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.

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.

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.

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.

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-() but not constitutive-() 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.

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.

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.

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.

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.

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/ysine-pecific emethylase 1 (LSD1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival ( = 0.

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.

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

The biologically active form of vitamin D (1,25(OH)D) regulates epithelial cell differentiation, proliferation, and apoptosis, lending weight to clinical evidence linking vitamin D insufficiency to breast cancer incidence and mortality. Local dysregulation of vitamin D metabolism has been identified in patients with breast cancer, implying that disruption of 1,25(OH)D 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)D synthesis (Cyp2r1 and Cyp27b1), degradation (Cyp24a1), as well as the vitamin D receptor (Vdr), and genetically modified mouse models have revealed a great deal about the role of vitamin D in cancer initiation and progression.

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.

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 β5 and β1 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.

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.

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.

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.

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.

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 PRIMA‑1MET (p53 reactivation and induction of massive apoptosis and its methylated form) were shown to have an antitumor effect on several types of cancer.

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.

Identification of vitamin D target genes in human breast cancer tissue.

Multiple epidemiological studies have shown that high vitamin D status is strongly associated with improved breast cancer survival. To determine the molecular pathways influenced by 1 alpha, 25-dihydroxyvitamin D (1,25D) in breast epithelial cells we isolated RNA from normal human breast and cancer tissues treated with 1,25D in an ex vivo explant system. RNA-Seq revealed 523 genes that were differentially expressed in breast cancer tissues in response to 1,25D treatment, and 127 genes with altered expression in normal breast tissues.

Lethal Neonatal Rigidity and Multifocal Seizure Syndrome--A Misnamed Disorder?

Objective: Lethal neonatal rigidity and multifocal seizure syndrome is a newly recognized genetic disorder associated with early onset of rigidity, multifocal epilepsy, developmental arrest, and early death. It is an autosomal recessive condition resulting from a mutation in the BRAT1 (BRCA1 [breast cancer-1]-associated ataxia telangiectasia mutated activator 1) gene. There are few cases in the literature, and all patients have died before age 2 years, most within the first 6 months of life.

Mutations in KCNT1 cause a spectrum of focal epilepsies.

Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI.

XI-006 induces potent p53-independent apoptosis in Ewing sarcoma.

There is an imperious need for the development of novel therapeutics for the treatment of Ewing sarcoma, the second most prevalent solid bone tumour observed in children and young adolescents. Recently, a 4-nitrobenzofuroxan derivative, XI-006 (NSC207895) was shown to diminish MDM4 promoter activity in breast cancer cell lines. As amplification of MDM4 is frequently observed in sarcomas, this study examined the therapeutic potential of XI-006 for the treatment of Ewing and osteosarcoma.