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.

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 both 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 HRR-deficiency (HRD) 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 to TMZ alone. CONCLUSIONS: The combination of three key features - PARP1 selectivity, PARP1 trapping profile, and high CNS 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 anti-cancer efficacy both as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594).

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.

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.

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.

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.

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.

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.

AKT-mTORC1 reactivation is the dominant resistance driver for PI3Kß/AKT inhibitors in PTEN-null breast cancer and can be overcome by combining with Mcl-1 inhibitors.

The PI3K pathway is commonly activated in breast cancer, with PI3K-AKT pathway inhibitors used clinically. However, mechanisms that limit or enhance the therapeutic effects of PI3K-AKT inhibitors are poorly understood at a genome-wide level. Parallel CRISPR screens in 3 PTEN-null breast cancer cell lines identified genes mediating resistance to capivasertib (AKT inhibitor) and AZD8186 (PI3Kß inhibitor). The dominant mechanism causing resistance is reactivated PI3K-AKT-mTOR signalling, but not other canonical signalling pathways. Deletion of TSC1/2 conferred resistance to PI3Kßi and AKTi through mTORC1. However, deletion of PIK3R2 and INPPL1 drove specific PI3Kßi resistance through AKT. Conversely deletion of PIK3CA, ERBB2, ERBB3 increased PI3Kßi sensitivity while modulation of RRAGC, LAMTOR1, LAMTOR4 increased AKTi sensitivity. Significantly, we found that Mcl-1 loss enhanced response through rapid apoptosis induction with AKTi and PI3Kßi in both sensitive and drug resistant TSC1/2 null cells. The combination effect was BAK but not BAX dependent. The Mcl-1i + PI3Kß/AKTi combination was effective across a panel of breast cancer cell lines with PIK3CA and PTEN mutations, and delivered increased anti-tumor benefit in vivo. This study demonstrates that different resistance drivers to PI3Kßi and AKTi converge to reactivate PI3K-AKT or mTOR signalling and combined inhibition of Mcl-1 and PI3K-AKT has potential as a treatment strategy for PI3Kßi/AKTi sensitive and resistant breast tumours.

Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper.

PURPOSE: We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide a paradigm shift in clinical outcomes achieved by first-generation PARPi, particularly in combination. EXPERIMENTAL DESIGN: AZD5305 was tested in vitro for PARylation inhibition, PARP-DNA trapping, and antiproliferative abilities. In vivo efficacy was determined in mouse xenograft and PDX models. The potential for hematologic toxicity was evaluated in rat models, as monotherapy and combination. RESULTS: AZD5305 is a highly potent and selective inhibitor of PARP1 with 500-fold selectivity for PARP1 over PARP2. AZD5305 inhibits growth in cells with deficiencies in DNA repair, with minimal/no effects in other cells. Unlike first-generation PARPi, AZD5305 has minimal effects on hematologic parameters in a rat pre-clinical model at predicted clinically efficacious exposures. Animal models treated with AZD5305 at doses ≥0.1 mg/kg once daily achieved greater depth of tumor regression compared to olaparib 100 mg/kg once daily, and longer duration of response. CONCLUSIONS: AZD5305 potently and selectively inhibits PARP1 resulting in excellent antiproliferative activity and unprecedented selectivity for DNA repair deficient versus proficient cells. These data confirm the hypothesis that targeting only PARP1 can retain the therapeutic benefit of nonselective PARPi, while reducing potential for hematotoxicity. AZD5305 is currently in phase I trials (NCT04644068).

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.

PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors.

PARP inhibitors are synthetically lethal with BRCA1/2 mutations, and in this setting, accumulation of DNA damage leads to cell death. Because increased DNA damage and subsequent immune activation can prime an anti-tumor immune response, we studied the impact of olaparib ± immune checkpoint blockade (ICB) on anti-tumor activity and the immune microenvironment. Concurrent combination of olaparib, at clinically relevant exposures, with ICB gave durable and deeper anti-tumor activity in the Brca1m BR5 model vs. monotherapies. Olaparib and combination treatment modulated the immune microenvironment, including increases in CD8+ T cells and NK cells, and upregulation of immune pathways, including type I IFN and STING signaling. Olaparib also induced a dose-dependent upregulation of immune pathways, including JAK/STAT, STING and type I IFN, in the tumor cell compartment of a BRCA1m (HBCx-10) but not a BRCA WT (HBCx-9) breast PDX model. In vitro, olaparib induced BRCAm tumor cell-specific dendritic cell transactivation. Relevance to human disease was assessed using patient samples from the MEDIOLA (NCT02734004) trial, which showed increased type I IFN, STING, and JAK/STAT pathway expression following olaparib treatment, in line with preclinical findings. These data together provide evidence for a mechanism and schedule underpinning potential benefit of ICB combination with olaparib.

A Comparative Analysis of Quality of Life in Women Diagnosed with Breast and Ovarian Cancer.

Background: Previous studies showed that cancer significantly reduces the quality of life of patients. The purpose of this study was to analyze changes in the quality of life of women diagnosed with ovarian and breast cancer after surgical treatment followed by adjuvant cancer therapy. Methods: The study covered 220 women diagnosed with ovarian (n = 89) or breast cancer (n = 131) after surgical treatment followed by adjuvant cancer therapy (chemotherapy, radiotherapy, hormone therapy). The tools used to measure the patients' quality of life were the standardized EORTC QLQ-C30 questionnaire, the QLQ-BR23 module for breast cancer and the QLQ-OV28 module for ovarian cancer. Results: The subjective assessment of the health and quality of life of the women was carried out using the EORTC QLQ-C30 questionnaire and the QLQ-OV28 and QLQ-BR23 modules. Women with breast cancer rated their health higher than women with ovarian cancer. The health assessment performed by the patients was not related to the type of cancer (p > 0.05). They experienced pain, dyspnea and weakness regardless of the cancer location. Moreover, women's health status had a clinically significant impact on their family and social life, although no statistically significant differences were found between the two groups (p > 0.05). Whilst the patients with breast cancer rated their quality of life and health higher than the patients with ovarian cancer, the differences were not statistically significant (p > 0.05). Conclusions: Changes in the quality of life of women with breast and ovarian cancer concern the physical sphere, hobbies, fatigue/rest, pain, family and social spheres, and material conditions. It is necessary to support specialists at every stage of treatment of these patients, which may improve the results of the treatment and patients' perception of health and quality of life.

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.

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.

Willingness to Oppose Smoking among Pregnant Women.

Even though smoking causes numerous threats to the developing foetus, it is the most common addiction in Polish women of reproductive age. Most studies undertake to examine the subject of opposing second-hand smoking or creating tools to reprimand pregnant women more effectively using a qualitative methodology. The study aimed to determine the profile of a pregnant woman who is willing to oppose the smoking of another pregnant woman. The research was conducted using an original multiple-choice questionnaire. The survey was shared on websites for expecting parents. Completed questionnaires were collected from 11,448 pregnant women. The Wald test for logistic regression was used for statistical analysis. Predictors of whether someone would draw another pregnant women's attention to the fact that smoking is harmful were: intellectual work (OR 1.136; p-value 0.020) and currently being a student (OR 1.363; p-value 0.004), involvement of the child's father (OR 1.377; p-value < 0.001), contact with social campaigns (OR 1.150; p-value 0.005) and knowledge about the consequences of smoking, as well as talking to the midwife about the harmfulness of cigarettes during pregnancy (OR 1.655; p-value < 0.001). Interpersonal relationships leave scope for public health interventions. It is worth enhancing criticism against smoking by specialists through information and education campaigns.

Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs.

Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.

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.

Dyslipidaemia, carbohydrate metabolism disorders and arterial hypertension detected in academic employees during examinations in occupational medicine.

INTRODUCTION: Many people have CVD risk factors without realising it and it is important to recognise the risk factors as soon as possible. Periodic examinations are a mandatory form of control for all employes in Poland. They provide an excellent opportunity to screen for the most common civilization diseases in the population. OBJECTIVE: The aim of this study is to evaluate the prevalence of dyslipidaemia, hyperglycaemia and hypertension among academics in a Polish university, and to compare the results between postdoctoral fellows and other academics. MATERIAL AND METHODS: The study group were postdoctoral fellows (HAB; N=135, 53 females) and other academics (NHAB; N=286, 179 females) over the age of 40 who reported for a periodic occupational medical check-up. Fasting blood samples were drawn, serum glucose, lipids and blood pressure (BP) were measured. RESULTS: The mean age was 56.7 (SD 9.8) in HAB and 49.8 (SD 8.1) in NHAB. Mean systolic BP and glycaemia were significantly higher in male HAB group than male NHAB (135.8 vs 130.9 mmHg and 6.0 vs 5.6 mmol/l, respectively). The relationship in females was non-significant. The age-adjusted odds ratios (OR [95% CI]) of having elevated low density lipoprotein cholesterol, total cholesterol, glucose and blood pressure in male HAB vs male NHAB were 0.61 [0.32. 1.16], 0.64 [0.33, 1.23], 1.52 [0.80, 2.88] and 2.11 [0.88, 5.23], and in female HAB vs female NHAB - 0.59 [0.31, 1.12], 0.64 [0.32, 1.26], 0.87 [0.40, 1.79] and 1.86 [0.70, 4.68], respectively. CONCLUSIONS: Adequately planned occupational medicine examinations provide an opportunity to diagnose dyslipidaemia, hyperglycaemia, or high BP in all groups of employees, including highly educated academics.