Search

The lack of efficient and cost-effective diagnostic tools contributes to poor control of tuberculosis in endemic countries. Moreover, host biological processes influence susceptibility, and infection resolution. It is well known that comorbidities such as type 2 diabetes mellitus (DM2) affect the host immune response, making individuals more susceptible to Mycobacterium tuberculosis infection. Currently, there are no laboratory tools that can identify those subjects who have a higher risk of developing the disease. In this study, we used a whole blood mycobacterial growth inhibition assay to assess the immune response capacity to inhibit mycobacterial growth between healthy subjects and those living with DM2 with optimal and poor glycemic control. We also measured cytokine levels in the culture supernatant by cytokine bead arrays. We included 89 patients with DM2: 54 patients with optimal control (mean age 56.2 ± 11.75 years) and 35 patients with poor control (mean age 52.05 ± 9.94 years). We also included 44 healthy subjects as controls (mean age 42.12 ± 11.75 years). We compared the Δlog UFC (a value that represents the difference between mycobacterial growth in the control tube versus the subject’s blood) between each group. Our results demonstrate that patients with DM2 had a lower capacity to inhibit M. tuberculosis growth (Δlog UFC DM2 subjects 0.9581 (-0.3897 to 2.495) vs Δlog UFC healthy subjects 0.7190 (-0.2678 to 2.098); p=0.013). Comparing subjects living with DM2 (optimal and poor glycemic control) vs healthy subjects, we found only significant differences between healthy subjects and patients poorly controlled (Δlog UFC optimal control group 0.876 (-0.3897 to 2.495); Δlog UFC poor control group 1.078 (0.068 to 2.33); Δlog UFC healthy subjects 0.7190 (-0.2678 to 2.098); p= 0.022). Therefore, glycemic control assessed by glycosylated hemoglobin values influences the capacity of the host to control the infection. Our results confirm that the whole blood mycobacterial growth inhibition assay has potential utility as an in vitro marker of M. tuberculosis immunological control in vivo in subjects living with DM2. This assay can be used to evaluate the immune response of each individual against M. tuberculosis, allowing clinicians to choose a more specific host-directed therapy.

Background An essential component of the “Polio Eradication and Endgame Strategic Plan 2013–2018” is the evaluation of population immunity. Mexico introduced the inactivated polio vaccine (IPV) into its routine immunization schedule in 2007 but continued to give trivalent oral polio vaccine OPV twice a year during National Health Weeks through 2016. Methods To describe the seroprevalence of poliomyelitis among children one to four years old in Mexico and analyze risk factors for susceptibility. We detected antibodies to poliovirus type 1 by microneutralization test in 966 serum samples randomly selected from the National Health and Nutrition Survey, 2012. We assessed variables associated with susceptibility using multivariable logistic regression. Results The overall weighted seroprevalence of the general population was 98.39% (95% confidence interval [CI] 96.76–99.21). We found significant differences of prevalence according to age (94.39%, 95% CI 87.56–97.58; 99.02%, 95% CI 95.68–99.79; 99.82%, 95% CI 98.77–99.98; and 100% among children 1, 2, 3, and 4 years old respectively) and number of IPV doses (96.91%, 95% CI 90.55–99.44; 100%; 97.85%, 95% CI 94.46–99.18; and 99.92%, 95% CI 99.45–99.98 for 1 2, 3, and 4 number of doses, respectively). Multivariate analyses showed that susceptibility was associated with younger age, fewer doses of IPV, and certain socioeconomic levels. Conclusions Overall seroprevalence was high. However, we found susceptible children among younger ages and children with fewer or unknown IPV doses belonging to certain socioeconomic strata. Results are relevant for countries transitioning from OPV to IPV and underline the importance of achieving high coverage with IPV.

Background We aimed to elucidate household and community-level shedding and transmission of trivalent oral polio vaccine (tOPV) in communities with inactivated polio vaccine (IPV) routine immunization after tOPV is administered during a national health week (NHW). Methods We conducted a 3-arm, randomized trial with data collected at baseline through 10 weeks post-NHW in households with at least 1 child

Background The World Health Assembly 2012 Polio Eradication and Endgame Strategic Plan calls for the eventual cessation of all oral polio vaccines (OPVs), to be replaced with inactivated polio vaccine (IPV); however, IPV induces less robust mucosal immunity than OPV. This study characterized household and community OPV shedding and transmission after OPV vaccination within primarily IPV-vaccinated communities. Methods Households in 3 IPV-vaccinated Mexican communities were randomized to receive 3 levels of OPV vaccination coverage (70%, 30%, or 10%). Ten stool samples were collected from all household members over 71 days. Analysis compared vaccinated subjects, household contacts of vaccinated subjects, and subjects in unvaccinated households. Logistic and Cox regression models were fitted to characterize transmission of OPV by coverage and household vaccination status. Results Among 148 vaccinated children, 380 household contacts, and 1124 unvaccinated community contacts, 78%, 18%, and 7%, respectively, shed OPV. Community and household contacts showed no differences in transmission (odds ratio [OR], 0.67; 95% confidence interval [CI], .37–1.20), in shedding trajectory (OR, 0.61; 95% CI, .35–1.07), or in time to shedding (hazard ratio, 0.68; 95% CI, .39–1.19). Transmission began as quickly as 1 day after vaccination and persisted as long as 71 days after vaccination. Transmission within unvaccinated households differed significantly across vaccination coverage communities, with the 70% community experiencing the most transmissions (15%), and the 10% community experiencing the least (4%). These trends persisted over time and in the time to first shedding analyses. Conclusions Transmission did not differ between household contacts of vaccinees and unvaccinated households. Understanding poliovirus transmission dynamics is important for postcertification control.

Tuberculosis is a global human health threat, especially in developing countries. The present study aimed to describe the genetic diversity of Mycobacterium tuberculosis and to measure the transmission rates of primary and acquired resistance. A total of 755 M. tuberculosis isolates from a cohort study of patients with culture-confirmed pulmonary tuberculosis in Orizaba, Veracruz, performed between 1995 and 2010 were genotyped by the 24-locus mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR) method. Drug susceptibility was determined. Logistic regression models were constructed to identify the variables associated with resistance and clusters. The recent transmission index (RTI), the Hunter-Gaston discrimination index (HGDI) for the MIRU-VNTR test and allelic diversity (h) were calculated. The Haarlem and LAM lineages were the most common in the population. A total of 519 isolates were grouped into 128 clusters. The overall drug resistance rate was 19%, isoniazid monoresistance (10%) was the most common, and 3.4% of the isolates were multidrug resistant. Among the 116 isolates resistant to at least one drug, the primary and acquired resistance rates were 81.9% and 18.1%, respectively. Primary resistance was associated with belonging to a cluster (aOR 4.05, 95% CI 1.5-11.2, p = 0.007). Previous treatment history (aOR 9.05, 95% CI 3.6-22.5, p

Galectin-4 has been reported to be altered in different cancer types. Its expression changes have been associated with early recurrence and metastasis. In cervical cancer (CC), galectin-4 has not been studied. The aim of the study was to determine the expression level and subcellular localization of galectin-4 in CC tissue and the concentration in the serum of patients with CC. For the analysis of serum levels of galectin-4, an ELISA assay was performed. To assess the expression in cervical tissue, immunohistochemical staining was performed. The results showed that the concentration of galectin-4 in the serum of patients with CC was higher (647.9 pg/ml) than that in the serum of women with normal cytology (382.1 pg/ml). The immunohistochemical analysis of CC samples showed a higher expression in keratinizing tumor than nonkeratinizing tumors and a trend of increased expression in tumors from patients with advanced clinical stage. In normal cervical tissue, galectin-4 was detected in the cytoplasm, and in tumor cells, the presence of galectin-4 was also detected in the nucleus, in both adenocarcinoma and squamous cervical cancer. The increase in serum concentration and different localization in the tumor cells suggest a possible role of galectin-4 in CC development.

Breast cancer implies a very important health problem worldwide since it represents the cancer with the highest incidence and mortality rate among women in 2018. Traditional treatments are not always totally efficient, causing severe systemic side effects, therefore the search for alternative treatments such as photodynamic therapy (PDT) is of vital importance. In the present work, we show the in vitro effects of rose bengal (RB) as a photosensitizer (PS) and green light (500-550 nm) to eliminate two breast cancer cell lines: MDA-MB-231, a triple negative line highly aggressive and invasive, and T47D, a luminal line of the infiltrating ductal type. RB concentrations of 0.5, 1 and 5 μM and radiation fluences of 2.5, 5 and 10 J/cm2 were evaluated. Cell viability was evaluated with the MTT test, obtaining the best effect with 5 μM concentration and 10 J/cm2 light dose.

Plants from the Bursera genus are widely distributed in the tropical dry forests of Mexico. In traditional medicine, extracts from different species of Bursera have been used for a wide range of biological activities, including the treatment of cancer-related symptoms. Compounds present in the Bursera genus include lignans, flavonoids, steroids, short-chain aliphatic alkanes, acetates, alcohols, ketones, and terpenoids. In some instances, secondary metabolites of these classes of compounds may induce cytotoxicity, and therefore we sought to investigate the effects of B. copallifera leaf extracts in breast cancer cell lines to evaluate their potential therapeutic value for the treatment of breast cancer, one of the most prevalent types of cancer in women worldwide. Two B. copallifera leaf extracts exerted cytotoxic effects on both the MCF7 and MDA-MB-231 breast cancer cell line models. The cytotoxic effect was more evident in the MDA-MB-231 triple negative cell line inhibiting also the migration of these cells. We identified hydroxycinnamic acid and flavonol derivatives as major phenolic components of the extracts. Our results strongly suggest a potential use of the Bursera leaf extracts rich in phenolic compounds, their individual phenolic compounds, or their combinations for the treatment of breast cancer.

Diabetes Mellitus type 2 (T2D) is a multifactorial disease. However, it is known that there is an important effect in pancreatic β-cells caused by apoptosis of pro-apoptotic proteins, possibly related to arsenic exposure and atorvastatin treatment.The goal of this study was to evaluate the effects of atorvastatin treatment on apoptosis of pancreatic β-cells in Wistar rats with induced diabetes type 2 exposed to arsenic.T2D in Wistar rats was induced by administration of Streptozotocin. The plasmatic glucose concentrations were measured using the glucose oxidase method, and the concentration of glycated hemoglobin (HbA1c) in whole blood was determined. Exposure to arsenic was measured from urine using atomic absorption with hydride generation, and pro-apoptotic proteins in pancreatic β-cells were observed using the Western blotting technique.Caspase-3 was present in rats that were treated with 10 mg/kg of oral atorvastatin and exposed to 0.01 and 0.025 mg/L of arsenic, but no others proteins were present, such as pro Caspase-8, bcl-2, and Fas. The glycemic levels were 129.2 ± 7.0 mg/dL in the control group and 161.8 ± 14.6 mg/dL and 198.3 ± 18.2 mg/dL (p .05) in the study groups. HbA1c increased from 2.53% to 3.64% (p .05) in the control and study groups.Atorvastatin treatment and arsenic exposure alone are capable of generating apoptosis in pancreatic β-cells of Wistar rats with T2D. Together, all of these factors induce apoptosis in pancreatic cells.

Background Mexico introduced inactivated polio vaccine (IPV) into its routine immunization (RI) schedule in 2007 but continued to give trivalent oral polio vaccine (tOPV) twice a year during national health weeks (NHW) through 2015. Objectives To evaluate individual variables associated with poliovirus (PV) shedding among children with IPV-induced immunity after vaccination with tOPV and their household contacts. Materials and methods We recruited 72 children (both genders, ≤30 months, vaccinated with at least two doses of IPV) and 144 household contacts (both genders, 2 per household, children and adults) between 08/2010 and 09/2010 in Orizaba, Veracruz. Three NHW took place (one before and two after enrollment). We collected fecal samples monthly for 12 months, and tested 2500 samples for polioviruses types 1, 2 and 3 with three serotype-specific singleplex real-time RT-PCR (rRT-PCR) assays. In order to increase the specificity for OPV virus, all positive and 112 negative samples were also processed with a two-step, OPV serotype-specific multiplex rRT-PCR. Analysis We estimated adjusted hazard ratios (HR) and 95% CI using Cox proportional hazards regression for recurrent events models accounting for individual clustering to assess the association of individual variables with the shedding of any poliovirus for all participants and stratifying according to whether the participant had received tOPV in the month of sample collection. Results 216 participants were included. Of the 2500 collected samples, using the singleplex rRT-PCR assay, PV was detected in 5.7% (n = 142); PV1 in 1.2% (n = 29), PV2 in 4.1% (n = 103), and PV3 in 1.9% (n = 48). Of the 256 samples processed by multiplex rRT-PCR, PV was detected in 106 (PV1 in 16.41% (n = 42), PV2 in 21.09% (n = 54), and PV3 in 23.05% (n = 59). Both using singleplex and multiplex assays, shedding of OPV among non-vaccinated children and subjects older than 5 years of age living in the same household was associated with shedding of PV2 by a household contact. All models were adjusted by sex, age, IPV vaccination and OPV shedding by the same individual during the previous month of sample collection. Conclusion Our results provide important evidence regarding the circulation of poliovirus in a mixed vaccination context (IPV+OPV) which mimics the “transitional phase” that occurs when countries use both vaccines simultaneously. Shedding of OPV2 by household contacts was most likely the source of infection of non-vaccinated children and subjects older than 5 years of age living in the same household.

Objective . To evaluate and compare vaccination coverage among children aged 12-23 and 24-35 months living in localities with less than 100 000 inhabitants in Encuesta Nacional de Salud y Nutricion (Ensanut) 2012 and Ensanut 100k (2018). Materials and methods . Estimate of coverage with both surveys. Results . Between 2012 and 2018, according to proof and self-report, the coverage of the basic scheme was maintained in children aged 12-23 (51.6 vs. 60.2%) and 24-35 months (51.4 vs. 50.0%). Similarly, only with proof (53.9 vs. 51.3% and 52.8 vs. 44.2%). In children aged 24-35 months, the coverage of the reinforced basic scheme reinforcements with probative document and self-report (30.9 vs. 34.0%) and only with reinforcements (30.2 vs. 27.8%) was maintained. Coverage with second and third doses of hepatitis B in both age groups decreased; additionally, first dose of measlesmumps-rubella vaccine (SRP, in Spanish) and third dose of Pentavalent in children aged 24-35 months. Conclusions . Coverages were maintained by schemes, despite reductions in hepatitis B, pentavalent and SRP.

Seaweed is an important dietary component and a rich source of iodine in several chemical forms in Asian communities. Their high consumption of this element (25 times higher than in Western countries) has been associated with the low incidence of benign and cancerous breast and prostate disease in Japanese people.We review evidence showing that, in addition to being a component of the thyroid hormone, iodine can be an antioxidant as well as an antiproliferative and differentiation agent that helps to maintain the integrity of several organs with the ability to take up iodine. In animal and human studies, molecular iodine (I2) supplementation exerts a suppressive effect on the development and size of both benign and cancerous neoplasias. Investigations by several groups have demonstrated that these effects can be mediated by a variety of mechanisms and pathways, including direct actions, in which the oxidized iodine dissipates the mitochondrial membrane potential, thereby triggering mitochondrion-mediated apoptosis, and indirect effects through iodolipid formation and the activation of peroxisome proliferator-activated receptors type gamma, which, in turn, trigger apoptotic or differentiation pathways.We propose that the International Council for the Control of Iodine Deficient Disorders recommend that iodine intake be increased to at least 3 mg/day of I2 in specific pathologies to obtain the potential extrathyroidal benefits described in the present review.

The present study was performed to assess the activity of the botulinum toxin A on breast cancer cells. The T47D cell line was exposed to diverse concentrations of the botulinum toxin A and cell viability and apoptosis were estimated using MTT and propidium iodine/annexin V methods, respectively. Botulinum toxin A exerted greater cytotoxic activity in T47D cells in comparison with MCF10A normal cells; this appeared to be via apoptotic processes caspase-3 and -7. In conclusion, botulinum toxin A induces caspase-3 and -7 dependent apoptotic processes in the T47D breast cancer cell line.

Background Isoniazid mono-resistance (IMR) is the most common form of mono-resistance; its world prevalence is estimated to range between 0.0 to 9.5% globally. There is no consensus on how these patients should be treated. Objective To describe the impact of IMR tuberculosis (TB) on treatment outcome and survival among pulmonary TB patients treated under programmatic conditions in Orizaba, Veracruz, Mexico. Materials and Methods We conducted a prospective cohort study of pulmonary TB patients in Southern Mexico. From 1995 to 2010 patients with acid-fast bacilli or culture proven Mycobacterium tuberculosis in sputum samples underwent epidemiological, clinical and microbiological evaluation. We included patients who harbored isoniazid mono-resistant (IMR) strains and patients with strains susceptible to isoniazid, rifampicin, ethambutol and streptomycin. All patients were treated following Mexican TB Program guidelines. We performed annual follow-up to ascertain treatment outcome, recurrence, relapse and mortality. Results Between 1995 and 2010 1,243 patients with pulmonary TB were recruited; 902/1,243 (72.57%) had drug susceptibility testing; 716 (79.38%) harbored pan-susceptible and 88 (9.75%) IMR strains. Having any contact with a person with TB (adjusted odds ratio (aOR)) 1.85, 95% Confidence interval (CI) 1.15–2.96) and homelessness (adjusted odds ratio (aOR) 2.76, 95% CI 1.08–6.99) were associated with IMR. IMR patients had a higher probability of failure (adjusted hazard ratio (HR) 12.35, 95% CI 3.38–45.15) and death due to TB among HIV negative patients (aHR 3.30. 95% CI 1.00–10.84). All the models were adjusted for socio-demographic and clinical variables. Conclusions The results from our study provide evidence that the standardized treatment schedule with first line drugs in new and previously treated cases with pulmonary TB and IMR produces a high frequency of treatment failure and death due to tuberculosis. We recommend re-evaluating the optimal schedule for patients harboring IMR. It is necessary to strengthen scientific research for the evaluation of alternative treatment schedules in similar settings.

Objective To determine the clinical consequences of pulmonary tuberculosis (TB) among patients with diabetes mellitus (DM). Methods We conducted a prospective study of patients with TB in Southern Mexico. From 1995 to 2010, patients with acid-fast bacilli or Mycobacterium tuberculosis in sputum samples underwent epidemiological, clinical and microbiological evaluation. Annual follow-ups were performed to ascertain treatment outcome, recurrence, relapse and reinfection. Results The prevalence of DM among 1262 patients with pulmonary TB was 29.63% (n=374). Patients with DM and pulmonary TB had more severe clinical manifestations (cavities of any size on the chest x-ray, adjusted OR (aOR) 1.80, 95% CI 1.35 to 2.41), delayed sputum conversion (aOR 1.51, 95% CI 1.09 to 2.10), a higher probability of treatment failure (aOR 2.93, 95% CI 1.18 to 7.23), recurrence (adjusted HR (aHR) 1.76, 95% CI 1.11 to 2.79) and relapse (aHR 1.83, 95% CI 1.04 to 3.23). Most of the second episodes among patients with DM were caused by bacteria with the same genotype but, in 5/26 instances (19.23%), reinfection with a different strain occurred. Conclusions Given the growing epidemic of DM worldwide, it is necessary to add DM prevention and control strategies to TB control programmes and vice versa and to evaluate their effectiveness. The concurrence of both diseases potentially carries a risk of global spreading, with serious implications for TB control and the achievement of the United Nations Millennium Development Goals.

Background: worldwide, the frequency of tuberculosis among older people almost triples that observed among young adults. Objective: to describe clinical and epidemiological consequences of pulmonary tuberculosis among older people. Methods: we screened persons with a cough lasting more than 2 weeks in Southern Mexico from March 1995 to February 2007. We collected clinical and mycobacteriological information (isolation, identification, drug-susceptibility testing and IS6110-based genotyping and spoligotyping) from individuals with bacteriologically confirmed pulmonary tuberculosis. Patients were treated in accordance with official norms and followed to ascertain treatment outcomes, retreatment, and vital status. Results: eight hundred ninety-three tuberculosis patients were older than 15 years of age; of these, 147 (16.5%) were 65 years of age or older. Individuals ≥65 years had significantly higher rates of recently transmitted and reactivated tuberculosis. Older age was associated with treatment failure (OR = 5.37; 95% CI: 1.06–27.23; P = 0.042), and death due to tuberculosis (HR = 3.52; 95% CI: 1.78–6.96; P

Background As wild poliovirus is eradicated and countries switch from oral polio vaccine (OPV) to inactivated polio vaccine (IPV), preventing circulating vaccine-derived poliovirus is a top priority. However, the stability of Sabin vaccine serotypes remains a concern in undervaccinated communities. We sought to measure the canonical point mutation rates associated with OPV serotype neuroreversion and vaccine-associated paralytic polio (VAPP) as possible markers of serotype fitness. Mexico provides a natural environment to study these patterns as it provides routine IPV immunization and bi-annual OPV campaigns. Methods We enrolled 450 households with children eligible for OPV before the February 2015 national immunization week from three communities near Orizaba, Mexico. In each community, a different proportion of eligible children received OPV (10, 30, and 70%). Transmission was measured by PCR detection of OPV in samples collected serially from vaccinated children, their households, and other families in the community. Positive samples were reanalyzed to quantify revertant proportion (RP), the percent of OPV VAPP mutants found in positive samples. Results 15,109 samples were collected and analyzed from 1,828 participants. 554 (3.7%) were OPV positive, and 194 have been reanalyzed for RP to date. The majority of OPV 1 positive samples showed 75% revertant by Day 7 (Figure 2), while the majority of OPV 3 positive samples were >75% revertant by Day 4 (Figure 3). Conclusion OPV 1 appears to be more stable than OPV 2 and OPV 3, remaining

Mammary cancer is the world's most common malignant neoplasia for women. Recently, the mortality for breast cancer has fallen due principally to early detection and to use of neoadjuvant chemotherapy. Anthracycline antibiotics are the most commonly used anticancer drugs, and Doxorubicin (DOX) is the first choice to treat mammary cancer. Nevertheless, its use has limited by its cadiotoxic side effects, which are generated by free radicals. Our studies in methylnitrosourea (MNU)-induced mammary cancer models have shown that supplementation with moderately high doses of molecular iodine (I2) exhibits two distinctive and beneficial effects: antineoplastic and antioxidant. In the present work we explored these dual characteristic of I2 (0.05%) as an adjuvant to DOX16 (therapeutic dose of 16 mg/kg) and DOX8 (8 mg/kg) in female Sprague Dawley rats (200 g) with tumors induced by a single dose of 50 mg MNU per Kg. Iodine intake is initiated 2 days before DOX application and continues up to sacrifice 7 days later. The following parameters were registered: body weight, tumor size, tumor proliferation rate (proliferating cell nuclear antigen, PCNA), serum creatinine kinase-MB activity (CK-MB), cardiac lipoperoxidation (cLPO), and cardiac catalase activity (cCAT). Values correspond to mean± SD. Different superscripts represent significant (p≥0.05). Tumor reduction was greater in the DOX16 + I2 group than in the DOX 16 group (75% vs. 50%, respectively), and was associated with a significantly greater decrease in the rate of tumor cell proliferation (25% vs 10% decrease in PCNA-positive cells), showing the synergistic effect of I2. In contrast, at both DOX doses, the DOX + I2, groups had lower body weight loss and less cardiac damage (CK-MB; 280% vs 100%, cLPO 100% vs 0%) than with DOX alone. cCAT was not changed by any of the treatments.Conclusions: Iodine acts as an adjuvant by significantly enhancing the antiproliferative effect of DOX at a therapeutic dose (DOX16), and it exerts significant general and cardiac protective effects that do not involve catalase activation. Cellular and molecular mechanisms involved in these dual effects of iodine are currently being analyzed. The authors thank Drs. Mauricio Diaz, Marcela Lizano, and Brenda Anguiano as well as Biol. Felipe Ortiz for their technical assistance and Leonor Casanova for academic supports. We also thank Dr. Dorothy Pless for proof-reading. Supported in part by PAPIIT/UNAM 201210 and CONACYT 78955 and 47928/47928. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-16.

Several laboratories including ours have shown that iodine (I2) intake exhibits potent antiproliferative and apoptotic effects in vivo and in vitro models of mammary cancer. Molecular analysis of these effects indicates that antioxidant; cellular arrest and apoptotic pathways are involved. As the cellular mechanism that triggers these antineoplastic effects we have proposed that I2 could act in 2 possible ways, directly as antioxidant or indirectly by generating an iodinated arachidonic acid (6-iodoloctone) which exhibits apoptotic effects and is a specific ligand of proliferative peroxisome activated receptor gamma (PPARg). In previous preliminary reports, we corroborated an antiproliferative I2 effect (decreased PCNA) in premenopausal (pre-M) and an apoptotic action (triggering the Bax-Caspase pathway) in both pre-M and post menopausal (post-M) women with early stage breast cancer. In the present report we raise the casuistic and deeply in the analysis of mechanisms involved in this antineoplastic effect of I2. This study includes 22 women (average age 52.9 ± 12.6) diagnosed with early stage breast cancer (IIa and IIb). Patients were divided according to hormonal status into pre-M and post-M groups and were supplemented with I2 (5 mg daily) or placebo (vegetable dye) for2-5 weeks before surgery. Thyroid status (T3 and TSH; RIA) and iodine intake (urine, HPLC) were analyzed. In biopsies (beginning) and/or tumors (final), the level and location (cytosol or nuclear) of estrogen receptor alfa (ERα) and beta (ERb) were analyzed by immunohistochemistry. In tumors, we measured PPARg expression, invasive potential [hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF) by real time PCR] and fibrosis content (Masson's trichromic method). The results show that I2 supplementation in pre-M women is accompanied by a significant increase in the concentration of total ERα and PPARg and no change in total ERb; however, the fraction of ERα in the nucleus was significant lower, and the fibrosis content was higher (70%) than in the placebo group (40%). In contrast, I2 supplements significantly decreased HIF and VEGF expression in both pre-and post-M women. In conclusion, our data show that, in addition to the apoptotic and anti-invasive effects on mammary cancer exhibited by I2 that are independent of hormonal status, in pre-M women, I2 also acts to diminish the effects of estrogen (decreases nuclear translocation of ERα). Experiments that analyze the possible role of PPARg in these actions are in progress. We thank Dr. Jorge Alvarez-Aguirre2,3, Dr. Alonso Gallegos-Corona2, Lic. Concepción Correa-Tinajero3, Alejandro Nuñez-Nolasco2,3, Dra. Norma Uribe Uribe4, Jaime Ayala García4 and Dr. Dorothy Pless1. This work was supported by in part by PAPIIT-UNAM IN201210 and CONACyT 78955 and 85952. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-15.

BACKGROUND Thyroxine (T4) and triiodothyronine (T3) are involved in the development and function of the male reproductive system. The type 1 deiodinase enzyme (D1) plays a major role in the intracellular conversion of T4 to the active form, T3. D1 is expressed in the prostate of pubescent rats, but it is unknown whether locally generated T3 is involved in the development and function of this gland. METHODS D1 activity was analyzed in prostates from neonatal to old rats. Local T3 generation (D1 and T3 levels) was evaluated in adult animals with 1–5 months of continuous sexual activity. D1 activity was measured by the radiolabeled-iodide-release method and T3 concentration by radioimmunoassay. Secretory activity of the prostate was evaluated by a morphological analysis of epithelium (hematoxilin-eosin stain) and by measuring the activity of acid phosphatase as a marker enzyme for secretion. RESULTS The highest prostate D1 activity was expressed around puberty, and it was almost undetectable during the neonatal period and with aging. Interestingly, 1 and 4 months of sexual activity avoided the decrease of D1 activity associated with aging. Sexual activity provoked a hypertrophy and functional hyperplasia in all lobes, but D1 and acid phosphatase activity increased only in the ventral lobe. D1 activity correlated with an increase in the prostatic T3 concentration. CONCLUSIONS The increased local generation of T3 in prostate might be related to: (1) the differentiation/maturation that occurs at puberty and (2) the energy expenditure associated with maintaining the secretory activity of the glandular epithelium. Prostate 69: 1651–1659, 2009. © 2009 Wiley-Liss, Inc.

Previous reports have documented the antiproliferative properties of I(2) and the arachidonic acid (AA) derivative 6-iodolactone (6-IL) in both thyroid and mammary glands. In this study, we characterized the cellular pathways activated by these molecules and their effects on cell cycle arrest and apoptosis in normal (MCF-12F) and cancerous (MCF-7) breast cells. Low-to-moderate concentrations of I(2) (10-20 microM) cause G1 and G2/M phase arrest in MCF-12F and caspase-dependent apoptosis in MCF-7 cells. In normal cells, only high doses of I(2) (40 microM) induced apoptosis, and this effect was mediated by poly (ADP-ribose) polymerase-1 (PARP1) and the apoptosis-induced factor, suggesting an oxidative influence of iodine at high concentrations. Our data indicate that both I(2) and 6-IL trigger the same intracellular pathways and suggest that the antineoplasic effect of I(2) in mammary cancer involves the intracellular formation of 6-IL. Mammary cancer cells are known to contain high concentrations of AA, which might explain why I(2) exerts apoptotic effects at lower concentrations only in tumoral cells.

Background Respiratory manifestations of HIV disease differ globally due to differences in current availability of effective highly active antiretroviral therapy (HAART) programs and epidemiology of infectious diseases. Objective To describe the association between HAART and discharge diagnosis and all-cause in-hospital mortality among hospitalized patients with infectious respiratory disease and HIV/AIDS. Material and Methods We retrospectively reviewed the records of patients hospitalized at a specialty hospital for respiratory diseases in Mexico City between January 1st, 2010 and December 31st, 2011. We included patients whose discharge diagnosis included HIV or AIDS and at least one infectious respiratory diagnosis. The information source was the clinical chart. We analyzed the association between HAART for 180 days or more and type of respiratory disease using polytomous logistic regression and all-cause hospital mortality by multiple logistic regressions. Results We studied 308 patients, of whom 206 (66.9%) had been diagnosed with HIV infection before admission to the hospital. The CD4+ lymphocyte median count was 68 cells/mm3 [interquartile range (IQR): 30–150]. Seventy-five (24.4%) cases had received HAART for more than 180 days. Pneumocystis jirovecii pneumonia (PJP) (n = 142), tuberculosis (n = 63), and bacterial community-acquired pneumonia (n = 60) were the most frequent discharge diagnoses. Receiving HAART for more than 180 days was associated with a lower probability of PJP [Adjusted odd ratio (aOR): 0.245, 95% Confidence Interval (CI): 0.08–0.8, p = 0.02], adjusted for sociodemographic and clinical covariates. HAART was independently associated with reduced odds (aOR 0.214, 95% CI 0.06–0.75) of all-cause in-hospital mortality, adjusting for HIV diagnosis previous to hospitalization, age, access to social security, low socioeconomic level, CD4 cell count, viral load, and discharge diagnoses. Conclusions HAART for 180 days or more was associated with 79% decrease in all-cause in-hospital mortality and lower frequency of PJP as discharge diagnosis. The prevalence of poorly controlled HIV was high, regardless of whether HIV was diagnosed before or during admission. HIV diagnosis and treatment resources should be improved, and strengthening of HAART program needs to be promoted.

We analyzed the effect of molecular iodine (I2), potassium iodide (KI) and a subclinical concentration of thyroxine (T4) on the induction and promotion of mammary cancer induced by N-methyl-N-nitrosourea. Virgin Sprague-Dawley rats received short or continuous treatment. Continuous I2 treated rats exhibited a strong and persistent reduction in mammary cancer incidence (30%) compared to controls (72.7%). Interruption of short or long term treatments resulted in a higher incidence in mammary cancer compared to the control groups. The protective effect of I2 was correlated with the highest expression of the I-/Cl- transporter pendrin and with the lowest levels of lipoperoxidation expression in mammary glands. Triiodothyronine serum levels and Na+/I- symporter, lactoperoxidase, or p53 expression did not show any changes. In conclusion continuous I2 treatment has a potent antineoplastic effect on the progression of mammary cancer and its effect may be related to a decrease in the oxidative cell environment.

Background As wild poliovirus is eradicated and countries switch from Oral Polio Vaccine (OPV) to Inactivated Polio Vaccine (IPV) per WHO recommendations, preventing circulation of vaccine-derived poliovirus is a top priority. However, spatial dynamics of OPV transmission are not well understood. Understanding these trends will improve resource targeting in the event of OPV reintroduction in undervaccinated communities. Mexico provides a natural environment to study OPV as it provides IPV routinely and bi-annual OPV campaigns. Methods Children in three villages near Orizaba, Mexico were randomized to three levels (10%, 30%, 70%) to receive OPV. We measured distance to nearest OPV shedding, and the amount of shedding close to unvaccinated individuals. We used maps to show the proximity and amount of shedding. Distance and density of shedding was analyzed separately using mixed effects logistic regression with random effects for household and time, adjusted for age, gender, area, and running water. Results The median distance to nearest OPV shedding was 85 meters (IQR 46, 145). The median number of shedding individuals within 200m was 3 (2, 6). Shedding and between household transmission occurred rapidly with unvaccinated individuals shedding on day one of the study (Figure 1). There was little evidence (Odds Ratio [OR] 1.04 (95% Highest Posterior Density [HPD] 0.92, 1.16)) of an association between distance (per 100 m) from OPV shedding and odds of shedding. There was some suggestion that the number of OPV shedding within 200 m may have some effect on unvaccinated shedding with OR 0.93 (HPD 0.·84, 1·01) but not at 100 or 500m. Results were consistent across the three villages. Conclusion Household structure appears to have limited value in predicting transmission of poliovirus shedding. The use of OPV results in rapid but low levels of transmission throughout the community and this would usually go undetected. The only way to avoid this is to not use OPV or to have strong controls such as quarantine, or strict hygiene protocols. After withdrawal of OPV worldwide the decision to reintroduce due to an outbreak should not be taken lightly as it appears a small amount of OPV is needed to result in transmission. Disclosures All authors: No reported disclosures.

Introduction Many studies have explored the relationship between diabetes mellitus (DM) and tuberculosis (TB) demonstrating increased risk of TB among patients with DM and poor prognosis of patients suffering from the association of DM/TB. Owing to a paucity of studies addressing this question, it remains unclear whether patients with DM and TB are more likely than TB patients without DM to be grouped into molecular clusters defined according to the genotype of the infecting Mycobacterium tuberculosis bacillus. That is, whether there is convincing molecular epidemiological evidence for TB transmission among DM patients. Objective: We performed a systematic review and meta-analysis to quantitatively evaluate the propensity for patients with DM and pulmonary TB (PTB) to cluster according to the genotype of the infecting M. tuberculosis bacillus. Materials and methods We conducted a systematic search in MEDLINE and LILACS from 1990 to June, 2016 with the following combinations of key words “tuberculosis AND transmission” OR “tuberculosis diabetes mellitus” OR “Mycobacterium tuberculosis molecular epidemiology” OR “RFLP-IS6110” OR “Spoligotyping” OR “MIRU-VNTR”. Studies were included if they met the following criteria: (i) studies based on populations from defined geographical areas; (ii) use of genotyping by IS6110- restriction fragment length polymorphism (RFLP) analysis and spoligotyping or mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR) or other amplification methods to identify molecular clustering; (iii) genotyping and analysis of 50 or more cases of PTB; (iv) study duration of 11 months or more; (v) identification of quantitative risk factors for molecular clustering including DM; (vi) > 60% coverage of the study population; and (vii) patients with PTB confirmed bacteriologically. The exclusion criteria were: (i) Extrapulmonary TB; (ii) TB caused by nontuberculous mycobacteria; (iii) patients with PTB and HIV; (iv) pediatric PTB patients; (v) TB in closed environments (e.g. prisons, elderly homes, etc.); (vi) diabetes insipidus and (vii) outbreak reports. Hartung-Knapp-Sidik-Jonkman method was used to estimate the odds ratio (OR) of the association between DM with molecular clustering of cases with TB. In order to evaluate the degree of heterogeneity a statistical Q test was done. The publication bias was examined with Begg and Egger tests. Review Manager 5.3.5 CMA v.3 and Biostat and Software package R were used. Results Selection criteria were met by six articles which included 4076 patients with PTB of which 13% had DM. Twenty seven percent of the cases were clustered. The majority of cases (48%) were reported in a study in China with 31% clustering. The highest incidence of TB occurred in two studies from China. The global OR for molecular clustering was 0.84 (IC 95% 0.40–1.72). The heterogeneity between studies was moderate (I2 = 55%, p = 0.05), although there was no publication bias (Beggs test p = 0.353 and Eggers p = 0.429). Conclusion There were very few studies meeting our selection criteria. The wide confidence interval indicates that there is not enough evidence to draw conclusions about the association. Clustering of patients with DM in TB transmission chains should be investigated in areas where both diseases are prevalent and focus on specific contexts.

BackgroundRecently, the World Health Organisation and the International Union Against Tuberculosis and Lung Disease published a Collaborative Framework for the Care and Control of Tuberculosis (TB) and Diabetes (DM) (CFTB/DM) proposing bidirectional screening and joint management.ObjectiveTo evaluate the feasibility and effectiveness of the CFTB/DM in Mexico.DesignProspective observational cohort.Setting15 primary care units in 5 states in Mexico.ParticipantsPatients aged ≥20 years diagnosed with DM or pulmonary TB who sought care at participating clinics.InterventionThe WHO/Union CFTB/DM was adapted and implemented according to official Mexican guidelines. We recruited participants from July 2012 to April 2013 and followed up until March 2014. Bidirectional screening was performed. Patients diagnosed with TB and DM were invited to receive TB treatment under joint management.Main outcome measuresDiagnoses of TB among DM, of DM among TB, and treatment outcomes among patients with DM and TB.ResultsOf 783 DM patients, 11 (1.4%) were unaware of their TB. Of 361 TB patients, 16 (4.4%) were unaware of their DM. 95 TB/DM patients accepted to be treated under joint management, of whom 85 (89.5%) successfully completed treatment. Multiple linear regression analysis with change in HbA1c and random capillary glucose as dependent variables revealed significant decrease with time (regression coefficients (β) = -0.660, (95% confidence interval (CI), -0.96 to -0.35); and β = -1.889 (95% CI, -2.77 to -1.01, respectively)) adjusting by sex, age and having been treated for a previous TB episode. Patients treated under joint management were more likely to experience treatment success than patients treated under routine DM and TB programs as compared to historical (adjusted OR (aOR), 2.8, 95%CI 1.28-6.13) and same period (aOR 2.37, 95% CI 1.13-4.96) comparison groups.ConclusionsJoint management of TB and DM is feasible and appears to improve clinical outcomes.

Iodine supplementation exerts antitumor effects in several types of cancer. Iodide (I−) and Iodine (I2) reduce cell proliferation and induce apoptosis in human prostate cancer cells (LNCaP and DU-145). Both chemical species decrease tumor growth in athymic mice xenografted with DU-145 cells. The aim of this study was to analyze the uptake and effects of iodine in a preclinical model of prostate cancer (transgenic adenocarcinoma of the mouse prostate [TRAMP] mice/SV40-TAG antigens), which develops cancer by 12 wks of age. 125I− and 125I2 uptake was analyzed in prostates from wild-type and TRAMP mice of 12 and 24 wks in the presence of perchlorate (inhibitor of the Na+/I− symporter [NIS]). NIS expression was quantified by quantitative polymerase chain reaction (qPCR). Mice (6 wks old) were supplemented with 0.125 mg I− plus 0.062 mg I2/mouse/day for 12 or 24 wks. The weight of the genitourinary tract (GUT), the number of acini with lesions, cell proliferation (levels of proliferating cell nuclear antigen [PCNA] by immunohistochemistry), p53 and p21 expression (by qPCR) and apoptosis (relative amount of nucleosomes by enzyme-linked immunosorbent assay) were evaluated. In both age-groups, normal and tumoral prostates take up both forms of iodine, but only I− uptake was blocked by perchlorate. Iodine supplementation prevented the overexpression of NIS in the TRAMP mice, but had no effect on the GUT weight, cell phenotype, proliferation or apoptosis. In TRAMP mice, iodine increased p53 expression but had no effect on p21 (a p53-dependent gene). Our data corroborate NIS involvement in I− uptake and support the notion that another transporter mediates I2 uptake. Iodine did not prevent cancer progression. This result could be explained by a strong inactivation of the p53 pathway by TAG antigens.

Objective To evaluate the impact of rubella vaccination strategies on the rates of acquired rubella and congenital rubella syndrome in the Americas. Methods We conducted a systematic review of the literature (MEDLINE, PubMed, EMBASE, Cochrane Library, Artemisa Database, LILACS Database, Evidence Portal, VHL-PAHO Portal, Scielo, and Grey-Literature sources) that was published from 1969–2010. We included studies on rubella incidence and seroprevalence rates that were associated with rubella vaccination. The quality of the studies was evaluated according to international guidelines. Results A total of 14 studies were identified: 2 clinical trials, 2 cohort studies, 3 transversal studies, 5 ecological studies, and 2 mathematical models. Childhood vaccination reduced the incidence of rubella by 23.6% to 99.6%, increased the occurrence of epidemic cycles in Argentina and in the United States, and shifted the illness to susceptible adults. Vaccination strategies that focused on women and children in Brazil were associated with a 5.5-fold greater incidence of rubella in men leading to new outbreaks and CRS. A combined vaccination strategy with a universal approach that included routine vaccination for boys, girls, women, and men in Mexico and in Costa Rica reduced the incidence of rubella by more than 98% and led to absence of CRS since 2008. A medium and a low risk of bias were found in 3 and 4 articles, respectively. Conclusion The results of this review demonstrate that the combined vaccination strategy with a universal approach was the most effective strategy as evidenced by a drastic reduction in the number of cases and the interruption of endemic transmission of rubella in the Americas.

Summary Objectives To examine the relationship between cigarette smoking and incidence and mortality rates of pulmonary tuberculosis (TB) and treatment outcomes. Materials From 1995 to 2010, we analyzed data from 1062 patients with TB and from 2001 to 2004, 2951 contacts in Southern Mexico. Patients with acid-fast bacilli or Mycobacterium tuberculosis in sputum samples underwent epidemiological, clinical and mycobacteriological evaluation and received treatment by the local DOTS program. Results Consumers of 1–10 (LS) or 11 or more (HS) cigarettes per day incidence (1.75 and 11.79) and mortality (HS, 17.74) smoker–non-smoker rate ratios were significantly higher for smokers. Smoker population was more likely to experience unfavorable treatment outcomes (HS, adjusted OR 2.36) and retreatment (LS and HS, adjusted hazard ratio (HR) 2.14 and 2.37). Contacts that smoked had a higher probability of developing active TB (HR 2.38) during follow up. Conclusions Results indicate the need of incorporating smoking prevention and cessation, especially among men, into international TB control strategies.

Several studies have demonstrated that moderately high concentrations of molecular iodine (I(2)) diminish the symptoms of mammary fibrosis in women, reduce the occurrence of mammary cancer induced chemically in rats (50-70%), and have a clear antiproliferative and apoptotic effect in the human tumoral mammary cell line MCF-7. Nevertheless, the importance of these effects has been underestimated, in part because of the notion that exposure to excess iodine represents a potential risk to thyroid physiology. In the present work we demonstrate that uptake and metabolism of iodine differ in an organ-specific manner and also depend on the chemical form of the iodine ingested (potassium iodide vs. I(2)). Further, we show that a moderately high I(2) supplement (0.05%) causes some of the characteristics of the "acute Wolff-Chaikoff effect"; namely, it lowers expression of the sodium/iodide symporter, pendrin, thyroperoxidase (TPO), and deiodinase type 1 in thyroid gland without diminishing circulating levels of thyroid hormone. Finally, we confirm that I(2) metabolism is independent of TPO, and we demonstrate that, at the doses used here, which are potentially useful to treat mammary tumors, chronic I(2) supplement is not accompanied by any harmful secondary effects on the thyroid or general physiology. Thus, we suggest that I(2) could be considered for use in clinical trials of breast cancer therapies.

Background Tuberculosis (TB) remains a public health problem in Mexico while the incidence of diabetes mellitus type 2 (DM) has increased rapidly in recent years. Objective To describe the trends of incidence rates of pulmonary TB associated with DM and not associated with DM and to compare the results of treatment outcomes in patients with and without DM. Materials and Methods We analysed the National Tuberculosis Registry from 2000 to 2012 including patients with pulmonary TB among individuals older than 20 years of age. The association between DM and treatment failure was analysed using logistic regression, accounting for clustering due to regional distribution. Results In Mexico from 2000 to 2012, the incidence rates of pulmonary TB associated to DM increased by 82.64%, (p

This paper reviews evidence showing iodine as an antioxidant and antiproliferative agent contributing to the integrity of normal mammary gland. Seaweed is an important dietary component in Asian communities and a rich source of iodine in several chemical forms. The high consumption of this element (25 times more than in Occident) has been associated with the low incidence of benign and cancer breast disease in Japanese women. In animal and human studies, molecular iodine (I(2)) supplementation exerts a suppressive effect on the development and size of both benign and cancer neoplasias. This effect is accompanied by a significant reduction in cellular lipoperoxidation. Iodine, in addition to its incorporation into thyroid hormones, is bound into antiproliferative iodolipids in the thyroid called iodolactones, which may also play a role in the proliferative control of mammary gland. We propose that an I(2) supplement should be considered as an adjuvant in breast cancer therapy.

Background Although mammary cancer (MC) is the most common malignant neoplasia in women, the mortality for this cancer has decreased principally because of early detection and the use of neoadjuvant chemotherapy. Of several preparations that cause MC regression, doxorubicin (DOX) is the most active, first-line monotherapeutic. Nevertheless, its use is limited due to the rapid development of chemoresistance and to the cardiotoxicity caused by free radicals. In previous studies we have shown that supplementation with molecular iodine (I2) has a powerful antineoplastic effect in methylnitrosourea (MNU)-induced experimental models of MC. These studies also showed a consistent antioxidant effect of I2 in normal and tumoral tissues. Methods Here, we analyzed the effect of I2 in combination with DOX treatment in female Sprague Dawley rats with MNU-induced MC. In the first experiment (short) animals were treated with the therapeutic DOX dose (16 mg/kg) or with lower doses (8 and 4 mg/Kg), in each case with and without 0.05% I2 in drinking water. Iodine treatment began on day 0, a single dose of DOX was injected (ip) on day 2, and the analysis was carried out on day 7. In the second experiment (long) animals with and without iodine supplement were treated with one or two injections of 4 mg/kg DOX (on days 0 and 14) and were analyzed on day 56. Results At all DOX doses, the short I2 treatment induced adjuvant antineoplastic effects (decreased tumor size and proliferating cell nuclear antigen level) with significant protection against body weight loss and cardiotoxicity (creatine kinase MB, cardiac lipoperoxidation, and heart damage). With long-term I2, mammary tumor tissue became more sensitive to DOX, since a single injection of the lowest dose of DOX (4 mg/Kg) was enough to stop tumor progression and a second DOX4 injection on day 14 caused a significant and rapid decrease in tumor size, decreased the expression of chemoresistance markers (Bcl2 and survivin), and increased the expression of the apoptotic protein Bax and peroxisome proliferator-activated receptor type gamma. Conclusions The DOX-I2 combination exerts antineoplastic, chemosensitivity, and cardioprotective effects and could be a promising strategy against breast cancer progression.

Mortality for mammary cancer (MC) has decreased in the past decade, owing principally to early detection and the use of neoadjuvant chemotherapy. Of several preparations that cause regression of MC, Doxorubicin (DOX) is the most active, first-line monotherapeutic. Nevertheless, its use has been limited due to the rapid development of chemoresistance and cardiotoxicity caused by free radicals. In previous studies we have shown that supplementation with moderately high doses of molecular iodine (I2) has a powerful antineoplastic effect in methylnitrosourea (MNU)-induced MC models. These studies also showed a consistent antioxidant effect of I2 in normal and tumoral tissues. In the present study we analyzed the effect of I2 in combination with DOX treatment. Female Sprague Dawley rats with MNU-induced MC were treated with the therapeutic DOX dose (16 mg/kg) and with two lower doses (8 and 4 mg/kg) with and without 0.05% I2 in drinking water. In a first, short-term experiment, iodine treatment began 2 days before a single DOX injection (ip), and the animals were analyzed after 7 days. In a second experiment, animals received two injections (days zero and 14) of 4 mg/kg DOX without or with long-term I2 treatment throughout the 56 days of observation. The results showed that at every DOX dose, short-term I2 treatment induced synergic antineoplastic effects (decreasing tumor size and PCNA signal) with significant protection against body weight loss and cardiotoxicity (CK-MB enzyme and cardiac lipoperoxidation). With long-term I2 treatment, mammary tumors became more sensitive to 4 mg/kg DOX, decreasing chemoresistance markers (Bcl2 and survivin) and increasing peroxisome proliferator-activated receptor type gamma expression, indicating a specific interaction of I2 with these receptors. The authors thank Felipe Ortóz for his technical assistance and Leonor Casanova for academic supports. Supported in part by PAPIIT/UNAM 201210 and CONACYT 78955. Citation Format: Carmen Aceves, Yunuen Alfaro-Hernandez, Guadalupe Delgado. Iodine supplement exerts antineoplastic adjuvancy, chemoresistance inhibition and cardioprotection in mammary cancer treatment with anthracyclines. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B38.

Prostate cancer is the second most frequently diagnosed cancer in men worldwide, but incidence rates vary, being lower in Japan than in the USA. This low incidence in Japanese populations has been explained by the high intake of iodine (5280 μg/day in Japan vs 209 μg in USA), among other factors. Studies in thyroid and breast cancer have shown that iodine supplementation induces apoptosis, reduces cell proliferation, and decreases the expression of cell invasion factors (VEGF, uPa, uPAR). In both tissues, iodide (I−) uptake is mediated by the Na+/I− symporter (NIS), whereas iodine (I2) uptake depends on a facilitated diffusion mechanism. Our group showed that I− or I2 supplementation of rats with prostate hyperplasia (induced with sex hormones) decreases the DNA content and has no harmful effect on normal tissue. In human prostate cancer cells (LNCaP), I− uptake is mediated via NIS, while I2 uptake is independent from NIS. Both I− and I2 treatment activated the apoptotic pathway mediated by Bax/Bcl2, and caspases, suggesting that either form of iodine might be used as an antineoplastic agent against prostate cancer. Here, we determined the uptake of I− and I2 in normal (WT) and tumoral mouse prostate, and analyzed the effect of a mixed iodide/iodine (0.5 mg I−+ 0.25 mg I2) supplement (starting at 6 weeks of age) on the progression of prostate cancer in a transgenic model (Transgenic Adenocarcinoma of Mouse Prostate, TRAMP). The TRAMP mice developed intraepithelial neoplastic lesions (PIN) and cancer around 12 and 24 weeks of age, respectively. Iodine uptake was analyzed with radioactive tracers (125I− and 125I2), which were ip injected into WT and TRAMP mice at these two ages. The radiolabel was quantified at 120 min post-injection in a gamma counter. The results showed that normal and tumoral prostates take up both chemical forms of iodine, but only I− uptake is blocked by the classic NIS inhibitor perchlorate. These data corroborate NIS participation in I− uptake and support the notion that another transporter mediates I2 uptake. Iodine supplementation had no effect on the genitourinary tract weight, histopathological acini aspect (hematoxylin-eosina stain), or proliferative rate (immunoreactivity to proliferating cell nuclear antigen) of any groups. Currently, we are analyzing the effect of iodine on tumor apoptosis and the expression of molecular factors associated with cell invasion and metastasis (epithelial-mesenchymal transition). The authors are grateful to Felipe Ortiz and Martín García for their technical assistance. Supported by CONACYT (78955, 87196, 127368), PAPIIT (IN201210). Citation Format: Paloma Olvera, Guadalupe Delgado, Carmen Aceves, Brenda Anguiano. Uptake and potential antineoplasic effects of iodine on prostate cancer in the TRAMP model [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B40.

In spite of advances in therapeutics and screening programs, breast cancer metastasis to vital organs (brain, lungs, and bone) is the main cause of death of the patients diagnosed with this disease. The process of metastasis requires a series of steps including the expression of several molecular factors that permit the invasion, angiogenesis, and colonization of other organs. Data generated in different laboratories including ours have shown that molecular iodine (I2) exerts a potent antineoplastic effect on in vitro and in vivo cancer models. Molecular analyses of this effect in methylnitrosourea-induced mammary cancer showed that, besides activating the Bax-caspase apoptotic pathway, I2 also interfered with the metastatic potential by decreasing the expression of urokinase-type plasminogen activator (uPA) and vascular endothelial growth factor (VEGF), proteins intimately related to invasion and vascularization, respectively. To determine the role of I2 in the implantation and metastatic potential of human mammary cancer, we used xenografts of two human breast cancer cell lines with different metastatic potential (MCF-7 and MDA-MB231). Female athymic homozygotic (Foxn1 nu/nu) mice (8 weeks old) were injected subcutaneously with 5 million parental cells of each cell line in 50 µl PBS and 50 µl matrigel. Drinking water for the control group was deionized water, which was supplemented with 0.025% I2 for the iodine group. All animals were monitored for 6 weeks at weekly intervals for the development of tumors. Tumor sizes were calculated by the ellipsoid formula, proliferation rate was measured by Proliferating Cell Nuclear Antigen (PCNA) immunohistochemistry, and the metastatic potential was estimated by uPA activity (enzymatic assay). The results showed that the I2 supplement decreases the implantation capacity (incidence), tumoral growth, and cell proliferation of both cell lines, MDA-MB231 (20%; 0.18 ± 0.08 cm3; 34.8% PCNA-positive cells/field) and MCF-7 (50%; 0.5 ± 0.07 cm3; 34.3% PCNA-positive cells/field) in comparison with the control (95.1%; 2.2 ± 0.3 cm3; 42.8% PCNA-positive cells/field). In contrast, I2 decreased the metastatic potential (uPA activity) only in those tumors that had been generated from MCF-7 (32 ± 5.6 vs 52 ± 2.8 IU/mg protein control). In conclusion, our data suggest that I2 supplementation interferes primarily with the implantation and proliferation of mammary cancer cells, but it may be ineffective in decreasing the metastatic potential of those cancer cells with a more aggressive phenotype. Acknowledgements to Biol. Felipe Ortíz, Dr. Laura Vega for the technical support, and Dr. Dorothy Pless for proofreading. Study partially supported by UNAM/DGAPA IN201210 and CONACYT 78955. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4224. doi:10.1158/1538-7445.AM2011-4224

Breast cancer (BC) is the most common type of cancer worldwide in reproductive-age women. Genetic (mutations in the gene BRCA), reproductive (menarche, pregnancy, and menopause), and environmental factors (lipids, alcohol, iodine, etc.) are known to be involved in BC etiology. Previous studies have demonstrated that molecular iodine (I2) has an antineoplastic effect on mammary cancer cells in vivo as well as in vitro through activation of caspase-dependant apoptotic pathways. It has also been demonstrated that this element has a powerful antioxidant effect, even greater than that of vitamin E. These dual beneficial effects of I2 were corroborated in rats with methyl-nitrosourea-induced mammary cancers treated with anthracyclines (AC) – an antineoplastic drug that also has a free radical cardiopathic secondary effect but is commonly used in humans. In combination with AC, I2 acted as an adjuvant, decreasing tumoral size and providing significant cardioprotection. In the present study we did a clinical evaluation of the additive effect of I2 (5 mg/day) or placebo (vegetable dye) with a common antineoplastic cocktail containing AC (Fluorouracil, Epirubicyn, Cyclophosphamide, Taxotere [FEC/TE], four to six cycles) in advanced BC patients (stages III and IV). Preliminary results (N=14) show a significant antineoplastic adjuvant effect of I2 when administered together with FEC/TE, and complete remission in 33 % of the cases. This result permitted conservative surgery on 3 of the 14 patients. Molecular analysis showed that in the tumoral mass of I2-supplemented patients, there was a significant decrease of the cell proliferation rate, as tested with Proliferating Cell Nuclear Antigen, PCNA immunohistochemistry (98.6% vs 80.8%), and of cyclin D1 expression (1.2 ±0.6 vs 0.3 ± 0.06; real time PCR) when compared with the control group (FEC/TE+ placebo). We also found a significant increase in the apoptosis rate (Terminal deoxynucleotidyl transferase dUTP nick end labeling; TUNEL) in the FEC/TE + I2 group (42.2 ± 4.8 vs 73.2 ± 1.8) Significantly lower serum levels of the cardiac kinase CK-MB were found in FEC/TE +I2 patients (21.5 ± 3.8 vs 8.0 ± 2.6 UI/ml) indicating a protective effect against myocardial damage. We confirmed the iodine intake of our patients by measuring the levels of this molecule in urine samples (44 ± 4.5 vs 256 ± 13 ug/dl). In conclusion, our results show a significant dual effect of iodine with FEC/TE that lead us to propose its implementation as a novel treatment for BC that could, in the future, allow lower doses of standard chemotherapy, reducing adverse effects and cost. Acknowledgements to Biol. Felipe Ortíz and Biol. Paloma Olvera for the technical support, and Dr. Dorothy Pless for proofreading. Study partially supported by UNAM/DGAPA IN201210 and CONACYT 78955 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3509. doi:10.1158/1538-7445.AM2011-3509

Abstract #3082 Breast cancer is the most frequent malignant neoplasia in women. One factor thought to influence the incidence of breast cancer is diet. Japanese women, who have a high dietary intake of iodine (5280 vs 209 µg/day in western population) due to ingestion of seaweed, have the lowest incidence of breast cancer in the world. In normal mammary gland, iodine deficiency is involved in dysplasias, which are reversible with I2 but not with iodide administration. Recent data generated in our laboratory showed that continuous treatment with I2, but not iodide, has a potent antineoplastic effect on tumoral progression in N-methyl-N-nitrosourea-treated virgin rats (50-70%). Also I2 treatment in MCF-7 human breast cancer cells, but not in normal mammary cells (MCF-12F), shows a significant apoptotic effect induced by activation of Bax-caspases and AIF-PARP-1 pathways. Based on these findings, a study of women diagnosed with cancer (mammography and tru-cut biopsy) was initiated. Patients were divided into placebo or I2 (5 mg/day) groups for 2 to 5 weeks before surgery. One day before beginning the I2 treatment and the day of the surgery, urine and blood samples were collected. The day before surgery, a second mammography was obtained. In the tumor samples proliferation (PCNA), apoptosis (TUNEL), and vasculature area (CD-31) were analyzed by immunohistochemistry. Bax, Bcl2, p53, and VEGF proteins were analyzed by Western blot. Circulating TSH and T3 levels were measured by RIA and urinary iodide by HPLC. The results showed that although tumor size did not differ between groups, a significantly lower proliferation and increased apoptotic rate were observed in tumors from women supplemented with iodine. In these tumors the ratio Bax/Bcl2 increased, p53 levels were unchanged, and VEGF levels and vasculature area diminished significantly. Serum TSH and T3 showed no changes in any group, indicating that I2 treatment had not compromised the thyroid status. We propose that I2 supplements should be considered for use in clinical trials of breast cancer therapies. We thank Dr. Jorge Álvarez-Aguirre2,3, Dr. Alonso Gallegos-Corona2, Lic. Concepción Correa-Tinajero3, Alejandro Núñez-Nolasco2,3, and Silvia Serrato-Águila2. This work was partially supported by: PAPIIT-UNAM IN201207, and CONACyT 44976-M and 85952. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3082.