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Ferroptosis is considered a distinctive form of cell death compared to other types of death such as apoptosis. It is known to result from iron-dependent accumulation of lipid peroxides rather than caspase activation. However, we reported recently that ferroptosis interplays with apoptosis. In this study, we investigated a possible mechanism of this interplay between ferroptosis and apoptosis. Results from our studies reveal that combined treatment of the ferroptotic agent erastin and the apoptotic agent TRAIL effectively disrupted mitochondrial membrane potential (ΔΨm) and subsequently promoted caspase activation. The alterations of mitochondrial membrane potential are probably due to an increase in oligomerization of BAX and its accumulation at the mitochondria during treatment with erastin and TRAIL. Interestingly, the combined treatment-promoted apoptosis was effectively inhibited in BAX-deficient HCT116 cells, but not BAK-deficient cells. These results indicate that the BAX-associated mitochondria-dependent pathway plays a pivotal role in erastin-enhanced TRAIL-induced apoptosis.

Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for patients with malignant peritoneal mesothelioma has resulted in improved disease control and increased survival. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection. The molecular pathogenesis of peritoneal mesothelioma remains relatively unknown, but extrapolation of findings from their pleural counterpart would suggest frequent alterations in CDKN2A , NF2 , and BAP1 . Homozygous deletions in CDKN2A portend a worse overall survival in peritoneal mesothelioma. However, the prevalence and prognostic significance of NF2 and BAP1 abnormalities has not been studied. Dual-color fluorescence in situ hybridization using CDKN2A and NF2 locus-specific probes and BAP1 immunohistochemistry identified homozygous CDKN2A deletions ( n =25, 29%), hemizygous NF2 loss ( n =30, 35%), and/or loss of BAP1 protein expression ( n =49, 57%) in 68 of 86 (79%) peritoneal mesotheliomas. Homozygous CDKN2A deletions or hemizygous NF2 loss correlated with shorter progression-free survival ( P <0.02) and poor overall survival ( P <0.03). Moreover, the significance of these findings was cumulative. Patients harboring both homozygous CDKN2A deletions and hemizygous NF2 loss had a 2-year progression-free survival rate of 9% with a median of 6 months ( P <0.01) and overall survival rate of 18% with a median of 8 months ( P <0.01). By multivariate analysis, combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for both progression-free survival and overall survival, independent of patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion. In contrast, loss of BAP1 was not associated with clinical outcome. In summary, homozygous deletions in CDKN2A and hemizygous loss of NF2 as detected by fluorescence in situ hybridization would confer a poor clinical outcome and may guide future treatment decisions for patients with peritoneal mesothelioma.

The growth and spread of non-governmental organizations (NGOs) at local and international levels has attracted considerable interest and attention from policy-makers, development practitioners, academics and activists around the world. But how has this phenomenon impacted on struggles for social and environmental justice? How has it challenged - or reinforced - the forces of capitalism and colonialism? And what political, economic, social and cultural interests does this serve? NGOization - the professionalization and institutionalization of social action - has long been a hotly contested issue in grassroots social movements and communities of resistance. This book pulls together for the first time unique perspectives of social struggles and critically engaged scholars from a wide range of geographical and political contexts to offer insights into the tensions and challenges of the NGO model, while considering the feasibility of alternatives.

Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with P<0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (P<0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P=0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P=0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2–6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7–14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.

In this Review, the authors present evidence for a causal relationship between the presence of large, dense, reactive platelets in the circulation and the onset of acute coronary syndromes (ACS). The increase in mean platelet volume in the pathogenesis of ACS can potentially overwhelm current therapeutics. Therefore, the control system for the production of these large platelets should be further researched to facilitate the development of new therapeutics that comprehensively prevent ACS. Platelets are causally involved in coronary artery obstruction in acute coronary syndromes (ACS). This cell type is unique to mammals and its production, which is unlike that of any other mammalian cell, involves polyploid nuclear change in the mother cell (megakaryocyte) and the production of anucleate cells with a log Gaussian distribution of volume. Platelets vary more in cellular volume than any other circulating blood element in mammals. Larger platelets are denser, contain more secretory granules, and are more reactive than their smaller counterparts. A causal relationship between the presence of large, dense, reactive platelets in the circulation and ACS is supported by many clinical studies. Furthermore, the results of two large, prospective, epidemiological studies have demonstrated that mean platelet volume was the strongest independent predictor of outcome in patients with acute myocardial infarction. Notably, evidence indicates that an increase in mean platelet volume in the pathogenesis of ACS can potentially overwhelm current therapeutics. The control system for the physiological and pathophysiological production of large platelets should, therefore, be researched. An understanding of this system might give rise to new therapeutics that could control platelet reactivity and thereby comprehensively prevent ACS. Key Points The megakaryocyte–platelet hemostatic system is unique to mammals, and has a complex control system that is not yet fully understood Larger platelets are denser and more reactive than smaller platelets, and are associated with megakaryocyte change Large clinical studies have shown a relationship between large platelets and incidence of acute coronary syndromes Two large prospective epidemiological studies have shown that the presence of large platelets can independently predict outcome related to acute myocardial infarction, including death Platelet physiological change has the potential to overwhelm current therapeutic interventions Future research should address the physiological and pathological production of large platelets

Background Most patients with malignant peritoneal mesothelioma (MPM) present with late-stage, unresectable disease that responds poorly to systemic chemotherapy while, at the same time, effective targeted therapies are lacking. We assessed the efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) in MPM. Methods We prospectively analyzed 65 patients with MPM undergoing CRS/HIPEC between 2001 and 2010. Kaplan–Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting oncologic outcomes. Results Adequate CRS was achieved in 56 patients (CC-0 = 35; CC-1 = 21), and median simplified peritoneal cancer index (SPCI) was 12. Pathologic assessment revealed predominantly epithelioid histology (81 %) and biphasic histology (8 %), while lymph node involvement was uncommon (8 %). Major postoperative morbidity (grade III/IV) occurred in 23 patients (35 %), and 60-day mortality rate was 6 %. With median follow-up of 37 months, median overall survival was 46.2 months, with 1-, 2-, and 5-year overall survival probability of 77, 57, and 39 %, respectively. Median progression-free survival was 13.9 months, with 1-, 2-, and 5-year disease failure probability of 47, 68, and 83 %, respectively. In a multivariate Cox-regression model, age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), aggressive histology (epithelioid, biphasic), and postoperative sepsis were joint significant predictors of poor survival (chi square = 42.8; p  = 0.00001), while age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), and aggressive histology (epithelioid, biphasic) were joint significant predictors of disease progression (Chi square = 30.6; p  = 0.00001). Conclusions Tumor histology, disease burden, and the ability to achieve adequate surgical cytoreduction are essential prognostic factors in MPM patients undergoing CRS/HIPEC.

Background Mucinous colon cancers (MCC) are characterized by abundant production of mucin 2 (MUC2) protein and are less sensitive to standard systemic chemotherapy. We postulated that severe/persistent endoplasmic reticulum stress (ERS) aggravation in MCC would overwhelm compensatory cytoprotective pathways and induce apoptosis. Results Basal levels of ERS markers were higher in MCC and dnTCF-LS174T cells than non-mucinous tumors and these levels were significantly increased by combinatorial treatment with ERS aggravators celecoxib + orlistat. Combination treatment inhibited cell viability and synergistically induced apoptosis. Treatment-induced cell death was ERS-dependent, apoptotic pathways were not activated following knockdown of ERS protein CHOP. Dual drug treatment significantly reduced mucinous tumor growth in vivo and induced ERS and apoptosis, consistent with in vitro experiments. Conclusions Novel therapies are needed since MCC are more resistant to standard systemic chemotherapy. This study suggests ERS aggravation is a viable therapeutic strategy to reduce tumor growth in MCC.

Molecular‐targeted therapies have demonstrated disappointing results against most advanced solid cancers. This may largey be attributed to irrational drug use against unselected cancers. We investigated the efficacy of dual MEK‐PI3K drug therapy against KRAS mutated mucin 2 (MUC2)‐secreting LS174T cells and patient‐derived ex vivo and in vivo models of KRAS mutated mucinous colon/appendix cancers. These tumors demonstrate unique phenotypic and genotypic features that likely predict sensitivity to this targeted co‐therapy. Co‐treatment with MEK inhibitor (trametinib) and PI3K inhibitor (pictilisib)‐induced synergistic cytotoxicity and intrinsic mitochondrial‐mediated apoptosis in LS174T cells and tumor explants in vitro. Dual drug therapy also induced endoplasmic reticulum stress (ERS)‐associated proteins (GRP78/BiP, ATF4, and CHOP). However, CHOP knock‐down assays demonstrated that mitochondrial‐mediated apoptosis in LS174T cells was not ERS‐dependent. Dual drug therapy also significantly decreased MUC2 expression, MUC2 post‐translational modification (palmitoylation) and secretion in LS174T cells, suggesting a simultaneous cytotoxic and mucin suppressive mechanism of action. We also demonstrated effective mucinous tumor growth suppression in ex vivo epithelial organoid (colonoid) cultures and in in vivo intraperitoneal patient‐derived xenograft models derived from mucinous colon/appendix cancer. These promising preclinical data support a role for dual MEK‐PI3K inhibitor therapy in mucinous colon/appendix cancers. We postulate that mucinous KRAS mutated cancers are especially vulnerable to this co‐treatment based on their unique phenotypic and genotypic characteristics. Mucinous KRAS mutated colon/appendix cancers demonstrate unique genotypic and phenotypic characteristics that allow for the rational application of MEK‐PI3K inhibitor therapy. The present study demonstrates that dual MEK‐PI3K inhibitor therapy (trametinib plus pictilisib) reduces mucinous tumor growth in patient‐derived ex vivo and in vivo models of KRAS mutated mucinous colon/appendix cancer.