tbuckley/cabot-search huggingface dataset:
<i>miR-34a</i> and <i>miR-34b/c</i> Suppress Intestinal Tumorigenesis
Authors: Longchang Jiang, Heiko Hermeking
Journal: Cancer Research (2017)

Abstract The p53-inducible miR-34a and miR-34b/c genes are frequently silenced in colorectal cancer. To address the in vivo relevance of miR-34a/b/c function for suppression of intestinal tumor formation, we generated ApcMin/+ mice with deletions of the miR-34a and/or miR-34b/c genes separately or in combination. Combined deletion of miR-34a/b/c increased the number of intestinal stem cells as well as Paneth and Goblet cells, resulting in enlarged intestinal crypts. miR-34a/b/c-deficient ApcMin/+ mice displayed an increased tumor burden and grade and decreased survival. miR-34a/b/c-deficient adenomas showed elevated proliferation and decreased apoptosis and displayed pronounced bacterial infiltration, which may be due to an observed decrease in infiltrating immune cells and downregulation of barrier proteins. mRNA induction in miR-34a/b/c-deficient tumors was enriched for miR-34a/b/c seed-matching sites and for mRNAs encoding proteins related to epithelial–mesenchymal transition, stemness, and Wnt signaling. Accordingly, cells explanted from miR-34a/b/c-deficient adenomas formed tumor organoids at an increased rate. Several upregulated miR-34 targets displayed elevated expression in primary human colorectal cancers that was associated with lymph-node metastases (INHBB, AXL, FGFR1, and PDFGRB) and upregulation of INHBB and AXL in primary colorectal cancer was associated with poor patient survival. In conclusion, our results show that miR-34a/b/c suppress tumor formation caused by loss of Apc and control intestinal stem cell and secretory cell homeostasis by downregulation of multiple target mRNAs. Cancer Res; 77(10); 2746–58. ©2017 AACR.
Is Pregabalin Ineffective in Acute or Chronic Sciatica?
Authors: Nadine Attal, Michel Barrot
Journal: New England Journal of Medicine (2017)

Sciatica with or without low back pain is not easily managed,1 and few treatments have established efficacy for these conditions.2,3 Although the antiepileptic drug pregabalin has been recommended for the treatment of neuropathic pain (i.e., the broad category of pain associated with a lesion or disease of the somatosensory system, such as postherpetic neuralgia, polyneuropathy, or nerve trauma), a randomized, placebo-controlled trial of pregabalin involving patients with chronic lumbosacral painful radiculopathy did not show a benefit with pregabalin.4 However, the trial did not allow definitive conclusions because of methodologic limitations.In this issue of the Journal, Mathieson and colleagues . . .
Early tumor shrinkage in patients with metastatic colorectal cancer receiving first-line treatment with cetuximab combined with either CAPIRI or CAPOX: An analysis of the AIO KRK 0104 trial.
Authors: Dominik Paul Modest, Ruediger Paul Laubender, Ludwig Fischer von Weikersthal, Ursula Vehling-Kaiser, Martina Stauch, Holger Hass, Hermann F. Dietzfelbinger, Daniel V. Oruzio, Stefan Klein, Klaus Zellmann, Thomas Decker, Mathias Schulze, Wolfgang Abenhardt, Gerhard Puchtler, Herbert W. Kappauf, Johann Mittermueller, Christopher Haberl, Sebastian Stintzing, Ulrich Robert Mansmann, Volker Heinemann
Journal: Journal of Clinical Oncology (2012)

3588 Background: This study investigated the impact of early tumor-shrinkage (ETS) on progression-free (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated within the AIO KRK-0104-trial. ETS was previously shown to be a predictor of treatment response to cetuximab. The present analysis, for the first time, evaluates the correlation of ETS with outcome parameters in patients undergoing capecitabine-based therapy. It also aims to correlate the predictive value of ETS and cetuximab-induced skin toxicity. Methods: The AIO KRK0104 trial was performed as a randomised study comparing capecitabine/oxaliplatin (CAPOX) plus cetuximab to capecitabine/irinotecan (CAPIRI) plus cetuximab in the first-line treatment of mCRC. 121 patients were available for evaluation of ETS at 6 weeks. ETS was defined as a relative change of ≥20% in the sum of the longest diameters of target lesions compared to baseline. Results: Tumors of 63 patients (71% KRAS wild-type (wt), 100% skin reactions) developed ETS, 58 tumors did not develop ETS (53% KRAS wt, 86% skin reactions). ETS was associated with prolonged PFS (8.9 vs. 4.7 months, p&lt;0.001, hazard ratio: 0.37) and OS (31.6 vs. 15.8 months, p=0.005, hazard ratio: 0.48) in patients with KRAS wt tumors but not in patients with KRAS mutant mCRC. ETS occurred more frequently with CAPOX- vs CAPIRI-based therapy (p=0.05). There was a highly significant correlation between the occurrence of ETS and cetuximab-related skin toxicity of any grade (I-III) (p=0.002). ETS was documented more frequently in patients with liver metastasis (p=0.09), metastatic involvement of &lt;2 organs (p=0.09), KRAS wild-type tumors (p=0.06) and no previous adjuvant chemotherapy (p=0.06). Conclusions: In patients with KRAS wild-type mCRC receiving capecitabine- and cetuximab-based first -line therapy ETS correlates with prolonged PFS and OS. ETS also correlates with cetuximab-induced skin toxicity. Both parameters may therefore serve as post-randomisation surrogate markers of favourable outcome for cetuximab-based treatment.
Tolerance Induction by Immature Dendritic Cells Is Mediated by Distinct MHC Dependent and Independent Mechanisms: A Novel Role for Perforin, Granzyme A and Toll Like Receptor 7.
Authors: Lior Zangi, Yaki Edelshtein, Yael Klionsky, Esther Bachar-Lustig, Elias Shezen, Shlomit Reich-Zeliger, Assaf Lask, Oren Milstein, Vera Shinder, Yair Reisner
Journal: Blood (2009)
Study of setup errors and planing target volume margins by kilovoltage cone beam CT in patients with pelvic tumors.
Authors: Gang Wang, Wenling Wang, Yiqun Liu, Hongmin Dong, Lei Han, Yinxiang Hu, Zhiyong Wang, Yigui Chai
Journal: Journal of Clinical Oncology (2014)

e22242 Background: This study was to analyze the setup errors of pelvic tumor patients in image-guided radiotherapy (IGRT) so as to calculate the margin required from clinical target volume (CTV) to planning target volume (PTV). Methods: 19 patients with pelvic tumors were treated by IGRT (Elekta Synergys). 283 images were acquired for all patients before treatment through kilovoltage cone beam CT (kVCBCT), which were compared with the ones through planning CT in order to obtain 3 linear shifts, left- right (Lx), antero-posterior (LY), supero-inferior (LZ) and rotational errors Rx, RY and Rz centered on Lx, LY and LZrespectively. 159 kVCBCT images were obtained by correcting beyond-scope setup errors using Synergy system and 6-dimensional treatment bed. Results: Beforecorrection, the 159 setup errors in Lx, LY and LZ were respectively (0.057±0.206) cm, (−0.095±0.401) cm and (−0.112±0.259) cm, whereas the errors were (−0.015±0.080) cm, (−0.029±0.072) cm and (−0.055±0.069) cm accordingly after correction, all of which showed significant differences (p=0.000, 0.037, 0.004). However, the only distinct difference in the setup errors of 3 rotational directions (Rx, RY and Rz) before and after correction showed at Rx (p=0.044). According to the formula M=2.5∑+0.7δ, Mptv was 0.61 cm in Lx, 0.78 cm in LY and 0.41 cm in LZbefore correction while was 0.17 cm, 0.12 cm and 0.17 cm after correction. Conclusions: kVCBCT can measure the setup errors of patients with pelvic tumors during radiotherapy and make the real-time correction, which can greatly increase the setup accuracy and decrease the margin from CTV to PTV (Mptv).
Abstract #127: Anti-tumor efficacy of the 3.19.3 ANG-2 antibody in combination with VEGF inhibitors in tumor xenograft models
Authors: Jeff Brown, Zhu (Alex) Cao, Corinne Reimer, Qing (Joe) Zhou, Jane Kendrew, Anderson Ryan, Juliane Jürgensmeier, Steve Emery, David Blakey
Journal: Cancer Research (2009)

Antibody 3.19.3 is a novel human antibody that binds to the angiogenic ligand ANG-2 leading to inhibition of Tie-2 receptor phosphoryation in vitro and significant anti-tumor activity as a single agent in preclinical tumor models. In these studies the ability of antibody 3.19.3 to enhance the activity of both small molecule and antibody VEGF pathway inhibitors has been investigated. Human colorectal tumour cells (LoVo, HT29, SW620) were implanted subcutaneously in athymic nude mice and once tumors had reached ~ 100-150 mm3 treatment with either 3.19.3 antibody alone (10 mg/kg twice weekly), VEGF inhibitor alone (Vandetanib-50mg/kg daily, Cediranib- 1.5 mg/kg daily or DC101 murine KDR antibody - 15 mg/kg twice weekly) or a combination of the two agents was initiated. The results of these studies are summarized in Table 1. In all 3 tumor models both the 3.19.3 antibody and the VEGF pathway inhibitor demonstrated significant anti-tumor activity that was enhanced by combining both agents. The combination arm gave significantly (P $$table_{EBEA0BC8-25DC-487B-A178-CFADB600BA2B}$$ >  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 127.
Time to ReSPECT personal resuscitation plans for adults?
Authors: Toni Wolff, William P Whitehouse
Journal: BMJ (2017)

We agree with Pitcher and colleagues that resuscitation should be discussed earlier in the patient journey.1 This is easiest and most appropriate in the context of an emergency care plan (ECP), detailing how the patient may deteriorate and emphasising what to do, rather than discussing this in the context of a …
Genome-Wide Identification of the Mutation Underlying Fleece Variation and Discriminating Ancestral Hairy Species from Modern Woolly Sheep
Authors: Julie Demars, Margarita Cano, Laurence Drouilhet, Florence Plisson-Petit, Philippe Bardou, Stéphane Fabre, Bertrand Servin, Julien Sarry, Florent Woloszyn, Philippe Mulsant, Didier Foulquier, Fabien Carrière, Mathias Aletru, Nathalie Rodde, Stéphane Cauet, Olivier Bouchez, Maarten Pirson, Gwenola Tosser-Klopp, Daniel Allain
Journal: Molecular Biology and Evolution (2017)

The composition and structure of fleece variation observed in mammals is a consequence of a strong selective pressure for fiber production after domestication. In sheep, fleece variation discriminates ancestral species carrying a long and hairy fleece from modern domestic sheep (Ovis aries) owning a short and woolly fleece. Here, we report that the “woolly” allele results from the insertion of an antisense EIF2S2 retrogene (called asEIF2S2) into the 3′ UTR of the IRF2BP2 gene leading to an abnormal IRF2BP2 transcript. We provide evidence that this chimeric IRF2BP2/asEIF2S2 messenger 1) targets the genuine sense EIF2S2 RNA and 2) creates a long endogenous double-stranded RNA which alters the expression of both EIF2S2 and IRF2BP2 mRNA. This represents a unique example of a phenotype arising via a RNA-RNA hybrid, itself generated through a retroposition mechanism. Our results bring new insights on the sheep population history thanks to the identification of the molecular origin of an evolutionary phenotypic variation.
The impact of body mass index (BMI) on treatment outcome of targeted therapy in metastatic renal cell carcinoma (mRCC): Results from the International Metastatic Renal Cell Cancer Database Consortium.
Authors: Laurence Albiges, Wanling Xie, Jae-Lyun Lee, Brian I. Rini, Sandy Srinivas, Georg A. Bjarnason, D. Scott Ernst, Lori Wood, Ulka N. Vaishamayan, Sun Young Rha, Neeraj Agarwal, Takeshi Yuasa, Sumanta Kumar Pal, Konstantinos Koutsoukos, Andre Poisl Fay, Mark A Preston, Eunyoung Cho, Daniel Yick Chin Heng, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2014)

4576 Background: Obesity increases risk for RCC, yet recent report suggest that tumors developing in an obesogenic environment may be more indolent. We investigated the effect of BMI on treatment outcome in patients (pts) treated with targeted therapy (TT) for mRCC. Methods: Baseline characteristics and outcomes on 1975 pts from 19 centers of the IMDC were analyzed to study the impact of BMI on survival and treatment outcome of first and second line TT. Toxicity profile in relation to BMI was also assessed. Results: Median follow-up was 21.1 months. Median time to treatment failure on first-line TT was 7.2 months and median overall survival (mOS) was 21.5 months [95%CI: 20.1-23.3]. At therapy initiation, 785(40%) pts were considered underweight or normal weight (BMI<25 kg/m2), 663(33.5%) overweight (BMI 25-<30 kg/m2) and 527 (26.5%) obese (BMI≥30 kg/m2). Overweight/obese pts had a longer mOS (25.6 vs. 17.1 months) than underweight/normal weight pts (p<0.0001). After adjusting for the IMDC prognostic risk factors, the mOS difference persisted in favor of the overweight/obese pts group (HR=0.84, (95%CI: 0.73-0.95), p=0.008). In addition, pts with higher BMI indices (overweight/obese) had improved time on therapy in both first-line (8.1 vs. 5.7 months, p<0.0001) and second-line (4.2 vs. 3.0 months, p=0.0006), and the difference remained after adjustment for the IMDC prognostic risk factors (p<0.01). Estimates of the cumulative incidence of treatment failure because of toxicity did not differ between the underweight/normal and overweight/obese groups (p=0.936), but the cumulative incidence of treatment failure because of progression/death favored the overweight/obese group after adjustment for the IMDC risk groups (p<0.002). Conclusions: We found that being overweight or obese is independently associated with an improved outcome in mRCC pts treated with TT. Increased toxicity was ruled out as a potential bias for treatment discontinuation or dose reduction in normal/underweight pts. Biological investigation in tissues collected from the IMDC cohort is in process to better characterize the obesity paradox in mRCC.
Biallelic Mutations in Hamp in Type 2b Hemochromatosis
Authors: Serge Pissard, Ka Chandran, Florence Houriez, Ichrache Benmaad, Martial Saunier, Thibault Lefebvre, Patricia Aguilar-Martinez, Patricia A. Bignell, Gerald Le Gac, Jacques Rochette
Journal: Blood (2016)
Phase I trial of the anti-idiotypic monoclonal antibody (mAb) ACA-125 in patients with epithelial ovarian, fallopian tube or primary peritoneal cancer
Authors: P. Sabbatini, C. Aghajanian, J. Dupont, F. Derosa, S. Anderson, W. McGuire, K. Rodabaugh, S. Ferrone, S. Lele, K. Odunsi
Journal: Journal of Clinical Oncology (2004)

5018 Background: Novel agents to prolong remission in ovarian cancer are needed. ACA-125 is a murine anti-idiotypic mAb which mimics the tumor associated antigen CA-125. A prior phase I/II study associated longer survival with an immune response to vaccination (C Ca Res 7:1154–62, 2001) prompting the need to evaluate the optimal dose and administration route for prospective study. Methods: Three institution, open label, phase I study evaluating two doses and routes: Four subcutaneous (SC) versus intramuscular (IM) injections at 2.0 mg or 0.2 mg administered every two weeks, and then monthly for two additional doses. Eligible patients had epithelial ovarian, fallopian tube, or peritoneal cancer who relapsed; and had completed cytotoxic therapy for recurrence with partial or complete response. Planned evaluation included interval physical examination and routine laboratory studies, with immune assessments including HLA-typing, HAMA, ELISA and ELISPOT. Primary endpoints were: 1) safety and 2) immunogenicity primarily defined by Ab3 response. Results: 44 patients were planned and all have been enrolled, 28 patients completed 6 vaccinations (10 withdrawn for progression, 3 withdrew consent), 3 patients are still receiving vaccinations. No grade II or greater hematologic or non-hematologic toxicity related to vaccine was seen. Most common side effects were G 1 pain at injection site, G I fever, and G 1 myalgia resolving < 48 hours. HAMA was absent at baseline (n=37), and present (range 488 –45,000ng/ml) in all patients at week 16 (n=20). Conclusions: mAb ACA-125 vaccination is well tolerated and induced Ab3 response in all patients at both doses and routes evaluated to date. The optimal dose and route for future study with additional immune data will be presented when all patients have completed vaccination. (supported by CellControl, AG, Germany). Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Control Cell Control, Germany
Preoperative evaluation of heat shock protein 47 expression to identify patients with colorectal cancer with lymph node metastasis and poor prognosis.
Authors: Koichiro Mori, Yuji Toiyama, Yoshinaga Okugawa, Takashi Ichikawa, Yuka Nagano, Satoshi Oki, Hiroki Imaoka, Masato Okigami, Hiroyuki Fujikawa, Junichiro Hiro, Susumu Saigusa, Minako Kobayashi, Yasuhiro Inoue, Yasuhiko Mohri, Masato Kusunoki
Journal: Journal of Clinical Oncology (2017)

546 Background: Accumulating evidences reveal that overexpression of Heat shock protein 47 (HSP47) increase cancer progression, and that HSP47 expression in the tumor-associated stroma serve as diagnostic marker in various cancers. In addition, we recently performed immunohistochemistry to evaluate HSP47 expression in surgical colorectal cancer (CRC) specimens, and showed that the count of HSP47 positive spindle cell in cancer stroma was significantly associated with lymph node (LN) metastasis, early recurrence and poor prognosis in CRC patients. Thus, evaluating HSP47 expression in CRCs preoperatively may be valuable for planning the treatment of patients with CRC. In this study, we quantified the messenger RNA(mRNA) expression of HSP47 in CRCs by using preoperative biopsy samples, and analyzed the association between HSP47 mRNA expression and clinico-pathological factors including prognosis in patients with CRC. Methods: A total of 139 CRC samples, which were taken by biopsy before surgery at Mie University Hospital from 2000 to 2005, were enrolled. HSP47 gene expression was determined by quantitative real-time reverse transcription–PCR using Power SYBR Green PCR methods. Results: All CRC patients were classified according to the tumor-node-metastasis (TNM) classification system as follows: stage I (n = 33); stage II (n = 44); stage III (n = 33), and stage IV (n = 29). High HSP47 expression in CRC was significantly associated with higher T stage (p = 0.0163), LN metastasis (p = 0.0186), vessel invasion (p = 0.0328) and higher TNM staging (p = 0.0115). Kaplan-Meier analysis showed that patients with high HSP47 expression had significantly poorer overall survival (OS) than those with low (p = 0.0003). Furthermore, multivariate analyses revealed that HSP47 expression was an independent predictive marker for LN metastasis and poor OS in CRC patients, respectively (LN metastasis; OR; 2.3946, p = 0.0249, OS; HR; 2.7407, p = 0.00224). Conclusions: In conclusion, quantification of HSP47 expression using biopsy samples can identify the CRC patients who may suffer from LN metastasis and poor prognosis, preoperatively.
Characteristics of Immunoglobulin Deficiency in Patients with Untreated Multiple Myeloma Stage II and III.
Authors: Markus Hamel, Wolfram Poenisch, Dirk Hasenclever, Goetz Gelbrich, Markus Loeffler, Haifa K. Al Ali, Stefanie Lehmann, Dietger Niederwieser, Karlheinz Merkle
Journal: Blood (2004)
MET in small cell lung carcinoma (SCLC): Effects of a MET inhibitor in SCLC cell lines and prognostic role of MET status in patients
Authors: I. Cañadas, M. Arumi, L. Lema, A. Martinez, E. Grande, B. Bellosillo, F. Rojo, A. Rovira, J. Albanell, E. Arriola
Journal: Journal of Clinical Oncology (2009)

e14617 Purpose: HGF/MET pathway is aberrantly activated by receptor overexpression and mutations in SCLC preclinical models, enhancing their oncogenicity. The significance of MET expression in SCLC remains unclear. Our aim was to analyze the effects of MET inhibition in chemosensitive/refractory SCLC models and to study the expression pattern and prognostic impact of total and phosphorylated (p) MET in SCLC patients. Methods: Total and p-MET expression (Western Blot), gene copy number (FISH), and exon 14 activating mutations (sequencing) were evaluated in H69 and H69AR SCLC cell lines. PHA-665752 (PHA), alone or combined with doxorubicin, was used to study the effects of pathway inhibition on viability, colony formation and invasion assays in basal/stimulated conditions (HGF). Fifty-eight SCLC cases were evaluated for MET and p-MET expression by immunohistochemistry. Survival analyses were performed. Results: H69 and H69AR (both R988C mutated) expressed MET at basal conditions, but not p-MET. HGF induced MET phosphorylation, increased proliferation (20%) and protected cells from doxorubicin cytotoxicity. PHA 0.5μM blocked MET phosphorylation, decreased colony formation by 50% in H69, counteracted the cytoprotective effect of HGF and inhibited invasion in H69AR. MET expression was found in 98% normal bronchial epithelia, and 78% tumor samples (overexpression 38%). Activated MET was focally detected in normal and metaplastic mucosa and expressed in 22% tumors. MET expression was associated with improved overall and disease free survival (p: 0.06 and 0.051, respectively). All p-MET positive cases within MET expressing tumors, showed relapsed disease (83% in negative p-MET samples, p=0.065), suggesting MET activation may revert the good prognosis linked to total MET expression. Conclusions: MET activation, results in a more aggressive phenotype in SCLC cells. PHA at MET inhibiting concentrations reverses this phenotype. In SCLC specimens, MET expression was more prevalent than p-MET and associated with raised prognosis. All these data suggest that studies with MET inhibitors should focus on p-MET positive SCLC. [Table: see text]