Current status of human papillomavirus vaccination in India's cervical cancer prevention efforts.

Efforts are being made to scale up human papillomavirus (HPV) vaccination for adolescent girls in India. Bivalent and quadrivalent HPV vaccines were licensed in the country in 2008, and a nonavalent vaccine was licensed in 2018. Demonstration projects initiated in Andhra Pradesh and Gujarat in 2009 introduced HPV vaccination in public health services in India. Following a few deaths in these projects, although subsequently deemed unrelated to vaccination, HPV vaccination in research projects was suspended. This suspension by default resulted in some participants in a trial evaluating two versus three doses receiving only one dose. Since 2016, the successful introduction of HPV vaccination in immunisation programmes in Punjab and Sikkim (with high coverage and safety), government-sponsored opportunistic vaccination in Delhi, prospects of a single dose providing protection, and future availability of an affordable Indian vaccine shows promise for future widespread implementation and evaluation of HPV vaccination in India.

Antibodies from combinatorial libraries use functional receptor pleiotropism to regulate cell fates.

To date, most antibodies from combinatorial libraries have been selected purely on the basis of binding. However, new methods now allow selection on the basis of function in animal cells. These selected agonist antibodies have given new insights into the important problem of signal transduction. Remarkably, when some antibodies bind to a given receptor they induce a cell fate that is different than that induced by the natural agonist to the same receptor. The fact that receptors can be functionally pleiotropic may yield new insights into the important problem of signal transduction.

Staphylococcus hominis subsp. novobiosepticus, an emerging multidrug-resistant bacterium, as a causative agent of septicaemia in cancer patients.

Staphylococcus hominis subsp. novobiosepticus is a new sub-species of S. hominis, thus dividing S. hominis into subsp. hominis and novobiosepticus. This study was designed to identify subsp. novobiosepticus isolates amongst the S. hominis isolated from blood samples of patients with malignancy and septicaemia and to study their resistance profile. The identification was performed by using three simple tests which differentiated between the two sub-species. It was found that 22.8 per cent of S. hominis isolates belonged to subsp. novobiosepticus.

The costimulatory immunogen LPS induces the B-Cell clones that infiltrate transplanted human kidneys.

The mechanism of chronic rejection of transplanted human kidneys is unknown. An understanding of this process is important because, chronic rejection ultimately leads to loss of the kidney allograft in most transplants. One feature of chronic rejection is the infiltration of ectopic B-cell clusters that are clonal into the transplanted kidney. We now show that the antibodies produced by these B-cells react strongly with the core carbohydrate region of LPS. Since LPS is a costimulatory immunogen that can react with both the B-cell receptor (BCR) and the Toll-like receptor 4 (TLR4), these results suggest a mechanism for the selective pressure that leads to clonality of these B-cell clusters and opens the possibility that infection and the attendant exposure to LPS plays a role in the chronic rejection of human kidney transplants. If confirmed by clinical studies, these results suggest that treating patients with signs of chronic rejection with antibiotics may improve kidney allograft survival.

Ectopic B-cell clusters that infiltrate transplanted human kidneys are clonal.

B cells and their immunoglobulin products participate in allograft rejection of transplanted human kidneys in which an interesting feature is the presence of a germinal center like B-cell clusters in the allograft. We report here that the immunoglobulin repertoires of these infiltrating B cells are highly restricted and the B cells within a cluster are clonal. Antibody libraries made from the infiltrating B cells of individual patients unexpectedly revealed that each patient utilizes a particular set of dominant germ line genes as well as dominant complementarity determining region 3. Comparison of kidney and peripheral blood from the same patient showed that the immunoglobulin genes from both compartments had dominant clones, but they differed. The lymphocytes that infiltrate the kidneys express the immunoglobulin gene somatic recombination machinery usually restricted to highly activated lymphocytes in germinal centers and lymphomas. An analogy can be made between the inescapable antigenic drive in chronic infection versus that in an allograft, both of which may lead to emergence of dominant B-cell clones and even lymphoid malignancy.

The structural basis for recognition of base J containing DNA by a novel DNA binding domain in JBP1.

The J-binding protein 1 (JBP1) is essential for biosynthesis and maintenance of DNA base-J (ß-d-glucosyl-hydroxymethyluracil). Base-J and JBP1 are confined to some pathogenic protozoa and are absent from higher eukaryotes, prokaryotes and viruses. We show that JBP1 recognizes J-containing DNA (J-DNA) through a 160-residue domain, DB-JBP1, with 10 000-fold preference over normal DNA. The crystal structure of DB-JBP1 revealed a helix-turn-helix variant fold, a 'helical bouquet' with a 'ribbon' helix encompassing the amino acids responsible for DNA binding. Mutation of a single residue (Asp525) in the ribbon helix abrogates specificity toward J-DNA. The same mutation renders JBP1 unable to rescue the targeted deletion of endogenous JBP1 genes in Leishmania and changes its distribution in the nucleus. Based on mutational analysis and hydrogen/deuterium-exchange mass-spectrometry data, a model of JBP1 bound to J-DNA was constructed and validated by small-angle X-ray scattering data. Our results open new possibilities for targeted prevention of J-DNA recognition as a therapeutic intervention for parasitic diseases.

Clinical significance of interleukin-6 in diagnosis of lung, oral, esophageal, and gall bladder carcinomas.

INTRODUCTION: Chronic inflammation predisposes to cancer. Cytokines play an essential role in cancer pathogenesis. Interleukin-6 (IL-6) is a pleiotropic cytokine that enables growth and differentiation of tumors. The effects of IL-6 are mediated by signal transducers and activators of transcription 3 (STAT3). STAT3 deficiency reduced tumor incidence and growth while STAT3 hyperactivation has an opposite effect; also it negatively regulates p53 gene. IL-6/STAT3 signaling is crucial in carcinogenesis linked to inflammation. Increased IL-6 levels are observed in cancer. Studies investigating the role of IL-6 is limited. AIM: This study aims at determining IL-6 levels in lung, oral, esophageal, and gallbladder cancer patients. MATERIALS AND METHODS: Subjects consisted of 175 patients with lung, oral, gall bladder, and esophageal cancers. The patients included 68 females and 107 males with an average age of 52 years. Fifty healthy individuals served as controls. IL-6 was detected by electrochemiluminescent immunoassay principle. RESULTS: IL-6 values were determined in 175 (21 lung, 55 oral, 17 esophageal and 82 gallbladder) cancer patients. Of these, 147/175 (18 lung, 43 oral, 13 esophageal and 73 gallbladder) cancer patients (84%) showed higher IL-6 levels as compared to control group (normal range: <7 pg/ml). CONCLUSION: This indicates a significant correlation between IL-6 overexpression and cancer development, highlighting the significance of IL-6 in oral, lung, esophageal, and gallbladder carcinomas. IL-6 may be used as a tumor marker for cancer diagnosis. It may be a clinically significant predictor and may represent a target for cancer treatment. However, to definitely conclude this, further extensive studies would be required.

Identification of Specific miRNA Signature in Paired Sera and Tissue Samples of Indian Women with Triple Negative Breast Cancer.

Of several subtypes of breast cancer, triple negative breast cancer (TNBC) is a highly aggressive tumor that lacks expression of hormone receptors for estrogen, progesterone and human epidermal growth factor receptor 2 and shows a worst prognosis. The small noncoding RNAs (miRNAs) considered as master regulator of gene expression play a key role in cancer initiation, progression and drug resistance and have emerged as attractive molecular biomarkers for diagnosis, prognosis and treatment targets in cancer. We have done expression profiling of selected miRNAs in paired serum and tissue samples of TNBC patients and corresponding cell lines and compared with that of other subtypes, in order to identify novel serum miRNA biomarkers for early detection and progression of TNBC. A total of 85 paired tumor tissues and sera with an equal number of adjacent normal tissue margins and normal sera from age matched healthy women including tissue and sera samples from 15 benign fibroadenomas were employed for the study. We report for the first time an extremely high prevalence (73.9%) of TNBC in premenopausal women below 35 years of age and a significant altered expression of a panel of three specific oncogenic miRNAs- miR-21, miR-221, miR-210, and three tumor suppressor miRNAs- miR-195, miR-145 and Let-7a in both tissues and corresponding sera of TNBC patients when compared with triple positive breast cancer (TPBC) patients. While miR-21, miR-221 and miR-210 showed significant over-expression, miR-195 and miR-145 were downregulated and well correlated with various clinicopathological and demographic risk factors, tumor grade, clinical stage and hormone receptor status. Interestingly, despite being a known tumor suppressor, Let-7a showed a significant overexpression in TNBCs. It is suggested that this panel of six miRNA signature may serve as a minimally invasive biomarker for an early detection of TNBC patients.

Achromobacter Xylosoxidans Bloodstream Infection in Elderly Patient with Hepatocellular Carcinoma: Case Report and Review of Literature.

Achromobacter xylosoxidansis a nonfermentative Gram-negative organism, known to cause opportunistic infection in humans. We report a case of septicemia in a 76-year-old male patient with underlying hepatocellular carcinoma due to A. xylosoxidans, which showed a different antimicrobial susceptibility pattern from what is usually reported. From aerobic blood culture of the patient, A. xylosoxidans was isolated which was found to be sensitive to amoxicillin-clavulanic acid, piperacillin-tazobactam, ceftazidime, cefoperazone-sulbactam, meropenem, minocycline, tigecycline, and trimethoprim/sulfamethoxazole. The patient recovered with amoxicillin-clavulanic acid treatment, which was given empirically to the patient. The present case highlights the possible role of amoxicillin-clavulanic acid for treatment of bloodstream infection with A. xylosoxidans.

Antibiotic Resistance Pattern of Uropathogens: An Experience from North Indian Cancer Patient.

Empirical treatment of urinary tract infections (UTIs) can be made evidence based if it is governed by the resistance pattern of common uropathogens. A retrospective study was carried out at a tertiary care cancer institute to identify the common uropathogens and to know their resistance profile. 20.82% of the outpatients' urine samples (community-acquired urinary tract infection (CA-UTI)) and 24.83% of the indoor patients' urine samples (hospital-acquired urinary tract infection (HA-UTI)) grew uropathogens. Escherichia coli was the predominant pathogen both in CA-UTI (68%) and HA-UTI (45%) followed by Klebsiella spp and Enterococcus spp. High level of resistance to fluoroquinolones and third generation cephalosporins was noted. Nitrofurantoin was found to be a reliable oral drug for treatment of most of the uropathogens.

XRCC-1 Gene Polymorphism (Arg399Gln) and Susceptibility to Development of Lung Cancer in Cohort of North Indian Population: A Pilot Study.

BACKGROUND: Smoking has been considered to be the major cause of lung cancer. However, only a fraction of cigarette smokers develop this disease. This suggests the importance of genetic constitution in predicting the individual's susceptibility towards lung cancer. This genetic susceptibility may result from inherited polymorphisms in genes controlling carcinogen metabolism and repair of damaged deoxyribonucleic acid (DNA). These repair systems are fundamental to the maintenance of genomic integrity. X-ray repair cross complimenting group I (XRCC1), a major DNA repair gene in the base excision repair (BER) pathway. It is involved in repair by interacting with components of DNA at the site of damage. Inconsistent results have been reported regarding the associations between the Arg399Gln polymorphism of XRCC1. This study demonstrates the importance of recognition of this relationship of lung carcinoma and genetic constitution of the person which will help guide clinicians on the optimal screening of this disease. AIM: To assess the role of XRCC1 gene polymorphism (Arg399Gln) directly on the variation in susceptibility to development of lung cancer in North Indian subjects. MATERIALS AND METHODS: One hundred males with diagnosed cases of lung cancer were recruited from Delhi State Cancer Institute (DSCI). Hundred healthy volunteers were taken as controls. DNA isolation was done and Polymerase chain reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) procedure undertaken to amplify the region containing Arg/Gln substitution at codon 399 (in exon 10). RESULTS: XRCC1 gene polymorphism is associated with increased risk of lung cancer when the Arg/Arg genotype was used as the reference group. The Arg/Gln and Gln/Gln was associated with statistically increased risk for cancer. CONCLUSION: Arg399Gln polymorphism in XRCC1 gene polymorphism is associated with lung cancer in North Indian subjects and screening for this polymorphism will help in targeting predisposed individuals and its prevention.

Blood stream infection by an emerging pathogen Oligella ureolytica in a cancer patient: case report and review of literature.

Oligella ureolytica is an emerging bacteria rarely implicated as a human pathogen. It is infrequently recovered from clinical specimens probably because of inadequate processing of non-fermenting oxidase positive Gram negative bacilli. We present here a case of a 30 year old male suffering from right lung adenocarcinoma (moderately differentiated) with multiple abdominal lymph node metastasis with Syringohydromyelia whose blood culture yielded Oligella ureolytica in pure culture. Oligella ureolytica isolation in pure culture and the patient's response to targeted treatment supported that Oligella ureolytica was the true causative agent of the blood stream infection. Early suspicion, diagnosis and treatment with potent antibiotics are needed to prevent further complications resulting from infection with this emerging pathogen.

Multi-targeted approach to cancer treatment: an international translational cancer research symposium.

Whether it is chronic myeloid leukemia, ALK-expressing malignancies, or HER2-positive breast cancer, targeted-therapies for treatment of human cancers have shown great promise. However, as they hit a single molecule expressed in neoplastic cells, their use is frequently associated with development of resistance. In cancer cells many signaling pathways operate in parallel, hence the idea of multi-targeted therapy is prevailing. The Society of Translational Cancer Research held its biennial meeting in the capital city of India, Delhi from February 6th through 9th, 2014 to discuss 'Multi-targeted Approach to Treatment of Cancer'. Over 200 scientists, clinicians, trainees, and industry representatives from different countries gathered in Vigyan Bhavan, the hotspot of Delhi for four days to talk and discuss on a variety of topics related to multi-targeted therapeutic approaches. Talks were presented by leaders in the cancer research field from various countries. It became clear from this conference that coupling multiple targeted-agents or using an agent that hits an individual target in several independent locations in the disease-causing pathway(s) may be the best approach to treat different cancers.

A structurally distinct human mycoplasma protein that generically blocks antigen-antibody union.

We report the discovery of a broadly reactive antibody-binding protein (Protein M) from human mycoplasma. The crystal structure of the ectodomain of transmembrane Protein M differs from other known protein structures, as does its mechanism of antibody binding. Protein M binds with high affinity to all types of human and nonhuman immunoglobulin G, predominantly through attachment to the conserved portions of the variable region of the κ and λ light chains. Protein M blocks antibody-antigen union, likely because of its large C-terminal domain extending over the antibody-combining site, blocking entry to large antigens. Similar to the other immunoglobulin-binding proteins such as Protein A, Protein M as well as its orthologs in other Mycoplasma species could become invaluable reagents in the antibody field.

Cholesterol secosterol aldehydes induce amyloidogenesis and dysfunction of wild-type tumor protein p53.

Epidemiologic and clinical evidence points to an increased risk for cancer when coupled with chronic inflammation. However, the molecular mechanisms that underpin this interrelationship remain largely unresolved. Herein we show that the inflammation-derived cholesterol 5,6-secosterol aldehydes, atheronal-A (KA) and -B (ALD), but not the polyunsaturated fatty acid (PUFA)-derived aldehydes 4-hydroxynonenal (HNE) and 4-hydroxyhexenal (HHE), induce misfolding of wild-type p53 into an amyloidogenic form that binds thioflavin T and Congo red dyes but cannot bind to a consensus DNA sequence. Treatment of lung carcinoma cells with KA and ALD leads to a loss of function of extracted p53, as determined by the analysis of extracted nuclear protein and in activation of p21. Our results uncover a plausible chemical link between inflammation and cancer and expand the already pivotal role of p53 dysfunction and cancer risk.

Spectrum of brain abnormalities detected on whole body F-18 FDG PET/CT in patients undergoing evaluation for non-CNS malignancies.

We present the pattern of metabolic brain abnormalities detected in patients undergoing whole body (WB) F-18 flurodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) examination for non-central nervous system (CNS) malignancies. Knowledge of the PET/CT appearance of various intracranial metabolic abnormalities enables correct interpretation of PET scans in oncological patients where differentiation of metastasis from benign intracranial pathologies is important and improves specificity of the PET study. A complete clinical history and correlation with CT and MRI greatly helps in arriving at a correct imaging diagnosis.

Apricoxib, a COX-2 inhibitor for the potential treatment of pain and cancer.

Apricoxib (CS-706), a small-molecule, orally active, selective COX-2 inhibitor, is under development by Tragara Pharmaceuticals Inc as an analgesic and anti-inflammatory agent, and also for its anticancer potential. The compound has desirable pharmacokinetic parameters, and has demonstrated good gastrointestinal tolerability and safety in preclinical studies and clinical trials. Phase IIa trial data indicated that apricoxib was a potent analgesic in the treatment of pain in postoperative dental surgery. At the time of publication, phase II trials assessing apricoxib in combination with anticancer drugs in patients with breast, lung and pancreatic cancer were ongoing. Evidence for the anticancer activity of oral apricoxib appears to be highly promising. However, the market success of apricoxib will depend mainly on long-term safety trials, which are needed to establish the cardiovascular safety of the drug when administered alone or in combination with other agents in cancer chemotherapy.