BACKGROUND: No data exist on the population prevalence of, or risk factors for, human papillomavirus (HPV) infection in predominantly Muslim countries in Asia. METHODS: Cervical specimens were obtained from 899 married women aged 15 -59 years from the general population of Karachi, Pakistan and from 91 locally diagnosed invasive cervical cancers (ICCs). HPV was detected using a GP5 þ /6 þ PCR-based assay. RESULTS: The prevalence of HPV in the general population was 2.8%, with no evidence of higher HPV prevalence in young women. The positivity of HPV was associated with women's lifetime number of sexual partners, but particularly with the age difference between spouses and other husbands' characteristics, such as extramarital sexual relationships and regular absence from home. The HPV16/18 accounted for 24 and 88% of HPV-positive women in the general population and ICC, respectively. CONCLUSION: Cervical cancer prevention policies should take into account the low HPV prevalence and low acceptability of gynaecological examination in this population. To date, there are no data on the population prevalence of, or risk factors for, human papillomavirus (HPV) infection in predominantly Muslim countries in Asia, where sexual mores differ from many other world populations (Wellings et al, 2006). These data are essential to assess the potential relevance of HPV vaccination and HPV test-based screening to invasive cervical cancer (ICC) prevention in the region, as well as to identify any changes in risk occurring in young generations. Thus, a study of women with and without cervical cancer was carried out in Karachi, Pakistan, according to the standardised protocol of the International Agency for Research on Cancer (IARC) HPV Prevalence Surveys (Clifford et al, 2005), which was approved by both the IARC and local ethical review committees. METHODSA total of 3882 married women aged 15 -59 years living in Orangi, a densely populated suburb of Karachi, were visited at their homes and invited to join the study, with the aim to enrol B100 women in each 5-year age group. Participation rates were 24.1, 25.7, 25.1 and 23.6% among women aged 15 -24, 25 -34, 35 -44 and 45 -59 years, respectively. All participants signed an informed consent form and were administered a questionnaire. In all, 915 participants came to the study clinic located in the Sindh Government Qatar Hospital, where a sample of exfoliated cervical cells was collected and placed into PreservCyt media (Hologic, Marlborough, MA, USA) for HPV testing and liquid-based cytology.In parallel, formalin-fixed tumour biopsies were retrieved from women presenting with histologically confirmed ICC between 2004 and 2008 to the Ziauddin and Aga Khan University Hospitals, Karachi. After exclusion of 40 biopsies that were b-globin negative and/or without histological evidence of tumour, 91 ICCs remained (79 squamous cell, 3 adeno, 4 small cell and 5 other or unspecified carcinomas).Liquid-based cytology and HPV testing were carried out at the Vrije University, Amsterdam, the Neth...
Our results show a strong relationship between HPV infection and cervical cancer among Pakistani women. These results underscore the need to implement regular HPV screening for Pakistani women. An early diagnosis of HPV infection will allow better health management to reduce the risk of developing cervical cancer.
Anaplastic Large Cell Lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive Anaplastic Lymphoma Kinase (ALK) fusion protein. ALK inhibitors such as crizotinib provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by NPM1-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54-90% in clinical trials. However, a subset of patients progress within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide CRISPR activation and knockout screens in ALCL cell lines combined with RNA-seq data derived from ALK inhibitor relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of IL10RA. Elevated IL10RA expression rewires the STAT3 signaling pathway bypassing otherwise critical phosphorylation by NPM1-ALK. IL10RA expression does not correlate with response to standard chemotherapy in pediatric patients suggesting that combination of crizotinib with chemotherapy could prevent ALK-inhibitor resistance-specific relapse. Trials registered as NCT01979536/NCT02034981/UMIN000028075.
We describe 2-step and 3-step strategies for intraperitoneal tumor radio-localization by means of monoclonal antibodies (MAbs). Nude mice bearing intraperitoneal human colon carcinoma tumors were injected i.p. with biotinylated MAb AUAI, followed 24 hr later by radioiodinated streptavidin (2-step). The uptake of radioactivity in tumor and normal tissues was measured 4 hr after injection of radioactive compound. A 3-step strategy consisted in administering biotinylated antibody, cold avidin after 24 hr and 111In-labelled biotin after a further 4 hr; mice were then killed 2 hr later. Tumor localization of intraperitoneally-administered biotinylated antibody and direct targeting of radioactive streptavidin to biotinylated antibody bound to tumor sites were demonstrated using immunohistochemistry and autoradiography. Our results show that (i) the 2-step approach increased the percentage of radioactivity uptake by tumor with respect to directly labelled antibodies (24% vs. 6%) and improved the tumor/non-tumor ratio; (ii) the 3-step approach allowed faster blood clearance of the radioactive probe (111In-biotin) and yielded high tumor/non-tumor ratios. "Pre-targeting" methods appear to have advantages over the conventional 1-step approach with directly radiolabelled antibody.
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