tbuckley/cabot-search huggingface dataset:
Behavior of P388 Mouse Leukemia in the Chick Embryo and Hatched Chick&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: B CLARKSON, A KATZ, M A DANN, D A KARNOFSKY
Journal: JNCI Journal of the National Cancer Institute (1964)

P388 and several other mouse leukemias grow poorly on the chorio-allantoic membrane of the chick embryo, but may proliferate rapidly when introduced into the embryo by intravenous injection, or by metastasis from chorio-allantoic explants. Proliferation of P388 cells in the embryo probably continues until shortly after it has hatched, and then stops; however, viable leukemic cells may persist in the chick brain for as long as 6 weeks after hatching. The brain appears to be the most favorable site for growth and long-term survival of P388 cells. P388 cells injected intravenously or intracerebrally into 1-day-old hatched chicks will survive for long periods, but, when given to 7-day-old and older chicks, the cells fail to survive. This suggests the rapid maturation of immunological competence by the chick shortly after hatching. Marked splenomegaly and hematopoietic stimulation in the embryo may result from injection of P388 and several other mouse leukemias. The splenomegaly is due to proliferation of host cells, particularly the granulocytic elements. The significance of the increased hematopoiesis and splenomegaly and its relation to that reported after the transplantation of homologous adult spleen into the embryo require further study.
PSA and Kallikrein 4 expression in PC3 prostate cancer cells leads to a loss of cell adhesion molecules and an epithelial-mesenchymal transition (EMT)
Authors: Mitchell Lawrence, Tara Veveris-Lowe, Astrid Whitbread, Rachael Collard, Adrian Herington, David Nicol, Judith Clements
Journal: Cancer Research (2006)

4372  Prostate-specific antigen (PSA) and several other members of the kallikrein family of serine proteases are current or potential biomarkers for prostate cancer. Biochemical studies have suggested that the kallikreins may have roles in tumor progression. Therefore, PC3 cell lines stably expressing pre-pro PSA, KLK2 and KLK4 were established to investigate kallikrein functionality in a cellular context. We have previously shown no change in proliferation or invasion through the synthetic extracellular matrix, Matrigel. In contrast, PSA- and KLK4-expressing clones demonstrated a significant increase in migration through microporous membrane barriers compared with parental, vector only and KLK2-expressing cells. In PSA- and KLK4-expressing clones a morphological change towards more irregular, spindle-shaped cells and rearrangement of focal contacts accompanied the increase in migration. Furthermore, the epithelial cell-cell adhesion protein E-cadherin was down-regulated in the PSA- and KLK4-expressing clones while the mesenchymal marker vimentin was up-regulated. These findings suggested that the PSA- and KLK4-expressing clones have undergone an epithelial-mesenchymal transition (EMT)-like transformation. We next compared the gene expression profiles of the transfected and untransfected PC3 cells using Affymetrix microarrays. In addition to the loss of E-cadherin, the expression of a number of other cell-cell and cell-ECM adhesion molecules was reduced in the PSA and KLK4 but not KLK2 clones. These include desmoplakin, junction plakoglobin, claudin-3 and claudin-7 as well as integrin-α2, integrin-β2 and integrin-β4. Further studies are underway to determine the mechanisms underlying these phenotypic changes.
Molecularly-guided therapeutic options beyond tyrosine kinase inhibitors (TKIs) for gastrointestinal stromal tumors (GIST).
Authors: Rebecca Feldman, Zoran Gatalica, Sandeep K. Reddy, Sant P. Chawla, Kamalesh Kumar Sankhala
Journal: Journal of Clinical Oncology (2015)

58 Background: GISTs are characterized by KIT/PDGFRA mutations. A range of multi-targeted tyrosine kinase inhibitors (TKIs) are available for treatment, however, resistance mechanisms inevitably emerge. Recent data (Boichuk, et al 2014) suggests the potential efficacy of various cytotoxic therapies that were identified as being able to effectively kill TKI-responsive and -resistant GIST cells. We sought to investigate the theranostic markers associated with non-TKI therapy options for their potential role in treatment of GIST. Methods: 147 GIST cases were evaluated. A multiplatform approach of biomarker testing was used and included a combination of sequencing (NGS, Sanger), protein expression (IHC) and gene amplification (ISH). Results: Multidrug resistance phenotype was found in 52-68% (PGP, MRP1). Tubulin-binding agents (taxanes, vinca alkaloids) may be of potential use due to the high frequency of low TUBB3 expression (72% or 39/54). Anthracyclines and topoisomerase inhibitors may be of potential benefit in 1/3 of patients based on expression of TOPO2A (32% or 32/99) and TOPO1 (34% or 37/110). Cytotoxic agents used in non-GIST solid tumors, may also be considered, based on high frequency of low expressin of MGMT (47% or 57/122), TS (70% or 76/109) and RRM1 (79% or 88/111). PTEN was intact (positive expression) in the majority of GIST (87%). Nine patients were examined for PD1/PDL1: 56% exhibited positive tumor infiltrating lymphocytes and 33% exhibited PDL1 tumor expression. Only one amplification event was observed: cMET (0/53), HER2 (0/69), EGFR (0/16), PIK3CA (0/1) and TOP2A (1/11). Mutational screening using a hot spot cancer panel (and Sanger sequencing for some genes) resulted in the detection of variants in only 10 genes, excluding KIT (97/132) and PDGFRA (5/55). Variants were detected in the following genes, in decreasing order of frequency: RB1, APC and JAK3 (2/55; 2/55; 2/57), PIK3CA (2/69) and ABL1, cMET, EGFR, KDR, VHL and BRAF (1/55, 1/57, 1/57, 1/57, 1/52, 1/78). Conclusions: A multi-platform approach of theranostic biomarkers identified therapies beyond TKIs for GIST. Various cytotoxics and non-KIT/PDGFRA targeted therapies were identified based on protein expression or gene variations.
Phase II study of irinotecan plus oral etoposide in patients with platinum and taxane-resistant ovarian cancer
Authors: S. Nishio, T. Sugiyama, T. Shoji, R. Kitagawa, K. Ushijima, T. Kamura
Journal: Journal of Clinical Oncology (2005)

5099 Background: Although there are many difficulties in the management for platinum-and taxane-resistant ovarian cancer patients, topoisomerase-1 inhibitor or oral etoposide (topoisomerase-2 inhibitor) has been chosen singly as a salvage therapy and showed 14–25% of response rate. Still we have no promising combination therapy for refractory ovarian cancer. Patients and Methods: We conducted a phase II study with the combination of irinotecan (topoisomerase-1 inhibitor) (60 or 70mg/m2 iv, day 1 and 15) and oral etoposide (50mg/body day 1–21) every four weeks. Cycles were repeated in the absence of progressive disease or prohibitive toxicity. Patients with advanced ovarian cancer who had prior-exposure to at least one platinum and taxane regimen, age 18–75, PS 0–2 and adequate organ function were eligible. Resistance to platinum and taxane was defined as progression during initial chemotherapy with platinum and taxane regimen, or relapsed within 6 months after completion of platinum and taxane regimen. Toxicity profile was assessed according to NCI-CTC ver.2 and response was measured by RECIST criteria or assessed by CA-125 (Rustin’s criteria). Response rate and toxicity were the primary endopoints and the progression free survival and over all survival were secondary endopoints. Results: Twenty-six patients entered the study. The median interval from the previous chemotherapy was 3 months. The median number of previous chemotherapeutic regimens was 2 (range: 1–4). Grade 3/4 hematologic toxicities included neutropenia (46% of patients), leukopenia (50%) and anemia (31%). Grade 3/4 non-hematologic toxicities included diarrhea (7.7%), and nausea/vomiting (15%). No treatment related death was observed. Twelve patients (46%) responded and seven patients (27%) demonstrated stabilization of their disease (PR+SD rate:73%). After a median follow-up of 11 months, progression free survival was 6 months (range: 1–18), duration of response was 6 months (0–17) and median survival was 9 months (2–20). Conclusions: The combination of irinotecan plus oral etoposide appears to have manageable toxicities and encouraging active regimen in patients with platinum-and taxane-resistant ovarian cancer. No significant financial relationships to disclose.
Abstract 16789: Adherence to Medications for Atrial Fibrillation
Authors: Cynthia Jackevicius, Jack V Tu, Michael Ho, Vidal Essebag, Meytal Avgil, Elham Rahme, Mark Eisenberg, Limei Zhou, Karin Humphries, Clare Atzema, Louise Pilote
Journal: Circulation (2012)

Background: Atrial fibrillation (AF) is an emerging epidemic, primarily managed pharmacologically with complex medication regimens. Even if AF medications are prescribed according to evidence and g...
The duration of obstructive sleep apnea disease is predictive of efficacy or othodontic therapy in children
Authors: Jole Rabasco, Ottavio Vitelli, Nicoletta Pietropaoli, Alessandra Rizzoli, Rosa Castaldo, Mariachiara Paolino, Martina Forlani, Maria Pia Villa
Journal: European Respiratory Journal (2014)

Introduction   OSAS is a multifactorial disease with a coexistence of different risk factors. Despite primary treatment in children is adenotonsillectomy (AT), there is evidence suggesting that rapid maxillary expansion (RME) is a potential additional treatment in children presenting OSA. The aim of this study is to confirm, with a larger sample, our previous findings in order to underline the efficacy of RME in children with sleep disordered breathing (SDB) who did not undergo AT .   Methods   Children between 4 and 8 years old who referred to our Pediatric Sleep Centre because of SDB, were enrolled. After the orthodontic evaluation all children presented with a high, narrow palate, that in some patients was associated with signs of malocclusion underwentan endo-oral RME treatment for 12 months. Standard overnight polisomnography recordings were obtained before starting orthodontic treatment (T0) and after 12 months of treatment (T1).   Results   40 patients were eligible for recruitment .The AHI decreased significantly from T0 ( 4,7 ± 4.4 ev/h) to T1 (1.6 ± 1.4 ev/h)(p= 0,000) as well as the arousal Index, whereas total sleep time and mean overnight oxygen saturation increased significantly. We obtained resolution of the disease (AHI   The analysis of different influencing predictive factors on treatment efficacy revealed a significant influence of the disease duration (p 0.03 ).   Conclusions   Our data confirm the usefulness and efficacy of early orthodontic treatment in children with mild and moderate OSA and stressed the importance of an early treatment in order to achieve a best outcome.
Barriers to phase I clinical trial protocol IRB approval at KCI
Authors: D. Wang, E. Heath, A. Powell, T. Chaperon, F. LaGrone, P. LoRusso
Journal: Journal of Clinical Oncology (2007)

9080 Phase I oncology clinical trials are critical in the oncology drug development process. To protect human subjects, every phase 1 protocol must be approved by an institutional review board (IRB) to assure safety before patient accrual. As the volume and complexity of phase 1 trials have increased, the amount of time spent on IRB protocol reviews have also increased for various reasons. Objectives: 1) Determine the average time spent on protocol approval by IRB at KCI/WSU; 2) Identify potential issues raised by IRB resulting in approval delays; 3) Identify the redundancies for which “standard language” implementation could facilitate future IRB applications thereby expediting approval. Methods: 96 Phase 1 research IRB applications at KCI/WSU between 8/1/2005 and 10/31/2006 were reviewed. These applications were stratified based on submission (new protocol versus amendment) and IRB approval (tabled, provisional or approved) status. Concerns frequently brought up by the IRB were identified. Results: The average and median time spent from initial submission to final approval of all 96 applications were 41.4 days and 43 days, respectively. Forty eight of 96 applications (50%) were provisionally approved from the initial review. Average and median time of obtaining final approval were 52.5 days and 52 days. Nine of 96 (9.4%) protocols were tabled with their average approval 83 days. The most common concerns raised by IRB were risks/benefit issues. These concerns were an even greater approval barrier when protocols involved specialized technologies of molecular therapeutics or complicated study designs. Regulatory policy changes issued by oversight organizations also required “real-time” updates into protocols and consent form amendments. Areas of “standard language” for future IRB applications are being compiled and will be discussed upon presentation. Conclusion: Phase 1 clinical trials are essential to anti-cancer drug development. The complicated ethical issues and science warrant an ongoing constructive collaboration of both parties. Identification of commonalities that delay IRB approval will lead to more expeditious IRB approval not only at our institution, but could also benefit other institutions. No significant financial relationships to disclose.
Physiotherapy and occupational therapy do not improve early Parkinson’s disease, study finds
Authors: Ingrid Torjesen
Journal: BMJ (2016)

Physiotherapy and occupational therapy provide no clinically meaningful benefits to activities of daily living or quality of life, either immediately or in the medium term, for patients with mild to moderate Parkinson’s disease, a study has found . 1

Parkinson’s disease causes problems with activities of daily living such as putting on clothes or brushing teeth, and the National Institute for Health and Care Excellence recommended in 2006 that physiotherapy and occupational therapy should be available to all patients with Parkinson’s disease.2 But provision of these services varies widely, as some areas offer them from diagnosis and others not …
Myeloma during a decade: Clinical experience in a single centre
Authors: J.S. Malpas, R.K. Ganjoo, P.W.M. Johnson, M.M. Mahmoud, M. Carter, W. Gregory, J.M. Lim, P.I. Clark, R.J. Osborne, M.A. Richards, A.Z.S. Rohatiner, M.L. Slevin, P.F.M. Wrigley, T.A. Lister, A.H. Williams, S.B. Love, J.A.L. Amess
Journal: Annals of Oncology (1995)
Enhanced Production of Mouse Mammary Tumor Virus in DexamethasoneTreated, 5-Iododeoxyuridine-Stimulated Mammary Tumor Cell Cultures 2
Authors: Donald L. Fine, Jonathan K. Plowman, Susan P. Kelley, Larry O. Arthur, Elizabeth A. Hillman
Journal: JNCI Journal of the National Cancer Institute (1974)

The production of virus-related RNA-dependent DNA polymerase, cell-associated mouse mammary tumor virus (MMTV) antigens, and B particles by 5-iododeoxyuridine in C3H mouse mammary tumor cell cultures was enhanced by dexamethasone, a synthetic glucocorticoid hormone. This enhancement further implicates hormones in MMTV replication and provides the basis for an in vitro MMTV production system.
Attempts To Obtion Virus-Free Rous Tumors in Tissue Culture&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;
Authors: H. Rabin, C.F.A. Heijen, M. Foard, F.B. Bang
Journal: JNCI Journal of the National Cancer Institute (1963)

Attempts to free Rous tumors from infectious virus were made by serial alternate passage of the tumor in tissue culture in the presence of antiviral antibody. Such tissues were then reinoculated into chickens in the presence of specific antiviral antibody. When it was found that lowering the temperature ot in vitro incubation from 38 to 32µ C inhibited virus production, this procedure also was followed at the lower temperature. We tested for virus by growing tissue cultures of tumors obtained from the chicken in culture media containing horse serum (which lacks neutralizing substances). On four occasions, three in succession, tumors grew in tissue cultures without producing detectable virus. However, continued serial alternate passage yielded virus up to the 25th passage, at which time the study was discontinued. Virus yield from primary explants of the Rous tumors on collagen was markedly affected by temperature of incubation. One tenth as much virus was produced at 30 to 32µ C as at 38µ C, and in three different tumors incubation at 30 or 32µ for several days reduced virus to the point where none was found. Cells were, however, active. Virus production in temperature-inhibited cultures was stimulated by a return to 38µ C. Cultures of two tumors were impaired in the ability to produce tumors after cultivation at 32µ C, but subsequent tumors, obtained by inoculation of chickens, again had large amounts of virus.
Abstract 027: Therapeutic Potential of a Novel Necrosis Inhibitor in Myocardial Ischemia-Reperfusion Injury
Authors: Hyun-Jai Cho, In-Chang Hwang, Ju-Young Kim, Ji-Hyun Kim, Yoo-Wook Kwon, Jonghanne Park, Han-Mo Yang, Kyung-Woo Park, Soon-Ha Kim, Hyo-Soo Kim
Journal: Circulation Research (2013)

Background: Reperfusion, although essential for salvage of myocardium in the myocardial infarction, paradoxically causes a wide variety of injuries. The opening of the mitochondrial permeability pore and Ca 2+ overload contribute to myocardial ischemia-reperfusion (I/R) injury. Objectives: Necrosis, the main mechanism of cell death during I/R injury to the myocardium, is an uncontrolled cell death, a pathologic condition accompanying inflammatory responses. We aimed to examine the protective role of this novel necrosis inhibitor against myocardial I/R injury using in vitro and in vivo models through anti-necrosis pathway. Methods and Results: Rat cardiomyocytes were exposed to hypoxia-reoxygenation injury after pretreatment with dimethyl sulfoxide (vehicle), necrosis inhibitor (NecX), antioxidant (vitamin C) or apoptosis inhibitor (Z-VAD-fmk). NecX-treated cells, compared with vehicle, showed fewer necrosis (Annexin-V/PI) (13.5±1.9% versus 44.1±3.1%; P=0.049) and more viable cells (fluorescein diacetate) (98.0±0.5% versus 51.3±2.1%; P=0.021). We next analyzed the mechanisms of cell death, mitochondrial membrane potential and mitochondrial Ca 2+ level. NecX-treated group showed higher mitochondrial membrane potential and lower Ca 2+ level, resulting in the prevention of mitochondrial swelling and necrosis. In the rat model of myocardial ischemia for 45 minutes followed by reperfusion, we compared the therapeutic efficacy of NecX and cyclosporine A (CsA) with 5% dextrose (control), each administrated 5 minutes before reperfusion. Pretreatment with NecX markedly inhibited myocardial necrosis (NecX, 7.8±7.8%; control, 65.4±2.4%, P=0.017; CsA, 32.3±5.1%, P=0.041) and reduced the area of fibrosis (NecX, 4.8±0.9%; control, 25.7±1.6%, P=0.011; CsA, 18.8±1.3%, P=0.006). Additionally, it preserved systolic function and prevented pathologic remodeling of left ventricle. Conclusion: The novel necrosis inhibitor demonstrates a significant protective effect against myocardial I/R injury and has advantages over CsA, based more on the direct necrosis inhibition on cardiomyocytes, indicating that it is a promising candidate for cardioprotective adjunctive therapy with reperfusion in patients with myocardial infarction.
p53 nuclear overexpression: an independent predictor of survival in lymph node--positive colorectal cancer patients.
Authors: Z S Zeng, A S Sarkis, Z F Zhang, D S Klimstra, E Charytonowicz, J G Guillem, C Cordon-Cardo, A M Cohen
Journal: Journal of Clinical Oncology (1994)

PURPOSE This study was performed to determine the prognostic significance of p53 gene overexpression in a homogeneous group of node-positive colorectal cancer patients. MATERIALS AND METHODS Paraffin sections from the primary tumors in 107 colorectal cancer patients who had preoperative serum carcinoembryonic antigen (CEA) levels less than five were examined for the expression of p53 nuclear protein by immunohistochemical staining using the monoclonal antibody PAb 1801. The nuclear p53 overexpression was compared with clinicopathologic variables and follow-up data. RESULTS Positive staining was not observed in normal colorectal mucosal cells. Specific p53 nuclear staining was detected in primary tumor from 50 patients (46.7%). p53 nuclear overexpression was not significantly correlated with patients' sex, age, tumor location, differentiation, T stage, N stage, and lymphatic and/or vascular vessel invasion. With a median follow-up of 61.7 months, 60% of the p53-positive patients have had disease recurrence, versus only 35% of the p53-negative group (P = .02). Forty-two percent of the p53-positive patients died of colorectal cancer compared with 21.1% of the p53-negative patients (P = .03). By multivariate analysis, p53 overexpression was found to be an independent predictor for disease-free and disease-specific survival. CONCLUSION In node-positive colorectal cancer patients with low preoperative CEA levels, nuclear p53 overexpression as determined by immunohistochemistry on archived tissue is an independent predictor for prognosis.
Factor XIIIa Cross-Linking of the Marburg Fibrin: Formation of αm·γn-Heteromultimers and the α-Chain–Linked Albumin·γ Complex, and Disturbed Protofibril Assembly Resulting in Acquisition of Plasmin Resistance Relevant to Thrombophila
Authors: Teruko Sugo, Chizuko Nakamikawa, Mikihiro Takebe, Isao Kohno, Rudorf Egbring, Michio Matsuda
Journal: Blood (1998)
A phase II study of the safety and efficacy of the MDR inhibitor VX-710 combined with doxorubicin and vincristine in small cell lung cancer
Authors: L. Gandhi, M. Harding, M. Neubauer, C. J. Langer, J. Crawford, M. Moore, J. Rooney, H. Ross, L. H. Einhorn, B. E. Johnson, T. J. Lynch
Journal: Journal of Clinical Oncology (2006)

17001 Background: Tumors with multidrug resistance (MDR) frequently show upregulation of efflux proteins MDR protein (MRP-1) and P-glycoprotein (Pgp). MDR represents a major obstacle to successful chemotherapy treatment and can be reversed in Pgp or MRP1-expressing cells by the MDR inhibitor VX-710. A phase II study was designed to evaluate the safety/tolerability and efficacy of VX-710 combined with doxorubicin (D) and vincristine (V) in patients (pts) with relapsed SCLC. Methods: Eligible pts had progressive, measurable disease and a PS &lt;2 after response to 1st-line chemotherapy. Stage I safety evaluation was done with planned expansion to a second stage if 9 responses were confirmed in the first 35 pts. Pts were treated with VX-710 (120 mg/m 2 /h) for 72 hours with D (45 mg/m 2 ) and V (1.4 mg/m 2 ) given 4 hours after the start of VX-710. Pts were treated q 21 days until progression or intolerable adverse events (AEs). Severe neutropenia was noted in the first 15 pts, so the protocol was amended to include prophylactic G-CSF or ciprofloxacin. Interim analysis was performed after 36 pts were treated. Results: 36 pts were enrolled from 12/98 to 12/00. Neutropenia was the major toxicity, occurring in 25/36 (69%) pts. This was more severe (30% vs. 20% grade 4) and occurred earlier (58% vs. 38% in cycle 1) among the 15 pts enrolled prior to an amendment requiring neutropenia prophylaxis vs. those enrolled afterward. Other common treatment-related AE’s: asthenia (53%), nausea (50%), constipation (44%), alopecia (42%), dyspnea (42%), anemia (42%). 67% were grade 1 or 2 in severity. Four pts died on study or within 30 days of termination: 2 from infections likely related to therapy and 2 from disease progression. Among 32 evaluable pts, 7 (22%) had partial responses; 6 of these sustained responses through 6 cycles (with one response lasting 3 years). Three additional pts had unconfirmed responses. Median survival was 6 months (95% CI 4–7 months). Conclusions: The addition of VX-710 to D and V therapy did not improve anti-tumor activity or survival. Hematologic toxicity was severe, causing 2 pt deaths from neutopenic fever. Although there were some durable responses, response criteria were not met to proceed with stage 2. Further development with VX-710 has since stopped. [Table: see text]