Differential Effects of HDAC6 Inhibition Versus Knockout During Hepatic Ischemia-reperfusion Injury Highlight Importance of HDAC6 C-terminal Zinc-finger Ubiquitin-binding Domain.

BACKGROUND: Ischemia-reperfusion injury (IRI) causes significant morbidity in liver transplantation among other medical conditions. IRI following liver transplantation contributes to poor outcomes and early graft loss. Histone/protein deacetylases (HDACs) regulate diverse cellular processes, play a role in mediating tissue responses to IRI, and may represent a novel therapeutic target in preventing IRI in liver transplantation. METHODS: Using a previously described standardized model of murine liver warm IRI, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were assessed at 24 and 48 h after reperfusion to determine the effect of different HDAC inhibitors. RESULTS: Broad HDAC inhibition with trichostatin-A (TSA) was protective against hepatocellular damage (P < 0.01 for AST and P < 0.05 for ALT). Although HDAC class I inhibition with MS-275 provided statistically insignificant benefit, tubastatin-A (TubA), an HDAC6 inhibitor with additional activity against HDAC10, provided significant protection against liver IRI (P < 0.01 for AST and P < 0.001 for ALT). Surprisingly genetic deletion of HDAC6 or -10 did not replicate the protective effects of HDAC6 inhibition with TubA, whereas treatment with an HDAC6 BUZ-domain inhibitor, LakZnFD, eliminated the protective effect of TubA treatment in liver ischemia (P < 0.01 for AST and P < 0.01 for ALT). CONCLUSIONS: Our findings suggest TubA, a class IIb HDAC inhibitor, can mitigate hepatic IRI in a manner distinct from previously described class I HDAC inhibition and requires the HDAC6 BUZ-domain activity. Our data corroborate previous findings that HDAC targets for therapeutic intervention of IRI may be tissue-specific, and identify HDAC6 inhibition as a possible target in the treatment of liver IRI.

A low appendiceal mucinous neoplasm lesion in an inflamed appendix within an inguinal hernia.

Amyand's hernia, an incarcerated appendix inside an inguinal hernia, accounts for <1% of hernias in children and even less in adults. Similarly, low-grade appendiceal mucinous (LAMN) lesions are only found in <1% of removed appendices. We present the case of a 72-year-old man with a 15-year history of a large right inguinoscrotal hernia that presented with right lower quadrant pain, was found by computed tomography imaging to have an incarcerated appendix with a large fluid collection, and was post-operatively diagnosed with an LAMN lesion. Although our case is rare due to the simultaneity of the Amyand's hernia and LAMN conditions, each separate condition is prevalent enough for most surgical providers to encounter at least one of these. For our case, we discuss the decisions made in the pre-operative and post-operative management and relevant literature.

Diagnosis of Anastomotic Leak.

Anastomotic leaks after colorectal surgery is associated with increased morbidity and mortality. Understanding the impact of anastomotic leaks and their risk factors can help the surgeon avoid any modifiable pitfalls. The diagnosis of an anastomotic leak can be elusive but can be discerned by the patient's global clinical assessment, adjunctive laboratory data and radiological assessment. The use of inflammatory markers such as C-Reactive Protein and Procalcitonin have recently gained traction as harbingers for a leak. A CT scan and/or a water soluble contrast study can further elucidate the location and severity of a leak. Further intervention is then individualized on the spectrum of simple observation with resolution or surgical intervention.

Counter Regulation of Spic by NF-κB and STAT Signaling Controls Inflammation and Iron Metabolism in Macrophages.

Activated macrophages must carefully calibrate their inflammatory responses to balance efficient pathogen control with inflammation-mediated tissue damage, but the molecular underpinnings of this "balancing act" remain unclear. Using genetically engineered mouse models and primary macrophage cultures, we show that Toll-like receptor (TLR) signaling induces the expression of the transcription factor Spic selectively in patrolling monocytes and tissue macrophages by a nuclear factor κB (NF-κB)-dependent mechanism. Functionally, Spic downregulates pro-inflammatory cytokines and promotes iron efflux by regulating ferroportin expression in activated macrophages. Notably, interferon-gamma blocks Spic expression in a STAT1-dependent manner. High levels of interferon-gamma are indicative of ongoing infection, and in its absence, activated macrophages appear to engage a "default" Spic-dependent anti-inflammatory pathway. We also provide evidence for the engagement of this pathway in sterile inflammation. Taken together, our findings uncover a pathway wherein counter-regulation of Spic by NF-κB and STATs attune inflammatory responses and iron metabolism in macrophages.

Tissue metabolic profiling shows that saccharopine accumulates during renal ischemic-reperfusion injury, while kynurenine and itaconate accumulate in renal allograft rejection.

To examine metabolic differences between renal allograft acute cellular rejection (ACR) and ischemic-reperfusion injury (IRI), we transplanted MHC-mismatched kidneys and induced 28 min warm-IRI, and collected the ACR and IRI kidneys as well as their respective native and collateral control kidneys. We extracted metabolites from the kidney tissues and found the lysine catabolite saccharopine 12.5-fold enriched in IRI kidneys, as well as the immunometabolites itaconate and kynurenine in ACR kidneys. Saccharopine accumulation is known to be toxic to mitochondria and may contribute to IRI pathophysiology, while itaconate and kynurenine may be reflective of counterregulatory responses to immune activation in ACR.

The volume-outcome relationship in robotic protectectomy: does center volume matter? Results of a national cohort study.

BACKGROUND: Utilization of robotic proctectomy (RP) for rectal cancer has steadily increased since the inception of robotic surgery in 2002. Randomized control trials evaluating the safety of RP are in process to better understand the role of robotic assistance in proctectomy. This study aimed to characterize the trends in the use of RP for rectal cancer, and to compare oncologic outcomes with center-level RP volume. MATERIALS AND METHODS: 8107 patients with rectal adenocarcinoma who underwent RP were identified in the National Cancer Database (2010-2015). Logistic regression was used to evaluate associations between center-level volume and conversion to open proctectomy, margin status, lymph node yield, 30- and 90-day post-operative mortality, and overall survival. RESULTS: The utilization of RP increased from 2010 to 2015. On multivariate regression, lower center-level volume of RP was associated with significantly higher rates of conversion to open, positive margins, inadequate lymph node harvest (≥ 12), and lower overall survival. The present study was limited by its retrospective design and lack of information regarding disease-specific survival. CONCLUSIONS: This series suggests a volume-outcome relationship association; patients who have robot-assisted proctectomies performed at low-volume centers are more likely to have poorer overall survival, positive margins, inadequate lymph node harvest, and require conversion to open surgery. While these data demonstrate the increased adoption of robot-assisted proctectomy, an understanding of the appropriateness of this intervention is still lacking. As with any new intervention, further information from ongoing randomized controlled trials is needed to better clarify the role of RP in order to optimize patient outcomes.

Exploring biosynthetic relationships among furanocembranoids: synthesis of (-)-bipinnatin J, (+)-intricarene, (+)-rubifolide, and (+)-isoepilophodione B.

The asymmetric total synthesis of (-)-bipinnatin J and its conversion into (+)-intricarene through a transannular 1,3-dipolar cycloaddition is described. In addition, the conversion of (-)-bipinnatin J into (+)-rubifolide and (+)-isoepilophodione B is reported. Biosynthetic relationships among furanocembranoids and the possible role of 1,3-dipolar cycloadditions in biosynthesis are discussed. [reaction: see text]