Polθ Inhibitor (ART558) Demonstrates a Synthetic Lethal Effect with PARP and RAD52 Inhibitors in Glioblastoma Cells.

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.

Microanatomical study of arachnoid granulations and meningeal architecture around Meckel's cave.

Although the microanatomy of Meckel's cave (MC) has been well studied, there are still controversies regarding the meningeal architecture of the space. Moreover, there are only general mentions of the arachnoid granulations near MC in just a few sources. This study is aimed at determining the frequency, location, and anatomical variability of the main clusters of arachnoid granulations around MC. The dissection involved 26 isolated specimens of MC fixed in formalin (neutral buffered, 10%). This number included five freshly harvested specimens examined histologically. Additional paraffin block with MC horizontal section was taken from our neuroanatomical collection. Carefully selected anatomical and histological techniques were applied to assess the complex relationships between the arachnoid granulations and adjacent structures. Arachnoid granulations were found around MC in all specimens with different anatomical variations. The main clusters of arachnoid granulations were close to the trigeminal ganglion and its divisions. The dorsolateral wall of MC was a thick layer formed by interweaving bundles of collagen fibers arranged in various directions. The entire MC was surrounded by a dural sleeve (envelope). This sleeve separated MC from the lateral sellar compartment. At its anterior (rostral) end, it formed a cribriform area pierced by individual fascicles of the trigeminal nerve's primary divisions. The connective tissue forming the sleeve was not only continuous with the epineurium but also shifted to the perineuria surrounding individual nerve fascicles. The meningeal architecture around MC has a complex and multilayer arrangement with a collagenous sleeve closely related to the trigeminal ganglion. Arachnoid granulations are typically found around MC.

Glomangioma in the hand: diagnosis, treatment, and challenges.

INTRODUCTION: In this paper, we have analysed all hand glomangioma cases referred to our clinic in the context of symptoms, time to diagnosis, and the role of surgical resection of the lesion. MATERIAL AND METHODS: We have collected the following data: the presence of risk factors, manifestation, time to diagnosis, the treatment applied, and follow-up of patients. RESULTS: We have collected medical records from six patients, three males and three females. The median age was 45 (IQR: 29.5-65.75). The main symptom in all patients was severe pain and tenderness. The first-choice physician(s) were: general practitioners, general surgeons, and neurologists. The median time to diagnosis was 7 (IQR: 5-10) years. The main complaint of our patients was severe pain - 9 (IQR: 9-10) on the VAS scale, which was significantly alleviated after surgical treatment - 0 (IQR: 0-0; p = 0.043). CONCLUSIONS: Extremely long times to final diagnosis, and excellent outcomes of surgical treatment, highlight the necessity of raising awareness of glomangiomas among clinicians.

The Role of ER Stress-Related Phenomena in the Biology of Malignant Peripheral Nerve Sheath Tumors.

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.

Diabetes and Cardiovascular Risk in Renal Transplant Patients.

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.

Induction of apoptosis in human glioma cell lines of various grades through the ROS-mediated mitochondrial pathway and caspase activation by Rhaponticum carthamoides transformed root extract.

The present study is the first investigation of the inhibitory effect of Rhaponticum carthamoides transformed roots (TR) extract on the proliferation of grade II and III human glioma cells. TR extract showed the cytotoxic effect and inhibited the colony formation of both glioma cell lines in dose-dependent manner. The root extract induced apoptosis by increasing of the reactive oxygen species (about threefold compared to the control cells) leading to a disruption of mitochondrial membrane potential. Additionally, the mRNA levels of the apoptotic factors such as Bax, Tp53, caspase-3, and caspase-9 were observed to increase. These results indicate that the TR extract possesses anticancer activity by inhibiting glioma cell proliferation and inducing apoptotic cell death, and may be used as a promising anticancer agent.

The antero-lateral approach with corpectomy in the management of the ventral meningioma of the spinal canal.

The authors present the anterior approach to cervical spine, which enabled complete resection of tumor located in the anterior part of the spinal canal. Considering there are not many reports in the literature, the authors present a case of a meningioma at the level C5-C6 resected with good result through anterolateral approach.

Neurofibromatosis type 2 (NF 2) or schwannomatosis?--Case report study and diagnostic criteria.

INTRODUCTION: Neurofibromatosis type 2 (NF2) and schwannomatosis are entities that may, due to the similarity of clinical symptoms, cause diagnostic difficulties. Incidence rate of both diseases is similar and estimated between 1:25,000 and 1:40,000. The genes associated with the development of the aforementioned disorders are located on chromosome 22 and lay in proxmity. Schwannomatosis is characterized by an incomplete penetrance and the risk of its transmission to the offspring is significantly lower than in the case of NF 2. Schwannomatosis clinical characteristic is similar to the NF2, however vestibular schwannomas are not present. Therefore the imaging studies evaluated by an experienced radiologist play a key role in the diagnostic process. CASE REPORT: Forty two-year-old female hospitalized three times because of the tumors of the spinal canal was admitted to the Department of Neurosurgery and Peripheral Nerve Surgery in 2008 because of the cervical pain syndrome with concomitant headache. She was diagnosed with a schwannomatosis, recently distinguished, the third form of neurofibromatosis. MRI imaging revealed craniocervical junction tumor. Suboccipital craniectomy with concomitant C1-C2 laminectomy was done in order to remove the lesion. After the surgery the patient did not present any deficits in neurological examination and was discharged from hospital in good general condition. CONCLUSIONS: The patient was diagnosed with schwannomatosis, recently established neurofibromatosis entity which may resemble NF2 clinically. In patients after the age of 30, in whom we observe multiple schwannomas without the concomitant hearing impairment, the diagnosis of schwannomatosis is very likely.

Characterization of metabolites determined by means of 1H HR MAS NMR in intervertebral disc degeneration.

OBJECT: The objective of this study is the identification of metabolites by means of (1)H high resolution magic angle spinning nuclear magnetic resonance ((1)H HR MAS NMR) spectroscopy and the evaluation of their applicability in distinguishing between healthy and degenerated disc tissues. MATERIALS AND METHODS: Differences between the metabolic profiles of healthy and degenerated disc tissues were studied by means of (1)H HR MAS NMR. Analysis was performed for 81 disc tissue samples (control samples n = 21, degenerated disc tissue samples n = 60). Twenty six metabolites (amino acids, carbohydrates, and alcohols) were identified and quantified. RESULTS: The results indicate that the metabolic profile of degenerated discs is characterized by the presence of 2-propanol and the absence of scyllo-inositol and taurine. The concentrations of 2-propanol and lactate increase with age. CONCLUSION: PCA analysis of ex vivo (1)H HR MAS NMR data revealed the occurrence of two groups: healthy and degenerative disc tissues. The effects of insufficient nutrient supply of discs, leading to their degeneration and back pain, are discussed.

Percutaneous balloon kyphoplasty in the treatment of painful vertebral compression fractures: effect on local kyphosis and one-year outcomes in pain and disability.

BACKGROUND AND PURPOSE: The aim of the study was to determine the effectiveness of percutaneous balloon kyphoplasty for treatment of compressive vertebral fractures. MATERIALS AND METHODS: A retrospective analysis was conducted on 24 patients with 58 symptomatic vertebral fractures treated by balloon kyphoplasty. Visual Analogue Pain Scale (VAS) and Oswestry Disability Index (ODI) were used to assess fracture-related pain and patient's disability: preoperatively and within 12-months follow-up. Following the procedures to evaluate the change of vertebral deformity, the angle of local kyphosis was measured. RESULTS: Preoperative VAS score was 6.54, at discharge it significantly regressed in 95.8% of patients. The overall VAS score at discharge was 1.25 and within 12 months decreased to 0.26. Preoperative ODI score was 50%, at follows-up in all patients it decreased, ranging from 21% to 10%. Reduction of local kyphosis was achieved in 30 (51.7%) vertebrae by average 4.3°. In 9 (37.5%) patients kyphosis of all augmented vertebrae was reduced, in 7 (29.2%) patients procedures reduced kyphosis in part of augmented vertebrae and in 8 patients (33.3%) kyphosis remained unchanged. Asymptomatic complications included cement leak in 10 (17%) vertebrae and intraoperative rupture of 4 (4%) balloons. CONCLUSIONS: Rapid significant pain relief after kyphoplasty followed by long-term pain release and disability reduction obtained in all patients was most probably the result of vertebral augmentation. The correction of local kyphosis had no influence on the outcome.

Delayed perforation of posterior pharyngeal wall caused by dislodged bioresorbable interbody cage. Case report.

A 48-year-old man was admitted for the management of congenital anomalies: Arnold-Chiari type I malformation combined with odontoid upward migration. He also had degenerative stenosis of the spinal canal by spurs at C2/C3 and C3/C4 levels. Osseous deformities caused ischaemic changes of the brainstem as well as spinal cord compression. Authors used the Biocage - interbody cage covered by bioresorbable layer to fill the surgically created gap after removal of the right part of C3 vertebral body. Twenty-seven months after implantation, the implant was extruded through posterior pharyngeal wall. Authors describe this unusual case and discuss possible causes of Biocage extrusion.

[Spinal cord diffusion tensor tractography as a diagnostic tool in difficult cases of spinal cord intramedullary tumours]. / Traktografia rdzenia jako metoda diagnostyczna w trudnych przypadkach guzów sródrdzeniowych.

Diffusion tensor-based spinal cord tractography is a technically complicated but rapidly evolving diagnostic method. The difficulties result from the volume of the spinal cord, the constant pulsing of the cerebrospinal fluid and respiratory movements. The method is being used more and more frequently to examine long spinal tracts in patients with intramedullary tumours. The method can be especially useful for ambiguous cases investigation. The presented case with coincidental intramedullary tumour and severe cervical spondylosis has been described by the authors to show their own experience with spinal cord tractography as a useful tool in determining an effective treatment method.

The Superior Cerebellar Artery: Variability and Clinical Significance.

The superior cerebellar artery (SCA) arises from the distal part of the basilar artery and passes by the oculomotor, trochlear, and trigeminal nerves. SCA is known to play a crucial role in the development of trigeminal neuralgia. However, due to its anatomical variability, it may also trigger other neurovascular compression (NVC), including hemifacial spasm, oculomotor nerve palsy, and ocular neuromyotonia. Additionally, it may be associated with ischemic syndromes and aneurysm development, highlighting its clinical significance. The most common anatomical variations of the SCA include duplication, a single vessel origin from the posterior cerebral artery (PCA), and a common trunk with PCA. Rarely observed variants include bifurcation and origin from the internal carotid artery. Certain anatomical variants such as early bifurcation and caudal course of duplicated SCA trunk may increase the risk of NVC. In this narrative review, we aimed to examine the impact of the anatomical variations of SCA on the NVCs based on papers published in Pubmed, Scopus, and Web of Science databases with a snowballing approach. Our review emphasizes the importance of a thorough understanding of the anatomical variability of SCA to optimize the management of patients with NVCs associated with this artery.

Class I HDAC Inhibition Leads to a Downregulation of FANCD2 and RAD51, and the Eradication of Glioblastoma Cells.

HDAC inhibitors (HDACi) hold great potential as anticancer therapies due to their ability to regulate the acetylation of both histone and non-histone proteins, which is frequently disrupted in cancer and contributes to the development and advancement of the disease. Additionally, HDACi have been shown to enhance the cytotoxic effects of DNA-damaging agents such as radiation and cisplatin. In this study, we found that histone deacetylase inhibits valproic acid (VPA), synergized with PARP1 inhibitor (PARPi), talazoparib (BMN-673), and alkylating agent, and temozolomide (TMZ) to induce DNA damage and reduce glioblastoma multiforme. At the molecular level, VPA leads to a downregulation of FANCD2 and RAD51, and the eradication of glioblastoma cells. The results of this study indicate that combining HDACi with PARPi could potentially enhance the treatment of glioblastoma, the most aggressive type of cancer that originates in the brain.

Histone Deacetylases (HDAC) Inhibitor-Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor.

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 Morphology of the Pituitary Gland: A Meta-Analysis with Implications for Diagnostic Imaging.

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 mm3 (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 mm3), and males from Europe have the lowest (456.42 mm3). 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.

Telovelar versus transvermian approach to tumors of the fourth ventricle and their impact on postoperative neurological complications: A multicenter study.

Background: Tumors of the fourth ventricle are exceedingly rare; however, such lesions are formidable due to the severe postoperative neurological complications (pNCs) which often occur. The adoption of the telovelar approach over the transvermian was created to supposedly mitigate the pNCs; however, there is a lack of sufficient data supporting this theory. Methods: Records from six hospitals were reviewed for patients surgically treated for a single tumor within the 4th ventricle from 2016 to 2022. The pNCs which had 10 or more occurrences among the patients were individually assessed as the dependent variable in a binary logistic regression model against covariates which included the surgical approach. Results: This study of 67 patients confirms no significant differences in risk for pNCs between the transvermian and telovelar approach. Rather, multivariate analysis identified neurophysiological monitoring (IONM) as a protective factor for postoperative speech and swallowing defects (odds ratio [OR]: 0.076, 95% confidence interval [CI] 0.011-0.525). Furthermore, intraoperative external ventricular drainage (EVD) was a protective factor for postoperative gait and focal motor defects (OR: 0.075, 95% CI 0.009-0.648) and for postoperative hydrocephalus (OR: 0.020, 95% CI 0.002-0.233). A univariate meta-analysis pooling the present study's patients and an additional 304 patients from the three additional studies in the literature confirms no significant differences in risk between the transvermian and telovelar approach for pNCs. Conclusion: Intraoperative adjuncts including IONM and EVD may play a significant role in the postoperative outcome. Despite the present study's sample size being a major limitation, the findings may provide great value to neurosurgeons given the scarcity of the current literature.

[Depression or apathy? A diagnostic trap: a huge right frontal lobe meningioma diagnosed and treated as mild atypical depression episode--a case study]. / Depresja czy apatia? Pulapki diagnostyczne: olbrzymi oponiak prawego plata czolowego rozpoznany i leczony jako epizod depresji umiarkowanej atypowej--opis przypadku.

Neurobehavioral changes observed in patients with brain tumours may appear as cognitive deficits, mood disturbances, changes in behaviour or decreased adaptability (e.g., drowsiness, apathy, loss of spontaneity, fatigue). They are initially subtle, develop insidiously, and their severity often changes. Serious diagnostic problems can be caused by mood disorders, psychotic symptoms, personality changes, from disinhibition to apathy, observed in such patients. The problem in distinguishing them from organic psychiatric disorders, often poses a challenge for psychiatrists, neurologists and general practitioners. We describe a case difficult to diagnose because of apathy, due to a brain tumour in the right frontal lobe, diagnosed as depression. Another difficulty, rather suggesting mood disorder, was rheumatoid arthritis. Thorough and meticulous analysis of clinical data, neuropsychological assessment and neuroimaging diagnosis may help to assess aetiology of the observed disorders which can have similar clinical pictures but various causes.

Cervical Paraspinal Chordoma: A Literature Review with a Novel Case Report.

Chordomas are rare malignant neoplasms, accounting for 1-4% of all primary bone tumors. Most spinal chordomas occur in the sacrococcygeal region and the base of the skull; however, 6% of chordomas are observed in the cervical spine. In these cases, the lesion is mainly located in the midline. These tumors slowly grow before becoming symptomatic and encase the surrounding vascular and nerve structures. Patients with advanced chordoma have a poor prognosis due to local recurrence with infiltration and destruction of adjacent bone and tissues. Systemic chemotherapy options have not been fully effective in these tumors, especially for recurrent chordomas. Thus, new combinations of currently available targeted molecular and biological therapies with radiotherapy have been proposed as potential treatment modalities. Here, the present paper describes the case of a 41-year-old male with a C2-C4 chordoma located paravertebrally, who underwent surgical resection with a debulking procedure for a cervical chordoma. Computed tomography angiography revealed a paraspinal mass with bone remodeling and the MRI showed a paravertebral mass penetrating to the spinal canal with a widening of the intervertebral C2-C3 foramen. Initially, the tumor was diagnosed as schwannoma based on its localization and imaging features; however, the histopathology specimen confirmed the diagnosis of chordoma. This case study highlights the effectivity of radical surgical resection as a mainstay treatment for chordomas, discusses neuroimaging, diagnosis, and the use of currently available targeted therapies and forthcoming treatment strategies, as alternative treatment options for chordoma.

Intramedullary Spinal Cord Abscess with Concomitant Spinal Degenerative Diseases: A Case Report and Systematic Literature Review.

Intramedullary spinal cord abscess (ISCA) is a rare clinical pathology of the central nervous system that usually accompanies other underlying comorbidities. Traditionally it has been associated with significant mortality and neurological morbidities because it is often difficult to diagnose promptly, owing to its nonspecific clinical and neuroimaging features. The mortality rate and the outcome of these infections have been improved by the introduction into clinical practice of antibiotics, advanced neuroimaging modalities, and immediate surgery. We report the case of a 65-year-old male patient who presented with a progressive spastic gait and lumbar pain, predominantly in the left leg. An MRI image revealed an expansile intramedullary cystic mass in the thoracic spinal cord, which was initially diagnosed as a spinal tumor. He underwent laminectomy and myelotomy, and eventually the pus was drained from the abscess. The follow-up MRI showed improvement, but the patient's paraplegia persisted. In light of his persistent hypoesthesia and paraplegic gait with developing neuropathic pain, he was readmitted, and an MRI of his lumbar spine revealed multilevel degenerative disease and tethered spinal cord syndrome with compression of the medulla at the L2-L3 level. The patient underwent central flavectomy with bilateral foraminotomy at the L2-L3 level, and the medulla was decompressed. Postoperatively, his neurological symptoms were significantly improved, and he was discharged from hospital on the third day after admission. In support of our case, we systematically reviewed the recent literature and analyzed cases published between 1949 and May 2022, including clinical features, mechanisms of infection, predisposing factors, radiological investigations, microbial etiologies, therapies and their duration, follow-ups, and outcomes. Initial clinical presentation can be misleading, and the diagnosis can be challenging, because this condition is rare and coexists with other spinal diseases. Hence, a high index of suspicion for making an accurate diagnosis and timely intervention is required to preclude mortality and unfavorable outcomes. Our case is a clear example thereof. Long-term follow-up is also essential to monitor for abscess recurrences.