tbuckley/cabot-search huggingface dataset:
Association of an Extracellular Matrix Gene Cluster with Breast Cancer Prognosis and Endocrine Therapy Response
Authors: Jozien Helleman, Maurice P.H.M. Jansen, Kirsten Ruigrok-Ritstier, Iris L. van Staveren, Maxime P. Look, Marion E. Meijer-van Gelder, Anieta M. Sieuwerts, Jan G.M. Klijn, Stefan Sleijfer, John A. Foekens, Els M.J.J. Berns
Journal: Clinical Cancer Research (2008)

Abstract Purpose: We previously discovered an extracellular matrix (ECM) gene cluster associated with resistance to first-line tamoxifen therapy of patients with metastatic breast cancer. In this study, we determined whether the six individual ECM genes [collagen 1A1 (COL1A1), fibronectin 1 (FN1), lysyl oxidase (LOX), secreted protein acidic cysteine-rich (SPARC), tissue inhibitor of metalloproteinase 3 (TIMP3), and tenascin C (TNC)] were associated with treatment response, prognosis, or both. Experimental Design: In 1,286 primary breast tumors, mRNA expression (quantitative real-time PCR) was related to clinicopathologic factors and disease outcome in univariate and multivariate analysis including traditional factors. Results: TIMP3, FN1, LOX, and SPARC expression levels (continuous variables) were significantly associated with distant metastasis-free survival (MFS) in 680 lymph node–negative untreated patients (P &amp;lt; 0.03). Using a calculated linear prognostic score, these patients were evenly divided into five prognostic groups with a significant difference in 10-year MFS of ∼40% between the two extreme prognostic groups. Furthermore, high TNC expression as continuous variable was associated with (a) shorter MFS in 139 estrogen receptor–positive and lymph node–positive patients who received adjuvant tamoxifen therapy (hazard ratio, 1.53; P = 0.001), and (b) no clinical benefit (odds ratio, 0.81; P = 0.035) and shorter progression-free survival (hazard ratio, 1.19; P = 0.002) in 240 patients in whom recurrence was treated with tamoxifen as first-line monotherapy. These results were also significant in multivariate analyses. Conclusion: FN1, LOX, SPARC, and TIMP3 expression levels are associated with the prognosis of patients with breast cancers, whereas TNC is associated with resistance to tamoxifen therapy. Further validation and functional studies are necessary to determine the use of these ECM genes in decisions regarding treatment and whether they can serve as targets for therapy.
Neurotoxicity and Vincristine
Authors: Barry R. Miller
Journal: JAMA (1985)

To the Editor.—  I found the recent article by Hogan-Dann et al1interesting. I think caution is due when patients with malignant neoplasms who have or have had a serious neurological disease are considered for treatment with a vinca alkaloid.  I had the experience of treating a 51-year-old woman with adjuvant chemotherapy for stage II breast cancer following modified radical mastectomy. As a child aged 12 years, she had developed poliomyelitis, from which she became tetraparetic. She recovered completely by age 18 years. However, when the first dose of intravenous vincristine sulfate (1.5 mg) was administered 39 years later, she developed a severe neurotoxic reaction by the following day. She complained of bilateral ear and jaw pain, aching gums, severe constipation, dysphagia, generalized weakness, and severe dysesthesias in the fingers and toes. She became tetraparetic again, having difficulty getting out of bed and a chair. These symptoms persisted for
Magnetic Resonance Imaging in Follow-up Assessment of Sciatica
Authors: Abdelilah el Barzouhi, Carmen L.A.M. Vleggeert-Lankamp, Geert J. Lycklama à Nijeholt, Bas F. Van der Kallen, Wilbert B. van den Hout, Wilco C.H. Jacobs, Bart W. Koes, Wilco C. Peul
Journal: New England Journal of Medicine (2013)

Magnetic resonance imaging (MRI) is frequently performed during follow-up in patients with known lumbar-disk herniation and persistent symptoms of sciatica. The association between findings on MRI and clinical outcome is controversial.We studied 283 patients in a randomized trial comparing surgery and prolonged conservative care for sciatica and lumbar-disk herniation. Patients underwent MRI at baseline and after 1 year. We used a 4-point scale to assess disk herniation on MRI, ranging from 1 for "definitely present" to 4 for "definitely absent." A favorable clinical outcome was defined as complete or nearly complete disappearance of symptoms at 1 year. We compared proportions of patients with a favorable outcome among those with a definite absence of disk herniation and those with a definite, probable, or possible presence of disk herniation at 1 year. The area under the receiver-operating-characteristic (ROC) curve was used to assess the prognostic accuracy of the 4-point scores regarding a favorable or unfavorable outcome, with 1 indicating perfect discriminatory value and 0.5 or less indicating no discriminatory value.At 1 year, 84% of the patients reported having a favorable outcome. Disk herniation was visible in 35% with a favorable outcome and in 33% with an unfavorable outcome (P=0.70). A favorable outcome was reported in 85% of patients with disk herniation and 83% without disk herniation (P=0.70). MRI assessment of disk herniation did not distinguish between patients with a favorable outcome and those with an unfavorable outcome (area under ROC curve, 0.48).MRI performed at 1-year follow-up in patients who had been treated for sciatica and lumbar-disk herniation did not distinguish between those with a favorable outcome and those with an unfavorable outcome. (Funded by the Netherlands Organization for Health Research and Development and the Hoelen Foundation; Controlled Clinical Trials number, ISRCTN26872154.).
Detection of Cardiac Allograft Rejection and Response to Immunosuppressive Therapy With Peripheral Blood Gene Expression
Authors: Phillip A. Horwitz, Emily J. Tsai, Mary E. Putt, Joan M. Gilmore, John J. Lepore, Michael S. Parmacek, Andrew C. Kao, Shashank S. Desai, Lee R. Goldberg, Susan C. Brozena, Mariell L. Jessup, Jonathan A. Epstein, Thomas P. Cappola
Journal: Circulation (2004)

Assessment of gene expression in peripheral blood may provide a noninvasive screening test for allograft rejection. We hypothesized that changes in peripheral blood expression profiles would correlate with biopsy-proven rejection and would resolve after treatment of rejection episodes.We performed a case-control study nested within a cohort of 189 cardiac transplant patients who had blood samples obtained during endomyocardial biopsy (EMB). Using Affymetrix HU133A microarrays, we analyzed whole-blood expression profiles from 3 groups: (1) control samples with negative EMB (n=7); (2) samples obtained during rejection (at least International Society for Heart and Lung Transplantation grade 3A; n=7); and (3) samples obtained after rejection, after treatment and normalization of the EMB (n=7). We identified 91 transcripts differentially expressed in rejection compared with control (false discovery rate <0.10). In postrejection samples, 98% of transcripts returned toward control levels, displaying an intermediate expression profile for patients with treated rejection (P<0.0001). Cluster analysis of the 40 transcripts with >25% change in expression levels during rejection demonstrated good discrimination between control and rejection samples and verified the intermediate expression profile of postrejection samples. Quantitative real-time polymerase chain reaction confirmed significant differential expression for the predictive markers CFLAR and SOD2 (UniGene ID No. 355724 and No. 384944).These data demonstrate that peripheral blood expression profiles correlate with biopsy-proven allograft rejection. Intermediate expression profiles of treated rejection suggest persistent immune activation despite normalization of the EMB. If validated in larger studies, expression profiling may prove to be a more sensitive screening test for allograft rejection than EMB.
Treatment of Human Colon Cancer Xenografts with TRA-8 Anti-death Receptor 5 Antibody Alone or in Combination with CPT-11
Authors: Patsy G. Oliver, Albert F. LoBuglio, Kurt R. Zinn, Hyunki Kim, Li Nan, Tong Zhou, Wenquan Wang, Donald J. Buchsbaum
Journal: Clinical Cancer Research (2008)

Abstract Purpose: This study was designed to evaluate the in vitro cytotoxicity and in vivo efficacy of TRA-8, a mouse monoclonal antibody that binds to the DR5 death receptor for tumor necrosis factor–related apoptosis-inducing ligand (also called Apo2L), alone and in combination with CPT-11, against human colon cancer cells and xenografts. Experimental Design: DR5 expression was assessed on human colon cancer cell lines using flow cytometry, and cellular cytotoxicity after TRA-8 treatment, alone and in combination with SN-38, was determined by measuring cellular ATP levels. Tumor growth inhibition and regression rates of well-established subcutaneous COLO 205, SW948, HCT116, and HT-29 colon cancer xenografts in athymic nude mice treated with TRA-8 or CPT-11 alone and in combination were determined. 99mTc-TRA-8 was used to examine tumor localization of TRA-8 in animals bearing each of the four xenografts. In addition, whole-body biodistribution and imaging was carried out in COLO 205–bearing animals using in vivo single-photon emission computed tomography imaging and tissue counting. Results: DR5 expression was highest on HCT116, intermediate on SW948 and COLO 205 cells, and lowest on HT-29 cells. COLO 205 cells were the most sensitive to TRA-8–induced cytotoxicity in vitro, SW948 and HCT116 cell lines were moderately sensitive, and HT-29 cells were resistant. Combination treatment with TRA-8 and SN-38 produced additive to synergistic cytotoxicity against all cell lines compared with either single agent. The levels of apoptosis in all cell lines, including HT-29, were increased by combination treatment with SN-38. In vivo, combination therapy with TRA-8 and CPT-11 was superior to either single-agent regimen for three of the xenografts: COLO 205, SW948, and HCT116. COLO 205 tumors were most responsive to therapy with 73% complete regressions after combination therapy. HT-29 cells derived no antitumor efficacy from TRA-8 therapy. Tumor xenografts established from the four colon cancer cell lines had comparable specific localization of 99mTc-TRA-8. Conclusions: In vitro and in vivo effects of TRA-8 anti-DR5 monoclonal antibody on four different colon cancer cell lines and xenografts were quite variable. The HT-29 cell line had low surface DR5 expression and was resistant to TRA-8 both in vitro and in vivo. Three cell lines (COLO 205, SW948, and HCT116) exhibited moderate to high sensitivity to TRA-8–mediated cytotoxicity which was further enhanced by the addition of SN-38, the active metabolite of CPT-11. In vivo, the combination of TRA-8 and CPT-11 treatment produced the highest antitumor efficacy against xenografts established from the three TRA-8–sensitive tumor cell lines. All four colon cancer xenografts had comparable localization of 99mTc-TRA-8. These studies support the strategy of TRA-8/CPT-11 combined treatment in human colon cancer clinical trials.
Haloperidol Plasma Levels and Dose Optimization
Authors: William Coryell, Del D. Miller, Paul J. Perry
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: This study was designed to test the practical utility of haloperidol plasma level determinations in the management of schizophrenic patients who show poor initial responses to haloperidol. METHOD: Inpatients with acute exacerbations of DSM-III schizophrenia (N=66) were randomly assigned to receive fixed haloperidol doses intended to achieve plasma levels of 8–18 ng/ml or of 25–35 ng/ml. Patients whose scores on the Brief Psychiatric Rating Scale (BPRS) failed to improve by at least 30% at the end of 3 weeks were then subject to dose reassignment. RESULTS: Among the patients who completed the first phase of the protocol, 30 had steady-state haloperidol plasma levels of less than 18 ng/ml, and 22 had levels that exceeded 25 ng/ml; 14 had intermediate plasma levels of 18–25 ng/ml. A survival analysis of time to 30% improvement significantly favored the two lower plasma level groups, although side effect ratings did not differ. Of the 30 patients whose BPRS scores failed to improve by 30% after 3 weeks, 11 and five were randomly assigned to receive lower and higher doses, respectively. Those whose dose was lowered experienced significantly more improvement in the subsequent weeks than did those whose dose was increased. CONCLUSIONS: Haloperidol plasma levels that substantially exceed 18 ng/ml may be countertherapeutic. In particular, increases in dose beyond this level are not efficacious for patients who have not responded to lower doses. (Am J Psychiatry 1998; 155:48–53)
NOD2-expressing bone marrow-derived cells appear to regulate epithelial innate immunity of the transplanted human small intestine
Authors: T Fishbein, G Novitskiy, L Mishra, C Matsumoto, S Kaufman, S Goyal, K Shetty, L Johnson, A Lu, A Wang, F Hu, B Kallakury, D Lough, M Zasloff
Journal: Gut (2007)

<h3>Background:</h3> Intestinal allograft rejection resembles Crohn’s disease clinically and pathologically. An understanding of its mechanism could impact this life-saving procedure, as well as provide insight into the pathophysiology of inflammatory bowel disease. The NOD2 protein has been implicated as a key player in intestinal immune health, as a consequence of the discovery of three polymorphisms linked with Crohn’s disease. An investigation was carried out to determine whether epithelial immune function and graft survival were influenced by NOD2 mutations in an intestinal transplant population. <h3>Methods:</h3> The NOD2 genotypes of 34 transplants performed consecutively over the past 3 years were determined. The NOD2 genotypes were related to clinical outcomes and the expression of certain intestinal antimicrobial peptides (AMPs) believed to protect the epithelium. <h3>Results:</h3> An unexpectedly high percentage of recipients, 35%, possessed NOD2 polymorphisms, while 8.6% of donors had comparable mutations. The likelihood of allograft failure was about 100-fold higher in recipients with mutant NOD2 alleles compared with recipients with wild-type NOD2 loci. Rejection in NOD2 mutant recipients was characterised by decreased expression of certain Paneth cell and enterocyte AMPs, prior to the onset of epithelial injury and inflammation. <h3>Conclusions:</h3> Crohn’s disease-associated polymorphisms in the NOD2 gene in the recipient represent a critical immunological risk factor for intestinal allograft rejection. Compromised epithelial defences precede visible epithelial injury and inflammatory infiltration. The association of impaired epithelial immunity with the recipient’s genotype suggests that certain NOD2-expressing cells of haematopoietic origin play a role in the process, perhaps by regulating expression of certain epithelial AMPs within the allograft.
Increasing Evidence That Estrogen Is an Important Modulator of Bone Marrow–Mediated Cardiac Repair After Acute Infarction
Authors: Buddhadeb Dawn, Roberto Bolli
Journal: Circulation (2006)

xtensive experimental and clinical evidence accumulated over the past several years indicates that the infarcted heart can be repaired by endogenous as well as exogenous stem/progenitor cells.Experimental studies from several laboratories have reported that bone marrowderived endothelial progenitor cells (EPCs) are mobilized after acute myocardial infarction (MI), home to the infarcted myocardium, and improve left ventricular (LV) perfusion and function. 1Although EPCs have been shown to differentiate into a cardiomyocytic phenotype in vitro, EPC-induced beneficial effects appear to stem primarily from myocardial neovascularization.In an effort to enhance EPC-mediated cardiovascular reparative benefits, current studies are focused on the molecular mechanistic aspects of this phenomenon and on the modulation of EPC kinetics.
Severe hypernatraemia in adults.
Authors: P Daggett, J Deanfield, F Moss, D Reynolds
Journal: BMJ (1979)

In a prospective study of abnormalities of plasma sodium concentration carried out over one year 20 patients were identified who had a concentration exceeding 154 mmol(mEq)/1. Of these, eight patients had diabetes mellitus, eight had primary intracranial disorder, and four had become dehydrated. Five of the eight diabetics presented with hyperosmolar, non-ketotic precoma, and in all eight hypernatraemia developed despite treatment with hypotonic (0.45%) saline. There was a good correlation (r = -0.93) between the rates of change of plasma sodium and blood glucose concentrations, and thus a rise in plasma sodium concentration appeared to be a consequence of the treatment. In the early phase of treatment urinary sodium loss was extremely low despite a brisk diuresis, the infused sodium then predisposing the patients to hypernatraemia. All of the eight patients with intracranial disorders showed evidence of abnormal production of the antidiuretic hormone, six having frank diabetes insipidus. Severe hypernatraemia in this group was associated with a high mortality, fluid balance being difficult to maintain. Two of the four patients who had become dehydrated had had a recent gastrointestinal haemorrhage. In these patients infusion of 0.9% saline contributed to the hypernatraemia since urinary sodium loss was low. Severe hypernatraemia in adults is uncommon, but in established cases plasma and urinary biochemical indices should be measured frequently. Monitoring of the central venous pressure is usually necessary, and patients are best managed in an intensive care unit.
Apoptosis Factor EI24/PIG8 Is a Novel Endoplasmic Reticulum–Localized Bcl-2–Binding Protein which Is Associated with Suppression of Breast Cancer Invasiveness
Authors: Xiansi Zhao, Robert E. Ayer, Shannon L. Davis, Sarah J. Ames, Brian Florence, Cyrus Torchinsky, James S. Liou, Ling Shen, Remco A. Spanjaard
Journal: Cancer Research (2005)

Abstract p53 is a critical tumor suppressor which removes cells with DNA damage by regulating expression and activity of a select group of p53-induced genes (PIG) that subsequently induce apoptosis. PIG8 was also identified as a gene induced by etoposide and named etoposide-induced gene 24 (EI24). Later experiments established EI24/PIG8 as a proapoptotic factor and suggested that it may function as a tumor suppressor. Indeed, EI24/PIG8 is relatively highly mutated in aggressive breast cancers and is located in a region which expresses frequent loss of heterozygosity. However, despite these important observations, the activity and role of EI24/PIG8 remain largely unknown. We used (immmuno)fluorescence microscopy and subcellular fractionation techniques to show that EI24/PIG8 is localized in the endoplasmic reticulum (ER). Pull-down experiments showed that it specifically binds with Bcl-2, a death regulator known to reside in mitochondria, ER, and the nuclear envelope. EI24/PIG8-Bcl-2 binding was corroborated by coimmunoprecipitation and other in vitro and in vivo protein-protein binding assays. Further analysis showed that EI24/PIG8 uses its N-terminal region to bind the BH3 domain in Bcl-2. Finally, we used immunohistochemical techniques to analyze expression of EI24/PIG8 in breast cancer tissue progression arrays and showed that loss of EI24/PIG8 is associated with tumor invasiveness but not with the development of the primary tumor. These results suggest that EI24/PIG8 is a novel, ER-localized Bcl-2–binding protein which may contribute to apoptosis by modulating the activity and/or function of Bcl-2 in this organelle. EI24/PIG8 may serve to prevent tumor spreading, consistent with its suspected role as a tumor suppressor.
Multiple Myeloma Mesenchymal Stem Cells: Characterization, Origin, and Tumor-Promoting Effects
Authors: Michaela R. Reagan, Irene M. Ghobrial
Journal: Clinical Cancer Research (2011)

Hematologic malignancies rely heavily on support from host cells through a number of well-documented mechanisms. Host cells, specifically mesenchymal stem cells (MSC), support tumor cell growth, metastasis, survival, bone marrow colonization, and evasion of the immune system. In multiple myeloma, similar to solid tumors, supporting cells have typically been considered healthy host cells. However, recent evidence reveals that many MSCs derived from patients with multiple myeloma (MM-MSC) show significant defects compared with MSCs from nondiseased donors (ND-MSC). These abnormalities range from differences in gene and protein expression to allelic abnormalities and can initiate after less than 1 day of coculture with myeloma cells or persist for months, perhaps years, after removal from myeloma influence. Alterations in MM-MSC function contribute to disease progression and provide new therapeutic targets. However, before the scientific community can capitalize on the distinctions between MM-MSCs and ND-MSCs, a number of confusions must be clarified, as we have done in this review, including the origin(s) of MM-MSCs, identification and characterization of MM-MSCs, and downstream effects and feedback circuits that support cancer progression. Further advances require more genetic analysis of MM-MSCs and disease models that accurately represent MSC-MM cell interactions.
HOXB7 Promotes Malignant Progression by Activating the TGFβ Signaling Pathway
Authors: Shou Liu, Kideok Jin, Yvonne Hui, Jie Fu, Chunfa Jie, Sheng Feng, David Reisman, Qian Wang, Daping Fan, Saraswati Sukumar, Hexin Chen
Journal: Cancer Research (2014)

Overexpression of HOXB7 in breast cancer cells induces an epithelial-mesenchymal transition and promotes tumor progression and lung metastasis. However, the underlying mechanisms for HOXB7-induced aggressive phenotypes in breast cancer remain largely unknown. Here, we report that phosphorylation of SMAD3 was detected in a higher percentage in primary mammary tumor tissues from double-transgenic MMTV-Hoxb7/Her2 mice than tumors from single-transgenic Her2/neu mice, suggesting activation of TGFβ/SMAD3 signaling by HOXB7 in breast tumor tissues. As predicted, TGFβ2 was high in four MMTV-Hoxb7/Her2 transgenic mouse tumor cell lines and two breast cancer cell lines transfected with HOXB7, whereas TGFβ2 was low in HOXB7-depleted cells. HOXB7 directly bound to and activated the TGFβ2 promoter in luciferase and chromatin immunoprecipitation assays. Increased migration and invasion as a result of HOXB7 overexpression in breast cancer cells were reversed by knockdown of TGFβ2 or pharmacologic inhibition of TGFβ signaling. Furthermore, knockdown of TGFβ2 in HOXB7-overexpressing MDA-MB-231 breast cancer cells dramatically inhibited metastasis to the lung. Interestingly, HOXB7 overexpression also induced tumor-associated macrophage (TAM) recruitment and acquisition of an M2 tumor-promoting phenotype. TGFβ2 mediated HOXB7-induced activation of macrophages, suggesting that TAMs may contribute to HOXB7-promoted tumor metastasis. Providing clinical relevance to these findings, by real-time PCR analysis, there was a strong correlation between HOXB7 and TGFβ2 expression in primary breast carcinomas. Taken together, our results suggest that HOXB7 promotes tumor progression in a cell-autonomous and non-cell-autonomous manner through activation of the TGFβ signaling pathway.