tbuckley/cabot-search huggingface dataset:
Endothelial Dimethylarginine Dimethylaminohydrolase 1 Is an Important Regulator of Angiogenesis but Does Not Regulate Vascular Reactivity or Hemodynamic Homeostasis
Authors: Laura Dowsett, Sophie Piper, Anna Slaviero, Neil Dufton, Zhen Wang, Olga Boruc, Matthew Delahaye, Lucy Colman, Eliza Kalk, James Tomlinson, Graeme Birdsey, Anna M. Randi, James Leiper
Journal: Circulation (2015)

Background— Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthesis and a risk factor for cardiovascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) enzymes are responsible for ADMA breakdown. It has been reported that endothelial DDAH1 accounts for the majority of ADMA metabolism. However, we and others have shown strong DDAH1 expression in a range of nonendothelial cell types, suggesting that the endothelium is not the only site of metabolism. We have developed a new endothelium-specific DDAH1 knockout mouse (DDAH1 En−/− ) to investigate the significance of endothelial ADMA in cardiovascular homeostasis. Methods and Results— DDAH1 deletion in the DDAH1 En−/− mouse was mediated by Tie-2 driven Cre expression. DDAH1 deletion was confirmed through immunocytochemistry, whereas Western blotting showed that DDAH1 remained in the kidney and liver, confirming expression in nonendothelial cells. Plasma ADMA was unchanged in DDAH1 En−/− mice, and cultured aortas released amounts of ADMA to similar to controls. Consistent with these observations, vasoreactivity ex vivo and hemodynamics in vivo were unaltered in DDAH1 En−/− mice. In contrast, we observed significantly impaired angiogenic responses both ex vivo and in vivo. Conclusions— We demonstrate that endothelial DDAH1 is not a critical determinant of plasma ADMA, vascular reactivity, or hemodynamic homeostasis. DDAH1 is widely expressed in a range of vascular and nonvascular cell types; therefore, the additive effect of DDAH1 expression in multiple organ systems determines plasma ADMA concentrations. Endothelial deletion of DDAH1 profoundly impairs the angiogenic capacity of endothelial cells, indicating that intracellular ADMA is a critical determinant of endothelial cell response.
Long-term second-line chemotherapy consisting of oral S-1 and gemcitabine for NSCLC: A phase II study—TORG 0705.
Authors: Y. Takiguchi, T. Seto, Y. Ichinose, N. Nogami, H. Okamoto, K. Minato, N. Seki, K. Kishi, M. Nishikawa, K. Watanabe
Journal: Journal of Clinical Oncology (2010)

e18007 Background: S-1 is a recently developed oral fluorinated pyrimidine. Our previous phase I/II study with S-1 and gemcitabine determined its recommended dose and suggested its feasibility and effectiveness for elderly patients with untreated NSCLC. The same regime was tested in the second-line setting for NSCLC. Methods: Patients meeting all following criteria were eligible: proven NSCLC refractory or recurrent after previous single- or 2-regimen chemotherapy consisting of platinum, PS (0-1), adequate organ functions, measurable lesions by RECIST, and life expectancy exceeding 3 months. Patients with any of the following conditions were ineligible: primary site resected, requirement of thoracic irradiation, interstitial lung disease, pleural, pericardial effusion or ascites requiring treatment, symptomatic brain metastasis, concomitant malignancy or other inadequate condition. S-1 (60 mg/m2/day, bid, p.o. days 1 to 14) and gemcitabin (1,000 mg/m2, days 8 and 15) were administered every 3- week until disease progression. Calculated minimum sample size was 29 based on Simon two-stage optimal design with p0 = 0.05, p1 = 0.20, α error = 0.05 and β error = 0.10; planned sample size was 32. The primary endpoint was response rate, and the secondary ones were toxicity and survival time. Results: From Nov. 2007 to Sep. 2008, 34 patients (29 with adeno-, 3 with squamous, 1 with large cell carcinoma and 1 with NSCLC, NOS) with a median age of 61.5-years were enrolled. Chemotherapy was administered for a median 4 courses (range; 1 to 13) or for 15 weeks in median (range; 1 to 54). Post-chemotherapy was delivered to 65% patients. Response rate was 23.5% (95% CI: 9.1-38.0%), and disease control rate was 64.7%. Prevailing toxicity of grade 3 or 4 in entire courses consisted of neutropenia (50%), thrombocytopenia (12%) and anemia (18%). Grade 3 pneumonitis was seen in 3 patients (9%). PFS and MST from enrollment were 6.6 and 20.4 months, respectively. Conclusions: This seond-line chemotherapy for NSCLC showed promising efficacy with tolerable toxicity for extended period. The excellent survival data might be attributed to long-term treatment until disease progression. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Chugai Pharma, Kyowa Hakko Kirin, Lilly, Taiho Pharmaceutical Taiho Pharmaceutical, Takeda Bio Development Center
Invasive micropapillary breast cancer: Single-institution experience in the modern era.
Authors: Amy E. Voci, Camilla Boafo, Anne Eaton, Michelle Stempel, Jorge Reis- Filho, Tari A. King
Journal: Journal of Clinical Oncology (2013)

150 Background: Invasive micropapillary breast cancer (IMPC) is a rare special histologic type of breast cancer with a propensity for nodal metastases. Molecularly, IMPCs have been classified as luminal B; however, clinical outcome data in the era of targeted therapy are limited. Here we report our institutional experience with IMPC. Methods: We retrospectively reviewed our prospective database from 1995-2009 to identify patients who had surgery for IMPC. Clinical characteristics and outcomes were abstracted from the medical record. Overall survival (OS) was estimated using Kaplan-Meier methods. Factors associated with OS and trends over time were assessed using the log-rank test and Cox regression. Results: We identified 258 patients with IMPC. Median patient age 56yrs (range 26-91), 157(61%) postmenopausal, 147(57%) presented with a palpable mass. The majority of IMPCs were grade 3 (83%), estrogen receptor (ER)-positive (86%) and HER2-neg (81%) with LVI (60%) and nodal metastasis (62%). 194 (75%) patients received chemotherapy (CTX), 204 (81%) hormonal therapy and 37/48 (77%) HER2-pos patients received trastuzumab. At a median follow-up of 55 months (range 1-173mos), 5yr OS is 89.5% with a trend towards improved survival in later yrs; 5 year OS 1995-2005 vs 2006-2009, 85% vs 91%, respectively (p=0.06) Clinical factors associated with OS are shown (Table). Among ER-pos/HER2-neg patients, progesterone receptor (PR) status was strongly associated with 5yr OS. Conclusions: In this large cohort of patients with IMPC treated at a single center, OS was associated with tumor size, PR status, use of CTX and trastuzumab but not with ER or hormonal therapy. These clinical data support the molecular classification of IMPC as luminal B cancers which have a more aggressive clinical behavior than other ER+ cancers. The trend towards improved survival in later years likely reflects the benefits of targeted therapy. [Table: see text]
Relationship of myeloid-derived suppressor cells (MDSC) and immune suppression, nutritional impairment, and inflammatory markers in patients with gastrointestinal cancer.
Authors: Masahiko Shibata, Kenji Gonda, Izumi Nakamura, Shinji Ohki, Kenichi Sakurai, Tatsuo Shimura, Seiichi Takenoshita
Journal: Journal of Clinical Oncology (2012)

675 Background: A suppression of cell mediated immunity and malnutrition are commonly seen in patients with advanced cancer and it has been reported that chronic inflammation plays a key role in induction of these conditions. MDSC: myeloid-derived suppressor cells, found as a new type of immune suppressor cells that is closely related to chronic inflammation, have reported to be present in blood circulation in patients with cancer. MDSC have been reported to suppress immune function through several pathways. Methods: Peripheral blood mononuclear cells (PBMC) were collected from 18 normal healthy volunteers, and 53 patients with gastrointestinal cancer including 5 patients with esophageal, 16 with gastric, 26 with colorectal, 3 with bile duct, 1 with pancreatic and 1 with hepatocellular carcinomas, and these cells were used for the detection of MDSC (CD11b+CD14-CD33+) by flow cytometry. PBMC was also used for the PHA-blastogenesis of lymphocytes which is a marker of cell mediated immunity (stimulation indices: SI). Results: MDSC(%PBMC) of whole patients with gastrointestinal cancer, those with gastric cancer and those with colorectal cancer were higher than those of healthy volunteer (3.76+4.90%, 5.18+1.86%, 4.21+1.43% vs 1.59+1.08%, p&lt;0.05, p&lt;0.05, p&lt;0.10, respectively). MDSC of patients with gastrointestinal cancer were also inversely correlated to the SI (r=−0.271, p&lt;0.05) and to the serum concentrations of total protein (r=−0.490, p&lt;0.005). It also tended to correlate to neutrophil counts (r=0.287, p&lt;0.10) and neutrophil/lymphocyte ratios (NLR, r=0.623, p=0.10), and inversely did to lymphocyte counts (r=−0.251, p&lt;0.10).Thus MDSC was successfully detected in peripheral blood and was significantly higher in patients with gastrointestinal cancer. It was related to the inhibition of cell-mediated immunity, hypoaproteinemia and inflammatory markers such as NLR. Conclusions: MDSC seemed to work in the mechanisms of suppression of immune reaction and malnutrition, typically seen in cancer cachexia, in patients with gastrointestinal cancer and may be important as a marker of advancement of malignant diseases.
Safety results from a randomized trial of perioperative epirubicin, cisplatin plus capecitabine (ECX) with or without bevacizumab (B) in patients (pts) with gastric or type II/III oesophagogastric junction (OGJ) adenocarcinoma.
Authors: A. F. C. Okines, R. E. Langley, L. C. Thompson, S. P. Stenning, L. Stevenson, S. Falk, M. T. Seymour, F. Y. Coxon, G. W. Middleton, D. Smith, L. Evans, S. Slater, J. S. Waters, D. Ford, M. Hall, T. Iveson, R. D. Petty, C. Plummer, W. Allum, D. Cunningham
Journal: Journal of Clinical Oncology (2011)

4092 Background: Perioperative chemotherapy is a standard treatment for localised gastric/OGJ adenocarcinoma. B is a monoclonal antibody targeting vascular endothelial growth factor A. Addition of B to CX chemotherapy improves response rate and PFS in advanced gastric cancer. ST03 is an ongoing randomised phase II/III trial of perioperative ECX +/- B in pts with operable gastric or OGJ adenocarcinoma. Methods: Pts receive 3 preoperative and 3 postoperative ECX+/-B 7.5mg/kg, then 6 maintenance B (investigational arm only). Left ventricular ejection fraction (LVEF) ≥50% is required for eligibility and re-measured before surgery and after postoperative ECX+/-B. The primary endpoint of the phase II study (n=200) is safety and feasibility of preoperative ECX+B. Results: 200 pts were randomised to ECX+/-B Oct 07-April 10. Median age 63, 78% male, gastric:OGJ 107:93, Stage Ib:II:III 20:68:109. All cycles of preoperative chemotherapy were received by 91/101 ECX (90%) and 86/99 ECX+B pts (87%), 13 pts (6 ECX, 7 ECX+B) stopped due to toxicity. Pre-defined primary endpoint events by treatment are shown in the table. Venous thromboembolism (TE) any grade occurred in 10 ECX, 8 ECX+B, other arterial TE in 1 ECX+B (post op CVA), grade 3/4 hypertension in 2 ECX+B and grade 3/4 proteinuria in 1 ECX+B. Asymptomatic drops in LVEF to <50% and/or ≥15% occurred in 8 ECX and 13 ECX+B pts. Drops of ≥10% and to <normal occurred in 6 ECX and 9 ECX+B. E+/-B was stopped for asymptomatic LVEF drop in 4 ECX, 11 ECX+B pts. HF in 1 pt (ECX+B) was associated with sepsis, venous TE and MI; LVEF recovered. LVEF also recovered to ≥50% in 3/7 ECX and 4/7 ECX+B whose LVEF fell <50%, with no follow-up LVEF results for the remaining 7 pts. Conclusions: The rate of complications in the 2 arms is similar. Accrual continues to the phase III study and 338 of the planned 950 pts have been randomised so far. Event ECX ECX+B Perforation -at primary tumour -other GI 2 1 2 0 Cardiovascular events -MI -MI + heart failure (HF) -Symptomatic arrhythmia 2 0 3 3 1 2 Wound healing complications:-Infected -Noninfected -Anastamotic leak -Biliary leak 7 1 3 0 6 1 3 1 GI bleed 4 0 Total events (pts) 23 (21) 19 (17)
The Impact of Native State Switching on Protein Sequence Evolution
Authors: Avital Sharir-Ivry, Yu Xia
Journal: Molecular Biology and Evolution (2017)

For proteins with a single well-defined native state, protein 3Dstructure is a major determinant of sequence evolution. On the other hand, many proteins adopt multiple, distinct native structures under different conditions ("conformational switches"), yet the impact of such native state switching on protein evolution is not fully understood. Here, we performed a proteome-wide analysis of how protein structure impacts sequence evolution for protein conformational switches in Saccharomyces cerevisiae using pooled analysis of sites with similar packing or burial. We observed a strong linear relationship between residue evolutionary rate and residue burial for conformational switches. In addition, we found that conformational switches evolve significantly and consistently more slowly than proteins with a single native state, even after controlling for degree of residue burial or packing. Next, we focused on proteins that switch conformations upon molecular binding. We found that interfacial residues in these conformational switches evolve more slowly than interfacial residues in proteins with a single native state, and that the bound conformation is a better predictor for residue evolutionary rate than the unbound conformation. Our findings suggest that for conformational switches, the necessity to encode multiple distinct native structures under different conditions imposes strong evolutionary constraints on the entire protein, rather than just a few key residues. Our results provide new insights into the structure-evolution relationship of protein conformational switches.
Intracardiac, mediastinal and CNS metastases in pediatric osteosarcoma: extending survival
Authors: D. P. Hughes, A. Mahajan, F. W. Tsai, M. Pearson, R. M. Kline, J. S. Weinberg, P. M. Anderson, C. Costelloe, W. I. Douglas
Journal: Journal of Clinical Oncology (2008)

10036 Background: Extrapulmonary osteosarcoma (OS) metastases portend poor outcome and short survival. Local control is essential for durable remission. Intracardiac, mediastinal and CNS metastases are ominous: many oncologists cease therapy when they occur. We present a series of 19 patients with relapse in poor-prognosis locations, and focus on one patient in 3rd relapse of OS in whom widespread disease, including intraventricular and CNS metastases, was controlled with chemotherapy, radiotherapy, novel agents, cardiac tumor resection and neurosurgery. Methods: Imaging included CT, PET-CT, bone scan, echocardiogram, and MRI. Systemic therapy included liposomal doxorubicin (D), bevacizumab (A), rapamycin (R), cisplatin (C), valproic acid (V), and zoledronic acid (ZA). Other patients received ifosfamide, samarium with gemcitabine, cyclophosphamide, temezolomide, and L-MTP-PE. Local control included surgery for cardiac and mediastinal metastasis and XRT or surgery for CNS metastasis. Results: D+A caused tumor shrinkage. The patient received XRT to 9 sites over 4 courses with C (q 2 wk), R (daily), V (daily) or ZA (q 4 wk) for radiosensitization. PET-CT after 8 weeks showed metabolic resolution of most lesions, regardless of XRT. Echocardiogram identified 2 LV cardiac metastases, which were resected without complication. A left parietal mass was resected with no complication and normal neurologic exam post-surgery. The patient is doing well on treatment 11 months after relapse, with few sites of active disease and good quality of life. The majority of patients had reduced tumor burden and objective responses on PET-CT. Good post-operative quality of life was achieved after resection of cardiac (1), mediastinal (5) or CNS (2) metastases. XRT with chemotherapy was used for 6 mediastinal and 5 skull/CNS patients. 2/12 mediastinal and 0/7 CNS patients had developed recurrent disease in these sites. Conclusions: Novel agents were well-tolerated and effective, enabling aggressive local control in difficult-to- treat locations. PET-CT gave an earlier and more accurate measure of response than CT alone. Resection of cardiac, mediastinal and CNS metastases in pediatric patients is feasible and can be well-tolerated, prolonging survival and improving quality of life. No significant financial relationships to disclose.
Socioeconomic position, stage of lung cancer, and time between referral and diagnosis in Denmark, 2001-2008.
Authors: S. O. Dalton, B. L. Frederiksen, E. Jakobsen, M. Steding-Jessen, K. Oesterlind, J. Schuz, M. Osler, C. Johansen
Journal: Journal of Clinical Oncology (2011)

6050 Background: Social inequality in short-term relative survival has been reported among men with lung cancer in Denmark. We investigated the association between socioeconomic position, stage at diagnosis and length of period between referral and diagnosis in a nationwide cohort of patients with lung cancer diagnosed in Denmark. Methods: From the Danish Lung Cancer Register, we identified all 18 103 people in whom non-small cell lung cancer or small cell lung cancer was diagnosed in 2001–2008 for whom we could identify socioeconomic position and comorbidity in nationwide administrative registries. The risks for a diagnosis of advanced-stage lung cancer (stages IIIB–IV) and for a diagnosis more than 28 days after referral were analyzed by multivariate logistic regression, with adjustment for age, gender, socioeconomic factors and comorbidity. Results: The adjusted odds ratio (OR) for advanced-stage lung cancer was reduced by 8% among people with longer education (95% confidence interval (CI), 0.84;0.99) and was increased in people living alone (OR, 1.06; 95% CI, 1.01;1.13). The ORs decreased in a stepwise fashion with increasing comorbidity score. Higher education was associated with a reduced OR of a period > 28 days between referral and diagnosis (0.82; 95% CI, 0.70;0.96 for early-stage and 0.82, 95% CI, 0.72;0.93 for advanced-stage), as was high income in early-stage cases. Male gender, age and severe comorbidity were associated with increased ORs in advanced-stage cases. Conclusions: Differences by socioeconomic position and comorbidity were found in the period between referral and diagnosis and in stage at diagnosis, indicating that vulnerable patients presenting with lung cancer symptoms require special attention.
Impending Atypical Femoral Fracture in Patients With Medullary Thyroid Cancer With Skeletal Metastasis Treated With Long-term Bisphosphonate and Denosumab
Authors: Mitsuru Koizumi, Tabu Gokita, Kazuhisa Toda
Journal: Clinical Nuclear Medicine (2017)

Atypical femoral fractures (AFFs) occur in osteoporosis patients receiving long-term bisphosphonate. Atypical femoral fractures also occur in cancer patients receiving long-term bisphosphonate or denosumab, but the prevalence is low. We describe a 53-year-old woman with a history of medullary thyroid cancer and skull metastasis who was prescribed bisphosphonate for 6 years and denosumab for 1.5 years, consecutively. Bone scintigraphy performed because of spontaneous groin pain showed uptake in the lateral aspect of the left femur, which was confirmed as impending AFF. In oncological patients receiving long-term bisphosphonate or denosumab, AFF should be included as a differential diagnosis with focal femoral findings.
Eradication of osteolytic and osteoblastic metastases of HRBC with pegylated trispecific disulfide linked Fv (sdFv) targeting epitopes of EGFr, PTHrP, and RANKL conjugated to vinorelbine
Authors: P. Ginopoulos, J. Giannios, E. Seraj, J. Peristeris, N. Alexandropoulos
Journal: Journal of Clinical Oncology (2008)

3056 Background: Bone metastasis is a common complication of HRBC and one for which only palliative treatment is available. We aim to inhibit the vicious cycle between tumor cells and the bone microenvironment, which results in increased tumor burden and bone destruction. Methods: HRBC cells (ER-) obtained from a metastatic patient were inoculated into the left cardia ventricle of nude mice. After osteoclastic and osteoblastic metastases were observed radiographically, the mice were treated with pegylated trispecific disulfide linked Fv (sdFv) targeting epitopes of PTHrP, RANKL, and EGFR conjugated covalently with SATA to vinorelbine. Results: Post-treatment, we observed autocrine inhibition of HRBC cells, paracrine inhibition of tumor associated endothelial cells (ECs), and bone microvascular ECs. Downregulation of EGFR led to inhibition of expression of AP1 blocking transcription of VEGF and its receptors KDR and Flt-1 exerting an angiocidal effect. EGFR downregulation led to reduced activity of osteoclasts and inhibition of PI3K, MAPK, and MMP-9. Downregulation of PTHrP and RANKL inhibited osteoclastogenesis and proliferation of stromal/osteoblastic cells. Release of TGF-a and IGF from the bone matrix was blocked. Vinorelbine destabilized MT dynamics of tumor and ECs blocking cell cycle at G2/M. It also phosphorylated bcl-2 blocking uPAR and SP1 DNA binding activity through ERK. This led to inhibition of osteoblast proliferation by inhibiting hydrolysis of IGF-binding proteins and downregulation of MMP-1,3,9. We observed ADCC and antibody mediated phagocytosis. In HRBC cells, tumor associated and bone derived ECs, we observed inhibition of DNA synthesis and metabolic activity by BrdU and MTT. TEM exhibited nuclear PCD type III with pyknosis and zeiosis leading to secondary necrosis. Type I PCD caspase-3 dept and autophagic type II PCD led to a bystander killing effect of tumor and ECs. There was not radiographic evidence of osteolytic and sclerotic bone metastases of HRBC cells. Conclusions: These findings suggest that this strategy may provide a new therapeutic approach to inhibiting the processes involved in bone metastases from hormone refractory breast cancer (HRBC). No significant financial relationships to disclose.