in headache frequency (F (2.88) = 5.862; p = 0.004) and improvement in daily functioning (F (2.92) = 5.340; p = 0.006). There was no gender-specific treatment response. DISCUSSION: The DreKiP therapy shows effects in girls and boys with primary headache. Higher headache frequencies and everyday life restrictions in girls may have hormonal but also psychosocial causes and should be addressed in educational measures.

9-Month observational Dia-Vacc study of vaccine type influence on SARS-CoV-2 immunity in dialysis and kidney transplant patients.

BACKGROUND: SARS-CoV-2mRNA vaccination related seroconversion rates are reduced in dialysis and kidney transplant patients. METHODS: We evaluated nine months follow up data in our observational Dia-Vacc study exploring specific cellular (interferon-γ release assay) or/and humoral immune responses after 2x SARS-CoV-2mRNA vaccination in 880 participants including healthy medical personnel (125-MP), dialysis patients (595-DP), kidney transplant recipients (111-KTR), and apheresis patients (49-AP) with positive seroconversion (de novo IgA or IgG antibody positivity by ELISA) after eight weeks. FINDINGS: Nine months after first vaccination, receptor binding domain (RBD) antibodies were still positive in 90 % of MP, 86 % of AP, but only 55 %/48 % of DP/KTR, respectively. Seroconversion remained positive in 100 % of AP and 99·2 % of MP, but 86 %/81 % of DP/KTR, respectively. Compared to MP, DP but not KTR or AP were at risk for a strong RBD decline, while KTR kept lowest RBD values over time. By multivariate analysis, BNT162b2mRNA versus 1273-mRNA vaccine type was an independent risk factor for a strong decline of RBD antibodies. Within the DP group, only time on dialysis was another (inverse) risk factor for the DP group. Compared to humoral immunity, T-cell immunity decline was less prominent. INTERPRETATION: While seroconverted KTR reach lowest RBD values over time, DP are at specific risk for a strong decline of RBD antibodies after successful SARS-CoV-2mRNA vaccination, which also depends on the vaccine type being used. Therefore, booster vaccinations for DP should be considered earlier compared to normal population.

Serum immune checkpoint profiling identifies soluble CD40 as a biomarker for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to systemic treatment, including new immunotherapeutic approaches. Biomarkers are urgently needed for early disease detection, patient stratification for treatment, and response prediction. The role of soluble CD40 (sCD40) is unknown in PDAC. In this study, we performed a quantitative multiplex analysis of 17 immune checkpoint proteins in serum samples from patients with various stages of PDAC in a discovery study (n = 107) and analyzed sCD40 by ELISA in a validation study (n = 317). Youden's J statistic was used for diagnostic cut-off optimization. A Cox proportional hazards regression model was applied in an empiric approach for prognostic threshold optimization. Kaplan-Meier estimator and multivariable Cox regression analyses were used for survival analysis. sCD40 was significantly increased in the serum of patients with PDAC compared to healthy cohorts and patients with IPMN. In the validation cohort, the area under the receiver operating characteristic (ROC) c-statistic was 0.8, and combining sCD40 with CA19-9 yielded a c-statistic of 0.95. sCD40 levels were independent of the tumor stage. However, patients who received neoadjuvant chemotherapy had significantly lower sCD40 levels than those who underwent upfront surgery. Patients with a sCD40 level above the empirical threshold of 0.83 ng/ml had a significantly reduced overall survival with a hazard ratio of 1.4. This observation was pronounced in patients after neoadjuvant chemotherapy. Collectively, soluble CD40 may be considered as both a diagnostic and prognostic non-invasive biomarker in PDAC.

COMPASS: deCOMPressing stomA and two-Stage elective resection vs. emergency reSection in patients with left-sided obstructive colon cancer.

BACKGROUND: Colorectal cancer stands as a prevalent cause of cancer-related mortality, necessitating effective treatment strategies. Acute colonic obstruction occurs in approximately 20% of patients and represents a surgical emergency with substantial morbidity and mortality. The optimal approach for managing left-sided colon cancer with acute colonic obstruction remains debatable, with no consensus on whether emergency resection or bridge-to-surgery, involving initial decompressing stoma and subsequent elective resection after recovery, should be employed. Current studies show a decrease in morbidity and short-term mortality for the bridge-to-surgery approach, yet it remains unclear if the long-term oncological outcome is equivalent to emergency resection. METHODS: This prospective, randomized, multicenter trial aims to investigate the management of obstructive left-sided colon cancer in a comprehensive manner. The study will be conducted across 26 university hospitals and 40 academic hospitals in Germany. A total of 468 patients will be enrolled, providing a cohort of 420 evaluable patients, with an equal distribution of 210 patients in each treatment arm. Patients with left-sided colon cancer, defined as cancer between the left splenic flexure and > 12 cm ab ano and obstruction confirmed by X-ray or CT scan, are eligible. Randomization will be performed in a 1:1 ratio, assigning patients either to the oncological emergency resection group or the bridge-to-surgery group, wherein patients will undergo diverting stoma and subsequent elective oncological resection after recovery. The primary endpoint of this trial will be 120-day mortality, allowing for consideration of the time interval between diverting stoma and resection. DISCUSSION: The findings derived from this trial possess the potential to reshape the current clinical approach of emergency resection for obstructive left-sided colon cancer by favoring the bridge-to-surgery practice, provided that a reduction in morbidity can be achieved without compromising the oncological long-term outcome. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) under the identifier DRKS00031827. Registered on May 15, 2023. PROTOCOL: 28.04.2023, protocol version 2.0F.

Biochemical Aspects of the Spiral Grain Formation in Scots Pine (Pinus Sylvestris L.) Wood. Some Differences and Similarities with Biochemical Indicators of Abnormal Xylogenesis in Karelian Birch (Betula Pendula Roth Var. Carelica (Mercl.) Hämet-Ahti).

BACKGROUND: AOS enzymes can be biochemical indicators of abnormal xylogenesis in Scots pine, and this mechanism has similar features with the metabolic base of abnormal xylogenesis in Karelian birch. OBJECTIVE: AOS enzymes' activity in 150-300-year-old Pinus sylvestris L. wood with straight-- grained wood and right-twisted spiral-grained wood, expressed in varying degrees (5-20 angle), grew in three sample plots in lingonberry and blueberry pine forest stands of different ages (100-300 years) in the middle taiga subzone in the Republic of Karelia. METHODS: Plant tissues were ground in liquid nitrogen in a uniform mass and homogenized at 4°C in the buffer containing 50 mM HEPES (pH 7.5), 1 mM EDTA, 1 mM EGTA, 3 mM DTT, 5 mM MgCl2 and 0.5 mM PMSF. After 20 min extraction, the homogenate was centrifuged at 10000 g for 20 min (MPW-351R, Poland). The sediment was washed in the buffer thrice. The pooled supernatant and sediment were dialyzed at 4°C for 18-20 h against a tenfold diluted homogenization buffer. The enzymes' activity was determined spectrophotometrically (Spectrophotometer SF-2000, OKB Spectr, Russia). Proteins in the extracts were quantified by the method of Bradford. RESULTS: The study showed that the activity of SS, ApInv, CAT, POD and PPO in xylem and PPO in phloem were biochemical indicators for abnormal wood of P. sylvestris. We noticed an increase in sucrose metabolism in the apoplast and the activity of POD and PPO under spiral-grain wood formation like under figured wood formation earlier. We assume that the alternative pathway of sucrose metabolism (an indicator of abnormal xylogenesis in B. pendula var. carelica plants) that lead to restructuring of AOS enzymes have the same biochemical regularities in the spiral-grain wood formation in P. sylvestris. CONCLUSION: The study showed that the differences in the AOS enzyme's activity in P. sylvestris during the formation of straight-grained and spiral-grained wood were revealed for the first time. The increased CAT, POD and PPO activities in xylem with a decrease in SS and an increase in Ap- Inv during spiral-grained wood formation can be biochemical markers of these structural anomalies. Metabolic regularities found in the AOS enzyme complex during spiral-grained wood formation do not contradict those found earlier during figured wood formation in B. pendula var. carelica. The identified patterns can form the base for diagnostics of P. sylvestris wood quality in forest seed plantations and in their natural growth, which is necessary both for fundamental science and in various industry areas while high-quality material harvesting.

Associations of Tissue and Soluble LOX-1 with Human Abdominal Aortic Aneurysm.

Background Indication for prophylactic surgical abdominal aortic aneurysm (AAA) repair depends on the maximal aortic diameter. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for uptake of oxidized low-density lipoprotein cholesterol and is implicated in atherosclerosis. A soluble form of LOX-1 (sLOX-1) has been discussed as a novel biomarker in coronary artery disease and stroke. Herein, we assessed the regulation of aortic LOX-1 as well as the diagnostic and risk stratification potential of sLOX-1 in patients with AAA. Methods and Results Serum sLOX-1 was assessed in a case-control study in AAA (n=104) and peripheral artery disease (n=104). sLOX-1 was not statistically different between AAA and peripheral artery disease but was higher in AAA (ß=1.28, P=0.04) after adjusting for age, atherosclerosis, type 2 diabetes, prescription of statins, ß-blockers, ACE inhibitors, and therapeutic anticoagulation. sLOX-1 was not associated with the aortic diameter, AAA volume, or the thickness of the intraluminal thrombus. Aortic LOX-1 mRNA expression tended to be higher in AAA when compared with disease, and expression was positively associated with cleaved caspase-3, smooth muscle actin, collagen, and macrophage content. Conclusions In AAA, sLOX-1 was differently affected by age, cardiometabolic diseases, and corresponding medical therapies. Comparison with nonatherosclerotic disease would be beneficial to further elucidate the diagnostic potential of sLOX-1, although it was not useful for risk stratification. Aneurysmal LOX-1 mRNA expression was increased and positively associated with smooth muscle cells and collagen content, suggesting that LOX-1 is eventually not deleterious in human AAA and could counteract AAA rupture.

Impact of a 12-week olfactory training programme in women with migraine with aura: protocol for a double-blind, randomised, placebo-controlled trial.

INTRODUCTION: Migraine is a leading cause of disability and suffering worldwide. However, conventional pharmacological migraine preventive therapies are often challenging and accompanied by adverse effects. Recently, structured odour exposure has shown to successfully increase pain thresholds in patients with chronic back pain. Despite the importance of the olfactory system in migraine, there are no studies investigating the impact of structured odour exposure in patients with migraine. METHODS AND ANALYSIS: This double-blind randomised placebo-controlled trial will be conducted at the Headache Clinic of the University Pain Center at TU Dresden, Germany and aims at investigating the impact of a 12-week structured exposure to odours in women with migraine. Fifty-four women between 18 and 55 years with migraine with aura will be recruited and randomised to training with odours and odourless training. The primary outcomes are mechanical and electrical pain thresholds. Secondary outcomes comprise olfactory threshold and the number of headache days. Other exploratory measurements are headache associated pain intensity, acute analgesic intake, symptoms of anxiety and depression, and quality of life. Additionally, this protocol assesses neuroanatomical and neurofunctional changes associated with the 12-week olfactory training. Data analysis will be executed on the basis of the general linear model considering repeated measurements. ETHICS AND DISSEMINATION: Ethical approvals were obtained from the Ethics Board of the TU Dresden (Protocol No. BO-EK-353082020). Participation will only be possible after written informed consent is provided. Findings will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER: DRKS00027399.

TIGIT Expression Delineates T-cell Populations with Distinct Functional and Prognostic Impact in Pancreatic Cancer.

PURPOSE: Immunotherapy has led to a fundamental shift in the treatment of several cancers. However, its efficacy in pancreatic ductal adenocarcinoma (PDAC) is limited. Understanding the expression of inhibitory immune checkpoint receptors (ICR) by intratumoral T cells may help to unravel their involvement in insufficient T-cell-mediated antitumor immunity. EXPERIMENTAL DESIGN: Using multicolor flow cytometry, we analyzed circulating and intratumoral T cells from blood (n = 144) and matched tumor samples (n = 107) of patients with PDAC. We determined the expression of programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif (ITIM) domains (TIGIT) by CD8+ T-cells, conventional CD4+ T-cells (Tconv) and regulatory T cells (Treg) and their association with T-cell differentiation, tumor reactivity, and cytokine expression. A comprehensive follow-up was used to determine their prognostic value. RESULTS: Intratumoral T cells were characterized by increased PD-1 and TIGIT expression. Both markers delineated distinct T-cell subpopulations. PD-1+TIGIT- T cells highly expressed proinflammatory cytokines and markers of tumor reactivity (CD39, CD103), whereas TIGIT expression was linked to antiinflammatory and exhausted phenotypes. In addition, the enhanced presence of intratumoral PD-1+TIGIT- Tconv was associated with improved clinical outcomes, while high ICR expression on blood T cells was a significant hazard for overall survival (OS). CONCLUSIONS: Our results uncover the association between ICR expression and T-cell functionality. PD-1 and TIGIT characterized intratumoral T cells with highly divergent phenotypes linked to clinical outcomes, further underscoring the relevance of TIGIT for immunotherapeutic approaches in PDAC. The prognostic value of ICR expression in patient blood may be a valuable tool for patient stratification.

Regulation of CD163 Receptor in Patients with Abdominal Aortic Aneurysm and Associations with Antioxidant Enzymes HO-1 and NQO1.

Red blood cells are found within the abdominal aortic aneurysm (AAA), in the intraluminal thrombus (ILT), and in neovessels. Hemolysis promotes aortic degeneration, e.g., by heme-induced reactive oxygen species formation. To reduce its toxicity, hemoglobin is endocytosed by the CD163 receptor and heme is degraded by heme oxygenase-1 (HO-1). A soluble form (sCD163) is discussed as an inflammatory biomarker representing the activation of monocytes and macrophages. HO-1 and NAD(P)H quinone dehydrogenase 1 (NQO1) are antioxidant genes that are induced by the Nrf2 transcription factor, but their regulation in AAA is only poorly understood. The aim of the present study was to analyze linkages between CD163, Nrf2, HO-1, and NQO1 and to clarify if plasma sCD163 has diagnostic and risk stratification potential. Soluble CD163 was 1.3-fold (p = 0.015) higher in AAA compared to patients without arterial disease. The difference remained significant after adjusting for age and sex. sCD163 correlated with the thickness of the ILT (rs = 0.26; p = 0.02) but not with the AAA diameter or volume. A high aneurysmal CD163 mRNA was connected to increases in NQO1, HMOX1, and Nrf2 mRNA. Further studies are needed to analyze the modulation of the CD163/HO-1/NQO1 pathway with the overall goal of minimizing the detrimental effects of hemolysis.

Olfactory training reduces pain sensitivity in children and adolescents with primary headaches.

Objective: Headache prevalence among children and adolescents has increased over the last few years. Evidence-based treatment options for pediatric headaches remain limited. Research suggests a positive influence of odors on pain and mood. We investigated the effect of repeated exposure to odors on pain perception, headache-related disability, and olfactory function in children and adolescents with primary headaches. Methods: Eighty patients with migraine or tension-type headache (mean 13.1 ± 3.29 years) participated, of whom 40 underwent daily olfactory training with individually selected pleasant odors for 3 months and 40 received state-of-the-art outpatient therapy as a control group. At baseline and after a 3-month follow-up, olfactory function [odor threshold; odor discrimination; odor identification; comprehensive Threshold, Discrimination, Identification (TDI) score], mechanical detection and pain threshold (quantitative sensory testing), electrical pain threshold, patient-reported outcomes on headache-related disability [Pediatric Migraine Disability Assessment (PedMIDAS)], pain disability [Pediatric Pain Disability Index (P-PDI)], and headache frequency were assessed. Results: Training with odors significantly increased the electrical pain threshold compared to the control group (U = 470.000; z = -3.177; p = 0.001). Additionally, olfactory training significantly increased the olfactory function (TDI score [t(39) = -2.851; p = 0.007], in particular, olfactory threshold, compared to controls (U = 530.500; z = -2.647; p = 0.008). Headache frequency, PedMIDAS, and P-PDI decreased significantly in both groups without a group difference. Conclusions: Exposure to odors has a positive effect on olfactory function and pain threshold in children and adolescents with primary headaches. Increased electrical pain thresholds might reduce sensitization for pain in patients with frequent headaches. The additional favorable effect on headache disability without relevant side effects underlines the potential of olfactory training as valuable nonpharmacological therapy in pediatric headaches.

An Indicating Role of Antioxidant System Enzymes at the Stage of Active Structural Anomalies Formation in Karelian Birch (Betula pendula Roth var. carelica (Mercl.) Hämet-Ahti).

INTRODUCTION: A complex study of the antioxidant system enzymes (AOS) is an important subject of biochemical research; changes in the activity of these enzymes can be used as a biochemical marker of various processes in plants. At the same time, practically little attention has been paid to describing the regularities of these enzymatic reactions in different wood formation processes, such as xylogenesis. This article discusses the outcomes of different behaviors of AOS enzymes, which are involved in both the redistribution of the ROS balance and phenolic compounds at the early stages of wood formation in young plants of silver birch (Betula pendula Roth) with straight-grained wood and Karelian birch (Betula pendula Roth var. carelica (Merckl.) Hamet-Ahti) with non-figured and figured parts within the single trunk. BACKGROUND: Spectrophotometric determination of AOS enzymes' activity can be used as a biochemical marker in the different wood formation processes, including xylogenesis. In this study, we studied structural anomalies of the woody plant trunk of Karelian birch (Betula pendula Roth var. carelica (Merckl.) Hamet- Ahti). OBJECTIVE: This study aimed to study AOS enzymes' activity in 12-year-old plants of silver birch (Betula pendula Roth) with straight-grained wood and Karelian birch (Betula pendula Roth var. carelica (Merckl.) Hamet-Ahti) with non-figured and figured parts within the single trunk. METHODS: Plant tissues were ground in liquid nitrogen to a uniform mass and homogenized at 4°C in the buffer containing 50 mM HEPES (pH 7.5), 1 mM EDTA, 1 mM EGTA, 3 mM DTT, 5 mM MgCl2, and 0.5 mM PMSF. After 20 min extraction, the homogenate was centrifuged at 10000 g for 20 min (MPW-351R, Poland). The sediment was washed in the buffer thrice. The pooled supernatant and sediment were dialyzed at 4°C for 18-20 h against a tenfold diluted homogenization buffer. The enzymes' activity was determined spectrophotometrically (Spectrophotometer SF-2000, OKB Spectr, Russia). Proteins in the extracts were quantified by the method of Bradford. RESULTS: We observed different behaviors of the studied enzymes involved in both the redistribution of the ROS balance and phenolic compounds with subsequent lignification even at the early stages of wood formation in young plants and even in different trunk parts within a tree, which was consistent with results obtained earlier on adult plants. High SOD activity in the phloem compared to the activity in the xylem was accompanied by higher CAT activity. The POD/SOD ratio was significantly higher in the figured trunk parts in Karelian birch compared to other variants in the xylem and higher in Karelian birch plants compared to plants of common birch in the phloem. The CAT/POD ratio was significantly higher in plants with no signs of anomalies. The high POD and PPO activity in the xylem of figured trunk parts and in the phloem of figured and non-figured trunk parts of B. pendula var. carelica can be associated with the high activity of apoplast invertase. CONCLUSION: The study showed that at the stage of active formation of structural anomalies in the figured trunk parts in young plants of Karelian birch, hydrogen peroxide utilization occurred mainly due to increased POD activity. An increase in PPO activity in the trunk of figured plants could also be considered an indicator of the formation of structural anomalies. At the same time, in areas with developing abnormal wood, the POD/SOD ratio increased, and the CAT/POD ratio decreased, indicating a fine-tuning of the balance between superoxide radical and hydrogen peroxide, which, when changed, might regulate the rearrangement of xylogenesis towards proliferation in relation to differentiation.

Relationship between epilarynx tube shape and the radiated sound pressure level during phonation is gender specific.

OBJECTIVE/HYPOTHESIS: The aim of the study was to measure the morphology of the epilaryngeal tube during sustained phonation as a function of loudness variation and to compare subjects of different genders. STUDY DESIGN: This is a prospective study. METHODS: Five female and five male classically trained singers were recorded by magnetic resonance imaging with simultaneous audio recordings while sustaining phonation at three different loudness conditions. Three-dimensional subsections of the vocal tract were segmented on multi-image-based cross-sections. Different volume and area measures were determined and their relation to sound pressure level and loudness condition was analyzed. RESULTS: Male singers tended to narrow the epilaryngeal tube when increasing sound pressure level whereas female singers did not. CONCLUSION: Strategies of vocal tract adjustments during loudness variation in classical singing appear to be gender specific.

Study of the Deep Processes of COVID-19 in Russia: Finding Ways to Identify Preventive Measures.

The novel coronavirus disease 2019 (COVID-19) pandemic has had a huge impact on all areas of human life. Since the risk of biological threats will persist in the future, it is very important to ensure mobilization readiness for a prompt response to the possible emergence of epidemics of infectious diseases. Therefore, from both a theoretical and practical standpoint, it is currently necessary to conduct a thorough examination of the COVID-19 epidemic. The goal of this research is to investigate the underlying processes that led to the COVID-19 pandemic in Russia and to identify ways to improve preventive measures and ensure mobilization readiness for a quick response to potential COVID-19-like pandemics. This research will analyze the daily dynamics of the number of infection cases and the number of new lethal cases of COVID-19. We analyzed the daily number of new cases of COVID-19 infection N(d), the daily number of new lethal cases L(d), their percentage ratio L(d)/N(d) 100% in Russia for 2 years of the pandemic (from the beginning of the pandemic to 23 March 2022), the rate of increase and decrease of these indicators (dN(d)/dd and dL(d)/dd), as well as their spectra created on the basis of wavelet analysis. Wavelet analysis of the deep structure of the N(d) and L(d) wavelet spectra made it possible to identify the presence of internal cycles, the study of which makes it possible to predict the presence of days with the maximum number of infections and new deaths in a pandemic similar to COVID-19 and outline ways and methods for improving preventive measures and measures to ensure mobilization readiness for a rapid response to the potential emergence of pandemics similar to COVID-19.

Analysis of the Face Mask Use by Public Transport Passengers and Workers during the COVID-19 Pandemic.

(1) Background: The use of face masks and gloves in public places directly shows the commitment of the population to the established regulations. Public transport is one of the most-at-risk places of contamination. The aim of the study was to analyze the face mask use by public transport passengers and workers during the COVID-19 pandemic. (2) Methods: Public transport passengers and workers were surveyed. Periodic intermittent selective observation was used to gauge the level of adherence to the established regulations among public transport passengers. Factor analysis was used to identify factors determining the face-mask-wearing comfort. (3) Results: The majority of passengers (87.5%) and all transport workers (100%) used face masks and gloves. Most of the users wore only face masks. Only 41.6% of passengers and 74.7% of transport workers wore face masks correctly. Motivational attitudes at the implementation of preventive measures were determined: established regulations in the public place (55.8%) and the protection of one's own health and the health of family members (44.2%). Only 22.5% of those wearing face masks believed that doing so will have any effect on the spread of an infectious disease, and 10.8% wore masks to maintain the health of people around themselves. A low level of social responsibility was demonstrated. For 53.4% of workers, face mask wearing was uncomfortable. The majority of workers had adverse reactions to mask wearing: feeling short of breath (52.8%), hyperemia of face skin (33.8%), and facial hyperhidrosis (67.4%). (4) Conclusions: The comfort of wearing a mask is determined by adverse reactions occurrence, the properties of the mask, working conditions, and the duration of wearing the face mask. It is necessary to develop recommendations to reduce wearing discomfort. These recommendations, along with methods of raising the social responsibility of the population, can contribute to a greater commitment of the population to non-specific prevention measures.

Sensitization of Patient-Derived Colorectal Cancer Organoids to Photon and Proton Radiation by Targeting DNA Damage Response Mechanisms.

Pathological complete response (pCR) has been correlated with overall survival in several cancer entities including colorectal cancer. Novel total neoadjuvant treatment (TNT) in rectal cancer has achieved pathological complete response in one-third of the patients. To define better treatment options for nonresponding patients, we used patient-derived organoids (PDOs) as avatars of the patient's tumor to apply both photon- and proton-based irradiation as well as single and combined chemo(radio)therapeutic treatments. While response to photon and proton therapy was similar, PDOs revealed heterogeneous responses to irradiation and different chemotherapeutic drugs. Radiotherapeutic response of the PDOs was significantly correlated with their ability to repair irradiation-induced DNA damage. The classical combination of 5-FU and irradiation could not sensitize radioresistant tumor cells. Ataxia-telangiectasia mutated (ATM) kinase was activated upon radiation, and by inhibition of this central sensor of DNA damage, radioresistant PDOs were resensitized. The study underlined the capability of PDOs to define nonresponders to irradiation and could delineate therapeutic approaches for radioresistant patients.