Is killing or capturing insurgent leaders an effective tactic? Previous research on interstate war and counterterrorism has suggested that targeting enemy leaders does not work. Most studies of the ...efficacy of leadership decapitation, however, have relied on unsystematic evidence and poor research design. An analysis based on fresh evidence and a new research design indicates the opposite relationship and yields four key findings. First, campaigns are more likely to end quickly when counterinsurgents successfully target enemy leaders. Second, counterinsurgents who capture or kill insurgent leaders are significantly more likely to defeat insurgencies than those who fail to capture or kill such leaders. Third, the intensity of a conflict is likelier to decrease following the successful removal of an enemy leader than it is after a failed attempt. Fourth, insurgent attacks are more likely to decrease after successful leadership decapitations than after failed attempts. Additional analysis suggests that these findings are attributable to successful leadership decapitation, and that the relationship between decapitation and campaign success holds across different types of insurgencies.
Cancer drug resistance: an evolving paradigm Holohan, Caitriona; Van Schaeybroeck, Sandra; Longley, Daniel B ...
Nature reviews. Cancer,
10/2013, Letnik:
13, Številka:
10
Journal Article
Recenzirano
Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to ...therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. With the increasing arsenal of anticancer agents, improving preclinical models and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.
•PE, PP, PS and PET were catalytically pyrolyzed in a tandem micro-pyrolyzer.•Product distribution and composition were varied at in-situ and ex-situ pyrolysis.•Hydrogen carrier gas suppressed coke ...formation and reduced polyaromatic content.•Positive synergies between PE and PS, or PE and PET were found.
In the present study, polyethylene (PE), polypropylene (PP), polystyrene (PS) and polyethylene terephthalate (PET) were pyrolyzed using HZSM-5 zeolite in a tandem micro-pyrolyzer to investigate the effects of plastic type, catalyst and feedstock contact mode, as well as the type of carrier gas on product distribution. Among the four plastics, PS produced highest aromatic yields up to 85% whereas PE and PP mainly produced aliphatic hydrocarbons. In comparison to ex-situ pyrolysis, in-situ pyrolysis of the plastics produced more solid residue but also promoted the formation of aromatic hydrocarbons, except PS. For PS, ex-situ pyrolysis produced a higher yield of aromatics than in-situ pyrolysis, mostly contributed by high styrene yield. During in-situ pyrolysis, the catalyst reduced the decomposition temperatures of the plastics in the order of PE, PP, PS and PET from high to low. Hydrogen carrier gas reduced solid residue and also increased the selectivity of single ring aromatics in comparison to inert pyrolysis. Hydrogen was more beneficial to PS and PET than PE and PP in terms of reducing coke yield and increasing hydrocarbon yield. The present study also showed that catalytically co-pyrolyzing PS and PE, or PET and PE increases the yield of aromatics and reduces the yield of solid residue due to hydrogen transfer from PE to PS or PET and alkylation reactions among the plastic-derivatives.
We estimate the causal effect of a large development program on conflict in the Philippines through a regression discontinuity design that exploits an arbitrary poverty threshold used to assign ...eligibility for the program. We find that barely eligible municipalities experienced a large increase in conflict casualties compared to barely ineligible ones. This increase is mostly due to insurgent-initiated incidents in the early stages of program preparation. Our results are consistent with the hypothesis that insurgents try to sabotage the program because its success would weaken their support in the population.
In this study, we compared ex-situ catalytic pyrolysis (CP) and in-situ CP of hybrid poplar in a micro-reactor system. When both pyrolysis and catalysis were performed at 700 °C, the carbon yield of ...olefins was greater for ex-situ CP than for in-situ CP (17.4% vs. 5.4%). On the other hand, in-situ CP produced more aromatic hydrocarbons than ex-situ CP (26.1% vs. 18.9%). The remarkably high yield of olefins from ex-situ CP indicates the potential of exploiting the process to preferentially produce olefins as a primary product from biomass, with aromatics being the secondary products. The carbon yield of carbonaceous residues from ex-situ CP was 18.6% compared to 31.3% for in-situ CP. Substantial carbon was deposited as char during ex-situ CP, which could be easily recovered as by-product, simplifying catalyst regeneration. The effects of catalyst loading, pyrolysis temperature and catalysis temperature on product distributions for ex-situ CP were also investigated. Our results showed that catalyst temperature strongly affected product distribution. While high catalyst temperature enhanced both olefin and aromatic production, yield of olefin increased to a greater extent than did aromatics. Neither pyrolysis temperature nor catalyst loadings had significant effect on product distribution for ex-situ CP.
Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had ...relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.
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•Zanubrutinib is a potent and selective BTK inhibitor with greater selectivity and potentially fewer off-target effects than ibrutinib.•In this study, zanubrutinib was tolerable and demonstrated encouraging activity in relapsed/refractory or treatment-naive CLL patients.
This study analyzes the effects of US drone strikes on terrorism in Pakistan. We find that drone strikes are associated with decreases in the incidence and lethality of terrorist attacks, as well as ...decreases in selective targeting of tribal elders. This matters for key ongoing debates. Some suggest that drone strikes anger Muslim populations and that consequent blowback facilitates recruitment and incites Islamist terrorism. Others argue that drone strikes disrupt and degrade terrorist organizations, reducing their ability to conduct attacks. We use detailed data on US drone strikes and terrorism in Pakistan from 2007-2011 to test each theory's implications. The available data do not enable us to evaluate if drone strikes resulted in increased recruitment, but the data do allow us to examine if these strikes resulted in changes in terrorist activities. While our findings do not suggest long-term effects, the results still lend some credence to the argument that drone strikes, while unpopular, bolster US counterterrorism efforts in Pakistan.
The development of flow cytometric biomarkers in human studies and clinical trials has been slowed by inconsistent sample processing, use of cell surface markers, and reporting of immunophenotypes. ...Additionally, the function(s) of distinct cell types as biomarkers cannot be accurately defined without the proper identification of homogeneous populations. As such, we developed a method for the identification and analysis of human leukocyte populations by the use of eight 10-color flow cytometric protocols in combination with novel software analyses. This method utilizes un-manipulated biological sample preparation that allows for the direct quantitation of leukocytes and non-overlapping immunophenotypes. We specifically designed myeloid protocols that enable us to define distinct phenotypes that include mature monocytes, granulocytes, circulating dendritic cells, immature myeloid cells, and myeloid derived suppressor cells (MDSCs). We also identified CD123 as an additional distinguishing marker for the phenotypic characterization of immature LIN-CD33+HLA-DR- MDSCs. Our approach permits the comprehensive analysis of all peripheral blood leukocytes and yields data that is highly amenable for standardization across inter-laboratory comparisons for human studies.
•Liso-cel significantly improved EFS, CR rate, and PFS vs chemotherapy ± ASCT as a second-line treatment for LBCL.•Liso-cel was well tolerated as a second-line therapy, with low rates of any grade or ...severe cytokine release syndrome and neurological events.
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This global phase 3 study compared lisocabtagene maraleucel (liso-cel) with a standard of care (SOC) as second-line therapy for primary refractory or early relapsed (≤12 months) large B-cell lymphoma (LBCL). Adults eligible for autologous stem cell transplantation (ASCT; N = 184) were randomly assigned in a 1:1 ratio to liso-cel (100 × 106 chimeric antigen receptor–positive T cells) or SOC (3 cycles of platinum-based immunochemotherapy followed by high-dose chemotherapy and ASCT in responders). The primary end point was event-free survival (EFS). In this primary analysis with a 17.5-month median follow-up, median EFS was not reached (NR) for liso-cel vs 2.4 months for SOC. Complete response (CR) rate was 74% for liso-cel vs 43% for SOC (P < .0001) and median progression-free survival (PFS) was NR for liso-cel vs 6.2 months for SOC (hazard ratio HR = 0.400; P < .0001). Median overall survival (OS) was NR for liso-cel vs 29.9 months for SOC (HR = 0.724; P = .0987). When adjusted for crossover from SOC to liso-cel, 18-month OS rates were 73% for liso-cel and 54% for SOC (HR = 0.415). Grade 3 cytokine release syndrome and neurological events occurred in 1% and 4% of patients in the liso-cel arm, respectively (no grade 4 or 5 events). These data show significant improvements in EFS, CR rate, and PFS for liso-cel compared with SOC and support liso-cel as a preferred second-line treatment compared with SOC in patients with primary refractory or early relapsed LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03575351.
Abramson and colleagues report on the primary analysis of the TRANSFORM study, a randomized trial of lisocabtagene maraleucel (liso-cel) following a cycle of bridging therapy (if needed) vs standard-of-care salvage chemotherapy and autologous transplantation in second-line therapy of patients with primary refractory or early relapse large B-cell lymphoma. Liso-cel significantly improves event-free survival as well as complete response rate and progression-free survival but not overall survival after a median of 18 months follow-up. These data establish liso-cel as a standard of care for these patients with a previous poor prognosis.
Patients with large B-cell lymphoma (LBCL) primary refractory to or relapsed within 12 months of first-line therapy are at high risk for poor outcomes with current standard of care, platinum-based ...salvage immunochemotherapy and autologous haematopoietic stem cell transplantation (HSCT). Lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has previously demonstrated efficacy and manageable safety in third-line or later LBCL. In this Article, we report a prespecified interim analysis of liso-cel versus standard of care as second-line treatment for primary refractory or early relapsed (within 12 months after response to initial therapy) LBCL.
TRANSFORM is a global, phase 3 study, conducted in 47 sites in the USA, Europe, and Japan, comparing liso-cel with standard of care as second-line therapy in patients with primary refractory or early (≤12 months) relapsed LBCL. Adults aged 18–75 years, Eastern Cooperative Oncology Group performance status score of 1 or less, adequate organ function, PET–positive disease per Lugano 2014 criteria, and candidates for autologous HSCT were randomly assigned (1:1), by use of interactive response technology, to liso-cel (100 × 106 CAR+ T cells intravenously) or standard of care. Standard of care consisted of three cycles of salvage immunochemotherapy delivered intravenously—R-DHAP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1–4, two infusions of cytarabine 2000 mg/m2 on day 2, and cisplatin 100 mg/m2 on day 1), R-ICE (rituximab 375 mg/m2 on day 1, ifosfamide 5000 mg/m2 on day 2, etoposide 100 mg/m2 on days 1–3, and carboplatin area under the curve 5 maximum dose of 800 mg on day 2), or R-GDP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1–4, gemcitabine 1000 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1)—followed by high-dose chemotherapy and autologous HSCT in responders. Primary endpoint was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. Efficacy was assessed per intention-to-treat (ie, all randomly assigned patients) and safety in patients who received any treatment. This trial is registered with ClinicalTrials.gov, NCT03575351, and is ongoing.
Between Oct 23, 2018, and Dec 8, 2020, 232 patients were screened and 184 were assigned to the liso-cel (n=92) or standard of care (n=92) groups. At the data cutoff for this interim analysis, March 8, 2021, the median follow-up was 6·2 months (IQR 4·4–11·5). Median event-free survival was significantly improved in the liso-cel group (10·1 months 95% CI 6·1–not reached) compared with the standard-of-care group (2·3 months 2·2–4·3; stratified hazard ratio 0·35; 95% CI 0·23–0·53; stratified Cox proportional hazards model one-sided p<0·0001). The most common grade 3 or worse adverse events were neutropenia (74 80% of 92 patients in the liso-cel group vs 46 51% of 91 patients in the standard-of-care group), anaemia (45 49% vs 45 49%), thrombocytopenia (45 49% vs 58 64%), and prolonged cytopenia (40 43% vs three 3%). Grade 3 cytokine release syndrome and neurological events, which are associated with CAR T-cell therapy, occurred in one (1%) and four (4%) of 92 patients in the liso-cel group, respectively (no grade 4 or 5 events). Serious treatment-emergent adverse events were reported in 44 (48%) patients in the liso-cel group and 44 (48%) in the standard-of-care group. No new liso-cel safety concerns were identified in the second-line setting. There were no treatment-related deaths in the liso-cel group and one treatment-related death due to sepsis in the standard-of-care group.
These results support liso-cel as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL.
Celgene, a Bristol-Myers Squibb Company.
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