The Modified Alternate Healthy Eating Index-2010 and Breast Cancer Risk among Women from Karachi, Pakistan.

OBJECTIVE: To determine any relationship of diet with breast cancer risk. METHODS: The case-control study was conducted at Aga Khan University Hospital and the Karachi Institute of Radiation and Nuclear Medicine, Karachi, from February 2015 to July 2017, and comprised of cases with a confirmed diagnosis of breast cancer and healthy controls. Data was collected using the Alternate Healthy Eating Index 2010, which was modified according to the particular cultural patterns of diet in the Pakistani population. Data was analysed using SPSS 21. RESULTS: Of the 1124 subjects, 374(33.3%) were breast cancer cases and 750(66.7%) were controls. High intake of grains, both whole and refined including white rice, was associated with breast cancer (odds ratio: 2.53; 95% confidence interval: 1.69-3.79; p<0.001). There was no association of breast cancer with Alternate Healthy Eating Index 2010 score (odds ratio: 1.85; 95% confidence interval: 0.61-1.17; p=0.291). CONCLUSIONS: There was found a need for awareness of a healthy diet based on more of whole grains and brown rice replacement with refined grains and white rice, respectively. Limiting refined carbohydrate intake might be a useful public health message and may reduce breast cancer incidence in the long term.

Frequency and determinants of vitamin D deficiency among premenopausal and postmenopausal women in Karachi Pakistan.

BACKGROUND: Vitamin D deficiency is becoming a serious public health problem, even in sun-drenched cities like Karachi, Pakistan. We investigated the prevalence of vitamin D deficiency and its association with sociodemographic characteristics, anthropometric measures, and lifestyle factors among premenopausal and postmenopausal women (n = 784). METHODS: Face-to-face interviews were conducted to collect information and serum concentrations of 25-hydroxyvitamin D were measured after the interviews. RESULTS: A total of 57% of women were vitamin D deficient with higher vitamin D deficiency found among premenopausal women (64.7%) compared to postmenopausal women (49%). The median serum concentrations of 25-hydroxyvitamin D (IQR) were 16.7 ng/ml (IQR 9.8-30.0). Factors associated with vitamin D deficiency were lower socioeconomic status (OR 2.00; 95% CI 1.15-3.48), younger age with highest vitamin D deficiency found in < 35 years of age group (OR 3.11; 95% CI 1.76-5.51), and winter season (OR 1.51, 95% CI 1.07-2.15) after adjusting for multiple confounders. The use of vitamin D supplement (OR 0.59, 95% CI 0.38-0.92) and vigorous exercise (OR 0.20, 95% CI 0.05-0.80) were protective against vitamin D deficiency. CONCLUSIONS: The study shows a high prevalence of vitamin D deficiency, with detrimental health effects, among younger women belonging to lower socioeconomic status and during the winter season. The use of vitamin D supplements and vigorous exercise were protective measures. Public health campaigns are needed for education and awareness about vitamin D deficiency to improve vitamin D status for younger women living in poor environments.

Factors associated with mammographic breast density among women in Karachi Pakistan.

BACKGROUND: There are no studies done to evaluate the distribution of mammographic breast density and factors associated with it among Pakistani women. METHODS: Participants included 477 women, who had received either diagnostic or screening mammography at two hospitals in Karachi Pakistan. Mammographic breast density was assessed using the Breast Imaging Reporting and Data System. In person interviews were conducted using a detailed questionnaire, to assess risk factors of interest, and venous blood was collected to measure serum vitamin D level at the end of the interview. To determine the association of potential factors with mammographic breast density, multivariable polytomous logistic regression was used. RESULTS: High-density mammographic breast density (heterogeneously and dense categories) was high and found in 62.4% of women. There was a significant association of both heterogeneously dense and dense breasts with women of a younger age group < 45 years (OR 2.68, 95% CI 1.60-4.49) and (OR 4.83, 95% CI 2.54-9.16) respectively. Women with heterogeneously dense and dense breasts versus fatty and fibroglandular breasts had a higher history of benign breast disease (OR 1.90, 95% CI 1.14-3.17) and (OR 3.61, 95% CI 1.90-6.86) respectively. There was an inverse relationship between breast density and body mass index. Women with dense breasts and heterogeneously dense breasts had lower body mass index (OR 0.94 95% CI 0.90-0.99) and (OR 0.81, 95% CI 0.76-0.87) respectively. There was no association of mammographic breast density with serum vitamin D levels, diet, and breast cancer. CONCLUSIONS: The findings of a positive association of higher mammographic density with younger age and benign breast disease and a negative association between body mass index and breast density are important findings that need to be considered in developing screening guidelines for the Pakistani population.

Patient Delay in Breast Cancer Diagnosis in Two Hospitals in Karachi, Pakistan: Preventive and Life-Saving Measures Needed.

PURPOSE: Patients with breast cancer in Pakistan commonly present with advanced disease. The objectives of this study were to evaluate the frequency and length of delays in seeking medical consultation and to assess the factors associated with them. METHODS: Four hundred ninety-nine patients with newly diagnosed breast cancer were enrolled and interviewed over the period from February 2015 to August 2017. Information on sociodemographic factors, delay to medical consultation, stage of breast cancer at presentation, and tumor characteristics of the breast cancer were collected through face-to-face interviews and medical file review. RESULTS: The mean (standard deviation) age of patients with breast cancer was 48.0 (12.3) years. The mean (standard deviation) patient delay was 15.7 (25.9) months, with 55.2% of women detecting a breast lump but not seeking a medical consultation because of a lack of awareness about the significance of the lump. A total of 9.4% of the women decided to seek treatment initially using complementary and alternative medicine and traditional treatment; 9.4% of the women presented to a health care provider with a breast lump but no action was taken, and they were wrongly reassured about the lump without mammography or biopsy. For 26% of the women, the delay in presentation was caused by anxiety, fears and misconceptions regarding diagnosis and treatment, and other social factors including possible adverse effects on their relationship with their husband. Multivariable analysis showed a strong association of lower socioeconomic status (odds ratio [OR], 8.11 [95% CI, 2.46 to 26.69]) and late stage of breast cancer (OR, 4.83 [95% CI, 1.74 to 13.39]) with a patient delay of ≥ 3 months. CONCLUSION: Patient delay is a serious problem in Pakistan. There is an urgent need for intensive and comprehensive breast cancer education that addresses the myths and misconceptions related to breast cancer.

Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer.

In vitro studies have suggested proteasome inhibitors could be effective in triple-negative breast cancer (TNBC). We found that bortezomib and carfilzomib induce proteotoxic stress and apoptosis via the unfolded protein response (UPR) in TNBC cell lines, with sensitivity correlated with expression of immuno-(PSMB8/9/10) but not constitutive-(PSMB5/6/7) proteasome subunits. Equally, the transcriptomes of i-proteasome-high human TNBCs are enriched with UPR gene sets, and the genomic copy number landscape reflects positive selection pressure favoring i-proteasome activity, but in the setting of adjuvant treatment, this is actually associated with favorable prognosis. Tumor expression of PSMB8 protein (ß5i) is associated with levels of MHC-I, interferon-γ-inducible proteasome activator PA28ß, and the densities of stromal antigen-presenting cells and lymphocytes (TILs). Crucially, TILs were protective among TNBCs that maintain high ß5i but did not stratify survival amongst ß5i-low TNBCs. Moreover, ß5i expression was lower in brain metastases than in patient-matched primary breast tumors (n = 34; P = 0.007), suggesting that suppression contributes to immune evasion and metastatic progression. Hence, inhibiting proteasome activity could be counterproductive in the adjuvant treatment setting because it potentiates anti-TNBC immunity.

A multicenter case control study of association of vitamin D with breast cancer among women in Karachi, Pakistan.

BACKGROUND: The prevalence of vitamin D inadequacy and breast cancer are both high among women living in Karachi, Pakistan. METHODS: A matched case control study was conducted in two hospitals of Karachi, Pakistan to evaluate the association of vitamin D (serum 25-hydroxyvitamin D) concentrations, vitamin D supplementation and sun exposure with breast cancer among Pakistani women. A total of 411 newly diagnosed histologically confirmed primary breast cancer cases were enrolled and 784 controls, free of breast and any other cancers, were matched by age (year of birth ± 5 years), residence in the same geographic area and study site. Information was collected on sociodemographic history, history of vitamin D supplementation, past medical and obstetrical history, family history of breast cancer, sun exposure history, histopathology reports and anthropometric measurement and venous blood was collected to measure serum 25-hydroxyvitamin D (25(OH)D) concentration. RESULTS: Compared to patients with sufficient serum vitamin D (>30 ng/ml), women with serum vitamin D deficiency (<20ng/ml), had a higher risk of breast cancer (OR = 1.65, 95%CI: 1.10, 2.50). Women with history of vitamin D supplementation one year prior to enrollment, had significant protective effect against breast cancer (OR = 0.32, 95% CI: 0.24, 0.43). CONCLUSIONS AND RECOMMENDATION: Serum vitamin D deficiency was associated with increased risk of breast cancer, while vitamin D supplementation was associated with decreased risk of breast cancer. In Pakistani women, where vitamin D deficiency is common, raising and maintaining serum vitamin D at population level is a safe and affordable strategy. It may play a role in reducing the incidence of both vitamin D deficiency and breast cancer, particularly among poor women where the breast cancer mortality is highest due to limited resources for early detection, diagnosis, and treatment. The effects of vitamin D with regard to breast cancer risk in Karachi Pakistan should be further evaluated.

Pediatric Neurology Workforce in Canada: A 5-Year Update.

BACKGROUND: In 2013, a task force was developed to discuss the future of the Canadian pediatric neurology workforce. The consensus was that there was no indication to reduce the number of training positions, but that the issue required continued surveillance. The current study provides a 5-year update on Canadian pediatric neurology workforce data. METHODS: Names, practice types, number of weekly outpatient clinics, and dates of certification of all physicians currently practicing pediatric neurology in Canada were obtained. International data were used to compute comparisons between countries. National data sets were used to provide information about the number of residency positions available and the number of Canadian graduates per year. Models for future projections were developed based on published projected population data and trends from the past decade. RESULTS: The number of pediatric neurologists practicing in Canada has increased 165% since 1994. During this period, wait times have not significantly shortened. There are regional discrepancies in access to child neurologists. The Canadian pediatric neurology workforce available to see outpatient consultations is proportionally less than that of USA. After accounting for retirements and emigrations, the number of child neurologists being added to the workforce each year is 4.9. This will result in an expected 10-year increase in Canadian pediatric neurologists from 151 to 200. CONCLUSIONS: Despite an increase in the number of Canadian child neurologists over the last two decades, we do not predict that there will be problems with underemployment over the next decade.

Les effectifs en neurologie pédiatrique au Canada : une mise à jour tenant compte des cinq dernières années.Contexte:En 2013, un comité de réflexion a été mis sur pied afin de discuter de l'avenir des effectifs canadiens en neurologie pédiatrique. Un consensus s'est alors dessiné : bien que rien n'indique qu'il faille réduire le nombre de places disponibles dans ce domaine de formation, cette question nécessite toutefois un suivi continu. La présente étude vise ainsi à offrir une mise à jour des données qui concernent ces effectifs en tenant compte des cinq dernières années.Méthodes:Les données suivantes ont été obtenues : noms des praticiens, types de pratique, nombre de consultations hebdomadaires en clinique externe et dates de certification de tous les médecins pratiquant actuellement la neurologie pédiatrique au Canada. Des données internationales ont également été utilisées pour effectuer des comparaisons entre divers pays. Des données au niveau national ont été rassemblées pour établir le nombre de places disponibles en résidence et le nombre de diplômés canadiens par année. Des modèles de projection ont aussi été élaborés en se fondant sur des projections de population déjà publiées et sur les tendances ayant marqué la décennie précédente.Résultats:Le nombre de neurologues pédiatriques qui pratiquent au Canada a augmenté de 165 % depuis 1994. Fait à noter, les temps d'attente n'ont pas été notablement raccourcis durant cette période. Il existe aussi des disparités régionales en matière d'accès à cette spécialité de la neurologie. Les effectifs canadiens en neurologie pédiatrique disponibles pour des consultations en clinique externe demeurent proportionnellement moins importants qu'aux États-Unis. Après avoir tenu compte des départs à la retraite et des apports de l'extérieur, le nombre de neurologues pédiatriques ajoutés chaque année a été en moyenne de 4,9. Pendant une période de 10 ans, on anticipe donc qu'on devrait passer de 151 à 200 neurologues pédiatriques canadiens.Conclusions:En dépit d'une hausse du nombre de neurologues pédiatriques canadiens au cours des deux dernières décennies, nous ne prédisons pas de problèmes de sous-emploi au cours de la prochaine décennie.

Mammary-specific ablation of Cyp24a1 inhibits development, reduces proliferation and increases sensitivity to vitamin D.

Active vitamin D (1,25(OH)2D) has been shown to regulate numerous cell processes in mammary cells. Degradation of 1,25(OH)2D is initiated by the mitochondrial enzyme, 25-hydroxyvitamin D 24-hydroxylase (CYP24 A1), and provides local control of 1,25(OH)2D bioactivity. Several reports of the association between elevated CYP24 A1 activity and breast cancer incidence, suggest that CYP24 A1 may be a target for therapeutic intervention. Whether CYP24 A1 activity within the mammary epithelium regulates 1,25(OH)2D levels and mammary gland development is yet to shown. We have used a conditional knockout of the Cyp24a1 gene specifically in the mammary epithelium to demonstrate reduced terminal end bud number, ductal outgrowth and branching during puberty and alveologenesis at early pregnancy, by inhibiting proliferation but not apoptosis in both basal and luminal MECs. In vitro study showed increased sensitivity of luminal MECs to lower levels of 1,25(OH)2D with the ablation of Cyp24a1 activity. In summary, Cyp24a1 within MECs plays an important role in modulating postnatal and pregnancy-associated mammary gland development which provides support for inhibiting CYP24 A1 as a potential approach to activating the vitamin D pathway in breast cancer prevention and therapy.

BAFopathies' DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes.

Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across a wide range of neurodevelopmental conditions including other chromatin remodeling and epigenetic machinery disorders. We demonstrate that a machine-learning model trained on this DNA methylation profile can resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects through targeted population screening.

Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response.

Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, the second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches that specifically target the drivers of Ewing sarcoma oncogenesis. As KDM1A/lysine-specific demethylase 1 (LSD1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival (P = 0.033), this study has examined biomarkers of sensitivity and mechanisms of cytotoxicity to targeted KDM1A inhibition using SP-2509 (reversible KDM1A inhibitor). We report, that innate resistance to SP-2509 was not observed in our Ewing sarcoma cell line cohort (n = 17; IC50 range, 81 -1,593 nmol/L), in contrast resistance to the next-generation KDM1A irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (IC50 > 300 µmol/L). Although TP53/STAG2/CDKN2A status and basal KDM1A mRNA and protein levels did not correlate with SP-2509 response, induction of KDM1B following SP-2509 treatment was strongly associated with SP-2509 hypersensitivity. We show that the transcriptional profile driven by SP-2509 strongly mirrors KDM1A genetic depletion. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts robust apoptosis through engagement of the endoplasmic reticulum stress pathway. In addition, ETS1/HIST1H2BM were specifically induced/repressed, respectively following SP-2509 treatment only in our hypersensitive cell lines. Together, our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict KDM1A inhibitor sensitivity in Ewing sarcoma. Mol Cancer Ther; 17(9); 1902-16. ©2018 AACR.

Breast cancer in women with neurofibromatosis type 1 (NF1): a comprehensive case series with molecular insights into its aggressive phenotype.

PURPOSE: The purpose of the study was to improve the understanding of NF1-associated breast cancer, given the increased risk of breast cancer in this tumour predisposition syndrome and the limited data. METHODS: We identified 18 women with NF1 and breast cancer at our institution. Clinical and pathologic characteristics of NF1-associated breast cancers were compared with 7132 breast cancers in patients without NF1 from our institutional database. Next generation sequencing was performed on DNA from blood and breast cancer specimens available. Blood specimens negative for NF1 mutation were subjected to multiplex ligation-dependent probe amplification (MLPA) to identify complete/partial deletions or duplications. Expression of neurofibromin in the NF1-associated breast cancers was evaluated using immunohistochemistry. RESULTS: There was a higher frequency of grade 3 (83.3% vs 45.4%, p = 0.005), oestrogen receptor (ER) negative (66.7% vs 26.3%, p < 0.001) and human epidermal growth factor receptor 2 (HER2)-positive (66.7% vs 23.4%, p < 0.001) tumours among NF1 patients compared to non-NF1 breast cancers. Overall survival was inferior in NF1 patients in multivariable analysis (hazard ratio 2.25, 95% CI 1.11-4.60; p = 0.025). Apart from germline NF1 mutations (11/16; 69%), somatic mutations in TP53 (8/10; 80%), second-hit NF1 (2/10; 20%), KMT2C (4/10; 40%), KMT2D (2/10; 20%), and PIK3CA (2/10; 20%) were observed. Immunohistochemical expression of neurofibromin was seen in the nuclei and/or cytoplasm of all specimens, but without any consistent pattern in the intensity or extent. CONCLUSIONS: This comprehensive series of NF1-associated breast cancers suggests that their aggressive features are related to germline NF1 mutations in cooperation with somatic mutations in TP53, KMT2C and other genes.

Vitamin D3 signaling and breast cancer: Insights from transgenic mouse models.

The biologically active form of vitamin D3 (1,25(OH)2D) regulates epithelial cell differentiation, proliferation, and apoptosis, lending weight to clinical evidence linking vitamin D3 insufficiency to breast cancer incidence and mortality. Local dysregulation of vitamin D3 metabolism has been identified in patients with breast cancer, implying that disruption of 1,25(OH)2D signaling may contribute to breast cancer development in an autocrine or paracrine manner. Mouse mammary glands express the critical enzymes responsible for 1,25(OH)2D synthesis (Cyp2r1 and Cyp27b1), degradation (Cyp24a1), as well as the vitamin D3 receptor (Vdr), and genetically modified mouse models have revealed a great deal about the role of vitamin D3 in cancer initiation and progression. Ablation of Vdr or Cyp27b1 in murine models of mammary cancer reduces the anti-tumor effects of vitamin D3, while elevation of Cyp24a1 levels increases degradation of 1,25(OH)2D, leading to diminished anti-tumor effects. This review discusses the recent transgenic mouse models of vitamin D3 metabolism and the Vdr signaling network, and how these contribute to mammary gland development, and cancer tumorigenesis and progression. Collectively, these mouse models have helped clarify mechanisms of action of vitamin D3 signaling and suggest that activation or restoration of the vitamin D3 regulated pathway is a potential approach for human breast cancer prevention.

Circulating Vitamin D and Overall Survival in Breast Cancer Patients: A Dose-Response Meta-Analysis of Cohort Studies.

Studies have shown that vitamin D could have a role in breast cancer survival; however, the evidence of the relationship between patients' vitamin D levels and their survival has been inconsistent. This meta-analysis explores possible dose-response relationships between vitamin D levels and overall survival by allowing for differences in vitamin D levels among populations of the various studies. Studies relating vitamin D (25-OH-D [25-hydroxyvitamin D]) levels in breast cancer patients with their survival were identified by searching PubMed and Embase. A pooled HR (hazard ratio) comparing the highest with the lowest category of circulating 25-OH-D levels were synthesized using the Mantel-Haenszel method under a fixed-effects model. A two-stage fixed-effects dose-response model including both linear (a log-linear dose-response regression) and nonlinear (a restricted cubic spline regression) models were used to further explore possible dose-response relationships. Six studies with a total number of 5984 patients were identified. A pooled HR comparing the highest with the lowest category of circulating 25-OH-D levels under a fixed-effects model was 0.67 (95% confidence interval = 0.56-0.79, P < .001). Utilizing a dose-response meta-analysis, the pooled HR for overall survival in breast cancer patients was 0.994 (per 1 nmol/L), Pfor linear trend < .001. At or above a 23.3 nmol/L threshold, for a 10 nmol/L, 20 nmol/L, or 25 nmol/L increment in circulating 25-OH-D levels, the risk of breast cancer overall mortality decreased by 6%, 12%, and 14%, respectively. There was no significant nonlinearity in the relationship between overall survival and circulating 25-OH-D levels. Our findings suggest that there is a highly significant linear dose-response relationship between circulating 25-OH-D levels and overall survival in patients with breast cancer. However, better designed prospective cohort studies and clinical trials are needed to further confirm these findings.

Naturally existing isoforms of miR-222 have distinct functions.

Deep-sequencing reveals extensive variation in the sequence of endogenously expressed microRNAs (termed 'isomiRs') in human cell lines and tissues, especially in relation to the 3' end. From the immunoprecipitation of the microRNA-binding protein Argonaute and the sequencing of associated small RNAs, we observe extensive 3'-isomiR variation, including for miR-222 where the majority of endogenously expressed miR-222 is extended by 1-5 nt compared to the canonical sequence. We demonstrate this 3' heterogeneity has dramatic implications for the phenotype of miR-222 transfected cells, with longer isoforms promoting apoptosis in a size (but not 3' sequence)-dependent manner. The transfection of longer miR-222 isomiRs did not induce an interferon response, but did downregulate the expression of many components of the pro-survival PI3K-AKT pathway including PIK3R3, a regulatory subunit whose knockdown phenocopied the expression of longer 222 isoforms in terms of apoptosis and the inhibition of other PI3K-AKT genes. As this work demonstrates the capacity for 3' isomiRs to mediate differential functions, we contend more attention needs to be given to 3' variance given the prevalence of this class of isomiR.

Azobenzene-containing photoswitchable proteasome inhibitors with selective activity and cellular toxicity.

A series of azobenzene-containing peptidic boronate esters was prepared and the activity of the thermally adapted states (TAS), enriched in trans isomer, and the photostationary states (PSS), enriched in cis isomer, for each compound were evaluated against ß5 and ß1 proteasome subunits. Compounds with a sterically demanding phenyl-substituted azobenzene at P2 (4c), and a less sterically demanding unsubstituted azobenzene at the N-terminus (5a), showed the greatest difference in activity between the two states. In both cases, the more active trans-enriched TAS had activity comparable to bortezomib and delanzomib. Furthermore, cis-enriched 4c inhibited tumor growth in both breast and colorectal carcinoma cell lines. Significantly, the initial trans-enriched TAS of 4c was not cytotoxic against the non-malignant MCF-10A cells.

MiR-766 induces p53 accumulation and G2/M arrest by directly targeting MDM4.

p53, a transcription factor that participates in multiple cellular functions, is considered the most important tumor suppressor. Previous evidence suggests that post-transcriptional deregulation of p53 by microRNAs contributes to tumorigenesis, tumor progression and therapeutic resistance. In the present study, we found that the microRNA miR-766 was aberrantly expressed in breast cancer, and that over-expression of miR-766 caused accumulation of wild-type p53 protein in multiple cancer cell lines. Supporting its role in the p53 signalling pathway, miR-766 decreased cell proliferation and colony formation in several cancer cell lines, and cell cycle analyses revealed that miR-766 causes G2 arrest. At a mechanistic level, we demonstrate that miR-766 enhances p53 signalling by directly targeting MDM4, an oncogene and negative regulator of p53. Analysis of clinical genomic data from multiple cancer types supports the relevance of miR-766 in p53 signalling. Collectively, our study demonstrates that miR-766 can function as a novel tumor suppressor by enhancing p53 signalling.

Cancer Detection in Human Tissue Samples Using a Fiber-Tip pH Probe.

Intraoperative detection of tumorous tissue is an important unresolved issue for cancer surgery. Difficulty in differentiating between tissue types commonly results in the requirement for additional surgeries to excise unremoved cancer tissue or alternatively in the removal of excess amounts of healthy tissue. Although pathologic methods exist to determine tissue type during surgery, these methods can compromise postoperative pathology, have a lag of minutes to hours before the surgeon receives the results of the tissue analysis, and are restricted to excised tissue. In this work, we report the development of an optical fiber probe that could potentially find use as an aid for margin detection during surgery. A fluorophore-doped polymer coating is deposited on the tip of an optical fiber, which can then be used to record the pH by monitoring the emission spectra from this dye. By measuring the tissue pH and comparing with the values from regular tissue, the tissue type can be determined quickly and accurately. The use of a novel lift-and-measure technique allows for these measurements to be performed without influence from the inherent autofluorescence that commonly affects fluorescence-based measurements on biological samples. The probe developed here shows strong potential for use during surgery, as the probe design can be readily adapted to a low-cost portable configuration, which could find use in the operating theater. Use of this probe in surgery either on excised or in vivo tissue has the potential to improve success rates for complete removal of cancers. Cancer Res; 76(23); 6795-801. ©2016 AACR.

New Peptidomimetic Boronates for Selective Inhibition of the Chymotrypsin-like Activity of the 26S Proteasome.

Proteasome is a large proteinase complex that degrades proteins via its three catalytic activities. Among these activities, the "chymotrypsin-like" activity has emerged as the focus of drug discovery in cancer therapy. Here, we report new peptidomimetic boronates that are highly specific for the chymotrypsin-like catalytic activity of the proteasome. These new specific proteasome inhibitors were demonstrated to have higher in vitro potency and selective cytotoxicity for cancer cells compared to benchmark proteasome inhibitors: bortezomib and carfilzomib. In breast cancer cell lines, treatment with 1a or 2a induced accumulation of the high molecular weight polyubiqutinated proteins at similar levels observed for bortezomib and carfilzomib, indicating that cancer cell death caused by 1a/2a is chiefly due to proteasome inhibition.

PRIMA-1MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells.

There is an intensive need for the development of novel drugs for the treatment of epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy due to the high recurrence rate. TP53 mutation is a common event in EOC, particularly in high-grade serous ovarian cancer, where it occurs in more than 90% of cases. Recently, PRIMA-1 and PRIMA­1MET (p53 reactivation and induction of massive apoptosis and its methylated form) were shown to have an antitumor effect on several types of cancer. Despite that PRIMA-1MET is the first compound evaluated in clinical trials, the antitumor effects of PRIMA-1MET on EOC remain unclear. In this study, we investigated the therapeutic potential of PRIMA-1MET for the treatment of EOC cells. PRIMA-1MET treatment of EOC cell lines (n=13) resulted in rapid apoptosis at various concentrations (24 h IC50 2.6-20.1 µM). The apoptotic response was independent of the p53 status and chemo-sensitivity. PRIMA­1MET treatment increased intracellular reactive oxygen species (ROS), and PRIMA-1MET-induced apoptosis was rescued by an ROS scavenger. Furthermore, RNA expression analysis revealed that the mechanism of action of PRIMA­1MET may be due to inhibition of antioxidant enzymes, such as Prx3 and GPx-1. In conclusion, our results suggest that PRIMA-1MET represents a novel therapeutic strategy for the treatment of ovarian cancer irrespective of p53 status and chemo-sensitivity.

Canadian Paediatric Neurology Workforce Survey and Consensus Statement.

BACKGROUND: Little knowledge exists on the availability of academic and community paediatric neurology positions. This knowledge is crucial for making workforce decisions. Our study aimed to: 1) obtain information regarding the availability of positions for paediatric neurologists in academic centres; 2) survey paediatric neurology trainees regarding their perceptions of employment issues and career plans; 3) survey practicing community paediatric neurologists 4) convene a group of paediatric neurologists to develop consensus regarding how to address these workforce issues. METHODS: Surveys addressing workforce issues regarding paediatric neurology in Canada were sent to: 1) all paediatric neurology program directors in Canada (n=9) who then solicited information from division heads and from paediatric neurologists in surrounding areas; 2) paediatric neurology trainees in Canada (n=57) and; 3) community paediatric neurologists (n=27). A meeting was held with relevant stakeholders to develop a consensus on how to approach employment issues. RESULTS: The response rate was 100% from program directors, 57.9% from residents and 44% from community paediatric neurologists. We found that the number of projected positions in academic paediatric neurology is fewer than the number of paediatric neurologists that are being trained over the next five to ten years, despite a clinical need for paediatric neurologists. Paediatric neurology residents are concerned about job availability and desire more career counselling. CONCLUSIONS: There is a current and projected clinical demand for paediatric neurologists despite a lack of academic positions. Training programs should focus on community neurology as a viable career option.