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Despite decades of progress in providing breast cancer patients with the most effective treatment methods, successful management of triple-negative subtype of this neoplasm remains an unmet need of oncology. Molecular heterogeneity, immunological evasion mechanisms and genomic instability all contribute to this cancer’s troubling picture. Nevertheless, there have been substantial advances in exploration of the molecular landscape and innovative therapy of this entity. Discovery of molecular subtypes of triple-negative breast cancer has led to better understanding of the pathophysiological basis of the disease and gives hope for highly demanded personalized therapies. Work on targeted treatments is underway, including anti-Trop-2 antibodies, as well as PARP and PD-1/PD-L1 inhibitors. Efficacy of these drugs often relies on the presence of specific molecular targets; therefore there is a need for fast, affordable, and widely available molecular analysis methods. There is still a long road ahead, but with each discovery researchers are getting closer to making the diagnosis of triple-negative breast cancer less dire for the patient, with more effective tools at hand for the therapeutic team.

Abstract Despite the introduction of new molecular classifications, advanced colorectal cancer (CRC) is treated with chemotherapy supplemented with anti-EGFR and anti-VEGF targeted therapy. In this study, 552 CRC cases with different primary tumor locations (250 left side, 190 rectum, and 112 right side) were retrospectively analyzed by next generation sequencing for mutations in 50 genes. The most frequently mutated genes were TP53 in left-sided tumors compared to right-sided tumors and BRAF in right-sided tumors compared to left-sided tumors. Mutations in KRAS, NRAS, and BRAF were not detected in 45% of patients with left-sided tumors and in 28.6% of patients with right-sided tumors. Liver metastases were more common in patients with left-sided tumors. Tumors on the right side were larger at diagnosis and had a higher grade (G3) than tumors on the left. Rectal tumors exhibit distinctive biological characteristics when compared to left-sided tumors, including a higher absence rate of KRAS, NRAS, and BRAF mutations (47.4% in rectal versus 42.8% in left-sided tumors). These rectal tumors are also unique in their primary metastasis site, which is predominantly the lungs, and they have varying mutation rates, particularly in genes such as BRAF, FBXW7, and TP53, that distinguish them from tumors found in other locations. Primary tumor location has implications for the potential treatment of CRC with anti-EGFR therapy.

Szczepan Kaliniak,1 Krzysztof Fiedoruk,2 Jakub Spałek,1,3 Ewelina Piktel,2 Bonita Durnaś,1,3 Stanisław Góźdź,1,3 Robert Bucki,2,3 Sławomir Okła1,3 1Holy-Cross Cancer Center, Kielce, Poland; 2Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Białystok, Poland; 3Institute of Medical Science, Collegium Medicum, Jan Kochanowski University of Kielce, Kielce, 25-317, PolandCorrespondence: Sławomir Okła, Department of Otolaryngology, Head and Neck Surgery, Holy-Cross Cancer Center, Kielce, 25-734, Poland, Tel/Fax +48 41 367 43 36, Email laryngologsco@gmail.comAbstract: Rhinosinusitis (RS) is an acute (ARS) or chronic (CRS) inflammatory disease of the nasal and paranasal sinus mucosa. CRS is a heterogeneous condition characterized by distinct inflammatory patterns (endotypes) and phenotypes associated with the presence (CRSwNP) or absence (CRSsNP) of nasal polyps. Mucosal barrier and mucociliary clearance dysfunction, inflammatory cell infiltration, mucus hypersecretion, and tissue remodeling are the hallmarks of CRS. However, the underlying factors, their priority, and the mechanisms of inflammatory responses remain unclear. Several hypotheses have been proposed that link CRS etiology and pathogenesis with host (eg, “immune barrier”) and exogenous factors (eg, bacterial/fungal pathogens, dysbiotic microbiota/biofilms, or staphylococcal superantigens). The abnormal interplay between these factors is likely central to the pathophysiology of CRS by triggering compensatory immune responses. Here, we discuss the role of the sinonasal microbiota in CRS and its biofilms in the context of mucosal zinc (Zn) deficiency, serving as a possible unifying link between five host and “bacterial” hypotheses of CRS that lead to sinus mucosa remodeling. To date, no clear correlation between sinonasal microbiota and CRS has been established. However, the predominance of Corynebacteria and Staphylococci and their interspecies relationships likely play a vital role in the formation of the CRS-associated microbiota. Zn-mediated “nutritional immunity”, exerted via calprotectin, alongside the dysregulation of Zn-dependent cellular processes, could be a crucial microbiota-shaping factor in CRS. Similar to cystic fibrosis (CF), the role of SPLUNC1-mediated regulation of mucus volume and pH in CRS has been considered. We complement the biofilms’ “mechanistic” and “mucin” hypotheses behind CRS pathogenesis with the “structural” one – associated with bacterial “corncob” structures. Finally, microbiota restoration approaches for CRS prevention and treatment are reviewed, including pre- and probiotics, as well as Nasal Microbiota Transplantation (NMT).Keywords: rhinosinusitis, chronic rhinosinusitis, nasal polyps, rhinosinusitis pathophysiology, rhinosinusitis pathophysiology, microbiota, nutritional immunity

Abstract We quantize the Oppenheimer–Snyder model of black holes using the integral quantization method. We treat spatial and temporal coordinates on the same footing at both the classical and quantum levels. Our quantization resolves or smears the singularities of the classical curvature invariants. Quantum trajectories with bounces can replace singular classical trajectories. The considered quantum black hole may have finite bouncing time. As a by-product, we obtain the resolution of the gravitational singularity of the Schwarzschild black hole at the quantum level.

Abstract Aims In recent years, survival in patients with breast cancer has increased. Despite the improvement in outcomes of those patients, the risk of treatment‐related cardiotoxicity remains high, and its presence has been associated with a higher risk of treatment termination and thus lower therapeutic efficacy. Prior trials demonstrated that a preventive initiation of heart failure drugs, including the renin–angiotensin–aldosterone inhibitors, might reduce the risk of treatment‐related cardiotoxicity. However, to date, no study investigated the efficacy of sacubitril/valsartan, a novel antineurohormonal drug shown to be superior to the previous therapies, in the prevention of cardiotoxicity in patients with early‐stage breast cancer, which is the aim of the trial. Methods and results MAINSTREAM is a randomized, placebo‐controlled, double‐blind, multicentre, clinical trial. After the run‐in period, a total of 480 patients with early breast cancer undergoing treatment with anthracyclines and/or anti‐human epidermal growth factor receptor 2 drugs will be randomized to the highest tolerated dose of sacubitril/valsartan, being preferably 97/103 mg twice daily or placebo in 1:1 ratio. The patients will be monitored, including routine transthoracic echocardiography (TTE) and laboratory biomarker monitoring, for 24 months. The primary endpoint of the trial will be the occurrence of a decrease in left ventricular ejection fraction by ≥5% in TTE within 24 months. The key secondary endpoints will be the composite endpoint of death from any cause or hospitalization for heart failure, as well as other imaging, laboratory, and clinical outcomes, including the occurrence of the cancer therapy‐related cardiac dysfunction resulting in the necessity to initiate treatment. The first patients are expected to be recruited in the coming months, and the estimated completion of the study and publication of the results are expected in December 2027, pending recruitment. Conclusions The MAINSTREAM trial will determine the efficacy and safety of treatment with sacubitril/valsartan as a prevention of cardiotoxicity in patients with early breast cancer (ClinicalTrials.gov number: NCT05465031).

Adsorption of nanoparticles on a spherical colloidal particle is studied by molecular dynamics simulations. We consider a generic model for a mixture of nanoparticles with energetically favored self-assembly into alternating layers of the two components. When both components are attracted to the colloidal particle, the adsorbed nanoparticles self-assemble either into alternating parallel tori and clusters at the two poles of the colloidal particle, or into alternating spirals wrapped around the spherical surface. The long-lived metastable states obtained in simulations follow from the spherical shape of the adsorbing surface and the requirement that the neighboring chains of the nanoparticles are composed of different components. A geometrical construction leading to all such patterns is presented. When the second component particles are repelled from the colloidal particle and the attraction of the first component is strong, the attracted particles form a monolayer at the surface of the colloidal particle that screens the repulsion of the second component. The subsequent adsorbed alternating spherical layers of the two components form together a thick shell. This structure leads to the adsorption that is larger than in the case of the same attraction of the two components to the colloidal particle.

Using the projection evolution (PEv) approach, time can be included in quantum mechanics as an observable. Having the time operator, it is possible to explore the temporal structure of various quantum events. In the present paper, we discuss the possibility of constructing a quantum clock which advances in time during its quantum evolution, in each step having some probability to localize itself on the time axis in the new position. We propose a working two-state model as the simplest example of such a clock.

Abstract The impact of the intrinsic curvature of in-plane orientationally ordered curved flexible nematic molecules attached to closed 3D flexible shells was studied numerically. A Helfrich-Landau-de Gennes-type mesoscopic approach was adopted where the flexible shell’s curvature field and in-plane nematic field are coupled and concomitantly determined in the process of free energy minimisation. We demonstrate that this coupling has the potential to generate a rich diversity of qualitatively new shapes of closed 3D nematic shells and the corresponding specific in-plane orientational ordering textures, which strongly depend on the shell’s volume-to-surface area ratio, so far not predicted in mesoscopic-type numerical studies of 3D shapes of closed flexible nematic shells.

Abstract Background A causal link between microbiota composition (dysbiosis) and oncogenesis has been demonstrated for several types of cancer. Neutrophils play a role in both immune protection against bacterial threats and carcinogenesis. This study aimed to characterise intratumoral bacteria in vulvar squamous cell carcinoma (VSCC) and their putative effect on neutrophil recruitment and cancer progression. Methods Clinical material was obtained from 89 patients with VSCC. Next-generation sequencing (NGS) of 16S rRNA and quantitative polymerase chain reaction (qPCR) were used to detect bacterial species in VSCC. To verify neutrophil activation, CD66b expression in tumour specimens was analysed by immunohistochemistry (IHC). Subsequently, IHC was applied to detect the main neutrophil serine proteases (NSPs), cathepsin G (CTSG), neutrophil elastase (ELANE), and proteinase 3 (PRTN3) in VSCC. Results Fusobacterium nucleatum and Pseudomonas aeruginosa were identified as tumour-promoting bacteria, and their presence was found to be associated with a shorter time to progression in VSCC patients. Furthermore, high abundance of CD66b, the neutrophil activation marker, in VSCC samples, was found to relate to poor survival of patients with VSCC. The selected NSPs were shown to be expressed in vulvar tumours, also within microabscess. The increased numbers of microabscesess were correlated with poor survival in VSCC patients. Conclusions Our results show that neutrophilic inflammation seem to be permissive for tumour-promoting bacteria growth in VSCC. The findings provide new therapeutic opportunities, such as based on shifting the balance of neutrophil populations to those with antitumorigenic activity and on targeting NSPs produced by activated neutrophils at the inflammation sites.

Celem artykułu jest prezentacja obszarów, w zakresie których warto i należy kształtować kompetencje młodego człowieka. Każdy z obszarów został opisany i przeanalizowany w oparciu o wyniki badań naukowych, które wskazują na wartościowość zaprezentowanych celów wychowania z punktu widzenia rozwoju człowieka i jego efektywnego funkcjonowania w życiu. Człowiek, którego proces wychowania przebiega pomyślnie, to człowiek kompetentny – radzący sobie z życiowymi problemami i wyzwaniami w sposób skuteczny, a także dalekowzroczny.

Abstract We quantize the solution to the Belinski– Khalatnikov–Lifshitz (BKL) scenario using the integral quantization method. Quantization smears the gravitational singularity, preventing its localization in the configuration space. The latter is defined in terms of spatial and temporal coordinates, which are treated on the same footing that enables the respective covariance of general relativity. The relative quantum perturbations grow as the system evolves towards the gravitational singularity. The quantum randomness amplifies the deterministic classical chaos of the BKL scenario. Additionally, our results suggest that the generic singularity of general relativity can be avoided at a quantum level, giving support to the expectation that quantum gravity has a good chance of being a regular theory.

Introduction: Individuals with psychosis spectrum disorders may be negatively affected by exclusion and rejection. It is important to answer “why”? This article presents social representations of schizophrenia in Polish society. Aims: The study’s aim was to examine the properties of the sixty-item questionnaire on attitudes, attribution and beliefs about schizophrenia in the Polish sample and to compare the results with the results obtained in the English-Chinese sample. Methods: The study included 398 participants (aged 19–74); all were working persons. Furnham and Chan created the questionnaire, a tool containing 60 items describing general beliefs about schizophrenia, causal explanations in the etiology of schizophrenia, as well as beliefs about the role of hospitals and society in the treatment of schizophrenia. Factor analysis (PAF) was carried out separately for three parts of the tool. Results: The structure of the questionnaire that was obtained on the Polish sample differs from that obtained on the English-Chinese sample. Some factors remain similar. Reliability analysis based on Cronbach’s Alpha values reached satisfactory levels in most of the factors revealed. Conclusions: The questionnaire is a reliable tool for examining social representations of schizophrenia. The Polish sample does not show punitive inclinations, does not attribute negative traits to schizophrenics, and does not agree to creating social distance.

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is a well-known oncogene with a high prevalence of mutation in breast cancer patients. The effect of the mutation is a deregulation in phosphatidylinositol 3-kinase-related pathways, and, consequently, in unrestricted cell growth and differentiation. With the advent of precision oncology, PIK3CA has emerged as a pivotal treatment target, culminating in the recent approval of alpelisib. Despite years of research on this genetic alteration, certain aspects of its influence on the prognosis of breast cancer remain ambiguous. The purpose of this analysis is to characterize the clinical picture of breast cancer patients with PIK3CA mutation in comparison to the PIK3CA-wild-type group. We examined 103 tumor samples from 100 breast cancer patients using a next-generation sequencing panel. Presence of the mutation was linked to an older age at diagnosis, a lower expression of Ki67 protein, a greater percentage of tumors expressing progesterone receptors, and a notably higher incidence of metastatic disease at presentation. No significant differences were identified in overall and progression-free survival between the two groups. Our findings enhance the understanding of how PIK3CA mutations shape the clinical and prognostic landscape for breast cancer patients.