Epidermal growth factor receptor expression and gene copy number in conventional hepatocellular carcinoma

Epidermal growth factor receptor (EGFR) is frequently overexpressed in hepatocellular carcinoma, but its relationship with EGFR gene copy number has not been studied. This study examined EGFR expression and gene copy number in hepatocellular carcinoma and evaluated their relationship to clinicopathologic features in 76 tumors. Moderate to strong expression of EGFR was observed by immunohistochemical analysis in 50 (66%) of 76 hepatocellular carcinomas. Fluorescence in situ hybridization (FISH) showed extra EGFR gene copies in 17 (45%) of 38 tumors. This was accompanied by gains of chromosome 7, indicating that this was the result of balanced polysomy rather than gene amplification. There was no correlation between EGFR expression by immunohistochemical analysis and gene copy number by FISH. EGFR expression showed borderline association with cirrhosis but not with other clinicopathologic parameters examined. EGFR overexpression is present in a majority of hepatocellular carcinomas, suggesting a role for EGFR antagonists in therapy. The increased expression does not correlate with an increase in the EGFR gene copy number.     

Expression of nectin-1 in normal and herpes simplex virus type 1-infected murine brain.

Nectin-1 is an adherens junction protein that serves as an entry receptor for neurotropic herpes simplex virus (HSV). The expression of nectin-1 in the central nervous system (CNS) has not been well defined. Furthermore, it is not known whether HSV infection has an effect on nectin-1 expression in the brain. To better understand nectin-1 expression in normal and HSV-infected brain, the authors used immunohistochemistry to characterize the expression of nectin-1 in brain tissue of uninfected adult mice and mice infected with HSV-1. In the CNS of untreated and mock-infected mice, virtually all neurons, ependymal cells, choroid plexus epithelial cells, meningothelial cells, and vascular endothelial cells expressed nectin-1. Many oligodendrocytes, astrocytes, and vascular smooth muscle cells also demonstrated nectin-1 expression, but a minority of these cells did not stain for nectin-1. Brain tissue derived from mice euthanized 5 to 8 days after intracerebral inoculation of HSV-1 showed inflammation and widespread expression of HSV-1 proteins in neurons. In HSV-1-infected brains, many inflammatory cells showed nectin-1 expression and neuronal nectin-1 staining showed a wider variation in signal strength than that detected in uninfected tissues. Many neurons showing nuclear fragmentation consistent with the morphologic appearance of apoptosis showed little or no evidence of nectin-1 expression, whereas occasional neurons stained more intensely positive for nectin-1 than those in uninfected brain tissue. These findings confirm and extend previous observations of nectin-1 expression in the nervous system and suggest that HSV-1 infection leads to changes in nectin-1 expression in the CNS, which may contribute to HSV-induced pathology and dissemination.     

Differential response of A 68930 and sulpiride in stress-induced gastric ulcers in rats

Dopamine is linked to gastrointestinal functions. However, its exact nature in stress-induced gastric pathology is still not clear. In the present study, an attempt has been made to identify the effects of dopamine in stress-induced gastric ulcers, and concurrent alterations in various ulcer-influencing factors such as plasma corticosterone levels, gastric mucosal PGE₂ content and proton pump activity. The dopamine D₁ receptor agonist (A 68930) and antagonist (SCH 23390), and D₂ receptor agonist (quinpirole) and antagonist (sulpiride) were used to evaluate their effects on acute stress (single immobilization for 150 min) and chronic unpredictable stress (two different types of stressors for 7 days) induced gastric ulcers in rats. Acute and chronic unpredictable stress significantly increased the gastric ulcer severity, adrenal hypertrophy and corticosterone levels, while gastric mucosal dopamine levels were decreased. Pretreatment of sulpiride (60 mg/kg) significantly reverted the acute stress-induced alterations, while A 68930 (0.25 mg/kg) significantly restored the acute and chronic unpredictable stress-induced alterations. In contrast, administration of SCH 23390 (0.1-0.5 mg/kg) and quinpirole (0.1-0.5 mg/kg) failed to alter acute stress-induced alterations. Further, A 68930 and sulpiride showed different response on proton pump inhibition under in-vitro condition. A 68930 (10-50 μg/ml) inhibited the gastric H⁺ K⁺-ATPase activity comparable to positive control omeprazole, while sulpiride (10-50 μg/ml) had no effect. A 68930 also normalized the decreased gastric PGE2 content observed during chronic unpredictable stress. The histopathological evaluation of gastric mucosal tissue supported the observations regarding the gastroprotective effect of sulpiride during acute stress and of A 68930 during both acute and chronic unpredictable stress conditions. Our results provide important insights into the mechanism of dopamine-regulated pathways, which cause an overall pathophysiology of gastric stress ulcers and implicating the importance of D₁ agonist in ulcer protection. Thus, current study highlights the need to evaluate anti-stress and anti-ulcer agents in terms of their ability to modulate dopaminergic transmissions.     

Presurgical Nasoalveolar Molding (PNAM) for a Unilateral Cleft Lip and Palate: A Clinical Report

Cleft lip and palate deformity is a congenital defect of the middle third of the face. Incidence varies from 1:500 to 1:2500 live births. Etiology depends upon hereditary and environmental factors. Restoration of these defects is important not only for functional and esthetic reasons, but also because there may be a positive psychological impact for the patient and parents. The goal of primary closure of the lip for unilateral cleft lip is to ensure a normal and symmetrical lip and nose. Presurgical infant orthopedics has been employed since the 1950s as an adjunctive neonatal therapy for the correction of cleft lip and palate. Presurgical nasoalveolar molding (PNAM) represents a paradigm shift from the traditional methods of presurgical infant orthopedics. PNAM consists of active molding of the alveolar segments as well as the surrounding soft tissues. This clinical report describes a new approach of PNAM therapy for an infant with complete unilateral cleft lip and palate showing significant reduction in cleft defect size and improved contour and topography of deformed surrounding soft tissues.     

Step-Down Approach for Pharyngoesophageal Corrosive Stricture: Outcome and Analysis

Background

Pharyngoesophageal stricture (PES) is an Achilles’ heel in the management of corrosive injury. Advances in endoscopic techniques were utilized in its management. We classified the stricture as per its dilatability and then planned their treatment.

Methods

PES was sub-categorized based on endoscopic dilatation and availability of cervical oesophagus: group-1 stricture with available cervical oesophagus; group-2 stricture with some part of upper oesophagus made available after endoscopic dilatation and anastomosis in cervico-pharyngeal area; group-3 stricture not amenable for dilatation, anastomosis done at the pharynx. Endoscopic dilatation was performed using through-the-scope pyloric balloon. Number and duration of dilatation sessions before surgery, incidence of tracheostomy, time and incidence for re-stricture and present status of swallowing were evaluated.

Results

Of 226 patients managed, 46 underwent oesophageal replacement for PES. Group 1, 2 and 3 had 12, 14 and 20 patients, respectively. An average 3 (2–4) preoperative balloon dilatation sessions were performed over 6–8 weeks. Tracheostomy was required in 1, 0, 8 patients (p = 0.010), and median hospital stay was 10, 9 and 13 days (p = 0.09) in group 1, 2, 3, respectively. Re-stricture developed in 4/12, 4/14, 9/20 patients with average sessions of dilatation required in post-operative period was 4, 3.5 and 8 in group 1, 2, 3, respectively. >90% of patients are taking normal diet in each group.

Conclusion

We attempted to avoid the high anastomosis by dilating the PES and step down the level of anastomosis in two-third patients. We thereby avoided tracheostomy, aspiration and swallowing problems related to high strictures.

     

Subcutaneous hyalohyphomycosis caused by Fusarium in a kidney transplant recipient

Fusarium is a filamentous opportunistic pathogenic fungus responsible for superficial as well as invasive infection in immunocompromized hosts. Net state of immunosuppression and cytomegalovirus (CMV) infection appear to predispose to this disease which is life-threatening when disseminated. Though infections with Fusarium have been widely described in hematological malignancies and hematopoietic stem cell transplant cases, they have been reported to be rare in solid organ transplant recipients, are often localized and carry a favorable prognosis. We here describe a rare case of subcutaneous non-invasive infection with Fusarium in a renal allograft recipient two and half years after transplantation. Patient had a previous history of CMV infection along with multiple other recurrent co-infections. Diagnosis was based on culture of tissue specimens yielding Fusarium species. The infection had a protracted course with persistence of lesions after treatment with voriconazole alone, requiring a combination of complete surgical excision and therapy with the anti-fungal drug.     

Phase 2 Trial of Gemcitabine,Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes

Background

Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive biomarkers, remain unexplored.

Domain 5 of cleaved high molecular weight kininogen inhibits endothelial cell migration through Akt

Domain 5 (D5) of cleaved high molecular weight kininogen (HKa) inhibits angiogenesis in vivo and endothelial cell migration in vitro, but the cell signaling pathways involved in HKa and D5 inhibition of endothelial cell migration are incompletely delineated. This study examines the mechanism of HKa and D5 inhibition of two potent stimulators of endothelial cell migration, sphingosine 1-phosphate (S1P) and vascular endothelial growth factor (VEGF), that act through the P13-kinase-Akt signaling pathway. HKa and D5 inhibit bovine pulmonary artery endothelial cell (BPAE) or human umbilical vein endothelial cell chemotaxis in the modified-Boyden chamber in response toVEGF or S1P. The inhibition of migration by HKa is reversed by antibodies to urokinase-type plasminogen activator receptor. Both HKa and D5 decrease the speed of BPAE cell migration and alter the morphology in live, time-lapse microscopy after stimulation with S1P or VEGF. HKa and D5 reduce the localization of paxillin to the focal adhesions after S1P and VEGF stimulation. To better understand the intracellular signaling pathways, we examined the effect of HKa on the phosphorylation of Akt and its downstream effector, GSK-3alpha HKa and D5 inhibit phosphorylation of Akt and GSK-3alpha after stimulation withVEGF and S1P. Inhibitors of Akt and P13-kinase, the upstream activator of Akt, block endothelial cell migration and disrupt paxillin localization to the focal adhesions after stimulation with VEGF and S1P.Therefore we suggest that HKa through its D5 domain alters P13-kinase-Akt signaling to inhibit endothelial cell migration through alterations in the focal adhesions.     

Disodium octaborate tetrahydrate (DOT) application and vacuum cleaning,a combined strategy to control house dust mites

BACKGROUND: The effectiveness of acaricides in homes is controversial. OBJECTIVE: To determine whether disodium octaborate tetrahydrate (DOT) combined with vacuuming lowers dust mite numbers and their allergens in carpets and sofas. METHODS: A 6-month study was carried out with 93 homes, which were randomized into three groups: (i). active, received DOT; (ii). placebo, received water; and (iii). control, received no application. Active and placebo homes were vacuumed weekly. Dust was collected from carpets and sofas at the start of the study and every 2 months thereafter and quantified for live, total mites, and mite allergen levels. RESULTS: At 2 months, live mite numbers in active carpets were 3 +/- 1, in placebo carpets 129 +/- 48, and in control carpets 177 +/- 39 mites/g. The corresponding numbers in sofas were 3 +/- 2, 81 +/- 31, and 134 +/- 45 mites/g, respectively (P < 0.001 active vs placebo and vs. control). Live mites in carpets and sofas remained lower in the active group at 6 months (P < 0.001). Total mites in active carpets decreased from 555 +/- 69 at baseline to 223 +/- 32 mites/g at 6 months (P < 0.001) and mite allergen levels from 1.36 +/- 0.13 to 0.85 +/- 0.16 microg/g (P < 0.001). Total mites in active sofas remained unchanged, but mite allergen levels decreased from 1.48 +/- 0.25 at baseline to 0.7 +/- 0.15 microg/g at month 6 (P < 0.05). CONCLUSION: DOT kills mites in carpets and sofas, and, combined with vacuuming, effectively reduces total mites in carpets and mite allergen levels in carpets and sofas.     

Novel technique of repair of large tracheo-esophageal fistula following battery ingestion in children: review of two cases

Surgical repair of acquired tracheo-esophageal fistula may result in tracheal stenosis or esophageal stricture. We used fistula with esophageal cuff as flap to repair the tracheal defect. Esophageal repair was performed by rotating ends through 90° in opposite direction. This technique offers excellent repair in a single stage.