Metabolome-wide association identifies altered metabolites and metabolic pathways in the serum of patients with cholangiocarcinoma.

Background & Aims: Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA. Methods: Leveraging a biospecimen collection, including samples from patients with digestive diseases and normal controls, global serum metabolomic and lipidomic profiling was performed on 213 patients with CCA and 98 healthy controls. The CCA cohort of patients included representation of intrahepatic, perihilar, and distal CCA tumours. Metabolome-wide association studies utilizing multivariable linear regression were used to perform case-control comparisons, followed by pathway enrichment analysis, CCA subtype analysis, and disease stage analysis. The impact of biliary obstruction was evaluated by repeating analyses in subsets of patients only with normal bilirubin levels. Results: Of the 420 metabolites that discriminated patients with CCA from controls, decreased abundance of cysteine-glutathione disulfide was most closely associated with CCA. Additional conjugated bile acid species were found in increased abundance even in the absence of clinically relevant biliary obstruction denoted by elevated serum bilirubin levels. Pathway enrichment analysis also revealed alterations in caffeine metabolism and mitochondrial redox-associated pathways in the serum of patients with CCA. Conclusions: The presented metabolomic and lipidomic profiling demonstrated multiple alterations in the serum of patients with CCA. These exploratory data highlight novel metabolic pathways in CCA and support future work in therapeutic targeting of these pathways and the development of a precision biomarker panel for diagnosis. Impact and implications: Cholangiocarcinoma (CCA) is a highly lethal hepatobiliary cancer with limited treatment response, highlighting the need for a better understanding of the disease biology. Using a global metabolomics and lipidomics platform, we characterized distinct changes in the serum of 213 patients with CCA compared with healthy controls. The results of this study elucidate novel metabolic pathways in CCA. These findings benefit stakeholders in both the clinical and research realms by providing a foundation for improved disease diagnostics and identifying novel targets for therapeutic design.

Linoleic acid-derived diol 12,13-DiHOME enhances NLRP3 inflammasome activation in macrophages.

12,13-dihydroxy-9z-octadecenoic acid (12,13-DiHOME) is a linoleic acid diol derived from cytochrome P-450 (CYP) epoxygenase and epoxide hydrolase (EH) metabolism. 12,13-DiHOME is associated with inflammation and mitochondrial damage in the innate immune response, but how 12,13-DiHOME contributes to these effects is unclear. We hypothesized that 12,13-DiHOME enhances macrophage inflammation through effects on NOD-like receptor protein 3 (NLRP3) inflammasome activation. To test this hypothesis, we utilized human monocytic THP1 cells differentiated into macrophage-like cells with phorbol myristate acetate (PMA). 12,13-DiHOME present during lipopolysaccharide (LPS)-priming of THP1 macrophages exacerbated nigericin-induced NLRP3 inflammasome activation. Using high-resolution respirometry, we observed that priming with LPS+12,13-DiHOME altered mitochondrial respiratory function. Mitophagy, measured using mito-Keima, was also modulated by 12,13-DiHOME present during priming. These mitochondrial effects were associated with increased sensitivity to nigericin-induced mitochondrial depolarization and reactive oxygen species production in LPS+12,13-DiHOME-primed macrophages. Nigericin-induced mitochondrial damage and NLRP3 inflammasome activation in LPS+12,13-DiHOME-primed macrophages were ablated by the mitochondrial calcium uniporter (MCU) inhibitor, Ru265. 12,13-DiHOME present during LPS-priming also enhanced nigericin-induced NLRP3 inflammasome activation in primary murine bone marrow-derived macrophages. In summary, these data demonstrate a pro-inflammatory role for 12,13-DiHOME by enhancing NLRP3 inflammasome activation in macrophages.

Coarse-grained force field for ZIF-8: A study on adsorption, diffusion, and structural properties.

Metal-organic frameworks (MOFs) are revolutionizing a spectrum of industries, from groundbreaking gas storage solutions to transformative biological system applications. The intricate architecture of these materials necessitates the use of advanced computational techniques for a comprehensive understanding of their molecular structure and prediction of their physical properties. Coarse-grained (CG) simulations shine a spotlight on the often-neglected influences of defects, pressure effects, and spatial disorders on the performance of MOFs. These simulations are not just beneficial but indispensable for high-demand applications, such as mixed matrix membranes and intricate biological system interfaces. In this work, we propose an optimized CG force field tailored for ZIF-8. Our work provides a deep dive into sorption isotherms and diffusion coefficients of small molecules. We demonstrate the structural dynamics of ZIF-8, particularly how it responds to pressurization, which affects its crystal structure and leads to local changes in aperture size and area. Emphasizing the game-changing potential of CG simulations, we explore the characteristics of amorphization in ZIF-8. Through computational exploration, we aim to bridge the knowledge gap, enhancing the potential applications of nanoporous materials for various applications.

Prevalence of Internet Addiction and Its Associated Risk Factors Among Medical Students in Sudan: A Cross-Sectional Study.

Background Internet addiction has been studied extensively worldwide and shown to have adverse social, psychological, and functional consequences. It has become a global health issue, particularly among young adults. Unfortunately, few studies have been conducted among medical students in Sudan. This study aimed to measure the prevalence of internet addiction and determine its associated risk factors among medical students in Sudan. Methods This cross-sectional study was conducted among medical students using a systematic sampling technique. An online structured questionnaire was used, which included sociodemographic data and the Internet Addiction Test (IAT) to assess the presence and severity of internet addiction, as well as the Kessler Questionnaire to assess psychological distress. Results Among the 307 medical students who participated in this study, 63.8% (n=196) were female. The majority 78.5% (n=242) were aged 18-22 years, and the prevalence of internet addiction was 75.5% (n=232). The addiction levels were as follows: mild, 39.7% (n=122); moderate, 33.2% (n=102); and severe, 2.6% (n=8). Multivariate regression analysis revealed that being a female medical student was associated with a 1.9 times higher risk of internet addiction (adjusted odds ratio (AOR) = 1.87, p = 0.033). Psychological distress was associated with a 6.368-fold higher risk of internet addiction compared to non-distressed students (AOR = 6.368, p < 0.001). Additionally, students in the clinical years had a lower risk of internet addiction, specifically in the fourth and fifth years (AOR = 0.325, p = 0.010; AOR = 0.398, p = 0.043, respectively). Conclusions This study found a high prevalence of internet addiction among medical students at the National University, Khartoum, Sudan, which was strongly associated with mental distress. Effective awareness programs, potentially initiated by educational authorities, are required to educate students on limiting excessive internet usage and addressing associated risk factors. Future research should include longitudinal and multi-university studies to obtain more generalizable results and to investigate the relationship between internet addiction and mental distress more robustly.

Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts.

Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.

Role of Endoscopic Ultrasound in Staging and Vascular Assessment of Pancreatic Cancer.

Introduction Computed tomography (CT) of the abdomen with contrast stands as the gold standard for assessing pancreatic cancer, encompassing both staging and vascular analysis. However, not all patients are suitable candidates for contrast-enhanced CT (CECT) scans due to factors such as contrast agent allergies, pregnancy, renal impairment, radiation risks, and limited tissue sampling capability in CECT scans of the abdomen. In light of these challenges, this study evaluated the diagnostic capabilities of endoscopic ultrasound (EUS) compared to CECT for staging and vascular assessment of pancreatic cancer. Methods Fifty patients diagnosed with pancreatic cancer underwent evaluations using both CECT scans and EUS, focusing on staging and vascular invasion assessment. Vascular evaluation was carried out using a categorization system based on EUS findings, classifying them into three types based on the tumor-vessel relationship: Type 1 indicating clear invasion or encasement of a vessel by a tumor or contact with a vessel wall exceeding 180 degrees, Type 2 representing abutment, wherein a tumor contacts a vessel wall but at an angle less than 180 degrees, and Type 3 implying clear non-invasion, where a discernible distance exists between a tumor and a vessel. In this categorization, Type 1 and Type 2 indicated signs of vascular invasion, while Type 3 indicated vascular non-invasion. These findings were subsequently compared to the results from CECT scans. The endoscopist performing EUS was blinded to the CT outcomes prior to the examination. Results Regarding pancreatic cancer staging, EUS exhibited remarkable sensitivity, specificity, and accuracy rates of 100% according to the T criterion.As for vascular invasion assessment, EUS demonstrated sensitivity, specificity, and accuracy of 100%, 95.93%, and 96%, respectively, for venous invasion. For arterial invasion, the figures were 95.65% sensitivity, 100% specificity, and an overall accuracy of 99.5%. Conclusion EUS is an effective modality for evaluating both staging and vascular invasion in pancreatic cancer, boasting exceptional sensitivity, specificity, and accuracy rates. The findings are robust enough to consider EUS a viable alternative to CT scans in evaluation, with the added advantage of EUS offering tissue sampling capability.

Unexpectedly High Propylene/Propane Separation Performance of Asymmetric Mixed-Matrix Membranes through Additive-Assisted In Situ ZIF-8 Filler Formation: Experimental and Computational Studies.

Zeolitic-imidazolate framework-8 (ZIF-8), composed of a zinc center tetrahedrally coordinated with 2-methylimidazolate linkers, has garnered extensive attention as a selective filler for propylene-selective mixed-matrix membranes (MMMs). Recently, we reported an innovative and scalable MMM fabrication approach, termed "phase-inversion in sync with in situ MOF formation" (PIMOF), aimed at addressing the prevailing challenges in MMM processing. In this study, we intend to investigate the effect of additives, specifically sodium formate and 1,4-butanediol, on the modification of ZIF-8 filler formation within the polymer matrix in order to further improve the separation performance of the asymmetric MMMs prepared by the PIMOF. Remarkably, MMMs prepared with sodium formate as an additive in the coagulation bath exhibited an unprecedented C3H6/C3H8 separation factor of 222.5 ± 1.8 with a C3H6 permeance of 10.1 ± 0.3 GPU, surpassing that of MMMs prepared without additives (a C3 separation factor of 57.7 ± 11.2 with a C3 permeance of 22.5 ± 4.5 GPU). Our computational work complements the experimental investigation by studying the effect of ZIF-8 nanoparticle size on the specific surface interaction energy and apertures of ZIF-8. Calculations indicate that by having smaller ZIF-8 nanoparticles, stronger interactions are present with the polymer affecting the aperture of ZIF-8 nanoparticles. This reduction in aperture size is expected to improve selectivity toward propylene by reducing the permeability of propylene. These results represent a significant advancement, surpassing the performance of all previously reported propylene-selective MMMs and most high-quality polycrystalline ZIF-8 membranes. The notably enhanced separation performance primarily arises from the formation of exceedingly small ZIF-8-like particles with an amorphous or poorly crystalline structure, corroborated by our computational work.

Baseline Characteristics and Use of Pretherapeutic 18 F-Fluorodeoxyglucose-PET for Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy. Surgical resection is the only curative modality combined with neoadjuvant chemotherapy to improve survival. Given the limitations of traditional responses such as cross-sectional imaging (CT/MRI) or tumor markers, carbohydrate antigen 19-9 (CA19-9), the 2023 National Comprehensive Cancer Network guidelines included 18 F-fluorodeoxyglucose (FDG)-PET as an adjunct to assess response to neoadjuvant chemotherapy. There are common misconceptions on the metabolic activity (tumor avidity) in PDAC so we aimed to describe the baseline characteristics and use of FDG-PET in a cohort of treatment-naive patients with PDAC. STUDY DESIGN: A single-center retrospective study was conducted capturing all biopsy-proven, treatment-naive patients with PDAC who underwent either baseline FDG-PET/CT or FDG-PET/MRI imaging between 2008 and 2023. Baseline FDG-PET characteristics were collected, including primary tumors' maximum standardized uptake value defined as metabolic activity (FDG uptake) of tumor compared with surrounding pancreatic parenchymal background, and the identification of extrapancreatic metastatic disease. RESULTS: We identified 1,095 treatment-naive patients with PDAC who underwent baseline FDG-PET imaging at diagnosis. CA19-9 was elevated in 76% of patients. Overall, 96.3% (1,054) of patients had FDG-avid tumors with a median maximum standardized uptake value of 6.4. FDG-PET also identified suspicious extrapancreatic metastatic lesions in 50% of patients, with a higher proportion (p < 0.001) in PET/MRI (59.9%) vs PET/CT (44.3%). After controlling for CA19-9 elevation, PET/MRI was superior in detection of extrapancreatic lesions compared with PET/CT. CONCLUSIONS: FDG-PET has significant use in PDAC as a baseline imaging modality earlier neoadjuvant therapy given the majority of tumors are FDG-avid. FDG-PET can identify additional extrapancreatic suspicious lesions allowing for optimal initial staging, with PET/MRI having increased sensitivity over PET/CT.

Prevalence and risk factors of erectile dysfunction in cirrhotic patients: An observational study.

Background: Erectile dysfunction (ED) is a prevalent complication observed in male patients with liver cirrhosis; however, there is limited understanding of the etiological determinants responsible for its occurrence. The objective of this investigation is to explore potential contributory factors that underlie the development of ED in male patients with liver cirrhosis. Method: A cross-sectional study was conducted on 200 male patients with liver cirrhosis, who were divided into three groups according to the Child score. ED was studied using the International Index of Erectile Function (IIEF-5) Questionnaire and penile Doppler. Results: The prevalence of ED among the cirrhotic patients was 80%, and it was more frequent in patients with advanced liver disease (Child C). Penile venous leakage was observed in 20% of cirrhotic patients, which increased to 28.6% in those with advanced liver cirrhosis. Multivariate logistic regression analysis showed that age, low albumin levels, elevated INR, high hemoglobin levels, and Child C were predictors of ED in cirrhotic patients. Conclusion: Several clinical variables have been identified as potential contributors to the development of erectile dysfunction (ED) in patients with cirrhosis. These variables include advanced age, decreased levels of albumin, elevated INR, increased hemoglobin levels, and Child C classification. Early identification and treatment of these factors could potentially improve the quality of life for cirrhotic patients with ED. Notably, patients with ED in this population were observed to have elevated levels of INR, serum bilirubin, and hemoglobin, as well as reduced levels of serum albumin.

Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose.

BACKGROUND: Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy. METHODS: This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. RESULTS: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58-77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1-40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (-0.95, 95% CI -1.81 to -0.09) and total IgM (-162 mg/dL, 95% CI -298 to -26) showed signs of improvement by month 12. CONCLUSIONS: Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. TRIAL REGISTRATION: Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.

Mechanical replication of natural fever enhances protection against Aeromonas veronii infection in a teleost fish.

There is a long-standing debate on the attributes of temperature for fish health. We recently showed that thermoregulatory programs exerted through natural behavioural fever drive molecular and cellular responses that contribute to pathogen clearance, inflammation control, and tissue repair. These offered a mechanistic basis for the survival advantage conferred through fever. Herein, we show the attributes of mechanical replication of this fever response. Central to our approach was consideration of both, the maximal temperatures naturally selected by fish after infection, as well as the dynamics of thermal changes induced through this response. Coarse replication of the febrile thermal program as well as shorter truncated thermal schedules offered immune-regulatory capacity. Most notably, these promoted induction of acute inflammation and significant enhancements to pathogen clearance. However, the coarse protocols tested only partially recapitulated enhancements to induction and control of tissue repair. Our findings highlight a promising new alternative to combat infections in fish using a natural, drug-free, sustainable approach.

Bariatric Surgery Reduces Weight Loss, Comorbidities Prevalence, and Improves Quality of Life in the Southern Region of Saudi Arabia.

Background and Objectives: Bariatric surgery has been proposed as a treatment option for type 2 diabetes, but there is limited research on its efficacy and the use of standardized outcome measures. Therefore, this study aimed to evaluate the efficacy of bariatric surgery in managing type 2 diabetes and to assess the BAROS protocol postoperatively. Material and Methods: This cross-sectional study was conducted in southern Saudi Arabia, involving 346 bariatric surgery patients aged 18-60. This study collected data through an electronic questionnaire distributed via a Telegram group and Twitter hashtag. Anthropometric data, postoperative complications, and the evolution of obesity-related comorbidities were collected. The quality of life was evaluated using the Moorehead-Ardelt questionnaire of the BAROS protocol. The total BAROS score was classified as "Insufficient", "Moderate", "Good", "Very good", or "Excellent", considering the presence of comorbidities. The data were analyzed using SPSS software ver.23. Results: The mean age of the participants was 30.97 ± 8.49 years, and 70.81% were female. Sleeve Vertical Gastrectomy was the most common surgical technique used (n = 336). The excess weight loss percentage (EWL%) was 70.55 ± 22.57%, and 27.75% of participants achieved complete remission of type 2 diabetes. The total BAROS score was "Excellent" for 40.17% of participants and "Moderate" for 27.16%. The presence of comorbidities was negatively correlated with the BAROS score (r = -0.651, p < 0.001). Conclusions: Bariatric surgery effectively manages type 2 diabetes with a high rate of EWL% and complete remission. The BAROS protocol is a valuable tool for assessing the quality of life postoperatively, with most participants achieving a "Moderate" to "Excellent" score. Comorbidities negatively impact the BAROS score, highlighting the importance of managing these conditions postoperatively.

In vivo label-free optical signatures of chemotherapy response in human pancreatic ductal adenocarcinoma patient-derived xenografts.

Pancreatic cancer is a devastating disease often detected at later stages, necessitating swift and effective chemotherapy treatment. However, chemoresistance is common and its mechanisms are poorly understood. Here, label-free multi-modal nonlinear optical microscopy was applied to study microstructural and functional features of pancreatic tumors in vivo to monitor inter- and intra-tumor heterogeneity and treatment response. Patient-derived xenografts with human pancreatic ductal adenocarcinoma were implanted into mice and characterized over five weeks of intraperitoneal chemotherapy (FIRINOX or Gem/NabP) with known responsiveness/resistance. Resistant and responsive tumors exhibited a similar initial metabolic response, but by week 5 the resistant tumor deviated significantly from the responsive tumor, indicating that a representative response may take up to five weeks to appear. This biphasic metabolic response in a chemoresistant tumor reveals the possibility of intra-tumor spatiotemporal heterogeneity of drug responsiveness. These results, though limited by small sample size, suggest the possibility for further work characterizing chemoresistance mechanisms using nonlinear optical microscopy.

Therapeutic Efficacy of Temsirolimus in a Patient-derived Model of Metastatic Fibrolamellar Hepatocellular Carcinoma.

BACKGROUND/AIM: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare tumor presenting in younger patients without chronic liver disease. Up to 80-100% develop recurrent disease, necessitating additional surgery or systemic treatment. Systemic options and pre-clinical treatment studies are lacking. We previously described patient-derived xenograft (PDX) development, allowing for pre-clinical studies. Herein, we develop FLHCC PDX models and utilize these to define tumor characteristics and determine the efficacy of systemic agents. MATERIALS AND METHODS: Primary and lymph node metastatic tumor tissues were obtained at the time of FLHCC resection in two patients. Tumor lysates were screened for protein upregulation. Cell lines were generated from metastatic and primary tumor tissue. The viability of the cell lines was assessed after treatment with temsirolimus, gemcitabine/oxaliplatin, and FOLFIRINOX. Two PDX models were developed from metastatic tissue. For in vivo studies, tumor-bearing mice were treated with temsirolimus, FOLFIRINOX, and Gemcitabine/oxaliplatin. RESULTS: PDX models were successfully generated from metastatic FLHCC, which closely recapitulated the original tumor. Upregulation of mTOR was seen in metastatic tissue compared to primary tumors. Cell lines from metastatic tissue demonstrated significant sensitivity to temsirolimus. In vivo testing of PDX models demonstrated a significant response to single-agent temsirolimus with minimal toxicity. CONCLUSION: Herein, we demonstrate the feasibility of developing PDX models that closely recapitulate FLHCC. Upregulation of mTOR was seen in metastatic tissue compared to primary tissue. The efficacy of mTOR inhibition with temsirolimus treatment suggests that the upregulation of the mTOR pathway may be a significant mechanism for growth in metastatic lesions and a potential target for therapeutics.

Molecular detection of different virulence factors genes harbor pslA, pelA, exoS, toxA and algD among biofilm-forming clinical isolates of Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) is considered as the foremost cause of hospital-acquired infections due to its innate and plasmid-mediated resistance to multiple antibiotics making it a multi-drug resistant (MDR) pathogen. This study aimed to determine the biofilm formation ability and the presence of different virulence factors genes (pslA, pelA, exoS, toxA and algD) among biofilm-forming strains of P. aeruginosa clinical isolates from burn units in Ismailia Hospitals, Egypt. In our cross-sectional study, one hundred and twenty-six (126) non-duplicate clinical P. aeruginosa isolates were recovered from 450 clinical specimens from burn units in Ismailia Hospitals. The antibiotic sensitivity of strong and moderate biofilm producer isolates was investigated using the disc diffusion method. The isolated bacteria were tested for their ability to form biofilm using a microtiter plate assay. The expression of (pslA, pelA, exoS, toxA and algD) genes in biofilm producers isolates was detected using PCR. The MPA detected 80% (95 /126) isolates as biofilm producers, 18% (22/126) were strong biofilm producers, 34% (43/126) were moderate biofilm producers, 28% (35/126) were weak biofilm producers and 20% (31/126) non-biofilm producers. Susceptibility pattern analysis of biofilm-forming P. aeruginosa isolates (95) detected that 60% (68/ 95) were multi-drug resistant isolates (MDR). Resistance to all used antibiotics and multidrug resistance was higher among biofilm-producing than non-biofilm-producing strains, but the difference was statistically non-significant. Investigation of virulence factors associated genes revealed that 96%, 94%, 86.4%, 80.0% and 74% of the biofilm producers isolates were harboring algD, pslA, pel A, toxA and exoS gene, respectively. The present study confirmed that antimicrobial resistance and virulence genes were more prominent in biofilm-producing P. aeruginosa than in non-biofilm-producers.

Resective epilepsy surgery in a limited-resource settings: A cohort from a multi-disciplinary epilepsy team in a developing country.

Background: Multidisciplinary pre-surgical evaluation is vital for epilepsy surgery decision and outcomes. Resective epilepsy surgery with assisted monitoring is currently a standard treatment for focal drug resistant epilepsy (DRE). In resource-limited countries, lack of epilepsy surgery center is a huge challenge. We presented and illustrated how to create a multidisciplinary protocol with resource-limited settings in a developing country and epilepsy surgery outcome using brain mapping and monitoring techniques for ensuring satisfactory resection. Methods: We created multicentric incomplete but complementary units covering all epilepsy-related sub-specialties and covering a wide geographical area in our country. Then, we conducted a prospective and multicentric study with low resource settings on patients with focal DRE, who underwent resective epilepsy surgery and were followed up for at least 12 months and were evaluated for postoperative seizure outcome and complications if present. Preoperative comprehensive clinical, neurophysiological, neuropsychological, and radiological evaluations were performed by multidisciplinary epilepsy team. Intraoperative brain mapping including awake craniotomy and direct stimulation techniques, neurophysiological monitoring, and electrocorticography was carried out during surgical resection. Results: The study included 47 patients (18 females and 29 males) with mean age 20.4 ± 10.02 years. Twenty-two (46.8%) patients were temporal epilepsy while 25 (53.2%) were extra-temporal epilepsy. The epilepsy surgery outcome at the last follow up was Engel Class I (seizure free) in 35 (74.5%), Class II (almost seizure free) in 8 (17%), Class III (worthwhile improvement) in 3 (6.4%), and Class IV (no worthwhile improvement) in 1 patient (2.1%). Conclusion: With low resource settings and lack of single fully equipped epilepsy center, favorable outcomes after resective surgery in patients with focal DRE could be achieved using careful presurgical multidisciplinary selection, especially with using intraoperative brain mapping and electrocorticography techniques.

Multi-omics analysis of fecal samples in colorectal cancer Egyptians patients: a pilot study.

BACKGROUND: Colorectal cancer (CRC) is a public health concern and the second most common disease worldwide. This is due to genetic coding and is influenced by environmental aspects, in which the gut microbiota plays a significant role. The purpose of this study was to compare the microbiota makeup of CRC patients with that of healthy control and to identify upregulated and downregulated proteins and metabolites in CRC patients. Using a next-generation sequencing approach, fecal samples of five females (4 CRC patients and one healthy control) were analyzed by BGI DNBSEQ-T7, Hong Kong, China. Furthermore, proteomics and metabolomics analysis were performed using LC-MS/MS technique. RESULTS: Dysbiosis of gut microbiota has been observed in patients with CRC, with an increase in microbiota diversity at all taxonomic levels relative to healthy control. Where, at the functional level the bacterial species participate in many different pathways among them de novo nucleotide synthesis and amino acids pathways were aberrantly upregulated in CRC patients. Proteomics and metabolomics profiles of CRC patients showed different proteins and metabolites, a total of 360 and 158 proteins and metabolites, respectively were highly expressed compared to healthy control with fold change ≥ 1.2. Among the highly expressed proteins were transketolase, sushi domain-containing protein, sulfide quinone oxidoreductase protein, AAA family ATPase protein, carbonic anhydrase, IgG Fc-binding protein, nucleoside diphosphate kinase protein, arylsulfatase, alkaline phosphatase protein, phosphoglycerate kinase, protein kinase domain-containing protein, non-specific serine/threonine protein kinase, Acyl-CoA synthetase and EF-hand domain-containing protein. Some of the differential metabolites, Taurine, Taurocholic acid, 7-ketodeoxycholic acid, Glycochenodeoxycholic acid, Glycocholic acid, and Taurochenodeoxycholic acid that belong to bile acids metabolites. CONCLUSIONS: Some bacterial species, proteins, and metabolites could be used as diagnostic biomarkers for CRC. Our study paves an insight into using multi-omics technology to address the relationship between gut microbiota and CRC.

Identification of a ΔNp63-Dependent Basal-Like A Subtype-Specific Transcribed Enhancer Program (B-STEP) in Aggressive Pancreatic Ductal Adenocarcinoma.

A major hurdle to the application of precision oncology in pancreatic cancer is the lack of molecular stratification approaches and targeted therapy for defined molecular subtypes. In this work, we sought to gain further insight and identify molecular and epigenetic signatures of the Basal-like A pancreatic ductal adenocarcinoma (PDAC) subgroup that can be applied to clinical samples for patient stratification and/or therapy monitoring. We generated and integrated global gene expression and epigenome mapping data from patient-derived xenograft models to identify subtype-specific enhancer regions that were validated in patient-derived samples. In addition, complementary nascent transcription and chromatin topology (HiChIP) analyses revealed a Basal-like A subtype-specific transcribed enhancer program in PDAC characterized by enhancer RNA (eRNA) production that is associated with more frequent chromatin interactions and subtype-specific gene activation. Importantly, we successfully confirmed the validity of eRNA detection as a possible histologic approach for PDAC patient stratification by performing RNA-ISH analyses for subtype-specific eRNAs on pathologic tissue samples. Thus, this study provides proof-of-concept that subtype-specific epigenetic changes relevant for PDAC progression can be detected at a single-cell level in complex, heterogeneous, primary tumor material. IMPLICATIONS: Subtype-specific enhancer activity analysis via detection of eRNAs on a single-cell level in patient material can be used as a potential tool for treatment stratification.

Cancer "Avatars": Patient-Derived Xenograft Growth Correlation with Postoperative Recurrence and Survival in Pancreaticobiliary Cancer.

BACKGROUND: Pancreaticobiliary (PB) cancers are a diverse group of cancers with poor prognoses and high rates of recurrence after resection. Patient-derived xenografts (PDX), created from surgical specimens, provide a reliable preclinical research platform and high-fidelity cancer model from which to study these malignancies with consistent recapitulation of their original patient tumors in vivo. However, the relationship between PDX engraftment success (growth or no growth) and patient oncologic outcomes has not been well studied. We sought to evaluate the correlation between successful PDX engraftment and survival in several PB exocrine carcinomas, including the pancreatic and biliary tract. STUDY DESIGN: In accordance with IRB and Institutional Animal Care and Use Committee protocols and with appropriate consent and approval, excess tumor tissue obtained from surgical patients was implanted into immunocompromised mice. Mice were monitored for tumor growth to determine engraftment success. PDX tumors were verified to recapitulate their tumors of origin by a hepatobiliary pathologist. Xenograft growth was correlated with clinical recurrence and overall survival data. RESULTS: A total of 384 PB xenografts were implanted. The successful engraftment rate was 41% (158/384). We found that successful PDX engraftment was highly associated with both recurrence-free survival (p < 0.001) and overall survival (p < 0.001) outcomes. Successful PDX tumor generation occurs significantly in advance of clinical recurrences in their corresponding patients (p < 0.001). CONCLUSIONS: Successful PB cancer PDX models predict recurrence and survival across tumor types and may provide critical lead time to alter patients' surveillance or treatment plans before cancer recurrence.