tbuckley/cabot-search huggingface dataset:
Schedule-dependent interaction between epidermal growth factor inhibitors (EGFRI) and G2/M blocking chemotherapeutic agents (G2/MB) on human NSCLC cell lines in vitro
Authors: B. Piperdi, Y.-H. Ling, G. Kroog, R. Perez-Soler
Journal: Journal of Clinical Oncology (2004)

7028 Background: EGFRI have shown clinical activity in NSCLC patients. Despite single agent activity, addition of EGFRI to chemotherapy has so far failed to improve outcome. EGFRI cause G1 cell cycle arrest. Cytotoxic chemotherapies act on dividing cells. G2/MB such as taxanes are essential part of standard chemotherapy. We examined the effects of combining EGFRI with G2/MB on human NSCLC cells in vitro using different schedules. Methods: H322 and our strain of A549 cells were used based on their differential sensitivity to EGFRI, erlotinib. The following G2/MB were used: paclitaxel, vinblastine and bortezomib. The cells were treated with the EGFRI alone, G2/MB alone, or a combination of two given together or sequentially 24-hrs apart. Cell cycle analysis and apoptotic fractions were determined by flow cytometry after staining with PI at 48-hr after exposure. Cytotoxicity was determined using a MTT assay. Results: The IC50s of erlotinib for H322 and A549 are 1.04 uM and >20 uM respectively. The cell cycle effects of EGFRI and G2/MB are as expected. The concomitant and the sequential treatment of G2/MB followed by EGFRI result in accumulation of cells in both G1 and G2/M. However, pre-treatment with erlotinib causes G1 arrest and effectively abrogates the action of G2/MB. This antagonistic effect is seen in both H322 and A549, although more prominent in H322 cells. This is accompanied by increase in cell survival and decrease in apoptosis. Similar effects are obtained with cetuximab, indicating the general effect of EGFRI. Conclusions: Sequential therapy using EGFRI followed by G2/MB antagonized cell cycle effects of G2/MB and reduced their efficacy. Since studies of the combination of EGFRI with standard chemotherapy utilized schedules involving continuous exposure to EGFRI, our results suggest that their failure may be (in part) due to choice of schedule. Possibly, continuous exposure to EGFRI, by causing G1 arrest, may decrease the effectiveness of chemotherapy in subsequent cycles. Further in vivo studies will be required to further evaluate this hypothesis. Supported by NIH CA 91784 and OSIP. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI Pharmaceuticals OSI Pharmaceuticals OSI Pharmaceuticals OSI Pharmaceuticals
PTH-077 Fertility and pregnancy related misconceptions in female patients with inflammatory bowel disease
Authors: S Chetcuti Zammit, M Caruana, K Katsanos, G Mantzaris, M Cesarini, U Kopylov, L Zammit, M Brookes, P Ellul
Journal: Gut (2015)

<h3>Introduction</h3> Reproductive issues in patients with inflammatory bowel disease (IBD) have been shown to be inadequately addressed by clinicians. Patients appear to opt for voluntary childlessness due to misconceptions about fertility and pregnancy. <h3>Method</h3> Female IBD patients were prospectively recruited from 5 different European centres. They were interviewed through the use of a questionnaire. <h3>Results</h3> 233 patients were recruited (mean age 40; SD±11.9). The mean age at diagnosis was 31.4 years (SD±11.2). 85.5% patients with ulcerative colitis (UC) had a Montreal classification of E2 or E3. Crohn’s disease (CD) patients predominantly (64.7%) had a non-stricturing and non-penetrating phenotype. Only 57.9% of patients were counselled on IBD and fertility (gastroenterologists 46.8%; gynaecologists 7.30%). 27.5% had admitted to considering voluntary childlessness. This correlated with lack of counselling delivered by health care professionals (coefficient 1.147; p &lt; 0.003). Reasons included: (i) fear of harm from the disease to the baby (52.8%); (ii) fear of harm from medications to the baby (61.4%); (iii) fear of passing on IBD to the baby (57.9%); (iv) fear of having a complicated pregnancy (51.5%); (v) being incapable of taking care of their child after birth (8.6%). 19.7% expressed fear of infertility following the diagnosis of IBD. 8.2% were aware that the mode of delivery could be influenced by IBD. 15.5% and 36.5% knew that surgery could influence fertility and mode of delivery respectively. Regarding IBD medications during pregnancy: (i) 15.0% thought that all medications should be stopped; (ii) 12.0% believed that some medications should be stopped; (iii) 63.1% were unsure about what to do with medications. 1.7% of patients stopped medications without consultation with clinical teams. 26.6% of patients were uncertain if patients with IBD could breast feed. 37.0% said that they could not. 47.0% thought that females with IBD could not breastfeed due to medications crossing into the breast milk. 15.9% were counselled to undergo regular pap smears. 61.8% received information about the HPV vaccine. <h3>Conclusion</h3> The effects of inadequate fertility counselling in patients with IBD in Europe might contribute to the high levels of voluntary childlessness. A number of misconceptions about pregnancy and delivery exist. This study highlights the need to improve care for this cohort of patients through the development of a multidisciplinary team management. Further studies might allow us to evaluate the most effective way of delivering improved support for these patients. <h3>Disclosure of interest</h3> None Declared.
Aeroallergen-induced IL-33 predisposes to respiratory virus–induced asthma by dampening antiviral immunity
Authors: Jason P. Lynch, Rhiannon B. Werder, Jennifer Simpson, Zhixuan Loh, Vivian Zhang, Ashraful Haque, Kirsten Spann, Peter D. Sly, Stuart B. Mazzone, John W. Upham, Simon Phipps
Journal: Journal of Allergy and Clinical Immunology (2016)
Acute Impact of Hourly Ambient Air Pollution on Preterm Birth
Authors: Shanshan Li, Yuming Guo, Gail Williams
Journal: Environmental Health Perspectives (2016)

Background:Preterm birth is a major perinatal health problem, but factors leading to it are still not completely understood.Objectives:Our goal was to identify the relation between acute increase in ambient air pollution in a few hours before onset of labor and the risk of preterm birth.Methods:We collected registered birth outcome data and hourly ambient air pollution measurements during 2009‒2013 in Brisbane, Australia. Using a time-stratified case-crossover design and conditional logistic regression models with natural cubic splines, we assessed the shape of air pollution-preterm birth curve, after controlling for potential confounders. We also examined the effect modification of other factors.Results:The association between air pollution [nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO)] and preterm birth was nonlinear. Threshold concentrations for the mean of 0‒24 hr NO2, 24‒48 hr SO2, and 24‒48 hr CO before onset of labor were 7.6 parts per billion (ppb), 3.8 ppb, and 162.5 ppb, respectively. Increases in air pollution concentrations above thresholds were associated with increased risks of preterm birth. The odds ratios of preterm birth at the 95th percentile of NO2, SO2, and CO against the thresholds were 1.17 (95% CI: 1.08, 1.27), 1.01 (95% CI: 0.99, 1.04), and 1.18 (95% CI: 1.06, 1.32), respectively. The associations were modified by demographic factors, such as maternal smoking and socioeconomic status.Conclusion:Acute increases in ambient air pollution concentrations above certain levels before onset of labor may stimulate preterm birth.Citation:Li S, Guo Y, Williams G. 2016. Acute impact of hourly ambient air pollution on preterm birth. Environ Health Perspect 124:1623–1629; http://dx.doi.org/10.1289/EHP200
Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis
Authors: Jeffrey R Curtis, Fenglong Xie, Huifeng Yun, Sasha Bernatsky, Kevin L Winthrop
Journal: Annals of the Rheumatic Diseases (2016)

To evaluate the risks of herpes zoster (HZ) and herpes simplex virus (HSV) infection associated with tofacitinib compared with biologic agents among patients with rheumatoid arthritis (RA).Using health plan data from 2010 to 2014, patients with RA initiating tofacitinib or biologics with no history of HZ or HSV were identified, as were incident cases of HZ or HSV. Crude incidence rates were calculated by drug exposure. Cox proportional hazards models evaluated the adjusted association between tofacitinib and HZ, and a composite outcome of HZ or HSV.A total of 2526 patients initiating tofacitinib were compared with initiations of other biologics: anti-tumour necrosis factor (TNF) (n=42 850), abatacept (n=12 305), rituximab (n=5078) and tocilizumab (n=6967). Patients receiving tofacitinib were somewhat younger (mean age 55 years) versus those on other biologics, and somewhat less likely to use concomitant methotrexate (MTX) (39% vs 43%-56%, depending on drug). Crude incidence of HZ associated with tofacitinib was 3.87/100 patient-years (py). After multivariable adjustment, HZ risk was significantly elevated, HR 2.01 (95% CI 1.40 to 2.88) compared with abatacept. Rates and adjusted HRs for all other RA biologics were comparable with each other and abatacept. Older age, female sex, prednisone >7.5 mg/day, prior outpatient infection and greater number of hospitalisations were also associated with increased HZ risk. Incidence rates for the combined outcome were greatest for tofacitinib (7.61/100 py) and also significantly elevated after adjustment (HR=1.40, 95% CI 1.09 to 1.81).The rate of zoster associated with tofacitinib was approximately double that observed in patients using biologics.
Two doses of polatuzumab vedotin (PoV, anti-CD79b antibody-drug conjugate) in patients (pts) with relapsed/refractory (RR) follicular lymphoma (FL): Durable responses at lower dose level.
Authors: Ranjana H. Advani, Ian Flinn, Jeff Porter Sharman, Catherine S. Magid Diefenbach, Kathryn S. Kolibaba, Oliver W. Press, Laurie Helen Sehn, Andy I. Chen, Gilles A. Salles, Herve Tilly, Bruce D. Cheson, Sarit E. Assouline, Martin H. Dreyling, Anton Hagenbeek, Pier Luigi Zinzani, Cheryl Jones, Yu-Waye Chu, Jamie Hirata, Michael Wenger, Franck Morschhauser
Journal: Journal of Clinical Oncology (2015)

8503 Background: Based on early evidence of cumulative toxicity of PoV at a dose of 2.4 mg/kg (Morschhauser ASH 2014 NCT01691898), a dose of 1.8 mg/kg was explored. We report updated results of the dose comparison. Methods: Pts with RR FL received PoV at 2.4 mg/kg or 1.8 mg/kg with R at 375mg/m2 q21d until progression or unacceptable toxicity. 5 pts from PhI (Palanca-Wessels ASH 2013) treated at the 2.4 mg/kg dose were included. Data at completion of PoV treatment were compared with data after 8 cycles. Results: 25 pts received PoV+R at 2.4 mg/kg, and 20 at 1.8 mg/kg. Median follow up was 14 mos for 2.4 mg/kg and 8 mos for 1.8 mg/kg. Baseline characteristics were balanced, except for age (median 68 yrs 2.4 mg/kg, 62 yrs 1.8 mg/kg) and tumor volume (SPD 1824 mm2 2.4 mg/kg, 2655 mm21.8 mg/kg). 40% (10/25, 2.4 mg/kg) and 50% (10/20, 1.8 mg/kg) of pts were refractory to their last treatment. Pts received a median of 10 cycles of PoV+R at 2.4 mg/kg vs. 9.5 at 1.8 mg/kg. Dose intensity through cycle 8 was 88% for 2.4 mg/kg and 99% for 1.8 mg/kg. Safety is shown in Table. An 84 yr old pt in the 2.4 mg/kg cohort died 2 months after cycle 12 due to pulmonary congestion. ORR was similar for both dose levels: 19/25 (76%) at 2.4 mg/kg, 15/20 (75%) at 1.8 mg/kg. CR: 11/25 (44%) at 2.4 mg/kg, 2/20 (10%) at 1.8 mg/kg. After 8 cycles, CR: 32% at 2.4 mg/kg and 10% at 1.8 mg/kg. Median PFS: 15 mo at 2.4 mg/kg, n.r. at 1.8 mg/kg. Conclusions: PoV+R in RR FL showed high ORR at both doses, with higher CR at 2.4 mg/kg. AEs and d/c rates were reduced at both doses if only the first 8 cycles are considered vs. those reported through study completion. The safety of PoV can be improved by shorter treatment and/or lower dose. Updated PFS will be presented. Clinical trial information: NCT01691898.Safety of PoV+R. PoV+R 1.8 mg/kg all cycles 2.4 mg/kg all cycles 1.8 mg/kg 8 cycles 2.4 mg/kg 8 cycles n (%) 20 25 20 25 Any AE G3-4 Neutropenia Febr neutropenia SAE Deaths AE leading to d/c G2-4 PN1 G3+ infection 10 (50) 7 (35) 2 (10) 6 (30) - 6 (30) 8 (40) 1 (5) 13 (52) 4 (16) 1 (4) 8 (32) 1 (4) 14 (56) 18 (72) 3(12) 10 (50) 7 (35) 2 (10) 6 (30) - 5 (25) 5 (25) 1 (5) 13 (52) 4 (16) 1 (4) 6 (24) - 7 (28) 10 (40) 2 (8) AE per CTCAE V4.03. AEs G3/4 ≥ 10% reported. 1MedDRA SMQ peripheral neuropathy.
Case 33-2012
Authors: J. Carl Pallais, Michael A. Blake, Vikram Deshpande
Journal: New England Journal of Medicine (2012)

A 34-year-old woman, 2.5 months post partum, was admitted to the hospital because of episodic paresthesias and altered mental status, with amnesia for the events. During one episode, hypoglycemia was noted. A diagnostic test was performed.
Continuous Effector CD8 + T Cell Production in a Controlled Persistent Infection Is Sustained by a Proliferative Intermediate Population
Authors: H. Hamlet Chu, Shiao-Wei Chan, John Paul Gosling, Nicolas Blanchard, Alexandra Tsitsiklis, Grant Lythe, Nilabh Shastri, Carmen Molina-París, Ellen A. Robey
Journal: Immunity (2016)
Enzalutamide (ENZA) in combination with abiraterone acetate (AA) in bone metastatic castration resistant prostate cancer (mCRPC).
Authors: Eleni Efstathiou, Mark Anton Titus, Sijin Wen, Aileen SanMiguel, Anh Hoang, Angela De Haas-Amatsaleh, Frank Perabo, De Phung, Patricia Troncoso, Taoufik Ouatas, Christopher Logothetis
Journal: Journal of Clinical Oncology (2014)

5000 Background: Co-targeting the androgen receptor (AR) and paracrine androgen biosynthesis in mCRPC may be more effective than either alone. This study aims to evaluate safety, pharmacokinetic (PK) drug-drug interactions (DDI), androgen signaling and steroid metabolome modulation and efficacy of ENZA with AA in mCRPC Methods: We enrolled patients (pts) with progressive bone mCRPC, castrate level serum testosterone (≤ 50 ng/dl) consenting to bone marrow (BM) biopsy. Pts were treated with ENZA 160 mg QD and AA 1g QD + prednisone 5 mg bid and monitored every 4-week with CBC, chemistry, physical exams. mCRPC was assessed clinically by PSA, ALP and imaging. Tumor was characterized by IHC and LC mass spectrometry (blood and BM). Ctroughplasma concentrations of AA were measured on days 4 & 29, and ENZA and its active metabolite M2 on d29 in pt subset. Results: We enrolled (07/12-09/13) 60 pts with median age 66 yrs (range 40-82), PS-ECOG 1 (range 0-2) and PSA 20.8 ng/ml (range1-670). Gleason Score (GS) at diagnosis ≥ 8 in 38/53 (72%), [GS ≥ 9 29/53 (55%)/7 unknown]. Thirty (50%) had > 20 bone lesions, 19/60 (32%) lymph node lesions and 2/60 (3%) visceral metastases. Interim data on evaluable pts: PSA changes for 49 pts: maximum PSA decline ≥ 50% (37/49 [76%]), ≥ 90% (22/49 [45%]), PSA ≤ 0.1ng/ml (5/49 [10%]) and PSA progression (6 [12%]). Grade 3 adverse events: ALT rise (5), hypertension (5), ALP rise (4 ), arthralgia (3), bone pain (2). No Grade 4 AEs reported. At ENZA steady state (d29), Ctrough of AA was ~23% lower than d4 (pt n=14; LS means ratio 77.67 %; 90% CI 47.51-126.98) and Ctroughfor ENZA, M2, and the sum of both (pt n=15) were comparable to those reported previously. Following 8 weeks treatment, serum and BM testosterone were undetectable (<1pg/ml) in 29/39 (74%) and 31/36 (86%) evaluated pts respectively, and androstenedione in all pts. Nuclear AR expression was reduced following treatment in 5/6 of evaluable paired tumor specimens. Conclusions: ENZA+ AA combination has a favorable safety profile, without clinically meaningful PK DDI. Feedback mechanisms observed by either agent are dissipated. These promising findings are indicative of more efficacious androgen signaling inhibition in men with mCRPC. Clinical trial information: NCT01650194.
Abstract P4-02-11: Value of magnetic resonance imaging in preoperative predicting tumor extent in each subtypes of breast cancer
Authors: BS Yang, HW Lee, JT Park, HM Lee, SG Ahn, J Jeong
Journal: Cancer Research (2016)

Abstract Background: It is well known that patients with triple-negative breast cancer (TNBC) have a high risk of local tumor recurrence in ipsilateral breast. To know the additional value of breast magnetic resonance imaging (MRI) in preoperative prediction of tumor extent for TNBC, we tested the accuracy of MRI in correlation with pathologic tumor size according to subtypes. In addition, we investigated the margin-positive rates by subtypes among the patients receiving breast-conservative surgery (BCS). Methods: We retrospectively identified patients with invasive breast cancer who had preoperative breast MRI and ultrasound between 2011 and 2014. We excluded patients having large tumor more than 5cm or multiple tumors. Patients were classified into 4 subtypes (luminal A, luminal B/HER2, HER2, triple-negative breast cancer (TNBC)) based on the immunohistochemistry. Lin's concordance correlation coefficient was used to measure the agreement between the MRI or ultrasound and tumor extent. Also, patients were classified into three groups according to the accuracy of MRI in correlation with tumor extent (concordance, underestimation, and overestimation). Tumor extent was defined as pathologic tumor size including in situ carcinoma. Results: In a total of 589 patients, 397(67.4%) women received BCS. Means of tumor size were 1.99 ± 0.91 cm by pathologic review, 1.91 ± 1.01 cm by MRI, and 1.76 ± 0.92 cm by ultrasonography, respectively. Correlation analysis revealed a similar concordance rate between MRI and ultrasound to pathologic tumor size (r= 0.622 and 0.573). Lin's concordance analysis showed that MRI showed more significant correlation with pathologic tumor size than ultrasound in patients with TNBC (r= 0.735 VS 0.593, p=0.0052). However, the proportion of concordant group did not differ significantly according to subtypes (p=0.279). Conclusions: Our findings suggest that preoperative MRI does not increase the accuracy in predicting tumor extent or reduce the margin-positive rates in breast cancer. Citation Format: Yang BS, Lee HW, Park JT, Lee HM, Ahn SG, Jeong J. Value of magnetic resonance imaging in preoperative predicting tumor extent in each subtypes of breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-02-11.
LOCALIZATION OF ANTIGEN IN TISSUE CELLS
Authors: Albert H. Coons, John C. Snyder, F. Sargent Cheever, Edward S. Murray
Journal: The Journal of Experimental Medicine (1950)

Rickettsiae of epidemic typhus fever and Rocky Mountain spotted fever have been microscopically localized and identified in smears of exudates and tissue sections from infected cotton rats by means of homologous antibody labelled with fluorescein. Epidemic typhus has also been identified in smears from single infected human body lice. Mumps virus antigen has been microscopically localized in the parotid of the experimentally infected monkey by the same method. The antigenic material, probably active virus, was found in the cytoplasm of the acinar cells. Such infected acini were scattered irregularly throughout the gland. Some antigen could be seen in the lumens of the parotid ducts and small amounts were present in the cytoplasm of the epithelial cells lining the ducts.
NfP2X<sub>7</sub>, a novel target for immune therapeutic approaches in cancer treatment.
Authors: Jan Nesselhut, Julian Barden, Dagmar Marx, Nicole Cillien, Wiebke Goebel, Michael Herrmann, Raymond Y. Chang, Thomas Nesselhut
Journal: Journal of Clinical Oncology (2013)

3094 Background: P2X 7 receptor, a ligand-gated channel, is activated by extracellular ATP and mediates ATP induced apoptosis. Several polymorphisms leading to loss of function of P2X 7 have been described. Overexpression of non-functioning P2X 7 receptor (nfP2X 7 ), able to form a Ca 2+ channel but not an apoptotic pore, is found on every type of cancer cell but no normal cells, making it a perfectly selective target for immune therapy approaches. Methods: Samples from various tumor types were analyzed for the expression of nfP2X 7 using immunohistochemistry. MoDC from n=6 patients with advanced metastatic sarcoma (2 osteosarcoma, 4 soft tissue sarcoma) with disease progression after failure of extensive standard therapies were primed against the nfP2X 7 using a specific peptide. MoDC were harvested, analyzed by flow cytometry and applied to the patient intradermaly. Specific T-cell response was analyzed by IFN-gamma Elispot. Results: nfP2X 7 is overexpressed in essentially all analyzed tumor samples from all cell types: epithelial, mesenchymal, neural, germinal examined in large numbers (n = 5 to &gt;1,000). The uniquely displayed epitope associated with the ATP binding site exposed on nfP2X 7 but hidden in P2X 7 was found on the cancer cell surface but not on the surface of any normal cells. MoDC primed with a specific peptide against nfP2X 7 show a distinct DC morphology and an up-regulation of the maturation marker CD83. Patients are 6-9 months (onset June 2012) under treatment at time of abstract submission. 2 patients have a disease stabilization. One further patient with a metastatic, rapidly growing osteosarcoma showed a mixed response. IFN-gamma Elispot, which was exemplarily performed, shows a nfP2X 7 -specific T-cell response. Conclusions: Efficient inductions of an antitumor response by dendritic cell therapy require the definition and choice of an optimal target, being expressed in almost all kinds of tumors. nfP2X 7 , a set of non-functioning forms of the P2X 7 receptor unable to initiate apoptosis but maintaining channel activity, could therefore be an optimal universal candidate. The efficacy of dendritic-cell based therapy may be improved by priming the MoDC against nfP2X 7 and thus may improve the clinical outcome.