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Background: 40 million people in the world are in need of palliative care, but only one-seventh of that population receive services. Underuse of palliative care in low resource countries exacerbates suffering in patients with life limiting illnesses such as cancer. Objectives: The current study was conducted to identify barriers, facilitators and recommended strategies for informing development of a home-based palliative care intervention for poor and medically underserved rural patients in Kolkata, India. Methods: Semi-structured interviews were conducted with 20 clinical and patient stakeholders in Kolkata, India. Questions queried current practices for delivering palliative care, along with barriers, facilitators and optimal strategies for implementing homebased palliative care. Results: We identified some key barriers to palliative care delivery in rural areas: lack of access to palliative care till late stages; patients unaware of their cancer stage; lack of affordability of medication and treatment costs; transportation challenges to access care; strict morphine distribution regulations making it challenging for patients to obtain morphine; cultural factors discouraging patients from seeking palliative care; resistance from medical community to use “rural medical practitioners (RMPs)” to deliver care. We also identified important facilitators, including availability of existing palliative care infrastructure at the cancer center, network of RMPs to serve as CHWs to facilitate palliative care delivery, low morphine cost and family support system for patients. Conclusion: Our findings provide evidence that a palliative care intervention which leverages an existing CHW infrastructure may be a feasible model for expanding the reach of palliative care to rural underserved patients.

Background: Supportive care interventions can improve quality of life and health outcomes of advanced prostate cancer survivors. Despite the high prevalence of unmet needs, supportive care for this population is sparse. Methods: The databases PubMed, SCOPUS, CINAHL, and ProQuest were searched for relevant articles. Data were extracted, organized by thematic matrix, and categorized according to the seven domains of the Supportive Care Framework for Cancer Care. Results: The search yielded 1678 articles, of which 18 were included in the review and critically appraised. Most studies were cross-sectional with small, non-diverse samples. Supportive care interventions reported for advanced prostate cancer survivors are limited with some positive trends. Most outcomes were symptom-focused and patient self-reported (e.g., anxiety, pain, self-efficacy) evaluated by questionnaires or interview. Interventions delivered in group format reported improvements in more outcomes. Conclusions: Additional supportive care intervention are needed for men with advanced prostate cancer. Because of their crucial position in caring for cancer patients, nurse scientists and clinicians must partner to research and develop patient-centered, culturally relevant supportive care interventions that improve this population’s quality of life and health outcomes. Efforts must concentrate on sampling, domains of needs, theoretical framework, guidelines, and measurement instruments.

Background Community-based interventions are vital for facilitating poststroke recovery, increasing community participation, and raising awareness about stroke survivors. To optimize recovery and community reintegration, there is a need to understand research findings on community-based interventions that focus on stroke survivors and their caregivers. Although nurses and community health workers (CHWs) are commonly involved in community-based interventions, less is known about their roles relative to other poststroke rehabilitation professionals (physical therapists, occupational therapists, and speech-language pathologists). Thus, the purpose of this review is to explore research focused on improving community-based stroke recovery for adult stroke survivors, caregivers, or both when delivered by nurses or CHWs. Methods A systematic review using Scopus, PubMed, EBSCOhost, MEDLINE, CINAHL Complete, and PsycInfo was completed to identify community-based poststroke intervention studies using nurses or CHWs through August 2018. Results Eighteen studies meeting inclusion criteria from 9 countries were identified. Details regarding nurses' and CHWs' roles were limited or not discussed. Interventions emphasized stroke survivor self-care and caregiver support and were offered face-to-face and in group sessions in the community and home. A wide range of instruments were used to measure outcomes. The results of the interventions provided were mixed. Improvements were observed in perceptions of health, quality of life, knowledge, self-efficacy, self-management, and caregiver support. Conclusion Nurses and CHWs play a pivotal role in community-based care. Evidence suggests community-based interventions facilitate the necessary support for stroke survivors, caregivers, families, and communities to optimize stroke recovery. Data from this review illustrate a continued need for comprehensive programs designed to address the complex needs of stroke survivors and families when they return to their homes and communities.

Background Persons with dementia with mild to moderate cognitive impairment are at risk for developing impairments with activities of daily living such as the ability to feed oneself, that negatively influence health. Lack of caregiver skills related to mealtime planning for persons with dementia and the ability to cope with dysfunctional behaviors are well-documented factors that influence nutritional status outcomes, lead to weight loss, poor quality of life, and impact their ability to remain at home. Methods A cluster randomized controlled trial with a parallel mixed methods evaluation processes will be conducted to examine the efficacy of a train-the-trainer program using non-paid volunteers in respite care centers to deliver a telehealth mealtime intervention guided by the theory-based C3P Model—Change the Person, Change the People, Change the Place (C3P). In this six-month study, dyads of caregivers and persons with mild to moderate dementia receiving respite care services will be randomized to receive either the telehealth intervention or enhanced usual care. Within the intervention group, dyads will be partnered with a C3P trained volunteer who will work with caregivers via videoconference to devise and implement mealtime plans. Under usual care, dyads will receive standardized educational materials modified from The Savvy Caregiver Program for Alzheimer’s disease. The primary outcomes include weight maintenance or gain of the person with dementia and quality of life of the caregiver. A multi-level evaluation process utilizing respite center administrators and directors, volunteers, and caregivers will explore intervention fidelity, acceptability and sustainability. Using both the CONSORT and SPIRIT checklists as guidance, the comprehensive study design is more fully described in this manuscript. Discussion In this trial, we will lay the groundwork to examine the efficacy and sustainability of a train-the-trainer telehealth program that could be widely disseminated by national Alzheimer’s organizations and readily adopted by community agencies to provide additional resources to assist families in managing mealtimes at home, while promoting the quality of life of both the caregiver and the person with dementia. Trial registration This study was registered with clinicaltrials.gov: NCT03622814 on August 9, 2018..

Background There has been a tremendous surge in stroke prevalence in sub-Saharan Africa. Hypertension (HTN), the most potent, modifiable risk factor for stroke, is a particular challenge in sub-Saharan Africa. Culturally sensitive, efficacious HTN control programs that are timely and sustainable are needed, especially among stroke survivors. Mobile health (mHealth) technology and task-shifting offer promising approaches to address this need. Methods Using a concurrent triangulation design, we collected data from stroke survivors, caregivers, community leaders, clinicians and hospital personnel to explore the barriers, facilitators and perceptions toward mHealth related to HTN management among poststroke survivors in Ghana. Exploration included perceptions of a nurse-led navigational model to facilitate care delivery and willingness of stroke survivors and caregivers to use mHealth technology. Results Two hundred stroke survivors completed study surveys while focus groups (n = 4) were conducted with stroke survivors, caregivers and community leaders (n = 28). Key informant interviews were completed with clinicians and hospital personnel (n = 10). A total of 93% of survey respondents had HTN (60% uncontrolled). Findings support mHealth strategies for poststroke care delivery and HTN management and for task-shifting through a nurse-led model. Of survey and focus group participants, 76% and 78.6%, respectively, have access to mobile phones and 90% express comfort in using mobile phones and conveyed assurance that task-shifting through a nurse-led model could facilitate management of HTN. Findings also identified barriers to care delivery and medication adherence across all levels of the social ecological model. Conclusions Participants strongly supported enhanced care delivery through mobile health and were receptive toward a nurse-led navigational model.

Telemedicine implementation in ambulances can reduce time to treatment for stroke patients, which is important as "time is brain" for these patients. Limited research has explored the demands placed on acute stroke caregivers in a telemedicine-integrated ambulance system. This study investigates the impact of telemedicine on workload, teamwork, workflow, and communication of geographically distributed caregivers delivering stroke care in ambulance-based telemedicine and usability of the system. Simulated stroke sessions were conducted with 27 caregivers, who subsequently completed a survey measuring workload, usability, and teamwork. Follow-up interviews with each caregiver ascertained how telemedicine affected workflow and demands which were analyzed for barriers and facilitators to using telemedicine. Caregivers experienced moderate workload and rated team effectiveness and usability high. Barriers included frustration with equipment and with the training of caregivers increasing demands, the loss of personal connection of the neurologists with the patients, and physical constraints in the ambulance. Facilitators were more common with live visual communication increasing teamwork and efficiency, the ease of access to neurologist, increased flexibility, and high overall satisfaction and usability. Future research should focus on eliminating these barriers and supporting the distributed cognition of caregivers.

Background and Purpose Sleep apnea (SA) has emerged as a potent risk factor for stroke recurrence and mortality. The burden of SA among stroke survivors in sub-Saharan Africa where stroke incidence and mortality are escalating is unknown. We sought to assess the prevalence of SA risk and its clinical correlates and predictors among Ghanaian stroke survivors. Methods This cross-sectional study involved 200 consecutive stroke survivors attending a neurology clinic in a tertiary medical center in Kumasi, Ghana. The validated Berlin, STOP-BANG, and Epworth Sleepiness Scale questionnaires were administered to all eligible subjects to assess SA risk and daytime somnolence, and their demographic and clinical information, health-related quality of life, and symptoms of depression were collected using the questionnaires. Results The median (interquartile range) age of stroke survivors was 62 (52-72) years and 52.5% were male. Ninety-nine (49.5%) subjects were identified as high risk for SA using the Berlin questionnaire, whereas 26 (13%), 137 (68.5%), and 37 (18.5%) subjects were classified as low, intermediate, and high risk for SA, respectively, using the STOP-BANG questionnaire. Patients at high risk of SA were significantly older, used excess alcohol, and were less able to perform activities of daily living, although their mean National Institutes of Health Stroke Scale scores were significantly lower than those with low risk for SA. None of the stroke survivors had ever been screened for SA. Conclusions One out of every 2 stroke survivors attending a neurology clinic in Ghana is at high risk for undiagnosed SA. Greater regional awareness about SA presence and outcomes among patients and providers is warranted.

Background: As the aging population continues to increase, it is estimated that persons with dementias (PWDs) will reach 13 million by 2050. Lack of caregiver skills related to mealtime planning and the ability to cope with dysfunctional behaviors are well-documented factors that influence nutritional outcomes for PWDs, leading to social isolation, and negatively impacting their home stay. The aim of this study protocol is to test the effectiveness of a train-the-trainer program in which non-paid volunteers in respite care centers deliver a telehealth mealtime intervention for caregivers of PWDs, Partners at Meals. The program is based on the C3P Model of Changing the Place, People and Person. Methods: A cluster-randomized controlled trial with parallel mixed methods evaluation processes is being conducted. Caregivers and PWD dyads, receiving respite services are randomized to receive Partners at Meals or enhanced-usual-care for six months. Within the intervention group, dyads are partnered with a C3P-trained volunteer who works with caregivers to devise monthly mealtime plans. Under enhanced-usual-care, dyads receive standardized educational materials modified from The Savvy Caregiver Program for Alzheimer’s caregiving. Primary outcomes include weight, calorie, protein and fluid intake of the PWDs and quality of life of the caregiver. Respite center administrators, program directors, volunteers and caregivers are evaluated for intervention fidelity, acceptability and sustainability. Implications: In this trial, we lay the groundwork to examine effectiveness and sustainability of a train-the-trainer telehealth program that could be widely disseminated for managing mealtimes in-the-home, while promoting quality of life of both the caregiver and PWDs.

Lack of recruitment of qualified research participants continues to be a significant bottleneck in clinical trials, often resulting in costly time extensions, underpowered results, and in some cases early termination. Some of the reasons for suboptimal recruitment include laborious consent processes and access to participants at remote locations. While new electronic consents technologies (eConsent) help overcome challenges related to readability and consent management, they do not adequately address challenges related to remote access. To address this, we have developed an innovative solution called “teleconsent”, which embeds the informed consent process into a telemedicine session. Teleconsent allows a researcher to remotely video conference with a prospective research participant, display and interactively guide participants in real-time through a consent form. When finished, the researcher and participant can electronically sign the consent form and print or download the signed document for archiving. This process can eliminate challenges related to travel and management of personnel at remote sites. Teleconsent has been successfully implemented in several clinical trials. Teleconsent can improve research recruitment by reducing the barriers related to informed consent, while preserving human interaction.

BACKGROUND Uncontrolled treatment-resistant hypertension (TRH), i.e., blood pressure (BP, mm Hg) ≥140/≥90mm Hg in and out of office on ≥3 different BP medications at optimal doses, is common and has a poor prognosis. Aldosterone antagonist (AA) and renin-guided therapy (RGT) are effective strategies for improving BP control in TRH but have not been compared. METHODS A comparative effectiveness TRH pilot study of AA vs. RGT was conducted in 4 primary care clinics with 2 each randomized to AA or RGT. The primary outcome was change in clinic BP defined by means of 5 automated office BP values. Eighty-nine patients with apparent TRH were screened and 44 met criteria for true TRH. RESULTS Baseline characteristics of 20 patients in the AA (70% Black, 45% female, mean age: 57.4 years) and 24 patients in RGT (79% Black, 50% female, 57.8 years) arms were similar with baseline BP 162±5/90±3 vs. 153±3/84±3, respectively, P = 0.11/0.20. BP declined to 144±5/86±4 in AA vs. 132±4/75±3 in RGT, P = 0.07/0.01; BP was controlled to JNC7 (Seventh Joint National Committee Report) goal in 25% vs. 62.5%, respectively, P < 0.01. Although BP changes from baseline, the primary outcome, were not different (-17.6±5.1/-4.0±3.0 AA vs. -20.4±3.8/-9.7±2.0 RGT, P = 0.65/0.10.), more BP medications were added with AA than RGT (+0.9±0.1 vs. +0.4±0.1 per patient, P < 0.01). CONCLUSIONS In this TRH pilot study, AA and RGT lowered BP similarly, although fewer additional medications were required with RGT. A larger comparative effectiveness study could establish the utility of these treatment strategies for lowering BP of uncontrolled TRH patients in primary care.

Context To meet the growing need for palliative care in low-resource countries, palliative care programs should be evidence based and contextually appropriate. This study was conducted to synthesize the current evidence to guide future programmatic and research efforts. Objectives This systematic review evaluated palliative care outcome measures, outcomes, and interventions in low-resource countries. Methods After title searches, abstracts and full-text articles were screened for inclusion. Data were extracted to report on intervention models, outcome measures used, and intervention outcomes. Results Eighteen papers were reviewed, reporting on interventions conducted across nine low-resource countries. These interventions evaluated home-based palliative care models; a community-managed model; palliative care integrated with hospitals, hospices, or HIV clinics; and models focused on patients' self-management. Three studies were randomized controlled trials. Other studies used nonrandomized trials, cohort studies, mixed methods, pre-post test evaluation, cost-accounting evaluation, and cross-sectional surveys. Thirteen studies measured physical outcomes, 10 using multidimensional instruments. Nine studies measured psychological outcomes, eight using multidimensional instruments. Nine studies measured social outcomes, seven using multidimensional instruments. Nine studies measured outcomes across multiple domains. Across outcomes evaluated, results were reported in the direction of benefit associated with palliative care interventions. Conclusion Many palliative care intervention models exist to serve patients in low-resource countries. Yet, limited high-quality evidence from low-resource countries is available to document intervention outcomes. Rigorous experimental studies and greater measurement of multidimensional aspects of palliative care are needed to advance the science of palliative care in low-resource settings.

Disability-adjusted life-years lost after stroke in LowMiddle-Income Countries (LMICs) is almost seven times those lost in High-income countries. Although individuals living with chronic neurological and mental disorders are prone to stigma, there is a striking paucity of literature on stroke-related stigma particularly from LMICs.To assess the prevalence, severity, determinants and psycho-social consequences of stigma among LMIC stroke survivors.Between November 2015 and February 2016, we conducted a cross-sectional survey of 200 consecutive stroke survivors attending a neurology clinic in a tertiary medical center in Ghana. The validated 8-Item Stigma Scale for Chronic Illness (SSCI-8) questionnaire was administered to study participants to assess internalized and enacted domains of stigma at the personal dimension with further adaptation to capture family and community stigma experienced by stroke participants. Responses on the SSCI-8 were scored from 1 to 5 for each item, where 1=never, 2=rarely, 3=sometimes, 4=often and 5=always with a score range of 8-40. Demographic and clinical data on stroke type and severity as well as depression and Health-Related Quality of Life indicators were also collected. Predictors of stroke-related stigma were assessed using Linear Models (GLM) via Proc GENMOD in SAS 9.4.105 (52.5%) subjects recruited were males and the mean±SD age of stroke survivors in this survey was 62.0±14.4years. Mean SSCI-8 score was highest for personal stigma (13.7±5.7), which was significantly higher than family stigma (11.9±4.6; p=0.0005) and social/community stigma (11.4±4.4; p0.0001). Approximately 80% of the cohort reported experiencing mild-to-moderate degrees of stigma. A graded increase in scores on the Geriatric Depression Scale and Centre for Epidemiological Studies-Depression scale was observed across the three categories. Living in an urban setting was associated with higher SSCI-8 scores. Moreover, stroke subjects with more severe post-stroke residual symptom deficits reported a significantly higher frequency of stigma.Four out of five stroke survivors in this Ghanaian cohort reported experiencing some form of stigma. Stigmatized individuals were also more likely to be depressed and have lower levels of quality of life. Further studies are required to assess the consequences of stigma from stroke in LMIC.

Aim: In India, the need for rural palliative care is increasing with the rising number of people diagnosed with late-stage cancers. Rural areas also have a shortage of trained medical personnel to deliver palliative care. To address these needs, a home-based palliative care program using community health workers (CHWs) to facilitate care delivery was developed to extend the reach of a cancer center's palliative care services outside of Kolkata, India. The research question guiding this qualitative study was, how feasible, useful, and acceptable was this program from the perspectives of the clinical team and CHWs who delivered the intervention? Methods: This qualitative descriptive study used a grounded theory approach and the iterative constant comparative method to collect and analyze data from the key stakeholder interviews. Ten qualitative interviews took place at the Saroj Gupta Cancer Center and Research Institute and were conducted with the CHWs who delivered the home-based palliative care intervention (n = 3) and the clinical team who provided them with training, support, and supervision (n = 7). Results: Three major themes emerged (a) CHWs' desire and need for more training, (b) the need for tailoring of existing intervention protocols and modifying expectations of stakeholders, and (c) the need for considerations for ensuring program sustainability. Conclusions: The study provided evidence that the utilization of CHWs to facilitate delivery of palliative care is a feasible model worthy of consideration and further research testing in low-resource settings.

Background— Hypertension doubles coronary heart disease (CHD) risk. Treating hypertension only reduces CHD risk ≈25%. Treating hypercholesterolemia in hypertensive patients reduces residual CHD risk >35%. Methods and Results— To assess progress in concurrent hypertension and hypercholesterolemia control, National Health and Nutrition Examination Surveys 1988 to 1994, 1999 to 2004, and 2005 to 2010 were analyzed. Hypertension was defined by blood pressure ≥140/≥90 mm Hg, current medication treatment, and 2-told hypertension status; blood pressure Conclusions— Despite progress, opportunities for improving concomitant hypertension and hypercholesterolemia control persist. Prescribing antihypertensive and antihyperlipidemic medications to achieve treatment goals, especially for older, minority, diabetic, and cardiovascular disease patients, and accessing healthcare at least biannually could improve concurrent risk factor control and CHD prevention.

Background Approximately 20% of children with sickle cell disease (SCD) have microalbuminuria (MA). Very little is known about the progression of MA in children and young adults with SCD. Methods In this study, we analyzed 5-year EMR data of 373 children [with ≥2 microalbumin-to-creatinine (MA/Cr) ratio measurements] followed at the Medical University of South Carolina to determine the rate, direction, magnitude, and predictors of MA/Cr change over time. Results Age range was 1–22 years; mean 10.2 ± 5.2 years, 49.5% were males. Median follow-up duration was 3.12 ± 1.16 years. At baseline, 328 children had normal (

Cardiomyocyte apoptosis is a well-established contributor to irreversible injury following myocardial infarction (MI). Increased cardiomyocyte apoptosis is associated also with aging in animal models, exacerbated by MI; however, mechanisms for this increased sensitivity to oxidative stress are unknown. Protein mixed-disulfide formation with glutathione (protein glutathionylation) is known to change the function of intermediates that regulate apoptosis. Since glutaredoxin (Grx) specifically catalyzes protein deglutathionylation, we examined its status with aging and its influence on regulation of apoptosis. Grx1 content and activity are decreased by approximately 40% in elderly (24-mo) Fischer 344 rat hearts compared to adult (6-mo) controls. A similar extent of Grx1 knockdown in H9c2 cardiomyocytes led to increased apoptosis, decreased NFkappaB-dependent transcriptional activity, and decreased production (mRNA and protein) of anti-apoptotic NFkappaB target genes, Bcl-2 and Bcl-xL. Knockdown of Bcl-2 and/or Bcl-xL in wild-type H9c2 cells to the same extent ( approximately 50%) as observed in Grx1-knockdown cells increased baseline apoptosis; and knockdown of Bcl-xL, but not Bcl-2, also increased oxidant-induced apoptosis analogous to Grx1-knockdown cells. Natural Grx1-deficient cardiomyocytes isolated from elderly rats also displayed diminished NFkappaB activity and Bcl-xL content. Taken together, these data indicate diminution of Grx1 in elderly animals contributes to increased apoptotic susceptibility via regulation of NFkappaB function.

In murine embryonic fibroblasts, N-acetyl-L-cysteine (NAC), a GSH generating agent, enhances hypoxic apoptosis by blocking the NFkappaB survival pathway (Qanungo, S., Wang, M., and Nieminen, A. L. (2004) J. Biol. Chem. 279, 50455-50464). Here, we examined sulfhydryl modifications of the p65 subunit of NFkappaB that are responsible for NFkappaB inactivation. In MIA PaCa-2 pancreatic cancer cells, hypoxia increased p65-NFkappaB DNA binding and NFkappaB transactivation by 2.6- and 2.8-fold, respectively. NAC blocked these events without having an effect on p65-NFkappaB protein levels and p65-NFkappaB nuclear translocation during hypoxia. Pharmacological inhibition of the NFkappaB pathway also induced hypoxic apoptosis, indicating that the NFkappaB signaling pathway is a major protective mechanism against hypoxic apoptosis. In cell lysates after hypoxia and treatment with N-ethylmaleimide (thiol alkylating agent), dithiothreitol (disulfide reducing agent) was not able to increase binding of p65-NFkappaB to DNA, suggesting that most sulfhydryls in p65-NFkappaB protein were in reduced and activated forms after hypoxia, thereby being blocked by N-ethylmaleimide. In contrast, with hypoxic cells that were also treated with NAC, dithiothreitol increased p65-NFkappaB DNA binding. Glutaredoxin (GRx), which specifically catalyzes reduction of protein-SSG mixed disulfides, reversed inhibition of p65-NFkappaB DNA binding in extracts from cells treated with hypoxia plus NAC and restored NFkappaB activity. This finding indicated that p65-NFkappaB-SSG was formed in situ under hypoxia plus NAC conditions. In cells, knock-down of endogenous GRx1, which also promotes protein glutathionylation under hypoxic radical generating conditions, prevented NAC-induced NFkappaB inactivation and hypoxic apoptosis. The results indicate that GRx-dependent S-glutathionylation of p65-NFkappaB is most likely responsible for NAC-mediated NFkappaB inactivation and enhanced hypoxic apoptosis.

Germ line mutations of the LKB1 tumor suppressor gene lead to Peutz-Jeghers syndrome (PJS) with a predisposition to cancer. Previous reports suggest that inactivation of this tumor-suppressor gene plays a role in the pathogenesis of gastrointestinal hamartomas as well as several cancers, including adenocarcinoma of the pancreas. Here, we have shown that LKB1 gene is silenced in the pancreatic cancer cell line AsPC-1, but can be recovered by treatment with the methylation inhibitor, 5-aza-2'-deoxycytidine (5aza2dC). Restoring the level of LKB1 through gene transfer initiated mitochondria-mediated apoptosis in AsPC-1 cells, as evidenced by the release of cytochrome c from the mitochondria. By confocal microscopy as well as biochemical fractionation, we demonstrate that LKB1 is present in the nuclear and mitochondrial compartments of pancreatic cancer cells. Our observations also indicate that although functional p53 is absent, the p53 kin, p73, is inducible by doxorubicin in AsPC-1 cells. This suggests that LKB1-induced apoptosis is p53 independent but might be p73-mediated in the pancreatic tumor cell line, AsPC-1.

The antiproliferative action of 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite is specific for cancer cells and is mediated by the induction of programmed cell death or apoptosis. But the identity of the downstream effectors of apoptotic signaling induced by 2-ME is not known. In the present study, we explored the effect of 2-ME on apoptosis in a panel of human pancreatic cancer cell lines. We have identified two categories of pancreatic cancer cell lines, which are either sensitive to 2-ME such as MIA PaCa-2, CFPAC-1, PANC-1, or non-sensitive to 2-ME such as Hs 766T. The results presented here indicated that the cell lines responsive to 2-ME could undergo apoptosis either by G2-M arrest (PANC-1) with Bcl-x(L) phosphorylation or by the accumulation of tetraploid cells in G1-S region (MIA PaCa-2) without Bcl-2/ Bcl-x(L) phosphorylation. Furthermore, 2-ME induced apoptosis in pancreatic cancer cells is mitochondria dependent as evident by the release of cytochrome c into the cytosol. 2-ME exposed cells exhibit Bid cleavage that is accompanied by the translocation of Bax into the mitochondria. Also 2-ME could induce phosphorylation of Bcl-x(L) in G2-M arrested cells, thus indicating the involvement of various anti- and pro-apoptotic regulators in the signaling cascade. The dissection of differential response of pancreatic cancer cell lines holds promise for future therapeutic intervention.

The human feto-placental unit being in the environment of the materno-fetal circulation is very much susceptible to the danger of reactive oxygen species-induced oxidative damage. The present study reports the status of various antioxidants in the feto-placental system at birth. The activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase as well as concentrations of non-enzymic antioxidants viz, ascorbic acid, alpha-tocopherol, bilirubin and glutathione have been determined in term placental brush border membrane (BBM) and umbilical cord (UC) blood. The extent of lipid peroxidation in developing and term BBM and UC blood has been studied by estimation of malondialdehyde and conjugated dienes, both being the end products of lipid peroxidation. The results indicate the presence of a protective mechanism against oxygen toxicity in the feto-placental system at the time of parturition.

Pancreatic cancer has the worst prognosis of all major cancers with 97% treatment failure. First-line systemic therapy for pancreatic cancer is the antimetabolite gemcitabine. Although, tumors may initially respond to the gemcitabine treatment, soon tumor resistance and excessive toxicity develops leading to treatment failure. Efforts to optimize and improve the efficacy of gemcitabine therapy through combination with other agents have little success. Previously, we demonstrated that N-acetyl-L-cysteine (NAC), a glutathione (GSH) precursor prevents NFκB activation and promotes pancreatic cancer cell death. The mechanism of inactivation of NFκB by NAC supplementation is a post-translational sulfhydryl modification called S-glutathionylation on p65-NFκB that inhibits its DNA-binding capacity and thus prevents activation of the survival genes. Mass spectrometric analysis indicated that four of the 9 cysteines of p65 are potentially S-glutathionylated. Our hypothesis is that chemoresistance against gemcitabine arises from a combination of hypoxia- and gemcitabine-induced NFκB activation. The objective of this study is to test the hypothesis and investigate if thiol donors like NAC can suppress NFκB signaling and augment a therapeutic response to gemcitabine in vivo. Here we determined the anti-tumor effect of gemcitabine and NAC on pancreatic tumors in mice. MIA PaCa-2 pancreatic cancer cells were injected into nude mice to grow subcutaneous tumors. Treatment groups were untreated, NAC, gemcitabine and gemcitabine+NAC. Results indicated that neither gemcitabine nor NAC by itself was effective in decreasing tumor growth. However, NAC and gemcitabine in combination inhibited tumor growth by 33%. Gemcitabine activates NFκB, although the mechanism for this phenomenon is unclear. NFκB activity was indeed increased in gemcitabine-treated tumors (3-fold) and combination with NAC treatment blunted this effect (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1316. doi:1538-7445.AM2012-1316