Smac mimetics induce apoptosis synergistically with TNF-alpha by triggering the formation of a caspase-8-activating complex containing receptor interacting protein kinase-1 (RIPK1). Caspase inhibitors block this form of apoptosis in many types of cells. However, in several other cell lines, caspase inhibitors switch the apoptotic response to necrosis. A genome wide siRNA screen revealed another member of the RIP kinase family, RIP3, to be required for necrosis. The expression of RIP3 in different cell lines correlates with their responsiveness to necrosis induction. The kinase activity of RIP3 is essential for necrosis execution. Upon induction of necrosis, RIP3 is recruited to RIPK1 to form a necrosis-inducing complex. Embryonic fibroblasts from RIP3 knockout mice are resistant to necrosis and RIP3 knockout animals are devoid of inflammation inflicted tissue damage in an acute pancreatitis model. These data indicate RIP3 as the determinant for cellular necrosis in response to TNF-alpha family of death-inducing cytokines.

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IMPORTANCEThe application of indocyanine green (ICG) imaging in laparoscopic radical gastrectomy is in the preliminary stages of clinical practice, and its safety and efficacy remain controversial.OBJECTIVE To investigate the safety and efficacy of ICG near-infrared tracer-guided imaging during laparoscopic D2 lymphadenectomy in patients with gastric cancer. DESIGN, SETTING, AND PARTICIPANTSPatients with potentially resectable gastric adenocarcinoma (clinical tumor stage cT1-cT4a, N0/+, M0) were enrolled in a prospective randomized clinical trial at a tertiary referral teaching hospital between November 2018 and July 2019. Patients were randomly assigned to the ICG group or the non-ICG group. The number of retrieved lymph nodes, rate of lymph node noncompliance, and postoperative recovery data were compared between the groups in a modified intention-to-treat analysis. Statistical analysis was performed from August to September 2019. INTERVENTIONSThe ICG group underwent laparoscopic gastrectomy using near-infrared imaging after receiving an endoscopic peritumoral injection of ICG to the submucosa 1 day before surgery. MAIN OUTCOMES AND MEASURES Total number of retrieved lymph nodes.RESULTS Of 266 participants randomized, 133 underwent ICG tracer-guided laparoscopic gastrectomy, and 133 underwent conventional laparoscopic gastrectomy. After postsurgical exclusions, 258 patients were included in the modified intention-to-treat analysis, which comprised 129 patients (86 men and 43 women; mean [SD] age, 57.8 [10.7] years) in the ICG group and 129 patients (87 men and 42 women; mean [SD] age, 60.1 [9.1] years) in the non-ICG group. The mean number of lymph nodes retrieved in the ICG group was significantly more than the mean number retrieved in the non-ICG group (mean [SD], 50.5 [15.9] lymph nodes vs 42.0 [10.3] lymph nodes, respectively; P < .001). Significantly more perigastric and extraperigastric lymph nodes were retrieved in the ICG group than in the non-ICG group. In addition, the mean total number of lymph nodes retrieved in the ICG group within the scope of D2 lymphadenectomy was also significantly greater than the mean number retrieved in the non-ICG group (mean [SD], 49.6 [15.0] lymph nodes vs 41.7 [10.2] lymph nodes, respectively; P < .001). The lymph node noncompliance rate of the ICG group (41 of 129 patients [31.8%]) was lower than that of the non-ICG group (74 of 129 patients [57.4%]; P < .001). The postoperative recovery process was comparable, and no significant difference was found between the ICG and non-ICG groups in the incidence (20 of 129 patients [15.5%] vs 21 of 129 [16.3%], respectively; P = .86) or severity of complications within 30 days after surgery.CONCLUSIONS AND RELEVANCE Indocyanine green can noticeably improve the number of lymph node dissections and reduce lymph node noncompliance without increased complications in patients undergoing D2 lymphadenectomy. Indocyanine green fluorescence imaging can be performed for routine lymphatic mapping during laparoscopic gastrectomy, especially t...

(2015) The autophagy gene Wdr45/Wipi4 regulates learning and memory function and axonal homeostasis, Autophagy, 11:6, 881-890, DOI: 10.1080/15548627.2015 Abbreviations: ACTB, b-actin; AMC, aminomethylcoumarin; Atg, autophagy-related; BPAN, b-propeller protein-associated neurodegeneration; CALB, calbindin; CNS, central nervous system; DCN, deep cerebellar nuclei; Ei24, etoposide-induced gene 24; epg, ectopic P granule; fEPSP, field excitatory postsynaptic potential; GFAP, glial fibrillary acid protein; H&E, hematoxylin and eosin; KO, knockout; LC3, microtubule-associated protein 1 light chain 3; LTP, long-term potentiation; MBP, myelin basic protein; NBIA, neurodegeneration with brain iron accumulation; RBFOX3, RNA binding protein, fox-1 homolog (C. elegans) 3; rpm, rotations per min; SENDA, static encephalopathy of childhood with neurodegeneration in adulthood; SQSTM1, sequestosome-1; WDR5/WIPI4, WD repeat domain 45; WT, wild type.WDR45/WIPI4, encoding a WD40 repeat-containing PtdIns(3)P binding protein, is essential for the basal autophagy pathway. Mutations in WDR45 cause the neurodegenerative disease b-propeller protein-associated neurodegeneration (BPAN), a subtype of NBIA. We generated CNS-specific Wdr45 knockout mice, which exhibit poor motor coordination, greatly impaired learning and memory, and extensive axon swelling with numerous axon spheroids. Autophagic flux is defective and SQSTM1 (sequestosome-1)/p62 and ubiquitin-positive protein aggregates accumulate in neurons and swollen axons. Nes-Wdr45 fl/Y mice recapitulate some hallmarks of BPAN, including cognitive impairment and defective axonal homeostasis, providing a model for revealing the disease pathogenesis of BPAN and also for investigating the possible role of autophagy in axon maintenance.