EVI1 upregulates PTGS1 (COX1) and decreases the action of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia cells.

Tyrosine kinase inhibitors (TKIs) are highly effective in treating chronic myelogenous leukemia (CML). However, primary and acquired drug resistance to TKIs have been reported. In this study, we used RNA sequencing followed by RQ-PCR to show that the proto-oncogene EVI1 targets the drug-metabolizing gene PTGS1 in CML. The PTGS1 promoter element had an EVI1 binding site, and CHIP assay confirmed its presence. Data from a publicly available CML microarray dataset and an independent set of CML samples showed a significant positive correlation between EVI1 and PTGS1 expression in CML. Downregulation of EVI1 in K562 cells and subsequent treatment with TKIs resulted in a lower IC50 in the control cells. Furthermore, combined inhibition of BCR-ABL with imatinib and PTGS1 with FR122047 (PTGS1 inhibitor) synergistically reduced the viability of imatinib-resistant K562 cells. We conclude that elevated EVI1 expression contributes to TKIs resistance and that combined inhibition of PTGS1 and BCR-ABL may represent a novel therapeutic approach.

Exploring Challenges of Access to Non-Communicable Disease (NCD) Prevention, Treatment and Care: A Qualitative Study on People Living with NCDs (PLWNCDs) in West Bengal, India.

BACKGROUND: People living with noncommunicable diseases (PLWNCDs) are often disproportionately affected due to adverse interaction with socioecological and biological factors. Hence, it is imperative to learn from their lived experience to gain a greater understanding of interactions as well as explore their priorities and needs in accessing care and identify areas of priority action through multistakeholder engagement. MATERIALS AND METHODS: The qualitative study with grounded theory approach was conducted between October and December 2020. An online key-informant interview with the health policymaker, virtual group discussion with eight PLWNCDs, and in-depth telephonic interviews with five PLWNCDs were conducted, after obtaining informed consent using interview guide, developed, and validated by the experts. Data collection continued till data saturation was achieved. Transcripts generated from the interview recordings were coded using hand-code technique and analyzed thematically. RESULTS: Challenges faced by PLWNCDs in accessing care were lack of empathy and support from health-care professionals, stigma, financial hardship, and hospital overcrowding. Caregivers emphasized on the felt need to involve civil society organizations (CSOs) in raising awareness toward noncommunicable diseases (NCDs) at family, community, and policymaking levels. The need for home-based NCD care and rehabilitation centers was voiced by the PLWNCDs. Impediments toward effective implementation of NCD policies were adoption of a "top-down" approach, poor awareness about government health insurance schemes, skewed distribution of empanelled hospitals in and around cities, nonavailability of qualified health-care professionals in underserved areas, aggravated allocation-utilization disparity during COVID-19 pandemic, and lack of robust information technology infrastructure to support access to telemedicine services. CONCLUSION: The collective role of governments, CSOs, and health-care providers, along with meaningful involvement of PLWNCDs, would help to create an enabling environment for overcoming the challenges of access to care and thus achieve universal health coverage.

Awareness, perceptions, and choices of physicians pertaining to human papillomavirus (HPV) vaccination in India: A formative research study.

Introduction: India accounts for one-fifth of the global burden of cervical cancer cases and mortality. A safe and effective vaccine to prevent human papillomavirus (HPV) infections, the primary cause of cervical malignancies, is available in India but multiple barriers lead to its low uptake in the country. Physicians are a key stakeholder and communicator in the Indian health system and have the potential to increase HPV vaccine uptake. Objective: We undertook formative research to understand awareness, perceptions and choices of physicians when recommending the HPV vaccine to parents of adolescent girls. Methods: We conducted in-depth interviews with 32 physicians in two districts of West Bengal. Data collection was carried out between July and August 2019. The data was transcribed, coded, and analyzed using NVivo software using the thematic analysis technique. Results: Our findings suggest that while physicians are generally aware about the burden of cervical cancer and its prevention by HPV vaccination, they face several barriers to recommending the HPV vaccine routinely and strongly. These include the lack of national-level guidance on the age eligibility and dosage, lack of practice-level opportunities such as well or non-sick visits and other routine adolescent vaccines, practice-level barriers like out-of-pocket cost and vaccine availability, and perceived parental hesitancy arising from reluctance to discuss cervical cancer, its prevention, and HPV vaccination. Conclusions: Physicians in our study exhibited hesitancy when recommending the HPV vaccine. They also faced logistical barriers. It is important that the barriers pertaining to when and how physicians recommend the vaccine be tackled through further education, policy change, and development and implementation of interventions that are evidenced-based.

Influence of fruit-based beverages on efficacy of Lacticaseibacillus rhamnosus GG (Lactobacillus rhamnosus GG) against DSS-induced intestinal inflammation.

Different lines of evidences from clinical, epidemiological and biochemical studies have established that optimal nutrition including probiotic and fruit phenolics can mitigate the risk and morbidity associated with some chronic diseases. The basis for this observation is the potential synergies that may exist between probiotic strains and different bioactive components of food matrices. This study was conceptualized to compare the efficiency of a probiotic strain in two different fruit matrices. Two fruits, viz., sea buckthorn (Hippophae rhamnoides) (SBT) and apples (Malus pumila) (APJ) were chosen and the anti-inflammatory effects of L. rhamnosus GG (ATCC 53103) (LR) fortified in SBT and APJ were analysed against dextran sulphate sodium (DSS) induced colitis in zebrafish (Danio rerio). The results showed that administration of probiotic (LR) fortified, malt supplemented SBT beverage (SBT + M + LR) had better restorative potential on the intestinal barrier function and mucosal damage, in comparison to LR fortified, malt supplemented APJ beverage (APJ + M + LR). SBT + M + LR demonstrated adequate anti-oxidant potential by enhancing the CAT, SOD, GPx and GSH activities, impaired due to DSS administration. The increase in the expressions of toll like receptor (TLR)-2, TLR-4 and TLR-5 induced by DSS were significantly inhibited by SBT + M + LR administration. Gene expression of pro-inflammatory markers, (NF-κB, TNF-α, IL-1ß, IL-6, IL-8, CCL20, MPO and MMP9) were attenuated by SBT + M + LR treatment in intestinal tissues of DSS-treated zebrafishes. Notably, SBT + M + LR increased the expression of anti-inflammatory cytokine, IL-10. The study provides evidence that specific interactions between fruit matrix and probiotic strain can provide adjunct therapeutic strategy to manage intestinal inflammation.

Prevalence of Tobacco Use in Young Adult Literate Girls of 18-25 Years in Meghalaya, India: A Cross-Sectional Study.

BACKGROUND: Several national-level surveys have recognized a high prevalence of tobacco use in North-eastern (NE) India. However, information on tobacco use in specific population subgroups still lacks from the region. The present study determines the prevalence and influence of determinants like education and family income on tobacco use in senior school and college-going girls in Shillong, Meghalaya. Additionally, the prevalence of dual use of smoking and smokeless (SLT) tobacco with alcohol and non-tobacco Pan Masala has been examined. METHODS: A cross-sectional study was conducted among 18-25 years girls in educational institutions in Shillong.  Data were analysed using statistical software SPSS version 22. The categorical data presented as frequency (%). Chi-square was employed to see the association between variables. RESULTS: (i) 8.10% of girls were current users of all forms of tobacco; 1.85% were smokers, 4.0% used SLT, and 2.25% were dual users of tobacco (ii) Of the 6.25% current users of SLT, 5.4% used a single smokeless tobacco product whereas 0.85% used multiple products of SLT (iii) 79.5% of tobacco smokers and 30.2% of current SLT users were dual users with alcohol (iv) 37.2% tobacco smokers and 18.5% SLT users were dual users with non-tobacco Pan Masala (v) Tobacco smoking was positively associated with educational status and family income whereas SLT use was independent of educational status and income of girls' families. CONCLUSIONS: The study shows a relatively high prevalence of tobacco use and dual tobacco use with alcohol in the study population of educated young adult girls, underscoring a public health concern. It is recommended that an education-based comprehensive awareness program be initiated for tobacco and alcohol control in Meghalaya to improve knowledge and health-seeking behaviour change in this high- risk subgroup to control increasing NCDs.

Impact of Educational Level and Family income on Breast Cancer Awareness among College-Going Girls in Shillong (Meghalaya), India.

BACKGROUND: Breast cancer (BC) is the most common cancer among women in India and shows an increasing trend. The mammography screening seems unfeasible as a public health service in India. Thus, breast self-examination (BSE), followed by clinical breast examination (CBE), is the affordable method to downstage BC. A cross-sectional study was conducted with senior school and college-going girls in Shillong (Meghalaya) to study the impact of girls' academic level and family income on breast cancer knowledge and the prevalence of BC's known risk factors in girls.  Methods: A self-administered questionnaire was employed to collect relevant information. The data were analysed using statistical software SPSS version 22. The categorical data presented as frequency (%) and the comparison made using Chi-square or Fisher exact test. RESULTS: (i) 78.2% girls knew about breast cancer, 19.2% of these were aware of BSE, and 22.9% of BSE knowing ever performed it (ii) Awareness of breast cancer and BSE, and its practice is significantly associated with their academic level and family income (iii) The consumption of alcohol beverages and physical activity of girls was positively associated with educational level and family income (iv) Body mass index (BMI) was weakly associated with family income with an insignificant relationship with academic level (v) oily food consumption related inversely with the level of education irrespective of family income (vi) there was a positive correlation between parents education and family income. CONCLUSIONS: The results show a severe lack of breast cancer knowledge in senior school and college-going girls under the survey. To spread community awareness, we suggest a public health policy-driven educational intervention through culturally relevant mass/social media on the risk factors of breast cancer and practice of BSE. It is also recommended that dedicated facilities be created for breast cancer early diagnosis in the public health system.

Adhesion and anti-inflammatory potential of Lactobacillus rhamnosus GG in a sea buckthorn based beverage matrix.

The consumption of probiotic based foods due to their health promoting effects has increased over the years. The consumption of probiotic based foods, due to their health promoting effects, has increased over the years. Due to this rising demands, the application platforms of the food industry have directed their efforts in the development of novel functional probiotic beverages. The presence of dietary phenolics and other beneficial components has made fruit-based matrices more popular for probiotic delivery. However, very few studies to date have evaluated the impact of carrier matrices on the in vivo functionality of probiotic strains with specific biomarkers and targeted towards specific disease conditions. In this study, we investigated the effect of a sea buckthorn (Hippophae rhamnoides L.) based, malt supplemented, beverage matrix (SBT + M) on the physiological characteristics of the probiotic strain L. rhamnosus GG (ATCC 53103) (LR). No significant difference in the auto-aggregation and co-aggregation rates of LR fortified in SBT + M was observed compared to LR alone. Storage conditions (4 °C for 14 days) did not affect the survival and the adhesion potential of LR to the HCT116 cell line. More importantly, this study also determined the protective effect of SBT + M on the in vivo functionality of LR in alleviating LPS induced inflammation in zebrafish (Danio rerio). The results showed that administration with SBT + M + LR significantly alleviated the LPS induced colonic damage, evidenced by the decrease in the overall histological and goblet cell scores compared to the LPS-treated group. The protective effect of SBT + M + LR was higher compared to the effects of SBT + M or LR alone. The colonic expression of pro-inflammatory cytokines (TNF-α and IL-1ß) showed a marked decline by 84.7% and 86.5% respectively. The highest expression of the anti-inflammatory cytokine IL-10 was recorded in the SBT + M + LR treated group (p < 0.001). The overall results reveal that the administration of SBT + M + LR showed the best effects in alleviating the LPS induced intestinal damage compared to the other test groups (SBT + M and LR). These protective effects could be attributed to the phenolic compounds present in the SBT matrix. Our study indicates the contributory role of the carrier matrix and merits further investigation for its use as a potential therapeutic agent for gastrointestinal inflammation.

PTBP2 exon 10 inclusion is associated with the progression of CML and it is BCR-ABL1 dependent.

Altered or aberrant expression of several splicing factors leads to the progression of different cancers. Though there are several ongoing studies underscoring the role of the splicing regulator polypyrimidine tract binding protein 2 (PTBP2) in neuronal cells, we unveil the role of PTBP2 in chronic myeloid leukemia (CML). Different RNA binding proteins (RBP's) earlier reported in chronic myeloid leukemia blast crisis (CML-BC) cases (n = 28) from Radich Oncomine leukemia dataset, were compared. We observed increased expression of MSI2 followed by PTBP2 in BC cases and increased PTBP2 expression in relapsed cases (n = 10) from the same dataset compared to other RBPs. We also observed increased PTBP2 exon 10 inclusion in KCL22, a granulocytic lineage CML cell line when compared to other CML cell lines of different lineages. As PTBP2 protein expression is associated with PTBP2 exon 10 inclusion, we observed in cell lines and in a set of progressed cases (n = 4) that increased BCR-ABL1 expression potentiates PTBP2 exon 10 inclusion and thus confers the existence of a functional protein. Inhibition of BCR-ABL1 with imatinib not only blocks the inclusion of exon 10 but also deregulates PTBP2 expression in CML cells. Knockdown of PTBP2 in KCL22 cells leads to reduced cell proliferation, increased G2/M cell cycle arrest and increased apoptosis. Taken together our study portrays PTBP2 as a new possible target for CML and progressive inclusion/exclusion of PTBP2 exon 10 might play an important role in CML progression.

Ecotropic viral integration site I regulates alpha1, 6-fucosyl transferase expression and blocks erythropoiesis in chronic myeloid leukemia.

Although BCR-ABL is the hallmark genetic abnormality of chronic myeloid leukemia (CML), secondary molecular events responsible for the evolution of the disease to blast crisis are yet to be deciphered. Taking into account the significant association of ecotropic viral integration site I (EVI1) in CML drug resistance, it is necessary to decipher the other roles played by EVI1 in CML disease progression. In this regard, we cross-hybridized three microarray datasets and deduced a set of 11 genes that seems to be regulated by EVI1 in CML. We observed a strong correlation between EVI1 and alpha1, 6-fucosyltransferase (FUT8) in the chronic phase of the disease and both of them were found to be up-regulated with the progression of the disease. Knockdown of EVI1 in a CML cell line not only down-regulated FUT8, but also rendered the cells towards erythroid differentiation. Our study shows the involvement of EVI1 and FUT8 axis in blocking erythropoiesis in CML.

Dual transcripts of BCR-ABL & different polymorphisms in chronic myeloid leukaemia patients.

BACKGROUND & OBJECTIVES: Chronic myeloid leukaemia is (CML) characterized by the presence of a hallmark chromosomal translocation, the Philadelphia chromosome. Although there are many reports available regarding the different variants of BCR-ABL in CML, we studied the co-expression of e13a2 and e14a2 transcripts and a few polymorphisms in CML patients. METHODS: Molecular genetics approach was adapted to screen for polymorphisms, mutation and translocation in BCR, ABL kinase domain and BCR-ABL breakpoint region in 73 CML patients. RESULTS: All eight patients with dual transcripts were found to harbour an exonic polymorphism (c.2700 T>C) and an intronic polymorphism (g.109366A>G) that were earlier reported to be associated with co-expression of both the transcripts. We also observed c.763G>A mutation in ABL kinase domain and two polymorphisms, c.2387 A>G and c.2736A>G in the BCR gene. INTERPRETATION & CONCLUSIONS: Though our data support the previous findings that co-expression of BCR-ABL transcripts is due to the occurrence of exonic and intronic polymorphisms in the BCR gene, it also shows that the intronic polymorphism can arise without the linked exonic polymorphism. The occurrence of ABL kinase domain mutation is less frequent in Indian population.

Sporadic Multicentric Right Atrial and Right Ventricular Myxoma Presenting as Acute Pulmonary Thromboembolism.

Multicentric cardiac myxoma is a rare syndrome; usually it is familial. We report a rare case of sporadic right atrium (RA) and right ventricle (RV) myxoma in a 26-year-old female presenting to our hospital for the evaluation of sudden onset of dyspnea and left precordial pain attributed to the embolization of degenerating tumor fragments to the pulmonary artery (PA). The exact incidence of sporadic multicentric RA and RV myxoma presenting as acute pulmonary embolism is unknown as multicentric RA and RV myxoma are very rare. Myxomas presenting as pulmonary embolism is <10%. Majority of cardiac myxomas present as exertional dyspnea, chest pain, positional syncope, fever, weight loss and other constitutional symptoms. Any young patient presenting with acute onset dyspnea with multiple cardiac masses may have tumor embolization to the PA diagnosis with transthoracic echocardiography and high-resolution computed tomography of thorax, fast-tracks patient transfer for urgent cardiac surgery to prevent further embolization.

Home Video Telemetry vs inpatient telemetry: A comparative study looking at video quality.

OBJECTIVE: To compare the quality of home video recording with inpatient telemetry (IPT) to evaluate our current Home Video Telemetry (HVT) practice. METHOD: To assess our HVT practice, a retrospective comparison of the video quality against IPT was conducted with the latter as the gold standard. A pilot study had been conducted in 2008 on 5 patients.Patients (n = 28) were included in each group over a period of one year.The data was collected from referral spreadsheets, King's EPR and telemetry archive.Scoring of the events captured was by consensus using two scorers.The variables compared included: visibility of the body part of interest, visibility of eyes, time of event, illumination, contrast, sound quality and picture clarity when amplified to 200%.Statistical evaluation was carried out using Shapiro-Wilk and Chi-square tests. The P-value of ⩽0.05 was considered statistically significant. RESULTS: Significant differences were demonstrated in lighting and contrast between the two groups (HVT performed better in both).Amplified picture quality was slightly better in the HVT group. CONCLUSION: Video quality of HVT is comparable to IPT, even surpassing IPT in certain aspects such as the level of illumination and contrast. Results were reconfirmed in a larger sample of patients with more variables. SIGNIFICANCE: Despite the user and environmental variability in HVT, it looks promising and can be seriously considered as a preferable alternative for patients who may require investigation at locations remote from an EEG laboratory.

Neoadjuvant chemotherapy in recurrent sebaceous carcinoma of eyelid with orbital invasion and regional lymphadenopathy.

A 35-year-old man presented with a recurrent temporal conjunctival mass (25 × 12 mm) involving about six-clock hours of the limbus in the left eye. The mass encroached onto the temporal half of cornea and showed surface keratin, large intrinsic and feeder vessels. It infiltrated the deep corneal stroma. There were no cells in the anterior chamber. Ultrasound biomicroscopy confirmed infiltration of deep corneal stroma without intraocular invasion. Surgery involved excision of the conjunctival component with 4-mm margin, lamellar sclerectomy and a penetrating sclerokeratoplasty with 3 mm of healthy corneal margin. Cryotherapy (double-freeze-thaw) was done to the conjunctival margins. Histopathology showed it to be invasive sebaceous cell carcinoma. A thin layer of deep corneal stroma and all conjunctival margins were uninvolved. At thirty-six weeks after treatment the left eye recorded a visual acuity of finger counting at 1 meter distance and no recurrence.

Human papillomavirus genotype distribution in cervical cancer in India: results from a multi-center study.

The prevalence of HPV genotypes in cervical cancer differs in various regions, though types 16 and 18 generally account for the majority. Knowledge of HPV genotypes in cervical cancer covering the diverse Indian population is important in consideration of the potential future impact of HPV prophylactic vaccination and HPV-based screening strategies. To determine HPV genotype distribution in cervical cancers representing different regions a total of 278 cervical cancer cases were enrolled from cancer centers in North, East, Central and South India. Cervical scrape specimens were tested for HPV DNA using the MY09/11 L1 consensus PCR method followed by sequencing for genotyping, as well as for HPV mRNA utilizing the PreTectTM HPV-Proofer assay. In instances of negative or discrepant results between the two tests, biopsy specimens were tested. HPV DNA and/or mRNA were detected in 91.7% of the cases. Genotype 16 was the most common type, detected alone in 59.4% and in association with type 18 in 3.6% of cases. Genotype 18 was detected as a monotype in 13.3% cases. In total, types 16 and 18 alone or in co-infection with each other were detected in 76.3% cases. Genotype 33 was the third most common type. Overall, genotypes 16, 18, 31, 33, and 45 were the five most common types, detected in 87.1% of the total cases. There were no significant regional differences. In conclusion, the currently available HPV prophylactic vaccines targeting types 16 and 18 have the potential to reduce the burden of cervical cancer in India by over 75%.

Women's perceptions and social barriers determine compliance to cervical screening: results from a population based study in India.

BACKGROUND: Success of cervical screening initiatives depends on high participation of the target population, which in turn is determined by the women's perceptions, health orientation and other socio-cultural issues. The present study identifies the immediate social and cultural barriers that prevent women to attend cervical screening facilities. METHODS: Women non-compliant to a community-based cervical screening program were identified. From them 500 were randomly selected for interview using a structured questionnaire that was designed on the basis of feedbacks received from several focused group discussions. Questionnaire listed 24 possible reasons for non-compliance. The women were asked to select the most pertinent reason(s) for her non-attendance or to reveal if they had any reason other than the listed ones. RESULTS: A total of 469 non-compliant women were interviewed. They had significantly lower literacy rate compared to the compliant women (OR=2.25; 95% CI: 1.23-4.13). Nearly half of the interviewed women responded that they themselves opted to stay away from the program. Most common reasons cited for non-attendance in this group were reluctance to go for medical test in the absence of any symptoms and apprehension to have a test that detects cancer. Second major group of responders comprised of women who were willing, yet could not attend due to various hurdles. Most common hurdles were inability to leave household chores, pre-occupation with family problems and lack of approval from husbands. CONCLUSIONS: Modification of health behavior through education and social empowerment of women are essential for a population based cervical screening program to succeed in India.