Delay in diagnosis of breast cancer in a developing country: a single centre observational study in a tertiary care hospital in North Kerala, India

Background: Around the world breast cancer is the most common cancer in women. In India, peak incidence is between 45-50 years of age. Early diagnosis improves survival, hence reducing diagnostic delay in breast cancer will have major social and economic implications besides improving the quality of life. This observational study aims to decipher various factors influencing diagnostic delay so that early treatment can be instituted.Methods: We interviewed 212 consecutive patients who attended the twice weekly breast clinic conducted by Department of general surgery and department of radiotherapy, government medical college, Kozhikode between September 2014 and February 2015. All patients with primary breast cancer were included in the study. Exclusion criteria included recurrence, second primaries, history of partial treatment and incomplete records. Finally, we interviewed 202 patients with the help of a pretested semi-structured questionnaire.Results: In present study, the commonest age group was 40-50 years with 62.4% participants presenting with early breast cancer and 37.6% having advanced breast cancer. Most of present study subjects were educated up to high school and unemployed. Awareness about breast cancer was 74.25% but many were ignorant of its symptomatology. Practice of breast self-examination (BSE) was low at 32.1%. Side and quadrant were statistically significant factor.Conclusions: In present study religion, educational status, marital status, breast cancer awareness, practice of BSE and location of tumor were statistically significant factors influencing delay in diagnosis. There was a general lack of knowledge about the importance of self-examination in breast cancer which needs health education and need for active social propaganda in print and electronic media regarding its importance. In future institution of a screening programme will hasten diagnosis and improve survival of breast cancer patients

Arsenite binds to the RING finger domains of RNF20-RNF40 histone E3 ubiquitin ligase and inhibits DNA double-strand break repair.

Arsenic is a widespread environmental contaminant. However, the exact molecular mechanisms underlying the carcinogenic effects of arsenic remain incompletely understood. Core histones can be ubiquitinated by RING finger E3 ubiquitin ligases, among which the RNF20-RNF40 heterodimer catalyzes the ubiquitination of histone H2B at lysine 120. This ubiquitination event is important for the formation of open and biochemically accessible chromatin fiber that is conducive for DNA repair. Herein, we found that arsenite could bind directly to the RING finger domains of RNF20 and RNF40 in vitro and in cells, and treatment with arsenite resulted in substantially impaired H2B ubiquitination in multiple cell lines. Exposure to arsenite also diminished the recruitment of BRCA1 and RAD51 to laser-induced DNA double-strand break (DSB) sites, compromised DNA DSB repair in human cells, and rendered cells sensitive toward a radiomimetic agent, neocarzinostatin. Together, the results from the present study revealed, for the first time, that arsenite may exert its carcinogenic effect by targeting cysteine residues in the RING finger domains of histone E3 ubiquitin ligase, thereby altering histone epigenetic mark and compromising DNA DSB repair. Our results also suggest arsenite as a general inhibitor for RING finger E3 ubiquitin ligases

Participation Traders Separating Waste In Pasar Baru Tampan Sub District Pekanbaru City

Garbage is defined as something that is not used anymore, unused, or something that is thrown away, which is derived from human activities and does not happen by itself. The market is one of the human activities that produce large amounts of garbage every day, when the waste sorting system is not good, it will make it difficult to carry out waste management and will have an impact on health directly or indirectly. This study aims to determine the factors associated with the participation of traders in waste sorting in Tampan Sub district  Pasar Baru  Pekanbaru.This study is quantitative research with cross sectional design. This research was conducted April 2015, sample in this study is 79 merchants. Data were collected by using questionnaires and observation. Data analysis for bivariate with chi-square test with 95% confidence level with α = 0.05. The results showed that there is a relationship between education (OR = 2,60  ; CI: 1,08-3,67),  socialization  (OR = 3,10; CI: 2,58-5,99) availability of trash waste (OR = 8,25 ; CI: 2,98-7,55 with waste sorting participation

Structural polymorphism within a regulatory element of the human KRAS promoter: formation of G4-DNA recognized by nuclear proteins

The human KRAS proto-oncogene contains a critical nuclease hypersensitive element (NHE) upstream of the major transcription initiation site. In this article, we demonstrate by primer-extension experiments, PAGE, chemical footprinting, CD, UV and FRET experiments that the G-rich strand of NHE (32R) folds into intra-molecular G-quadruplex structures. Fluorescence data show that 32R in 100 mM KCl melts with a biphasic profile, showing the formation of two distinct G-quadruplexes with Tm of ∼55°C (Q1) and ∼72°C (Q2). DMS-footprinting and CD suggest that Q1 can be a parallel and Q2 a mixed parallel/antiparallel G-quadruplex. When dsNHE (32R hybridized to its complementary) is incubated with a nuclear extract from Panc-1 cells, three DNA–protein complexes are observed by EMSA. The complex of slower mobility is competed by quadruplex 32R, but not by mutant oligonucleotides, which cannot form a quadruplex structure. Using paramagnetic beads coupled with 32R, we pulled down from the Panc-1 extract proteins with affinity for quadruplex 32R. One of these is the heterogeneous nuclear ribonucleoprotein A1, which was previously reported to unfold quadruplex DNA. Our study suggests a role of quadruplex DNA in KRAS transcription and provides the basis for the rationale design of molecular strategies to inhibit the expression of KRAS

Purine twisted-intercalating nucleic acids: a new class of anti-gene molecules resistant to potassium-induced aggregation

Sequence-specific targeting of genomic DNA by triplex-forming oligonucleotides (TFOs) is a promising strategy to modulate in vivo gene expression. Triplex formation involving G-rich oligonucleotides as third strand is, however, strongly inhibited by potassium-induced TFO self-association into G-quartet structures. We report here that G-rich TFOs with bulge insertions of (R)-1-O-[4-(1-pyrenylethynyl)-phenylmethyl] glycerol (called twisted intercalating nucleic acids, TINA) show a much lower tendency to aggregate in potassium than wild-type analogues do. We designed purine-motif TINA–TFOs for binding to a regulatory polypurine-polypyrimidine (pur/pyr) motif present in the promoter of the KRAS proto-oncogene. The binding of TINA–TFOs to the KRAS target has been analysed by electrophoresis mobility shift assays and DNase I footprinting experiments. We discovered that in the presence of potassium the wild-type TFOs did not bind to the KRAS target, differently from the TINA analogues, whose binding was observed up to 140 mM KCl. The designed TINA–TFOs were found to abrogate the formation of a DNA–protein complex at the pur/pyr site and to down-regulate the transcription of CAT driven by the murine KRAS promoter. Molecular modelling of the DNA/TINA–TFO triplexes are also reported. This study provides a new and promising approach to create TFOs to target in vivo the genome

Protein hnRNP A1 and its derivative Up1 unfold quadruplex DNA in the human KRAS promoter: implications for transcription

The promoter of the human KRAS proto-oncogene contains a structurally polymorphic nuclease hypersensitive element (NHE) whose purine strand forms a parallel G-quadruplex structure (called 32R). In a previous work we reported that quadruplex 32R is recognized by three nuclear proteins: PARP-1, Ku70 and hnRNP A1. In this study we describe the interaction of recombinant hnRNP A1 (A1) and its derivative Up1 with the KRAS G-quadruplex. Mobility-shift experiments show that A1/Up1 binds specifically, and also with a high affinity, to quadruplex 32R, while CD demonstrates that the proteins strongly reduce the intensity of the 260 nm-ellipticity—the hallmark for parallel G4-DNA—and unfold the G-quadruplex. Fluorescence resonance energy transfer melting experiments reveal that A1/Up1 completely abrogates the cooperative quadruplex-to-ssDNA transition that characterizes the KRAS quadruplex and facilitates the association between quadruplex 32R and its complementary polypyrimidine strand. When quadruplex 32R is stabilized by TMPyP4, A1/Up1 brings about only a partial destabilization of the G4-DNA structure. The possible role played by hnRNP A1 in the mechanism of KRAS transcription is discussed