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PDF file - 2503K, Influence of minocycline on inducible NF-кB activation.

PDF file - 1507K, Effect of minocycline on constitutive and TNF-α-induce NF-кB activation in HUVEC and HOSE cells.

Substantial evidence supports the critical role of NF-κB in ovarian cancer. Minocycline, a tetracycline, has been shown to exhibit beneficial effects in this malignancy through regulation of a cohort of genes that overlap significantly with the NF-κB transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-κB signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-κB activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of IκBα kinase (IKK) activation, IκBα phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-β-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-β and TAK1. Further studies demonstrated that minocycline downregulated TGF-β1 expression. Enforced TGF-β1 expression induced NF-κB activity, and minocycline rescued this effect. Consistent with this finding, TGF-β1 knockdown suppressed NF-κB activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-κB activity is mediated, in part, through inhibition of TGF-β1. Furthermore, the influence of minocycline on NF-κB pathway activation was examined in female nude mice harboring intraperitoneal OVCAR-3 tumors. Both acute and chronic administration of minocycline led to suppression of p65 phosphorylation and nuclear translocation accompanied by downregulation of NF-κB activity and endogenous protein levels of its target gene products. These data reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-β—NF-κB axis in ovarian cancer.Implications: This preclinical study lends support to the notion that ovarian cancer management would benefit from administration of minocycline. Mol Cancer Res; 11(10); 1279–91. ©2013 AACR.

Objective: To determine the frequency of academic misconduct among students of medical colleges affiliated with University of Health sciences in Punjab. Study Design: Cross-sectional analytical study. Place and Duration of Study: Different public and private sector medical colleges in Punjab affiliated with University of Health Sciences, from Jan 2018 to Dec 2018. Methodology: Sample size calculated at 95% level of confidence, 1% required precision and 4.7% 6 anticipated population proportion was 1721. However, to increase the validity of study it was taken as 2000. Multistage stratified random sampling technique was used to select the study subjects. Information was collected on a self-administered questionnaire containing the common trends of academic misconducts. Data was entered and analyzed through SPSS version 22. Results: Total 2000 students were enrolled in the study with equal participation from public and private sector. Mean age of the respondents was 21.82 ± 1.82 years. Overall frequency of academic misconduct was high i.e. 1928 (96.4%). The most frequent academic misconduct was “asking friend to mark the proxy (84.45%)” and the least frequent reported misconduct was “using cell phone for exchange of answers (14.25%).” The difference of academic misconduct among students of public and private sector medical college students was significant (p

Background Bromelain (Brom) and Acetylcysteine (Ac) have synergistic activity resulting in dissolution of tumour-produced mucin both in vitro and in vivo. The aim of this study was to determine whether treatment of mucinous peritoneal tumour with BromAc can be performed with an acceptable safety profile and to conduct a preliminary assessment of efficacy in a clinical setting. Methods Under radiological guidance, a drain was inserted into the tumour mass or intraperitoneally. Each patient could have more than one tumour site treated. Brom 20–60 mg and Ac 1·5-2 g was administered in 5% glucose. At 24 h, the patient was assessed for symptoms including treatment-related adverse events (AEs) and the drain was aspirated. The volume of tumour removed was measured. A repeat dose via the drain was given in most patients. All patients that received at least one dose of BromAc were included in the safety and response analysis. Findings Between March 2018 and July 2019, 20 patients with mucinous tumours were treated with BromAc. Seventeen (85%) of patients had at least one treatment-emergent AE. The most frequent treatment-related AEs were CRP rise (n = 16, 80%), WCC rise (n = 11, 55%), fever (n = 7, 35%, grade I) and pain (n = 6, 30%, grade II/III). Serious treatment-related AEs accounted for 12·5% of all AEs. There were no anaphylactic reactions. There were no deaths due to treatment-related AEs. An objective response to treatment was seen in 73·2% of treated sites. Conclusion Based on these preliminary results and our preclinical data, injection of BromAc into mucinous tumours had a manageable safety profile. Considerable mucolytic activity was seen by volume of mucin extracted and radiological appearance. These results support further investigation of BromAC for patients with inoperable mucinous tumours and may provide a new and minimally invasive treatment for these patients.

Gemcitabine (GEM) is commonly chosen for treating pancreatic cancer. However, its use is limited by toxicity. Earlier in vitro studies with GEM in combination with Bromelain (Brom) and Acetylcysteine (Ac) indicated a substantial reduction in IC(50). In this study, immunocytochemistry and Western blot were used to explore the mechanistic effects of Brom and Ac (BromAc(®)) in vitro. Then, we explored the efficacy and safety of BromAc(®) only and with GEM in a pancreatic cancer model in vivo. Immunocytochemistry results revealed a reduction in both MUC1 and MUC4 post-treatment. There was a decrease in VEGF, MMP-9, NF-κβ and cleavage of PARP. There was also a decrease in the cell cycle regulators Cyclin B and D as well as TGF-β and the anti-apoptotic Bcl-2. In vivo, the low and high doses of BromAc(®) alone and with chemotherapy agents were safe. A very significant reduction in pancreatic tumour volume, weight, and ki67 were seen with BromAc(®) therapy and was equal to treatment with GEM alone and better than treatment with 5-FU. In addition, tumour density was significantly reduced by BromAc(®). In conclusion, the anticancer effect of BromAc(®) is probably related to its mucin depletion activity as well as its effect on proteins involved in cell cycle arrest, apoptosis and modulation of the tumour microenvironment. The in vivo results are encouraging and are considered the first evidence of the efficacy of BromAc(®) in pancreatic cancer. These results also provide some mechanistic leads of BromAc(®).

Background: Weaning is the key to the proper growth and development of a child. Mothers must do proper weaning practices in order to prevent malnutrition and infection in children. Objective: To determine the weaning practice among mothers with infants aged 6 months to one year of age, and causes of delayed weaning. Methodology: A cross-sectional descriptive study was carried out among the residents of the slum area of Jahangirabad, Multan, from 31st March to 25th May 2018. A close-ended questionnaire was used for collecting data from 85 mothers using a non-probability convenient sampling technique. Frequency and percentages were calculated for qualitative variables like education, occupation, socio-economic status, the start of weaning time. Data were analyzed using SPSS version 20. Results: Mothers who started weaning of their children at age of 6 months and above were 91%. Mothers who felt their milk was enough for the baby were only 37%. Mothers using marketed food for weaning were, 48 %. Illiterate mothers were, 45%. Those who were doing weaning less than 6 times per day were 98%. Families belonging to low socioeconomic status were, 61%. On applying the chi-square test there was no significant association found between the start of weaning time and mother's education (p=0.3) or occupation (p=0.3). Conclusion: A large proportion of children's population has started weaning above 6 months of age. There was no significant association found between the start of weaning time with the mother’s education and occupation.

Single-agent doxorubicin currently forms part of standard care for patients with sarcomas. However, efficacy is limited by the presence of dose-dependent cardiotoxicity and toxicity to renal, hepatic, and neurological systems. Therefore, there is a pressing need for novel drug regimens which can provide increased efficacy and safety. BromAc is a novel drug combination developed as a mucolytic agent which has demonstrated anticancer activity both in vitro and in vivo in several cancers. Here, we investigated the efficacy of BromAc in combination with doxorubicin for four subtypes of sarcoma. Cell proliferation, alongside western blot for a variety of cell cycle, apoptosis, and autophagy biomarkers assays was performed following treatment of cell lines in vitro at various concentrations of BromAc and doxorubicin. The impact of drug treatment on MUC1 and MUC4 levels was assessed through immune-cytological methods. Drug agent synergy was assessed through the Chou-Talalay framework. BromAc treatment in combination with doxorubicin was more efficacious than single-agent doxorubicin, with synergistic effects observed. The immuno-cytological analysis demonstrated significant mucin depletion following treatment with BromAc and doxorubicin used in combination, providing a potential mechanistic underpinning for the observed anticancer effects.

Doxorubicin loaded DC beads (microspheres) has been used for treating un-resectable tumours by transarterial chemoembolization (TACE). We have shown that bromelain, an enzyme from the pineapple plant, enhances the cytotoxic effect of a number of chemotherapeutic drugs and in an earlier study we have demonstrated that it can be loaded into DC beads. Therefore, in the current study we have investigated how certain physical and chemical parameters affect its loading and release for future development of DC beads in cancer therapy. Aliquots of 40-60 µL of DC beads (100-300 µm) were treated to bromelain in distilled water and various parameters such as pH of solution, bromelain concentration, temperature, loading period, presence/absence of agitation and the cytotoxic effect of bromelain loaded beads were investigated. Further release kinetics was also studied with additional investigation of pH effect on the proteolytic activity of bromelain. Results indicate that higher loading of bromelin was achieved in the beads at lower pH, higher concentration of bromelain, with agitation, 24 hours loading and ambient room temperature. Proteolytic activity of bromelain was maximal at pH 4.5 whilst cytotoxicity was at par if not better in the bromelain loaded DC beads. Release kinetics indicated that bromelain can be delivered over several hours. Hence, we conclude that bromelain can be loaded more efficiently with manipulation of certain parameters with noticeable cytotoxicity in tumour cells.

ObjectiveGemcitabine (GEM) is commonly chosen for treating pancreatic cancer. However, its use is limited by toxicity. Earlier in vitro studies with GEM in combination with Bromelain (Brom) and Acetylcysteine (Ac) indicated a substantial reduction in IC50. Here, we investigated the efficacy and safety of Brom and Ac (BromAc) in the pancreatic cancer model in vivo.DesignBoth low dose and high dose studies for safety and efficacy of BromAc and GEM were conducted in nude mice. Body weight, wellbeing and tumor volume were monitored. At autopsy, tumor weight, tumor density, percentage of tumor necrosis, expression of Ki67 antigen, and immunohistological evaluation of vital organs were compared between the treatment groups.ResultsThe low and high doses of BromAc alone and with chemotherapy agents were safe. A very significant reduction in pancreatic tumor volume, weight, and ki67 were seen with BromAc therapy and was equal to treatment with GEM alone and better than treatment with 5-FU. In addition, tumor density was significantly reduced by BromAc.ConclusionThese encouraging results are the first in vivo evidence of the efficacy of BromAc in pancreatic cancer and provide some mechanistic leads.

In women, epithelial ovarian cancer is the leading cause of gynaecological malignancy-related deaths. Development of resistance to standard platinum and taxane based chemotherapy and recurrence of the disease necessitate development of novel drugs to halt disease progression. An established concept is to target molecular and signaling pathways that substantially contribute to development of drug resistance and disease progression. We have previously shown that, monepantel (MPL) a novel small molecule acetonitrile derivative is highly effective in suppressing growth, proliferation and colony formation of ovarian cancer cells. These effects are achieved through inhibition of the mTOR/p70S6K pathway in cancer cells. The present study was conducted to find in vivo corroboration and explore the effect of MPL om other growth stimulating putative signaling pathways. Here, female nude mice with subcutaneous OVCAR-3 xenografts were treated with 25 and 50 mg/kg doses of MPL administered (IP) three times weekly for 2 weeks. At the doses employed, MPL was modestly effective at suppressing tumor growth, but highly effective in inhibiting, mTOR, P70S6K and 4EBP1. There were also modest reductions in tumor cyclin D1 and retinoblastoma protein expression. Furthermore, it was found that MPL treatment causes down-regulation of IGF-1R, and c-MYC thus unveiling new dimensions to the growing antitumor actions of this potential anticancer drug. MPL treatment led to reduced tumor volume and weights without causing any detectable side effects. Coupled with the recent human safety data published on this molecule, expanded future trials are highly anticipated.

The combinations of Bromelain and Acetylcysteine (BromAc(®)) with cytotoxics such as Gemcitabine, 5-Fluorouracil or Oxaliplatin have shown a dramatic reduction in IC50 values in a variety of cancers, including colon cancer, suggesting the possibility of effective treatment without undesired side effects. In the current study, we investigated whether a similar effect is present in vivo using the colorectal cell line LS174T. Animals after acclimatization were randomized and allocated equally in the groups for the different studies (safety, dose-escalation, and efficacy). Drugs were delivered by the intraperitoneal route and animals were monitored for wellbeing. Separately, an efficacy study was conducted with intraperitoneal drug delivery after intraperitoneal tumor induction. At the termination of the experiment, tumors and other tissues were collected for evaluation. BromAc(®) was safe when delivered intraperitoneally in a rat model at the concentrations used. Subsequent investigations of these adjuvants in combination with Gemcitabine, Oxaliplatin, and 5-Fluorouracil in mice were also proven to be safe. Preliminary efficacy studies with Oxaliplatin and 5-Fluorouracil on tumor growth (LS174T) were negative. Gemcitabine was assessed with BromAc(®) showing an almost 71% tumor inhibition compared to controls. This in vivo study indicates that Gemcitabine at 2 mg/kg in combination with BromAc(®) 3 mg/300 mg/Kg was effective and safe, supporting its potential for future clinical application.

Bromelain consisting of a number of proteolytic enzymes possess anticancer and thrombotic properties. Hence, four chromatically separated fractions were examined for their proteolytic, anticancer and antithrombotic activity. Bromelain fractions were separated using ion-exchange column chromatography. Proteolytic properties were assessed using standard azocasein assay. Anticancer properties were first assessed using four different cell lines PANC-1, HEP 2B, HEP 3G and OVCAR-3 on cells grown in 96 well plates. Subsequently, fraction 2 and fraction 3 combined with gemcitabine were tested in ASPC-1 cells. Then cytotoxicity of fraction 3 was compared to bromelain in combination with doxorubicin and N-acetylcysteine on HEP G2 and HEP 3B cells. Finally, the anticoagulation effect of fraction 3 or bromelain combined with N-acetylcysteine was evaluated using human blood. Fraction 3 showed the highest proteolytic activity (5% greater than standard bromelain) whilst others were less active. Cytotoxicity as assessed by IC50 indicated fraction 3 to be the most potent whilst the others did not follow their proteolytic potency order. OVCAR-3 was the most sensitive amongst the cell lines. Fraction 3 showed higher potency in combination with gemcitabine in ASPC-1 cells compared to fraction 2. Similarly, fraction 3 in combination with doxorubicin showed higher toxicity when compared to bromelain. Fraction 3 or bromelain only showed thrombolytic activity in combination with N-acetylcysteine. Fraction 3 may be developed for clinical use since it showed better cytotoxicity compared to bromelain.

Background and objectivesSARS-CoV-2 infection is the cause of a worldwide pandemic, currently with limited therapeutic options. Whilst vaccines are at the forefront of the therapeutic initiative, drug repurposing remains a promising approach for SARS-CoV-2 treatment. BromAc (Bromelain & Acetylcysteine) has synergistic action against glycoproteins by the synchronous breakage of glycosidic linkages and disulfide bonds. The spike protein of SARS-CoV-2, formed of glycoprotein and disulfide bridges for stabilization, represents an attractive target as it is essential for binding to the ACE2 receptor in host cells present in nasal mucosa. We sought to determine the effect of BromAc on the Spike and Envelope proteins and its potential to reduce infectivity in host cells.DesignRecombinant Spike and Envelope proteins were treated by single agent and combination BromAc at 50 and 100 µg/20mg/mL and analyzed by electrophoresis. Ultraviolet analysis of disulfide bond reduction was performed for both Spike and Envelope proteins after treatment with Acetylcysteine. In vitro whole virus culture inactivation of pre-treated wild type and an S1/S2 Spike mutant SARS-CoV-2 with BromAc from 25 to 250 µg/20mg/mL was measured by cytopathic effect, cell lysis assay, and replication capacity by RT-PCR.ResultsRecombinant Spike and Envelope SARS-CoV-2 proteins were fragmented by BromAc at both 50 and 100 µg/20mg/mL whilst single agents had minimal effect. Spike and Envelope protein disulfide bonds were reduced by Acetylcysteine. In vitro whole virus culture of both wild type and Spike mutant SARS-CoV-2 demonstrated a concentration-dependent inactivation from BromAc treatment but not from single agents.ConclusionBromAc disintegrates SARS-CoV-2 Spike and Envelope proteins. In vitro tests on whole virus support this finding with inactivation of its replication capacity most strongly at 100 and 250 µg/20mg/mL BromAc, even in Spike mutant virus. Clinical testing through nasal administration in patients with early SARS-CoV-2 infection is imminent.Author SummaryThere is currently no suitable therapeutic treatment for early SARS-CoV-2 aimed to prevent disease progression. BromAc is under clinical development by the authors for mucinous cancers due to its ability to alter complex glycoproteins structure. The potential of BromAc on SARS-CoV-2 Spike and Envelope glycoproteins stabilized by disulfide bonds was examined and found to disintegrate recombinant Spike and Envelope proteins whilst reducing disulfide stabilizer bridges. BromAc also showed an inhibitory effect on wild-type and Spike mutant SARS-CoV-2 by inactivation of its replication capacity in vitro. Hence, BromAc may be an effective therapeutic agent for early SARS-CoV-2 infection, despite mutations, and even have potential as a prophylactic in people at high risk of infection.

Background: Dysfunctional uterine bleeding (DUB) is a common disease. About 10% of patients registered with DUB in Gynecology OPD for treatment in developing countries. There has been a change in the rhythmic cyclic menstruation that causes excessive and irregular bleeding. Lack of ovulation or oligo-ovulation leads to permanent estrogenic effects without opposing the progesterone effects. Other causes of the estrogen domain may have similar effects. The relative estrogen domain causes several changes in the uterine vascular system that causes menstrual bleeding. Objective: To determine the frequency and significance of thickened blood vessels in curettage of the endometrium in dysfunctional uterine bleeding. Materials and methods: It was a Retrospective cross-sectional pilot study conducted at Department of Gynecology and Obstetrics, Jinnah Hospital Lahore for one-year duration from January 2017 to December 2017.Hematoxylin and eosin (H&E) stained sections 30 consecutive incident cases of endometrial curettage due to dysfunctional uterine bleeding were examined by an optical microscope, with particular regard to the number of thickened blood vessels. All patients with history of endometrial curettage with dysfunctional uterine bleeding were included while curettage of uterine mucosa in patients with a specific etiology, such as endometritis, atypical hypertrophy, retained products, intrauterine devices (intrauterine device) were excluded. Results: Over 50% of patients were perimenopausal, i.e. 40-55 years of age. All endometrial procedures included thickened blood vessels. On average, there were about 8 blood vessels thickened by curettage of the endometrium. Conclusion: Estrogen-induced vascular lesions result in greater permeability, which can lead to the accumulation of various plasma proteins with increased intramural vascular thickening. These thickened veins may not contract properly, causing excessive bleeding and prolongation.

Objective: Our goal was to investigate whether asymptomatic maternal hepatitis B (HB) infection affects early membrane rupture (PROM), fetal death, preeclampsia, eclampsia, gestational hypertension, or bleeding before delivery. Materials and Methods: This study was conducted in the Department of Community Medicine and Obstetrics and Gynecology department, KEMU Lahore for one-year duration from May 2017 to April 2018. The electronic literature surveys were conducted using gray literature studies (e.g. conference papers and final reports). (Technicians) and scanned reference lists of attached studies and systematically related studies. We study statistical heterogeneity using statistical tests I2 and tau square (Tau2). Results: 18 studies included. Early membrane ruptures (PROM), fetal death, preeclampsia, eclampsia, gestational hypertension and prenatal bleeding were obtained in this study. The results showed no significant relationship between inactive HB and these complications during pregnancy. Small amounts of P and chi-square and large amounts of I2 have revealed heterogeneity, which we are trying to modify using statistical methods such as subgroup analysis in this chapter. Conclusion: Inactive HB infection did not increase the risk of adverse effects in this study. In addition, well-designed tests should be performed to confirm the results.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is the cause of a worldwide pandemic, currently with limited therapeutic options. The spike glycoprotein and envelope protein of SARS-CoV-2, containing disulfide bridges for stabilization, represent an attractive target as they are essential for binding to the ACE2 receptor in host cells present in the nasal mucosa. Bromelain and Acetylcysteine (BromAc) has synergistic action against glycoproteins by breakage of glycosidic linkages and disulfide bonds. We sought to determine the effect of BromAc on the spike and envelope proteins and its potential to reduce infectivity in host cells. Recombinant spike and envelope SARS-CoV-2 proteins were disrupted by BromAc. Spike and envelope protein disulfide bonds were reduced by Acetylcysteine. In in vitro whole virus culture of both wild-type and spike mutants, SARS-CoV-2 demonstrated a concentration-dependent inactivation from BromAc treatment but not from single agents. Clinical testing through nasal administration in patients with early SARS-CoV-2 infection is imminent.

Objective: To assess the knowledge and practice of preventive measures againstdengue fever among medical students of Quaid-e-Azasm medical college and engineeringstudents of Islamia university, Bahawalpur. Design: Cross sectional descriptive study. Period:September 2012 to December 2012. Setting: Quaid-e-Azam Medial College and Engineeringwing of Islamia University Bahawalpur. Material and method: Sample size calculated for study8 by expecting prevalence of knowledge 78% in population of 1000 in each group with 5% marginof error and at 95% confidence interval was 263; by adding 10% response error sample became290 for each population. Individuals for study were selected by simple random sampling andinterviewed by using preformed questionnaire. Obtained data was analyzed by using SPSSversion 11. For categorization of knowledge and preventive practices against dengue fever intogood, satisfactory insufficient and poor scoring was done. Results: knowledge of protectivemeasures against dengue fever was found significantly better among medical than engineeringgroup (p85%while this knowledge with regard to covering of collected water, disposal of broken bottles andtins, daily change of water in room cooler and space spray was 50% or less. However, knowledgeof biological control for mosquito breed with regard to use of snail was very poor i.e. 20% or less.As for as the practices of preventive measures were concerned both groups had no significantdifference which were very poor in all aspects except screening of rooms which was more than90%. Conclusions: There is dire need for improvement in both knowledge and practices ofpreventive measures against dengue fever among students and general population.

Objectives To evaluate the effect of minocycline on the expression of cytokines and growth factors responsible for malignant ascite formation. Methods In vitro , cells obtained from malignant ascites were pre-treated with minocycline (0–100μmol/L) and exposed briefly to hypoxia. In vivo , female nude mice bearing OVCAR-3 tumors were treated orally in drinking water with minocycline for 4weeks. Plasma, ascites, and tumors were analyzed. Results Minocycline blocked hypoxia-induced surge in interleukin-6 (IL-6), its soluble receptor (sIL-6R) and vascular endothelial growth factor (VEGF) levels in concentration-dependent manner. In mice, orally administered minocycline led to dramatic reduction in tumor weight and malignant ascite volume. IL-6, sIL6R and in particular VEGF levels were highly suppressed in plasma, ascite fluid and tumor tissue by minocycline. In addition, tumors from minocycline treated mice expressed profoundly lower levels of phosphorylated extracellular regulated kinases (p-Erk1/2) and p-Akt. Minocycline was also effective at suppressing transforming growth factor beta (TGF-β1) and increasing vascular endothelial cadherin (VE-cadherin) expression thereby providing molecular confirmation for its effects on malignant ascite formation. Conclusion Orally administered minocycline is highly effective in suppressing ovarian cancer-induced malignant ascites by targeting cytokines and growth factors essential for tumor growth and malignant ascite formation.

Objective These studies were designed to determine whether minocycline inhibits ovarian cancer growth in vitro and in vivo and the molecular mechanisms involved. Materials and methods The effect of minocycline on ovarian cancer cell proliferation, cell cycle progression and apoptosis was assessed using human ovarian cancer cell lines OVCAR-3, SKOV-3 and A2780. Then, the capacity of minocycline to inhibit growth of OVCAR-3 xenografts in female nude mice was examined. Results Minocycline inhibited cell proliferation and colony formation, down-regulated cyclins A, B and E leading to arrest of cells in the G 0 phase of the cycle and suppression of DNA synthesis. Furthermore, exposure of these cells to minocycline led to DNA laddering, activation of caspase-3 and cleavage of PARP-1. In nude mice bearing sub-cutaneous tumors, minocycline suppressed tumor proliferation index, angiogenesis and tumor growth. Conclusion These findings provide the initial basis for further evaluation of minocycline in the treatment of ovarian cancer.

Objective: To find out the prevalence and determinants of dental caries among patients attending dental OPD. Design:Descriptive Cross sectional study. Place & Duration: Dental out Patient Department, Bahawal Victoria Hospital and period was August tillNovember, 2010. Methodology: Data was collected with the help of predesigned Questionnaire. A Convenient sample of 05 eligiblerespondents was examined on daily basis till completion of sample size. Caries was assessed by using DMFT scale. Analysis of data wascarried out with the help of computer SPSS version 11. Chi square test was used to see the association between different variables,(brushing atnight, daily brushing, sugary food intake) define the variables. The level of significance was taken as p

Objective: To find-out the determinants of malnutrition in children between sixmonths to five years age in Bahawalpur. Study Design: This was an observational descriptive cross – sectional study.Setting: At Paediatric Medicine out – patient department in Bahawal Victoria Hospital, Bahawalpur.. Period: From Feb.2005 to March 2007.Subjects: Eleven hundred children with malnutrition having ages six months to five years. Mainoutcome measures. Determinants of malnutrition in children under – 5 in Bahawalpur. Results: This study consistsof 1100 sick children between the ages six months to five years brought by their parents (mother) to the PediatricMedicine out-patient department in Bahawal Victoria Hospital, Bahawalpur. Only the children with malnutrition(undernutrition) were included in the study population. Mothers of these children were interviewed and clinicalexamination of each child was carried-out to find-out the causes of malnutrition in them. According to Gome’sclassification, 39.45% of them had first degree malnutrition, 37.10%, second degree and 23.45%, third degreemalnutrition. Conclusion: The major causes of malnutrition found in our study population included: Illiteracy; food –fads; poverty; lack of breast-feeding; improper weaning; diarrhea and respiratory diseases. All these factors werestatistically significant.

Objective: To find out the relationship, if any, between womenempowerment and their fertility behaviour. Design: A cross sectional descriptive study. Place & duration of study:The study was conducted in selected area of Bahawalpur City. The data was collected from March to June 2003.Subjects & methods: A total number of 872 households were selected by systematic random selection from upper,middle and lower class. Data was collected from eligible respondent (currently married women of reproductive agegroup 15-49 year having at least one child of 3 years age) through a pre-designed questionnaire. Independent variableempowerment of women was calculated by giving score to education, occupation and autonomy at micro level.Dependent variables (fertility and use of contraception) were assessed for significance by applying chi square test.Results: 41.9% high empowered women were in the opinion that birth of a male child did not provide security (p

Hypoxia-inducible factor (HIF)-1α is the key cellular survival protein under hypoxia, and is associated with tumor progression and angiogenesis. We have recently shown the inhibitory effects of minocycline on ovarian tumor growth correlated with attenuation of vascular endothelial growth factor (VEGF) and herein report a companion laboratory study to test if these effects were the result of HIF-1α inhibition. In vitro, human ovarian carcinoma cell lines (A2780, OVCAR-3 and SKOV-3) were utilized to examine the effect of minocycline on HIF-1 and its upstream pathway components to elucidate the underlying mechanism of action of minocycline. Mice harboring OVCAR-3 xenografts were treated with minocycline to assess the in vivo efficacy of minocycline in the context of HIF-1. Minocycline negatively regulated HIF-1α protein levels in a concentration-dependent manner and induced its degradation by a mechanism that is independent of prolyl-hydroxylation. The inhibition of HIF-1α was found to be associated with up-regulation of endogenous p53, a tumor suppressor with confirmed role in HIF-1α degradation. Further studies demonstrated that the effect of minocycline was not restricted to proteasomal degradation and that it also caused down-regulation of HIF-1α translation by suppressing the AKT/mTOR/p70S6K/4E-BP1 signaling pathway. Minocycline treatment of mice bearing established ovarian tumors, led to suppression of HIF-1α accompanied by up-regulation of p53 protein levels and inactivation of AKT/mTOR/p70S6K/4E-BP1 pathway. These data reveal the therapeutic potential of minocycline in ovarian cancer as an agent that targets the pro-oncogenic factor HIF-1α through multiple mechanisms.

normally poor however, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has increased survival in some patients. Hence, new therapies are needed. MUC1 is a glycosylation dependant protein associated with tumour invasiveness, metastasis and chemo resistance. Bromelain, a cysteine proteinase, hydrolyses glycosidic bonds, whilst N-Acetyl cysteine reduces disulphide bonds in glycoprotein. Hence, we investigated the anti-tumour effect of these agents in MUC 1 expressing MPM cell lines. Materials and Methods: The cell lines were treated to various concentrations of bromelain, NAC and combinations of NAC + bromelain, NAC + bromelain + cisplatin or 5-FU. Their cell viabilities were assessed at 48 hours with sulfhordamine B assay. Finally, with western blotting, the effect of NAC and the combination of NAC + bromelain on cellular survival proteins were investigated. Results: Combination of NAC (10 mM) with bromelain (75 ug/ml) showed 97% and 88% cell proliferation inhibition in YOU and PET cells, respectively. In triple combination, the addition of cisplatin to only 5.0 mM NAC and bromelain increased cytotoxicity in YOU cells but absent at 10.0 mM NAC concentration. However, in PET cells, triple combinations with cisplatin had no effect. The addition of 5-FU in triple combinations showed an increase in cytotoxicity with 5.0 mM NAC and bromelain in YOU cells. No increase in cytotoxicity was seen with addition of 10 mM NAC. In PET cells, the addition 5-FU to 5.0 mM NAC + 50 ug/ml bromelain, enhanced cytotoxicity significantly but was absent at all other combinations. Conclusion: The combination of bromelain and NAC may be developed as anti-tumour agents for treating MPM, with a possible role in combined therapy with current chemotherapeutic agents.

The angiogenic process begins with the cell proliferation and migration into the primary vascular network, and leads to vascularization of previously avascular tissues and organs as well to growth and remodeling of the initially homogeneous capillary plexus to form a new microcirculation. Additionally, an increase in microvascular permeability is a crucial step in angiogenesis. Vascular endothelial growth factor (VEGF) plays a central role in angiogenesis. We have previously reported that albendazole suppresses VEGF levels and inhibits malignant ascites formation, suggesting a possible effect on angiogenesis. This study was therefore designed to investigate the antiangiogenic effect of albendazole in non-cancerous models of angiogenesis. In vitro, treatment of human umbilical vein endothelial cells (HUVECs) with albendazole led to inhibition of tube formation, migration, permeability and down-regulation of the VEGF type 2 receptor (VEGFR-2). In vivo albendazole profoundly inhibited hyperoxia-induced retinal angiogenesis in mice. These results provide new insights into the antiangiogenic effects of albendazole.

Background Emerging reports suggest resistance, increased tumor invasiveness and metastasis arising from treatment with drugs targeting vascular endothelial growth factor (VEGF). It is believed that increased tumoral hypoxia plays a prominent role in the development of these phenomena. Inhibition of tumoral hypoxia inducible factor (HIF-1α) is thus becoming an increasingly attractive therapeutic target in the treatment of cancer. We hypothesized that the anti-VEGF effect of albendazole (ABZ) could be mediated through inhibition of tumoral HIF-1α. Method In vitro, the effects of ABZ on HIF-1α levels in human ovarian cancer cells (OVCAR-3) were investigated using hypoxic chamber or desferrioxamine (DFO) induced-hypoxia. In vivo, the effects of ABZ (150 mg/kg, i.p., single dose) on the tumor levels of HIF-1α and VEGF protein and mRNA were investigated by western blotting, RT-PCR and real time-PCR. Results In vitro, ABZ inhibited cellular HIF-1α protein accumulation resulting from placement of cells under hypoxic chamber or exposure to DFO. In vivo, tumors excised from vehicle treated mice showed high levels of both HIF-1α and VEGF. Whereas, tumoral HIF-1α and VEGF protein levels were highly suppressed in ABZ treated mice. Tumoral VEGFmRNA (but not HIF-1αmRNA) was also found to be highly suppressed by ABZ. Conclusion These results demonstrate for the first time the effects of an acute dose of ABZ in profoundly suppressing both HIF-1α and VEGF within the tumor. This dual inhibition may provide additional value in inhibiting angiogenesis and be at least partially effective in inhibiting tumoral HIF-1α surge, tumor invasiveness and metastasis.

Resistance to paclitaxel (PTX) is a major concern in treating ovarian cancer. Thus, agents effective in taxane-resistant tumours are highly sought. It has recently been shown that albendazole (ABZ) is a potent inhibitor of cell proliferation, angiogenesis and tumour growth. This study was designed to examine the efficacy of ABZ in PTX-resistant human ovarian cancer 1A9PTX22 cells.Using both the parent PTX-sensitive 1A9 and PTX-resistant sub-line 1A9PTX22 cells, the effects of both drugs on cell proliferation, tubulin polymerisation and microtubule distribution across the cell was investigated.Comparison of the inhibitory concentration to achieve 50% cell death (IC(50)) revealed that, unlike PTX, ABZ is highly efficacious in inhibiting proliferation of 1A9PTX22 cells. The finding that ABZ but not PTX is highly effective in disrupting tubulin polymerisation in these cells confirmed involvement of the tubulin pathway.Data from this study suggest that ABZ is effective in suppressing growth of PTX-resistant ovarian tumour cells.

Vascular endothelial growth factor (VEGF) is the key molecule mediating tumor growth and malignant ascites formation. We recently reported that, in an end stage OVCAR-3 xenograft model, albendazole (ABZ) suppresses ascites formation, but not tumor growth. Hence, in the present study, we assessed the effect of ABZ on in vitro OVCAR-3 cell proliferation plus in vivo tumor growth, however, initiating ABZ treatment at mid stage (3 weeks post cell inoculation) rather than end stage disease. Here, ABZ treatment led to potent inhibition of cell proliferation, VEGF suppression, complete inhibition of ascites formation and most strikingly arrest of tumor growth.

Purpose: To determine if albendazole (ABZ) interferes with the tumoral production of HIF-1α and VEGF proteins. Procedures: Human ovarian cancer OVCAR-3 cells were exposed to hypoxic conditions and the affect of ABZ on HIF-1α and VEGF expression was determined. In vivo, female nude mice bearing intraperitoneal tumors were treated with an acute dose of ABZ (150 mg/kg, i.p.), and then euthanased at various time points (1, 6, 24, 48 and 72 h). Excised tumors were analysed for HIF-1α and VEGF expression. Results: ABZ blocked the hypoxia-induced surge in HIF-1α protein. In mice, tumoral expression of HIF-1α and VEGF proteins were highly suppressed by ABZ in a reversible time-dependent manner. In drug treated mice, tumor VEGFmRNA levels were also profoundly suppressed. Conclusion: The results show that the anti-VEGF effect is mediated through the inhibition of HIF-1α. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 383.