tbuckley/cabot-search huggingface dataset:
Pharmacogenomic analysis of the triplet combination of gemcitabine, oxaliplatin, and cetuximab as salvage therapy for metastatic colorectal cancer (mCRC) patients
Authors: A. Hernandez, E. Bandres, J. Rodriguez, N. Bitarte, N. Ramirez, R. Zarate, A. Abajo, A. Chopitea, A. Viudez, J. Garcia-Foncillas
Journal: Journal of Clinical Oncology (2009)

e14531 Background: We have previously reported that biweekly gemcitabine-based therapy was active in pretreated mCRC pts (De la Cruz et al, ASCO GI 2008, abstr 377). We aimed to investigate whether germ line polymorphisms may be predictors of clinical outcome in mCRC pts treated with this combination. Methods: We evaluated SNPs of genes involved in gemcitabine metabolism (CDA, dCDK, RRM1, DCTD, SLC28A1), DNA repair (XRCC1, XRCC 3, ERCC1, XPD) and two IgG Fcγ R polymorphisms (Fcγ RIIa- H131R and Fcγ RIIIa-V158F), reported to be predictive of cetuximab-based therapy, even in K-ras mutated pts. Whole blood was collected and DNA extracted from peripheral lymphocytes using a DNA isolation Kit (Qiagen, CA). Polymorphisms were detected using the TaqMan genotyping assays (Applied Biosystems, CA). Clinical response was evaluated according to RECIST criteria. Univariate analysis (Fisher´s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: Blood samples of 35 out of 39 enrolled pts were tested for genomic analysis. Patient‘s characteristics are as follows; M/F: 26/13, median age: 59 years, median number of prior chemotherapy lines: 2 (1–4), Köhne risk groups; low: 8 pts, intermediate: 18 pts, high: 13 pts. After a median follow-up of 20 months, median progression-free survival (PFS) is 6.7 months (95% CI; 5.2–8.3) and median overall survival 15.4 m (95% CI; 14.7–16.1). Overall response rate (ORR) was 53.8%. RRM1 R284R SNPs (p=0.06), T741T (p=0.02) and RRM1–524CT (p=0.04) were linked to clinical responsiveness. All pts possessing 2 or 3 favourable RRM1 SNPs responded. ORR was 53.3% for pts with no favourable SNPs versus 85% for pts with any favourable SNP (p=0.04). ORR was also significantly higher in pts with any histidine allele in the Fcγ RIIa polymorphism (93% vs. 60%, p=0.034). Median PFS was adversely affected in pts harbouring no favourable RRM1 SNPs (4.2m versus 6.7 months, p=0.019) and in those pts with homozygous Fcγ RIIa-131R allele (4.4 vs. 7.5 months, p=0.007). Conclusions: Polymorphic variants of RRM1 and Fcγ RIIa may play a key role in the efficacy of gemcitabine and cetuximab-based therapy for mCRC pts. No significant financial relationships to disclose.
A randomized, phase II trial comparing sequential paclitaxel/cisplatin/gemcitabine/vinorelbine/ (PCGV) with cisplatin/gemcitabine/vinorelbine/ (CGV) in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: J. De Castro, C. Belda-Iniesta, E. Casado Saenz, J. Feliu, M. Sereno, J. Chacon, G. Martin, C. Madroñal, C. Jara, J. Torrego, M. Gonzalez-Baron
Journal: Journal of Clinical Oncology (2006)

17008 Background: New effective therapies are needed to improve the outcome of patients with advanced NSCLC. In this regard, new approaches such as cisplatin-based triplets have been explored with promising results but high toxicity. Furthermore, sequential chemotherapy schedules with taxanes followed by cisplatin-based regimens or viceversa could improve activity. A phase II study showed that sequential chemotherapy with weekly paclitaxel followed by CGV was highly active. Methods: A multicenter, randomized phase II trial of PCGV vs CGV in advanced NSCLC patients was conducted. Primary end-point: time to progression and survival. Eligible pts had unresectable, histologically confirmed NSCLC; no prior chemotherapy; PS 0–2; measurable disease. Pts received: Arm A (PCGV): P 150 mg /m 2 /week × 6, followed 2 weeks later by C 100 mg/m 2 on day 1, gemcitabine 1,000 mg/m 2 on days 1 and 14, and vinorelbine 25 mg/m 2 on days 1 and 14 (CGV), every 28 days for a maximum of six courses. Arm B (CGV): C 100 mg/m 2 on day 1, gemcitabine 1,000 mg/m 2 on days 1 and 14, and vinorelbine 25 mg/m 2 on days 1 and 14 (CGV), every 28 days for a maximum of six courses. Results: 106 Pts were included. Pts baseline characteristics (A/B: 52/54): male 82/79%; median age 60/59 (range 38–75 years); PS 0: 30/33%; 1 63/60%; 2: 7/7%; % squamous carcinoma:44/42%.WHO grade 3–4 toxicities for P were: neutropenia 18%; anemia 10%; thrombocytopenia 2%, peripheral neuropathy 18%. Grade 3–4 toxicities for CGV after P were: neutropenia 31%,nausea-vomiting 20%,thrombocytopenia 7%,anemia 5%,peripheral neuropathy 21%. WHO grade 3–4 toxicities for arm B were: neutropenia 35%,nausea-vomiting 19%, anemia 12%, thrombocytopenia 11% and peripheral neuropathy 15%. After therapy with arm A, 44% achieved a partial response, 15% had stabilization and 41% progressed. Arm B response rate were as follows: partial response 33%, stable disease 24% and progressive disease 43%. Median time to progression was (A/B) 7/6 months (log rank test, p 0.13) and median survival was (A/B): 11/10 months (log rank test, p 0.5). Conclusions: In spite of high response rate in TCGV arm, no survival benefit was detected in advanced NSCLC patients. No significant financial relationships to disclose.
Modulation of regulatory dendritic cell polarization in cancer by paclitaxel.
Authors: Hua Zhong, Runbo Zhong, Baohui Han, Galina Shurin, Michael Shurin
Journal: Journal of Clinical Oncology (2012)

e21001 Background: Tumors are dynamic organs, in which active processes of cell differentiation affect disease course by regulating the composition of cells at the tumor site. we hypothesize that regDC form the premalignant niche in the lung to support lung cancer development and sustain lung cancer growth and progression. Furthermore, we evaluated if paclitaxel affected regDC and paclitaxel in noncytotoxic concentrations prevents polarization of cDC into regDC.Methods: Bone marrow-derived cDC were treated with tumor conditioned media from 3LL lung cancer cell lines for 48 h, washed, depleted of GR1+ cells and added to ConA-stimulated syngeneic T cells. 3LL-induced regDC were isolated by cell sorting from the in vitro generated cultures or from lungs harvested from 3LL-bearing mice. Analysis of immunosuppressive DC revealed them as CD11clowCD11bhigh CD80lowCD86lowMHC-IIlowPDCA1negGR1neg cells. For the in vivo evaluation of the potential protumorigenic properties of regDC, sorted CD11clowCD11bhigh (regDC) and CD11chighCD11blow/neg (cDC) subsets were injected (5x105cells i.p.) into mice together with 1/15 of the minimum tumorigenic dose of 3LL tumor cells (2x104cells, i.v.). As expected, no tumor nodules were detected in lungs in mice treated with saline or cDC (0/6 mice).However, &gt;30% of mice injected with regDC developed lung tumors, suggesting that regDC exhibit a potent protumorigenic activity in vivo. Next, we asked if paclitaxel could alter regDC formation in vivo. Paclitaxel was administered in 3LL lung metastasis bearing mice. Lymphoid and non-lymphoid tissues were harvested 3 weeks later and analyzed for regDC subsets by flow cytometry.Results: The addition of tumor conditioned converts immunostimulatory cDC into regDC that can suppress proliferation of T cells. Paclitaxel in ultra low noncytotoxic concentrations in vitro could prevent tumor-induced polarization of conventional cDC into regDC. Furthermore, administration of paclitaxel prevented formation of regDC in the lung and significantly inhibited formation of metastases .Conclusions: These data suggest that paclitaxel in ultra low nontoxic doses is able to module the tumor immunoenvironment and support the anti-cancer efficacy of cancer vaccine.
Suppressor (CD8+/CD28-) T cells are increased in cancer patients and inhibit helper T-cell proliferation.
Authors: Todd S. Crocenzi, Christopher P. Tretter, Mary Waugh, Marc S. Ernstoff
Journal: Cancer Research (2004)

2169  Purpose: A dominant antitumor immune pathway is through cellular immunity. An effective immune response against tumor cells can be altered by proinflammatory and antagonistic pathways. Host anti-tumor immune responses can be attenuated by suppressor T cells of the phenotype CD8+/CD28- (Ts cells). We explored the presence and function of Ts cells in the peripheral blood compartment of melanoma and renal cell carcinoma (RCC) patients. We hypothesized that cancer patients would exhibit higher percentages of Ts cells in peripheral blood compared to healthy volunteers. We further attempted to determine the function of circulating Ts cells and whether their function would be attenuated by IL-2. Experimental Design: Peripheral blood mononuclear cells (PBMC) from 41 cancer patients (29 RCC patients, 12 melanoma patients) and 24 healthy volunteers were isolated by Ficoll-Paque gradient centrifugation. We utilized flow cytometry to determine the percent of CD8bright+ cells that expressed the CD8+/CD28- phenotype. Differences in the percentage of CD8+/CD28- cells between healthy volunteers and cancer patients were analyzed using the unpaired t test. We determined Ts function using a CD4+ cell proliferation assay. We used peripheral blood samples from representative cancer patients to obtain purified populations of CD4+ and CD8+/CD28- cells through magnetic bead separation. Ts cell function was ultimately determined by suppression of proliferation as measured by [3H] thymidine incorporation. Cell proliferation assays were performed in the absence and presence of IL-2. Results: A significant difference in the percent of Ts cell was observed when comparing peripheral blood samples from cancer patients to healthy volunteers (36.85% vs. 21.32%, p
Descriptive study on the lost productivity in breast cancer patients
Authors: L. Bordeleau, D. Warr, P. Goodwin, N. Lathia, O. Jugovic, N. Mittmann
Journal: Journal of Clinical Oncology (2007)

6542 Background: There is a paucity of data assessing the potential impact of breast cancer diagnosis on the productivity of affected women. The objective was to identify and quantify lost productivity, health utilities and quality of life experienced in women diagnosed with breast cancer. Methods: A consecutive cross-sectional cohort of women with breast cancer (at any stage) attending outpatient clinics at Mount Sinai Hospital/Princess Margaret Hospital were eligible and consented to participate in the study. Women completed questionnaires assessing demographic and disease related information, work productivity and activity impairment utility (EQ5D VAS) and quality of life (FACT-B). Results: Data from 103 patients age 56.5 ± 11.9 years (mean +SD) were collection. Distribution of stage at diagnosis was as follows: 0 (31%), I (26%), II (10%), III (5%), IV (17%), unknown (11%). Time since diagnosis was 30.0 ± 39.1 months. Most women had recently been on active treatment for their breast cancer: chemotherapy (47%), hormone manipulation (23%), herceptin (6%), radiation (27%) and unknown (15%). 9% of women had metastatic disease, 35% had an income between $0 and $30,000. 58% of women were working full time for pay before their diagnosis, whereas only 19% were working full time for pay at the time of the assessment. At the time of the assessment, 18% were on disability leave. 8.7% of the women retired between the times of their diagnosis to the current assessment. Of those still working, a mean of 8.7 ± 11.6 days were missed from work in the previous 30 days due to problems related to breast cancer. The average number of days that employed patients actually worked (N=27) was 16.0 ± 9.0 days (range 4–30 days). 8% of patients required paid health care assistance during the past 4 weeks. 44% of patients had a spouse as an unpaid caregiver, followed by child/parent (20%) and friend (13%). Mean overall health rated by the respondents using the EQ5D VAS was 73.2 ± 16.3. The FACT-B mean was 68.0 ± 12.5 (range 27 to 98). Conclusion: Breast cancer negatively impacts work productivity and overall activity. The significant use of both paid and unpaid assistance would amount to significant societal costs which are currently not included in most cost-effectiveness analyses. No significant financial relationships to disclose.
Combination therapy targeting both innate and adaptive immunity improves survival in a pre-clinical model of ovarian cancer
Authors: Christina A. Hartl, Adrian Bertschi, Regina Bou Puerto, Carolin Andresen, Emily M. Cheney, Elizabeth A. Mittendorf, Jennifer L. Guerriero, Michael S. Goldberg
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Despite major advancements in immunotherapy among a number of solid tumors, response rates among ovarian cancer patients remain modest. Standard treatment for ovarian cancer is still surgery followed by taxane- and platinum-based chemotherapy. Thus, there is an urgent need to develop novel treatment options for clinical translation. <h3>Methods</h3> Our approach was to analyze the effects of standard chemotherapy in the tumor microenvironment of mice harboring orthotopic, syngeneic ID8-Vegf-Defb29 ovarian tumors in order to mechanistically determine a complementary immunotherapy combination. Specifically, we interrogated the molecular and cellular consequences of chemotherapy by analyzing gene expression and flow cytometry data. <h3>Results</h3> These data show that there is an immunosuppressive shift in the myeloid compartment, with increased expression of IL-10 and ARG1, but no activation of CD3<sup>+</sup> T cells shortly after chemotherapy treatment. We therefore selected immunotherapies that target both the innate and adaptive arms of the immune system. Survival studies revealed that standard chemotherapy was complemented most effectively by a combination of anti-IL-10, 2′3'-cGAMP, and anti-PD-L1. Immunotherapy dramatically decreased the immunosuppressive myeloid population while chemotherapy effectively activated dendritic cells. Together, combination treatment increased the number of activated T and dendritic cells as well as expression of cytotoxic factors. It was also determined that the immunotherapy had to be administered concurrently with the chemotherapy to reverse the acute immunosuppression caused by chemotherapy. Mechanistic studies revealed that antitumor immunity in this context was driven by CD4<sup>+</sup> T cells, which acquired a highly activated phenotype. Our data suggest that these CD4<sup>+</sup> T cells can kill cancer cells directly via granzyme B-mediated cytotoxicity. Finally, we showed that this combination therapy is also effective at delaying tumor growth substantially in an aggressive model of lung cancer, which is also treated clinically with taxane- and platinum-based chemotherapy. <h3>Conclusions</h3> This work highlights the importance of CD4<sup>+</sup> T cells in tumor immunology. Furthermore, the data support the initiation of clinical trials in ovarian cancer that target both innate and adaptive immunity, with a focus on optimizing dosing schedules.
Development of a lipoplex-type mRNA carrier composed of an ionizable lipid with a vitamin E scaffold and the KALA peptide for use as an ex vivo dendritic cell-based cancer vaccine
Authors: Naho Tateshita, Naoya Miura, Hiroki Tanaka, Takeshi Masuda, Sumio Ohtsuki, Kota Tange, Yuta Nakai, Hiroki Yoshioka, Hidetaka Akita
Journal: Journal of Controlled Release (2019)
The Extracellular Matrix Receptor Discoidin Domain Receptor 1 Regulates Collagen Transcription by Translocating to the Nucleus
Authors: Manuel Chiusa, Wen Hu, Hong-Jun Liao, Yan Su, Corina M. Borza, Mark P. de Caestecker, Nataliya I. Skrypnyk, Agnes B. Fogo, Vadim Pedchenko, Xiyue Li, Ming-Zhi Zhang, Billy G. Hudson, Trayambak Basak, Roberto M. Vanacore, Roy Zent, Ambra Pozzi
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement The receptor discoidin domain receptor 1 (DDR1) is activated by collagen, upregulated in injured kidneys, and contributes to kidney fibrosis, but how DDR1 controls fibrosis is poorly understood. The authors show that upon collagen stimulation, DDR1 translocates to the nucleus. To do this, DDR1 must bind with SEC61B, a component of the Sec61 translocon, as well as with nonmuscle myosin IIA and β -actin. In the nucleus, DDR1 binds to chromatin to increase the transcription of collagen IV, a major collagen upregulated in fibrosis. The study reveals a novel mechanism whereby collagen-activated DDR1 moves to the nucleus to increase the production of profibrotic molecules. Background The discoidin domain receptor 1 (DDR1) is activated by collagens, upregulated in injured and fibrotic kidneys, and contributes to fibrosis by regulating extracellular matrix production, but how DDR1 controls fibrosis is poorly understood. DDR1 is a receptor tyrosine kinase (RTK). RTKs can translocate to the nucleus via a nuclear localization sequence (NLS) present on the receptor itself or a ligand it is bound to. In the nucleus, RTKs regulate gene expression by binding chromatin directly or by interacting with transcription factors. Methods To determine whether DDR1 translocates to the nucleus and whether this event is mediated by collagen-induced DDR1 activation, we generated renal cells expressing wild-type or mutant forms of DDR1 no longer able to bind collagen. Then, we determined the location of the DDR1 upon collagen stimulation. Using both biochemical assays and immunofluorescence, we analyzed the steps involved in DDR1 nuclear translocation. Results We show that although DDR1 and its natural ligand, collagen, lack an NLS, DDR1 is present in the nucleus of injured human and mouse kidney proximal tubules. We show that DDR1 nuclear translocation requires collagen-mediated receptor activation and interaction of DDR1 with SEC61B, a component of the Sec61 translocon, and nonmuscle myosin IIA and β -actin. Once in the nucleus, DDR1 binds to chromatin to increase the transcription of collagen IV, a major collagen upregulated in fibrosis. Conclusions These findings reveal a novel mechanism whereby activated DDR1 translates to the nucleus to regulate synthesis of profibrotic molecules.
When alpha meets beta, mast cells get hyper
Authors: Michelle Shuling Ong, Vinay Tergaonkar
Journal: The Journal of Experimental Medicine (2019)

The evolutionary conservation of the catalytically inactive α-tryptase gene has remained a mystery. In this issue of JEM, Le et al. (2019. J. Exp. Med. https://doi.org/10.1084/jem.20190701) unveil the existence of a novel but natural tryptase, heteromeric α/β-tryptase, a critical mediator of α-tryptase–associated diseases.
Examining the impact of frequent versus infrequent screenings for breast cancer on employer costs.
Authors: Kavita V. Nair, Vahram Ghushchyan, Lisa A Thompson, Cindy L. O'Bryant, Richard Read Allen, Robert Brett McQueen
Journal: Journal of Clinical Oncology (2012)

e16550 Background: Studies have shown an effective way to reduce breast cancer mortality is through early detection with periodic mammographic screening. Screening can increase the likelihood that cancer is detected at an earlier stage when treatment can be more effective and less expensively. Employers may be motivated to improve screening efforts if it results in improved survival and lower healthcare costs. We estimated differences in breast cancer and all cause related costs for women between 40-65 years who received regular screenings compared to those who did not. Methods: Data obtained from the LifeLink™ Health Plan Claims Database (2000 – 2010). ICD-9 codes (174.xx and 233.xx) were used to identify women between 40-65 with a diagnosis for breast cancer, who had an mammogram in the 6 months prior to diagnosis (baseline period) and had a minimum of 12 months following the diagnosis. Two cohorts were created. Those with at least one additional mammogram in the 12 months prior to the start of the baseline period (frequent mammogram group) and those with no additional mammograms (infrequent group). Both groups were followed for a minimum of 12 months and a maximum of 10 years. Adjusted differences in breast cancer and all cause costs were examined controlling for age, chronic condition index, number of mammograms in the baseline period, region and years of follow up using generalized linear models. Results: Mean age was 54 in the frequent (n=1582) and 56 in the infrequent (n=1379) group. Infrequent group had 29.7% of women between 40-49 years compared to 23.6% in the frequent group. Majority of the frequent group (85%) had one additional mammogram in the 12 months preceding the baseline period while 15% had &gt; 2 mammograms. Infrequent group incurred on average $5715 higher breast cancer costs in year one compared to the frequent group (p &lt;0.001). All cause costs in year one were also $6222 higher in the infrequent group (p&lt;0.001). Similar trends were seen in years 2-5 for breast cancer and years 2-3 for all cause costs. Differences were consistent for each year of age from 40-65. Conclusions: Our findings suggest that efforts to improve screening rates can affect employer costs for treating breast cancer between 1-5 years following diagnosis.
Effect of p53 gene transfection on proliferation, apoptosis, and radiosensitivity of cervical cancer cells.
Authors: Xiaofan Li, Shao Wen, Shanwen Zhang
Journal: Journal of Clinical Oncology (2013)

e22024 Background: To investigate the effects of p53 gene transfection on proliferation, apoptosis and radio-sensitivity of cervical cancer cells. Methods: Two cervical cell lines: Siha with wild-type p53 gene and C33a with mutant p53 gene, were transfected with human wild-type p53 gene. Un-transfected cells and transfected cells were exposed to 6 Gy of radiation. Cell proliferation, apoptosis, and protein expressions of p53, MDM2, p21, and bax in the un-treated, p53- transfected, and irradiated cells were analyzed. Results: The protein expression of p53, MDM2, p21, and bax in the untreated Siha cells is very low; High level p53 and MDM2 proteins and low level of p21 and bax proteins were found in the untreated C33a cells. When transfected with recombinant adenoviral human wild-type p53 gene (rAd-p53) the protein levels of p53, MDM2, p21, and bax in both Siha and C33a increased. Highest levels of these proteins were detected at 48 hours after transfection. The increased protein expressions were accompanied with inhibition of cell proliferation. At 72 hours after transfection, 12.3% and 5.5% of Siha and C33a cells became apoptotic, respectively. When exposed to 6 Gy of radiation after 48 hours of the transfection, 46.2% and 38.3% apoptotic Siha and C33a cells were detected, respectively; but only 5.6% and 6.3% of apoptotic cells of their un-transfected counterparts detected at 24 hours after the radiation treatment. Conclusions: Wild-type p53 gene transfection can inhibit cell proliferation, promote apoptosis, and sensitize to radiation of both Siha and C33a cells. The effects on Siha cells are stronger.
Abstract 17325: Vorticity is a Sensitive Marker of Left Ventricular Diastolic Dysfunction in Repaired Tetralogy of Fallot
Authors: Richard M Friesen, Michal Schafer, Benjamin Frank, Uyen Truong, Lorna P Browne
Journal: Circulation (2017)

Introduction: Much attention is paid to right ventricular dysfunction after repair of Tetralogy of Fallot (TOF), yet left ventricular dysfunction has also been shown to be a risk factor for heart f...