Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}--methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor.

PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper.

Advancing Pharmaceutical Care in Community Pharmacies in Poland: A Blueprint for Enhanced Patient Care Quality.

: This article reviews the current state of pharmaceutical care in community pharmacies in Poland and proposes a collaborative framework for its advancement. While pharmaceutical care has evolved significantly worldwide, with Europe leading the way, Poland has lagged in its development. Although Polish pharmacists are well-qualified and community pharmacies are numerous, pharmaceutical care remains underdeveloped.

The PARP1 selective inhibitor saruparib (AZD5305) elicits potent and durable antitumor activity in patient-derived BRCA1/2-associated cancer models.

Background: Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors.

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.

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.

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.

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.

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

Unlabelled: 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.

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.

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 () was carried out.

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.

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.

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.

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 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.

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.

Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}--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.

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.

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.

Patients with epilepsy as drivers in Poland.

Background: Drivers suffering from epilepsy are commonly regarded as a threat to road safety. However, inability to use their own means of transport very often implies specific professional effects and lowers the quality of life. The aim of this study was to analyze the driving status of patients with epilepsy in Poland.