To investigate whether the immunohistochemical expression of p53, p63 and her2/neu is correlated with the prognosis of tumour recurrence and progression in patients with non-muscle invasive (NMI) bladder cancer.
Patients and methods
In all, 88 patients diagnosed with NMI transitional cell carcinoma of the bladder in a Urology Department from May 2009 to April 2014 were included in the study. Paraffin-embedded specimens were obtained by transurethral resection of the bladder tumours. Sections on haematoxylin and eosin-stained slides were examined histologically and tumour grade was classified according to the World Health Organisation system (2004) Mostofi classification. The sections were evaluated using p63, p53 and her2/neu immunohistochemical staining before and after immunotherapy with bacille Calmette–Guerin (BCG), and patients were followed up for 36 months in the Urology Department.
For tumour grade there was a significant relationship with the overexpression of p53 (P = 0.010), her2 (P = 0.025) and negativity of p63 (P = 0.025). There was no significant relationship between p53 or her2/neu overexpression and tumour stage. However, there was a significant correlation (P = 0.005) between p63 negativity and tumour stage. There was a significant relationship between p53 (P = 0.01), her2/neu (P = 0.025) overexpression and p63 negativity (P = 0.005) and tumour recurrence and progression.
Patients with transitional cell carcinoma who are selected for BCG treatment should preferably be positively immunoreactive for p63, but negative for both p53 and her2/neu. These patients were less susceptible to recurrence and/or progression after BCG adjuvant therapy. Further studies are needed to investigate the relationship between these three markers and treatment with anti-her2/neu therapies.
NMI, non-muscle invasive; TURBT, transurethral resection of the bladder tumour; H&E, haematoxylin and eosin; Cis, carcinoma in situ; Bladder cancer; P53, P63, Her2; BCG
Despite the increasing recognition of the functional and clinical importance of lumbar lordosis, little is known about its description, particularly in Egypt. At the same time, magnetic resonance imaging (MRI) has been introduced as a noninvasive diagnostic technique. The aim of this study was to investigate the anatomy of the lumbar lordosis using midsagittal MRIs. Normal lumbar spine MRIs obtained from 93 individuals (46 males, 47 females; 25–57 years old) were evaluated retrospectively. The lumbar spine curvature and its segments “vertebrae and discs” were described and measured. The lumbar lordosis angle (LLA) was larger in females than in males. Its mean values increased by age. The lumbar height (LH) was longer in males than in females. At the same time, the lumbar breadth (LB) was higher in females than in males. Lumbar index (LI = LB/LH × 100) showed significant gender differences (P < 0.0001). Lordosis was formed by wedging of intervertebral discs and bodies of lower lumbar vertebrae. In conclusion, MRI might clearly reveal the anatomy of the lumbar lordosis. Use of LI in association with LLA could be useful in evaluation of lumbar lordosis.
Cerebral revascularization is a useful microsurgical technique for the treatment of steno-occlusive intracranial ischemic disease, complex intracranial aneurysms that require deliberate occlusion of a parent artery and invasive skull base tumors. We describe our preliminary experience with extracranial-to-intracranial by-passes at a low volume center; and discuss clinical indications and microsurgical techniques, challenges in comparison to large advanced referral centers.
Materials and Methods:
Twenty-seven patients with hemodynamic ischemia or complex aneurysms or skull base tumors were operated at Cairo University Hospitals in the period between May 2009 and June 2014. All patients operated by a low flow by-pass were operated through a superficial temporal artery to middle cerebral artery (MCA) anastomosis. All patients chosen for a high flow by-pass were operated using a radial artery graft interposed between the MCAs distally and the common or the external carotid artery proximally. Patency was confirmed at the end of surgery using appearance on the table and confirmed after surgery by transcranial color-coded duplex or computed tomography angiography. All patient data were prospectively collected and retrospectively analyzed at the end of surgery.
Nineteen patients (70.4%) were operated upon for flow augmentation and eight patients (29.6%) were operated upon for flow replacement. A total of 30 anastomoses were performed. All except one were patent which gives a patency rate of 96.3%. There was one death in the present series resulting from a hyperperfusion syndrome. 89.5% of patients with hemodynamic ischemia stopped having symptoms after surgery. All but one patient operated for hemodynamic ischemia showed a considerable cognitive improvement after surgery. None of the patients operated upon for flow replacement showed improvement of oculomotor nerve function in spite of adequate intraoperative decompression. All patients treated for flow replacement showed the absence of recurrence on follow-up.
Our initial results for both low and high flow by-pass procedures in our low volume center indicate that such complex surgical procedures are possible with results comparable to those obtained in other larger referral centers throughout the world. This procedure not only represents a more definitive treatment when compared to other endovascular or radiation treatments but is also much less costly when compared to other treatment modalities.
Complex tumors; Extracranial-to–intracranial by-pass; hemodynamic ischemia; vascular lesions
ERG and androgen receptor (AR) are known to function cooperatively in prostate cancer (PCa) progression. However, the prognostic value of combined ERG and AR expression and potential pathways are not well characterized. We assessed ERG and AR protein expression by immunohistochemistry in a cohort of 312 men with PCa diagnosed by transurethral resection of the prostate (TURP). Patients were divided into those with no prior hormonal treatment (designated as PCa/AdvPCa) vs. those with castrate-resistant PCa (CRPC) undergoing channel TURP to relieve obstructive symptoms. The expression status was correlated with various clinical-pathological parameters. The Swedish watchful-waiting cohort was used for validation and characterization of potential gene signatures associated with ERG and AR.
Patients with combined ERG-positive/AR high expression profile demonstrated higher rates of PCa-specific mortality (PCSM) compared with patients with ERG-negative/AR low in patients with no prior treatment (n = 90, P = 0.032), but this was attenuated in the overall cohort which included the CRPC subgroup (n = 125, P = 0.096). The prognostic significance to PCSM was validated in the Swedish watchful waiting cohort in univariate (HR: 3.3; 95% CI: 1.9–5.6, P = 4.25E−5) and multivariate analysis (HR: 2; 95% CI: 0.97–4.1, P = 0.057), which included Gleason score. ERG/AR overexpression status characterized 152 genes signatures including WNT, PI3K/AKT and chemokine signaling pathways known to be deregulated in PCa.
In conclusion, combined ERG/AR overexpression signifies a class of patients at highest-risk of PCSM with specific key genetic alteration likely responsible for disease progression. The prognostic value of combined ERG/AR overexpression and its associated genes should be further investigated as potential prognostic and therapeutic targets in prostate cancer progression.
ERG protein expression; immunohistochemistry; Gleason score; tumor volume; hormone therapy; cancer specific mortality
Developmental dysplasia of the hip (DDH) is a term used to cover a broad spectrum of anomalies ranging from mild dysplasia to high-riding dislocations. We report the management of DDH in children using the Dega osteotomy and their long-term follow-up.
Fifty-eight hips from 48 children younger than 8 years treated using the Dega osteotomy between January 1988 and October 2000 were included in this multcenter study. Both prospective (41 hips) and retrospective (17 hips) cases were included, and follow-up was for a minimum of 13 years. Radiographs were made preoperatively, immediately postoperatively, after 6 weeks or at removal of the spica cast if any, at 6-month intervals and/or as indicated for 3 years postoperatively and then on annual basis until the last follow-up. A single-cut computed tomographic scan was performed for all prospective patients. Special attention was paid to the predictive measures of hip arthrosis and the survival of the hip after Dega osteotomy.
The final clinical outcome was favorable in 44 hips (75.9 %). Eleven hips needed a second surgery (acetabuloplasty and/or arthroplasty) during the follow-up period.
In our pediatric patient population the Dega osteotomy proved to be an adequate measure for the management of this complex condition. The worst complication was avascular necrosis, and all of the affected hips ended with failure (pain, another surgery, or both).
Dega; Pelvic osteotomy; Femoral osteotomy; Developmental dysplasia of the hip; Dysplasia
Transesophageal echocardiography (TEE) offers several advantages over transthoracic echocardiography (TTE). Despite these advantages, use of TEE by emergency physicians (EPs) remains rare, as no focused TEE protocol for emergency department (ED) use has been defined nor have methods of training been described.
This study aims to develop a focused TEE examination tailored for the ED and to evaluate TEE skill acquisition and retention by TEE-naïve EPs following a focused 4-h curriculum.
Academic EPs were invited to participate in a 4-h didactic and simulation-based workshop. The seminar emphasized TEE principles and views obtained from four vantage points. Following the training, participants engaged in an assessment of their abilities to carry out a focused TEE on a high-fidelity simulator. A 6-week follow-up session assessed skill retention.
Fourteen EPs participated in this study. Immediately following the seminar, 14 (100 %; k = 1.0) and 10 (71.4 %, k = 0.65) successfully obtained an acceptable mid-esophageal four-chamber and mid-esophageal long-axis view. Eleven (78.6 %, k = 1.0) participants were able to successfully obtain an acceptable transgastric short-axis view, and 11 (78.6 %, k = 1.0) EPs successfully obtained a bicaval view. Twelve participants engaged in a 6-week retention assessment, which revealed acceptable images and inter-rater agreement as follows: mid-esophageal four-chamber, 12 (100 %; k = 0.92); mid-esophageal long axis, 12 (100 %, k = 0.67); transgastric short-axis, 11 (91.7 %, k = 1.0); and bicaval view, 11 (91.7 %, k = 1.0).
This study has illustrated that EPs can successfully perform this focused TEE protocol after a 4-h workshop with retention of these skills at 6 weeks.
Electronic supplementary material
The online version of this article (doi:10.1186/s13089-015-0027-3) contains supplementary material, which is available to authorized users.
Transesophageal echocardiography; Echocardiography; Ultrasound; Point-of-care ultrasound, Education; Simulation
There are two molecules in the asymmetric unit of the title compound, C11H16N2O. The pyridine rings and amide groups overlap almost perfectly (r.m.s. overlay fit = 0.053 Å), but the tertiary butyl groups have different orientations: in one molecule, one of the methyl C atoms is syn to the amide O atom [O—C—C—C = −0.8 (3)°] and in the other the equivalent torsion angle is 31.0 (2)°. In the crystal, the two independent molecules are linked by a pair of N—H⋯N hydrogen bonds in the form of an R
2(8) loop to form a dimer. A C—H⋯O interaction connects the dimers into  chains.
crystal structure; propanamide; hydrogen bonding
Livestock grazing is one of the main causes of rangeland degradation in Saudi Arabia. Fencing to exclude grazers is one of the main management practices used to restore vegetation and conserve biodiversity. The main objectives of this study were to investigate the changes in plant diversity and abundance, floristic composition and plant groups of the major life forms in response to thirty-five years of grazing exclosure in western Saudi Arabia. These vegetation attributes and palatability were compared in 30 sampling stands located in the excluded and grazed sites. Our results showed that livestock exclusion significantly increased covers, density and species richness of annuals, grasses, perennial forbs, shrubs and trees. Exclosure enhanced the abundance and richness of palatable species and depressed the development of weedy species. About 66.7% of the recorded species at the excluded site were highly palatable compared to 34.5% at the grazed site. In contrary, about 55.2% unpalatable species were found in the grazed site compared to 25.8% in the protected site. Jaccard’s similarity index between the excluded and grazed sites showed lower values of 0.39%, 0.40% and 0.31% at levels of families, genus and species, respectively. The results suggest that establishing livestock exclusion may be a useful sustainable management tool for vegetation restoration and conservation of plant diversity in degraded rangelands of arid regions.
Protection; Fencing; Grazing impacts; Rangeland Steppes; Restoration
Prostaglandin D2 (PGD2) and cysteinyl leukotrienes (cysLTs) are lipid mediators derived from mast cells, which activate TH2 cells. The combination of PGD2 and cysLTs (notably cysteinyl leukotriene E4 [LTE4]) enhances TH2 cytokine production. However, the synergistic interaction of cysLTs with PGD2 in promoting TH2 cell activation is still poorly understood. The receptors for these mediators are drug targets in the treatment of allergic diseases, and hence understanding their interaction is likely to have clinical implications.
We aimed to comprehensively define the roles of PGD2, LTE4, and their combination in activating human TH2 cells and how such activation might allow the TH2 cells to engage downstream effectors, such as neutrophils, which contribute to the pathology of allergic responses.
The effects of PGD2, LTE4, and their combination on human TH2 cell gene expression were defined by using a microarray, and changes in specific inflammatory pathways were confirmed by means of PCR array, quantitative RT-PCR, ELISA, Luminex, flow cytometry, and functional assays, including analysis of downstream neutrophil activation. Blockade of PGD2 and LTE4 was tested by using TM30089, an antagonist of chemoattractant receptor-homologous molecule expressed on TH2 cells, and montelukast, an antagonist of cysteinyl leukotriene receptor 1.
PGD2 and LTE4 altered the transcription of a wide range of genes and induced diverse functional responses in TH2 cells, including cell adhesion, migration, and survival and cytokine production. The combination of these lipids synergistically or additively enhanced TH2 responses and, strikingly, induced marked production of diverse nonclassical TH2 inflammatory mediators, including IL-22, IL-8, and GM-CSF, at concentrations sufficient to affect neutrophil activation.
PGD2 and LTE4 activate TH2 cells through different pathways but act synergistically to promote multiple downstream effector functions, including neutrophil migration and survival. Combined inhibition of both PGD2 and LTE4 pathways might provide an effective therapeutic strategy for allergic responses, particularly those involving interaction between TH2 cells and neutrophils, such as in patients with severe asthma.
Prostaglandin D2; leukotriene E4; chemoattractant receptor-homologous molecule expressed on TH2 cells; TH2 cells; neutrophils; CAIA, Cell activation–induced aggregation; CRTH2, Chemoattractant receptor-homologous molecule expressed on TH2 cells; cysLT, Cysteinyl leukotriene; CysLT1, Cysteinyl leukotriene receptor 1; CysLT2, Cysteinyl leukotriene receptor 2; ICAM, Intercellular adhesion molecule; LTC4, Cysteinyl leukotriene C4; LTD4, Cysteinyl leukotriene D4; LTE4, Cysteinyl leukotriene E4; PGD2, Prostaglandin D2; PI3K, Phosphoinositide 3-kinase; PMA, Phorbol 12-myristate 13-acetate; qPCR, Quantitative PCR; RORγt, Retinoic acid–related orphan receptor γt
Marine invertebrates including sponges, soft coral, tunicates, mollusks and bryozoan have proved to be a prolific source of bioactive natural products. Among marine-derived metabolites, terpenoids have provided a vast array of molecular architectures. These isoprenoid-derived metabolites also exhibit highly specialized biological activities ranging from nerve regeneration to blood-sugar regulation. As a result, intense research activity has been devoted to characterizing invertebrate terpenes from both a chemical and biological standpoint. This review focuses on the chemistry and biology of terpene metabolites isolated from the Red Sea ecosystem, a unique marine biome with one of the highest levels of biodiversity and specifically rich in invertebrate species.
terpenes; Red Sea; marine ecosystem; marine invertebrates; biomedical leads
In the title molecule, C9H10N2S, one of the methyl groups is almost co-planar with the thiazolopyridine rings with a deviation of 0.311 (3) Å from the least-squares plane of the thiazolopyridine group. In the crystal, weak C—H⋯N hydrogen-bonding interactions lead to the formation of chains along .
crystal structure; thiazolopyridine; hydrogen bonding
Foxp3+ regulatory T cells are abundant in the intestine where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function1; however, key host factors controlling the Treg response in the intestine are poorly understood. IL-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites2 where it functions as an endogenous danger signal or alarmin following tissue damage3. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease (IBD) patients4-7 suggesting a role for this cytokine in the pathogenesis of IBD. In the intestine, both protective and pathologic roles for IL-33 have been described in murine models of acute colitis8-11 but its contribution to chronic inflammation remains ill defined. Here we show that the IL-33 receptor ST2 is preferentially expressed on colonic Treg (cTreg) cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signaling into T cells stimulates Treg responses in several ways. Firstly, it enhances transforming growth factor-β1 (TGF-β1) mediated differentiation of Treg cells and secondly, it provides a necessary signal for Treg accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of IBD, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses.
In the title compound, C10H14N2O, the pyridine ring is inclined to the mean plane of the amide moiety [N—C(=O)C] by 17.60 (8)°. There is an intramolecular C—H⋯O hydrogen bond present involving the carbonyl O atom. In the crystal, molecules are linked via N—H⋯N hydrogen bonds, forming chains propagating along . The tert-butyl group is disordered over two sets of sites with a refined occupancy ratio of 0.758 (12):0.242 (12).
crystal structure; pyridine; propanamide; N—H⋯N hydrogen bonds
Slipped capital femoral epiphysis (SCFE) is one of the most common adolescent hip conditions. Unstable SCFE is characterized by sudden and severe hip pain with the inability to weight bear, even with crutches. Osteonecrosis of the femoral head is increased in patients with unstable SCFE. The aim of our study was to systematically review the literature that compares hip decompression to no hip decompression of unstable SCFE.
We searched several databases from 1946 to 2014 for any observational or experimental studies that evaluated hip decompression and osteonecrosis of unstable SCFE. We performed a meta-analysis using a random effects model to pool odds ratios (ORs) for the comparison of osteonecrosis between patients undergoing hip decompression and no hip decompression. We also investigated the type of hip decompression performed. Descriptive, quantitative, and qualitative data were extracted.
Of the 17 articles identified, nine studies (eight case series and one retrospective cohort study) were eligible for the meta-analysis, with a total of 302 unstable SCFE. The pooled OR = 0.91 of osteonecrosis between hip decompression and no hip decompression was in favor of hip decompression, but was not statistically significant [95 % confidence interval (CI): 0.47, 1.75; p = 0.54, I2 = 0 %]. No significant differences in the rates of osteonecrosis were detected in unstable SCFE with open and percutaneous hip decompression alone (OR = 0.97, 95 % CI: 0.36, 2.62; p = 0.69, I2 = 19.1 %) or hip decompression with bony procedures (OR = 0.99, 95 % CI: 0.35, 2.79; p = 0.69, I2 = 0 %).
The cumulative evidence at present does not indicate an association between hip decompression and a lower rate of osteonecrosis of unstable SCFE. However, hip decompression of unstable SCFE remains an option that can potentially decompress the intracapsular hip pressure and optimize the blood flow to the femoral head. Thus, multicenter prospective cohort studies are required and will be able to answer this question with more certainty and a higher level of evidence.
Level of evidence
Slipped capital femoral epiphysis; Unstable; Osteonecrosis; Decompression; Meta-analysis
Snakehead fish vesiculovirus (SHVV) is a negative strand RNA virus which can cause great economic losses in fish culture. To facilitate the study of SHVV-host interactions, the susceptibility of zebrafish embryonic fibroblast cell line (ZF4) to the SHVV was investigated in this report. The results showed that high amount of viral mRNAs and cRNAs were detected at the 3 h post-infection. However, the expressions of the viral mRNAs and cRNA were decreased dramatically after 6 h post-infection. In addition, the expressions of interferon (IFN) and interferon-induced GTP-binding protein Mx were all up regulated significantly at the late stage of the infection. Meanwhile, the expressions of Retinoic acid-inducible gene I (RIG-I) and Melanoma differentiation-associated gene 5 (MDA5) were also all up-regulated significantly during the infection. Two isoforms of DrLGP2 from zebrafish were also cloned and analyzed. Interestingly, the expression of DrLGP2a but not DrLGP2b was significantly up-regulated at both mRNA and protein levels, indicating that the two DrLGP2 isoforms might play different roles during the SHVV infection. Transfection experiment showed that viral replicative intermediates were required for the activation of IFN-α expression. Taken together, the abortive infection of SHVV in ZF4 cells was associated with the activation of RLRs pathway, which was activated by viral replicative intermediates.
snakehead fish vesiculovirus; ZF4; infection; Retinoic acid-inducible gene I (RIG-I)-like receptors; interferon; viral replicative intermediates
The core-shell method is used as a novel synthetic process of micronized Ti-Zeolite Na-A which involves calcination at 700°C of coated Egyptian Kaolin with titanium tetrachloride in acidic medium as the first step. The produced Ti-coated metakaolinite is subjected to microwave irradiation at low temperature of 80°C for 2 h. The prepared micronized Ti-containing Zeolites-A (Ti-Z-A) is characterized by FTIR, XRF, XRD, SEM, and EDS elemental analysis. Ag-exchanged form of Ti-Z-Ag is also prepared and characterized. The Wt% of silver exchanged onto the Ti-Zeolite structure was determined by atomic absorption spectra. The in vitro cytotoxic activity of Ti-Z-Ag against human hepatocellular carcinoma cell line (HePG2), colon cell line carcinoma (HCT116), lung carcinoma cell line (A549), and human Caucasian breast adenocarcinoma (MCF7) is reported. The results were promising and revealed that the exchanged Ag form of micronized Ti-Zeolite-A can be used as novel antitumor drug.
Herein, novel hybrid compounds of celecoxib and 2-aminoanthraquinone derivatives have been synthesized using condensation reactions of celecoxib with 2-aminoanthraquinone derivatives or 2-aminoanthraquinon with celecoxib derivatives. Celecoxib was reacted with different acid chlorides, 2-chloroethylisocyanate and bis (2-chloroethyl) amine hydrochloride. These intermediates were then reacted with 2-aminoanthraquinone. Also the same different acid chlorides and 2-chloroethylisocyanate were reacted with 2-aminoanthraquinone and the resulting intermediates were reacted with celecoxib to give isomers for the previous compounds. The antitumor activities against hepatic carcinoma tumor cell line (HEPG2) have been investigated in vitro, and all these compounds showed promising activities, especially compound 3c, 7, and 12. Flexible docking studies involving AutoDock 4.2 was investigated to identify the potential binding affinities and the mode of interaction of the hybrid compounds into two protein tyrosine kinases namely, SRC (Pp60v-src) and platelet-derived growth factor receptor, PDGFR (c-Kit). The compounds in this study have a preferential affinity for the c-Kit PDGFR PTK over the non-receptor tyrosine kinase SRC (Pp60v-src).
antitumor; anthraquinone; celecoxib; HEPG2; docking; protein kinase activities
Natural products are structurally and biologically interesting metabolites, but they have been isolated in minute amounts. The syntheses of such natural products help in obtaining them in bulk amounts. The recognition of microbial biotransformation as important manufacturing tool has increased in chemical and pharmaceutical industries. In recent years, microbial transformation is increasing significantly from limited interest into highly active area in green chemistry including preparation of pharmaceutical products. This is the first review published on the usage of microbial biocatalysts for some natural product classes and natural product drugs.
Natural products; Biotransformation; Microbial biocatalysts; Pharmaceutical products
The title compound, C9H8N2O, is almost planar, with the C atom of the methoxy group deviating from the mean plane of the quinazoline ring system (r.m.s. deviation = 0.011 Å) by 0.068 (4) Å. In the crystal, molecules form π–π stacks parallel to the b-axis direction [centroid–centroid separation = 3.5140 (18) Å], leading to a herringbone packing arrangement.
crystal structure; 4-methoxyquinazoline; quinazoline derivatives; π–π stacks; herringbone packing
Background. Iatrogenic biliary injuries are considered as the most serious complications during cholecystectomy. Better outcomes of such injuries have been shown in cases managed in a specialized center. Objective. To evaluate biliary injuries management in major referral hepatobiliary center. Patients & Methods. Four hundred seventy-two consecutive patients with postcholecystectomy biliary injuries were managed with multidisciplinary team (hepatobiliary surgeon, gastroenterologist, and radiologist) at major Hepatobiliary Center in Egypt over 10-year period using endoscopy in 232 patients, percutaneous techniques in 42 patients, and surgery in 198 patients. Results. Endoscopy was very successful initial treatment of 232 patients (49%) with mild/moderate biliary leakage (68%) and biliary stricture (47%) with increased success by addition of percutaneous (Rendezvous technique) in 18 patients (3.8%). However, surgery was needed in 198 patients (42%) for major duct transection, ligation, major leakage, and massive stricture. Surgery was urgent in 62 patients and elective in 136 patients. Hepaticojejunostomy was done in most of cases with transanastomotic stents. There was one mortality after surgery due to biliary sepsis and postoperative stricture in 3 cases (1.5%) treated with percutaneous dilation and stenting. Conclusion. Management of biliary injuries was much better with multidisciplinary care team with initial minimal invasive technique to major surgery in major complex injury encouraging early referral to highly specialized hepatobiliary center.
We report an optimized set of CGenFF parameters that can be used to model small molecules containing acylphosphate and N-phosphonosulfonimidoyl functional groups in combination with the CHARMM force field. Standard CGenFF procedures were followed to obtain bonded interaction parameters, which were validated by geometry optimizations, comparison to the results of calculations at the MP2/6-31+G(d) level of theory, and molecular dynamics simulations. In addition, partial atomic charges were assigned so that the energy of hydrogen bonding of the model compounds with water was correctly reproduced. The availability of these parameters will facilitate computational studies of enzymes that generate acyladenylate intermediates during catalytic turnover. In addition, given that the N-phosphonosulfonimidoyl moiety is a stable transition state analog for the reaction of ammonia with an acyladenylate, the parameters developed in this study should find use in efforts to develop novel and potent inhibitors of various glutamine-dependent amidotransferases that have been validated as drug targets. Topology and parameter files for the model compounds used in this study, which can be combined with other CGenFF parameters in computational studies of more complicated acylphosphates and N-phosphonosulfonimidates are made available.
CGenFF; Parameters; Acylphosphates; Sulfoximines; N-Phosphonosulfonimidates; Force Field; Drug Discovery
Natural killer cells are a key component in the immune control of viral infections. Their functions are controlled by inhibitory receptors for major histocompatability complex (MHC) class I, including the killer cell immunoglobulin-like receptors (KIR). KIR2DL3 in combination with its cognate human leukocyte antigen (HLA)-C ligand has been shown to be associated with spontaneous resolution of viremia following hepatitis C virus (HCV) infection. In order to determine if this gene combination is advantageous across all potential outcomes following HCV exposure, we studied individuals with apparent resistance to HCV infection who remain seronegative and aviremic despite long-term injection drug use and also individuals chronically infected with HCV who successfully clear HCV with treatment. Homozygosity for KIR2DL3 in combination with group 1 HLA-C allotypes was more frequent in exposed seronegative aviremic individuals as compared to those with chronic HCV (25.0% versus 9.7%, P = 0.003, odds ratio [OR] = 3.1, 95% confidence interval [CI] = 1.3-7.1) in a model similar to that found for those spontaneously resolving HCV. In individuals undergoing treatment for HCV, those with KIR2DL3 and group 1 HLA-C were more likely to make a sustained virological response (SVR) (P = 0.013, OR = 2.3, 95% CI = 1.1-4.5). KIR and HLA-C protection in both treatment response and spontaneously resolving HCV was validated at the allelic level, in which KIR2DL3-HLA-Cw*03 was associated with SVR (P = 0.004, OR = 3.4, 95% CI = 1.5-8.7) and KIR2DL3/KIR2DL3-HLA-Cw*03 was associated with spontaneous resolution of HCV infection (P = 0.01, OR = 2.3, 95% CI = 1.2-4.4).
KIR and HLA-C genes are consistently beneficial determinants in the outcome of HCV infection. This advantage extends to the allelic level for both gene families.
In the molecule of the title compound, C17H16N2OS, the almost planar methylsulfanylquinazoline group [the methyl C atom deviates by 0.032 (2) Å from the plane through the ring system] forms an interplanar angle of 76.26 (4)° with the plane of the phenyl group. An intramolecular O—H⋯N hydrogen bond is present between the quinazoline and hydroxy groups. In the crystal, molecules are stacked along the b-axis direction.
crystal structure; 4-(methylsulfanyl)quinazoline derivative; hydrogen bonding