Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells.

Cancer is a complex devastating disease with enormous treatment challenges, including chemo- and radiotherapeutic resistance. Combination therapy demonstrated a promising strategy to target hard-to-treat cancers and sensitize cancer cells to conventional anti-cancer drugs such as doxorubicin. This study aimed to establish molecular profiling and therapeutic efficacy assessment of chloroquine and/or tioconazole (TIC) combination with doxorubicin (DOX) as anew combination model in MCF-7 breast cancer. The drugs are tested against apoptotic/autophagic pathways and related redox status. Molecular docking revealed that chloroquine (CQ) and TIC could be potential PI3K and ATG4B pathway inhibitors. Combination therapy significantly inhibited cancer cell viability, PI3K/AkT/mTOR pathway, and tumor-supporting autophagic flux, however, induced apoptotic pathways and altered nuclear genotoxic feature. Our data revealed that the combination cocktail therapy markedly inhibited tumor proliferation marker (KI-67) and cell growth, along with the accumulation of autophagosomes and elevation of LC3-II and p62 levels indicated autophagic flux blockage and increased apoptosis. Additionally, CQ and/or TIC combination therapy with DOX exerts its activity on the redox balance of cancer cells mediated ROS-dependent apoptosis induction achieved by GPX3 suppression. Besides, Autophagy inhibition causes moderately upregulation in ATGs 5,7 redundant proteins strengthened combinations induced apoptosis, whereas inhibition of PI3K/AKT/mTOR pathway with Beclin-1 upregulation leading to cytodestructive autophagy with overcome drug resistance effectively in curing cancer. Notably, the tumor growth inhibition and various antioxidant effects were observed in vivo. These results suggest CQ and/or TIC combination with DOX could act as effective cocktail therapy targeting autophagy and PI3K/AKT/mTOR pathways in MCF-7 breast cancer cells and hence, sensitizes cancer cells to doxorubicin treatment and combat its toxicity

Clinical impact of double protease inhibitor boosting with Lopinavir/Ritonavir and Amprenavir as part of salvage antiretroviral therapy

Purpose: Double protease inhibitor (PI) boosting is being explored as a new strategy in salvage antiretroviral (ARV) therapy. However, if a negative drug interaction leads to decreased drug levels of either or both PIs, double PI boosting could lead to decreased virologic response. A negative drug interaction has been described between amprenavir (APV) and lopinavir/ritonavir (LPV/r). This observational cohort study assessed the virologic impact of the addition of APV to a salvage ARV regimen, which also contains LPV/r, compared to a regimen containing LPV/r alone. Method: Patients initiated on a salvage ARV regimen that included LPV/r obtained from the expanded access program in Toronto, Canada, were evaluated. APV (600-1,200 mg bid) was added at the discretion of the treating physician. Results: Using multivariate Cox proportional hazards models, we found that the addition of APV to a LPV/r-containing salvage regimen was not significantly associated with time to virologic suppression (< 50 copies/mL; adjusted hazard ratio [HR] = 0.75, p = .12) or with time to virologic rebound (adjusted HR = 1.46, p = .34). Those patients who received higher doses of APV had an increased chance of virologic suppression (p = .03). In a subset of 27 patients, the median LPV Ctrough was significantly lower in patients receiving APV (p = .04), and the median APV Ctrough was reduced compared to reported controls. Conclusion: Our data do not support an additional benefit in virologic reduction of double boosting with APV and LPV/r relative to LPV/r alone in salvage ARV therapy. Our study's limitations include its retrospective nature and the imbalance between the two groups potentially confounding the results. Although these factors were adjusted for in the multivariate analysis, a prospective randomized controlled trial is warranted to confirm our findings

Presence of Human Herpes Virus 6 (HHV6) in pediatric lymphomas: impact on clinical course and association with cytomegalovirus infection

<p>Abstract</p> <p>Background</p> <p>Activation of herpes virus 6 (HHV6) has seen in Hodgkin's and non-Hodgkin's Lymphoma (HL&NHL) as a result of lymphoma associated immunosuppression. Multiple studies have suggested an association between both HHV6 and cytomegalovirus CMV for development of CMV disease affecting the pathogenesis of lymphoma. Therefore, this study investigated the frequency of HHV6, its impact on clinical manifestations of lymphoma and its possible association with risk for development of CMV infection in pediatric lymphoma patients.</p> <p>Methods</p> <p>Presence of HHV6 DNA and CMV DNA was investigated by PCR assay in both WBC's and plasma samples from 50 patients diagnosed with HL or NHL. CMV antibody titer was also determined in sera obtained from each patient. Twenty apparently healthy siblings were used as a control group.</p> <p>Results</p> <p>In a study group of 50 patients diagnosed with HL or NHL, 23/50 (46%) were found to be positive for herpes virus DNA (HHV6 or CMV) in WBC's or plasma by PCR assay and this was significantly higher than its presence in the pediatric control group 2/20 (10%) (p = 0.005). Ten out of these 23 (43%) were found to have active CMV infection. Fifty six percent of patients with CMV infection were found among NHL cases with B- subtype. The presence of both herpes viruses DNA was significantly associated with more frequent episodes of febrile neutropenia (median 3 episodes), absolute neutrophil count (< 0.8), lymphocytes (< 0.5), and low hemoglobin level (< 9.1), (p < 0.05).</p> <p>Conclusion</p> <p>The presence of HHV6 can be considered as a predicting indicator of cellular immunosuppression preceding the onset of CMV infection which may result in a severe outcome among pediatric lymphoma patients.</p

The Role of Nano-Technology in Sustainable Construction: A Case Study of Using Nano Granite Waste Particles in Cement Mortar

Better understanding of the properties of cement-based materials, one of the most widely used building materials, at the nano-scale is crucial to improve its functionality in the built environment. This paper presents areas of using nano-materials in improving the characteristics of cement-based materials as well as introducing a new role of nano-technology together with waste management in enhancing the concept of sustainable construction. A case study on the use of nano-granite waste particles as a replacement of cement and fine aggregate in mortar production is presented. The research concluded that replacing 5% cement and 10% sand with nano-granite waste in the mortar mix increased the compressive strength of the green mortar by 41% compared to that of the control mix (CM). SEM images reinforced this result as the green mortar mix showed maximum density and minimum micro cracks and number of pores. A comparative study between the green mortar and traditional mortar was carried out using sustainability indicators to examine the environmental, social and economic implications. The environmental and social attributes showed a saving of 10% in the field of resource consumption, whereas savings in energy consumption and CO2 emissions reached 5%. The economic field showed saving of 6.5% indicating promising results in enhancing the sustainable construction industry

Etravirine with 2 NRTIs: an effective switch option for ARV simplification and side effect management

Etravirine (ETV) has been approved for use in treatment-experienced patients based on results of the Duet clinical trials [1]. Less experience exists with ETV in earlier stages of treatment. ETV has a favorable genetic barrier, lipid profile, and little associated CNS toxicity. These characteristics make ETV attractive as a switch strategy for simplification and/or management of side effects. A retrospective chart review was conducted at a large urban HIV clinic in Toronto. All patients who were switched to ETV plus 2 nucleosides and whose viral load (VL) was &#60;200 copies/ml at the time of switch were included. Maintenance of viral suppression, CD4 and lipid changes at 24 weeks and reason for switch to ETV are reported. Seventy-three patients (67 male) were identified. Mean age was 46&#x00B1;10 and mean duration of HIV infection was 11.7&#x00B1;7.4 years. Switches were from efavirenz=29, atazanavir=23, lopinavir=16, other=5. Duration of prior regimen was long; median 195 weeks. CNS and GI intolerance were the most common reasons for switches. At the time of analysis, 63 patients had reached week 24. Three patients had discontinued ETV prior to week 24, 3 LTF/U, 4 had &#60;24 weeks follow-up. 92% (67/73) maintained VL suppression (ITT); failures were 6 patients who stopped/lost-to-follow-up prior to week 24. On treatment, CD4 increased and lipid decreased changes as seen below. All patients who switched due to CNS side effects had subjective improvement.Switch to ETV plus 2 nucleosides maintained viral suppression, improved lipid profiles and improved side effect profile in this selected group of patients. 48 week f/u will be presented

Regional Differences in Rates of HIV-1 Viral Load Monitoring in Canada: Insights and Implications for Antiretroviral Care in High Income Countries

Background: Viral load (VL) monitoring is an essential component of the care of HIV positive individuals. Rates ofVL monitoring have been shown to vary by HIV risk factor and clinical characteristics. The objective of this studywas to determine whether there are differences among regions in Canada in the rates of VL testing of HIV-positiveindividuals on combination antiretroviral therapy (cART), where the testing is available without financial barriersunder the coverage of provincial health insurance programs.Methods: The Canadian Observational Cohort (CANOC) is a collaboration of nine Canadian cohorts of HIV-positiveindividuals who initiated cART after January 1, 2000. The study included participants with at least one year offollow-up. Generalized Estimating Equation (GEE) regression models were used to determine the effect ofgeographic region on (1) the occurrence of an interval of 9 months or more between two consecutive recordedVL tests and (2) the number of days between VL tests, after adjusting for demographic and clinical covariates.Overall and regional annual rates of VL testing were also reported.Results: 3,648 individuals were included in the analysis with a median follow-up of 42.9 months and a median of15 VL tests. In multivariable GEE logistic regression models, gaps in VL testing &gt;9 months were more likely inQuebec (Odds Ratio (OR) = 1.72, p &lt; 0.0001) and Ontario (OR = 1.78, p &lt; 0.0001) than in British Columbia andamong injection drug users (OR = 1.68, p &lt; 0.0001) and were less likely among older individuals (OR = 0.77 per10 years, p &lt; 0.0001), among men having sex with men (OR = 0.62, p &lt; 0.0001), within the first year of cART(OR = 0.15, p &lt; 0.0001), among individuals on cART at the time of the blood draw (OR = 0.34, p &lt; 0.0001) andamong individuals with VL &lt; 50 copies/ml at the previous visit (OR = 0.56, p &lt; .0001).Conclusions: Significant variation in rates of VL testing and the probability of a significant gap in testing wererelated to geographic region, HIV risk factor, age, year of cART initiation, type of cART regimen, being in the firstyear of cART, AIDS-defining illness and whether or not the previous VL was below the limit of detection

Patterns of social determinants of health associated with drug use among women living with HIV in Canada: a latent class analysis

Background and AimsIdentifying typologies of social determinants of health (SDoH) vulnerability influencing drug use practices among women living with HIV (WLWH) can help to address associated harms. This research aimed to explore the association of SDoH clusters with drug use among WLWH.DesignLatent class analysis (LCA) was used to identify the distinct clusters of SDoH. Inverse probability weighting (IPW) was employed to account for confounding and potential selection bias. Associations were analyzed using generalized linear model with log link and Poisson distribution, and then weighted risk ratio (RR) and 95% confidence intervals (CI) were reported.Setting and ParticipantsData from 1422 WLWH recruited at timeâ point 1 of the Canadian HIV Women’s Sexual and Reproductive Health Cohort Study (CHIWOS, 2013â 15), with 1252 participants at 18 months followâ up (timeâ point 2).MeasurementsDrug use was defined as use of illicit/nonâ prescribed opioids/stimulants in the past 6 months. SDoH indicators included: race discrimination, gender discrimination, HIV stigma, social support, access to care, food security, income level, employment status, education, housing status and histories of recent sex work and incarceration.FindingsLCA identified four SDoH classes: no/least SDoH adversities (6.6%), discrimination/stigma (17.7%), economic hardship (30.8%) and most SDoH adversities (45.0%). Drug use was reported by 17.5% and 17.2% at timeâ points 1 and 2, respectively. WLWH with no/least SDoH adversities were less likely to report drug use than those in economic hardship class (weighted RR = 0.13; 95% CIs = 0.03, 0.63), discrimination/stigma class (weighted RR = 0.15; 95% CIs = 0.03, 0.78), and most SDoH adversities class (weighted RR = 0.13; 95% CIs = 0.03, 0.58).ConclusionsSocial determinants of health vulnerabilities are associated with greater likelihood of drug use, underscoring the significance of addressing interlinked social determinants and drug use through the course of HIV care and treatment.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149504/1/add14566_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149504/2/add14566.pd

Factors Associated With the Frequency of Monitoring of Liver Enzymes, Renal Function and Lipid Laboratory Markers Among Individuals Initiating Combination Antiretroviral Therapy: A Cohort Study

Background As the average age of the HIV-positive population increases, there is increasing need to monitor patients for the development of comorbidities as well as for drug toxicities. Methods We examined factors associated with the frequency of measurement of liver enzymes, renal function tests, and lipid levels among participants of the Canadian Observational Cohort (CANOC) collaboration which follows people who initiated HIV antiretroviral therapy in 2000 or later. We used zero-inflated negative binomial regression models to examine the associations of demographic and clinical characteristics with the rates of measurement during follow-up. Generalized estimating equations with a logit link were used to examine factors associated with gaps of 12&nbsp;months or more between measurements. Results Electronic laboratory data were available for 3940 of 7718 CANOC participants. The median duration of electronic follow-up was 3.5&nbsp;years. The median (interquartile) rates of tests per year were 2.76 (1.60, 3.73), 2.55 (1.44, 3.38) and 1.42 (0.50, 2.52) for liver, renal and lipid parameters, respectively. In multivariable zero-inflated negative binomial regression models, individuals infected through injection drug use (IDU) were significantly less likely to have any measurements. Among participants with at least one measurement, rates of measurement of liver, renal and lipid tests were significantly lower for younger individuals and Aboriginal Peoples. Hepatitis C co-infected individuals with a history of IDU had lower rates of measurement and were at greater risk of having 12&nbsp;month gaps between measurements. Conclusions Hepatitis C co-infected participants infected through IDU were at increased risk of gaps in testing, despite publicly funded health care and increased risk of comorbid conditions. This should be taken into consideration in analyses examining factors associated with outcomes based on laboratory parameters

Fertility Desires and Intentions of HIV-Positive Women of Reproductive Age in Ontario, Canada: A Cross-Sectional Study

Improvements in life expectancy and quality of life for HIV-positive women coupled with reduced vertical transmission will likely lead numerous HIV-positive women to consider becoming pregnant. In order to clarify the demand, and aid with appropriate health services planning for this population, our study aims to assess the fertility desires and intentions of HIV-positive women of reproductive age living in Ontario, Canada.A cross-sectional study with recruitment stratified to match the geographic distribution of HIV-positive women of reproductive age (18-52) living in Ontario was carried out. Women were recruited from 38 sites between October 2007 and April 2009 and invited to complete a 189-item self-administered survey entitled "The HIV Pregnancy Planning Questionnaire" designed to assess fertility desires, intentions and actions. Logistic regression models were fit to calculate unadjusted and adjusted odds ratios of significant predictors of fertility intentions. The median age of the 490 participating HIV-positive women was 38 (IQR, 32-43) and 61%, 52%, 47% and 74% were born outside of Canada, living in Toronto, of African ethnicity and currently on antiretroviral therapy, respectively. Of total respondents, 69% (95% CI, 64%-73%) desired to give birth and 57% (95% CI, 53%-62%) intended to give birth in the future. In the multivariable model, the significant predictors of fertility intentions were: younger age (age<40) (p<0.0001), African ethnicity (p<0.0001), living in Toronto (p = 0.002), and a lower number of lifetime births (p = 0.02).The proportions of HIV-positive women of reproductive age living in Ontario desiring and intending pregnancy were higher than reported in earlier North American studies. Proportions were more similar to those reported from African populations. Healthcare providers and policy makers need to consider increasing services and support for pregnancy planning for HIV-positive women. This may be particularly significant in jurisdictions with high levels of African immigration