tbuckley/cabot-search huggingface dataset:
P0466 : IL-33 knock out mice are sensitized to severe ConA liver injury but not CCl4-mediated liver injury
Authors: M. Imran Arshad, G. Noel, A. Filliol, V. Genet, C. Lucas-Leclerc, J.-P. Girard, C. Piquet-Pellorce, M. Samson
Journal: Journal of Hepatology (2015)
Combination intraperitoneal chemotherapy with cisplatin, cytarabine, and doxorubicin for refractory ovarian carcinoma and other malignancies principally confined to the peritoneal cavity.
Authors: M Markman, S B Howell, W E Lucas, C E Pfeifle, M R Green
Journal: Journal of Clinical Oncology (1984)

Thirty-one patients with refractory ovarian cancer and other malignancies principally confined to the abdominal cavity were treated with an intraperitoneal combination-chemotherapy regimen consisting of cisplatin (100 to 200 mg/m2), cytosine arabinoside (10(-4) to 10(-3) mol/L) and doxorubicin (2 to 18 mumol/L). Sodium thiosulfate was simultaneously administered intravenously to prevent cisplatin-induced nephrotoxicity. Eight of 26 evaluable patients demonstrated clinical response including seven of 17 (41%) with ovarian cancer refractory to frontline chemotherapy. Systemic toxicity was mild except for nausea and vomiting. Abdominal pain secondary to doxorubicin was the major complication of therapy. We conclude that combination intraperitoneal therapy with cisplatin, cytosine arabinoside, and doxorubicin can be safely administered with objective tumor responses observed in patients with ovarian cancer heavily pretreated and in individuals with other malignancies involving the peritoneal cavity. Doxorubicin-induced local pain limits the ability to administer multiple courses of this treatment regimen.
Innate Lymphoid Cells Are Depleted Irreversibly during Acute HIV-1 Infection in the Absence of Viral Suppression
Authors: Henrik N. Kløverpris, Samuel W. Kazer, Jenny Mjösberg, Jenniffer M. Mabuka, Amanda Wellmann, Zaza Ndhlovu, Marisa C. Yadon, Shepherd Nhamoyebonde, Maximilian Muenchhoff, Yannick Simoni, Frank Andersson, Warren Kuhn, Nigel Garrett, Wendy A. Burgers, Philomena Kamya, Karyn Pretorius, Krista Dong, Amber Moodley, Evan W. Newell, Victoria Kasprowicz, Salim S. Abdool Karim, Philip Goulder, Alex K. Shalek, Bruce D. Walker, Thumbi Ndung’u, Alasdair Leslie
Journal: Immunity (2016)
Sunitinib (SU) in combination with docetaxel (D) versus D alone for the first-line treatment of advanced breast cancer (ABC).
Authors: J. Bergh, R. Greil, N. Voytko, A. Makhson, J. Cortes, A. Lortholary, X. Huang, C. Giorgetti, K. A. Kern, M. Lichinitser
Journal: Journal of Clinical Oncology (2010)

LBA1010 Background: Taxane-based chemotherapy (CT) improves progression-free survival (PFS) in patients (pts) with newly diagnosed HER2-negative metastatic BC (MBC). SU, an oral multitargeted tyrosine kinase inhibitor (MTKI), demonstrated antitumor activity in combination with D in a phase I/II study in pts with MBC. A randomized, open-label, multicenter phase III trial in pts with newly diagnosed ABC tested the hypothesis that addition of a MTKI to D improves PFS vs. D alone. Methods: Eligible pts (female; ≥18 yrs) had an ECOG PS ≤1, and newly diagnosed HER2-negative MBC or ABC. If (neo)adjuvant therapy included a taxane, relapse must have occurred ≥12 mos after CT. Pts were randomized (1:1) to treatment (tx) with D 75 mg/m 2 iv on day 1 and SU 37.5 mg/day po from day 2–15 q3w (Schedule 2/1; Arm A), or to D 100 mg/m 2 iv 1-hr infusion q3w (Arm B) that could be given until progression. If D was discontinued in Arm A for reasons other than progressive disease (PD), single-agent SU 37.5 mg daily was permitted until PD. Median, independently assessed, PFS (primary endpoint) was compared between tx arms using stratified and unstratified log-rank tests. Overall objective response rate (ORR), overall survival (OS), pt-reported outcomes, and safety were secondary endpoints. Results: As of the data cutoff (February 1, 2010), the ITT population comprised 593 pts (SU+D, n=296; D, n=297). The trial did not meet its primary endpoint of prolonging PFS based on the independent radiologic assessment or in prolonging OS. Baseline characteristics were well balanced. Median relative dose intensity (RDI) was 94.2% and 92.4% for SU+D, and 92.6% for D arms, respectively. Median PFS was 8.6 mos (95% CI 8.2–10.3) in the SU+D arm vs 8.3 mos (95% CI 7.7–9.6) for the D arm (HR 0.922). Median OS was 24.8 mos (95% CI 21.5–33.1) in SU+D arm vs 25.5 mos (95% CI 22.8–27.8) for D arm (HR 1.207). ORR was significantly better for SU+D (51%) vs. D (39%) (p=0.0018). Frequent all causality grade 3/4 adverse events (≥10%) were neutropenia (46%), hand–foot syndrome (17%), and fatigue (12%) in the SU+D arm and neutropenia (44%) in the D arm. Conclusions: Based on these data, SU+D is not a recommended treatment option for patients with newly diagnosed ABC. Strategies using antiangiogenic TKIs that increase RR but not OS may need to be revisited. [Table: see text]
In Vitro Binding of the Food Mutagen 2-Amino-3-methylimidazo[4,5-&lt;italic&gt;f&lt;/italic&gt;]quinoline to Dietary Fibers&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: W S Barnes, J Maiello, J H Weisburger
Journal: JNCI Journal of the National Cancer Institute (1983)

The ability of three kinds of fiber to bind to 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a potent bacterial mutagen formed during the cooking of meat, was investigated to determine interactions among important food components. At pH 6.5 corn bran, wheat bran, and alfalfa meal each bound approximately 50% of the available IQ after incubation for 1 hour. Binding was pH-dependent, occurred optimally between pH 4 and 6, and was probably due to a cation-exchange mechanism. The pH at which IQ is efficiently bound to fiber overlaps the range of pH in the human gastrointestinal tract.
Natural killer (NK)-cell function and antileukemic activity of a large population of CD3+/CD8+ T cells expressing NK receptors for major histocompatibility complex class I after "three-loci" HLA-incompatible bone marrow transplantation
Authors: N Albi, L Ruggeri, F Aversa, C Merigiola, A Tosti, R Tognellini, CE Grossi, MF Martelli, A Velardi
Journal: Blood (1996)
Phase I study of oral LBH589, a novel deacetylase (DAC) inhibitor in advanced solid tumors and non-hodgkin’s lymphoma
Authors: H. M. Prince, D. George, A. Patnaik, M. Mita, M. Dugan, D. Butterfoss, E. Masson, K. W. Culver, H. A. Burris, J. Beck
Journal: Journal of Clinical Oncology (2007)

3500 Background: LBH589 is a novel deacetylase inhibitor (DACi) which induces apoptosis of tumor cells at nanomolar levels. In this phase 1 study, we evaluated the safety and tolerability of LBH589 in pts with advanced solid tumors or non-hodgkins lymphoma. Methods: LBH589 was administered orally on Monday, Wednesday, and Friday (MWF) weekly. Western blots on peripheral blood lymphocytes were used to study histone acetylation (HA). Plasma PK profiles were analyzed on Days 1 and 15. Results: Thirty two pts have been treated (Median age 63 years; 18 M, 14 F). Pts received 15 mg (3), 30 mg (10), the dose-limiting toxicity level (DLT), or 20 mg (19), the maximum tolerated dose (MTD). Tumor types included: CTCL (10), renal cell (6), melanoma (6), prostate (4), hepatic (1), rhabodomyosarcoma (1), mesothelioma (1), colon (1), bladder (1), and parotid gland (1). Three DLTs were reported; G3 diarrhea and transient G4 thrombocytopenia at 30 mg and G3 fatigue at 20 mg. The most common adverse events were anorexia, nausea, fatigue, diarrhea and transient thrombocytopenia. Of the 1,057 ECGs, 1 pt (20 mg) had a QTcF of 503 msec, an isolated event after the first dose with no recurrence on continued therapy. The mean change in QTcF from baseline was &lt; 10 msec during the first cycle in all cohorts. No increase in HA was seen at 15 mg, but did increase in 50% of pts at 72 hrs post dose in both the 20 mg and 30 mg cohorts. LBH589 was rapidly absorbed in plasma (Tmax 1.5 hr), then declined with a mean terminal half-life of 16 hrs. Cmax and AUC increased linearly with doses between 15–30 mg. Two cutaneous T- cell lymphoma (CTCL) pts achieved a complete response (5 and 7 months) and 4 CTCL pts attained a partial response (6.5, 8, 9 and 18+ months). Stable disease was achieved in 7 pts: CTCL-2 pts (2 and 3 months); RCC-2 pts (3.5 and 7 months); melanoma-1 pt (4 months), mesothelioma-1 pt (2.5 months) and parotid gland-1 pt (5 months). Fifteen pts progressed on treatment and 4 pts were not evaluable for response. Conclusions: At 20 mg MWF every week, LBH589 oral produced a sustained pharmacodynamic effect on HA for ≥72 hours post dose in 50% of pts. Cardiac data indicates no clinically-significant effect on QTcF. Preliminary evidence of tumor response was observed at this dose and schedule in CTCL pts. No significant financial relationships to disclose.
A noninterventional study of everolimus in metastatic renal cell cancer after use of one VEGFR-TKI: Results of a preplanned interim analysis of a prospective study.
Authors: L. Bergmann, U. Kube, M. Kindler, T. Koepke, G. Steiner, J. Janssen, S. Fries, P. Goebell, A. Jakob, T. Steiner, M. D. Staehler, F. Overkamp, M. Albrecht, C. Doehn
Journal: Journal of Clinical Oncology (2011)

4552 Background: Everolimus (EVE, Afinitor) was approved for treatment of patients with metastatic renal cell cancer (mRCC) after failure of anti-VEGF therapy. Nevertheless, only limited prospective data is available on EVE after failure of 1 VEGFR-TKI. Here we report for the first time prospective data on the use of EVE after failure of the 1st VEGFR-TKI. Methods: A prospective, non interventional study in mRCC after failure of the 1st VEGFR-TKI was initiated to observe effectiveness of EVE. A preplanned interim analysis was performed after 100 patients had been enrolled in the study and were followed for ≥3 months. Results: 59 German sites included 113 patients between 08/’09 and 07/’10, which were followed for a median of 116 days. Median age was 67 years, the median KPI was 80% and 88% had undergone nephrectomy. Most patients were previously treated with sunitinib (78%). Other prior therapies were sorafenib, cytokines and bevacizumab. Total duration of prior treatment was 15 months. Metastatic spread was detected in a median number of 2 organ systems. EVE-treatment information was available from 99 patients. At the cut-off date for interim analysis 47 of them had discontinued the study, because of disease progression (25), death (9) adverse events (7) and patient’s wish (6). Median TTP for EVE was 9.7 months (95% CI: 6 mo.; n.r.). At the cut-off date the majority of patients were still on treatment, thus the median was still not reached. Safety evaluation confirmed the known profile of EVE with 230 reported adverse event. Anemia, pruritus, fatigue, dyspnea and diarrhea of any grade were the most frequent reported adverse drug reactions (>5% incidence each). 9 patients required treatment interruption of 5-39 days. Treating physicians reported a high therapy compliance of patients (80-100%) and a favorable tolerability profile of EVE. Conclusions: This study of EVE in mRCC provides for the first time prospective data on the use of EVE after failure of the 1st VEGFR-TKI in routine use. It confirms prior reports about a longer TTP in a less pretreated population than evaluated in the pivotal trial. The results support EVE as the standard of care after failure of one VEGFR-TKI.
“Euthanasia kits” are prepared for Quebec doctors as palliative care centres rebel on right to die
Authors: Owen Dyer
Journal: BMJ (2015)

New guidelines from the College des Medecins du Quebec explain how doctors will provide medical aid in dying to terminally ill patients who request it, when Canada’s second largest province becomes North America’s biggest right to die jurisdiction on December 10.

Physicians will be able to end a patient’s life with three sequential injections: a benzodiazepine sedative to relieve anxiety, a barbiturate to induce coma, and a curare-type neuromuscular block to stop the heart and respiration. Special kits containing all three drugs, back-up doses, and detailed instructions will be prepared by pharmacists on a patient by patient basis and will be available to all licensed physicians.

The college decided that doctors should administer the drugs intravenously rather than simply prescribe an oral drug. Yves Robert, secretary of the college, said that …
Capecitabine (X) monotherapy as first-line chemotherapy (CT) for metastatic breast cancer (MBC): High efficacy regardless of prior therapy
Authors: L. Mauriac, A. Trainaud, A. Floquet, C. Donamaria, M. Durand, V. Brouste, M. Debled
Journal: Journal of Clinical Oncology (2007)

1092 Background: X is one of the most active agents in pretreated MBC. Data on X monotherapy as first-line CT are limited, although a recent randomized phase III trial showed a survival benefit vs oral CMF (Stockler et al SABCS 2006). We retrospectively analyzed MBC pts receiving first-line X at our institution. Methods: Between 01/2002 and 09/2006, 167 pts received X (bid, days 1–14 q3w). Response classifications (improvement in disease [ID], stable disease [SD], or progressive disease [PD]) were as described by Hennessy et al (Ann Oncol 2005). Results: Median age was 68 years (range 34–91). Prior adjuvant therapy included CT in 47% and tamoxifen in 49% of pts. Median interval between initial surgery and MBC was 4.4 years (range 0–39). Before X, most pts (79%) had received endocrine therapy (ET) for MBC (median 2 lines, median duration 2.1 years). Median no. of metastatic sites was 2; bone and visceral metastases were each present in 60% of pts. The initial X dose was 1,500–2,500mg/d in 23%, 3,000mg/d in 47%, and 3,150–4,800mg/d in 29% of pts. ID was seen in 57% of pts (median duration 11.7 months [95% CI 3.8–28.6]). A further 20% had SD for =6 weeks. Median time to X failure (TTF) and OS were 9.0 [95% CI 7.1–11.0] and 25.8 months [95% CI 22.1–29.5], respectively. None of the following influenced TTF: age (&lt;70/=70y), prior adjuvant CT (yes/no), prior ET for MBC (no/&lt;12m/=12m), visceral disease (yes/no), initial dose (&lt;3,000/3,000/&gt;3,000mg). Toxicities were typical of X monotherapy. X was continued for =12 months in 46 pts without cumulative toxicity. Conclusions: X appears highly active as first-line CT for MBC pts, including those who had received ET for MBC and/or adjuvant CT. Long-term treatment is well tolerated. The safety profile is consistent with previous reports. High activity, oral administration, lack of alopecia, and low hematologic toxicity make X a very attractive first- line CT for slowly progressing disease and/or after ET failure. No significant financial relationships to disclose.
Systemic Chromosome Instability Resulted in Colonic Transcriptomic Changes in Metabolic, Proliferation, and Stem Cell Regulators in <i>Sgo1</i> <i>−/+</i> Mice
Authors: Chinthalapally V. Rao, Saira Sanghera, Yuting Zhang, Laura Biddick, Arun Reddy, Stan Lightfoot, Naveena B. Janakiram, Altaf Mohammed, Wei Dai, Hiroshi Y. Yamada
Journal: Cancer Research (2016)

Abstract Colon cancer is the second most lethal cancer and is predicted to claim 49,700 lives in the United States this year. Chromosome instability (CIN) is observed in 80% to 90% of colon cancers and is thought to contribute to colon cancer progression and recurrence. To investigate the impact of CIN on colon cancer development, we developed shugoshin-1 (Sgo1) haploinsufficient (−/+) mice, an animal model focusing on mitotic error–induced CIN. In this study, we analyzed signature changes in the colonic transcriptome of Sgo1−/+ mice to examine the molecular events underlying the altered carcinogenesis profiles in Sgo1−/+ mice. We performed next-generation sequencing of normal-looking colonic mucosal tissue from mice treated with the carcinogen azoxymethane after 24 weeks. Transcriptome profiling revealed 349 hits with a 2-fold expression difference threshold (217 upregulated genes, 132 downregulated genes, P &amp;lt; 0.05). Pathway analyses indicated that the Sgo1-CIN tissues upregulated pathways known to be activated in colon cancer, including lipid metabolism (z score 4.47), Notch signaling (4.47), insulin signaling (3.81), and PPAR pathways (3.75), and downregulated pathways involved in immune responses including allograft rejection (6.69) and graft-versus-host disease (6.54). Notably, stem cell markers were also misregulated. Collectively, our findings demonstrate that systemic CIN results in transcriptomic changes in metabolism, proliferation, cell fate, and immune responses in the colon, which may foster a microenvironment amenable to cancer development. Therefore, therapeutic approaches focusing on these identified pathways may be valuable for colon cancer prevention and treatment. Cancer Res; 76(3); 630–42. ©2016 AACR.
A Novel Extrinsic Pathway for the Unfolded Protein Response in the Kidney
Authors: Iadh Mami, Quentin Tavernier, Nicolas Bouvier, Rim Aboukamis, Geoffroy Desbuissons, Marion Rabant, Virginie Poindessous, Pierre Laurent-Puig, Philippe Beaune, Pierre-Louis Tharaux, Eric Thervet, Eric Chevet, Dany Anglicheau, Nicolas Pallet
Journal: Journal of the American Society of Nephrology (2016)

The ribonuclease angiogenin is a component of the mammalian stress response, and functions in both cell-autonomous and non-cell-autonomous ways to promote tissue adaptation to injury. We recently showed that angiogenin regulates tissue homeostasis during AKI associated with endoplasmic reticulum (ER) stress through the production of transfer RNA fragments that interfere with translation initiation and thereby alleviate ER stress. However, whether the paracrine signaling mediated by angiogenin secretion is a genuine component of the ER stress response to kidney injury is unknown. Here, we explored the molecular mechanisms by which angiogenin is secreted upon ER stress, and determined how it modulates the inflammatory microenvironment. In cultured renal epithelial cells, ER stress specifically induced angiogenin secretion under the selective control of inositol-requiring enzyme 1 α , a key activator of the unfolded protein response. The transcription factors spliced X-box–binding protein 1 and p65, which are activated by inositol-requiring enzyme 1 α upon ER stress, each bound the angiogenin promoter and controlled the amount of angiogenin secreted. Furthermore, p65 promoted angiogenin transcription in an ER stress-dependent manner. Similar to secretion of the ER stress-induced proinflammatory cytokine IL-6, secretion of angiogenin required the ER-Golgi pathway. Notably, incubation of human macrophages with angiogenin promoted macrophage reprogramming toward an activated and proinflammatory phenotype. In patients, angiogenin expression increased upon renal inflammation, and the urinary concentration of angiogenin correlated with the extent of immune-mediated kidney injury. Collectively, our data identify angiogenin as a mediator of the ER stress-dependent inflammatory response and as a potential noninvasive biomarker of AKI.
Use of absolute lymphocyte counts to predict response to chemotherapy and survival in diffuse large B-cell lymphoma
Authors: D. Kim, Y. Chae, J. Baek, J. Kim, Y. Kim, Y. Park, Y. Do, J. Chung, M. Kim, H. Song
Journal: Journal of Clinical Oncology (2007)

8082 Background: Absolute lymphocyte counts (ALCs) at diagnosis has been shown to be an independent prognostic factor in patients with follicular lymphoma (FL) although the precise mechanism was not fully elucidated. The current study evaluated the impact of Absolute lymphocyte counts (ALCs) at diagnosis in patients with diffuse large B-cell lymphoma (DLBCL) on the response to chemotherapy and survival. Methods: The treatment outcomes of the patients receiving CHOP (n=101) or R-CHOP chemotherapy (n=122) were compared according to ALCs at diagnosis (&lt;1.0 vs. = 1.0×10 9 /L). Results: Forty-two patients (19%) had a lower ALC count at diagnosis (CHOP, 23 [23%]; R-CHOP, 19 [16%]). The lower ALCs showed a good correlation with IPI (p&lt;0.001), performance (p&lt;0.001), LDH (p&lt;0.001), stage (p=0.004), extranodal involvement (p=0.011), but not with age or sex. A significant difference of response rate was noted according to ALCs in favor of a higher ALCs (CR: 80% vs. 60%, p=0.005; ORR: 93% vs. 78%, p=0.003). In addition, event-free survival (EFS) was worse in a lower ALC group than higher ALC group: median duration of EFS, 1,773 days vs. 326 days (p&lt;0.001). The OS was also in favor of a higher ALC group: median duration of OS, 3,000 days vs. 695 days (p&lt;0.001). In multivariate analysis, ALC at diagnosis was an independent predictive factor for CR (HR 2.717, p=0.009) and prognostic factor for EFS (HR 2.148, p=0.004) or OS (HR 2.863, p=0.002). Conclusion: The ALCs at diagnosis appears to predict the survival of DLBCL patients. Our findings suggested that the ALCs at diagnosis may reflect host's immune status against DLBCL, implying that immune system of host will play a critical role on survival of DLBCL patients. No significant financial relationships to disclose.
Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation but resistant to temozolomide
Authors: Ralf S. Schmid, Jeremy M. Simon, Mark Vitucci, Robert S. McNeill, Ryan E. Bash, Andrea M. Werneke, Lauren Huey, Kristen K. White, Matthew G. Ewend, Jing Wu, C. Ryan Miller
Journal: Neuro-Oncology (2016)

Glioma stem cells (GSCs) from human glioblastomas (GBMs) are resistant to radiation and chemotherapy and may drive recurrence. Treatment efficacy may depend on GSCs, expression of DNA repair enzymes such as methylguanine methyltransferase (MGMT), or transcriptome subtype.To model genetic alterations in human GBM core signaling pathways, we induced Rb knockout, Kras activation, and Pten deletion mutations in cortical murine astrocytes. Neurosphere culture, differentiation, and orthotopic transplantation assays were used to assess whether these mutations induced de-differentiation into GSCs. Genome-wide chromatin landscape alterations and expression profiles were examined by formaldehyde-assisted isolation of regulatory elements (FAIRE) seq and RNA-seq. Radiation and temozolomide efficacy were examined in vitro and in an allograft model in vivo. Effects of radiation on transcriptome subtype were examined by microarray expression profiling.Cultured triple mutant astrocytes gained unlimited self-renewal and multilineage differentiation capacity. These cells harbored significantly altered chromatin landscapes that were associated with downregulation of astrocyte- and upregulation of stem cell-associated genes, particularly the Hoxa locus of embryonic transcription factors. Triple-mutant astrocytes formed serially transplantable glioblastoma allografts that were sensitive to radiation but expressed MGMT and were resistant to temozolomide. Radiation induced a shift in transcriptome subtype of GBM allografts from proneural to mesenchymal.A defined set of core signaling pathway mutations induces de-differentiation of cortical murine astrocytes into GSCs with altered chromatin landscapes and transcriptomes. This non-germline genetically engineered mouse model mimics human proneural GBM on histopathological, molecular, and treatment response levels. It may be useful for dissecting the mechanisms of treatment resistance and developing more effective therapies.
Patient selection bias and inappropriate stent selection leading to false conclusions in the comparison of metal and plastic stents
Authors: Ibrahim Köker
Journal: Endoscopy (2015)

In a recent article, Chung et al. compared the effectiveness of self-expandable metallic stents (SEMSs) with plastic stents in a cohort of patients with hepatocellular carcinoma [1]. They claimed that patient survival was better with plastic stents and that stent patency duration was similar between plastic stents and SEMSs.