Repression of Stress-Induced LINE-1 Expression Protects Cancer Cell Subpopulations from Lethal Drug Exposure

Publication date: Available online 3 August 2017
Source:Cancer Cell
Author(s): Gulfem Dilek Guler, Charles Albert Tindell, Robert Pitti, Catherine Wilson, Katrina Nichols, Tommy KaiWai Cheung, Hyo-Jin Kim, Matthew Wongchenko, Yibing Yan, Benjamin Haley, Trinna Cuellar, Joshua Webster, Navneet Alag, Ganapati Hegde, Erica Jackson, Tracy Leah Nance, Paul Garrett Giresi, Kuan-Bei Chen, Jinfeng Liu, Suchit Jhunjhunwala, Jeff Settleman, Jean-Philippe Stephan, David Arnott, Marie Classon
Maintenance of phenotypic heterogeneity within cell populations is an evolutionarily conserved mechanism that underlies population survival upon stressful exposures. We show that the genomes of a cancer cell subpopulation that survives treatment with otherwise lethal drugs, the drug-tolerant persisters (DTPs), exhibit a repressed chromatin state characterized by increased methylation of histone H3 lysines 9 and 27 (H3K9 and H3K27). We also show that survival of DTPs is, in part, maintained by regulators of H3K9me3-mediated heterochromatin formation and that the observed increase in H3K9me3 in DTPs is most prominent over long interspersed repeat element 1 (LINE-1). Disruption of the repressive chromatin over LINE-1 elements in DTPs results in DTP ablation, which is partially rescued by reducing LINE-1 expression or function.

Graphical abstract

Teaser

Guler et al. show that drug-tolerant persisters (DTPs), a cancer cell subpopulation surviving lethal drugs, are partly maintained by a repressed chromatin state, prominently at LINE-1 elements. Disrupting the repressive chromatin results in death of DTPs, which is partially rescued by reducing LINE-1 expression.


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JCAD Promotes Progression of Non-alcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity

Non-alcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents is rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared to peri-carcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation; whereas JCAD silencing yielded opposite effects. JCAD interacted with the kinase domain of the tumor suppressor kinase LATS2, a core component of the Hippo signaling pathway. JCAD overexpression inhibited the ability of LATS2 to phosphorylate YAP in this pathway, in turn upregulating CCND1 and GLI2 to promote hepatoma cell proliferation. JCAD was induced by fatty acid overload in hepatic cells and was highly expressed in a mouse model of NASH-precarcinoma lesions, where the ratio of phospho-YAP to YAP was decreased. In human NASH-HCC specimens, JCAD expression and YAP phosphorylation patterns paralleled with the mouse model. Our findings illuminate a new role for JCAD and its critical interplay in the Hippo signaling cascade during the transition of NASH to HCC, with potential implications for therapeutic development in this setting.

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Identification of Novel Breast Cancer Risk Loci

It has been estimated that >1,000 genetic loci have yet to be identified for breast cancer risk. Here we report the first study utilizing targeted next-generation sequencing to identify single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Targeted sequencing of 283 genes was performed in 240 women with early-onset breast cancer (≤ 40 years) or a family history of breast and/or ovarian cancer. Common coding variants with minor allele frequencies (MAF) >1% that were identified were presumed initially to be SNPs, but further database inspections revealed variants had MAF of ≤1% in the general population. Through prioritization and stringent selection criteria, we selected 24 SNPs for further genotyping in 1,516 breast cancer cases and 1,189 non-cancer controls. Overall, we identified the JAK2 SNP rs56118985 to be significantly associated with overall breast cancer risk. Subtype analysis performed for patient subgroups defined by ER, PR and HER2 status suggested additional associations of the NOTCH3 SNP rs200504060 and the HIF1A SNP rs142179458 with breast cancer risk. In silico analysis indicated that coding amino acids encoded at these three SNP sites were conserved evolutionarily and associated with decreased protein stability, suggesting a likely impact on protein function. Our results offer proof of concept for identifying novel cancer risk loci from next-generation sequencing data, with iterative data analysis from targeted, whole-exome or whole-genome sequencing a wellspring to identify new SNPs associated with cancer risk.

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EZH2 palmitoylation mediated by ZDHHC5 in p53 mutant glioma drives malignant development and progression

Gilomas with mutant p53 occurring in 30% of giloma patients exhibit therapeutic resistance and poor outcomes. In this study, we identify a novel mechanism through which mutant p53 drives cancer cell survival and malignant growth. We documented overexpression of the zinc finger protein ZDHHC5 in glioma compared to normal brain tissue and that this event to be tightly correlated with p53 mutations. Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2. Taken together, our work highlighted ZDHHC5 as a candidate therapeutic target for management of p53-mutated gliomas.

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Regulation of fine particulate matter (PM 2.5 ) in the Pacific Rim: perspectives from the APRU Global Health Program

Abstract

While the development of evidence-based air quality standards for airborne particulate matter (PM) for Europe and North America is well-documented, the standard-setting processes in other regions are less well characterized. Many Pacific Rim economies suffer from severe and worsening air pollution. Particulate matter less than 2.5 μm in aerodynamic diameter (PM_2.5) is associated with acute and chronic health effects and is a widely used air quality indicator. This paper reports on PM regulation in selected Pacific Rim economies, focusing on PM_2.5, and provides recommendations on air quality regulation to economies without current standards Through workshops held by the Association of Pacific Rim Universities (APRU) Global Health Program, experts in air pollution from eight universities in eight Pacific Rim economies characterized current PM_2.5 standards and monitoring in their economies, and then collaboratively created recommendations. A great diversity of air pollution exposures exists in the Pacific Rim. While some economies experience low levels of exposure, others have PM levels that are among the highest in the world. The health effects of air pollution are a concern everywhere, but few economies carry out in-depth, local impact assessments and comprehensive air quality monitoring to provide evidence for guidelines and standards. The development of regulations and policies addressing PM_2.5 pollution is urgently needed in many Pacific Rim economies. The international literature provides a robust guide to local risks and should be used, in combination with country-specific population-directed air monitoring, to guide decisions on policies addressing this important global health problem.

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Identifying time-delayed gene regulatory networks via an evolvable hierarchical recurrent neural network

The modeling of genetic interactions within a cell is crucial for a basic understanding of physiology and for applied areas such as drug design. Interactions in gene regulatory networks (GRNs) include effects ...

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Sputum conversion and treatment success among tuberculosis patients with diabetes treated under the Tuberculosis Control Programme in an Urban setting in South India

Velayutham Banurekha, Tarun Bhatnagar, Swaminathan Savithri, Natarajan Dinesh Kumar, Boopathi Kangusamy, Sanjay Mehendale

Indian Journal of Community Medicine 2017 42(3):180-182

Background: Studies from India on sputum conversion and tuberculosis (TB) treatment outcomes among TB patients with diabetes are limited. Objective: The objective of this study is to estimate the proportion of sputum smear conversion and successful treatment outcomes among diabetic–TB patients treated under Revised National TB Control Programme (RNTCP). Methodology: Information on TB disease, diabetes, sputum conversion, and treatment outcomes were collected from treatment cards of adult TB patients (age >18 years) treated in the District TB Centre TB Unit, Tiruchirapalli, Tamil Nadu from July 1, 2014, to October 31, 2015. Results: Diabetes was documented in 163 (14%) of 1131 TB patients. Sputum conversion was in 107 (94%) of 114 smear positive-TB patients. Successful TB treatment outcome was in 116 (85%) of 136 patients and 107 (86%) of 124 new TB patients. Conclusion: Sputum conversion was as per RNTCP target while treatment success rate among the new TB patients with diabetes was suboptimal.

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Teaching/Training and Practice of Public Health/PSM/Community Medicine

BS Garg

Indian Journal of Community Medicine 2017 42(3):127-130



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Epidemiological perspective of National Leprosy Eradication Programme in Maharashtra: Focusing on “Tribal Hot-spot” of Tribal District

Dhananjay Katkar, Balu Natha Mote, Ambadas Adhav, Thirumugam Muthuvel, Suhas Kadam

Indian Journal of Community Medicine 2017 42(3):174-176

Background: Leprosy or Hansen's disease, a chronic infectious disease caused by Mycobacterium leprae is a serious public health concern because of associated case load, morbidity and stigma attached to it. India achieved elimination of leprosy as a public health problem (prevalence rate [PR]<1 case/10,000 population) at the national level on January 1, 2006, still 19% districts in the country report PR more than one. In Maharashtra, it is found that very few districts within the state or very few pockets within the district are actually having leprosy burden. Objectives: (1) Identification of region-wise actual "hot-spot" districts/pockets within state of Maharashtra.(2) Further drop-down below the district and block to tribal belt for understanding the actual high risk area/belt within the tribal districts. Methods: Secondary data analysis of leprosy patients registered in the State during the period 2008–2015. Results: PR per 10,000 was found more in Vidharbha region followed by rest of Maharashtra and then Marathwada. Analysis showed that, there are tribal districts and tribal area within tribal districts which are having higher leprosy burden as compared to the all other districts indicating need of allocation of programme funds and facilities to these tribal belts for the effective control and elimination of leprosy. Conclusion: National Leprosy Eradication Programme should focus on tribal belt for effective control. Without giving extra attention to these tribal areas within high risk district/pockets efforts of eradication of leprosy by 2018 would be unrealistic and impractical.

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Evaluation of antenatal care services affecting neonatal health

Kishor Parashramji Brahmapurkar

Indian Journal of Community Medicine 2017 42(3):185-185



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An informal school-based, peer-led intervention for prevention of tobacco consumption in adolescence: A cluster randomized trial in rural Gandhinagar

Anjali Sunil Kumar Mall, Aroor Bhagyalaxmi

Indian Journal of Community Medicine 2017 42(3):143-146

Background: Tobacco use among adolescence is one of the important preventable causes of death as well as a leading public health problem all over the world. The present study was conducted with the objective of studying the effect of peer-led interventions on tobacco use among adolescents. Materials and Methods: Twenty schools were randomly selected and ten schools each were identified as cluster for intervention and control groups. A total of 402 students in intervention group and 422 in control group were studied. Results: About 48% and 41% of adolescents were consuming smokeless tobacco in any form in the intervention and control groups, respectively. Prevalence of consumption of smokeless tobacco was significantly high among boys as compared to girls. Pan masala was the most common form of consumption. After conducting A Stop Smoking in School Trial-like peer-led intervention, a significant reduction in tobacco consumption of any form was observed in the intervention group (48%–36%) during the follow-up (Z = 3.2, P < 0.01). A significant reduction in exposure to passive smoking in the intervention group (32%–29%) was also observed. All the students smoking initially had stopped smoking at the end of the follow-up in both the groups. Conclusion: It was found that peer-led intervention was effective in reducing the consumption of smokeless tobacco in any form. The rate of reduction was more in the first follow-up as compared to the end of the intervention. Sustained intervention in the form of retraining is needed for the long-term effect.

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Scorecard - An innovative simplified tool to supplement the existing monitoring mechanism to assess and improve performance of antiretroviral treatment centers

Sudhir Chawla, Bhautik Modi, Bharat Bhusan Rewari, Pramod B Verma, Sonia Chetandas Chhabra

Indian Journal of Community Medicine 2017 42(3):163-166

Introduction: All 26 antiretroviral treatment (ART) centers of Gujarat were monitored by Gujarat State AIDS Control Society under the National AIDS Control Program. A comprehensive tool is needed to identify gap in service delivery and to prioritize monitoring visits. Objectives: To supplement the existing monitoring system, identify strengths/weakness of ART centers, and give recommendations. Methodology: Scorecard was developed in spreadsheet format with 17 scoring indicators on monthly base from March 2014 onward. The centers were classified in three color zones: green (score ≥80%), yellow (score <80% and ≥50%), and red (score <50%). Visits were prioritized at centers with more indicators in yellow/red zone. The performance of centers was compared for March 2014 and March 2015. Results: The statistically significant improvement was observed in indicator "ART initiation within 2 months of eligibility," while after removing red zone from analysis, four more indicators named "eligible patients transferred out before ART initiation, general clients started on ART, antenatal women started on ART, and pre-ART follow-up CD4 done" reflect statistically significant improvement. Quadrant analysis was done for some indicators, which provide insight that less number of eligible patients may be a reason for low initiation of ART at one center, and at four other centers, the possible reasons for low retention are high death rate and high lost to follow-up rate. Based on these findings, the recommendations were made to regular mentoring centers, improve coordination between ART center and care and support centers (CSCs), and conduct verbal autopsy. Conclusion: Scorecard is a simple and cost-effective tool for monitoring, and by highlighting low-performing indicators, it helps in improving quality of services provided at ART centers.

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Violence against educated women by intimate partners in Urban Karnataka, India

Rashmi Kundapur, Shruthi M Shetty, Vinayak J Kempaller, Ashwini Kumar, M Anurupa

Indian Journal of Community Medicine 2017 42(3):147-150

Background: Initially viewed as a human rights issue, partner violence is increasingly seen as an important public health problem of international concern. Objectives: To assess the extent of physical, sexual, psychological, and controlling behavior of intimate partners against women in an educated society and find the association with age, age of marriage, married years, educational status of the women and that of partner. Materials and Methods: A prevalence of 15% was taken and final sample was 200, after considering loss of follow-up. Statistical Methods: Proportion, Z-test, Chi-square test. Results: The prevalence of violence against intimate partner in educated society was found to be 40.5% in a South Indian city. Physical assault was high in 30–50 years and increased with duration of marriage from 5.5% at 5 years to 33.3% in 10–20 years of married life. Sexual and psychological assault also increased in <5 years of married life to 35% and 47.6% in 10–20 years duration of marriage, which was statistically significant. Sexual and psychological assault showed a bimodal presentation. Less educated women and their partners were found to report more violence, which was statistically significant. Conclusion: Violence against women is not uncommon in the educated society.

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Feasibility of telecardiology solution to connect rural health clinics to a teaching hospital

Ranjan Shetty, Jyothi Samant, Krishnanand Nayak, Manjunatha Maiya, Shankar Reddy

Indian Journal of Community Medicine 2017 42(3):170-173

Background: In spite of enormous progress in cardiac care in India, rural communities lack access to even basic cardiac care. One possible solution to this problem is to employ telecardiology. Objectives: To demonstrate feasibility of telecardiology system to link rural clinics to a teaching hospital. Methods: Five rural clinics were linked to a teaching hospital, using an inexpensive system of cardiographs and tablet PCs to transmit ECGs to hospital and have them interpreted by cardiologist. Results: Three hundred eighty ECGs were acquired at clinics with 98.9% of them noise-free and transmitted to the hospital with 99.7% success on first attempt. Interpretation of ECG was provided to primary care physician at the clinic on the same day for 95.3% of ECGs. Abnormal ECG findings were seen on 22.6% of these ECGs. Conclusion: This system performed well with high success rate of acquisition and transmission. Staff at rural clinics successfully acquired quality ECGs and transmitted them and the staff at the hospital were able to provide timely interpretation of ECGs and advice to patients.

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Developing domains to assess understanding regarding sexually transmitted infections among sexually transmitted infection clinic attendees: A qualitative study

Bansari L Chawada, Jayesh K Kosambiya, Vipul P Chaudhari

Indian Journal of Community Medicine 2017 42(3):151-154

Objective: To develop and validate domains to assess attendee's gain at sexually transmitted infection (STI) clinic and their understanding after utilizing services at STI Clinic. Methods: Study was done in two phases. In-depth interviews were conducted to explore attendee's perception. Domains generated through the first phase were validated by conducting another 50 structured interviews. Results: Major domains developed were perceptions on STI, the source of information, treatment seeking behavior, understanding of treatment, laboratory test, and follow-up. Friends and counselor played an important role as the source of right information, while elder family female played a role in delayed seeking care. Conclusion: Developed domains can be used to assess STI clinic attendee's perspective on STI. Poor understanding of STI care component especially prevention, partner treatment, and referral was noted after the clinic visit.

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Knowledge and perception regarding autism among primary school teachers: A cross-sectional survey from Pakistan, South Asia

Adil Ayub, Buria Naeem, Wajahat Nazir Ahmed, Suraksha Srichand, Komal Aziz, Brooj Abro, Sehrish Najam, Duraiz Murtaza, Ali Ahmed Janjua, Sara Ali, Imtiaz Jehan

Indian Journal of Community Medicine 2017 42(3):177-179

Background: Early detection and intervention seem to improve development in autistic children, and teachers form an important part of their early social environment. Objectives: The objective of this study was to assess baseline knowledge and misconceptions regarding autism among school teachers and evaluate factors influencing their knowledge. Materials and Methods: This is a cross-sectional survey enrolling primary school teachers using a self-administered questionnaire. Results: Seventy-three teachers (mean age of 34 years, 66% females) responded. Gaps in awareness and knowledge were found. About 52 (71.2%) teachers identified themselves as having some knowledge about autism, with 23 (44.2%) among this group understanding autism as a neurological/mental disorder. The majority (73.1%) believe that special education is a helpful intervention. The only significant factor that influenced knowledge among teachers was attendance of behavioral classes (P = 0.01). Conclusion: Results suggest that teachers have an inadequate understanding of autism due to several misconceptions. This calls for increased education of teachers with regard to autism and other childhood disorders.

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Elevated blood pressure and its associated risk factors among adolescents of a North Indian City - A cross-sectional study

Senthamizh Prasad, Jamal Masood, Anand Kumar Srivastava, Prabhaker Mishra

Indian Journal of Community Medicine 2017 42(3):155-158

Context: Amidst the uncertainty in childhood blood pressure (BP) thresholds, besides the ambiguity in levels and duration of BP elevation causing organ damage, hypertension is present in substantial number of asymptomatic children and adolescents with only a few studies disclosing the setup. With projection of deaths due to noncommunicable diseases in 2030 rising to 52 million, it is necessary to know about the knowledge of present adolescents about BP and its modifiable risk factors. Aims: (1) To assess the prevalence of elevated BP among adolescents and to ascertain the associated risk factors. (2) To assess adolescent's knowledge about BP and its modifiable factors. Settings and Design: A community-based cross-sectional study was conducted on school going adolescents of Lucknow, from September 2014 to August 2015. Subjects and Methods: BP, height, and weight were measured following standard protocols, Centers for Disease Control and Prevention charts for finding respective cut-off values and oral questionnaire for assessing lifestyle risk factors were used. Statistical Analysis: Chi-square, unpaired t-test, and logistic regression were used. Results: Of the 1041 participants, elevated BP (BP percentile ≥90) was prevalent in 24.2%. On regression, factors such as obesity (adjusted odds ratio [aOR] = 5.8, 95% confidence interval [CI] = 3.6–9.4), low fruit diet (aOR = 3.3, 95% CI = 2.1–5.4), and frequent junk food consumption (aOR = 1.9, 95% CI = 1.3–2.8) raised the odds of elevated BP while it was lowered by being physically active (aOR = 0.67, 95% CI = 0.46–0.97). Of 86.3% of children (n = 898) who were fathomed of BP, only less than third (33% and 21.9%) acquainted of BP raising and lowering practices, respectively. Conclusions: Prevalence of high BP is colossal with only a few children knowing its amendable nature. Strenuous efforts targeting detrimental behaviors and imparting the sense of healthy lifestyle enhancing practices are vital to control this epidemic.

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Data envelopment analysis of components of comprehensive index for community health assessment of Maharashtra

Vinny Johny, A Rajeev

Indian Journal of Community Medicine 2017 42(3):183-184



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Utilization of antenatal healthcare services among fishermen population in Kanchipuram District, Tamil Nadu: A cross-sectional study

Raja Danasekaran, Pavithra Raja, Karnaboopathy Ranganathan

Indian Journal of Community Medicine 2017 42(3):159-162

Background: Considering the global and national level commitments in improving the maternal health as well as reducing the maternal mortality, assessment of factors influencing the delivery of antenatal healthcare services becomes essential. Objectives: The aim is to assess the utilization of antenatal health services and to identify the factors influencing their utilization among women of fishermen population in Kanchipuram district, Tamil Nadu. Materials and Methods: The cross-sectional study was carried out among the mothers in Kovalam area of Kanchipuram district. Details were collected using a pretested questionnaire and analyzed using statistical software. Results: The study included 284 mothers, of which 35% were illiterates. Nearly 60.21% have got registered with the Government sector, 59.51% of the mothers had three or more antenatal visits, 64.08% have received two doses of tetanus toxoid, and 73.24% have taken iron and folic acid tablets. Factors which were identified to have statistically significant association with better utilization of antenatal health services were age >30 years, higher educational status, skilled workers, those having their first child, and higher socioeconomic class. Conclusion: This study has reported the fact that antenatal healthcare services were not utilized fully by the community and the fishermen population being a special group has to be given the needed attention from the healthcare delivery system.

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Do We Care? India's Health System

Pradeep Kumar

Indian Journal of Community Medicine 2017 42(3):186-186



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