Radiation in Combination with Immune Checkpoint Blockade and DNA Damage Response Inhibitors in Mice: Dosage Optimization in MC38 Syngeneic Tumors via Modelling and Simulation.

Clinical trials assessing the impact of radiotherapy (RT) in combination with DNA damage response pathway inhibitors (DDRis) and/or immune checkpoint blockade are currently ongoing. However, current methods for optimizing dosage and schedule are limited. A mathematical model was developed to capture the impacts of RT in combination with DDRi and/or anti-PD-L1 [immune checkpoint inhibitor (ICI)] on tumor immune interactions in the MC38 syngeneic tumor model. The model was fitted to datasets that assessed the impact of RT in combination with the DNA protein kinase inhibitor (DNAPKi) AZD7648. The model was further fitted to datasets from studies that were used to assess both RT/ICI combinations as well as RT/ICI combinations followed by concurrent administration of the poly ADP ribose polymerase inhibitor (PARPi) olaparib. Nonlinear mixed-effects modeling was performed followed by internal validation with visual predictive checks (VPC). Simulations of alternative dosage regimens and scheduling were performed to identify optimal candidate dosage regimens of RT/DNAPKi and RT/PARPi/ICI. Model fits and VPCs confirmed a successful internal validation for both datasets and demonstrated very small differences in the median, lower, and upper percentile values of tumor diameters between RT/ICI and RT/PARPi/ICI, which indicated that the triple combination of RT/PARPi/ICI at the given dosage and schedule does not provide additional benefit compared with ICI in combination with RT. Simulation of alternative dosage regimens indicated that lowering the dosage of ICI to between 2 and 4 mg/kg could induce similar benefits to the full dosage regimen, which could be of translational benefit. SIGNIFICANCE STATEMENT: This work provides a mixed-effects model framework to quantify the effects of combination radiotherapy/DNA damage response pathway inhibitors/immune checkpoint inhibitors in preclinical tumor models and identify optimal dosage regimens, which could be of translational benefit.

Specific targeting of the KRAS mutational landscape in myeloma as a tool to unveil the elicited antitumor activity.

Alterations in KRAS have been identified as the most recurring somatic variants in the multiple myeloma (MM) mutational landscape. Combining DNA and RNA sequencing, we studied 756 patients and observed KRAS as the most frequently mutated gene in patients at diagnosis; in addition, we demonstrated the persistence or de novo occurrence of the KRAS aberration at disease relapse. Small-molecule inhibitors targeting KRAS have been developed; however, they are selective for tumors carrying the KRASG12C mutation. Therefore, there is still a need to develop novel therapeutic approaches to target the KRAS mutational events found in other tumor types, including MM. We used AZD4785, a potent and selective antisense oligonucleotide that selectively targets and downregulates all KRAS isoforms, as a tool to dissect the functional sequelae secondary to KRAS silencing in MM within the context of the bone marrow niche and demonstrated its ability to significantly silence KRAS, leading to inhibition of MM tumor growth, both in vitro and in vivo, and confirming KRAS as a driver and therapeutic target in MM.

The effect of a web-based psychoeducation on emotional functioning, eating behaviors, and body image among premenopausal women with excess body weight.

The aims of this study were twofold: (1) to investigate the effectiveness of web-based psychoeducation for emotional functioning, eating behaviors, and body image among premenopausal women with excess body weight, and (2) to compare the efficacy of two types of web-based psychoeducation. Three hundred individuals were asked to volunteer in the present study. All participants were recruited in Poland from September 2017 to July 2019. Finally, a total of 129 premenopausal women took part in the research and signed informed consent. Their ages ranged between 18 and 48 years old (M = 32.28, SD = 7.65). Self-reported weight and height were recorded. BMI was calculated using self-reported data. Their average body mass index was 30.54 kg/m2 (SD = 3.69). In our randomized experiment, the participants were allocated into three groups: experimental group I (EG I, N = 43), experimental group II (EG II, N = 46), and wait list control group (CG, N = 40). Five questionnaires were included in the online survey at the baseline measurement (Day 0), at the end of psychoeducational intervention (Day 16) and 75 days from the start of the 15-day intervention (Day 76). Measurement tools included the Difficulties in Emotion Regulation Scale, the Positive and Negative Affect Schedule, the Mindful Eating Scale, the Three-Factor Eating Questionnaire, and the Body Attitude Test. Our eHealth web-based psychoeducation consisted of three modules: emotional functioning module (EG I: theoretically consistent approach (TCA) vs EG II: eclectic approach; EA), eating behaviors module (EG I, EG II: based on mindfulness-based eating training; MET), body image module (EG I, EG II: based on Cash's prevention of body image disturbances; CPBID). The first experimental group (EG I) had intervention containing TCA, MET, and CPBID, while the second experimental group (EG II) EA, MET, and CPBID. According to between-group comparison, both types of web-based psychoeducation led to an increase in adaptive emotion regulation (Day 16: EG I vs CG: p < 0.001, EG II vs CG: p < 0.001; Day 76: EG I vs CG: p < 0.01, EG II vs CG: p < 0.001). In EG I, the intervention resulted in a higher reduction (than in CG) in emotional eating (Day 16: p < 0.01, Day 76: p < 0.01), uncontrolled eating (Day 16: p < 0.05, Day 76: p < 0.05), and negative appreciation of body size (Day 16: p < 0.01, Day 76: p < 0.01). In EG II, a lower level of emotional eating was found on Day 76 (EG II vs CG: p < 0.05). Two months after completion of the 15-day intervention, no statistically significant reduction for BMI was observed in either experimental group (p > 0.05). The effectiveness of both types of web-based psychoeducation was also confirmed in within-group comparison (Day 0 vs Day 16 and Day 0 vs Day 76). There was a significant increase in emotion regulation and mindful eating, as well as a decrease in emotional eating, uncontrolled eating, negative appreciation of body size, lack of familiarity with one's body, and the experiencing of negative emotions in both experimental groups (EG I, EG II). Both types of web-based psychoeducation might have to be considered in creating future web-based psychoeducation among premenopausal women with excess body weight.

Antifungal polybrominated proxyphylline derivative induces Candida albicans calcineurin stress response in Galleria mellonella.

Candida albicans CNB1 plays a role in the response in vitro and in vivo to stress generated by PB-WUT-01, namely 1,3-dimethyl-7-(2-((1-(3-(perbromo-2H-benzo[d][1,2,3]triazol-2-yl)propyl)-1H-1,2,3-triazol-4-yl)methoxy)propyl)-1H-purine-2,6(3H,7H)-dione. The antifungal mechanism involved the calcineurin pathway-regulated genes SAP9-10. Galleria mellonella treated with PB-WUT-01 (at 0.64 µg/mg) showed limited candidiasis and remained within the highest survival rates. The molecular mode of action of PB-WUT-01 was rationalized by in silico docking studies toward both human and C. albicans calcineurin A (CNA) and calcineurin B (CNB) complexes, respectively. PB-WUT-01 acting as a calcineurin inhibitor in the C. albicans cells enhances the cells' susceptibility. Therefore it could be a suitable alternative treatment in patients with candidiasis.

Alcohol Intoxication and Suicide by Hanging in Poland.

AIMS: An integral part of the World Health Organization (WHO) plan to reduce suicide by 10% by 2020 is to identify areas and demographic groups, which should be priority target groups for preventive activities. This study aimed to present the demographic differences between victims of suicide by hanging in the Warsaw metropolitan area, in Poland, by examining the sobriety of victims. METHODS: Data for analysis were obtained from the documentation of the Department of Forensic Medicine (DFM) at the Medical University of Warsaw (MUW). The retrospective analysis included 358 out of 466 victims of suicides by hanging in the Warsaw metropolitan area, in Poland, recorded in the DFM documentation covering 2011-2013. The data gathered included age, gender, the cause of death, a post-mortem examination as well as the level of ethanol in the blood and muscles of victims. RESULTS: In both groups, men accounted for a larger percentage of victims than women, P = 0.068. In the no-alcohol group, the victims were older than in the alcohol group (47.52 ± 19.21 vs. 40.88 ± 12.77) (P < 0.001). The majority of the studied population were victims aged 25-34 (22.90%), mainly men (20.95%). Young men were also the largest group among victims in the alcohol group (28.33%). The most numerous age group among no-alcohol group were older victims aged 55-64 (19.10%), especially men (16.29%). CONCLUSION: Regardless of sobriety, men were the largest group of suicide victims in the study population, which means that men die suicide more often than women. Differences in gender proportions are related to age. In the studied population, it was primarily young victims, mainly men. These are the groups that should be priority target groups for preventive activities aimed at reducing the number of suicides. The presence of ethanol in more than half of the victims of suicide in the study population indicates that alcohol is an important suicidal risk factor.

The Impact of Ischemic Cerebral Stroke on the Quality of Life of Patients Based on Clinical, Social, and Psychoemotional Factors.

BACKGROUND: Cerebral stroke is the major cause of disability in the modern world and, given its consequences, poses serious medical and social problems. The purpose of the study was to evaluate the quality of life of patients who suffered from an ischemic cerebral stroke with respect to various areas of life, including, in particular, clinical and psychoemotional factors. The study hypothesis states that the poststroke quality of life is reduced in the general context as well as in the context of specific areas of life. It was also considered of key importance to assess how the quality of life of patients is affected by depression. MATERIALS AND METHODS: The study included 44 patients with the first ischemic cerebral stroke of moderate and mild severity according to the National Institutes of Health Stroke Scale, currently treated in the Neurology Department of the Miedzyleski Specialist Hospital in Warsaw. The quality of life was measured based on the standardized Ferrans and Powers Quality of Life Index questionnaire and the Beck Depression Inventory. RESULTS: Based on the results, it was demonstrated that the quality of life of the patients was significantly reduced on the psychological and spiritual well-being subscale and that depression is a more frequent occurrence among patients with cerebral stroke of moderate severity. CONCLUSIONS: Continued and complex posthospitalization care, including treatment for depression and increased social support, may to a significant extent reduce the negative impact of the disease on the perceived quality of life.

Analysis of Quality of Life Subjective Perception by Patients Treated for Prostate Cancer with the EORTC QLQ-C30 Questionnaire and QLQ-PR25 Module.

Prostate cancer in men is the second most occurring cancer in Poland and represents approximately 13.2 % of all cancers. At the same time, it is the third largest cause of death in men, being responsible for approximately 8 % of deaths. The study was conducted among patients of Oncological Hospital in Wieliszew. The study included 83 men diagnosed with prostate cancer at the age of 51-84 years. The patients gave their written consent to participate in the study, to which the overall standardized questionnaires EORTC QLQ-C30 and QLQ-PR25 for patients with prostate cancer was applied. Significant deterioration of the state of health due to cancer was indicated by a total of 10.84 % of patients. At the same time, it was found that although there are differences between quality of life in various age groups of respondents, they are statistically insignificant (Chi2 = 59.96; p = 0.00734; R = 0.09; p > 0.05). Subjective QoL did not depend on the stage of cancer treatment, type of therapy, or significant deterioration in the patient's state of health in the last stage of disease. Both disease and therapy have impact on quality of life in all its dimensions, in particular as regards the patient's physical functioning and his frequent fatigue. There is a strong relationship between a patient's subjective assessment of quality of life and pain that significantly hampers everyday activities. This demonstrates the need for continuous monitoring and relieving pain directly associated with cancer and methods of its treatment.

[Professional activity of people with epilepsy]. / Aktywnosc zawodowa chorych na padaczke.

BACKGROUND: The aim of the study was to determine the occupational activity of epileptic patients. Particular attention was paid to employment of people with epilepsy, the way the workplace is informed about the disease, impact of education on employment opportunities and the relationship between clinical type of epilepsy and professional activity. MATERIAL AND METHODS: Patients were recruited from the neurological outpatient clinic in Warszawa and asked to fill in a customized questionnaire, containing questions on their socio-demographic, clinical and employment status. RESULTS: The study included 197 adult patients with epilepsy (64 professionally active and 133 inactive). As many as 47.7% of respondents declared that the disease impeded their employment, and 77.2% admitted that the occurrence of seizure at work had negatively affected their comfort. As many as 42.2% professionally active respondents had revealed the disease at work. There was a statistically significant difference between individuals with primarily generalized seizures and those with partial and secondarily generalized seizures (30.61% vs. 2.63%, p<0.05). Education had also a significant positive impact on employment (47.06% employed with university degree vs. 9.76% with primary education, p<0.05). No significant correlations between duration of the disease or number of the epileptic seizures, independent of their type and revealing the disease in the workplace, were observed (p>0.05). Neither current work status had impact on opinions about difficulties in finding a job (p>0.05). CONCLUSIONS: Epilepsy is a great obstacle to finding and maintaining employment. Less than 1/2 of patients inform the workplace about their illness, mainly due to previous negative experiences. Since education significantly enables the employment, programs aimed at promoting vocational activation of patients should facilitate access to learning.

Quality of Life of Residents in Seniors' Homes in Poland and Germany.

BACKGROUND: Homes for the elderly and care facilities are not only a place of treatment, but also a place of permanent residence for older people. It is assumed that older adults' quality of life in the centres may not be sufficient for their long well-being. The purpose of this study was to determine the level of quality of life among nursing home residents in Poland and Germany and the impact of disability on functioning in their major life domains. MATERIAL AND METHODS: This study was carried out using the WHOQOL-BREF questionnaire (abridged version) on 1000 people-500 residents of the centre in Poland and 500 residents in Germany. RESULTS: The quality of life of Polish and German residents is at an average level and is closely related to their degree of independence. People with greater independence assessed their quality of life higher. CONCLUSION: The degree of disability affects one's own health and the quality of life of the residents. Therefore, to improve older adults' quality of life, certain steps should be taken, including supporting them in maintaining their health and independence on a daily basis.

Opinions of Medical Staff Regarding Antibiotic Resistance.

INTRODUCTION: Antibiotic resistance poses a significant threat to public health, that can lead to reduced effectiveness of many therapies, increased morbidity, longer hospitalization times, increased deaths, and additional costs for health care systems. Unreasonable use of antibiotics may result from a lack of adequate knowledge about antibiotic therapy and a lack of knowledge of the risks associated with antibiotic resistance, both among medical personnel and patients. AIM: The primary objective of the study was to verify the opinion of medical personnel on the risks associated with antibiotic resistance. MATERIAL AND METHODS: The study was conducted in 2023 among 605 Polish sanitary workers. An anonymous survey designed specifically for the purpose of the study was used. The survey was made available on the Internet through the Trade Unions of Pharmacy Workers and directly to hospitals with the support of local authorities. RESULTS: The majority of respondents were women (77.36%). The largest group consisted of individuals over 40 years of age (55.04%). More than half of the respondents were nurses (56.20%), and every fourth of the respondents was a physician (23.64%). Most respondents consider antibiotic resistance to be a very serious (24.13%) or extremely serious (30.75%) problem. The problem of antibiotic resistance on a global scale was mentioned, especially in the opinions of physicians and nurses (p < 0.01), people working in the profession for over a year (p < 0.01), and people with a specialization or undergoing specialist training (p = 0.00). Similarly, these groups most often indicated that antibiotic resistance poses a problem in their workplace. The main problems of antibiotic resistance were the use of antibiotics in farm animals (36.69%), the pressure on patients to take antibiotics (38.84%), and the prophylactic use of antibiotics (43.15%). CONCLUSIONS: Medical personnel consider antibiotic resistance a somewhat serious problem, although not all agree in this regard. The risk of antibiotic resistance is much more seriously assessed by physicians and nurses, as well as by people with specializations or undergoing specialization training. Knowledge about antibiotic resistance should be further spread among all groups of medical personnel.

Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1.

PURPOSE: We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models. EXPERIMENTAL DESIGN: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models. Mouse, rat, and monkey were used to assess AZD9574 BBB penetration and rat models were used to evaluate potential hematotoxicity for AZD9574 monotherapy and the TMZ combination. RESULTS: AZD9574 demonstrated PARP1-selectivity in fluorescence anisotropy, PARylation, and PARP-DNA trapping assays and in vivo experiments demonstrated BBB penetration. AZD9574 showed potent single agent efficacy in preclinical models with homologous recombination repair deficiency in vitro and in vivo. In an O6-methylguanine-DNA methyltransferase (MGMT)-methylated orthotopic glioma model, AZD9574 in combination with TMZ was superior in extending the survival of tumor-bearing mice compared with TMZ alone. CONCLUSIONS: The combination of three key features-PARP1 selectivity, PARP1 trapping profile, and high central nervous system penetration in a single molecule-supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anticancer efficacy as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594). See related commentary by Lynce and Lin, p. 1217.

Opinion of Polish Patients with Epilepsy on Generic Medications.

AIM: The majority of medicines used in Poland are generic drugs and substitutions of the originals. The objective of this study was to obtain information on the current knowledge about generic medicines among Polish patients with epilepsy. MATERIAL AND METHODS: The conducted study was based on a self-developed questionnaire. The questionnaire consisted of 26 questions, including the questions regarding the respondents' knowledge about generics, their previous experience, and the factors behind these choices. RESULTS: Overall, 1220 questionnaires were analyzed. Among all patients, 66.4% reportedly had heard about generics. Of these, 61.5% of patients had used generic drugs in the past. A significant proportion of participants had never been recommended to switch to a generic medicine by their healthcare professional (23% physicians and 13.9% pharmacists). Statistically, relevant differences were observed regarding the respondents' kind and level of education, place of residence, and net income per household. CONCLUSIONS: Significant gaps were identified in the knowledge and perceptions among patients regarding generic medicines, especially in relation to their efficacy and safety. Efforts must be directed towards increasing public awareness of generic medicines and there should also be a focus on educating patients about generic medicines.

Sickness Presence among Teachers, Nurses and Private Sector Office Workers.

INTRODUCTION: Sickness presence is used to denote an employee who feels unwell but still attends work, thus avoiding absence. The intention of this paper is to compare sickness presence in a group of the following professions: teachers, nurses and private sector office workers. MATERIAL AND METHODS: For the purpose of this study, a survey based on the original PAPI form (Paper-and-Pen Personal Interview) was carried out. Non-probability sampling, the snowball method (N = 507: teachers n = 174, nurses n = 165 and private sector office workers n = 168), covering the whole of Poland, was adopted. Non-parametric hypotheses were verified using the chi-squared test with a statistical significance α = 0.05. RESULTS: Compared to nurses and private sector office workers, teachers more frequently attended work when sick (p < 0.05). Out of the reported ailments that respondents worked with, teachers more often indicated rhinitis (p < 0.05), sore throat and cough (p < 0.05) and increased temperature (p < 0.05). This may be associated with a threat to the health of individuals in their charge. Teachers commonly complained about joint and bone pain (p < 0.05) and gastrointestinal disorders (p < 0.05). Contrary to nurses and private sector office workers, teachers did not point to 'lack of a replacement' as the reason for their presence at work when sick (p < 0.05). Exclusively, teachers added financial issues and difficulties in access to healthcare if they are working fewer hours to the list of reasons for attending work when sick. CONCLUSIONS: Results suggest that there is a need for further studies on the presence of sick employees in the workplace, especially for teachers. The sickness presence of teachers and nurses may be a threat from a public health perspective. The workplace itself is a significant place to prevent many diseases.

Compassion Fatigue and Perceived Social Support among Polish Nurses.

BACKGROUND: Social support has a vital role in preventing traumatic stress in nurses. Nurses are regularly exposed to contact with violence, suffering, and death. The situation worsened during the pandemic because they were also faced with the possibility of infection SARS-CoV-2 and death from COVID-19. Many nurses are faced with increased pressure, stress, and other adverse effects on their mental health. The study aimed to measure the relationship between compassion fatigue and perceived social support in polish nurses. METHODS: The study was conducted on 862 professionally active nurses in Poland using the CAWI method (Computer-Assisted Web Interview). The professional Quality of Life scale (ProQOL) and the Multidimensional Scale of Perceived Social Support (MSPSS) were used for collecting the data. StatSoft, Inc. (2014) was used for data analysis. For comparisons between the groups: Mann-Whitney U test, ANOVA Kruskal-Wallis test, and multiple comparisons (post-hoc). The relationships between variables were tested using Spearman's rho, Tau Kendall, and the chi-square test. RESULTS: The research showed the presence of compassion satisfaction, compassion fatigue, and burnout in the group of Polish hospital nurses. A higher level of perceived social support was associated with lower compassion fatigue (r = -0.35; p < 0.001). A higher level of social support was associated with higher job satisfaction (r = 0.40; p < 0.001). The study also found that a higher level of social support was associated with a lower risk of burnout (r = -0.41; p < 0.001). CONCLUSIONS: Preventing compassion fatigue and burnout should be a priority for healthcare managers. Notably, an essential predictor of compassion fatigue is that Polish nurses often work overtime. It is necessary to pay more attention to the crucial role of social support in preventing compassion fatigue and burnout.

The PARP1 Inhibitor AZD5305 Impairs Ovarian Adenocarcinoma Progression and Visceral Metastases in Patient-derived Xenografts Alone and in Combination with Carboplatin.

PARP inhibitors (PARPi) have changed the management of patients with ovarian cancer and their effectiveness has been demonstrated especially in homologous recombination repair-deficient tumors. These first-generation drugs target PARP1, but also PARP2 and other family members potentially responsible for adverse effects that limit their therapeutic potential and restrict their use in combination with chemotherapeutic agents. We investigated ovarian cancer patient-derived xenografts (OC-PDXs) to assess whether malignant progression could be impaired by a novel inhibitor selective for PARP1 (AZD5305) and to assess the potential of its combination with carboplatin (CPT), the standard-of-care for patients with ovarian cancer. In BRCA-mutated OC-PDXs, AZD5305 achieved greater tumor regressions and longer duration of response as well as a superior impairment of visceral metastasis and improved survival benefit compared with the first-generation dual PARP1/2 inhibitors. The combination of AZD5305 plus CPT was more efficacious than single agents. Subcutaneously growing tumors experienced regression that persisted after therapy stopped. Combination efficacy was greater against tumors that did not respond well to platinum, even at a dose at which AZD5305 monotherapy was ineffective. The combination therapy impaired metastatic dissemination and significantly prolonged the lifespan of mice bearing OC-PDXs in their abdomen. This combination benefit was evident even when CPT was used at suboptimal doses, and was superior to full-dose platinum treatment. These preclinical studies demonstrate that the PARP1-selective inhibitor AZD5305 retains and improves the therapeutic benefit of the first-generation PARPi, providing an opportunity to maximize benefits for this class of anticancer agents. Significance: Selective PARP1i AZD5305 can exceed the efficacy of first-generation PARPi, which target both PARP1 and PARP2, and potentiates the efficacy of CPT when given in combination. AZD5305 alone or in combination with platinum delayed visceral metastasis, ultimately extending the lifespan of OC-PDX-bearing mice. These preclinical models mimic the progression of the disease occurring in patients after debulking surgery, and are translationally relevant.

Mixed effects modeling of radiotherapy in combination with immune checkpoint blockade or inhibitors of the DNA damage response pathway.

Dosage optimization to maximize efficacy and minimize toxicity is a potential issue when administering radiotherapy (RT) in combination with immune checkpoint blockade (ICB) or inhibitors of the DNA Damage Response Pathway (DDRi) in the clinic. Preclinical models and mathematical modeling can help identify ideal dosage schedules to observe beneficial effects of a tri-therapy. The aim of this study is to describe a mathematical model to capture the impact of RT in combination with inhibitors of the DNA Damage Response Pathway or blockade of the immune checkpoint protein - programmed death ligand 1 (PD-L1). This model describes how RT mediated activation of antigen presenting cells can induce an increase in cytolytic T cells capable of targeting tumor cells, and how combination drugs can potentiate the immune response by inhibiting the rate of T cell exhaustion. The model was fitted using preclinical data, where MC38 tumors were treated in vivo with RT alone or in combination with anti-PD-L1 as well as with either olaparib or the ataxia telangiectasia mutated (ATM) inhibitor-AZD0156. The model successfully described the observed data and goodness-of-fit, using visual predictive checks also confirmed a successful internal model validation for each treatment modality. The results demonstrated that the anti-PD-L1 effect in combination with RT was maximal in vivo and any additional benefit of DDRi at the given dosage and schedule used was undetectable. Model fit results indicated AZD0156 to be a more potent DDRi than olaparib. Simulations of alternative doses indicated that reducing efficacy of anti-PD-L1 by 68% would potentially provide evidence for a benefit of ATM inhibition in combination with ICB and increase the relative efficacy of tri-therapy.

Design and Preclinical Evaluation of a Novel B7-H4-Directed Antibody-Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305.

PURPOSE: We evaluated the activity of AZD8205, a B7-H4-directed antibody-drug conjugate (ADC) bearing a novel topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models. EXPERIMENTAL DESIGN: IHC and deep-learning-based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly-Gly-Phe-Gly peptide linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies. AZD8205 mechanism of action and efficacy studies were conducted in human cancer cell line and patient-derived xenograft (PDX) models. RESULTS: Evaluation of IHC-staining density on a per-cell basis revealed a range of heterogeneous B7-H4 expression across patient tumors. This informed selection of bystander-capable Val-Ala-PEG8-TOP1i payload AZ14170133 and development of AZD8205, which demonstrated improved stability, efficacy, and safety compared with other linker-payload ADCs. In a study of 26 PDX tumors, single administration of 3.5 mg/kg AZD8205 provided a 69% overall response rate, according to modified RECIST criteria, which correlated with homologous recombination repair (HRR) deficiency (HRD) and elevated levels of B7-H4 in HRR-proficient models. Addition of AZD5305 sensitized very low B7-H4-expressing tumors to AZD8205 treatment, independent of HRD status and in models representing clinically relevant mechanisms of PARPi resistance. CONCLUSIONS: These data provide evidence for the potential utility of AZD8205 for treatment of B7-H4-expressing tumors and support the rationale for an ongoing phase 1 clinical study (NCT05123482). See related commentary by Pommier and Thomas, p. 991.

Suicide Attempts and Suicides as a Result of Poisoning and under the Influence of Xenobiotics in Poland in 1999-2020.

BACKGROUND: The most common method of suicide in Poland is hanging, especially among men. However, women tend to overdose on medications to commit suicide. Considering suicide attempts, poisoning, which involves overdosing various substances, is the most commonly used method. The purpose of the present study was to analyze suicide attempts by intoxication, suicides, and substances that influenced the state of consciousness of suicide victims in Poland in the years covered by the study. METHODS: A descriptive analysis was made based on the data obtained from the registers of the General Police Headquarters of Poland and the Statistics Poland for the years 1999-2020. RESULTS: During the 21-year study period, 161,655 cases of suicide attempts were recorded in Poland, 106,169 of which resulted in suicides. Results showed that out of 14,660 self-poisoning suicide attempts, there were 2258 cases of suicide poisoning deaths in the analyzed study period. According to the data of the General Police Headquarters of Poland, the total number of suicides of all causes was 106,169. Self-poisoning suicides accounted for 2.1% of all cases of suicides. CONCLUSION: Due to the distribution of suicide registration systems in Poland, data available in this area should be interpreted with caution.

Coping with Stress in Neoplastic Diseases.

Introduction: Disease-related stress is a common phenomenon. It also occurs in neoplastic diseases. Since physical and mental health are interrelated, it is important to make sure that treatment covers these two areas. Therefore, it is essential to learn how patients with neoplastic diseases can cope with stress. Materials and Methods: The respondents are 306 patients suffering from neoplastic diseases, associated in patient advocacy groups. The method is the Brief-COPE (Coping Orientation to Problems Experienced) questionnaire. Results: The following stress management strategies were most commonly adopted by the patients: acceptance (median 2.25; 25−75% IQR 2.0−3.0), active coping (median 2.0; 25−75% IQR (interquartile range) 1.5−2.0), planning (median 2.0; 25−75% IQR 2.0−2.0), emotional support (median 2.0; 25−75% IQR 1.5−2.0), instrumental support (median 2.0; 25−75% IQR 2.0−2.0), self-distraction (median 2.0; 25−75% IQR 1.5−3.0), and venting (median 2.0; 25−75% IQR 1.5−3.0). A decision to adopt a particular stress management strategy by patients with neoplastic diseases was highly affected by demographic factors (p < 0.05), such as sex, education, age, place of residence and employment. Conclusions: Teaching stress management strategies should be a part of the education process among patients with neoplastic diseases. Before or in the course of treatment, an oncology patient should be educated on the prevention of mental health disorders. The ability to cope with stress is one of the key competences for the course of neoplastic diseases and it can affect the treatment process. Stress management in chronic diseases, including neoplastic diseases, should be approached not only at the level of an individual person but also at the level of the health system as a whole.

The Influence of Time of Day of Vaccination with BNT162b2 on the Adverse Drug Reactions and Efficacy of Humoral Response against SARS-CoV-2 in an Observational Study of Young Adults.

An increasing body of evidence from both academic and clinical studies shows that time-of-day exposure to antigens might significantly alter and modulate the development of adaptive immune responses. Considering the immense impact of the COVID-19 pandemic on global health and the diminished efficacy of vaccination in selected populations, such as older and immunocompromised patients, it is critical to search for the most optimal conditions for mounting immune responses against SARS-CoV-2. Hence, we conducted an observational study on 435 healthy young adults vaccinated with two doses of BNT162b2 (Pfizer-BioNTech) vaccine to determine whether time-of-day of vaccination influences either the magnitude of humoral response or number of adverse drug reactions (ADR) being reported. We found no significant differences between morning and afternoon vaccination in terms of both titers of anti-Spike antibodies and frequency of ADR in the studied population. In addition, our analysis of data on the occurrence of ADR in 1324 subjects demonstrated that the second administration of vaccine in those with previous SARS-CoV-2 infection was associated with lower incidence of ADR. In aggregate, vaccination against COVID-19 with two doses of BNT162b2 mRNA vaccine is presumed to generate an equally efficient anti-Spike humoral response.