Ethylene Glycol Poisoning: A Case Study of a 71-Year-Old Male with a History of Alcohol Abuse and Suicide Attempts.

A 71-year-old male with a history of alcohol abuse and multiple suicide attempts was brought to the emergency department in an unconscious state. Initial assessment revealed profound obtundation and malnutrition. Laboratory findings demonstrated a significant anion gap metabolic acidosis with a high osmolar gap, suggestive of possible toxic alcohol ingestion. Despite negative serum alcohol levels, ethylene glycol poisoning was confirmed with a level of 226. Treatment included fluid resuscitation, bicarbonate therapy, and fomepizole administration. However, due to progressive multi-organ failure, continuous veno-venous hemodialysis was initiated. Despite interventions, the patient deteriorated rapidly, leading to a decision for hospice care, ultimately resulting in death. Ethylene glycol poisoning presents significant challenges in management, with potential complications including renal failure and multi-organ dysfunction. Fomepizole remains the cornerstone of treatment, but additional therapies such as ethanol administration were considered but ultimately deemed unnecessary due to associated risks. This case highlights the complexity and severity of ethylene glycol poisoning, emphasizing the need for early recognition and aggressive management strategies.

Utilization of a Virtual Tumor Board for the Care of Patients With Renal Masses: Experience From a Quality Improvement Collaborative.

INTRODUCTION: Multidisciplinary tumor board meetings are useful sources of insight and collaboration when establishing treatment approaches for oncologic cases. However, such meetings can be time intensive and inconvenient. We implemented a virtual tumor board within the Michigan Urological Surgery Improvement Collaborative to discuss and improve the management of complicated renal masses. METHODS: Urologists were invited to discuss decision-making for renal masses through voluntary engagement. Communication was performed exclusively through email. Case details were collected and responses were tabulated. All participants were surveyed about their perceptions of the virtual tumor board. RESULTS: Fifty renal mass cases were reviewed in a virtual tumor board that included 53 urologists. Patients ranged from 20-90 years old and 94% had localized renal mass. The cases generated 355 messages, ranging from 2-16 (median 7) per case; 144 responses (40.6%) were sent via smartphone. All urologists (100%) who submitted to the virtual tumor board had their questions answered. The virtual tumor board provided suggestions to those with no stated treatment plan in 42% of cases, confirmed the physician's initial approach to their case in 36%, and offered alternative approaches in 16% of cases. Eighty-three percent of survey respondents felt the experience was "Beneficial" or "Very Beneficial," and 93% stated increased confidence in their case management. CONCLUSIONS: Michigan Urological Surgery Improvement Collaborative's initial experience with a virtual tumor board showed good engagement. The format reduced barriers to multi-institutional and multi-disciplinary discussions and improved the quality of care for selected patients with complex renal masses.

Prognostic value of E-Cadherin and its tumor suppressor role in Saudi women with advanced epithelial ovarian cancer.

The extracellular matrix (ECM) disruption and cytoskeleton reorganization are crucial events in tumor proliferation and invasion. E-Cadherin (E-CAD) is a member of cell adhesion molecules involved in cell-cell junctions and ECM stability. The loss of E-CAD expression is associated with cancer progression and metastasis. This retrospective study aimed to assess E-CAD protein expression in ovarian cancer (OC) tissues and to evaluate its prognostic value. PATIENTS AND METHODS: 143 formalin-fixed and paraffin-embedded (FFPE) blocks of primary advanced stages OC were retrieved and used to construct Tissue microarrays. Automated immunohistochemistry technique was performed to evaluate E-CAD protein expression patterns in OC. RESULTS: E-CAD protein expression was significantly correlated with OC histological subtype (p < 0.0001), while borderline significant correlations were observed with both tumor grade (p = 0.06) and stage (p = 0.07). Interestingly, Kaplan-Meier survival analysis showed that OC patients with membranous E-CAD expression survived longer than those with no E-CAD expression mainly those at advanced stages (p < 0.009). Further in silico analysis confirms the key roles of E-CAD in OC molecular functions. CONCLUSION: we reported a prognosis value of membranous E-CAD in advanced stage OC patients. Further validation using larger cohorts is recommended to extract clinically relevant outcomes towards better OC management and individualized oncology.

Assessment of prognostic value of tissue inhibitors of metalloproteinase 3 (TIMP3) protein in ovarian cancer.

Background: TIMP3 is a multifunctional proteolytic enzyme belonging to TIMPs family and acts as a potent inhibitor of matrix metalloproteinases (MMPs). TIMP3 possesses a tumor suppresive function by directly promoting tumor cell apoptosis, preventing angiogenesis and extracellular matrix remodelling. The lower expression of TIMP3 was associated with poor prognosis and overall survival in various cancer types. The aim of this study was to evaluate the association of TIMP3 protein expression with ovarian cancer (OC) clinicopathological features and survival outcomes.Patients and Methods: One hundred forty four of OC FFPE samples were collected from King Abdulaziz University Hospital, Saudi Arabia and constructed in tissue microarray (TMA) slides. Automated Ventana immunostainer platform was used to evaluate TIMP3 protein expression patterns.Results: The study showed that TIMP3 exhibits cytoplasmic localisation. This TIMP3 protein expression was not associated with age, tumor size and the involvement of lymph nodes (p > 0.05). However, it was significantly correlated with tumor stage (p < 0.05) and borderline significant with endpoint status (p = 0.07). Interestingly, the Kaplan-Meier analysis of disease specific survival (DSS) outcomes showed a significant association (p = 0.02, log rank) between OC patients with higher TIMP3 expression compared to those with lower expression. In fact, OC patients with high TIMP3 expression had longer survivals. Multivariate Cox's regression analysis suggests that low TIMP3 protein expression pattern is an independent poor survival marker (p = 0.025).Conclusion: Cytoplasmic TIMP3 protein expression could be used as a good prognosticator to stratify poorly prognostic OC patients in order to personlaize their disease management.

Overtreatment and Underutilization of Watchful Waiting in Men With Limited Life Expectancy: An Analysis of the Michigan Urological Surgery Improvement Collaborative Registry.

OBJECTIVE: To determine rates of watchful waiting (WW) vs treatment in prostate cancer (PCa) and limited life expectancy (LE) and assess determinants of management. MATERIALS AND METHODS: Patients diagnosed with PCa between 2012 and 2018 with <10 years LE were identified from the Michigan Urologic Surgery Improvement Collaborative registry. Multinomial logistic regression models were used to identify factors associated with management choice among NCCN low-risk PCa patients. Data from high-volume practices were analyzed to understand practice variation. RESULTS: Total 2393 patients were included. Overall, WW was performed in 8.1% compared to 23.3%, 25%, 11.2%, and 3.6% who underwent AS, radiation (XRT), prostatectomy (RP), and brachytherapy (BT), respectively. In men with NCCN low-risk disease (n = 358), WW was performed in 15.1%, compared to AS (69.3%), XRT (4.2%), RP (6.7%), and BT (2.5%). There was wide variation in management among practices in low-risk men; WW (6%-35%), AS (44%-81%), and definitive treatment (0%-30%). Older age was associated with less likelihood of undergoing AS vs WW (odds ratio [OR] 0.88, P < .001) or treatment vs WW (OR 0.83, P < .0001). Presence of ≥cT2 disease (OR 8.55, P = .014) and greater number of positive biopsy cores (OR 1.41, P = .014) was associated with greater likelihood of treatment vs WW and Charlson comorbidity score of 1 vs 0 (OR 0.23, P = .043) was associated with less likelihood of treatment vs WW. CONCLUSION: Wide practice level variation exists in management for patients with low- and favorable-risk PCa and <10-year LE. Utilization of WW is poor, suggesting overtreatment in men who will experience little benefit.

Bacterial Interactions as Detected by Pooled Antibiotic Susceptibility Testing (P-AST) in Polymicrobial Urine Specimens.

Introduction: Antimicrobial susceptibility is well characterized in monomicrobial infections, but bacterial species often coexist with other bacterial species. Antimicrobial susceptibility is often tested against single bacterial isolates; this approach ignores interactions between cohabiting bacteria that could impact susceptibility. Here, we use Pooled Antibiotic Susceptibility Testing to compare antimicrobial susceptibility patterns exhibited by polymicrobial and monomicrobial urine specimens obtained from patients with urinary tract infection symptoms. Methods: Urine samples were collected from patients who had symptoms consistent with a urinary tract infection. Multiplex polymerase chain reaction testing was performed to identify and quantify 31 bacterial species. Antibiotic susceptibility was determined using a novel Pooled Antibiotic Susceptibility Testing method. Antibiotic resistance rates in polymicrobial specimens were compared with those in monomicrobial infections. Using a logistic model, resistance rates were estimated when specific bacterial species were present. To assess interactions between pairs of bacteria, the predicted resistance rates were compared when a pair of bacterial species were present versus when just one bacterial species was present. Results: Urine specimens were collected from 3,124 patients with symptoms of urinary tract infection. Of these, multiplex polymerase chain reaction testing detected bacteria in 61.1% (1910) of specimens. Pooled Antibiotic Susceptibility Testing results were available for 70.8% (1352) of these positive specimens. Of these positive specimens, 43.9% (594) were monomicrobial, while 56.1% (758) were polymicrobial. The odds of resistance to ampicillin (p = 0.005), amoxicillin/clavulanate (p = 0.008), five different cephalosporins, vancomycin (p = <0.0001), and tetracycline (p = 0.010) increased with each additional species present in a polymicrobial specimen. In contrast, the odds of resistance to piperacillin/tazobactam decreased by 75% for each additional species present (95% CI 0.61, 0.94, p = 0.010). For one or more antibiotics tested, thirteen pairs of bacterial species exhibited statistically significant interactions compared with the expected resistance rate obtained with the Highest Single Agent Principle and Union Principle. Conclusion: Bacterial interactions in polymicrobial specimens can result in antimicrobial susceptibility patterns that are not detected when bacterial isolates are tested by themselves. Optimizing an effective treatment regimen for patients with polymicrobial infections may depend on accurate identification of the constituent species, as well as results obtained by Pooled Antibiotic Susceptibility Testing.

Paraneoplastic syndromes in lung cancer and their management.

Paraneoplastic syndromes are most frequently associated with lung cancer. This review considers a variety of paraneoplastic syndromes associated with lung cancer and discusses their pathophysiology, clinical features and management options.

Prognostic value of Osteopontin (SPP1) in colorectal carcinoma requires a personalized molecular approach.

Stratification of colorectal cancer for better management and tangible clinical outcomes is lacking in clinical practice. To reach this goal, the identification of reliable biomarker(s) is a prerequisite to deliver personalized colorectal cancer theranostics. Osteopontin (SPP1) is a key extracellular matrix protein involved in several pathophysiological processes including cancer progression and metastasis. However, the exact molecular mechanisms regulating its expression, localization, and molecular functions in cancer are still poorly understood. This study was designed to investigate the SPP1 expression profiles in Saudi colorectal cancer patients, and to assess its prognostic value. Hundred thirty-four (134) archival paraffin blocks of colorectal cancer were collected from King Abdulaziz University Hospital, Saudi Arabia. Tissue microarrays were constructed, and automated immunohistochemistry was performed to evaluate SPP1 protein expression patterns in colorectal cancer. About 20% and 23% of our colorectal cancer samples showed high SPP1 cytoplasmic and nuclear expression patterns, respectively. Cytoplasmic SPP1 did not correlate with age, gender, tumor size, and location. However, significant correlations were observed with tumor grade (p = 0.008), tumor invasion (p = 0.01), and distant metastasis (p = 0.04). Kaplan-Meier survival analysis showed a significantly lower recurrence rate in patients with higher SPP1 cytoplasmic expression (p = 0.05). At multivariate analysis, high SPP1 cytoplasmic expression was an independent favorable prognostic marker (p = 0.02). However, nuclear SPP1 expression did not show any prognostic value (p = 0.712). Our results showed a particular SPP1 prognostic relevance that is not in line with most colorectal cancer previous studies that may be attributed to the molecular pathophysiology of our colorectal cancer cohort. Saudi Arabia has both specific genomic makeup and particular environment that could lead to distinctive molecular roots of cancer. SPP1 has several isoforms, tissue localizations and molecular functions, signaling pathways, and downstream molecular functions. Therefore, a more individualized approach for CRC studies and particularly SPP1 prognosis outcomes' assessment is highly recommended toward precision oncology.

Hepato-protective effect of Allium sativum against immobilization stress in rats.

The purpose of the current study was to examine immobilization stress-induced antioxidant defense changes and estimation of the antioxidant potential of pre and post stress treatment of aqueous garlic extract in rat's liver. For this purpose, male Albino Wistar rats were treated with aqueous garlic extract both pre and after 6 h of immobilization stress. Pro-oxidant status of rat liver was evaluated by determining the levels of reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS), aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), glucose, uric acid and the activities of super oxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST). In response to 6 h of immobilization stress a significant rise in the level of above mentioned liver enzymes were recorded. However, SOD, CAT and GST enzymatic activities showed a sharp decline. The extract treatment before and after stress, almost reverted the activities of studied biochemical parameters towards their control values. Current study highlighted the antioxidant potential of garlic extracts. Based on our study, we recommend the use of garlic extract as nutritional supplement for combating oxidative stress induced damage.

Deciphering the Association of Cytokines, Chemokines, and Growth Factors in Chondrogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells Using an ex vivo Osteochondral Culture System.

Osteoarthritis (OA) is a chronic degenerative joint disorder associated with degradation and decreased production of the extracellular matrix, eventually leading to cartilage destruction. Limited chondrocyte turnover, structural damage, and prevailing inflammatory milieu prevent efficient cartilage repair and restoration of joint function. In the present study, we evaluated the role of secreted cytokines, chemokines, and growth factors present in the culture supernatant obtained from an ex vivo osteochondral model of cartilage differentiation using cartilage pellets (CP), bone marrow stem cells (BM-MSCs), and/or BM-MSCs + CP. Multiplex cytokine analysis showed differential secretion of growth factors (G-CSF, GM-CSF, HGF, EGF, VEGF); chemokines (MCP-1, MIP1α, MIP1ß, RANTES, Eotaxin, IP-10), pro-inflammatory cytokines (IL-1ß, IL-2, IL-5, IL-6, IL-8, TNFα, IL-12, IL-15, IL-17) and anti-inflammatory cytokines (IL-4, IL-10, and IL-13) in the experimental groups compared to the control. In silico analyses of the role of stem cells and CP in relation to the expression of various molecules, canonical pathways and hierarchical cluster patterns were deduced using the Ingenuity Pathway Analysis (IPA) software (Qiagen, United States). The interactions of the cytokines, chemokines, and growth factors that are involved in the cartilage differentiation showed that stem cells, when used together with CP, bring about a favorable cell signaling that supports cartilage differentiation and additionally helps to attenuate inflammatory cytokines and further downstream disease-associated pro-inflammatory pathways. Hence, the autologous or allogeneic stem cells and local cartilage tissues may be used for efficient cartilage differentiation and the management of OA.

A novel homozygous mutation in SZT2 gene in Saudi family with developmental delay, macrocephaly and epilepsy.

Epileptic encephalopathies are genetically heterogeneous disorders which leads to epilepsy and cause neurological disorders. Seizure threshold 2 (SZT2) gene located on chromosome 1p34.2 encodes protein mainly expressed predominantly in the parietal and frontal cortex and dorsal root ganglia in the brain. Previous studies in mice showed that mutation in this gene can confers low seizure threshold, enhance epileptogenesis and in human may leads to facial dysmorphism, intellectual disability, seizure and macrocephaly. Objective of this study was to find out novel gene or novel mutation related to the gene phenotype. We have identified a large consanguineous Saudi family segregating developmental delay, intellectual disability, epilepsy, high forehead and macrocephaly. Exome sequencing was performed in affected siblings of the family to study the novel mutation. Whole exome sequencing data analysis, confirmed by subsequent Sanger sequencing validation study. Our results showed a novel homozygous mutation (c.9368G>A) in a substitution of a conserved glycine residue into a glutamic acid in the exon 67 of SZT2 gene. The mutation was ruled out in 100 unrelated healthy controls. The missense variant has not yet been reported as pathogenic in literature or variant databases. In conclusion, the here detected homozygous SZT2 variant might be the causative mutation that further explain epilepsy and developmental delay in this Saudi family.

Role of miRNAs in human cancer metastasis: Implications for therapeutic intervention.

Metastasis is the spread and growth of localized cancer to new locations in the body and is considered the main cause of cancer-related deaths. Metastatic cancer cells display distinct genomic and epigenomic profiles and almost universally an aggressive pathophysiology. A better understanding of the molecular mechanisms and regulation of metastasis, including how metastatic tumors grow and survive in the nascent niche and the interactions of the emergent metastatic cancer cells within the local microenvironment may provide tools to design strategies to restrict metastatic dissemination. Aberrant microRNAs (miRNA) expression has been reported in metastatic cancer cells. MicroRNAs are known to regulate divergent and/or convergent metastatic gene pathways including activation of reprogramming switches during metastasis. An in-depth understanding of role of miRNAs in the metastatic cascade may lead to the identification of novel targets for anti-metastatic therapeutics as well as potential candidate miRNAs for cancer treatment. This review primarily focuses on the role of miRNAs in the mechanisms of cancer metastasis as well as implications for metastatic cancer treatment.

Role of Glutaraldehyde in Imparting Stability to Immobilized β-Galactosidase Systems

ABSTRACT This review article highlights the role of glutaraldehyde as a matrix activator/stabilizer in imparting higher operational and thermal stability to β-galactosidase (βG) for biotechnological applications. Glutaraldehyde has been used extensively as a crosslinking agent as well as for functionalization of matrices to immobilize β-galactosidase. Immobilized β-galactosidase systems (IβGS) obtained as a result of glutaraldehyde treatment has been employed to hydrolyze whey and milk lactose in batch reactors, continuous packed-bed and fluidized bed reactors under various operational conditions. Moreover, these IβGS have also been utilized for the production of galactooligosaccharides in food, dairy and fermentation industries. It was observed that glutaraldehyde provided remarkable stability to immobilize βG against various physical/chemical denaturants, thus enhancing thermal/operational stability and rendering it more suitable for repeated utilization in industrial scale operations.

Inhibition of endoplasmic reticulum stress and oxidative stress by vitamin D in endothelial cells.

Endoplasmic reticulum (ER) stress and oxidative stress promote endothelial dysfunction and atherosclerosis. Since vitamin D has been shown in several studies to lower the risk of cardiovascular disease, we examined the effects of vitamin D on ER stress and oxidative stress in endothelial cells. ER stress was measured using the placental secreted alkaline phosphatase assay and oxidative stress was measured by hydroethidine fluorescence. Expression of ER stress markers, including glucose-regulated protein 78, c-jun N-terminal kinase 1 phosphorylation, and eukaryotic initiation factor 2α phosphorylation, as well as X-box binding protein-1 splicing were measured in tunicamycin (TM)-treated human umbilical endothelial cells (HUVEC) treated with 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and other vitamin D analogs. When TM and 1,25-(OH)2D3 were added simultaneously, 1,25-(OH)2D3 prevented ER stress. However, the effect was much stronger when cells were pre-treated with 1,25-(OH)2D3 for 24-h. However, ER stress was not inhibited by 25-OH vitamin D3 (25-OHD3) or the vitamin D analog EB1089. Both ZK191784 and the vitamin D metabolite 24,25-dihydroxyvitamin D3 were as effective as 1,25-(OH)2D3 in preventing ER stress. Similar effects were observed dextrose-induced stress. All of the compounds tested, except for 25-OHD3, inhibited dextrose-induced (27.5mM) oxidative stress and ER stress. Although TM with and without 1,25-(OH)2D3 had no effect on VDR expression, inhibition of VDR expression via siRNA prevented 1,25-(OH)2D3, ZK191784, EB1089, and 24,25-dihydroxyvitamin D3 from inhibiting dextrose-mediated SO generation. Furthermore, each vitamin D analog, with the exception of 25-OHD3, prevented dextrose-induced toxicity. These results suggest that vitamin D has a protective effect on vascular endothelial cells.

Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies.

Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.

Role of Nanodiamonds in Drug Delivery and Stem Cell Therapy.

CONTEXT: The use of nanotechnology in medicine and more specifically drug delivery is set to spread rapidly. Currently many substances are under investigation for drug delivery and more specifically for cancer therapy. EVIDENCE ACQUISITION: Nanodiamonds (NDs) have contributed significantly in the development of highly efficient and successful drug delivery systems, and in stem cell therapy. Drug delivery through NDs is an intricate and complex process that deserves special attention to unravel underlying molecular mechanisms in order to overcome certain bottlenecks associated with it. It has already been established that NDs based drug delivery systems have excellent biocompatibility, nontoxicity, photostability and facile surface functionalization properties. RESULTS: There is mounting evidence that suggests that such conjugated delivery systems well retain the properties of nanoparticles like small size, large surface area to volume ratio that provide greater biocatalytic activity to the attached drug in terms of selectivity, loading and stability. CONCLUSIONS: NDs based drug delivery systems may form the basis for the development of effective novel drug delivery vehicles with salient features that may facilitate their utility in fluorescence imaging, target specificity and sustainedrelease.