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DNA repair proteins became the popular targets in research on cancer treatment. In our studies we hypothesized that inhibition of DNA polymerase theta (Polθ) and its combination with Poly (ADP-ribose) polymerase 1 (PARP1) or RAD52 inhibition and the alkylating drug temozolomide (TMZ) has an anticancer effect on glioblastoma cells (GBM21), whereas it has a low impact on normal human astrocytes (NHA). The effect of the compounds was assessed by analysis of cell viability, apoptosis, proliferation, DNA damage and cell cycle distribution, as well as gene expression. The main results show that Polθ inhibition causes a significant decrease in glioblastoma cell viability. It induces apoptosis, which is accompanied by a reduction in cell proliferation and DNA damage. Moreover, the effect was stronger when dual inhibition of Polθ with PARP1 or RAD52 was applied, and it is further enhanced by addition of TMZ. The impact on normal cells is much lower, especially when considering cell viability and DNA damage. In conclusion, we would like to highlight that Polθ inhibition used in combination with PARP1 or RAD52 inhibition has great potential to kill glioblastoma cells, and shows a synthetic lethal effect, while sparing normal astrocytes.

The inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in cancer, leading to cancer initiation and progression. Additionally, the use of a histone deacetylase inhibitor (HDACi) such as the class I HDAC inhibitor-valproic acid (VPA) has been shown to enhance the effectiveness of DNA-damaging factors, such as cisplatin or radiation. In this study, we found that the use of VPA in combination with talazoparib (BMN-673-PARP1 inhibitor-PARPi) and/or Dacarbazine (DTIC-alkylating agent) resulted in an increased rate of DNA double strand breaks (DSBs) and reduced survival (while not affecting primary melanocytes) and the proliferation of melanoma cells. Furthermore, the pharmacological inhibition of class I HDACs sensitizes melanoma cells to apoptosis following exposure to DTIC and BMN-673. In addition, the inhibition of HDACs causes the sensitization of melanoma cells to DTIV and BMN-673 in melanoma xenografts in vivo. At the mRNA and protein level, the histone deacetylase inhibitor downregulated RAD51 and FANCD2. This study aims to demonstrate that combining an HDACi, alkylating agent and PARPi could potentially enhance the treatment of melanoma, which is commonly recognized as being among the most aggressive malignant tumors. The findings presented here point to a scenario in which HDACs, via enhancing the HR-dependent repair of DSBs created during the processing of DNA lesions, are essential nodes in the resistance of malignant melanoma cells to methylating agent-based therapies.

The objective of this meta-analysis was to present transparent data on the morphology of the pituitary gland (PG) using the available data in the literature. The main online medical databases, such as PubMed, Embase, Scopus, and Web of Science, were searched to gather all relevant studies regarding PG morphology. The mean overall volume of the PG was found to be 597.23 mm 3 (SE = 28.81). The mean overall height of the PG was established to be 5.64 mm (SE = 0.11). The mean overall length of the PG was found to be 9.98 mm (SE = 0.26). In the present study, the PG's overall morphology and morphometric features were analyzed. Our results showed that, on average, females from Asia have the highest volume of PG (706.69 mm 3 ), and males from Europe have the lowest (456.42 mm 3 ). These values are crucial to be aware of because they represent the normal average properties of the PG, which may be used as reference points when trying to diagnose potential pathologies of this gland. Furthermore, the present study's results prove how the PG's size decreases with age. The results of the present study may be helpful for physicians, especially surgeons, performing procedures on the PG.

A single-center study was conducted on 120 patients with inherited disorders of primary hemostasis followed at our hematological center. These patients presented a variety of bleeding symptoms; however, they had no definitive diagnosis. Establishing a diagnosis has consequences for the investigation of probands in families and for treatment management; therefore, we aimed to improve the diagnosis rate in these patients by implementing advanced diagnostic methods. According to the accepted international guidelines at the time of study, we investigated platelet morphology, platelet function assay, light-transmission aggregometry, and flow cytometry. Using only these methods, we were unable to make a definitive diagnosis for most of our patients. However, next-generation sequencing (NGS), which was applied in 31 patients, allowed us to establish definitive diagnoses in six cases (variants in ANKRD26 , ITGA2B , and F8 ) and helped us to identify suspected variants ( NBEAL2 , F2 , BLOC1S6 , AP3D1 , GP1BB , ANO6 , CD36 , and ITGB3) and new suspected variants ( GFI1B , FGA , GP1BA , and ITGA2B ) in 11 patients. The role of NGS in patients with suspicious bleeding symptoms is growing and it changes the diagnostic algorithm. The greatest disadvantage of NGS, aside from the cost, is the occurrence of gene variants of uncertain significance.

Malignant peripheral nerve sheath tumors (MPNST) are rare but one of the most aggressive types of cancer. Currently, there are no effective chemotherapy strategies for these malignancies. The inactivation of the neurofibromatosis type I (NF1) gene, followed by loss of TP53, is an early stage in MPNST carcinogenesis. NF1 is a negative regulator of the Ras proteins family, which are key factors in regulating cell growth, homeostasis and survival. Cell cycle dysregulation induces a stress phenotype, such as proteotoxic stress, metabolic stress, and oxidative stress, which should result in cell death. However, in the case of neoplastic cells, we observe not only the avoidance of apoptosis, but also the impact of stress factors on the treatment effectiveness. This review focuses on the pathomechanisms underlying MPNST cells physiology, and discusses the possible ways to develop a successful treatment based on the molecular background of the disease.

The anterior cingulate cortex is considered to play a crucial role in cognitive and affective regulation. However, this area shows a high degree of morphological interindividual variability and asymmetry. It is especially true regarding the paracingulate sulcus and paracingulate gyrus (PCG). Since the reports described in the literature are mainly based on imaging techniques, the goal of this study was to verify the classification of the PCG based on anatomical material. Special attention was given to ambiguous cases. The PCG was absent in 26.4% of specimens. The gyrus was classified as present in 28.3% of cases. The prominent type of the PCG was observed in 37.7% of the total. Occasionally, the gyrus was well-developed and roughly only a few millimeters were missing for classifying the gyrus as prominent, as it ended slightly anterior the level of the VAC. The remaining four cases involved two inconclusive types. We observed that the callosomarginal artery ran within the cingulate sulcus and provided branches that crossed the PCG. Based on Klingler's dissection technique, we observed a close relationship of the PCG with the superior longitudinal fascicle. The awareness of the anatomical variability observed within the brain cortex is an essential starting point for in-depth research.

The present study aims to provide detailed observations on the cavernous segment of the abducens nerve (AN), emphasizing anatomical variations and the relationships between the nerve and the internal carotid plexus. A total of 60 sides underwent gross-anatomical study. Five specimens of the AN were stained using Sihler's method. An additional five specimens were subjected to histological examination. Four types of AN course were observed: a single nerve along its entire course, duplication of the nerve, division into separate rootlets at the point of contact with the cavernous part of the internal carotid artery (ICA), and early-branching before entering the orbit. Due to the relationships between the ICA and internal carotid plexus, the cavernous segment of the AN can be subdivided into a carotid portion located at the point of contact with the posterior vertical segment of the cavernous ICA and a prefissural portion. The carotid portion of the cavernous AN segment is a place of angulation, where the nerve always directly adheres to the ICA. The prefissural portion of the AN, in turn, is the primary site of fiber exchange between the internal carotid plexus and either the AN or the lateral wall of the cavernous sinus.

The inferomedial triangle is one of the two surgical triangles in the paraclival subregion of the skull base. It is delineated by the posterior clinoid process, the dural entrance of the trochlear nerve and the dural entrance of the abducens nerve. The aim of the present article is to describe the anatomical variations within the inferomedial triangle. Measurements of the triangle's borders and area were supplemented by detailed observations of the topographical anatomy and various arrangements of its contents. Nine adult cadaveric heads (18 sides) and 28 sagittal head sections were studied. The mean area of the inferomedial triangle was estimated to be 60.7 mm 2 . The mean lengths of its medial, lateral and superior borders were 16.1 mm, 11.9 mm and 10.4 mm, respectively. The dorsal meningeal artery was identified within the inferomedial triangle in 37 out of 46 sides (80.4%). A well-developed petrosphenoidal ligament of Grüber was identified within the triangle on 36 sides (78.3%). Although some structures were variable, the constant contents of the inferomedial triangle were the posterior petroclinoid dural fold, the upper end of the petroclival suture, the gulfar segment of the abducens nerve and the posterior genu of the intracavernous internal carotid artery.

End-stage kidney disease (ESKD) is a main public health problem, the prevalence of which is continuously increasing worldwide. Due to adverse effects of renal replacement therapies, kidney transplantation seems to be the optimal form of therapy with significantly improved survival, quality of life and diminished overall costs compared with dialysis. However, post-transplant patients frequently suffer from post-transplant diabetes mellitus (PTDM) which an important risk factor for cardiovascular and cardiovascular-related deaths after transplantation. The management of post-transplant diabetes resembles that of diabetes in the general population as it is based on strict glycemic control as well as screening and treatment of common complications. Lifestyle interventions accompanied by the tailoring of immunosuppressive regimen may be of key importance to mitigate PTDM-associated complications in kidney transplant patients. More transplant-specific approach can include the exchange of tacrolimus with an alternative immunosuppressant (cyclosporine or mammalian target of rapamycin (mTOR) inhibitor), the decrease or cessation of corticosteroid therapy and caution in the prescribing of diuretics since they are independently connected with post-transplant diabetes. Early identification of high-risk patients for cardiovascular diseases enables timely introduction of appropriate therapeutic strategy and results in higher survival rates for patients with a transplanted kidney.

To monitor redox state changes and biological mechanisms occurring in mitochondrial cytochromes in cancers improving methods are required. We used Raman spectroscopy and Raman imaging to monitor changes in the redox state of the mitochondrial cytochromes in ex vivo human brain and breast tissues at 532 nm, 633 nm, 785 nm. We identified the oncogenic processes that characterize human infiltrating ductal carcinoma (IDC) and human brain tumors: gliomas; astrocytoma and medulloblastoma based on the quantification of cytochrome redox status by exploiting the resonance-enhancement effect of Raman scattering. We visualized localization of cytochromes by Raman imaging in the breast and brain tissues and analyzed cytochrome c vibrations at 750, 1126, 1337 and 1584 cm -1 as a function of malignancy grade. We found that the concentration of reduced cytochrome c becomes abnormally high in human brain tumors and breast cancers and correlates with the grade of cancer. We showed that Raman imaging provides additional insight into the biology of astrocytomas and breast ductal invasive cancer, which can be used for noninvasive grading, differential diagnosis.

Crystalline and preamorphized isotope multilayers are utilized to investigate the dependence of ion beam mixing in silicon (Si), germanium (Ge), and silicon germanium (SiGe) on the atomic structure of the sample, temperature, ion flux, and electrical doping by the implanted ions. The magnitude of mixing is determined by secondary ion mass spectrometry. Rutherford backscattering spectrometry in channeling geometry, Raman spectroscopy, and transmission electron microscopy provide information about the structural state after ion irradiation. Different temperature regimes with characteristic mixing properties are identified. A disparity in atomic mixing of Si and Ge becomes evident while SiGe shows an intermediate behavior. Overall, atomic mixing increases with temperature, and it is stronger in the amorphous than in the crystalline state. Ion-beam-induced mixing in Ge shows no dependence on doping by the implanted ions. In contrast, a doping effect is found in Si at higher temperature. Molecular dynamics simulations clearly show that ion beam mixing in Ge is mainly determined by the thermal spike mechanism. In the case of Si thermal spike, mixing prevails at low temperature whereas ion beam-induced enhanced self-diffusion dominates the atomic mixing at high temperature. The latter process is attributed to highly mobile Si di-interstitials formed under irradiation and during damage annealing., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.