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author:("Popov, lorica")
1.  Long-lasting complete regression of established mouse tumors by counteracting Th2 inflammation 
Mice with intraperitoneal ID8 ovarian carcinoma or subcutaneous SW1 melanoma were injected with monoclonal antibodies (mAbs) to CD137+PD-1+CTLA4 7-15 days following tumor initiation. Survival of mice with ID8 tumors tripled and >40% of mice with SW1 tumors remain healthy >150 days after later treatment and are probably cured. Therapeutic efficacy was associated with a systemic immune response with memory and antigen specificity and required CD4+ cells and involved CD8+ cells and NK cells to a less extent. The 3 mAb combination significantly decreased CD19+ cells at tumor sites, increased IFNγ and TNFα producing CD4+ and CD8+ T cells and mature CD86+ DC, and it increased the ratios of effector CD4+ and CD8+ T cells to CD4+Foxp3+ regulatory T cells and to CD11b+Gr-1+ myeloid suppressor cells. This is consistent with shifting the tumor microenvironment from an immunosuppressive Th2 to an immunostimulatory Th1 type and is further supported by PCR data. Adding an anti-CD19 mAb to the 3 mAb combination in the SW1 model further increased therapeutic efficacy. Data from ongoing experiments show that intratumoral injection of a combination of mAbs to CD137+PD-1+CLA4+CD19 can induce complete regression and dramatically prolong survival also in the TC1 carcinoma and B16 melanoma models, suggesting that the approach has general validity.
PMCID: PMC3685275  PMID: 23603859
ovarian carcinoma; melanoma; CTLA4; PD-1; CD137; CD19; inflammation
2.  An Automated High-Throughput Counting Method for Screening Circulating Tumor Cells in Peripheral Blood 
Analytical chemistry  2013;85(4):2465-2471.
Enumeration of circulating tumor cells (CTCs) has proved valuable for early detection and prognosis in cancer treatment. This paper describes an automated high-throughput counting method for CTCs based on microfluidics and line-confocal microscopy. Peripheral blood was directly labeled with multiple antibodies, each conjugated with a different fluorophore, pneumatically pumped through a microfluidic channel and interrogated by a line-confocal microscope. Based on the fluorescence signals and labeling schemes, the count of CTCs was automatically reported. Due to the high flow rate, 1 mL of whole blood can be analyzed in less than 30 minutes. We applied this method in analyzing CTCs from 90 stage IV breast-cancer patient samples, and performed a side-by-side comparison with the results of the CellSearch assay, which is the only method approved by U.S. Food and Drug Administration (FDA) at present for enumeration of CTCs. This method has a recovery rate for cultured breast cancer cells of 94% (n=9), with an average of 1.2 counts/mL of background level of detected CTCs from healthy donors. It detected CTCs from breast-cancer patients, ranging from 15 to 3375 counts/7.5 mL. Using this method, we also demonstrate the ability to enumerate CTCs from breast-cancer patients that were positive for Her2 or CD44+/CD24−, which is a putative cancer stem cell marker. This automated method can enumerate CTCs from peripheral blood with high throughput and sensitivity. It could potentially benefit the clinical diagnosis and prognosis of cancer.
PMCID: PMC3586433  PMID: 23387387
3.  Human papillomavirus DNA is rarely detected in colorectal carcinomas and not associated with microsatellite instability: The Seattle Colon Cancer Family Registry 
Persistent infection with oncogenic human papillomavirus (HPV) types-16 and -18 is an established cause of cervical and other cancers. Some studies report detection of oncogenic HPV DNA in colorectal carcinomas, with prevalence estimates as high as 84%. However, other studies report detecting no HPV DNA in colorectal tumors.
To evaluate the prevalence of HPV in colorectal cancer subsets, we conducted a case-case comparison study. This study included 555 cases of incident colorectal cancer from the Seattle Colon Cancer Family Registry (CCFR), ages 20-74, and diagnosed between 1998-2002. Standardized interviews were used to elicit demographics and risk factor data. Tumor DNA was assayed for HPV-16 and -18 DNA using real-time PCR. Microsatellite instability (MSI) status was assessed using a standard 10-marker panel and confirmed with immunohistochemical staining. Prevalence estimates were calculated for the overall sample, and stratified by patient and tumor characteristics. Fisher’s exact test was used to compare prevalence between strata.
HPV-16 DNA was detected in 2% of colorectal tumors, but no HPV-18 DNA was detected. HPV-16 prevalence did not vary between cases according to sex, age, race, smoking-status, or MSI-status (P>0.05). HPV-16 prevalence in rectal carcinomas was 5% compared to 1% in colon carcinomas (P=0.03).
Among a large sample of colorectal carcinomas, prevalence of HPV-16 and -18 was very low. Prior studies detecting high HPV prevalence in colorectal carcinomas are likely the result of contamination from the anal canal or clinical processing.
HPV is unlikely to play a large role in colorectal carcinogenesis.
PMCID: PMC3565050  PMID: 23250932
HPV; colorectal cancer; anatomic site; microsatellite instability
4.  Evaluation of Transported Dry and Wet Cervical Exfoliated Samples for Detection of Human Papillomavirus Infection▿  
Journal of Clinical Microbiology  2010;48(9):3068-3072.
We determined the feasibility of human papillomavirus (HPV) detection in cervical exfoliated cells collected as dry swab samples. Both dry cervical swab and specimen transport medium (STM) cervical swab samples were collected from 135 patients attending either colposcopy or women's clinics in Guayaquil, Ecuador, who had a cytology diagnosis within 6 months. HPV was detected by dot blot hybridization and genotyped by the liquid bead microarray assay (LBMA). Overall, 23.1% of dry samples were positive for any high-risk HPV types, and 24.6% of STM samples were positive for any high-risk HPV types. Of 125 paired samples, the type-specific high-risk HPV proportion positive agreement was 60.7% (kappa, 0.69; 95% confidence interval [CI], 0.53 to 0.82). Of six women with cytological evidence of invasive cervical cancer, high-risk HPV DNA was detected in three of their STM samples and in five of their dry samples. Dry samples were more likely to be insufficient for HPV testing than STM samples. Consistent with this observation, the amount of genomic DNA quantitated with the β-actin gene was almost 20 times lower in dry samples than in STM samples when detected by the real-time TaqMan assay; however, HPV DNA viral loads in dry samples were only 1.6 times lower than those in matched STM samples. We concluded that exfoliated cervical cells could be collected as dry swab samples for HPV detection.
PMCID: PMC2937663  PMID: 20610686

Results 1-4 (4)