Reliability Study of Metal-Oxide Semiconductors in Integrated Circuits.

This paper is devoted to the study of CMOS IC parameter degradation during reliability testing. The paper presents a review of literature data on the issue of the reliability of semiconductor devices and integrated circuits and the types of failures leading to the degradation of IC parameters. It describes the tests carried out on the reliability of controlled parameters of integrated circuit TPS54332, such as quiescent current, quiescent current in standby mode, resistance of the open key, and instability of the set output voltage in the whole range of input voltages and in the whole range of load currents. The calculated values of activation energies and acceleration coefficients for different test temperature regimes are given. As a result of the work done, sample rejection tests have been carried out on the TPS54332 IC under study. Experimental fail-safe tests were carried out, with subsequent analysis of the chip samples by the controlled parameter quiescent current. On the basis of the obtained experimental values, the values of activation energy and acceleration coefficient at different temperature regimes were calculated. The dependencies of activation energy and acceleration coefficient on temperature were plotted, which show that activation energy linearly increases with increasing temperature, while the acceleration coefficient, on the contrary, decreases. It was also found that the value of the calculated activation energy of the chip is 0.1 eV less than the standard value of the activation energy.

Structure-based discovery of small molecule inhibitors of FKBP51-Hsp90 protein-protein interaction.

The heat shock protein 90 kDa (Hsp90) molecular chaperone machinery is responsible for the folding and activation of hundreds of important clients such as kinases, steroid hormone receptors, transcription factors, etc. This process is dynamically regulated in an ATP-dependent manner by Hsp90 co-chaperones including a group of tetratricopeptide (TPR) motif proteins that bind to the C-terminus of Hsp90. Among these TPR containing co-chaperones, FK506-binding protein 51 kDa (FKBP51) is reported to play an important role in stress-related pathologies, psychiatric disorders, Alzheimer's disease, and cancer, making FKBP51-Hsp90 interaction a potential therapeutic target. In this study, we report identification of potent and selective inhibitors of FKBP51-Hsp90 protein-protein interaction using a structure-based virtual screening approach. Upon in vitro evaluation, the identified hits show a considerable degree of selectivity towards FKBP51 over other TPR proteins, particularly for highly homologous FKBP52. Tyr355 of FKBP51 emerged as an important contributor to inhibitor's specificity. Additionally, we demonstrate the impact of these inhibitors on cellular energy metabolism, and neurite outgrowth, which are subjects of FKBP51 regulation. Overall, the results from this study highlight a novel pharmacological approach towards regulation of FKBP51 function and more generally, Hsp90 function via its interaction with TPR co-chaperones.

Metachronous Squamous Cell Carcinomas of the Uterine Cervix and Lung: True Metachrony or Metastasis.

Human papillomaviruses (HPV) are a big group of infection agents with oncogenic potential, especially regarding squamous epithelium. Some high-risk variants are key in the development of squamous cell carcinomas (SCC) across multiple systems, the most affected of which is the female reproductive system, but also parts of the gastrointestinal tract, head, and neck SCC, and cutaneous and pulmonary (bronchogenic) SCCs. In cases where a patient develops two SCCs in different systems, often the main question is whether these tumors are synchronous, metachronous, or if one of the tumors is a metastasis from the other, with HPV testing and stereotype identification often being of aid in differentiating between these. Herein, we report the case of a female patient in her 50s, initially diagnosed with SCC of the uterine cervix. The patient remained stable for three calendar years after completing preoperative radiotherapy, surgical resection, and postoperative chemo-radiotherapy. At that point, she developed respiratory symptoms, and radiography suggested a pulmonary malignancy. After undergoing surgical resection of the pulmonary lesion, histological specimens were initially interpreted to be a metachronous pulmonary SCC. Immunohistochemical testing proved that both the cervical and pulmonary lesions were HPV-associated, with further testing proving that both lesions were associated with high-risk HPV (genotype 16). Based on the clinical history and aggregated data, the pulmonary lesion was interpreted as a metastatic and not a metachronous one, and the patient is currently undergoing treatment for metastatic disease.

FKBP51-Hsp90 Interaction-Deficient Mice Exhibit Altered Endocrine Stress Response and Sex Differences Under High-Fat Diet.

FK506-binding protein 51 kDa (FKBP51), encoded by Fkbp5 gene, gained considerable attention as an important regulator of several aspects of human biology including stress response, metabolic dysfunction, inflammation, and age-dependent neurodegeneration. Its catalytic peptidyl-prolyl isomerase (PPIase) activity is mediated by the N-terminal FK506-binding (FK1) domain, whereas the C-terminal tetratricopeptide motif (TPR) domain is responsible for FKBP51 interaction with molecular chaperone heat shock protein 90 (Hsp90). To understand FKBP51-related biology, several mouse models have been created. These include Fkbp5 complete and conditional knockouts, overexpression, and humanized models. To dissect the role of FKBP51-Hsp90 interaction in FKBP51 biology, we have created an interaction-deficient mouse (Fkbp5TPRmut) by introducing two-point mutations in the TPR domain of FKBP51. FKBP51-Hsp90 interaction-deficient mice are viable, fertile and show Mendelian inheritance. Intracellular association of FKBP51 with Hsp90 is significantly reduced in homozygous mutants compared to wild-type animals. No behavioral differences between genotypes were seen at 2 months of age, however, sex-dependent differences were detected in Y-maze and fear conditioning tests at the age of 12 months. Moreover, we have found a significant reduction in plasma levels of corticosterone and adrenocorticotropic hormone in Fkbp5TPRmut mice after acute stress. In contrast to Fkbp5 knockout mice, females of Fkbp5TPRmut showed increased body weight gain under high-fat diet treatment. Our data confirm the importance of FKBP51-Hsp90 interactions for stress-related endocrine signaling. Also, Fkbp5TPRmut mice can serve as a useful in vivo tool to discriminate between Hsp90-dependent and independent functions of FKBP51.

Cauda Equina Neuroendocrine Tumor: A Histopathological Case Report.

Cauda equina neuroendocrine tumors (CENET) are rare neoplastic processes that develop in the cauda equina or filum terminale region of the spinal cord, which in previous incarnations of the World Health Organization (WHO) classification of the central nervous system (CNS) tumors were designated as paragangliomas. The change of terminology was carried out due to the rarity of the condition, its specific place of origin, the non-specific clinical and imaging characteristics with which the tumors present, and differences in biological properties (secretion and progression) as well as some minor differences in immunohistochemical protein expression patterns. Herein, we present a case of a male patient in his sixties who presented to us for a histopathological consultation of a previously excised tumor, which was grossly well-demarcated and connected to a nerve root in the cauda equina region. The tumor presented with histomorphological features of a sharply demarcated, non-infiltrative tumor growing in a nested to pseudopapillary pattern with a highly vascularized, intersecting stroma. Tumor cells were mildly atypical ovoid ones, with eosinophilic cytoplasm, central hyperchromatic nuclei, some with nucleoli, and salt and pepper chromatin. Intersecting stroma was rich in reticulin fibers, and the cell did not express epithelial membrane antigen, excluding the diagnosis of ependymoma as well as glial markers, excluding glial origin. Pan-cytokeratin was focally positive, neuroendocrine markers were diffusely positive, and the proliferative index was low. As such, the diagnosis of CENET, WHO CNS grade 1 was established, and the patient was referred back to the institution at which the surgery was performed for follow-up and further management.

Gastric Conduit Cancer following Ivor-Lewis Esophagectomy for Esophageal Adenocarcinoma: A Case Report and Literature Review.

The incidence of gastric cancer associated with esophageal cancer is notably high. In recent years, there has been an increase in patients with gastric conduit cancers due to early detection and radical treatment of esophageal cancer, leading to prolonged survival of the patients. Metachronous gastric cancer following esophagectomy sometimes can pose a clinical challenge for surgeons, while gastric tube reconstruction is a well-established procedure accompanying esophagectomy, treating gastric cancer within the gastric tube can be difficult in contrast. Surgical treatment of gastric tube cancers is often complex and life-threatening. Early detection of gastric tube cancer is crucial for improving prognosis as it allows for less invasive surgical interventions. However, no specific guidelines for detecting gastric tube cancer have been established. In this report, we present a case of gastric tube cancer in a patient that had Ivor-Lewis surgery 20 years ago for preinvasive adenocarcinoma of the thoracic esophagus against the background of Barrett's esophagus. Recommendations for earlier and more accurate diagnosis and treatment of this pathology are discussed.

A case report of colonic stent placement without X-ray control in the COVID-19 era: a practical method or a mistake?

Background: During the recent 2-year quarantine, the coronavirus disease 2019 (COVID-19) pandemic changed the course of medical treatment and posed some new challenges to the care of particularly vulnerable oncology patients. Despite the re-purposing of The Second University Clinic (Sechenov University), we still admitted many patients with colonic obstruction. The endoscopic unit was situated in a separate facility, but due to the intensive use of all of our X-ray equipment for COVID-19 patients, the question arose about the possibility of placing a stent without fluoroscopic control. Here, we present the first case report of colonic stent placement without X-ray guidance. Case Description: An 81-year-old woman was admitted in January 2021 with clinical signs of colonic obstruction. An emergency computed tomography (CT) abdominal scan revealed an irregular focal thickening of the wall of the rectosigmoid. At the medical case conference, a minimally invasive intervention was recommended to decompress the intestine and prepare the patient for radical surgery. A colonoscopy of the rectosigmoid area showed circumferential tumor infiltration with narrowing of the lumen to approximately 3 mm. Bowel decompression was performed by placing a self-expandable metallic stent (SEMS) via colonoscopy without fluoroscopic monitoring. After performing the stenting procedure, the patient's clinical symptoms were relieved, and she reported passing of stool and gases, pain reduction, and reduction of abdominal bloating. Conclusions: In 6 months we performed 13 colonic stentings with effective decompression of the intestines without any complications. From our point of view, our forced clinical experience showed us that in desperate situations with severely impacted patients, an experienced endoscopic team can perform colonic stenting without direct X-ray navigation (provided there is the appropriate selection of stent design and size according to findings on a preliminary CT scan), if due to unforeseen circumstances an X-ray is unavailable.

Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases.

The dysfunction of the proteostasis network is a molecular hallmark of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Molecular chaperones are a major component of the proteostasis network and maintain cellular homeostasis by folding client proteins, assisting with intracellular transport, and interfering with protein aggregation or degradation. Heat shock protein 70 kDa (Hsp70) and 90 kDa (Hsp90) are two of the most important chaperones whose functions are dependent on ATP hydrolysis and collaboration with their co-chaperones. Numerous studies implicate Hsp70, Hsp90, and their co-chaperones in neurodegenerative diseases. Targeting the specific protein-protein interactions between chaperones and their particular partner co-chaperones with small molecules provides an opportunity to specifically modulate Hsp70 or Hsp90 function for neurodegenerative diseases. Here, we review the roles of co-chaperones in Hsp70 or Hsp90 chaperone cycles, the impacts of co-chaperones in neurodegenerative diseases, and the development of small molecules modulating chaperone/co-chaperone interactions. We also provide a future perspective of drug development targeting chaperone/co-chaperone interactions for neurodegenerative diseases.

Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay.

Targeting the heat shock protein 90 (Hsp90)-cochaperone interactions provides the possibility to specifically regulate Hsp90-dependent intracellular processes. The conserved MEEVD pentapeptide at the C-terminus of Hsp90 is responsible for the interaction with the tetratricopeptide repeat (TPR) motif of co-chaperones. FK506-binding protein (FKBP) 51 and FKBP52 are two similar TPR-motif co-chaperones involved in steroid hormone-dependent diseases with different functions. Therefore, identifying molecules specifically blocking interactions between Hsp90 and FKBP51 or FKBP52 provides a promising therapeutic potential for several human diseases. Here, we describe the protocol for an amplified luminescent proximity homogenous assay to probe interactions between Hsp90 and its partner co-chaperones FKBP51 and FKBP52. First, we have purified the TPR motif-containing proteins FKBP51 and FKBP52 in glutathione S-transferase (GST)-tagged form. Using the glutathione-linked donor beads with GST-fused TPR-motif proteins and the acceptor beads coupled with a 10-mer C-terminal peptide of Hsp90, we have probed protein-protein interactions in a homogeneous environment. We have used this assay to screen small molecules to disrupt Hsp90-FKBP51 or Hsp90-FKBP52 interactions and identified potent and selective Hsp90-FKBP51 interaction inhibitors.

Radiation-induced low grade fibromyxoid sarcoma of the larynx: a case report and literature review.

Low grade fibromyxoid sarcoma (LGFMS) is an uncommon variant of fibrosarcoma with high risk of local recurrence, immense metastatic potential and frequently protracted period between tumour presentation and metastasis. This unusual malignancy rarely affects the region of the head and neck which makes cases of laryngeal LGFMS extremely infrequent. To date, LGFMS of the larynx has been scatteredly mentioned in the literature. Neither incidence nor causes and risk factors for laryngeal LGFMS have been clarified so far. To the authors' knowledge, this is the first case report that discusses the clinical course, imaging diagnosis, histopathological evaluation and surgical approach to radiation-induced laryngeal LGFMS.We present a case of a 70-year-old man who developed a LGFMS after previous radiotherapy (RT) for squamous cell carcinoma (SCC) of the larynx. The latency period between the time of radiation exposure and the diagnosis of LGFMS was twenty-seven months. After re-confirming the diagnosis with second biopsy and extensive imaging evaluation the patient was subjected to an open partial resection of the larynx. Owing to the rarity of the tumour, there is no established protocol with follow-up recommendations.This case highlights the importance of considering the RT history of the patient in order to monitor radiotherapy-related complications, including the occurrence of LGFMS.

Circulating miR-618 Has Prognostic Significance in Patients with Metastatic Colon Cancer.

The present study evaluated the prognostic role of circulating miRNA-618 in patients with metastatic colon cancer (mCC) and whether miR-618 gene rs2682818 single nucleotide polymorphisms (SNP) are associated with colon cancer susceptibility and expression levels of mature miR-618. In total, 104 patients with mCC before starting the chemotherapy were investigated. The expression status of circulating miR-618 in mCC was evaluated by quantitative PCR. TaqMan PCR assay was used for rs2682818 SNP genotyping. miR-618 was overexpressed in serum of mCC patients. Patients with high and intermediate expression of miR-618 had a significantly longer mean overall survival (OS) of 21 months than patients with low expression-16 months. In addition, multivariate Cox regression analysis confirmed the association between high/intermediate levels of miRNA-618 and longer OS, HR = 0.51, 95% CI: 0.30-0.86, p = 0.012. miR-618 rs2682818 SNP significantly decreased the risk of colon cancer susceptibility in both heterozygous codominant (AC vs. CC, OR = 0.39, 95% CI: 0.17-0.88, p = 0.024) and overdominant (AC vs. CC + AA, OR = 0.37, 95% CI: 0.16-0.85, p = 0.018) genetic models. Our data suggest that circulating miRNA-618 could be useful as a prognostic biomarker in mCC. Patients harboring AC rs2682818 genotype have a decreased risk for colon cancer in comparison with patients with CC and AA genotypes.

Small molecule therapeutics for tauopathy in Alzheimer's disease: Walking on the path of most resistance.

Alzheimer's disease (AD) is the most common form of dementia characterized by presence of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of tau protein. Currently there are close to 50 million people living with dementia and this figure is expected to increase to 75 million by 2030 putting a huge burden on the economy due to the health care cost. Considering the effects on quality of life of patients and the increasing burden on the economy, there is an enormous need of new disease modifying therapies to tackle this disease. The current therapies are dominated by only symptomatic treatments including cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers but no disease modifying treatments exist so far. After several failed attempts to develop drugs against amyloidopathy, tau targeting approaches have been in the main focus of drug development against AD. After an overview of the tauopathy in AD, this review summarizes recent findings on the development of small molecules as therapeutics targeting tau modification, aggregation, and degradation, and tau-oriented multi-target directed ligands. Overall, this work aims to provide a comprehensive and critical overview of small molecules which are being explored as a lead candidate for discovering drugs against tauopathy in AD.

Rhabdomyoma of the Larynx in a Child with Recurrent Airway Problems.

Rhabdomyoma is a rare benign tumor formed from striated muscle tissue and according to the literature occurs quite rarely in the larynx. We present a case of a rhabdomyoma of the larynx in a 5-year-old boy with recurrent airway problems. An extracardiac juvenile rhabdomyoma is extremely rarely found in the field of otorhinolaryngology. In this report, we presented the diagnostic and therapeutic features of this tumor with the review of the literature.

Metal Binding by GMP-1 and Its Pyrimido [1, 2]benzimidazole Analogs Confirms Protection Against Amyloid-ß Associated Neurotoxicity.

Alzheimer's disease (AD) represents a major public health threat and, unfortunately, available therapeutics provide only temporary symptomatic relief. AD is a complex multifactorial disease and failure of single target therapeutics targeting amyloid-ß (Aß) in recent clinical trials suggests that future AD drug development should be focused on simultaneous targeting of several pathological hallmarks of the disease. Recently, we have shown that GMP-1, a 2-(methoxymethyl)pyrimido [1, 2-a] benzimidazol-4-ol, protects mitochondrial function in drosophila and mice models of AD, and improved memory and behavior indicating neuroprotective effect of GMP-1 treatment. Here, we have found that GMP-1 specifically binds to copper and zinc, metals that are dysregulated in AD brain. Addition of GMP-1 does not inhibit metal-dependent enzymatic reactions. Also, binding of Zn(II) and Cu(II) by GMP-1 is weaker than the 8-hydroxyquinoline scaffold compound clioquinol previously tested in AD clinical trials. However, GMP-1 affects Cu(II)-dependent Aß fibrillization as well as oxidative damage and viability of SH-SY5Y cells upon addition of Cu(II) and Aß. Our data provide new insight on GMP-1 as a Zn(II) and Cu(II) specific metal chelator of moderate affinity that can be responsible for some of its neuroprotective effects observed in AD animal models.