tbuckley/cabot-search huggingface dataset:
Pathogenesis of Virus-Induced Rous Sarcoma. II. Dynamics of Tumor Development and Viral Growth Patterns in Chicks&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn2"&gt;3&lt;/xref&gt;
Authors: Herbert J. Spencer, Vincent Groupé
Journal: JNCI Journal of the National Cancer Institute (1962)

Studies were made of the dynamics of tumor development and of associated virus levels in chicks infected with very large doses of Rous sarcoma virus (RSV). Following intracerebral inoculation virus was detectable in the brain and lung by day 3, with titers reaching high levels by the 9th day after infection. Blood plasma contained appreciable amounts of RSV beyond day 6. Hyperplastic changes were noted in the meninges and lungs at the same time that virus was first detectable in these organs. Such changes gradually progressed to frank neoplasia during the course of the disease, with a parallel rise in viral titers. Following subcutaneous infection similar results were noted, again with infectious virus in the plasma. A study of liver lesions after infection with either standard RSV or chick-brain passage virus indicated a marked quantitative difference between the 2 strains. Chick-brain virus produced lesions of greater severity in higher frequency» However, no qualitative differences in histopathology were observed. Time studies on the infectivity of blood components showed that both buffy coat and sternal bone marrow contained high levels of infective virus by the 8th postinfective day, while titers in the plasma did not exceed 10 3.5 pock-forming units. These data indicate that the pathogenesis of both primary and metastatic tumors is characterized by progressive in situ changes of pre-existing cellular elements. These findings, coupled with the high viral titers present in blood, strongly suggest direct viral initiation of remote tumor foci following infection with large doses of RSV.
Hospitalisation associated with the 2009 H1N1 pandemic and seasonal influenza in Hong Kong, 2005 to 2010
Authors: L Yang, X L Wang, K P Chan, P H Cao, H Y Lau, J S Peiris, C M Wong
Journal: Eurosurveillance (2012)

Reliable estimates of the morbidity burden caused by the 2009 pandemic influenza (pH1N1) are important for assessing the severity of the pandemic. Poisson regression models were fitted to weekly numbers of cause-specific hospitalisation in Hong Kong from 2005 to 2010. Excess hospitalisation associated with the 2009 pandemic and seasonal influenza was derived from the model by incorporating the proxy variables of weekly proportions of specimens positive for the pandemic influenza A(H1N1)pdm09, seasonal influenza A (subtypes H3N2 and H1N1) and B viruses. Compared with seasonal influenza, pH1N1 influenza was associated with higher hospitalisation rates for acute respiratory disease (ARD) among children younger than 18 years and adults aged between 18 and 64 years, but among the elderly aged 65 years and older the hospitalisation rates were lower for pH1N1 than for seasonal H3N2 and H1N1 influenza. Hospitalisation rates for chronic diseases associated with pH1N1 influenza were generally higher than those associated with seasonal influenza. The reported hospitalised cases with laboratory-confirmed pandemic infections accounted for only 16% of pH1N1 influenza-associated hospitalisations for ARD in the age group 75 years and older, and 5?66% of hospitalisations for chronic diseases in those older than 40 years. The 2009 H1N1 influenza pandemic was associated with a dramatically increased risk of hospitalisation among children and young adults. The morbidity burden of pandemic was underreported in old people and in those with chronic conditions.
Phase II study of docetaxel (D) plus bevacizumab (B) in Her/2 negative metastatic breast carcinoma (MBC)
Authors: D. Chan, H. Allen, E. Hu, D. Reese, G. Patel, C. Gottlieb, A. Wax, J. Sosa, D. Slamon, F. Kabbinavar
Journal: Journal of Clinical Oncology (2006)

13047 Background: Taxol+Bevacizumab (B) has clinical activity in Her/2 negative chemotherapy naive MBC with a PFS (11.4 mo), RR (29.9%), and OS (28.4 mo). We are conducting a single arm Phase 2 trial to assess the efficacy of Docetaxel (D)+B. Primary endpoint: time to progression. Secondary endpoints: response rate (CR + PR), response duration, overall survival and safety. Methods: Eligibility criteria: MBC with no prior therapy; Her/2 negative by FISH, ECOG PS 0 or 1; measurable disease by RECIST, Hgb ≥ 9 g/dL, ANC ≥ 1.5 × 10 9 /L, Platelet count ≥ 100 × 10 9 /L, Creatinine ≤ 2.0 mg/dL, Total bilirubin ≤ 1.0 × upper limit of normal, no CNS metastasis, no MI or stroke within 6 mo, no GI perforation, no major surgery within 28 d, and no bleeding diathesis or coagulopathy. Pts receive B 15 mg/kg IV and D 75 mg/m 2 IV Q 3 wk. Response assessed radiographically Q 3 cycles. Treatment is until disease progression or unacceptable toxicity. Results: Since Apr 2005, 43 of the planned 75 pts have been enrolled. 21 pts have had at least one assessment resulting in approximately 40% response rate. Common Gr3/4 AE’s have been neutropenia, febrile neutropenia, hypertension. Gr3 LVEF decline seen in one pt. No treatment related deaths occurred. Conclusions: D+ B is well tolerated, with no new safety concerns and manageable toxicities. D+B appears active in MBC. Updated efficacy and safety data will be presented. Study supported by Genentech, Inc. San Francisco, CA. No significant financial relationships to disclose.
Unrelated donor bone marrow transplantation for children and adolescents with Philadelphia-positive acute lymphoblastic leukemia.
Authors: D I Marks, J M Bird, J M Cornish, N J Goulden, C G Jones, C J Knechtli, D H Pamphilon, C G Steward, A Oakhill
Journal: Journal of Clinical Oncology (1998)

PURPOSE Few patients with Philadelphia-positive acute lymphoblastic leukemia (Ph-positive ALL) have been cured by chemotherapy alone. Registry figures show that 38% of patients who have a matched-sibling bone marrow transplant (BMT) are disease-free 2 years after transplant, but the majority of patients lack a sibling donor. Most modern ALL protocols recommend unrelated donor (UD) BMT for patients with Ph-positive ALL in first complete remission (CR1), but the outcome of this is unknown. PATIENTS AND METHODS We report the results of 15 children and adolescents who had a T-cell depleted UD-BMT for Ph-positive ALL. Thirteen of 15 had been previously treated on United Kingdom ALL protocols. Nine were in CR1 and six had more advanced disease. Eleven donor recipient pairs were matched at HLA-A, HLA-B, HLA-DR, and HLA-DQ, and four were mismatched at one or two HLA loci. RESULTS The incidence of greater than grade I acute and chronic graft-versus-host disease (GVHD) was low (13% and 8%, respectively). Six patients have relapsed and seven patients survive at a median of 21 months post-BMT; six of seven are disease free. All seven survivors are in full-time education or work. The 2-year overall and disease-free survivals are 44% +/- 13% and 37% +/- 13% (+/- SE). None of four patients who had mismatched donors survived, but seven of 11 matched recipients survive (P &lt; .05). CONCLUSION UD-BMT can produce prolonged disease-free survival in young patients with Ph-positive ALL who otherwise would have an extremely poor outlook.
Individual genotyping to optimize chemotherapy in metastatic colorectal cancer (MCRC): The COLOGEN trial
Authors: C. Falandry, B. You, G. Milano, E. Chatelut, C. Rebischung, O. Glehen, D. Mille, J. Delord, G. Lledo, V. Trillet-Lenoir, G. Freyer
Journal: Journal of Clinical Oncology (2007)

2510 Background: Thymidilate synthase (TS) and UGT1A1 genetic polymorphisms assessment helps to predict 5-FU efficacy and irinotecan toxicity - SN38 inactivation - respectively. We used this information to individualize MCRC first-line chemotherapy in the multi-centre COLOGEN trial. Methods: Were included first-line histologically proven MCRC patients (pts) aged 18–85, PS=2. Genotyping was performed on pts’ lymphocytes sampled at most 10 days before chemotherapy. Pts with 2R/2R or 2R/3R TS profile had subsequent UGT1A1 polymorphism determination. Those with 6/6 or 6/7 UGT1A1 profile received high dose bimonthly FOLFIRI (Irinotecan 260 mg/m 2 ), whereas those with “defavorable” 7/7 polymorphism received standard FOLFIRI (Irinotecan 180 mg/m 2 ). In pts with overexpressed TS (3R/3R), chemotherapy was left to investigator’s decision. Results: To date, 32 pts/65 planned have been included, aged 44 to 83 (mean: 65,2, median: 64). Six pts (19 %) had 3R/3R TS profile. Among those with 2R/2R or 2R/3R profile, 15 % (4/26) had defavorable 7/7 UGT1A1 profile. Median time for genotypic determination was 5 days for UGTA1 and 5 for TS. Treatment was: high-dose FOLFIRI, 23 pts (72 %); standard FOLFIRI ± bevacizumab, 3 pts (9 %); other regimens including capecitabine and/or oxaliplatin, 6 pts (16 %). Toxicities: we observed no toxic death. Serious adverse events were: febrile neutropenia (1, high dose FOLFIRI regimen) and grade 4 hypokaliemia (1, non FOLFIRI regimen). Eight patients over 70 years old and 3 over 80 received high-dose FOLFIRI without significant toxicity. Conclusions: Those preliminary results are the first ever reported on individual genotyping as a tool for treatment optimization in a multi-centre setting. This strategy appears clearly feasible and allows to safely intensify chemotherapy, even in elderly patients. No significant financial relationships to disclose.
Irinotecan as a Third-Line Treatment of Advanced Gastric Cancer After Failure of Fluoropyrimidine, Platinum, and Taxanes
Authors: Takashi Nishimura, Satoru Iwasa, Hirokazu Shoji, Natsuko Okita, Atsuo Takashima, Yoshitaka Honma, Ken Kato, Tetsuya Hamaguchi, Yasuhide Yamada, Yasuhiro Shimada
Journal: Annals of Oncology (2014)
Surgical resection for stage IV melanoma: A Southwest Oncology Group trial (S9430)
Authors: V. K. Sondak, P. Y. Liu, J. Warneke, J. Vetto, R. Tuthill, B. Redman, J. A. Sosman
Journal: Journal of Clinical Oncology (2006)

8019 Background: Surgery is the treatment of choice for isolated distant metastases of melanoma. Based on a number of retrospective reports, patients (pts) who have undergone complete resection of metastatic disease can have an excellent survival. Methods: In SWOG, we prospectively evaluated surgical resection for stage IV melanoma. Pts enrolled prior to surgery; treatment following resection was at the discretion of the treating physician. Resected specimens were collected, whenever possible, for future molecular analyses. Results: Over a 9 year period from 1996 to 2005, 77 pts were enrolled from 18 centers, with 7 centers accruing ≥4 pts. Of 77 pts, 10 were incompletely resected and 5 had no evidence of stage IV disease. Therefore, 62 pts (81%) felt to have resectable stage IV actually did, and were included in the analysis. Pts characteristics were: median age 54 yrs (range 23–81); M:F 69%:31%; PS 0–1 100%; prior adjuvant IFN 45%. Resected sites included skin/soft tissue 40%; distant LN 21%; lung 13%; liver 8%; CNS 5%; bone 2%; other visceral sites 27%. Post-surgical complications included 1 grade IV pulmonary embolus and 1 grade III liver toxicity. Following surgery but prior to any further recurrence, 18 pts received adjuvant treatment including 8 with IFN and 7 with radiotherapy. After surgery, median progression-free survival (PFS) was 6 mos (95% CI 3–7 mos) with 9 patients (15%) remaining progression-free. Median overall survival (OS) was 21 mos (95% CI 15–28 mos); 3- and 4-yr OS was 33% and 29%, respectively. Conclusions: These results provide an estimate of prognosis for resected stage IV disease from a diverse patient base. They illustrate the potential for prolonged OS even with a short PFS. In some cases, pts can be repeatedly resected for long-term control of their disease. Pts with resectable stage IV melanoma are appropriate candidates for inclusion in adjuvant therapy trials. No significant financial relationships to disclose.
Zinc finger protein A20 is involved in the antipsoriatic effect of calcipotriol
Authors: X. Liu, Y. Liu, M. Xu, J. Li, X. Teng, H. Cheng, Y. Xia
Journal: British Journal of Dermatology (2016)

Calcipotriol ameliorates psoriasis through inducing keratinocyte apoptosis and inhibiting nuclear factor kappa B (NF-κB) activation, while zinc finger protein A20 exhibits an anti-apoptotic effect on various types of cells.To understand the potential role of A20 in calcipotriol function.The A20 levels were evaluated in the psoriatic skins from both human patients and K14-vascular endothelial growth factor (VEGF) transgenic mice that received or did not receive topical calcipotriol treatment. The in vitro effect of calcipotriol on A20 expression and the downstream NF-κB pathway was studied using a model of human foreskin keratinocytes (HFKs) that were stimulated with psoriatic cytokines [M5, a cocktail of interleukin (IL)-1a, IL-17A, IL-22, Oncostatin M and tumour necrosis factor-α, each at 10 ng mL(-1) ].A20 expression was enhanced in both psoriatic tissues and keratinocytes when compared with controls, but decreased on calcipotriol treatment. The transfection of A20 small interfering RNA (siRNA) improved cell differentiation, and inhibited psoriatic inflammation in a HFK model. Moreover, the nuclear expression of NF-κB p65 decreased on A20 downregulation in psoriatic tissues and keratinocytes. Interestingly, calcipotriol enhanced the binding of A20 to ring finger protein 114 (RNF114) and A20-binding inhibitor of NF-κB-1 (ABIN-1) in HFKs, two negative regulators of the NF-κB pathway.Calcipotriol exhibits its antipsoriatic function through suppressing A20 expression and stabilizing negative regulators of the NF-κB pathway.
Abstract 10633: Sleep Disordered Breathing in Patients Undergoing Transfemoral Aortic Valve Implantation for Severe Aortic Stenosis
Authors: Zisis Dimitriadis, Marcus Wiemer, Werner Scholtz, Lothar Faber, Thomas Bitter, Ippokratis Messaritakis, Kevin Bullert, Christian Prinz, Dieter Horstkotte, Olaf Oldenburg
Journal: Circulation (2012)

Purpose: Sleep disordered breathing (SDB) with obstructive (OSA) or central (CSA) respiratory events is of major prognostic impact for patients with cardiovascular disease. We examined the prevalen...
First-in-human dose escalation study of LY2875358 (LY), a bivalent MET antibody, as monotherapy and in combination with erlotinib (E) in patients with advanced cancer.
Authors: Jonathan Wade Goldman, Lee S. Rosen, Alain Patrick Algazi, Patricia Kellie Turner, Volker Wacheck, Jay Tuttle, James E Wooldridge, Michaela S. Banck
Journal: Journal of Clinical Oncology (2013)

8093 Background: Activation of the hepatocyte growth factor (HGF)/MET receptor pathway promotes tumor growth, invasion and dissemination. LY is a humanized IgG4 monoclonal bivalent antibody against MET which inhibits ligand dependent- and ligand independent activation of MET. Based on preclinical results, we examined LY alone in patients with advanced solid tumors and LY+E in advanced NSCLC patients. Methods: LY monotherapy was administered 20-2,000 mg Q2W IV to 23 patients with advanced solid tumors. Combination therapy with 700-2,000 mg Q2W IV of LY and E (150 mg QD) was completed in 14 patients with advanced NSCLC. The primary objective was to determine a recommended phase II dose (RPTD) for LY and LY+E. Secondary objectives included assessment of toxicity, PK, PD (including MET extracelluar domain and HGF), and antitumor activity. Results: LY and LY+E were well tolerated. No dose-limiting toxicities, serious adverse events, or ≥ Grade 3 adverse events (AEs) possibly related to LY have been observed. The most frequent (≥5% of patients) AEs possibly related to LY2875358 monotherapy were nausea (8.7 %), vomiting (8.7%), and diarrhea (8.7%). The most frequent (≥10% of patient) grade 1 or 2 adverse event possibly related to LY2875358 in patients treated with LY+E were fatigue (21.4%) and anorexia (14.3%). Durable PR according to RECIST were observed for LY (n=1) and LY+E (n=2 out of 13 evaluable patients; both PR patients positive for MET protein expression). Conclusions: LY appears to be safe when administered as single agent and in combination with E up to 2,000 mg Q2W IV. The RPTD of LY is 750 mg Q2W IV for monotherapy and in combination with E based on PK/PD data. Clinical trial information: NTC 01287546.
Differential Effect on Bone Lesions of Targeting Integrins: Randomized Phase II Trial of Abituzumab in Patients with Metastatic Castration-Resistant Prostate Cancer
Authors: Maha Hussain, Sylvestre Le Moulec, Claude Gimmi, Rolf Bruns, Josef Straub, Kurt Miller
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Integrins play a critical role in the progression of prostate cancer and its bone metastases. We investigated the use of the pan-αv integrin inhibitor abituzumab in chemotherapy-naïve patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer. Experimental Design: PERSEUS (NCT01360840) was a randomized, double-blind phase II study. Men with pathologically confirmed prostate cancer and radiologic progression of bone lesions in the 28 days prior to randomization were assigned to receive abituzumab 750 mg or 1,500 mg or placebo (1:1:1) every 3 weeks in combination with luteinizing hormone-releasing hormone agonist/antagonist therapy. The primary endpoint was progression-free survival (PFS). Results: The intent-to-treat population comprised 180 patients, 60 in each arm. The primary endpoint of PFS was not significantly different with abituzumab-based therapy compared with placebo [abituzumab 750 mg, 3.4 months, HR = 0.89; 95% confidence interval (CI), 0.57–1.39; abituzumab 1,500 mg, 4.3 months, HR = 0.81; 95% CI, 0.52–1.26; placebo, 3.3 months], but the cumulative incidence of bone lesion progression was lower with abituzumab than with placebo for up to 24 months (cumulative incidence 23.6% vs. 41.1% at 6 months, 26.1% vs. 45.4% at 12 months). Two partial tumor responses were observed (1 abituzumab 1,500 mg and 1 placebo). Approximately 85% to 90% of patients experienced at least one treatment-emergent adverse event (TEAE) in the different arms, but the incidences of serious TEAEs and TEAEs with fatal outcome were similar in the three arms. Conclusions: Although PFS was not significantly extended, abituzumab appears to have specific activity in prostate cancer–associated bone lesions that warrants further investigation. Clin Cancer Res; 22(13); 3192–200. ©2016 AACR.
Notch signaling negatively regulate the expression of MUC5AC in airway goblet cells
Authors: Hai Feng Ou Yang
Journal: European Respiratory Journal (2012)

Introduction and background: Goblet cell metaplasia and airway mucus hypersecretion contributed to the pathogenesis of asthma and COPD. Evidence has shown that Notch signaling modulates the development of lung epithelial and the differentiation of intestinal goblet cells. Whether Notch signaling can regulate the expression of MUC5AC, a major component of airway mucus, is still unknown. Aim and objective: To investigate whether Notch signaling can regulate MUC5AC expression in airway goblet cells. Methods: Expression of Notch receptors and downstream molecules in airway goblet cells was examined. Then, after transfected with pEFBOS-NIC (upregulating Notch signaling) or treated with γ-secretase inhibitor (downregulating Notch signaling), the MUC5AC expression in airway goblet cells was examined. Finally, the transcriptional regulatory mechanisms were analyzed. Results: Airway goblet cells express Notch1, Notch3 and downstream transcription factor hes1. Notch signaling can modulate the MUC5AC expression both in vivo and in vitro. Two N-box sites (hes1 binding site), -1439 and -893, were identified within mouse MUC5AC promoter. One N-box site (-293) was identified within human MUC5AC promoter. The Notch intracellular domain NIC, the active form of Notch receptors, activates the reporters driven by mouse or human MUC5AC promoters. Site-directed mutagenesis reporter assays confirmed that mouse N-box (-893) and human N-box (-293) negatively regulated MUC5AC promoter activity. ChIP assays showed that Hes1 bound to the MUC5AC promoter in both mouse and human airway goblet cells. Conclusions: Notch signaling negatively regulates the MUC5AC expression through Hes1-dependent mechanism in airway goblet cells.
Reactive astrocytes undergo M1 microglia/macrohpages-induced necroptosis in spinal cord injury
Authors: Hong Fan, Kun Zhang, Lequn Shan, Fang Kuang, Kun Chen, Keqing Zhu, Heng Ma, Gong Ju, Ya-Zhou Wang
Journal: Molecular Neurodegeneration (2016)

A unique feature of the pathological change after spinal cord injury (SCI) is the progressive enlargement of lesion area, which usually results in cavity formation and is accompanied by reactive astrogliosis and chronic inflammation. Reactive astrocytes line the spinal cavity, walling off the lesion core from the normal spinal tissue, and are thought to play multiple important roles in SCI. The contribution of cell death, particularly the apoptosis of neurons and oligodendrocytes during the process of cavitation has been extensively studied. However, how reactive astrocytes are eliminated following SCI remains largely unclear. By immunohistochemistry, in vivo propidium iodide (PI)-labeling and electron microscopic examination, here we reported that in mice, reactive astrocytes died by receptor-interacting protein 3 and mixed lineage kinase domain-like protein (RIP3/MLKL) mediated necroptosis, rather than apoptosis or autophagy. Inhibiting receptor-interacting protein 1 (RIP1) or depleting RIP3 not only significantly attenuated astrocyte death but also rescued the neurotrophic function of astrocytes. The astrocytic expression of necroptotic markers followed the polarization of M1 microglia/macrophages after SCI. Depleting M1 microglia/macrophages or transplantation of M1 macrophages could significantly reduce or increase the necroptosis of astrocytes. Further, the inflammatory responsive genes Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) are induced in necroptotic astrocytes. In vitro antagonizing MyD88 in astrocytes could significantly alleviate the M1 microglia/macrophages-induced cell death. Finally, our data showed that in human, necroptotic markers and TLR4/MyD88 were co-expressed in astrocytes of injured, but not normal spinal cord. Taken together, these results reveal that after SCI, reactive astrocytes undergo M1 microglia/macrophages-induced necroptosis, partially through TLR/MyD88 signaling, and suggest that inhibiting astrocytic necroptosis may be beneficial for preventing secondary SCI.