Counting Down the 2020 Goals for 9 Neglected Tropical Diseases: What Have We Learned From Quantitative Analysis and Transmission Modeling?

Abstract

The control of neglected tropical diseases (NTDs) has received huge investment in recent years, leading to large reductions in morbidity. In 2012, the World Health Organization set ambitious targets for eliminating many of these diseases as a public health problem by 2020, an aspiration that was supported by donations of treatments, intervention materials, and funding committed by a broad partnership of stakeholders in the London Declaration on NTDs. Alongside these efforts, there has been an increasing role for quantitative analysis and modeling to support the achievement of these goals through evaluation of the likely impact of interventions, the factors that could undermine these achievements, and the role of new diagnostics and treatments in reducing transmission. In this special issue, we aim to summarize those insights in an accessible way. This article acts as an introduction to the special issue, outlining key concepts in NTDs and insights from modeling as we approach 2020.

https://ift.tt/2xArkPy

Are We on Our Way to Achieving the 2020 Goals for Schistosomiasis Morbidity Control Using Current World Health Organization Guidelines?

Abstract

Background

Schistosomiasis remains an endemic parasitic disease affecting millions of people around the world. The World Health Organization (WHO) has set goals of controlling morbidity to be reached by 2020, along with elimination as a public health problem in certain regions by 2025. Mathematical models of parasite transmission and treatment impact have been developed to assist in controlling the morbidity caused by schistosomiasis. These models can inform and guide implementation policy for mass drug administration programs, and help design monitoring and evaluation activities.

Methods

We use these models to predict whether the guidelines set by the WHO are on track for achieving their 2020 goal for the control of morbidity, specifically for Schistosoma mansoni. We examine whether programmatic adaptations; namely increases in treatment coverage and/or expansion to adult inclusion in treatment, will improve the likelihood of reaching the WHO goals.

Results

We find that in low-prevalence settings, the goals are likely to be attainable under current WHO guidelines, but in moderate to high-prevalence settings, the goals are less likely to be achieved unless treatment coverage is increased and expanded to at least 85% for school-aged children and 40% for adults.

Conclusions

To improve the likelihood of reaching the WHO goals, programmatic adaptations are required, particularly for moderate- to high-prevalence settings. Furthermore, improvements in adherence to treatment, potential development of candidate vaccines, and enhanced snail control and WASH (water, sanitation, and hygiene) measures will all assist in achieving the goals.

https://ift.tt/2LQEqeC

Complementary Paths to Chagas Disease Elimination: The Impact of Combining Vector Control With Etiological Treatment

Abstract

Background

The World Health Organization's 2020 goals for Chagas disease are (1) interrupting vector-borne intradomiciliary transmission and (2) having all infected people under care in endemic countries. Insecticide spraying has proved efficacious for reaching the first goal, but active transmission remains in several regions. For the second, treatment has mostly been restricted to recently infected patients, who comprise only a small proportion of all infected individuals.

Methods

We extended our previous dynamic transmission model to simulate a domestic Chagas disease transmission cycle and examined the effects of both vector control and etiological treatment on achieving the operational criterion proposed by the Pan American Health Organization for intradomiciliary, vectorial transmission interruption (ie, <2% seroprevalence in children <5 years of age).

Results

Depending on endemicity, an antivectorial intervention that decreases vector density by 90% annually would achieve the transmission interruption criterion in 2–3 years (low endemicity) to >30 years (high endemicity). When this strategy is combined with annual etiological treatment in 10% of the infected human population, the seroprevalence criterion would be achieved, respectively, in 1 and 11 years.

Conclusions

Combining highly effective vector control with etiological (trypanocidal) treatment in humans would substantially reduce time to transmission interruption as well as infection incidence and prevalence. However, the success of vector control may depend on prevailing vector species. It will be crucial to improve the coverage of screening programs, the performance of diagnostic tests, the proportion of people treated, and the efficacy of trypanocidal drugs. While screening and access can be incremented as part of strengthening the health systems response, improving diagnostics performance and drug efficacy will require further research.

https://ift.tt/2xwIIEL

Investigating the Effectiveness of Current and Modified World Health Organization Guidelines for the Control of Soil-Transmitted Helminth Infections

Abstract

Background

Considerable efforts have been made to better understand the effectiveness of large-scale preventive chemotherapy therapy for the control of morbidity caused by infection with soil-transmitted helminths (STHs): Ascaris lumbricoides, Trichuris trichiura, and the 2 hookworm species, Necator americanus and Ancylostoma duodenale. Current World Health Organization (WHO) guidelines for STH control include mass drug administration (MDA) programs based on prevalence measurements, aiming at reducing morbidity in pre–school-aged children (pre-SAC) and school-aged children (SAC) by lowering the prevalence of moderate- to heavy-intensity infections to <1%.

Methods

We project the likely impact of following the current WHO guidelines and assess whether the WHO morbidity goals will be achieved across a range of transmission settings. We also investigate modifications that could be made to the current WHO treatment guidelines, and project their potential impacts in achieving morbidity and transmission control.

Results

While the standard guidelines are sufficient at low transmission levels, community-wide treatment (ie, involving pre-SAC, SAC, and adults) is essential if WHO morbidity goals are to be met in moderate- to high-transmission settings. Moreover, removing the recommendation of decreasing the treatment frequency at midline (5–6 years after the start of MDA) further improves the likelihood of achieving morbidity control in SAC.

Conclusions

We meld analyses based on 2 mathematical models of parasite transmission and control by MDA for the dominant STH species, to generate a unified treatment approach applicable across all settings, regardless of which STH infection is most common. We recommend clearly defined changes to the current WHO guidelines.

https://ift.tt/2LNMwof

Are Alternative Strategies Required to Accelerate the Global Elimination of Lymphatic Filariasis? Insights From Mathematical Models

Abstract

Background

With the 2020 target year for elimination of lymphatic filariasis (LF) approaching, there is an urgent need to assess how long mass drug administration (MDA) programs with annual ivermectin + albendazole (IA) or diethylcarbamazine + albendazole (DA) would still have to be continued, and how elimination can be accelerated. We addressed this using mathematical modeling.

Methods

We used 3 structurally different mathematical models for LF transmission (EPIFIL, LYMFASIM, TRANSFIL) to simulate trends in microfilariae (mf) prevalence for a range of endemic settings, both for the current annual MDA strategy and alternative strategies, assessing the required duration to bring mf prevalence below the critical threshold of 1%.

Results

Three annual MDA rounds with IA or DA and good coverage (≥65%) are sufficient to reach the threshold in settings that are currently at mf prevalence <4%, but the required duration increases with increasing mf prevalence. Switching to biannual MDA or employing triple-drug therapy (ivermectin, diethylcarbamazine, and albendazole [IDA]) could reduce program duration by about one-third. Optimization of coverage reduces the time to elimination and is particularly important for settings with a history of poorly implemented MDA (low coverage, high systematic noncompliance).

Conclusions

Modeling suggests that, in several settings, current annual MDA strategies will be insufficient to achieve the 2020 LF elimination targets, and programs could consider policy adjustment to accelerate, guided by recent monitoring and evaluation data. Biannual treatment and IDA hold promise in reducing program duration, provided that coverage is good, but their efficacy remains to be confirmed by more extensive field studies.

https://ift.tt/2LJ1VGp

How Can Onchocerciasis Elimination in Africa Be Accelerated? Modeling the Impact of Increased Ivermectin Treatment Frequency and Complementary Vector Control

Abstract

Background

Great strides have been made toward onchocerciasis elimination by mass drug administration (MDA) of ivermectin. Focusing on MDA-eligible areas, we investigated where the elimination goal can be achieved by 2025 by continuation of current practice (annual MDA with ivermectin) and where intensification or additional vector control is required. We did not consider areas hypoendemic for onchocerciasis with loiasis coendemicity where MDA is contraindicated.

Methods

We used 2 previously published mathematical models, ONCHOSIM and EPIONCHO, to simulate future trends in microfilarial prevalence for 80 different settings (defined by precontrol endemicity and past MDA frequency and coverage) under different future treatment scenarios (annual, biannual, or quarterly MDA with different treatment coverage through 2025, with or without vector control strategies), assessing for each strategy whether it eventually leads to elimination.

Results

Areas with 40%–50% precontrol microfilarial prevalence and ≥10 years of annual MDA may achieve elimination with a further 7 years of annual MDA, if not achieved already, according to both models. For most areas with 70%–80% precontrol prevalence, ONCHOSIM predicts that either annual or biannual MDA is sufficient to achieve elimination by 2025, whereas EPIONCHO predicts that elimination will not be achieved even with complementary vector control.

Conclusions

Whether elimination will be reached by 2025 depends on precontrol endemicity, control history, and strategies chosen from now until 2025. Biannual or quarterly MDA will accelerate progress toward elimination but cannot guarantee it by 2025 in high-endemicity areas. Long-term concomitant MDA and vector control for high-endemicity areas might be useful.

https://ift.tt/2LNklFT

Policy Recommendations From Transmission Modeling for the Elimination of Visceral Leishmaniasis in the Indian Subcontinent

Abstract

Background

Visceral leishmaniasis (VL) has been targeted by the World Health Organization (WHO) and 5 countries in the Indian subcontinent for elimination as a public health problem. To achieve this target, the WHO has developed guidelines consisting of 4 phases of different levels of interventions, based on vector control through indoor residual spraying of insecticide (IRS) and active case detection (ACD). Mathematical transmission models of VL are increasingly used for planning and assessing the efficacy of interventions and evaluating the intensity and timescale required to achieve the elimination target.

Methods

This paper draws together the key policy-relevant conclusions from recent transmission modeling of VL, and presents new predictions for VL incidence under the interventions recommended by the WHO using the latest transmission models.

Results

The model predictions suggest that the current WHO guidelines should be sufficient to reach the elimination target in areas that had medium VL endemicities (up to 5 VL cases per 10000 population per year) prior to the start of interventions. However, additional interventions, such as extending the WHO attack phase (intensive IRS and ACD), may be required to bring forward elimination in regions with high precontrol endemicities, depending on the relative infectiousness of different disease stages.

Conclusions

The potential hurdle that asymptomatic and, in particular, post-kala-azar dermal leishmaniasis cases may pose to reaching and sustaining the target needs to be addressed. As VL incidence decreases, the pool of immunologically naive individuals will grow, creating the potential for new outbreaks.

https://ift.tt/2J49fdT

Highlights of This Issue

https://ift.tt/2HdcfDa

Genome-Wide DNA Methylation in Prediagnostic Blood and Bladder Cancer Risk in the Women's Health Initiative

Background: Differential DNA methylation as measured in blood is a promising marker of bladder cancer susceptibility. However, previous studies have exclusively used postdiagnostic blood samples, meaning that observed associations may be markers of disease rather than susceptibility.

Methods: Genome-wide methylation was measured in prediagnostic blood samples, using the Illumina Infinium HumanMethylation450 Bead Array, among 440 bladder cancer cases with the transitional cell carcinoma (TCC) subtype and 440 matched cancer-free controls from the Women's Health Initiative cohort. After normalization and probe filtering, we used conditional logistic regression models to test for associations between methylation measurements at 361,184 CpG sites and bladder cancer risk.

Results: Increased methylation at cg22748573, located in a CpG island within the 5'-UTR/first exon of the CITED4 gene, was associated with an 82% decreased risk of bladder cancer after adjusting for race/ethnicity, smoking status, pack-years of smoking, and leukocyte cell profile and accounting for multiple testing (OR = 0.18, q-value = 0.05). The result was robust to sensitivity analyses accounting for time between enrollment and diagnosis, race, tumor subtype, and secondhand smoke exposure.

Conclusions: Although results need to be confirmed in additional prospective studies, differential methylation in CITED4, as measured in blood, is a promising marker of bladder cancer susceptibility.

Impact: Identification of biomarkers of bladder cancer susceptibility in easily accessible tissues may allow targeting of screening efforts so as to improve bladder cancer prognosis. This is particularly important among women, who tend to have poorer bladder cancer outcomes than men. Cancer Epidemiol Biomarkers Prev; 27(6); 689–95. ©2018 AACR.

https://ift.tt/2H91tOe

Differences in Breast Cancer Survival by Molecular Subtypes in the United States

Background: Although incidence rates of breast cancer molecular subtypes are well documented, effects of molecular subtypes on breast cancer–specific survival using the largest population coverage to date are unknown in the U.S. population.

Methods: Using Surveillance, Epidemiology and End Results cancer registry data, we assessed survival after breast cancer diagnosis among women diagnosed during 2010 to 2013 and followed through December 31, 2014. Breast cancer molecular subtypes defined by joint hormone receptor [HR, estrogen receptor (ER) and/or progesterone receptor (PR)] and HER2 status were assessed. Multiple imputation was used to fill in missing receptor status. Four-year breast cancer–specific survival per molecular subtypes and clinical/demographic factors were calculated. A Cox proportional hazards model was used to evaluate survival while controlling for clinical and demographic factors.

Results: The best survival pattern was observed among women with HR⁺/HER2^– subtype (survival rate of 92.5% at 4 years), followed by HR⁺/HER2⁺ (90.3%), HR^–/HER2⁺ (82.7%), and finally worst survival for triple-negative subtype (77.0%). Notably, failing to impute cases with missing receptor status leads to overestimation of survival because those with missing receptor status tend to have worse prognostic features. Survival differed substantially by stage at diagnosis. Among de novo stage IV disease, women with HR⁺/HER2⁺ subtype experienced better survival than those with HR⁺/HER2^– subtype (45.5% vs. 35.9%), even after controlling for other factors.

Conclusions: Divergence of survival curves in stage IV HR⁺/HER2⁺ versus HR⁺/HER2^– subtype is likely attributable to major advances in HER2-targeted treatment.

Impact: Contrary to conventional thought, HR⁺/HER2⁺ subtype experienced better survival than HR⁺/HER2^– in advanced-stage disease. Cancer Epidemiol Biomarkers Prev; 27(6); 619–26. ©2018 AACR.

https://ift.tt/2J22q0r

Association of Metformin with Breast Cancer Incidence and Mortality in Patients with Type II Diabetes: A GRADE-Assessed Systematic Review and Meta-analysis

Background: Preclinical data suggest that metformin may reduce breast cancer incidence and improve cancer prognosis. However, the current evidence in observational studies is inconclusive. A systematic review and meta-analysis was conducted to assess the effect of metformin on the incidence of breast cancer and all-cause mortality in patients with type II diabetes (T2D).

Methods: A literature search was performed on Medline, EMBASE, and the Cochrane library from inception to November 2016. Outcomes were incidence of breast cancer and all-cause mortality. Risk of bias and overall certainty of evidence was assessed using the Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development, and Evaluation (GRADE), respectively. Meta-analyses were performed using the most fully adjusted ORs or HRs and 95% confidence intervals (95% CI) as effect measures.

Results: A total of 12 observational studies were included for breast cancer incidence and 11 studies for all-cause mortality. No significant association was found between metformin exposure and incidence of breast cancer (OR = 0.93; 95% CI, 0.85–1.03; I² = 35%). A 45% risk reduction was observed for all-cause mortality (HR = 0.55; 95% CI, 0.44–0.70; I² = 81%). Presence of publication bias is strongly suspected for both outcomes using Egger's funnel plots.

Conclusions: The use of metformin may improve overall survival in patients with T2D and breast cancer. No effect of metformin on the incidence of breast cancer was observed. Interpretation of results is limited by the observational nature of the studies and resulting biases.

Impact: Clinical trials are warranted to determine the role of metformin in breast cancer risk reduction and prognosis. Cancer Epidemiol Biomarkers Prev; 27(6); 627–35. ©2018 AACR.

https://ift.tt/2srKl0w

Demand for Colonoscopy in Colorectal Cancer Screening Using a Quantitative Fecal Immunochemical Test and Age/Sex-Specific Thresholds for Test Positivity

Background: Despite age and sex differences in fecal hemoglobin (f-Hb) concentrations, most fecal immunochemical test (FIT) screening programs use population-average cut-points for test positivity. The impact of age/sex-specific threshold on FIT accuracy and colonoscopy demand for colorectal cancer screening are unknown.

Methods: Using data from 723,113 participants enrolled in a Taiwanese population-based colorectal cancer screening with single FIT between 2004 and 2009, sensitivity and specificity were estimated for various f-Hb thresholds for test positivity. This included estimates based on a "universal" threshold, receiver-operating-characteristic curve–derived threshold, targeted sensitivity, targeted false-positive rate, and a colonoscopy-capacity-adjusted method integrating colonoscopy workload with and without age/sex adjustments.

Results: Optimal age/sex-specific thresholds were found to be equal to or lower than the universal 20 μg Hb/g threshold. For older males, a higher threshold (24 μg Hb/g) was identified using a 5% false-positive rate. Importantly, a nonlinear relationship was observed between sensitivity and colonoscopy workload with workload rising disproportionately to sensitivity at 16 μg Hb/g. At this "colonoscopy-capacity-adjusted" threshold, the test positivity (colonoscopy workload) was 4.67% and sensitivity was 79.5%, compared with a lower 4.0% workload and a lower 78.7% sensitivity using 20 μg Hb/g. When constrained on capacity, age/sex-adjusted estimates were generally lower. However, optimizing age/-sex-adjusted thresholds increased colonoscopy demand across models by 17% or greater compared with a universal threshold.

Conclusions: Age/sex-specific thresholds improve FIT accuracy with modest increases in colonoscopy demand.

Impact: Colonoscopy-capacity-adjusted and age/sex-specific f-Hb thresholds may be useful in optimizing individual screening programs based on detection accuracy, population characteristics, and clinical capacity. Cancer Epidemiol Biomarkers Prev; 27(6); 704–9. ©2018 AACR.

https://ift.tt/2srKbWY

Smoking and Prostate Cancer-Specific Mortality after Diagnosis in a Large Prospective Cohort

Background: Prior studies of prostate cancer survivors suggest that smoking might be associated with higher prostate cancer–specific mortality (PCSM) after diagnosis with prostate cancer. However, most of these studies were small, and questions remain regarding this association's strength and whether it persists after adjustment for stage and Gleason score.

Methods: This analysis included men diagnosed with nonmetastatic prostate cancer between enrollment in the Cancer Prevention Study II Nutrition Cohort in 1992–1993 and June 2013. Cigarette smoking was self-reported at enrollment and updated in 1997 and every 2 years thereafter. Analyses of pre-diagnosis and post-diagnosis smoking included 9,781 and 9,111 prostate cancer cases, respectively, with vital status follow-up through 2014.

Results: There were 672 deaths from prostate cancer in analyses of pre-diagnosis smoking and 554 in analyses of post-diagnosis smoking. In multivariable-adjusted Cox proportional hazards regression models including stage and Gleason score, both current smoking before diagnosis [HR = 1.50; 95% confidence interval (CI), 1.06–2.13] and current smoking after diagnosis (HR = 1.71; 95% CI, 1.09–2.67) were associated with higher PCSM compared to never smoking. Prostate cancer survivors who quit smoking <20 years before diagnosis were also at significantly higher risk of PCSM (HR = 1.29; 95% CI, 1.04–1.61).

Conclusions: This large prospective study suggests that current smoking both before and after diagnosis of prostate cancer is associated with higher PCSM, even after accounting for stage and Gleason score.

Impact: Our results provide evidence that smoking is a relevant prognostic factor for prostate cancer patients and that prostate cancer may be among the causes of death attributable to smoking. Cancer Epidemiol Biomarkers Prev; 27(6); 665–72. ©2018 AACR.

https://ift.tt/2kC8TAy

Reparameterization of PAM50 Expression Identifies Novel Breast Tumor Dimensions and Leads to Discovery of a Genome-Wide Significant Breast Cancer Locus at 12q15

Background: Breast tumor subtyping has failed to provide impact in susceptibility genetics. The PAM50 assay categorizes breast tumors into: Luminal A, Luminal B, HER2-enriched and Basal-like. However, tumors are often more complex than simple categorization can describe. The identification of heritable tumor characteristics has potential to decrease heterogeneity and increase power for gene finding.

Methods: We used 911 sporadic breast tumors with PAM50 expression data to derive tumor dimensions using principal components (PC). Dimensions in 238 tumors from high-risk pedigrees were compared with the sporadic tumors. Proof-of-concept gene mapping, informed by tumor dimension, was performed using Shared Genomic Segment (SGS) analysis.

Results: Five dimensions (PC1-5) explained the majority of the PAM50 expression variance: three captured intrinsic subtype, two were novel (PC3, PC5). All five replicated in 745 TCGA tumors. Both novel dimensions were significantly enriched in the high-risk pedigrees (intrinsic subtypes were not). SGS gene-mapping in a pedigree identified a 0.5 Mb genome-wide significant region at 12q15. This region segregated through 32 meioses to 8 breast cancer cases with extreme PC3 tumors (P = 2.6 x 10^–8).

Conclusions: PC analysis of PAM50 gene expression revealed multiple independent, quantitative measures of tumor diversity. These tumor dimensions show evidence for heritability and potential as powerful traits for gene mapping.

Impact: Our study suggests a new approach to describe tumor expression diversity, provides new avenues for germline studies, and proposes a new breast cancer locus. Similar reparameterization of expression patterns may inform other studies attempting to model the effects of tumor heterogeneity. Cancer Epidemiol Biomarkers Prev; 27(6); 644–52. ©2018 AACR.

https://ift.tt/2Hdcgac

Transducin-Like Enhancer of Split 3 (TLE3) Expression Is Associated with Taxane Sensitivity in Nonserous Ovarian Carcinoma in a Three-Cohort Study

Background: Chemoresistance is a major challenge in ovarian cancer treatment, resulting in poor survival rates. Identifying markers of treatment response is imperative for improving outcome while minimizing unnecessary side effects. We have previously demonstrated that expression of transducin-like enhancer of split 3 (TLE3) is associated with favorable progression-free survival in taxane-treated ovarian cancer patients with nonserous histology. The purpose of this study was to perform an independent evaluation of the association of TLE3 expression with response to taxane-based chemotherapy in nonserous ovarian cancer, to validate its role as a potential therapeutic response marker for taxane-based chemotherapy.

Methods: We performed immunohistochemical staining of TLE3 on ovarian cancer specimens from the Australian Ovarian Cancer Study, the Westmead Gynaecological Oncology Biobank, and Memorial Sloan Kettering Cancer Center. Progression-free survival and overall survival were assessed to validate an association between TLE3 expression and response to taxane therapy that we previously observed in a smaller study.

Results: Expression of TLE3 was associated with favorable outcome only in patients who had received paclitaxel as part of their treatment regimen for both 3-year progression-free survival (n = 160; HR, 0.56; P = 0.03) and 5-year overall survival (HR, 0.53; P = 0.04). Further analysis revealed that the predictive association between TLE3 expression and outcome was strongest in tumors with clear cell histology.

Conclusions: The association between high TLE3 expression and a favorable response to taxane-containing chemotherapy regimens was validated in patients with nonserous ovarian cancer.

Impact: TLE3 expression may serve as a marker of chemosensitivity in taxane-treated patients with nonserous histologies. Cancer Epidemiol Biomarkers Prev; 27(6); 680–8. ©2018 AACR.

https://ift.tt/2kGMsu9

Stanniocalcin Expression as a Predictor of Late Breast Cancer Recurrence

Background: Expression of human paracrine hormones stanniocalcin 1 (STC1) and stanniocalcin 2 (STC2) may potentiate late breast cancer recurrence. We tested the hypothesis that expression of STC1 and STC2 in primary breast tumors is more strongly associated with late versus early recurrences.

Methods: A total of 541 estrogen receptor–positive, tamoxifen-treated (ER⁺/TAM⁺) and 300 ER-negative, tamoxifen-untreated (ER^–/TAM^–) breast cancer patients who experienced recurrence within 10 years of primary diagnosis and matched recurrence-free controls were selected from a cohort of 11,251 Danish breast cancer patients diagnosed with stage I, II, or III breast cancer during 1985 to 2001. The association between IHC expression of STC1 and STC2 in primary breast tumor tissue microarrays and breast cancer recurrence was evaluated within median time to recurrence quintiles.

Results: The association between STC1 expression, dichotomized as positive or negative, and recurrence was strongly positive for the final time quintile (6–10 years postdiagnosis) in the ER⁺/TAM⁺ group [aOR = 2.70; 95% confidence interval (CI): 1.22–5.98]. Regression of the log ORs relating dichotomous STC1 and STC2 expression to recurrence by median time to recurrence (year) resulted in a relatively large positive effect estimate for STC1 (β = 0.16; 95% CI, –0.03–0.36) and a near-null positive effect estimate for STC2 (β = 0.04; 95% CI, –0.14–0.21).

Conclusions: Our results suggest a stronger association between primary tumor STC1 expression and late recurrence, as opposed to early recurrence, although no clear trend was apparent.

Impact: STC1 expression in the primary tumor may potentiate late recurrences, suggesting dormancy pathways that merit further investigation. Cancer Epidemiol Biomarkers Prev; 27(6); 653–9. ©2018 AACR.

https://ift.tt/2J4LZ3H

Physical Activity and Outcomes in Patients with Stage III Colon Cancer: A Correlative Analysis of Phase III Trial NCCTG N0147 (Alliance)

Background: Prior studies have supported an inverse association between physical activity and colon cancer risk and suggest that higher physical activity may also improve cancer survival. Among participants in a phase III adjuvant trial for stage III colon cancer, we assessed the association of physical activity around the time of cancer diagnosis with subsequent outcomes.

Methods: Before treatment arm randomization (FOLFOX or FOLFOX + cetuximab), study participants completed a questionnaire including items regarding usual daily activity level and frequency of participation in recreational physical activity (N = 1,992). Using multivariable Cox models, we calculated HRs for associations of aspects of physical activity with disease-free (DFS) and overall survival (OS).

Results: Over follow-up, 505 participants died and 541 experienced a recurrence. Overall, 75% of participants reported recreational physical activity at least several times a month; for participants who reported physical activity at least that often (vs. once a month or less), the HRs for DFS and OS were 0.82 [95% confidence interval (CI), 0.69–0.99] and 0.76 (95% CI, 0.63–0.93), respectively. There was no evidence of material effect modification in these associations by patient or tumor attributes, except that physical activity was more strongly inversely associated with OS in patients with stage T3 versus T4 tumors (P_interaction = 0.03).

Conclusions: These findings suggest that higher physical activity around the time of colon cancer diagnosis may be associated with more favorable colon cancer outcomes.

Impact: Our findings support further research on whether colon cancer survival may be enhanced by physical activity. Cancer Epidemiol Biomarkers Prev; 27(6); 696–703. ©2018 AACR.

https://ift.tt/2J3JOgw

Appendicitis before Age 20 Years Is Associated with an Increased Risk of Later Prostate Cancer

Background: Appendicitis before age 20 years has been observed to influence the risk of several inflammatory conditions, possibly through underlying immunological mechanisms. Inflammation has further been suggested to be involved in prostate cancer development. We therefore hypothesized that immunological characteristics signaled by appendicitis before late adolescence might influence the risk of later prostate cancer, and aimed to evaluate this association in a population-based study.

Methods: We identified a large cohort of Swedish men who underwent assessment for military conscription around the age of 18 years (n = 242,573). Medical diagnoses at time of conscription were available through the Swedish Military Conscription Register. The Swedish Cancer Register was used to identify diagnoses of prostate cancer. Multivariable adjusted Cox regression analyses were used to estimate HR and 95% confidence intervals (95% CIs) for the association between appendicitis and prostate cancer.

Results: During a median of 36.7 years of follow-up, 1,684 diagnoses of prostate cancer occurred. We found a statistically significant association between appendicitis and overall prostate cancer (adjusted HR 1.70; 95% CI, 1.08–2.67). The risk was notably increased for advanced (HR 4.42; 95% CI, 1.74–11.22) and lethal (HR 8.95; 95% CI, 2.98–26.91) prostate cancer.

Conclusions: These results suggest that a diagnosis of appendicitis before adulthood potentially signals underlying immune characteristics and a pattern of inflammatory response relevant to prostate cancer risk.

Impact: The study lends support to the proposed role of inflammation in prostate carcinogenesis, and adds another area of investigation potentially relevant to prostate cancer development. Cancer Epidemiol Biomarkers Prev; 27(6); 660–4. ©2018 AACR.

https://ift.tt/2H8T7pT

Serum Exosomal Long Noncoding RNAs ENSG00000258332.1 and LINC00635 for the Diagnosis and Prognosis of Hepatocellular Carcinoma

Background: Increasing studies suggest that long noncoding RNAs (lncRNAs) are involved in carcinogenesis of human cancers and might be used as diagnostic biomarkers for cancers.

Methods: A total of 301 participants were recruited in the first part of the study, including a hepatocellular carcinoma (HCC) group (n = 60), liver cirrhosis (LC) group (n = 85), chronic hepatitis B (CHB) group (n = 96), and healthy subjects (n = 60). In the second part, we collected 55 HCC patients, 60 CHB patients, and 60 healthy subjects as an independent cohort to validate the ability of the experiential lncRNAs for identifying HCC from CHB. A commercial kit was used to isolate serum exosomes and total RNA. The relative levels of lnRNAs and GAPDH mRNA were measured with TaqMan PCR.

Results: The results showed that the levels of ENSG00000258332.1 and LINC00635 in the HCC group were significantly higher than those in the other groups (all P < 0.05). A high ENSG00000258332.1 level in HCC was associated with portal vein tumor emboli, lymph node metastasis, TNM stage, and overall survival (OS; all P < 0.05), and a high LINC00635 level was related to lymph node metastasis, TNM stage, and OS (all P < 0.05). ENSG00000258332.1 discriminated HCC from CHB, gaining an area under the ROC curve (AUC) of 0.719 (cutoff value of 1.345); LINC00635 gained an AUC of 0.750 (cutoff value of 1.690). Furthermore, the AUC for the combination of the 2 lncRNAs and serum AFP (cutoff value of 20 μg/L) was 0.894. The abilities of the 2 lncRNAs for identifying HCC from CHB were validated by an independent cohort.

Conclusions: The results suggested that the combination of serum exosomal ENSG00000258332.1, LINC00635, and AFP may be a valuable assay in diagnosis and prognosis of HCC.

Impact: Our data will shed light on exosomal lncRNAs as biomarkers for HCC. Cancer Epidemiol Biomarkers Prev; 27(6); 710–6. ©2018 AACR.

https://ift.tt/2J3JMVW

A Cryo-EM Structure Elucidates the Human Telomerase Holoenzyme [Telomerase]

The bilobal telomerase structure has a catalytic core lobe and a H/ACA ribonucleoprotein lobe.

https://ift.tt/2J9NXf7

Carboxyamidotriazole Orotate plus TMZ Is Safe and Active in Glioblastoma [Clinical Trials]

Carboxyamidotriazole orotate (CTO) plus temozolomide (TMZ) was well tolerated in patients with glioma.

https://ift.tt/2LP2wXa

A Cancer-Germline Antigen Signature Predicts Anti-CTLA4 Resistance [Immunotherapy]

High expression of the MAGE-A subcluster III is associated with anti-CTLA4 resistance in melanoma.

https://ift.tt/2LPXkCi

From Pluripotent Stem to CAR T Cells [News in Brief]

Within the field of allogeneic chimeric antigen receptor T-cell therapy, La Jolla, CA–based Fate Therapeutics is exploring in vitro differentiation of induced pluripotent stem cells, rather than T cells harvested from donors, as their source material. Preclinical data on the company's off-the-shelf candidate, FT819, look promising so far.

https://ift.tt/2J42EA9

The EZH2 Inhibitor Tazemetostat Is Well Tolerated in a Phase I Trial [Clinical Trials]

Tazemetostat has antitumor activity in B-cell non-Hodgkin lymphoma and advanced solid tumors.

https://ift.tt/2LPXjye

Vision for NCI Outlined by New Director [News in Brief]

Speaking at the American Association for Cancer Research Annual Meeting 2018, Norman "Ned" Sharpless, MD, the new director of the NCI, outlined his vision for the agency and spoke about four areas on which he'd like to focus its efforts: workforce training and development, basic science, "big data," and clinical trials.

https://ift.tt/2xy0PKB

Glioblastoma Stem Cell-Tumor Cell Cross-talk Drives Gliomagenesis [Brain Tumors]

Reciprocal paracrine signaling between GBM stem cells and GBM cells promotes tumor growth.

https://ift.tt/2LPXh9A

BLU-667 Targets RET-Altered Cancers [News in Brief]

Findings from a phase I study indicate that the investigational RET inhibitor BLU-667 is safe and well tolerated, inducing good responses in patients with RET-altered medullary thyroid cancer or non–small cell lung cancer.

https://ift.tt/2xy0NCt

Everolimus Enhances the Efficacy of Fulvestrant in ER+ Breast Cancer [Clinical Trials]

mTOR inhibition with everolimus extends progression-free survival in combination with fulvestrant.

https://ift.tt/2LORn8L

Early-Career Scientists Advocate for Funding on Capitol Hill [News in Brief]

Congress recently approved a $3 billion NIH budget increase for fiscal year 2018, the third year of a significant increase after a period of flat or declining funding, but early-career scientists deciding whether to pursue a career in research need stable, long-term funding over many years. Some of these investigators traveled to Capitol Hill last month and met with members of Congress and their staffs to advocate for sustainable, reliable government research funding.

https://ift.tt/2xy0Myp

The IL15 Superagonist ALT-803 plus Nivolumab Has Antitumor Activity [Clinical Trials]

Nivolumab in combination with ALT-803 is tolerable and achieves responses in patients with NSCLC.

https://ift.tt/2LORm4H

Tumor Cells Metastasize from Lymph Nodes [News in Brief]

Two mouse studies have found that tumor cells can metastasize via the lymph nodes. One study demonstrated that cancer cells from lymph-node metastases accounted for most cells in lung metastases. The other study found that tumor cells can spread from the lymph nodes to the lungs by entering the bloodstream.

https://ift.tt/2xD4Qx4

Ibrutinib plus Venetoclax May Be Effective in Mantle-Cell Lymphoma [Clinical Trials]

Ibrutinib plus venetoclax is superior to monotherapy in patients with mantle-cell lymphoma.

https://ift.tt/2LPXdqm

FDA Expands Indication for Nilotinib [News in Brief]

The FDA expanded the indication for nilotinib for the treatment of children with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia in the chronic phase who are at least a year old, as well as those who are resistant to or cannot tolerate imatinib. The drug is the third tyrosine kinase inhibitor approved for children with this rare cancer.

https://ift.tt/2JkBTL1

Blocking MICA/MICB Shedding Reactivates Antitumor Immunity [Immunology]

Inhibition of protease-driven MICA and MICB shedding enhances NK cell–mediated tumor immunity.

https://ift.tt/2L7KmhS

Consumption of Sugars, Sugary Foods, and Sugary Beverages in Relation to Adiposity-Related Cancer Risk in the Framingham Offspring Cohort (1991-2013)

Background: Higher sugar consumption may increase cancer risk by promoting insulin-glucose dysregulation, oxidative stress, hormonal imbalances, and excess adiposity. This prospective study investigates the association between dietary sugars (fructose and sucrose) and sugary foods and beverages in relation to combined and site-specific (breast, prostate, colorectal) adiposity-associated cancers.

Methods: The analytic sample consisted of 3,184 adults, aged 26–84 years, from the Framingham Offspring cohort. Diet data were first collected between 1991 and 1995 using a food frequency questionnaire. Intakes of fructose, sucrose, sugary foods, and sugary beverages (fruit juice and sugar-sweetened beverages) were derived. Participants were followed up until 2013 to ascertain cancer incidence; 565 doctor-diagnosed adiposity-related cancers, including 124 breast, 157 prostate, and 68 colorectal cancers occurred. Multivariable-adjusted Cox proportional hazards models were used to evaluate associations. Tests for interaction with BMI and waist circumference were conducted.

Results: No associations were observed between fructose, sucrose, sugary food consumption, and combined incidence of adiposity-related cancers or the examined site-specific cancers. While total consumption of sugary beverages was not associated with site-specific cancer risk, higher intakes of fruit juice were associated with 58% increased prostate cancer risk (HR: 1.58; 95% CI, 1.04–2.41) in multivariable-adjusted models. In exploratory stratified analyses, higher sugary beverage intakes increased overall adiposity-related cancer risk by 59% in participants with excessive central adiposity (HR: 1.59; 95% CI, 1.01–2.50; P_trend = 0.057).

Conclusions: In this cohort of American adults, higher sugary beverage consumption was associated with increased cancer risk among participants with central adiposity.

Impact: These analyses suggest that avoiding sugary beverages represents a simple dietary modification that may be used as an effective cancer control strategy. Cancer Prev Res; 11(6); 347–58. ©2018 AACR.

https://ift.tt/2LbT4Mh

The Combined Association of Modifiable Risk Factors with Breast Cancer Risk in the Women's Health Initiative

Although several modifiable risk factors have been independently associated with risk of breast cancer, few studies have investigated their joint association with breast cancer risk. Using a healthy lifestyle index (HLI) score, we assessed the association of a combination of selected modifiable risk factors (diet, alcohol, physical activity, BMI, and smoking) with risk of invasive breast cancer in the Women's Health Initiative (WHI). This study comprised 131,833 postmenopausal women, of whom 8,168 had breast cancer, who were enrolled in the WHI Observational Study or the WHI clinical trials. Cox proportional hazards regression was used to estimate the HRs and 95% confidence intervals (CI) for the association of the score with the risk of developing breast cancer overall and according to specific breast cancer clinicopathologic characteristics. There was a 4% reduction in the risk of breast cancer per unit increase in the HLI score. Compared with those with an HLI score in the lowest quintile level, those in the highest quintile level had 30%, 37%, and 30% lower risk for overall, ER⁺/PR⁺, and HER2⁺ breast cancer, respectively (HR = 0.70; 95% CI, 0.64–0.76; 0.63, 0.57–0.69; and 0.70; 0.55–0.90, respectively). We also observed inverse associations between the score and risk of breast cancer irrespective of nodal status, tumor grade, and stage of the disease. Most individual lifestyle factors were independently associated with the risk of breast cancer. Our findings support the view that promoting healthy lifestyle practices may be beneficial with respect to lowering risk of breast cancer among postmenopausal women. Cancer Prev Res; 11(6); 317–26. ©2018 AACR.

See related editorial by Friedenreich and McTiernan, p. 313

https://ift.tt/2Jkpbw4

Inhibition of Glycolysis in Prostate Cancer Chemoprevention by Phenethyl Isothiocyanate

We have shown previously that dietary administration of phenethyl isothiocyanate (PEITC), a small molecule from edible cruciferous vegetables, significantly decreases the incidence of poorly differentiated prostate cancer in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice without any side effects. In this study, we investigated the role of c-Myc–regulated glycolysis in prostate cancer chemoprevention by PEITC. Exposure of LNCaP (androgen-responsive) and 22Rv1 (castration-resistant) human prostate cancer cells to PEITC resulted in suppression of expression as well as transcriptional activity of c-Myc. Prostate cancer cell growth inhibition by PEITC was significantly attenuated by stable overexpression of c-Myc. Analysis of the RNA-Seq data from The Cancer Genome Atlas indicated a significant positive association between Myc expression and gene expression of many glycolysis-related genes, including hexokinase II and lactate dehydrogenase A. Expression of these enzyme proteins and lactate levels were decreased upon PEITC treatment in prostate cancer cells, and these effects were significantly attenuated by ectopic expression of c-Myc. A normal prostate stromal cell line (PrSC) was resistant to lactic acid suppression by PEITC treatment. Prostate cancer chemoprevention by PEITC in TRAMP mice was associated with a significant decrease in plasma lactate and pyruvate levels. However, a 1-week intervention with 10 mg PEITC (orally, 4 times/day) was not sufficient to decrease lactate levels in the serum of human subjects. These results indicated that although prostate cancer prevention by PEITC in TRAMP mice was associated with suppression of glycolysis, longer than 1-week intervention might be necessary to observe such an effect in human subjects. Cancer Prev Res; 11(6); 337–46. ©2018 AACR.

https://ift.tt/2L9FMQq

PAM50 and Risk of Recurrence Scores for Interval Breast Cancers

Breast cancers detected after a negative breast screening examination and prior to the next screening are referred to as interval cancers. These cancers generally have poor clinical characteristics compared with screen-detected cancers, but associations between interval cancer and genomic cancer characteristics are not well understood. Mammographically screened women diagnosed with primary invasive breast cancer from 1993 to 2013 (n = 370) were identified by linking the Carolina Breast Cancer Study and the Carolina Mammography Registry. Among women with a registry-identified screening mammogram 0 to 24 months before diagnosis, cancers were classified as screen-detected (N = 165) or interval-detected (N = 205). Using logistic regression, we examined the association of mode of detection with cancer characteristics (clinical, IHC, and genomic), overall, and in analyses stratified on mammographic density and race. Interval cancer was associated with large tumors [>2 cm; OR, 2.3; 95% confidence interval (CI), 1.5–3.7], positive nodal status (OR, 1.8; 95% CI, 1.1–2.8), and triple-negative subtype (OR, 2.5; 95% CI, 1.1–5.5). Interval cancers were more likely to have non-Luminal A subtype (OR, 2.9; 95% CI, 1.5–5.7), whereas screen-detected cancers tended to be more indolent (96% had low risk of recurrence genomic scores; 71% were PAM50 Luminal A). When stratifying by mammographic density and race, associations between interval detection and poor prognostic features were similar by race and density status. Strong associations between interval cancers and poor-prognosis genomic features (non-Luminal A subtype and high risk of recurrence score) suggest that aggressive tumor biology is an important contributor to interval cancer rates. Cancer Prev Res; 11(6); 327–36. ©2018 AACR.

https://ift.tt/2JhP6nV

Diagnosing Cervical Neoplasia in Rural Brazil Using a Mobile Van Equipped with In Vivo Microscopy: A Cluster-Randomized Community Trial

Cervical cancer is a leading cause of death in underserved areas of Brazil. This prospective randomized trial involved 200 women in southern/central Brazil with abnormal Papanicolaou tests. Participants were randomized by geographic cluster and referred for diagnostic evaluation either at a mobile van upon its scheduled visit to their local community, or at a central hospital. Participants in both arms underwent colposcopy, in vivo microscopy, and cervical biopsies. We compared rates of diagnostic follow-up completion between study arms, and also evaluated the diagnostic performance of in vivo microscopy compared with colposcopy. There was a 23% absolute and 37% relative increase in diagnostic follow-up completion rates for patients referred to the mobile van (102/117, 87%) compared with the central hospital (53/83, 64%; P = 0.0001; risk ratio = 1.37, 95% CI, 1.14–1.63). In 229 cervical sites in 144 patients, colposcopic examination identified sites diagnosed as cervical intraepithelial neoplasia grade 2 or more severe (CIN2+; 85 sites) with a sensitivity of 94% (95% CI, 87%–98%) and specificity of 50% (95% CI, 42%–58%). In vivo microscopy with real-time automated image analysis identified CIN2+ with a sensitivity of 92% (95% CI, 84%–97%) and specificity of 48% (95% CI, 40%–56%). Women referred to the mobile van were more likely to complete their diagnostic follow-up compared with those referred to a central hospital, without compromise in clinical care. In vivo microscopy in a mobile van provides automated diagnostic imaging with sensitivity and specificity similar to colposcopy. Cancer Prev Res; 11(6); 359–70. ©2018 AACR.

https://ift.tt/2LbxdEx

Transition of Mesenchymal and Epithelial Cancer Cells Depends on {alpha}1-4 Galactosyltransferase-Mediated Glycosphingolipids

The reversible transitions of cancer cells between epithelial and mesenchymal states comprise cellular and molecular processes essential for local tumor growth and respective dissemination. We report here that globoside glycosphingolipid (GSL) glycosyltransferase-encoding genes are elevated in epithelial cells and correlate with characteristic EMT signatures predictive of disease outcome. Depletion of globosides through CRISPR-Cas9–mediated deletion of the key enzyme A4GALT induces EMT, enhances chemoresistance, and increased CD24low/CD44high cells. The cholera toxin–induced mesenchymal-to-epithelial transition occurred only in cells with functional A4GALT. Cells undergoing EMT lost E-cadherin expression through epigenetic silencing at the promoter region of CDH1. However, in ΔA4GALT cells, demethylation was able to rescue E-cadherin–mediated cell–cell adhesion only in the presence of exogenous A4GALT. Overall, our data suggest another class of biomolecules vital for epithelial cancer cells and for maintaining cell integrity and function.Significance: This study highlights the essential role of glycosphingolipids in the maintenance of epithelial cancer cell properties. Cancer Res; 78(11); 2952–65. ©2018 AACR.

https://ift.tt/2J18vdA

Pericytes in the Premetastatic Niche

The premetastatic niche formed by primary tumor–derived molecules contributes to fixation of cancer metastasis. The design of efficient therapies is limited by the current lack of knowledge about the details of cellular and molecular mechanisms involved in the premetastatic niche formation. Recently, the role of pericytes in the premetastatic niche formation and lung metastatic tropism was explored by using state-of-the-art techniques, including in vivo lineage-tracing and mice with pericyte-specific KLF4 deletion. Strikingly, genetic inactivation of KLF4 in pericytes inhibits pulmonary pericyte expansion and decreases metastasis in the lung. Here, we summarize and evaluate recent advances in the understanding of pericyte contribution to premetastatic niche formation. Cancer Res; 78(11); 2779–86. ©2018 AACR.

https://ift.tt/2J1ClyA

Mechanistic Distinctions between CHK1 and WEE1 Inhibition Guide the Scheduling of Triple Therapy with Gemcitabine

Combination of cytotoxic therapy with emerging DNA damage response inhibitors (DDRi) has been limited by tolerability issues. However, the goal of most combination trials has been to administer DDRi with standard-of-care doses of chemotherapy. We hypothesized that mechanism-guided treatment scheduling could reduce the incidence of dose-limiting toxicities and enable tolerable multitherapeutic regimens. Integrative analyses of mathematical modeling and single-cell assays distinguished the synergy kinetics of WEE1 inhibitor (WEE1i) from CHEK1 inhibitor (CHK1i) by potency, spatiotemporal perturbation, and mitotic effects when combined with gemcitabine. These divergent properties collectively supported a triple-agent strategy, whereby a pulse of gemcitabine and CHK1i followed by WEE1i durably suppressed tumor cell growth. In xenografts, CHK1i exaggerated replication stress without mitotic CDK hyperactivation, enriching a geminin-positive subpopulation and intratumoral gemcitabine metabolite. Without overt toxicity, addition of WEE1i to low-dose gemcitabine and CHK1i was most effective in tumor control compared with single and double agents. Overall, our work provides quantitative insights into the mechanisms of DDRi chemosensitization, leading to the rational development of a tolerable multitherapeutic regimen.Significance: Multiple lines of mechanistic insight regarding DNA damage response inhibitors rationally guide the preclinical development of a tolerable multitherapeutic regimen.Graphical Abstract: https://ift.tt/2J195bg. Cancer Res; 78(11); 3054–66. ©2018 AACR.

https://ift.tt/2kDpnby

Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma

Glioblastoma (GBM) is a lethal disease with no effective therapies available. We previously observed upregulation of the TAM (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL in mesenchymal GBM and showed that knockdown of AXL induced apoptosis of mesenchymal, but not proneural, glioma sphere cultures (GSC). In this study, we report that BGB324, a novel small molecule inhibitor of AXL, prolongs the survival of immunocompromised mice bearing GSC-derived mesenchymal GBM-like tumors. We show that protein S (PROS1), a known ligand of other TAM receptors, was secreted by tumor-associated macrophages/microglia and subsequently physically associated with and activated AXL in mesenchymal GSC. PROS1-driven phosphorylation of AXL (pAXL) induced NFκB activation in mesenchymal GSC, which was inhibited by BGB324 treatment. We also found that treatment of GSC-derived mouse GBM tumors with nivolumab, a blocking antibody against the immune checkpoint protein PD-1, increased intratumoral macrophages/microglia and activation of AXL. Combinatorial therapy with nivolumab plus BGB324 effectively prolonged the survival of mice bearing GBM tumors. Clinically, expression of AXL or PROS1 was associated with poor prognosis for patients with GBM. Our results suggest that the PROS1–AXL pathway regulates intrinsic mesenchymal signaling and the extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors.Significance: These findings suggest that development of combination treatments of AXL and immune checkpoint inhibitors may provide benefit to patients with GBM. Cancer Res; 78(11); 3002–13. ©2018 AACR.

https://ift.tt/2J2nwvJ

Transketolase Regulates the Metabolic Switch to Control Breast Cancer Cell Metastasis via the {alpha}-Ketoglutarate Signaling Pathway

Although metabolic reprogramming is recognized as a hallmark of tumorigenesis and progression, little is known about metabolic enzymes and oncometabolites that regulate breast cancer metastasis, and very few metabolic molecules have been identified as potential therapeutic targets. In this study, the transketolase (TKT) expression correlated with tumor size in the 4T1/BALB/c syngeneic model. In addition, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival. Depletion of TKT or addition of alpha-ketoglutarate (αKG) enhanced the levels of tumor suppressors succinate dehydrogenase and fumarate hydratase (FH), decreasing oncometabolites succinate and fumarate, and further stabilizing HIF prolyl hydroxylase 2 (PHD2) and decreasing HIF1α, ultimately suppressing breast cancer metastasis. Reduced TKT or addition of αKG mediated a dynamic switch of glucose metabolism from glycolysis to oxidative phosphorylation. Various combinations of the TKT inhibitor oxythiamine, docetaxel, and doxorubicin enhanced cell death in triple-negative breast cancer (TNBC) cells. Furthermore, oxythiamine treatment led to increased levels of αKG in TNBC cells. Together, our study has identified a novel TKT-mediated αKG signaling pathway that regulates breast cancer oncogenesis and can be exploited as a modality for improving therapy.Significance: These findings uncover the clinical significance of TKT in breast cancer progression and metastasis and demonstrate effective therapy by inhibiting TKT or by adding αKG. Cancer Res; 78(11); 2799–812. ©2018 AACR.

https://ift.tt/2kFV586

Highlights from Recent Cancer Literature

https://ift.tt/2sxnosU

Human Elongation Factor 4 Regulates Cancer Bioenergetics by Acting as a Mitochondrial Translation Switch

Mitochondria regulate cellular bioenergetics and redox states and influence multiple signaling pathways required for tumorigenesis. In this study, we determined that the mitochondrial translation elongation factor 4 (EF4) is a critical component of tumor progression. EF4 was ubiquitous in human tissues with localization to the mitochondria (mtEF4) and performed quality control on respiratory chain biogenesis. Knockout of mtEF4 induced respiratory chain complex defects and apoptosis, while its overexpression stimulated cancer development. In multiple cancers, expression of mtEF4 was increased in patient tumor tissues. These findings reveal that mtEF4 expression may promote tumorigenesis via an imbalance in the regulation of mitochondrial activities and subsequent variation of cellular redox. Thus, dysregulated mitochondrial translation may play a vital role in the etiology and development of diverse human cancers.Significance: Dysregulated mitochondrial translation drives tumor development and progression. Cancer Res; 78(11); 2813–24. ©2018 AACR.

https://ift.tt/2svxpqN

Inhibin Is a Novel Paracrine Factor for Tumor Angiogenesis and Metastasis

Inhibin is a heterodimeric TGFβ family ligand that is expressed in many cancers and is a selective biomarker for ovarian cancers; however, its tumor-specific functions remain unknown. Here, we demonstrate that the α subunit of inhibin (INHA), which is critical for the functionality of dimeric inhibin A/B, correlates with microvessel density in human ovarian tissues and is predictive of poor clinical outcomes in multiple cancers. We demonstrate that inhibin-regulated angiogenesis is necessary for metastasis. Although inhibin had no direct impact on tumor cell signaling, both tumor cell-derived and recombinant inhibin elicit a strong paracrine response from endothelial cells by triggering SMAD1/5 activation and angiogenesis in vitro and in vivo. Inhibin-induced angiogenesis was abrogated via anti-inhibin α antibodies. The endothelial-specific TGFβ receptor complex comprising ALK1 and endoglin was a crucial mediator of inhibin signaling, offering a molecular mechanism for inhibin-mediated angiogenesis. These results are the first to define a role for inhibin in tumor metastasis and vascularization and offer an antibody-based approach for targeting inhibin therapeutically.Significance: Inhibin is a predictor of poor patient survival in multiple cancers and is a potential target for antiangiogenic therapies. Cancer Res; 78(11); 2978–89. ©2018 AACR.

https://ift.tt/2kFdodN

Acetylation within the N- and C-Terminal Domains of Src Regulates Distinct Roles of STAT3-Mediated Tumorigenesis

Posttranslational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions. Myristoylation of G2 controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src–cell membrane association–dissociation and catalytic activation–inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylates an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylates the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activates transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocates into nuclei, where it forms the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation.Significance: CBP-mediated acetylation of lysine clusters in both the N-terminal and C-terminal regions of c-Src provides additional levels of control over STAT3 transcriptional activity. Cancer Res; 78(11); 2825–38. ©2018 AACR.

https://ift.tt/2J3pf3W

The Circular RNA circPRKCI Promotes Tumor Growth in Lung Adenocarcinoma

Somatic copy number variations (CNV) may drive cancer progression through both coding and noncoding transcripts. However, noncoding transcripts resulting from CNV are largely unknown, especially for circular RNAs. By integrating bioinformatics analyses of alerted circRNAs and focal CNV in lung adenocarcinoma, we identify a proto-oncogenic circular RNA (circPRKCI) from the 3q26.2 amplicon, one of the most frequent genomic aberrations in multiple cancers. circPRKCI was overexpressed in lung adenocarcinoma tissues, in part due to amplification of the 3q26.2 locus, and promoted proliferation and tumorigenesis of lung adenocarcinoma. circPRKCI functioned as a sponge for both miR-545 and miR-589 and abrogated their suppression of the protumorigenic transcription factor E2F7. Intratumor injection of cholesterol-conjugated siRNA specifically targeting circPRKCI inhibited tumor growth in a patient-derived lung adenocarcinoma xenograft model. In summary, circPRKCI is crucial for tumorigenesis and may serve as a potential therapeutic target in patients with lung adenocarcinoma.Significance: These findings reveal high expression of the circular RNA circPRKCI drives lung adenocarcinoma tumorigenesis. Cancer Res; 78(11); 2839–51. ©2018 AACR.

https://ift.tt/2HaHrCR

Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells

Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110β-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those bearing various genetic abnormalities. Venetoclax/GDC-0980 markedly induced apoptosis in primitive CD34+/38−/123+ AML cell populations but not in normal hematopoietic progenitor CD34+ cells. The regimen was also active against AML cells displaying intrinsic or acquired venetoclax resistance or tumor microenvironment–associated resistance. Either combinatorial treatment markedly reduced AML growth and prolonged survival in a systemic AML xenograft mouse model and diminished AML growth in two patient-derived xenograft models. Venetoclax/GDC-0980 activity was partially diminished in BAK−/− cells and failed to induce apoptosis in BAX−/− and BAX−/−BAK−/− cells, whereas BIM−/− cells were fully sensitive. Similar results were observed with venetoclax alone in in vitro and in vivo systemic xenograft models. Collectively, these studies demonstrate that venetoclax/GDC-0980 exhibits potent anti-AML activity primarily through BAX and, to a lesser extent, BAK. These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML.Significance: Combined treatment with clinically relevant PI3K and BCL-2 inhibitors may prove effective in the treatment of acute myeloid leukemia. Cancer Res; 78(11); 3075–86. ©2018 AACR.

https://ift.tt/2H9JYgy

The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer Invasion

Although prostate cancer is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation-associated gene-9 [syntenin, or syndecan binding protein (SDCBP)] in prostate cancer progression. Using tissue samples from various Gleason stage prostate cancer patients with adjacent normal tissue, a series of normal prostate and prostate cancer cell lines (with differing tumorigenic/metastatic properties), mda-9/syntenin-manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/Syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/syntenin in prostate cancer invasion. MDA-9/Syntenin physically interacted with insulin-like growth factor-1 receptor following treatment with insulin-like growth factor binding protein-2 (IGFBP2), regulating downstream signaling processes that enabled STAT3 phosphorylation. This activation enhanced expression of MMP2 and MMP9, two established enzymes that positively regulate invasion. In addition, MDA-9/syntenin-mediated upregulation of proangiogenic factors including IGFBP2, IL6, IL8, and VEGFA also facilitated migration of prostate cancer cells. Collectively, our results draw attention to MDA-9/Syntenin as a positive regulator of prostate cancer metastasis, and the potential application of targeting this molecule to inhibit invasion and metastasis in prostate cancer and potentially other cancers.Significance: This study provides new mechanistic insight into the proinvasive role of MDA-9/Syntenin in prostate cancer and has potential for therapeutic application to prevent prostate cancer metastasis. Cancer Res; 78(11); 2852–63. ©2018 AACR.

https://ift.tt/2kC7z0y

I{kappa}B Kinase {alpha} Is Required for Development and Progression of KRAS-Mutant Lung Adenocarcinoma

Although oncogenic activation of NFκB has been identified in various tumors, the NFκB–activating kinases (inhibitor of NFκB kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKKα and IKKβ in KRAS-mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic KRASG12D. Using NFκB reporter mice and conditional deletions of IKKα and IKKβ, we identified two distinct early and late activation phases of NFκB during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of RelB, IκBβ, and IKKα in tumor-initiated cells. IKKα was a cardinal tumor promoter in chemical and genetic KRAS-mutant lung adenocarcinoma, and respiratory epithelial IKKα-deficient mice were markedly protected from the disease. IKKα specifically cooperated with mutant KRAS for tumor induction in a cell-autonomous fashion, providing mutant cells with a survival advantage in vitro and in vivo. IKKα was highly expressed in human lung adenocarcinoma, and a heat shock protein 90 inhibitor that blocks IKK function delivered superior effects against KRAS-mutant lung adenocarcinoma compared with a specific IKKβ inhibitor. These results demonstrate an actionable requirement for IKKα in KRAS-mutant lung adenocarcinoma, marking the kinase as a therapeutic target against this disease.Significance: These findings report a novel requirement for IKKα in mutant KRAS lung tumor formation, with potential therapeutic applications. Cancer Res; 78(11); 2939–51. ©2018 AACR.

https://ift.tt/2Haytpc

Plk1-Mediated Phosphorylation of TSC1 Enhances the Efficacy of Rapamycin

The AKT/TSC/mTOR axis is an important pathway controlling cell growth, survival, and proliferation in response to extracellular cues. Recently, it was reported that AKT activity fluctuates across the cell cycle. However, it remains unclear whether downstream targets of AKT are also regulated by the cell cycle. Here, we report that mTORC1 activity inversely correlates with AKT activity during the cell cycle. Mechanistically, Plk1 phosphorylation of TSC1 at S467 and S578 interfered with TSC1/TSC2 binding, destabilized TSC1, promoted dissociation of the TSC complex from the lysosome, and eventually led to mTORC1 activation. Tumors derived from cancer cells expressing the TSC1-S467E/S578E mutant exhibited greater sensitivity to rapamycin than those expressing WT TSC1. Collectively, our data support a model in which Plk1, instead of AKT, regulates the TSC/mTORC1 pathway during mitosis, eventually regulating the efficacy of rapamycin.Significance: This seminal report shows that activation of mTORC1 can be independent of AKT during mitosis. Cancer Res; 78(11); 2864–75. ©2018 AACR.

https://ift.tt/2swi2y6

Mutant IDH1 Cooperates with ATRX Loss to Drive the Alternative Lengthening of Telomere Phenotype in Glioma

A subset of tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Loss-of-function mutations in the chromatin remodeling factor ATRX are associated with ALT but are insufficient to drive the process. Because many ALT tumors express the mutant isocitrate dehydrogenase IDH1 R132H, including all lower grade astrocytomas and secondary glioblastoma, we examined a hypothesized role for IDH1 R132H in driving the ALT phenotype during gliomagenesis. In p53/pRb–deficient human astrocytes, combined deletion of ATRX and expression of mutant IDH1 were sufficient to create tumorigenic cells with ALT characteristics. The telomere capping complex component RAP1 and the nonhomologous DNA end joining repair factor XRCC1 were each downregulated consistently in these tumorigenic cells, where their coordinate reexpression was sufficient to suppress the ALT phenotype. RAP1 or XRCC1 downregulation cooperated with ATRX loss in driving the ALT phenotype. RAP1 silencing caused telomere dysfunction in ATRX-deficient cells, whereas XRCC1 silencing suppressed lethal fusion of dysfunctional telomeres by allowing IDH1-mutant ATRX-deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. Overall, our studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis.Significance: Studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis and suggesting new therapeutic options to treat low-grade gliomas. Cancer Res; 78(11); 2966–77. ©2018 AACR.

https://ift.tt/2Ha4TAf

RIPK1 Binds MCU to Mediate Induction of Mitochondrial Ca2+ Uptake and Promotes Colorectal Oncogenesis

The receptor-interacting protein kinase 1 (RIPK1) is an essential signaling molecule in pathways for cell survival, apoptosis, and necroptosis. We report here that RIPK1 is upregulated in human colorectal cancer and promotes cell proliferation when overexpressed in a colon cancer cell line. RIPK1 interacts with mitochondrial Ca2+ uniporter (MCU) to promote proliferation by increasing mitochondrial Ca2+ uptake and energy metabolism. The ubiquitination site of RIPK1 (RIPK1-K377) was critical for this interaction with MCU and function in promoting cell proliferation. These findings identify the RIPK1-MCU pathway as a promising target to treat colorectal cancer.Significance: RIPK1-mediated cell proliferation through MCU is a central mechanism underlying colorectal cancer progression and may prove to be an important therapeutic target for colorectal cancer treatment. Cancer Res; 78(11); 2876–85. ©2018 AACR.

https://ift.tt/2J3pcFi

Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche

Cancer progression and recurrence are linked to a rare population of cancer stem cells (CSC). Here, we hypothesized that interactions with the extracellular matrix drive CSC proliferation and tumor-initiating capacity and investigated the functions of scaffold protein tissue transglutaminase (TG2) in ovarian CSC. Complexes formed by TG2, fibronectin (FN), and integrin β1 were enriched in ovarian CSC and detectable in tumors. A function-inhibiting antibody against the TG2 FN-binding domain suppressed complex formation, CSC proliferation as spheroids, tumor-initiating capacity, and stemness-associated Wnt/β-catenin signaling. Disruption of the interaction between TG2 and FN also blocked spheroid formation and the response to Wnt ligands. TG2 and the Wnt receptor Frizzled 7 (Fzd7) form a complex in cancer cells and tumors, leading to Wnt pathway activation. Protein docking and peptide inhibition demonstrate that the interaction between TG2 and Fzd7 overlaps with the FN-binding domain of TG2. These results support a new function of TG2 in ovarian CSC, linked to spheroid proliferation and tumor-initiating capacity and mediated through direct interactions with Fzd7. We propose this complex as a new stem cell target.Significance: These findings reveal a new mechanism by which ovarian CSCs interact with the tumor microenvironment, promoting cell proliferation and tumor initiation. Cancer Res; 78(11); 2990–3001. ©2018 AACR.

https://ift.tt/2Hdam9y

Therapeutic Targeting of Sunitinib-Induced AR Phosphorylation in Renal Cell Carcinoma

Androgen receptor (AR) plays a crucial role in the development and progression of prostate cancer. AR expression has also been reported in other solid tumors, including renal cell carcinoma (RCC), but its biological role here remains unclear. Through integrative analysis of a reverse phase protein array, we discovered increased expression of AR in an RCC patient–derived xenograft model of acquired resistance to the receptor tyrosine kinase inhibitor (RTKi) sunitinib. AR expression was increased in RCC cell lines with either acquired or intrinsic sunitinib resistance in vitro. An AR signaling gene array profiler indicated elevated levels of AR target genes in sunitinib-resistant cells. Sunitinib-induced AR transcriptional activity was associated with increased phosphorylation of serine 81 (pS81) on AR. Additionally, AR overexpression resulted in acquired sunitinib resistance and the AR antagonist enzalutamide-induced AR degradation and attenuated AR downstream activity in sunitinib-resistant cells, also indicated by decreased secretion of human kallikrein 2. Enzalutamide-induced AR degradation was rescued by either proteasome inhibition or by knockdown of the AR ubiquitin ligase speckle-type POZ protein (SPOP). In vivo treatment with enzalutamide and sunitinib demonstrated that this combination efficiently induced tumor regression in a RCC model following acquired sunitinib resistance. Overall, our results suggest the potential role of AR as a target for therapeutic interventions, in combination with RTKi, to overcome drug resistance in RCC.Significance: These findings highlight the therapeutic potential of targeting the androgen receptor to overcome RCC resistance to receptor tyrosine kinase inhibitors. Cancer Res; 78(11); 2886–96. ©2018 AACR.

https://ift.tt/2svxhaN

IL21 Therapy Combined with PD-1 and Tim-3 Blockade Provides Enhanced NK Cell Antitumor Activity against MHC Class I-Deficient Tumors

Increased expression of coinhibitory molecules such as PD-1 and Tim-3 on NK cells has been demonstrated in advanced cancer patients who harbor MHC class I–deficient tumors. However, even in preclinical models, the antitumor effects of checkpoint blockade on NK cells have not been clearly elucidated. Here, we show that anti–PD-1/anti–Tim-3 treatment suppressed tumor progression in mice bearing MHC class I–deficient tumors, and the suppression was further enhanced by recombinant IL21 (rIL21) treatments through an NK-cell–dependent mechanism. We also show that the intratumoral delivery of rIL21 attracted NK cells to the tumor site in a CXCR3-dependent fashion. A combination of IL21 and checkpoint blockade facilitated the effector function of exhausted NK cells in cancer patients. Given the effects of the checkpoint blockade and rIL21 combination on NK cells infiltrating into MHC class I–deficient tumors, we suggest that the efficacy of checkpoint blockade can be enhanced through the administration of IL21 for advanced cancer patients with MHC class I–low/deficient tumors. Cancer Immunol Res; 6(6); 685–95. ©2018 AACR.

https://ift.tt/2xz1bR6

Introduction of Genetically Modified CD3{zeta} Improves Proliferation and Persistence of Antigen-Specific CTLs

The clinical efficacy of T-cell therapies based on T cells transduced with genes encoding tumor-specific T-cell receptors (TCR-T) is related to the in vivo persistence of the T cells. To improve persistence without modifying TCR affinity, we instead modified intracellular signaling, using artificial T cell–activating adapter molecules (ATAM), generated by inserting the intracellular domain (ICD) of activating T-cell signaling moieties into CD3. ATAMs with the ICD of either CD28 or 4-1BB were generated, assembled into the TCR complex as a part of CD3, and enhanced downstream signaling from the supramolecular activation cluster. ATAMs were retrovirally introduced into human CMV-specific or NY-ESO-1–specific TCR-transduced CD8⁺ T lymphocytes, and downstream functionality was then examined. ATAM-transduced NY-ESO-1 TCR-T cells were also investigated using the U266-xenograft mouse model. ATAMs were successfully transduced and localized to the cell membrane. ATAM-transduced CMV-specific T cells retained their cytotoxic activity and cytokine production against peptide-pulsed target cells without altering antigen-specificity and showed resistance to activation-induced cell death. Upon both single and repeated stimulation, CD3/4-1BB–transduced T cells had superior proliferation to the CD3-transduced T cells in both the CMV-specific and the NY-ESO-1 TCR-T models and significantly improved antitumor activity compared with untransduced T cells both in vitro and in a mouse xenograft model. ATAM-transduced TCR-T cells demonstrated improved proliferation and persistence in vitro and in vivo. This strategy to control the intracellular signaling of TCR-T cells by ATAM transduction in combination with various tumor-specific TCRs may improve the efficacy of TCR-T therapy. Cancer Immunol Res; 6(6); 733–44. ©2018 AACR.

https://ift.tt/2slgBDC

Sarcoid-Like Granulomatosis of the Lung Related to Immune-Checkpoint Inhibitors: Distinct Clinical and Imaging Features of a Unique Immune-Related Adverse Event

With the rapidly expanding role of immune-checkpoint inhibitor therapy in advanced cancer treatment, an increasing number of new immune-related adverse events (irAEs) are being reported. The present report describes sarcoid-like granulomatosis of the lung as a distinct type of irAE with characteristic clinical, imaging, and histologic features. In patients treated with immune-checkpoint inhibitors, sarcoid-like granulomatosis of the lung presented with a focal area of consolidation in the lung, which was often nodular or round, in the absence of new or enlarging lymphadenopathy on imaging. Histologic examination demonstrated nonnecrotizing granulomas and an absence of malignant cells. The patients were free of new or worsening respiratory symptoms, despite the development of lung parenchymal consolidations. Holding the immune-checkpoint inhibitors led to the spontaneous resolution of the findings, without any specific treatment for the abnormality. Awareness of the manifestations of sarcoid-like granulomatosis of the lung as a distinct type of irAE will improve management of patients treated with immune-checkpoint inhibitors. Cancer Immunol Res; 6(6); 630–5. ©2018 AACR.

https://ift.tt/2xxpnDf

TK Inhibitor Pazopanib Primes DCs by Downregulation of the {beta}-Catenin Pathway

Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting, for example, the VEGF receptors in tumors and have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have also been proposed for treatment of mRCC with encouraging results. A better understanding of the activity of immune cells in mRCC, the immunomodulatory effects of TKIs, and the characteristics defining patients most likely to benefit from various therapies will help optimize immunotherapeutic approaches. In this study, we investigated the influence of the TKI pazopanib on dendritic cell (DC) performance and immune priming. Pazopanib improved DC differentiation and performance by promoting upregulation of the maturation markers HLA-DR, CD40, and CCR7; decreasing IL10 production and endocytosis; and increasing T-cell proliferation. PD-L1 expression was also downregulated. Our results demonstrate that pazopanib inhibits the Erk/β-catenin pathway, suggesting this pathway might be involved in increased DC activation. Similar results were confirmed in DCs differentiated from mRCC patients during pazopanib treatment. In treated patients pazopanib appeared to enhance a circulating CD4⁺ T-cell population that expresses CD137 (4-1BB). These results suggest that a potentially exploitable immunomodulatory effect induced by pazopanib could improve responses of patients with mRCC in customized protocols combining TKIs with ICI immunotherapy. Cancer Immunol Res; 6(6); 711–22. ©2018 AACR.

https://ift.tt/2spG3Yv

NetH2pan: A Computational Tool to Guide MHC Peptide Prediction on Murine Tumors

With the advancement of personalized cancer immunotherapies, new tools are needed to identify tumor antigens and evaluate T-cell responses in model systems, specifically those that exhibit clinically relevant tumor progression. Key transgenic mouse models of breast cancer are generated and maintained on the FVB genetic background, and one such model is the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mouse—an immunocompetent transgenic mouse that exhibits spontaneous mammary tumor development and metastasis with high penetrance. Backcrossing the MMTV-PyMT mouse from the FVB strain onto a C57BL/6 genetic background, in order to leverage well-developed C57BL/6 immunologic tools, results in delayed tumor development and variable metastatic phenotypes. Therefore, we initiated characterization of the FVB MHC class I H-2^q haplotype to establish useful immunologic tools for evaluating antigen specificity in the murine FVB strain. Our study provides the first detailed molecular and immunoproteomic characterization of the FVB H-2^q MHC class I alleles, including >8,500 unique peptide ligands, a multiallele murine MHC peptide prediction tool, and in vivo validation of these data using MMTV-PyMT primary tumors. This work allows researchers to rapidly predict H-2 peptide ligands for immune testing, including, but not limited to, the MMTV-PyMT model for metastatic breast cancer. Cancer Immunol Res; 6(6); 636–44. ©2018 AACR.

https://ift.tt/2J3csua

Literature Round-Up: Impactful Published Papers: Article Recommendations from Our Deputy and Senior Editors

https://ift.tt/2J4Gnq9

IL17A Regulates Tumor Latency and Metastasis in Lung Adeno and Squamous SQ.2b and AD.1 Cancer

Somatic mutations can promote malignant transformation of airway epithelial cells and induce inflammatory responses directed against resultant tumors. Tumor-infiltrating T lymphocytes (TIL) in early-stage non–small cell lung cancer (NSCLC) secrete distinct proinflammatory cytokines, but the contribution of these TILs to tumor development and metastasis remains unknown. We show here that TILs in early-stage NSCLC are biased toward IL17A expression (Th17) when compared with adjacent tumor-free tissue, whereas Th17 cells are decreased in tumor infiltrating locoregional lymph nodes in advanced NSCLC. Mice in which Pten and Smad4 (Pts4^d/d) are deleted from airway epithelial cells develop spontaneous tumors, that share genetic signatures with squamous- (SQ.2b), and adeno- (AD.1) subtypes of human NSCLC. Pts4^d/d mice globally lacking in IL17a (Pts4^d/dIl17a^–/–) showed decreased tumor latency and increased metastasis. Th17 cells were required for recruitment of CD103⁺ dendritic cells, and adoptive transfer of IL17a-sufficient CD4⁺ T cells reversed early tumor development and metastasis in Pts4^d/dIl17a^–/– mice. Together, these findings support a key role for Th17 cells in TILs associated with the Pts4^d/d model of NSCLC and suggest therapeutic and biomarker strategies for human SQ2b and AD1 lung cancer. Cancer Immunol Res; 6(6); 645–57. ©2018 AACR.

https://ift.tt/2J3WVdx

Secretory IgM Exacerbates Tumor Progression by Inducing Accumulations of MDSCs in Mice

Chronic lymphocytic leukemia (CLL) cells can secrete immunoglobulin M. However, it is not clear whether secretory IgM (sIgM) plays a role in disease progression. We crossed the Eμ-TCL1 mouse model of CLL, in which the expression of human TCL1 oncogene was driven by the V(H) promoter-Ig(H)-Eμ enhancer, with MD4 mice whose B cells produced B-cell receptor (membrane-bound IgM) and sIgM with specificity for hen egg lysozyme (HEL). CLL cells that developed in these MD4/Eμ-TCL1 mice reactivated a parental Ig gene allele and secreted IgM, and did not recognize HEL. The MD4/Eμ-TCL1 mice had reduced survival, increased myeloid-derived suppressor cells (MDSC), and decreased numbers of T cells. We tested whether sIgM could contribute to the accumulation of MDSCs by crossing μS^–/– mice, which could not produce sIgM, with Eμ-TCL1 mice. The μS^–/–/Eμ-TCL1 mice survived longer than Eμ-TCL1 mice and developed decreased numbers of MDSCs which were less able to suppress proliferation of T cells. We targeted the synthesis of sIgM by deleting the function of XBP-1s and showed that targeting XBP-1s genetically or pharmacologically could lead to decreased sIgM, accompanied by decreased numbers and reduced functions of MDSCs in MD4/Eμ-TCL1 mice. Additionally, MDSCs from μS^–/– mice grafted with Lewis lung carcinoma were inefficient suppressors of T cells, resulting in slower tumor growth. These results demonstrate that sIgM produced by B cells can upregulate the functions of MDSCs in tumor-bearing mice to aggravate cancer progression. In a mouse model of CLL, production of secretory IgM led to more MDSCs, fewer T cells, and shorter survival times for the mice. Thus, secretory IgM may aggravate the progression of this cancer. Cancer Immunol Res; 6(6); 696–710. ©2018 AACR.

https://ift.tt/2snulOd

Disruption of IFN-I Signaling Promotes HER2/Neu Tumor Progression and Breast Cancer Stem Cells

Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1). Such mice are unresponsive to this family of cytokines. Compared with parental neu^+/– mice (neuT mice), IFNAR1^–/– neu^+/– mice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. IFNAR-neuT tumors exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including the breast cancer stem cell (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1). An increased number of BCSCs were observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay, and tumorigenic capacity. In vitro exposure of neuT⁺ mammospheres and cell lines to antibodies to IFN-I resulted in increased frequency of ALDH⁺ cells, suggesting that IFN-I controls stemness in tumor cells. Altogether, these results reveal a role of IFN-I in neuT-driven spontaneous carcinogenesis through intrinsic control of BCSCs. Cancer Immunol Res; 6(6); 658–70. ©2018 AACR.

https://ift.tt/2J5t98a

PPAR{gamma} Contributes to Immunity Induced by Cancer Cell Vaccines That Secrete GM-CSF

Peroxisome proliferator activated receptor- (PPAR) is a lipid-activated nuclear receptor that promotes immune tolerance through effects on macrophages, dendritic cells (DCs), and regulatory T cells (Tregs). Granulocyte–macrophage colony stimulating factor (GM-CSF) induces PPAR expression in multiple myeloid cell types. GM-CSF contributes to both immune tolerance and protection, but the role of PPAR in these pathways is poorly understood. Here, we reveal an unexpected stimulatory role for PPAR in the generation of antitumor immunity with irradiated, GM-CSF–secreting tumor-cell vaccines (GVAX). Mice harboring a deletion of pparg in lysozyme M (LysM)-expressing myeloid cells (KO) showed a decreased ratio of CD8⁺ T effectors to Tregs and impaired tumor rejection with GVAX. Diminished tumor protection was associated with altered DC responses and increased production of the Treg attracting chemokines CCL17 and CLL22. Correspondingly, the systemic administration of PPAR agonists to vaccinated mice elevated the CD8⁺ T effector to Treg ratio through effects on myeloid cells and intensified the antitumor activity of GVAX combined with cytotoxic T lymphocyte–associated antigen-4 antibody blockade. PPAR agonists similarly attenuated Treg induction and decreased CCL17 and CCL22 levels in cultures of human peripheral blood mononuclear cells with GM-CSF–secreting tumor cells. Together, these results highlight a key role for myeloid cell PPAR in GM-CSF–stimulated antitumor immunity and suggest that PPAR agonists might be useful in cancer immunotherapy. Cancer Immunol Res; 6(6); 723–32. ©2018 AACR.

https://ift.tt/2snutNH

Targeting Tissue Factor for Immunotherapy of Triple-Negative Breast Cancer Using a Second-Generation ICON

Triple-negative breast cancer (TNBC) is a leading cause of breast cancer death and is often associated with BRCA1 and BRCA2 mutation. Due to the lack of validated target molecules, no targeted therapy for TNBC is approved. Tissue factor (TF) is a common yet specific surface target receptor for cancer cells, tumor vascular endothelial cells, and cancer stem cells in several types of solid cancers, including breast cancer. Here, we report evidence supporting the idea that TF is a surface target in TNBC. We used in vitro cancer lines and in vivo tumor xenografts in mice, all with BRCA1 or BRCA2 mutations, derived from patients' tumors. We showed that TF is overexpressed on TNBC cells and tumor neovasculature in 50% to 85% of TNBC patients (n = 161) and in TNBC cell line–derived xenografts (CDX) and patient-derived xenografts (PDX) from mice, but was not detected in adjacent normal breast tissue. We then describe the development of a second-generation TF-targeting immunoconjugate (called L-ICON1, for lighter or light chain ICON) with improved efficacy and safety profiles compared with the original ICON. We showed that L-ICON1 kills TNBC cells in vitro via antibody-dependent cell-mediated cytotoxicity and can be used to treat human and murine TNBC CDX as well as PDX in vivo in orthotopic mouse models. Thus, TF could be a useful target for the development of immunotherapeutics for TNBC patients, with or without BRCA1 and BRCA2 mutations. Cancer Immunol Res; 6(6); 671–84. ©2018 AACR.

https://ift.tt/2xAdVac

Allelic Polymorphisms of KIRs and HLAs Predict Favorable Responses to Tyrosine Kinase Inhibitors in CML

Response to tyrosine kinase inhibitors (TKIs) is variable in chronic myeloid leukemia (CML), and elevated natural killer (NK) cells during TKI therapy are positively correlated with superior outcomes. NK cell function involves interactions of their killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I on target cells, and the avidity of KIR–HLA interactions depends on the combination of KIR and HLA alleles. We hypothesized that KIR and HLA polymorphisms may influence response to TKIs. KIR and HLA allele genotyping was performed by next-generation sequencing for 76 CML cases, and association with clinical outcome was analyzed. Second-generation TKIs as first-line therapy and patients' sex (female) were strongly associated with achievement of complete molecular response (CMR: MR^4.0) after 2 years (P < 0.001 and P = 0.002, respectively). After adjustment for these two characteristics, several KIR alleles remained associated with achievement of MR^4.0: KIR2DL4*005/011 or *008 (HR = 1.797, P = 0.032); KIR2DS4*003 or *007/010 (HR = 3.348, P < 0.001); KIR3DL1*005 (HR = 2.746, P = 0.003); and KIR3DL2*009 or *010 [HR = 1.980 (1.109–3.524), P = 0.021]. Strong linkage among these alleles exists, implying that they comprise favorable KIR allele haplotypes. Allelic polymorphisms of KIR3DL1 and HLA-B determine their differential avidity into strong/weak or no interaction. Patients carrying noninteracting KIR3DL1 and HLA-B allele pairs achieved better outcomes than those with strongly interacting pairs, and KIR3DL1*005 associated with a positive outcome among patients with weak-interacting pairs. Thus, KIR3DL1*005 and its associated haplotypes associated with superior TKI therapeutic effects. The combinations of these KIR and HLA alleles may correlate with potent NK cell immunity against CML. Cancer Immunol Res; 6(6); 745–54. ©2018 AACR.

https://ift.tt/2snuhhr

Determinants of frequent and infrequent STI testing and STI diagnosis related to test frequency among men who have sex with men in the eastern part of the Netherlands: a 6-year retrospective study

Objective

Men who have sex with men (MSM) remain vulnerable to sexually transmitted infections (STIs) and are advised to be tested at least twice a year. The aim of this study was to assess the determinants of test frequency and their associations with an STI diagnosis.

Design

A 6-year retrospective study.

Setting

5 STI clinics in the eastern part of the Netherlands.

Participants

MSM whose mean test interval was 6 months or more were grouped as 'infrequently tested' (n=953), and those with a mean test interval less than 6 months were grouped as 'frequently tested' (n=658).

Primary and secondary outcome measures

Test frequency and STI diagnosis and determinants.

Results

MSM who were ever diagnosed with an STI (OR=1.4, 95% CI 1.1 to 1.7), MSM who had never had STI symptoms (OR=0.8, 95% CI 0.6 to 1.0), and MSM who had ever had sex with both men and women (OR=0.6, 95% CI 0.5 to 0.8) were more often frequently tested. Moreover, in both groups, MSM who had ever been notified by a partner (OR=2.2, 95% CI 1.7 to 2.9 infrequently tested; OR=2.0, 95% CI 1.4 to 2.9 frequently tested), MSM who had ever had STI symptoms (OR=1.6, 95% CI 1.2 to 2.1 infrequently tested; OR=1.8, 95% CI 1.3 to 2.6 frequently tested) and MSM who were ever diagnosed with HIV (OR=2.7, 95% CI 1.5 to 4.6 infrequently tested; OR=6.8, 95% CI 2.6 to 17.5 frequently tested) were more likely to be diagnosed with an STI.

Conclusions

Among MSM visiting STI clinics, those who were ever diagnosed with HIV were more often diagnosed with an STI, but did not visit STI clinics more frequently than HIV-negative MSM. This highlights the necessity of encouraging MSM who are diagnosed with HIV to have STI tests more frequently.

https://ift.tt/2xxp7UN

Participant experiences of two successful habit-based weight-loss interventions in Australia: a qualitative study

Objectives

Habit-based weight-loss interventions have shown clinically important weight loss and weight-loss maintenance. Understanding why habit-based interventions work is therefore of great value, but there is little qualitative evidence about the experiences of participants in such programmes. We explored the perspectives of individuals who completed two habit-based weight-management programmes, Ten Top Tips and Do Something Different.

Design

One-on-one, face-to-face, semistructured interviews were conducted and analysed thematically.

Setting

Participants from the community were interviewed at Bond University, Australia.

Participants

Using a maximum variation design, we recruited 15 participants (eight men, seven women) aged 39–69 years (mean 53.3 years, SD 10.3) with a range of education levels (no high school to university degree) and percentage weight change on the programmes (+4.0% to –10.4%).

Main outcome measures

(1) The general experience of participants who completed the Ten Top Tips or Do Something Different intervention, (2) whether and how the interventions affected the participants' lifestyle postintervention, and (3) participants' views regarding the acceptability and practical application of Ten Top Tips and Do Something Different.

Results

Participants reported positive experiences of the two programmes, both during and after the interventions. Participants particularly enjoyed the novelty of the interventions as they shifted focus from diet and exercise, to practical everyday habit changes. They also reported indirect health benefits such as increased energy levels, increased confidence and improved self-awareness. Accountability throughout the programmes and convenience of the interventions were identified as key themes and facilitators for weight-loss success.

Conclusions

This study offers insight into how and why habit-based interventions might work. Overall, Ten Top Tips and Do Something Different are practical and convenient to implement, and are viewed favourably by participants when compared with conventional lifestyle programmes for weight control.

Trial registration number

ACTRN12615000114549.

https://ift.tt/2so5sBU

Quantifying the financial burden of households out-of-pocket payments on medicines in India: a repeated cross-sectional analysis of National Sample Survey data, 1994-2014

Objective

The objective of this research is to generate new evidence on financial implications of medicines out-of-pocket (OOP) payments for households. Another objective is to investigate which disease conditions contributed to a significant proportion of households' financial burden.

Setting

All Indian states including union territories, 1993–2014.

Design

Repeated cross-sectional household surveys.

Data

Secondary data of nationwide Consumer Expenditure Surveys for the years 1993–1994, 2004–2005 and 2011–2012 and one wave of Social Consumption: Health for the year 2014 from National Sample Survey Organisation.

Outcome measures

OOP expenditure on healthcare in general and medicines in specific.

Results

Total OOP payments and medicines OOP payments were estimated to be 6.77% (95% CI 6.70% to 6.84%) and 4.49% (95% CI 4.45% to 4.54%) of total consumption expenditure, respectively, in the year 2011–2012 which marked significant increase since 1993–1994. These proportions were 11.46% (95% CI 11.36% to 11.56%) and 7.60% (95% CI 7.54% to 7.67%) of non-food expenditure, respectively, in the same year. Total OOP payments and medicines OOP payments were catastrophic for 17.9% (95% CI 17.7% to 18.2%) and 11.2% (95% CI 11.0% to 11.4%) households, respectively, in 2011–2012 at the 10% of total consumption expenditure threshold, implying 29 million households incurred catastrophic OOP payments in the year 2011–2012. Further, medicines OOP payments pushed 3.09% (95% CI 2.99% to 3.20%), implying 38 million persons into poverty in the year 2011–2012. Among the leading cause of diseases that caused significant OOP payments are cancers, injuries, cardiovascular diseases, genitourinary conditions and mental disorders.

Conclusions

Purchase of medicines constitutes the single largest component of the total OOP payments by households. Hence, strengthening government intervention in providing medicines free in public healthcare facilities has the potential to considerably reduce medicine-related spending and total OOP payments of households and reduction in OOP-induced poverty.

https://ift.tt/2J7aRUc

Quantifying the incidence and burden of herpes zoster in New Zealand general practice: a retrospective cohort study using a natural language processing software inference algorithm

Objective

To investigate the incidence of primary care presentations for herpes zoster (zoster) in a representative New Zealand population and to evaluate the utilisation of primary healthcare services following zoster diagnosis.

Design

A cross-sectional retrospective cohort study used a natural language processing software inference algorithm to identify general practice consultations for zoster by interrogating 22 million electronic medical record (EMR) transactions routinely recorded from January 2005 to December 2015. Data linking enabled analysis of the demographics of each case. The frequency of doctor visits was assessed prior to and after the first consultation diagnosing zoster to determine health service utilisation.

Setting

General practice, using EMRs from two primary health organisations located in the lower North Island, New Zealand.

Participants

Thirty-nine general practices consented interrogation of their EMRs to access deidentified records for all enrolled patients. Out-of-hours and practice nurse consultations were excluded.

Main outcome measures

The incidence of first and repeated zoster-related visits to the doctor across all age groups and associated patient demographics. To determine whether zoster affects workload in general practice.

Results

Overall, for 6 189 019 doctor consultations, the incidence of zoster was 48.6 per 10 000 patient-years (95% CI 47.6 to 49.6). Incidence increased from the age of 50 years to a peak rate of 128 per 10 000 in the age group of 80–90 years and was significantly higher in females than males (p<0.001). Over this 11-year period, incidence increased gradually, notably in those aged 80–85 years. Only 19% of patients had one or more follow-up zoster consultations within 12 months of a zoster index consultation. The frequency of consultations, for any reason, did not change between periods before and after the diagnosis.

Conclusions

Zoster consultations in general practice are rare, and the burden of these cases on overall general practice caseload is low.

https://ift.tt/2snrkgC