Identification of new 5-(2,6-dichlorophenyl)-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-7-carboxylic acids as p38α MAPK inhibitors: Design, synthesis, antitumor evaluation, molecular docking and in silico studies.

In pursuit of discovering novel scaffolds that demonstrate potential inhibitory activity against p38α MAPK and possess strong antitumor effects, we herein report the design and synthesis of new series of 17 final target 5-(2,6-dichlorophenyl)-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-7-carboxylic acids (4-20). Chemical characterization of the compounds was performed using FT-IR, NMR, elemental analyses and mass spectra of some representative examples. With many compounds showing potential inhibitory activity against p38α MAPK, two derivatives, 8 and 9, demonstrated the highest activity (>70 % inhibition) among the series. Derivative 9 displayed IC50 value nearly 2.5 folds more potent than 8. As anticipated, they both showed explicit interactions inside the kinase active site with the key binding amino acid residues. Screening both compounds for cytotoxic effects, they exhibited strong antitumor activities against lung (A549), breast (MCF-7 and MDA MB-231), colon (HCT-116) and liver (Hep-G2) cancers more potent than reference 5-FU. Their noticeable strong antitumor activity pointed out to the possibility of an augmented DNA binding mechanism of antitumor action besides their kinase inhibition. Both 8 and 9 exhibited strong ctDNA damaging effects in nanomolar range. Further mechanistic antitumor studies revealed ability of compounds 8 and 9 to arrest cell cycle in MCF-7 cells at S phase, while in HCT-116 treated cells at G0-G1 and G2/M phases. They also displayed apoptotic induction effects in both MCF-7 and HCT-116 with total cell deaths more than control untreated cells in reference to 5-FU. Finally, the compounds were tested for their anti-migratory potential utilizing wound healing assay. They induced a significant decrease in wound closure percentage after 24 h treatment in the examined cancer cells when compared to untreated control MCF-7 and HCT-116 cells better than 5-FU. In silico computation of physicochemical parameters revealed the drug-like properties of 8 and 9 with no violation to Lipinski's rule of five as well as their tolerable ADMET parameters, thus suggesting their utilization as potential future drug leads amenable for further optimization and development.

Clinical outcomes of left hepatic trisectionectomy for hepatobiliary malignancy.

BACKGROUND: Left hepatic trisectionectomy (LHT) is a challenging major anatomical hepatectomy with a high complication rate and a worldwide experience that remains limited. The aim of this study was to describe changes in surgical practice over time, to analyse the outcomes of patients undergoing LHT for hepatobiliary malignancy, and to identify factors associated with morbidity and mortality. METHODS: A cohort study was undertaken of patients who underwent LHT at a single tertiary hepatobiliary referral centre between January 1993 and March 2013. Univariable and multivariable analysis was used to identify factors associated with short- and long-term outcomes following LHT. RESULT: Some 113 patients underwent LHT for colorectal liver metastasis (57), hilar cholangiocarcinoma (22), intrahepatic cholangiocarcinoma (12) and hepatocellular carcinoma (11); 11 patients had various other indications. Overall morbidity and 90-day mortality rates were 46.0 and 9.7 per cent respectively. Overall 1- and 3-year survival rates were 71.3 and 44.4 per cent respectively. Total hepatic vascular exclusion and intraoperative blood transfusion were independent predictors of postoperative morbidity, whereas blood transfusion was the only factor predictive of in-hospital mortality. Time period analysis revealed a decreasing trend in blood transfusion, duration of hospital stay, and postoperative morbidity and mortality in the last 5 years. CONCLUSION: Morbidity, mortality and long-term survival after LHT support its use in selected patients with a significant tumour burden.

Elevated preoperative recipient neutrophil-lymphocyte ratio is associated with delayed graft function following kidney transplantation.

INTRODUCTION: The neutrophil-lymphocyte ratio (NLR) is an indicator of inflammatory status. We studied the effect of preoperative elevated NLR in the recipient in relation to the risk of developing delayed graft function (DGF) after kidney transplantation. METHODS: We retrospectively analysed the preoperative white blood cell count of renal transplant recipients between 2003 and 2005. An NLR >3.5 was considered elevated. There were 398 kidney transplant recipients of whom 249 received organs from donors after brain death (DBD), 61 from donors after circulatory death (DCD), and 88 from living donors. RESULTS: One hundred three patients (26%) developed DGF, of which 67 (65%) had NLRs >3.5. Of 295 recipients with primary graft function, only 44 (15%) had elevated NLR. Univariate analysis revealed three factors that significantly influenced graft function: NLR >3.5, cold ischemic time (CIT) >15 hours, and donor type. On multivariate analysis, both donor type (DCD: hazard ratio [HR] = 2.421, confidence interval [CI] = 1.195-4.905, P = .014; LD: HR = 0.289, CI = 0.099-0.846, P = .024) and NLR (HR = 10.673, CI = 6.151-18.518, P < .0001) remained significant. CONCLUSIONS: Elevated recipient preoperative NLR could contribute to increase the risk of developing DGF, which appears to be more pronounced in patients receiving grafts from living donors.

Right salpingo-ovarian and distal ileal entrapment within a paracaecal hernia presenting as acute appendicits.

INTRODUCTION: Pericaecal hernias are a rare subgroup of internal abdominal hernias that present with abdominal pain and occasionally with features of bowel obstruction. PRESENTATION OF CASE: A 72 year old female presented with a 24-h history of sharp, localised right iliac fossa pain, and no other symptoms. Clinical examination confirmed localised peritonism in the right iliac fossa. A tentative diagnosis of acute appendicitis was considered but in view of age a CT scan was performed. An area of abnormality in the right iliac fossa region was noted. At laparoscopy a macroscopically normal appendix and caecum was found. A smooth non-indentable mass in the lateral right iliac fossa contained loops of distal ileum, passing through a retro-caecal mesenteric defect consistent with a paraceacal hernia, with entrapment of the right ovary and fallopian tube. A right salpingectomy as performed and subsequent histopathological examination confirmed infarction of the fallopian tube. DISCUSSION: Internal abdominal hernias are reported to have a post mortem incidence ranging between 0.2 and 0.9% of which only 10-15% are accounted for by pericaecal hernias. Types of pericaecal hernias include: ileocolic, retrocaecal, ileocaecal and paracaecal. These hernias are predisposed by the embryological development of the caecum retracting to the posterior abdominal wall and forming potential fossae. CONCLUSION: This case highlights the need to consider a pericaecal hernia as a differential cause of right iliac fossa peritonism, and an indication for radiological imaging such as CT scan when the history is atypical for acute appendicitis.