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An immunologic system attacking the body's own tissues is a hallmark of autoimmune disorders, which encompass a wide range of unique conditions. Numerous essential biologic functions, including the regulation of the immune system, inflammation, cell division, and tissue repair, are carried out by cytokines. Natural compounds are an effective treatment for autoimmune illnesses by modulation of inflammatory cytokines and infiltration of leukocytes into the inflamed tissue. Here, anti-arthritic study was carried out using oral administration of Azelaic acid (AzA) for 28 days with doses (20, 40, and 80 mg/kg) in Complete Freund's Adjuvant (CFA) induced arthritis model. AzA ameliorated the adjuvant-induced arthritis by decreasing arthritic score, paw volume, improved body-weight alterations and serum levels of PGE2, 5-LOX and anti-ccp. AzA showed significant down regulation of NF-κB, COX-II, TNF-α, IL-17, IL-1β, IL-6, and up regulation of IL4 and IL10. Hemoglobin and RBCs count remarkably increased and ESR, CRP, platelets, WBCs levels markedly reduced in post treatment. In addition, the weakened SOD (superoxide dismutase), Catalase (CAT), Glutathione (GSH) activity and the increased levels of malondialdehyde (MDA) were all reversed by AzA treatment. And showed improved radiographical and histologic alterations in the structure of the joints. Molecular docking studies targeting COX-II, iNOS, TNF-α, 5-LOX, IL4, IL10, IL-6, and IL-17 establish a correlation between theoretical and experimental results. Results showed that AzA inhibit pro-inflammatory cytokines (COX-II, TNF-α, 5-LOX, IL-17, NF-κB, IL-1β, and IL-6) and increase anti-inflammatory cytokines, which supported the anti-arthritic and immunomodulatory potential of AzA. [ABSTRACT FROM AUTHOR]

Background: A right- or left-sided liver resection can be considered in about half of patients with perihilar cholangiocarcinoma (pCCA), depending on tumor location and vascular involvement. This study compared postoperative mortality and long-term survival of right- versus left-sided liver resections for pCCA. Methods: Patients who underwent major liver resection for pCCA at 25 Western centers were stratified according to the type of hepatectomy—left, extended left, right, and extended right. The primary outcomes were 90-day mortality and overall survival (OS). Results: Between 2000 and 2022, 1701 patients underwent major liver resection for pCCA. The 90-day mortality was 9% after left-sided and 18% after right-sided liver resection (p < 0.001). The 90-day mortality rates were 8% (44/540) after left, 11% (29/276) after extended left, 17% (51/309) after right, and 19% (108/576) after extended right hepatectomy (p < 0.001). Median OS was 30 months (95% confidence interval [CI] 27–34) after left and 23 months (95% CI 20–25) after right liver resection (p < 0.001), and 33 months (95% CI 28–38), 27 months (95% CI 23–32), 25 months (95% CI 21–30), and 21 months (95% CI 18–24) after left, extended left, right, and extended right hepatectomy, respectively (p < 0.001). A left-sided resection was an independent favorable prognostic factor for both 90-day mortality and OS compared with right-sided resection, with similar results after excluding 90-day fatalities. Conclusions: A left or extended left hepatectomy is associated with a lower 90-day mortality and superior OS compared with an (extended) right hepatectomy for pCCA. When both a left and right liver resection are feasible, a left-sided liver resection is preferred. [ABSTRACT FROM AUTHOR]

The monoterpene oxide, Eucalyptol (1,8-Cineole), a primary component of eucalyptus oil, has been evaluated pharmacologically for anti-inflammatory and analgesic activity. Current research aimed to evaluate Eucalyptol's anti-arthritic potential in a Complete Freund's adjuvant induced arthritis that resembles human rheumatoid arthritis. Polyarthritis developed after 0.1 mL CFA injection into the left hind footpad in rats. Oral administration of Eucalyptol at various doses (100, 200 and 400 mg/kg) significantly reduced paw edema, body weight loss, 5-LOX, PGE2 and Anti-CCP levels. Real‐time PCR investigation showed significant downregulation of COX-2, TNF-α, NF-κB, IL-17, IL-6, IL-1β and upregulation of IL-4 and IL-10 in Eucalyptol treated groups. Hemoglobin and RBCs counts significantly increased post-treatment with Eucalyptol while ESR, CRP, WBCs and platelets count significantly decreased. Eucalyptol significantly increased Superoxide Dismutase, Catalase and Glutathione levels compared to CFA-induced arthritic control however, MDA significantly decreased post-treatment. Further, radiographic and histopathological examination of the ankle joints of rodents administered Eucalyptol revealed an improvement in the structure of the joints. Piroxicam was taken as standard. Furthermore, molecular docking findings supported the anti-arthritic efficacy of Eucalyptol exhibited high binding interaction against IL-17, TNF-α, IL-4, IL-10, iNOS NF-κB, 5-LOX, and COX-2. Eucalyptol has reduced the severity of CFA induced arthritis by promoting anti-inflammatory cytokines for example IL-4, IL-10 and by inhibiting pro-inflammatory cytokines such as 5-LOX, COX-2, IL-17, NF-κB, TNF-α, IL-6 and IL-1β. Therefore, Eucalyptol might be as a potential therapeutic agent because of its pronounced anti-oxidant and anti-arthritic activity. [ABSTRACT FROM AUTHOR]

Medicinal plants play a pivotal role in the prevention of chronic non-communicable diseases including arthritis. Despite the traditional use of Asparagus dumosus in arthritis, it has not been studied yet for its effectiveness in arthritis. This study was aimed to explore the antiarthritic potential of A. dumosus in formaldehyde and complete Freund's adjuvant (CFA)-induced arthritic rats. Body weight, arthritic index, hepatic oxidative stress, hematological, biochemical and inflammatory markers were assessed using ELISA, whilst qRT-PCR studies were carried out for the mRNA expression of IL-1b, IL-6, RANKL, OPG, TNF-α and COX-2 genes. GCMS and HPLC analysis were performed to identify the secondary metabolites of A. dumosus. From day 8 to 28 post-administration of formaldehyde and CFA, oral administration of A. dumosus (600, 300 and 150 mg/kg) showed a noteworthy improvement (p < 0.001) in the body weights, immune organ weights, serum levels of rheumatoid (RA) factor, C-reactive protein, TNF-α and IL-6 levels in arthritic rats similar to the effect of piroxicam and methotrexate. Subsequently, the administration of A. dumosus to formaldehyde and CFA-challenged rats, caused a marked decrease (p < 0.001) in the mRNA expression of IL-1b, IL-6, OPG, RANKL, TNF-α and COX-2 genes in treated rats. Likewise, when assessed for antioxidant potential, A. dumosus produced a pronounced (p < 0.001) reduction in malondialdehyde (MDA) levels and hydrogen peroxide (H2O2) production, whilst a dose-dependent (p < 0.001) increase in catalase (CAT) and superoxide dismutase (SOD) activities was recorded. GCMS profiling of A. dumosus presented benzaldehyde, 3-hydroxy-4-methoxy-, 1-decanol and undecane as plant compositions, whereas HPLC fingerprinting displayed quercetin, benzaldehyde, 3-hydroxy-4-methoxy-, gallic acid and cinnamic acid as plants constituents. These results depict that A. dumosus possesses anti-arthritic effect mediated possibly through attenuation of arthritic indices, chronic inflammatory and oxidative stress biomarkers along with down-regulation in the mRNA expression of arthritic candid genes. [ABSTRACT FROM AUTHOR]

Purpose: Only a few publications considered the influence of the spinopelvic parameters on below-hip anatomy. There is a lack of evidence about the relationship between the anatomic spinopelvic parameters and the posterior tibial slope (PTS). Therefore, the aim of this study was to analyze the association between fixed anatomic spinopelvic parameters and PTS. Methods: Adult patients presenting with lumbar, thoracic, or cervical complaints together with knee pain at a single hospital between 2017 to 2022 with available standing full-spine lateral radiograph and lateral knee radiograph were retrospectively reviewed. The measured parameters included the pelvic incidence (PI), the sacral kyphosis (SK), the pelvisacral angle, the sacral anatomic orientation (SAO), the sacral table angle, the sacropelvic angle and the PTS. Pearson's correlations and linear regression analyses were conducted. Results: A total of 80 patients (44 women), median age 63 years were analyzed. A strong positive correlation was identified between PI and PTS (r = 0.70, p < 0.001). A strong negative correlation was observed between PI and SAO (r = − 0.74, p < 0.001). A strong positive correlation was observed between PI and SK (r = 0.81, p < 0.001). A univariable linear regression analysis showed that PTS can be deduced from PI according to the following formula: PTS = 0.174 × PI − 1.138. Conclusion: This study is the first to support a positive correlation between the PI and the PTS. We demonstrate that knee anatomy is individually correlated to pelvic shape and therefore influences spinal posture. [ABSTRACT FROM AUTHOR]

Burn management is a natural and distinctly programmed process involving overlapping phases of hemostasis, inflammation, proliferation and remodeling. Burn wound healing involves initiation of inflammation, re-epithelialization, granulation, neovascularization and wound contraction. Despite the availability of multiple preparations for management of burn wound, there is dire need for efficacious alternative agents. Current approaches for burn wound management include pharmaceutical agents and antibiotics. However, high cost of synthetic drugs and accelerated resistance to antibiotics is challenging for both developed and developing nations. Among alternative options, medicinal plants have been a biocompatible, safe and affordable source of preventive/curative approaches. Due to cultural acceptance and patient compliance, there has been a focus on the use of botanical drugs and phytochemicals for burn wound healing. Keeping in consideration of medicinal herbs and phytochemicals as suitable therapeutic/adjuvant agents for burn wound management, this review highlights therapeutic potential of 35 medicinal herbs and 10 phytochemicals. Among these, Elaeis guineensis, Ephedra ciliate and Terminalia avicennioides showed better burn wound healing potential with varied mechanisms such as modulation of TNF-alpha, inflammatory cytokines, nitric oxide, eicosanoids, ROS and leukocyte response. Phytochemicals (oleanolic acid, ursolic acid, kirenol) also showed promising role in burn wound management though various pathways involving such as down regulation of TNF-alpha, IL-6 and inflammatory mediators including plasma proteases and arachidonic acid metabolites. This review provides a pavement for therapeutic/adjuvant use of potential botanical drugs and novel druggable phyto-compounds to target skin burn injury with diverse mechanisms, affordability and safety profile. [ABSTRACT FROM AUTHOR]

Peri-hilar cholangiocarcinoma (pCCA) is chemorefractory and limited genomic analyses have been undertaken in Western idiopathic disease. We undertook comprehensive genomic analyses of a U.K. idiopathic pCCA cohort to characterize its mutational profile and identify new targets. Whole exome and targeted DNA sequencing was performed on forty-two resected pCCA tumors and normal bile ducts, with Gene Set Enrichment Analysis (GSEA) using one-tailed testing to generate false discovery rates (FDR). 60% of patients harbored one cancer-associated mutation, with two mutations in 20%. High frequency somatic mutations in genes not typically associated with cholangiocarcinoma included mTOR, ABL1 and NOTCH1. We identified non-synonymous mutation (p.Glu38del) in MAP3K9 in ten tumors, associated with increased peri-vascular invasion (Fisher's exact, p < 0.018). Mutation-enriched pathways were primarily immunological, including innate Dectin-2 (FDR 0.001) and adaptive T-cell receptor pathways including PD-1 (FDR 0.007), CD4 phosphorylation (FDR 0.009) and ZAP70 translocation (FDR 0.009), with overlapping HLA genes. We observed cancer-associated mutations in over half of our patients. Many of these mutations are not typically associated with cholangiocarcinoma yet may increase eligibility for contemporary targeted trials. We also identified a targetable MAP3K9 mutation, in addition to oncogenic and immunological pathways hitherto not described in any cholangiocarcinoma subtype. [ABSTRACT FROM AUTHOR]

With the emergence of COVID-19, smart healthcare, the Internet of Medical Things, and big data-driven medical applications have become even more important. The biomedical data produced is highly confidential and private. Unfortunately, conventional health systems cannot support such a colossal amount of biomedical data. Hence, data is typically stored and shared through the cloud. The shared data is then used for different purposes, such as research and discovery of unprecedented facts. Typically, biomedical data appear in textual form (e.g., test reports, prescriptions, and diagnosis). Unfortunately, such data is prone to several security threats and attacks, for example, privacy and confidentiality breach. Although significant progress has been made on securing biomedical data, most existing approaches yield long delays and cannot accommodate real-time responses. This paper proposes a novel fog-enabled privacy-preserving model called δ r sanitizer, which uses deep learning to improve the healthcare system. The proposed model is based on a Convolutional Neural Network with Bidirectional-LSTM and effectively performs Medical Entity Recognition. The experimental results show that δ r sanitizer outperforms the state-of-the-art models with 91.14% recall, 92.63% in precision, and 92% F1-score. The sanitization model shows 28.77% improved utility preservation as compared to the state-of-the-art. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic inflammatory illness caused by an autoimmune disorder of synovial membrane resulting in synovial membrane dysfunction. The available treatment particularly focuses on inhibiting macrophage proliferation and reducing the generation of pro-inflammatory cytokines. However, therapeutic success of current treatment options at targeted site is limited; therefore, development of promising therapeutic strategy is the need of time that may provide better targeted delivery of drug with added safety. In development of precision medicine to manage RA, nanotechnology is a viable option to be considered. Recent research using nanoparticles for the treatment of RA, particularly polymeric nanoparticles, has been discussed in this article. Using polymeric nanoparticles as a therapeutic method has shown considerable promise of enhancing treatment success over standard medications used in routine. It is exclusively evident that the viability of using nanoparticles is mainly owed due to their biocompatibility, chemical stability, controlled drug release, and selective drug delivery to inflamed tissues in RA model animals. The current analysis focuses on the critical design characteristics of RA-targeted nanotechnology-based strategies in quest of better therapeutic strategies for RA, and to identify leading polymer as the most effective medications in RA therapy. [ABSTRACT FROM AUTHOR]

This document is a response to a letter to the editor regarding a study on the association between posterior tibial slope (PTS) and anatomic spinopelvic parameters. The study found a significant positive correlation between pelvic incidence (PI) and PTS, a significant negative correlation between PI and sacral anatomic orientation, and a strong positive correlation between PI and sacral kyphosis. The authors address the concerns raised about their methodology, explaining why lumbar lordosis was not included and discussing the limitations of their study, such as the lack of CT scans and rasterstereographic analysis. They express gratitude for the feedback and hope that they have adequately addressed the points raised. [Extracted from the article]

Background: Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear. Methods: Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006–2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern. Results: Eighty-three (48 male/35 female) patients were enrolled. The median age was 64 years (range 33–80). The median follow-up was 21.7 months (range 0.3–92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5 months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P < 0.05). No difference with respect to RFS and recurrence pattern was found between the groups (P > 0.05). Conclusion: Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker. [ABSTRACT FROM AUTHOR]

Robot-assisted laparoscopic surgery is yet another modification of minimally invasive liver surgery. It is described as feasible and safe from the surgical point of view; however, oncological outcomes need to be adequately analysed to justify the use of this technique when resecting malignant liver tumours. We reviewed existing English medical literature on robot-assisted laparoscopic liver surgery. We analysed surgical outcomes and oncological outcomes. We analysed operative parameters including operative time, type of hepatectomy, blood loss, conversion rate, morbidity and mortality rates and length of stay. We also analysed oncological outcomes including completeness of resection (R status), recurrence, survival and follow-up data. A total of 582 patients undergoing robot-assisted laparoscopic liver surgery were analysed from 17 eligible publications. Only 5 publications reported survival data. The overall morbidity was 19% with 0.2% reported mortality. R0 resection was achieved in 96% of patients. Robotic liver surgery is feasible and safe with acceptable morbidity and oncological outcomes including resection margins. However, well-designed trials are required to provide evidence in terms of survival and disease-free intervals when performed for malignancy. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is considered as xenoestrogen, a crucial component utilized for the manufacturing of plastic products. It has a potential to disrupt the endocrine system and induces endocrine-related metabolic disorders. We aimed to investigate the exposure of BPA in Pakistani population and its association with sociodemographic features, dietary habits, and risk factors of diabetes mellitus (DM). This cross-sectional study was conducted on 400 participants among which 61.75% participants were diabetic and 38.25% were non-diabetic. We developed a structured questionnaire, gathered sociodemographic data, and collected their urine and blood samples for the estimation of BPA and various biomarkers as risk factors of DM, respectively. Pearson correlation coefficient was determined for urinary BPA levels and DM risk factors. Urinary BPA values were adjusted for confounders. Sociodemographic data shown that urinary BPA level was significantly higher (p < 0.05) in obese people (BMI > 27) living in semi-urban and industrial areas. BPA was detectable in 75% of study participants. Urinary BPA level was found to be higher in diabetic participants compared with that of non-diabetics. A significant correlation is observed between BPA exposure and DM risk factors. We found that urinary BPA level was correlated with elevated levels of HbA1c (r = 0.6028), HOMA-IR (r = 0.5356), CRP (r = 0.6946), BUN (r = 0.6077), AST (r = 0.5151), FFA (r = 0.5759), TGs (r = 0.5608), and MDA (r = 0.6908). Hence, our study adds to the growing body of evidence supporting the role of BPA exposure as a risk factor for DM and may be associated with higher glycemic index, increased pro-inflammatory and oxidative stress biomarkers, dyslipidemia, and impaired functioning of the liver and kidney. Heating food in plastic containers and consumption of packed food items are the main sources of BPA exposure which are positively associated with DM. [ABSTRACT FROM AUTHOR]

Purpose: Emergency department thoracotomy (EDT) is a potentially life-saving procedure, performed on patients suffering traumatic cardiac arrest. Multiple indications have been reported, but overall survival remains unclear for each indication. The objective of this systematic review is to determine overall survival, survival stratified by indication, and survival stratified by geographical location for patients undergoing EDT across the world. Methods: Articles published between 2000 and 2016 were identified which detailed outcomes from EDT. All articles referring to pre-hospital, delayed, or operating room thoracotomy were excluded. Pooled odds ratios (OR) were calculated comparing differing indications. Results: Thirty-seven articles, containing 3251 patients who underwent EDT, were identified. There were 277 (8.5%) survivors. OR demonstrate improved survival for; penetrating vs blunt trauma (OR 2.10; p 0.0028); stab vs gun-shot (OR 5.45; p < 0.0001); signs of life (SOL) on admission vs no SOL (OR 5.36; p < 0.0001); and SOL in the field vs no SOL (OR 19.39; p < 0.0001). Equivalence of survival was demonstrated between cardiothoracic vs non-cardiothoracic injury (OR 1.038; p 1.000). Survival was worse for USA vs non-USA cohorts (OR 1.59; p 0.0012). Conclusions: Penetrating injury remains a robust indication for EDT. Non-cardiothoracic cause of cardiac arrest should not preclude EDT. In the absence of on scene SOL, survival following EDT is extremely unlikely. Survival is significantly higher in the non-USA publications; reasons for this are highly complex. A UK multicentre prospective study which collects standardised data on all EDTs could provide robust evidence for better patient stratification. [ABSTRACT FROM AUTHOR]

Background: Clinical decision-making around the management of liver-limited stage IV colorectal cancer involves careful assessment of the potential risks and benefits of surgery. This balance can often be optimised through appropriate patient selection to ensure long-term benefit of any operation, with fastidious perioperative care to minimize risk.Methods: We reviewed selected relevant articles from the existing literature.Results: Multi-platform imaging is routinely used to determine distribution of disease and whether lesions are technically resectable, but what remains less clear is how to identify patients in whom resection is likely to deliver long-term benefits. A number of prognostic markers have been identified, with growing interest in direct assessment of tumour biology; genotyping of RAS status is routine in specific situations. Following a multidisciplinary team decision to proceed to surgery, patients undergo perioperative assessment and optimisation. Cardiopulmonary exercise testing helps to stratify perioperative risk: patients with low uptake of oxygen at the anaerobic threshold are known to have worse perioperative outcomes, and prehabilitation may offer the chance to reduce this risk. Intraoperative anaesthetic management is on a patient-by-patient basis but sub-normal hydration, epidural anaesthesia and steroids play a key role. Enhanced recovery after surgery programmes have improved perioperative outcomes while providing a potential economic benefit.Conclusion: Despite very good perioperative results, surgical management is not curative for the majority of patients, highlighting the need to further refine patient selection and definition of treatment aim on a patient-by-patient basis. [ABSTRACT FROM AUTHOR]

Surgical resection remains the only proven curative treatment for peri-hilar cholangiocarcinoma. Despite recent advances in liver surgery techniques and perioperative care, resection for peri-hilar cholangiocarcinoma remains associated with significant morbidity and mortality. Considerable variation in the perioperative management of these patients exists. Optimal perioperative management has the potential to deliver improved outcomes. This article seeks to summarize the evidence underpinning best practice in the perioperative care of patients undergoing resection of peri-hilar cholangiocarcinoma. The authors also seek to identify areas where research efforts and future clinical trials should be targeted. [ABSTRACT FROM AUTHOR]

Background: Activating mutations in KRAS have been suggested as potential predictive and prognostic biomarkers. However, the prognostic impact of specific point mutations remains less clear. This study assessed the prognostic impact of specific KRAS mutations on survival for patients with colorectal cancer.Methods: Retrospective review of patients KRAS typed for advanced and recurrent colorectal cancer between 2010 and 2015 in a UK Cancer Network.Results: We evaluated the impact of KRAS genotype in 392 patients. Mutated KRAS was detected in 42.9% of tumours. KRAS mutations were more common in moderate vs well-differentiated tumours. On multivariate analysis, primary tumour T stage (HR 2.77 (1.54-4.98), P=0.001), N stage (HR 1.51 (1.01-2.26), P=0.04), curative intent surgery (HR 0.51 (0.34-0.76), P=0.001), tumour grade (HR 0.44 (0.30-0.65), P=0.001) and KRAS mutation (1.54 (1.23-2.12), P=0.005) were all predictive of overall survival. Patients with KRAS codon 12 mutations had worse overall survival (HR 1.76 (95% CI 1.27-2.43), P=0.001). Among the five most common codon 12 mutations, only p.G12C (HR 2.21 (1.15-4.25), P=0.01) and p.G12V (HR 1.69 (1.08-2.62), P=0.02) were predictive of overall survival.Conclusions: For patients with colorectal cancer, p.G12C and p.G12V mutations in codon 12 were independently associated with worse overall survival after diagnosis. [ABSTRACT FROM AUTHOR]

Opinion Statement: The role of physical interventions (surgical resection and surgical/radiological ablation) for liver metastases of colorectal cancer has changed dramatically over the last 10-15 years. Whereas in the 1990s, when only those patients with up to three unilobar metastases were considered for any form of such intervention, our present approach to these physical interventions is determined by how much viable disease-free liver can be preserved (most authorities accepting 25-30% disease-free future remnant liver volume) and the possibility of further such interventions if the disease recurs in the liver. There is increasing evidence that for smaller tumours (<3 cm diameter), ablation therapy may be therapeutically the equivalent of surgical resection and possibly safer in high-risk patients with multiple comorbidities. Therefore, we now consider the use of such ablation therapies (with or without surgical resection) to be clinically effective when treating patients with multiple bilobar metastases that have shown good radiologic response to prior systemic therapy. [ABSTRACT FROM AUTHOR]

The application of primary human hepatocytes following isolation from human tissue is well accepted to be compromised by the process of dedifferentiation. This phenomenon reduces many unique hepatocyte functions, limiting their use in drug disposition and toxicity assessment. The aetiology of dedifferentiation has not been well defined, and further understanding of the process would allow the development of novel strategies for sustaining the hepatocyte phenotype in culture or for improving protocols for maturation of hepatocytes generated from stem cells. We have therefore carried out the first proteomic comparison of primary human hepatocyte differentiation. Cells were cultured for 0, 24, 72 and 168 h as a monolayer in order to permit unrestricted hepatocyte dedifferentiation, so as to reveal the causative signalling pathways and factors in this process, by pathway analysis. A total of 3430 proteins were identified with a false detection rate of <1 %, of which 1117 were quantified at every time point. Increasing numbers of significantly differentially expressed proteins compared with the freshly isolated cells were observed at 24 h (40 proteins), 72 h (118 proteins) and 168 h (272 proteins) ( p < 0.05). In particular, cytochromes P450 and mitochondrial proteins underwent major changes, confirmed by functional studies and investigated by pathway analysis. We report the key factors and pathways which underlie the loss of hepatic phenotype in vitro, particularly those driving the large-scale and selective remodelling of the mitochondrial and metabolic proteomes. In summary, these findings expand the current understanding of dedifferentiation should facilitate further development of simple and complex hepatic culture systems. [ABSTRACT FROM AUTHOR]

Surgical resection is the gold standard treatment for colorectal liver metastasis, with reported five-year survival rates of 40 %. Unfortunately, despite progress in systemic therapies and surgical techniques, only 20-30 % of patients can be offered this potentially curative treatment modality. Ablative therapies have recently been suggested to treat unresectable lesions or to extend the margins of resectability. Additionally, cases of local recurrence after hepatic surgery might require alternative strategies and options for re-intervention. Microwave ablation (MWA) has recently become a matter of particular interest for such indications. We, herein, present a review of the literature published between January 1999 and June 2013 from a database search with the following keywords: microwave, ablation, liver metastases, colorectal neoplasm, resection, hepatectomy, colonic neoplasm, cancer. Furthermore, we provide insight based on our own data for 28 consecutive patients who underwent hepatic resection combined with MWA from 2005 to 2012 in a single centre. [ABSTRACT FROM AUTHOR]

Purpose: Liver resection offers the chance of a cure for liver cancer. However, when extended hepatectomies were performed in combination with resection of the inferior vena cava (IVC), the procedures were reported to have a surgical mortality rate in excess of 5 %. While most of these operations were performed with the use of veno-venous bypass, this study presents our experience performing the procedure without the bypass. Methods: Data were collected from a prospectively maintained database. A retrospective evaluation of a consecutive series of concomitant IVC and liver resections was performed. Results: Five hundred and seventy-five liver resections were performed between June 2008 and November 2011. Eleven patients (1.9 %) underwent concomitant IVC and liver resections. One patient required segmental IVC replacement, and four IVC defects were closed using a bovine pericardial patch without bypass. Only one patient had histologically confirmed IVC invasion. There was no postoperative mortality. Nine postoperative complications occurred in five patients. No complications in terms of IVC patency were seen. Five patients had disease recurrence, one of whom died within 12 months of surgery. Conclusion: Concomitant liver and IVC resection is safe without using a bypass procedure, with acceptable short-term results. Meticulous technique, careful patient selection and a specialized anesthetic team are key to obtaining low postoperative morbidity and mortality rates and an acceptable oncological outcome. [ABSTRACT FROM AUTHOR]

The Feature Weighting Classifier (FWC) is an efficient multi-class classification algorithm for text data that uses Information Gain to directly estimate per-class feature weights in the classifier. This classifier requires only a single pass over the dataset to compute the feature frequencies per class, is easy to implement, and has memory usage that is linear in the number of features. Results of experiments performed on 128 binary and multi-class text and web datasets show that FWC's performance is at least comparable to, and often better than that of Naive Bayes, TWCNB, Winnow, Balanced Winnow and linear SVM. On a large-scale web dataset with 12,294 classes and 135,973 training instances, FWC trained in 13 s and yielded comparable classification performance to a state of the art multi-class SVM implementation, which took over 15 min to train. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to determine the pharmacological basis of the medicinal use of psyllium husk (Ispaghula) in gastrointestinal motility disorders.Methods: In-vivo studies were conducted on mice, and isolated rabbit jejunum and guinea-pig ileum were used in in-vitro experiments.Results: The crude extract of Ispaghula (Po.Cr) had a laxative effect in mice at 100 and 300 mg/kg, which was partially sensitive to atropine or SB203186 (5-HT(4) antagonist). At higher doses (500 and 1,000 mg/kg), Po.Cr had antisecretory and antidiarrheal activity. In guinea-pig ileum, Po.Cr (1-10 mg/ml) had a stimulatory effect, which was partially sensitive to atropine or SB203186. In rabbit jejunum, Po.Cr had a partially atropine-sensitive stimulatory effect followed by relaxation at 10 mg/ml. The relaxation was inhibited by the presence of L-NAME, a nitric oxide (NO) synthase inhibitor, or methylene blue, a guanylyl cyclase inhibitor. Similarly, the relaxant effect of Po.Cr on K(+) (80 mM)-induced contractions, was attenuated in the presence of L-NAME or methylene blue. Activity-directed fractionation of Po.Cr revealed that the gut stimulatory and inhibitory constituents were widely distributed in the aqueous and organic fractions.Conclusion: This study demonstrates that Ispaghula has a gut-stimulatory effect, mediated partially by muscarinic and 5-HT(4) receptor activation, which may complement the laxative effect of its fiber content, and a gut-inhibitory activity possibly mediated by blockade of Ca(2+) channels and activation of NO-cyclic guanosine monophosphate pathways. This may explain its medicinal use in diarrhea. It is, perhaps, also intended by nature to offset an excessive stimulant effect. [ABSTRACT FROM AUTHOR]

The global pattern mining step in existing pattern-based hierarchical clustering algorithms may result in an unpredictable number of patterns. In this paper, we propose IDHC, a pattern-based hierarchical clustering algorithm that builds a cluster hierarchy without mining for globally significant patterns. IDHC first discovers locally promising patterns by allowing each instance to “vote” for its representative size-2 patterns in a way that ensures an effective balance between local pattern frequency and pattern significance in the dataset. The cluster hierarchy (i.e., the global model) is then directly constructed using these locally promising patterns as features. Each pattern forms an initial (possibly overlapping) cluster, and the rest of the cluster hierarchy is obtained by following a unique iterative cluster refinement process. By effectively utilizing instance-to-cluster relationships, this process directly identifies clusters for each level in the hierarchy, and efficiently prunes duplicate clusters. Furthermore, IDHC produces cluster labels that are more descriptive (patterns are not artificially restricted), and adapts a soft clustering scheme that allows instances to exist in suitable nodes at various levels in the cluster hierarchy. We present results of experiments performed on 16 standard text datasets, and show that IDHC outperforms state-of-the-art hierarchical clustering algorithms in terms of average entropy and FScore measures. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) has become a major problem for patients and for clinicians, academics and the pharmaceutical industry. To date, existing hepatotoxicity test systems are only poorly predictive and the underlying mechanisms are still unclear. One of the factors known to amplify hepatotoxicity is the tumor necrosis factor alpha (TNFα), especially due to its synergy with commonly used drugs such as diclofenac. However, the exact mechanism of how diclofenac in combination with TNFα induces liver injury remains elusive. Here, we combined time-resolved immunoblotting and live-cell imaging data of HepG2 cells and primary human hepatocytes (PHH) with dynamic pathway modeling using ordinary differential equations (ODEs) to describe the complex structure of TNFα-induced NFκB signal transduction and integrated the perturbations of the pathway caused by diclofenac. The resulting mathematical model was used to systematically identify parameters affected by diclofenac. These analyses showed that more than one regulatory module of TNFα-induced NFκB signal transduction is affected by diclofenac, suggesting that hepatotoxicity is the integrated consequence of multiple changes in hepatocytes and that multiple factors define toxicity thresholds. Applying our mathematical modeling approach to other DILI-causing compounds representing different putative DILI mechanism classes enabled us to quantify their impact on pathway activation, highlighting the potential of the dynamic pathway model as a quantitative tool for the analysis of DILI compounds. Drug-induced liver injury: mathematical model quantifies impact of liver-damaging drugs Drug-induced liver injury (DILI) is one of the most important obstacles during drug development. More than 1000 drugs have been identified to damage the liver, but the current test systems are poor in predicting DILI. A team of cell biologists, theoretical physicists, and clinical pharmacologists combined experimental data generated in cultured liver cells with mathematical modeling to quantify the impact of the anti-inflammatory drug diclofenac. The analysis demonstrated that diclofenac induces multiple changes in the signal transduction network activated by the tumor necrosis factor alpha (TNFα), one of the known factors to amplify liver toxicity. Data of other liver injury-causing compounds were integrated into the mathematical model and their impact was quantified, thereby demonstrating the potential use of the mathematical model for the further analysis of other compounds in order to improve DILI test systems. [ABSTRACT FROM AUTHOR]

The whitefly Bemisia tabaci (Genn.) is a pest and vector of plant viruses to crop and ornamental plants worldwide. Using RNA interference (RNAi) to down regulate whitefly genes by expressing their homologous double stranded RNAs in plants has great potential for management of whiteflies to reduce plant virus disease spread. Using a Tobacco rattle virus-derived plasmid for in planta transient expression of double stranded RNA (dsRNA) homologous to the acetylcholinesterase (AChE) and ecdysone receptor (EcR) genes of B. tabaci, resulted in significant adult whitefly mortality. Nicotiana tabacum L. plants expressing dsRNA homologous to B. tabaci AChE and EcR were constructed by fusing sequences derived from both genes. Mortality of adult whiteflies exposed to dsRNA by feeding on N. tabacum plants, compared to non-dsRNA expressing plants, recorded at 24-hr intervals post-ingestion for three days, was >90% and 10%, respectively. Analysis of gene expression by real time quantitative PCR indicated that whitefly mortality was attributable to the down-regulation of both target genes by RNAi. Results indicated that knock down of whitefly genes involved in neuronal transmission and transcriptional activation of developmental genes, has potential as a bio-pesticide to reduce whitefly population size and thereby decrease virus spread. [ABSTRACT FROM AUTHOR]

Background: In case of colorectal liver metastases invading the retrohepatic vena cava (RHVC) and the hepatocaval confluence major liver resection and venous resection are the treatment of choice. The use of venovenous bypass is still a matter of debate. We describe our technique without the use of venovenous bypass for resection of a tumor invading the RHVC. Methods: A 61-year-old woman was referred to us with a large colorectal liver metastases involving the right hemiliver and caudate lobe also involving the RHVC. Through a reverse-L incision, the liver was exposed. As a result of the RHVC involvement, the hanging maneuver was not attempted. The right liver was partially mobilized. Vascular control was achieved by encircling the supra and infrahepatic vena cava and hepatic pedicle. The right hepatic artery and right portal vein were divided before parenchymal transection with Cavitron Ultrasonic Surgical Aspirator (CUSA) (under intermittent Pringle maneuver). The middle hepatic vein was divided within the parenchyma. This maneuver enabled us to swing the remnant liver and expose the RHVC. The caudate lobe was mobilized from left to right, leaving the right hepatic vein attached. This exposed the origin of the RHVC involvement. This was controlled by Satinsky clamp. A cuff of vena cava was resected and over sewn with 3-0 Prolene. Finally, the right hepatic vein was divided. Results: Complete vascular control before resection and meticulous technique allowed a safe resection with minimal intraoperative blood loss. The patient was discharged on postoperative day 7 after an uneventful in-hospital stay. Conclusions: Complete vascular control of the liver before resection allows safe and controlled resection of tumour involving the RHVC without the need for venovenous bypass. However, such a technique should be limited to high-volume hepatobiliary centers. [ABSTRACT FROM AUTHOR]

Background: The current study aimed to evaluate the anti-inflammatory, anti-oxidant, and pronounced gastro-protective activities of β- Citronellol using in vitro, in vivo assays and in silico approaches.In vitro assays, denaturation of bovine serum albumin, egg protein, and human Red Blood Cells (RBCs) membrane stabilization were performed, using Piroxicam as standard. For in vivo assessment, Histamine (0.1 ml from 1% w/v) and Formaldehyde (0.1 ml from 2% v/v) were used to mediate inflammation. In silico molecular docking and network pharmacology were employed to probe the possible target genes mediating gastroprotective effect of β-Citronellol at 25, 50, and 100 mg/kg, using indomethacin-induced (25 mg/kg i.p) gastric ulcer in rats. Moreover, Gastric tissues were evaluated for morphological, histopathological, and bio-chemical analysis of PGE2, COX-I, COX-II, 5-LOX, eNOS, ICAM-1, oxygen-free radical scavengers (SOD, CAT), and oxidative stress marker (MDA).β-Citronellol prevented denaturation of proteins and RBCs membrane stabilization with maximum effect observed at 6,400 µg/mL. Citronellol decreased rat’s paw edema. Network pharmacology and docking studies revealed gastro-protective potential of Citronellol possibly mediated through arachidonic acid pathways by targeting COX-I, COX-II, PGE2, and 5-LOX. Citronellol reduced the ulcer indices, and histopathological changes. Further, β-Citronellol (50 and 100 mg/kg) increased gastric PGE2, COX-1, and eNOS; while suppressing COX-2, 5-LOX and ICAM-1. Citronellol markedly enhanced the oxidative balance in isolated rat stomach tissues.The anti-inflammatory, anti-oxidant, and gastro-protective effects of β-Citronellol against indomethacin-induced gastric ulcer model in rats through mediating COX-I, COX-II, PGE2, 5-LOX, eNOS, and ICAM-1 inflammatory markers.Methods: The current study aimed to evaluate the anti-inflammatory, anti-oxidant, and pronounced gastro-protective activities of β- Citronellol using in vitro, in vivo assays and in silico approaches.In vitro assays, denaturation of bovine serum albumin, egg protein, and human Red Blood Cells (RBCs) membrane stabilization were performed, using Piroxicam as standard. For in vivo assessment, Histamine (0.1 ml from 1% w/v) and Formaldehyde (0.1 ml from 2% v/v) were used to mediate inflammation. In silico molecular docking and network pharmacology were employed to probe the possible target genes mediating gastroprotective effect of β-Citronellol at 25, 50, and 100 mg/kg, using indomethacin-induced (25 mg/kg i.p) gastric ulcer in rats. Moreover, Gastric tissues were evaluated for morphological, histopathological, and bio-chemical analysis of PGE2, COX-I, COX-II, 5-LOX, eNOS, ICAM-1, oxygen-free radical scavengers (SOD, CAT), and oxidative stress marker (MDA).β-Citronellol prevented denaturation of proteins and RBCs membrane stabilization with maximum effect observed at 6,400 µg/mL. Citronellol decreased rat’s paw edema. Network pharmacology and docking studies revealed gastro-protective potential of Citronellol possibly mediated through arachidonic acid pathways by targeting COX-I, COX-II, PGE2, and 5-LOX. Citronellol reduced the ulcer indices, and histopathological changes. Further, β-Citronellol (50 and 100 mg/kg) increased gastric PGE2, COX-1, and eNOS; while suppressing COX-2, 5-LOX and ICAM-1. Citronellol markedly enhanced the oxidative balance in isolated rat stomach tissues.The anti-inflammatory, anti-oxidant, and gastro-protective effects of β-Citronellol against indomethacin-induced gastric ulcer model in rats through mediating COX-I, COX-II, PGE2, 5-LOX, eNOS, and ICAM-1 inflammatory markers.Results: The current study aimed to evaluate the anti-inflammatory, anti-oxidant, and pronounced gastro-protective activities of β- Citronellol using in vitro, in vivo assays and in silico approaches.In vitro assays, denaturation of bovine serum albumin, egg protein, and human Red Blood Cells (RBCs) membrane stabilization were performed, using Piroxicam as standard. For in vivo assessment, Histamine (0.1 ml from 1% w/v) and Formaldehyde (0.1 ml from 2% v/v) were used to mediate inflammation. In silico molecular docking and network pharmacology were employed to probe the possible target genes mediating gastroprotective effect of β-Citronellol at 25, 50, and 100 mg/kg, using indomethacin-induced (25 mg/kg i.p) gastric ulcer in rats. Moreover, Gastric tissues were evaluated for morphological, histopathological, and bio-chemical analysis of PGE2, COX-I, COX-II, 5-LOX, eNOS, ICAM-1, oxygen-free radical scavengers (SOD, CAT), and oxidative stress marker (MDA).β-Citronellol prevented denaturation of proteins and RBCs membrane stabilization with maximum effect observed at 6,400 µg/mL. Citronellol decreased rat’s paw edema. Network pharmacology and docking studies revealed gastro-protective potential of Citronellol possibly mediated through arachidonic acid pathways by targeting COX-I, COX-II, PGE2, and 5-LOX. Citronellol reduced the ulcer indices, and histopathological changes. Further, β-Citronellol (50 and 100 mg/kg) increased gastric PGE2, COX-1, and eNOS; while suppressing COX-2, 5-LOX and ICAM-1. Citronellol markedly enhanced the oxidative balance in isolated rat stomach tissues.The anti-inflammatory, anti-oxidant, and gastro-protective effects of β-Citronellol against indomethacin-induced gastric ulcer model in rats through mediating COX-I, COX-II, PGE2, 5-LOX, eNOS, and ICAM-1 inflammatory markers.Conclusions: The current study aimed to evaluate the anti-inflammatory, anti-oxidant, and pronounced gastro-protective activities of β- Citronellol using in vitro, in vivo assays and in silico approaches.In vitro assays, denaturation of bovine serum albumin, egg protein, and human Red Blood Cells (RBCs) membrane stabilization were performed, using Piroxicam as standard. For in vivo assessment, Histamine (0.1 ml from 1% w/v) and Formaldehyde (0.1 ml from 2% v/v) were used to mediate inflammation. In silico molecular docking and network pharmacology were employed to probe the possible target genes mediating gastroprotective effect of β-Citronellol at 25, 50, and 100 mg/kg, using indomethacin-induced (25 mg/kg i.p) gastric ulcer in rats. Moreover, Gastric tissues were evaluated for morphological, histopathological, and bio-chemical analysis of PGE2, COX-I, COX-II, 5-LOX, eNOS, ICAM-1, oxygen-free radical scavengers (SOD, CAT), and oxidative stress marker (MDA).β-Citronellol prevented denaturation of proteins and RBCs membrane stabilization with maximum effect observed at 6,400 µg/mL. Citronellol decreased rat’s paw edema. Network pharmacology and docking studies revealed gastro-protective potential of Citronellol possibly mediated through arachidonic acid pathways by targeting COX-I, COX-II, PGE2, and 5-LOX. Citronellol reduced the ulcer indices, and histopathological changes. Further, β-Citronellol (50 and 100 mg/kg) increased gastric PGE2, COX-1, and eNOS; while suppressing COX-2, 5-LOX and ICAM-1. Citronellol markedly enhanced the oxidative balance in isolated rat stomach tissues.The anti-inflammatory, anti-oxidant, and gastro-protective effects of β-Citronellol against indomethacin-induced gastric ulcer model in rats through mediating COX-I, COX-II, PGE2, 5-LOX, eNOS, and ICAM-1 inflammatory markers.Graphical abstract: The current study aimed to evaluate the anti-inflammatory, anti-oxidant, and pronounced gastro-protective activities of β- Citronellol using in vitro, in vivo assays and in silico approaches.In vitro assays, denaturation of bovine serum albumin, egg protein, and human Red Blood Cells (RBCs) membrane stabilization were performed, using Piroxicam as standard. For in vivo assessment, Histamine (0.1 ml from 1% w/v) and Formaldehyde (0.1 ml from 2% v/v) were used to mediate inflammation. In silico molecular docking and network pharmacology were employed to probe the possible target genes mediating gastroprotective effect of β-Citronellol at 25, 50, and 100 mg/kg, using indomethacin-induced (25 mg/kg i.p) gastric ulcer in rats. Moreover, Gastric tissues were evaluated for morphological, histopathological, and bio-chemical analysis of PGE2, COX-I, COX-II, 5-LOX, eNOS, ICAM-1, oxygen-free radical scavengers (SOD, CAT), and oxidative stress marker (MDA).β-Citronellol prevented denaturation of proteins and RBCs membrane stabilization with maximum effect observed at 6,400 µg/mL. Citronellol decreased rat’s paw edema. Network pharmacology and docking studies revealed gastro-protective potential of Citronellol possibly mediated through arachidonic acid pathways by targeting COX-I, COX-II, PGE2, and 5-LOX. Citronellol reduced the ulcer indices, and histopathological changes. Further, β-Citronellol (50 and 100 mg/kg) increased gastric PGE2, COX-1, and eNOS; while suppressing COX-2, 5-LOX and ICAM-1. Citronellol markedly enhanced the oxidative balance in isolated rat stomach tissues.The anti-inflammatory, anti-oxidant, and gastro-protective effects of β-Citronellol against indomethacin-induced gastric ulcer model in rats through mediating COX-I, COX-II, PGE2, 5-LOX, eNOS, and ICAM-1 inflammatory markers. [ABSTRACT FROM AUTHOR]