Citations

Previous studies have shown that human immunodeficiency virus (HIV) protease cleaves procaspase 8 to a fragment, termed Casp8p41, that lacks caspase activity but nonetheless contributes to T cell apoptosis. Herein, we show that Casp8p41 contains a domain that interacts with the BH3-binding groove of pro-apoptotic Bak to cause Bak oligomerization, Bak-mediated membrane permeabilization, and cell death. Levels of active Bak are higher in HIV-infected T cells that express Casp8p41. Conversely, targeted mutations in the Bak-interacting domain diminish Bak binding and Casp8p41-mediated cell death. Similar mutations in procaspase 8 impair the ability of HIV to kill infected T cells. These observations support a novel paradigm in which HIV converts a normal cellular constituent into a direct activator that functions like a BH3-only protein.

We conducted a retrospective cohort study to investigate the colorectal cancer (CRC) incidence and mortality prevention achievable in clinical practice with an optimized colonoscopy protocol targeting near‐complete polyp clearance. The protocol consisted of: ( i ) telephonic reinforcement of bowel preparation instructions; ( ii ) active inspection for polyps throughout insertion and circumferential withdrawal; and ( iii ) timely updating of the protocol and documentation to incorporate the latest guidelines. Of 17,312 patients provided screening colonoscopies by 59 endoscopists in South Carolina, USA from September 2001 through December 2008, 997 were excluded using accepted exclusion criteria. Data on 16,315 patients were merged with the South Carolina Central Cancer Registry and Vital Records Registry data from January 1996 to December 2009 to identify incident CRC cases and deaths, incident lung cancers and brain cancer deaths (comparison control cancers). The standardized incidence ratios (SIR) and standardized mortality ratios (SMR) relative to South Carolina and US SEER‐18 population rates were calculated. Over 78,375 person‐years of observation, 18 patients developed CRC versus 104.11 expected for an SIR of 0.17, or 83% CRC protection, the rates being 68% and 91%, respectively among the adenoma‐ and adenoma‐free subgroups (all p < 0.001). Restricting the cohort to ensure minimum 5‐year follow‐up (mean follow‐up 6.64 years) did not change the results. The CRC mortality reduction was 89% ( p < 0.001; four CRC deaths vs . 35.95 expected). The lung cancer SIR was 0.96 ( p = 0.67), and brain cancer SMR was 0.92 ( p = 0.35). Over 80% reduction in CRC incidence and mortality is achievable in routine practice by implementing key colonoscopy principles targeting near‐complete polyp clearance.

Chronic passive hepatic congestion (congestive hepatopathy) leads to hepatic fibrosis; however, the mechanisms involved in this process are not well understood. We developed a murine experimental model of congestive hepatopathy through partial ligation of the inferior vena cava (pIVCL). C57BL/6 and transgenic mice overexpressing tissue factor pathway inhibitor (SM22α‐TFPI) were subjected to pIVCL or sham. Liver and blood samples were collected and analyzed in immunohistochemical, morphometric, real‐time polymerase chain reaction, and western blot assays. Hepatic fibrosis and portal pressure were significantly increased after pIVCL concurrent with hepatic stellate cell (HSC) activation. Liver stiffness, as assessed by magnetic resonance elastography, correlated with portal pressure and preceded fibrosis in our model. Hepatic sinusoidal thrombosis as evidenced by fibrin deposition was demonstrated both in mice after pIVCL as well as in humans with congestive hepatopathy. Warfarin treatment and TFPI overexpression both had a protective effect on fibrosis development and HSC activation after pIVCL. In vitro studies show that congestion stimulates HSC fibronectin (FN) fibril assembly through direct effects of thrombi as well as by virtue of mechanical strain. Pretreatment with either Mab13 or Cytochalasin‐D, to inhibit β‐integrin or actin polymerization, respectively, significantly reduced fibrin and stretch‐induced FN fibril assembly. Conclusion : Chronic hepatic congestion leads to sinusoidal thrombosis and strain, which in turn promote hepatic fibrosis. These studies mechanistically link congestive hepatopathy to hepatic fibrosis. (H epatology 2015;61:648‐659)

BACKGROUNDWith the advent of limits to resident duty hours and the size of teaching services, many academic institutions have introduced nonteaching services, often triaging perceived better teaching cases to the resident services.OBJECTIVETo compare resident versus faculty perceptions of ideal cases for teaching services and compare these perceptions with actual triage decisions made by faculty who assigned patients to either teaching or nonteaching services.DESIGNResidents and hospitalist faculty were surveyed about their perceptions of ideal and actual teaching admissions, first with qualitative, open‐ended questions and then with quantitative, specific questions generated from responses to the first survey. Characteristics of patients admitted to teaching and nonteaching services were analyzed retrospectively and compared with resident and faculty perceptions.RESULTSResidents and faculty agreed that rare cases, patients with unique physical findings, and a variety of pathology were ideal for teaching services and that social admissions, benefactors, and patients with chronic or functional pain were not. Residents believed that traditional (“bread and butter”) medicine cases were under‐represented on the teaching services. Although residents perceived that they received a disproportionate number of older patients, outside transfers, patients with chronic pain, and patients with cancer, the only statistically significant difference was in patient age, with the teaching service actually receiving younger patients (66.7 vs 69.3 years; P = 0.008).CONCLUSIONSResidents and faculty have similar views about ideal teaching cases, but a triage system based on perceived educational merit creates the possibility of resident misperceptions about their case mix, even if patients are distributed relatively equitably. Journal of Hospital Medicine 2014;9:508–514. © 2014 Society of Hospital Medicine

ObjectivesAnalyze the effect of ipsilateral submandibular gland preservation on patients undergoing concurrent neck dissection and transoral surgery for oropharyngeal squamous cell carcinoma. Evaluate for (1) intraoperative and postoperative communications between the oropharynx and neck and (2) oncologic outcomes.Study DesignRetrospective chart review of prospectively collected data.SettingTertiary academic referral center.Methods and SubjectsRetrospective chart review of patients undergoing transoral laser resection of oropharyngeal squamous cell carcinoma with simultaneous neck dissection(s) for primary, persistent, recurrent, and second primary disease between January 1999 and February 2013. Data analyzed for operative technique, pathologic diagnosis, postoperative course, complications, and oncologic outcomes.ResultsOverall 253 patients were identified. Of these, 96 patients underwent ipsilateral submandibular gland preservation and 157 underwent ipsilateral submandibular gland removal at the time of neck dissection. The prevalence of intraoperative communication between the neck and oropharynx was significantly lower in cases with submandibular gland preservation (2/96, 2.08%) compared to those with submandibular gland removal (22/157, 14.13%). No postoperative leaks occurred in the gland preservation group (0/96, 0%) compared to a leak prevalence of 8.92% (14/157) when the gland was removed (P =. 0041). There was no difference in local, regional, or distant disease recurrence between submandibular gland preservation and gland removal. Similarly, Kaplan‐Meier analysis showed no difference in disease free survival, disease specific survival, or overall survival.ConclusionsSubmandibular gland preservation during neck dissection in patients undergoing transoral surgery for oropharyngeal squamous cell carcinoma significantly reduces the risk of intraoperative and postoperative salivary leaks without compromising oncologic outcomes.

Abstract Bcl-2 is phosphorylated on Ser70 after treatment of cells with spindle poisons. On the basis of effects observed in cells overexpressing Bcl-2 S70E or S70A mutants, various studies have concluded that Ser70 phosphorylation either enhances or diminishes Bcl-2 function. In the present study, the ability of phosphorylated Bcl-2, as well as the S70E and S70A mutants, to bind and neutralize proapoptotic Bcl-2 family members under cell-free conditions and in intact cells was examined in an attempt to resolve this controversy. Surface plasmon resonance indicated that phosphorylated Bcl-2, Bcl-2 S70E, and Bcl-2 S70A exhibit enhanced binding to Bim and Bak compared with unmodified Bcl-2. This enhanced binding reflected a readily detectable conformation change in the loop domain of Bcl-2. Furthermore, Bcl-2 S70E and S70A bound more Bak and Bim than wild-type Bcl-2 in pull-downs and afforded greater protection against several chemotherapeutic agents. Importantly, binding of endogenous Bcl-2 to Bim also increased during mitosis, when Bcl-2 is endogenously phosphorylated, and disruption of this mitotic Bcl-2/Bim binding with navitoclax or ABT-199, like Bcl-2 downregulation, enhanced the cytotoxicity of paclitaxel. Collectively, these results provide not only a mechanistic basis for the enhanced antiapoptotic activity of phosphorylated Bcl-2, but also an explanation for the ability of BH3 mimetics to enhance taxane sensitivity. Cancer Res; 73(23); 6998–7008. ©2013 AACR.

PurposeTo investigate the influence of portal pressure on the shear stiffness of the liver and spleen in a well‐controlled in vivo porcine model with magnetic resonance elastography (MRE). A significant correlation between portal pressure and tissue stiffness could be used to noninvasively assess increased portal venous pressure (portal hypertension), which is a frequent clinical condition caused by cirrhosis of the liver and is responsible for the development of many lethal complications.Materials and MethodsDuring multiple intraarterial infusions of Dextran‐40 in three adult domestic pigs in vivo, 3D abdominal MRE was performed with left ventricle and portal catheters measuring blood pressure simultaneously. Least‐squares linear regressions were used to analyze the relationship between tissue stiffness and portal pressure.ResultsLiver and spleen stiffness have a dynamic component that increases significantly following an increase in portal or left ventricular pressure. Correlation coefficients with the linear regressions between stiffness and pressure exceeded 0.8 in most cases.ConclusionThe observed stiffness–pressure relationship of the liver and spleen could provide a promising noninvasive method for assessing portal pressure. Using MRE to study the tissue mechanics associated with portal pressure may provide new insights into the natural history and pathophysiology of hepatic diseases and may have significant diagnostic value in the future. J. Magn. Reson. Imaging 2013;38:809–815. © 2013 Wiley Periodicals, Inc.

PurposeTo investigate the feasibility of using MR elastography (MRE) for the evaluation of the stiffness of in vivo aortic wall.Materials and MethodsTo validate the experimental approach for imaging the aorta in vivo, a gel phantom with an embedded porcine aorta was imaged in the presence of fluid flow within the aorta. The potential changes in the elasticity of the vessel wall with changes in pressure were investigated. The feasibility of performing MRE of abdominal aorta was assessed in five volunteers (age, 22–40 years; body mass index, 21.5–25.2 kg/m2). The pulse‐gated cine MRE technique was used to study the wave propagation along the aorta throughout the cardiac cycle and provide estimates of aortic stiffness in diastole.ResultsIn the phantom study, the wave propagation was well visualized within the porcine aorta embedded in the gel phantom. An increase of the Young's modulus‐wall thickness (E*t) product with the increase in static pressure was observed. In the in vivo study, the waves were well visualized within the lumen of abdominal aorta in the five volunteers in diastolic phase, but they were not well visualized during systole.ConclusionMRE is feasible for noninvasively assessing the stiffness of the abdominal aorta and merits further investigation. J. Magn. Reson. Imaging 2013;38:1549–1553. © 2013 Wiley Periodicals, Inc.