tbuckley/cabot-search huggingface dataset:
Src-Dependent DBL Family Members Drive Resistance to Vemurafenib in Human Melanoma
Authors: Charlotte R. Feddersen, Jacob L. Schillo, Afshin Varzavand, Hayley R. Vaughn, Lexy S. Wadsworth, Andrew P. Voigt, Eliot Y. Zhu, Brooke M. Jennings, Sarah A. Mullen, Jeremy Bobera, Jesse D. Riordan, Christopher S. Stipp, Adam J. Dupuy
Journal: Cancer Research (2019)

The use of selective BRAF inhibitors (BRAFi) has produced remarkable outcomes for patients with advanced cutaneous melanoma harboring a BRAFV600E mutation. Unfortunately, the majority of patients eventually develop drug-resistant disease. We employed a genetic screening approach to identify gain-of-function mechanisms of BRAFi resistance in two independent melanoma cell lines. Our screens identified both known and unappreciated drivers of BRAFi resistance, including multiple members of the DBL family. Mechanistic studies identified a DBL/RAC1/PAK signaling axis capable of driving resistance to both current and next-generation BRAFis. However, we show that the SRC inhibitor, saracatinib, can block the DBL-driven resistance. Our work highlights the utility of our straightforward genetic screening method in identifying new drug combinations to combat acquired BRAFi resistance. SIGNIFICANCE: A simple, rapid, and flexible genetic screening approach identifies genes that drive resistance to MAPK inhibitors when overexpressed in human melanoma cells.
Chemo-response biomarker discovery via expression profiling using soft-tissue sarcoma xenografts
Authors: S. Bruheim, Y. Xi, J. Ju, O. Fodstad
Journal: Journal of Clinical Oncology (2006)

9569 Background: Soft-tissue sarcoma (STS) constitute a heterogeneous group of tumours of mesenchymal origin. Whereas the mainstay of treatment has been surgery and radiation, these tumours are generally considered as quite chemoresistant. However, it is well known that subgroups of patients benefit from chemotherapy. Markers that could predict drug response would therefore be beneficial for the management of this malignancy. We have previously established panel of 17 unique human soft tissue xenografts, representing 7 different histological subgroups and assessed their responsiveness to doxorubicin, ifosfamide, etoposide, and cisplatin. We wanted to utilize these xenografts as a model system to discover for novel candidate marker genes for STS chemo-response. Methods: GE Uniset Human 20K microarrays were used to obtain gene expression profiles from the each xenografts. One-way ANOVA test with a Benjamini-Hochberg multiple test correction allowing a false discovery rate of 5% was used to identify genes with significantly differential expression. Results: Doxorubicin, ifosfamide, etoposide and cisplatin were efficient in 6/17, 10/17, 1/17 and 7/17 xenografts respectively. However, in the expression profiles obtained none of the genes showed significantly correlation with chemo-responsiveness to any of the drugs. Two of the xenografts, TAX 1 and TAX 2, both originate from a malignant fibrous histiocytoma (MFH) in the same patient, but show strikingly different sensitivity to ifosfamide (TAX1 resistant, TAX2 sensitive). When triplicate hybridizations of TAX1 and 2 were compared, 294 genes met the above criteria. In addition we identified a subset of 122 genes that were flagged absent in one of the specimens, present in the other. Among genes with an already described role in mediating drug resistance are GST-pi and glutathione peroxidase. Taken together, these results indicate that discovery of general response markers in STSs may be difficult due to the heterogeneity of the different subgroups constituting this malignancy. Conclusions: Gene expression profiling of the TAX 1 and TAX 2 xenografts revealed a number of interesting candidate marker genes for ifosfamide sensitivity of MFH. This list of genes will be further refined by validation in clinical samples. No significant financial relationships to disclose.
CXCR1 or CXCR2 knock-down inhibits cellular proliferation, survival, motility and tumor growth in human malignant melanoma
Authors: Michelle Varney, Seema Singh, Rakesh Singh
Journal: Cancer Research (2008)

5099  Melanoma is notorious for affecting young and middle-aged people, unlike most other solid tumors, which mainly affect older adults. Therapy for early disease is primarily surgery, with a minor benefit noted with adjuvant therapy; however, there is no effective treatment for advanced disease because of lack of effective treatment modalities. CXCL-8, a member of the CXC chemokine family, is constitutively expressed in malignant melanoma and functions as an autocrine/paracrine growth, invasive and angiogenic factor. Our recent data demonstrate that modulation of CXCR1 or CXCR2 expression in melanoma cells regulates CXCL-8-dependent growth, angiogenesis and motility. The precise functional significance of these receptors in malignant melanoma growth and angiogenesis is hitherto unclear. Thus, theobjective of this study is to determine the functional roles of CXCR1 and CXCR2 in CXCL-8-dependent melanoma growth and angiogenesis. We knocked-down CXCR1 or CXCR2 expression by using mammalian expression vectors (pSuper.neo) constitutively expressing short hairpin (sh)RNA for CXCR1 or CXCR2. A375SM malignant melanoma cells were transfected with pCXCR1-sh1 or pCXCR2-sh1 and were stably selected and analyzed for CXCR1 and CXCR2 expression. We observed a significant decrease in CXCR1 and CXCR2 expression in A375SM-CXCR1sh1 and A375SM-CXCR2sh1 knock-down cells respectively, compared to control cells. We examined whether knock-down of CXCR1 or CXCR2 modulates cellular phenotypes associated with melanoma growth, angiogenesis and metastasis. We observed decreases in CXCL-8 induced cell proliferation, survival, chemotaxis, invasion and actin reorganization in melanoma cells knocked-down for CXCR1 or CXCR2 as compared to control cells. Furthermore, when A375SM-CXCR1sh1, A375SM-CXCR2sh1 and A375SM-control cells were injected subcutaneously into nude mice, tumor growth was significantly inhibited in both A375SM-CXCR1sh1, A375SM-CXCR2sh1 tumors compared to control tumors. In addition, we observed a significant decrease in cell proliferation, survival and neovascularization in CXCR1 or CXCR2 knock-down tumors as compared to control tumors. In conclusion, our study provides experimental evidence that supports the functional significance of CXCR1 and CXCR2 in the regulation of human malignant melanoma and in addition, suggests the development of strategies that target both receptors.
Type I collagenase expression and activity in the osteoblastic stromal cells of giant cell tumor of bone
Authors: Robert Cowan, Isabella Mak, Gurmit Singh, Michelle Ghert
Journal: Cancer Research (2007)

570  Giant cell tumor of bone (GCT) is a locally aggressive osteolytic tumor with metastasic potential. Its name is derived from the osteoclast-like multinucleated giant cells that are present in the tumor. In addition, two other cell types are present within GCT: mononucleated spindle-like stromal cells of osteoblastic origin, and round, CD68-positive monocytes. The stromal cells are considered the neoplastic component of GCT and are thought to promote the formation of the multinucleated giant cells. The latter have classically been implicated in bone destruction due to their morphological resemblance to osteoclasts. Evidence suggests that proteases, including members from the family of matrix metalloproteinases (MMPs), are involved in the collagen-degrading activity of the tumor. Type I collagen constitutes approximately 90% of the bone microenvironment, and the type I collagenases, MMP-1, MMP-8 and MMP-13 are capable of degrading the intact triple-helix of type I collagen, whereas other members of the MMP family are not. Here we report that the stromal cells of GCT produce type I collagenases and are capable of degrading type I collagen independent of the giant cells. GCT samples from primary tissue were collected with patient consent and stromal cells were isolated and grown in culture through a process of selective trypsinization. PCR, western blot analysis, and the use of a multiplex protein assay system revealed the presence of type I collagenases. Immunohistochemistry on paraffin-embedded tissue samples confirmed the presence of these collagenases in the stromal cells in vivo. The activity of these collagenases was determined by standardized collagenase degradation assays using stromal cell conditioned media. These results suggest that, contrary to popular belief, the stromal cells of GCT play a key role in bone destruction and that these cells act through an MMP-mediated mechanism that can be targeted to improve the clinical management of these tumors.
A phase I dose escalation trial of ispinesib (SB-715992) administered days 1–3 of a 21-day cycle in patients with advanced solid tumors
Authors: E. I. Heath, A. Alousi, J. P. Eder, M. Valdivieso, L. S. Vasist, L. Appleman, P. Bhargava, A. D. Colevas, P. M. Lorusso, G. Shapiro
Journal: Journal of Clinical Oncology (2006)

2026 Background: Ispinesib, a novel cytotoxic agent inhibiting the kinesin spindle protein (KSP) has demonstrated significant antitumor activity in multiple murine tumor models. The primary objectives of the study were to assess the safety and tolerability of SB-715992, to determine the dose limiting toxicity (DLT), and the maximum tolerated dose (MTD). Methods: Ispinesib was administered days 1–3 intravenously over 1 hour every 21 days, starting at a dose of 1 mg/m 2 /day. Traditional 3-patient cohort trial design was utilized with dose levels of 2, 4, 6, 8 mg/m 2 /day. Results: Twenty-seven patients (24 Caucasians, 3 African-Americans, 16 males, 11 females) with various tumor types were enrolled; colorectal (7), renal (5), bladder (2), lung (2), pharynx (2), pancreas (2), others (7). Grade 3/4 toxicities were noted starting at the 4 mg/m 2 dose level with two patients developing grade 4 neutropenia; one for &lt; 5 days, one for &gt; 5 days (with grade 3 leukopenia). At the 6 mg/m 2 dose level, grade 3 neutropenia and leukopenia were reported. At the 8 mg/m 2 dose level, 3 of 3 patients had grade 4 neutropenia and leukopenia. The 6 mg/m 2 dose level was declared the MTD. Toxicities seen in the additional 6 patients included grade 1 fatigue (1/6), grade 1 infusion- related flushing (1/6), grade 3 febrile neutropenia (1/6), and grade 4 neutropenia and leukopenia (1/6). The MTD cohort has been expanded to 10 evaluable patients for confirmation of tolerability and pharmacodynamic endpoints including phosphohistone 3 (PH3), cyclin E, and TUNEL assay on serial tumor biopsies. Preliminary pharmacokinetic data appear linear, but not dose proportional. As predicted, between days 1 and 3, accumulation ranged from 40 to 106%. Exposures appear comparable between cycles 1 and 2. Stable disease in 2 patients with renal cell carcinoma (4 and 5 cycles) and minor response in one patient with bladder cancer were seen. Conclusions: Treatment with ispinesib at the MTD of 6 mg/m 2 /day x 3 days in patients with advanced solid tumors was well tolerated with consistent dose limiting toxicity of myelosuppression. No significant financial relationships to disclose.
Direct cholangioscopy for diagnosis and treatment guidance of suspected biliary papillomatosis with malignant transformation
Authors: Aymeric Becq, Marine Camus, Olivia Pietri, Lionel Arrivé, Francois Paye, Xavier Dray, Ulriikka Chaput
Journal: Endoscopy (2019)

A 48-year-old man with no significant past medical history was admitted with jaundice and abdominal pain. Total bilirubin was 6.5 mg/dL. The magnetic resonance cholangiopancreatography demonstrated intra- and extrahepatic bile duct dilation secondary to a stricture in the mid common bile duct (CBD) and a parietal thickening extending from the mid-CBD stricture to the hilum, and left and right hepatic ducts ([Fig. 1]). Biliary papillomatosis was suspected, with possible malignant transformation. On imaging, foramen of Winslow adenopathy was suspicious for malignant involvement.
Effects of Irritable Bowel Syndrome on Daily Activities Vary Among Subtypes Based on Results From the IBS in America Survey
Authors: Sarah Ballou, Courtney McMahon, Ha-Neul Lee, Jesse Katon, Andrea Shin, Vikram Rangan, Prashant Singh, Judy Nee, Michael Camilleri, Anthony Lembo, Johanna Iturrino
Journal: Clinical Gastroenterology and Hepatology (2019)
Don’t equate “reform” with “restructuring” of the NHS
Authors: Stephen Black
Journal: BMJ (2019)

Oliver is right that calls for major structural reforms to the NHS are futile.1 But there is a good argument for the NHS needing “reform.” The mistake is to assume that reform means changing the top-down structure, which costs a lot but yields very little improvement to services.

But plenty of practices need to be reformed. General practitioners can and should change the …
Role of tissue transglutaminase in conferring metastatic potential in breast cancer cells
Authors: Lingegowda S. Mangala, Jansina Fok, Kapil Mehta
Journal: Cancer Research (2005)

796  Tissue type II transglutaminase (TG2) is an important member of the transglutaminase family, which is expressed in endothelial cells and secreted into the extra cellular matrix where it is bound to fibronectin. It cross links the proteins involved in wound healing, tissue remodeling and ECM stabilization. TG2 helps in preventing the leakage of intracellular components and its expression up regulates in drug resistant and metastases breast cancer cells. To understand the role of TG2 in conferring metastatic potential to breast cancer cells, we used two MDA-MB231 clones, which were rich or deficient in TG2 level and studied the involvement of surface TG2 in cell adhesion, invasion, migration and other important parameters of metastases. The clone, which showed high TG2 expression was more adhesive, migrative and invasive compared to low TG2 expressed clone. Flow Cytometry results revealed that TG2 showed high affinity with β1 and β3 integrins. Immuno precipitation study revealed that TG2 co-precipitated with these integrins when grown on Fn coated surface and showed increased resistance to paclitaxel. Study on correlation between the expression of TG2 and other known breast cancer metastatic prognostic markers in six different cancer cell lines by reverse transcription-polymerase chain reaction showed that metastases depend on many genes including TG2 that modulates the metastases of tumors. The present study provides evidence that TG2 expression is up regulated in metastatic cancer cells and plays an important role in conferring metastases potential to breast cancer cells by helping them to become more adhesive, invasive and migrative.
Nomogram prediction for overall survival of patients diagnosed with cervical cancer.
Authors: Christoph Grimm, Alexander Reinthaller, Gerda Hofstetter, Nicole Concin, Christian Marth, Stephan Polterauer
Journal: Journal of Clinical Oncology (2012)

5111 Background: Cervical cancer is clinically staged based upon the International Federation of Gynecologists and Obstetricians (FIGO) system. FIGO stage is well established as prognostic parameter. It is well known that other additional parameters are useful to estimate overall survival (OS) in patients with cervical cancer. The aim of this multi-center was to create a nomogram to predict OS in patients diagnosed with cervical cancer. Methods: Cervical cancer databases of two large Austrian institutions were analysed. Characteristics known to predict OS were collected. For each patient association between each prognostic parameter and OS was assessed by multivariable modeling. The corresponding 3-year and 5-year OS probabilities were then determined using the nomogram. The constructed nomogram was then validated using the bootstrap correction technique. Results: Mean 5-year OS rates for patients with FIGO stage IA, IB, II, III, and IV were 99.0% (1.0), 88.6% (3.0), 65.8% (5.2), 58.7% (11.0), and 41.5% (14.7), respectively (p&lt;0.001). Mean five-year OS time was 44.2 (30.9) months. Based on the multivariable model FIGO stage, tumor size, age, histologic subtype, lymph node ratio, and parametrial involvement were identified as nomogram parameters. The bootstrap sample corrections provided an estimated concordance probability (interquartile range) of 0.794 (0.779-0.805). Conclusions: Based on 6 easily available parameters a novel nomogram to predict 3-year and 5-year OS of patients diagnosed with cervical cancer was constructed and internally validated. Application of this nomogram allows more accurate and individual prediction of patients’ prognosis.
Carboplatin plus paclitaxel versus carboplatin plus stealth liposomal doxorubicin in patients with advanced ovarian cancer (AOC): Final results of the MITO-2 randomized multicenter trial
Authors: S. Pignata, G. Scambia, A. Savarese, R. Sorio, E. Breda, G. Ferrandina, V. Gebbia, P. Musso, C. Gallo, F. Perrone
Journal: Journal of Clinical Oncology (2009)

LBA5508 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. No significant financial relationships to disclose.
Impact of cell cycle control and cellular proliferation of miR-192 via targeting dihydrofolate reductase and E2F-3 pathway
Authors: Bo Song, Yuan Wang, Kenji Kudo, Elaine Gavin, Yaguang Xi, Jingfang Ju
Journal: Cancer Research (2008)

5055  MicroRNAs are a class of non-coding small RNA molecules that negatively regulate gene expression at the post-transcriptional level by interacting with 3’-UTRs of their target mRNAs. Mounting experimental evidence indicates that microRNAs play important roles in human cancers acting either as oncogenes or tumor suppressor genes depending on their targets. Previous studies from our group have identified certain miRNAs maybe regulated by p53 tumor suppressor gene. To further elucidate the molecular and cellular impact of one of the candidate miRNAs, miR-192, in this study, the expression of miR-192 was over-expressed by transient transfection in HCT-116 (wt-p53) and HCT-116 (null-p53) colon cancer cell lines. We have identified that one of the miR-192 target gene is dihydrofolate reductase (DHFR). The DHFR 3’-UTR region of DHFR contains a putative miR-192 binding site using TargetScan analysis. The expression of DHFR was significantly decreased by miR-192 using Western immunoblot analysis. Further analysis indicates that such suppression was due to translation arrest rather than mRNA degradation. The proliferation of cells transfected with miR-192 was nearly completely decreased at 100 nM in HCT-116 (wt-p53) cells while the control miR has no effect. Inhibition of proliferation in HCT-116 (null-p53) cells by miR-192 was less than HCT-116 (wt-p53) cells at the same concentration. HCT-116 (wt-p53) cells transfected with miR-192 was arrested at G2/M phase of the cell cycle. The mechanism of this arrest was at least in part, due to the reduction of E2F-3 expression. The cell cycle check point control genes p53 and p21 were highly over-expressed in cells that over-expressing miR-192. The endogeneous miR-192 expression was induced in HCT-116 (wt-p53) cells treated with methotraxate (MTX) with the increased expression of p53. miR-192 maybe another miRNA candidate that was involved in the p53 tumor suppressor network with significant impact on cell cycle control and cell proliferation.
Increased Insulin Requirements in Twin Pregnancy in Type 1 Diabetes
Authors: Sarah De Fønss, Per G. Ovesen, Jens Fuglsang
Journal: Diabetes Care (2019)

During pregnancy in type 1 diabetes, insulin requirements increase from the second trimester onward, reaching maximum in the third trimester. In twin pregnancies, the larger placental mass leads to elevated circulating levels of placental hormones, many of which have been attributed to the insulin resistance of pregnancy (1,2). Hence, higher insulin requirements are anticipated in twin pregnant women with type 1 diabetes. Only one study has reported longitudinal insulin requirements during twin pregnancy; the research showed larger increments in insulin doses until mid-gestation among twin pregnant women but no differences in absolute insulin requirements (3).

A retrospective case-control study was undertaken in all identifiable twin pregnant women at Aarhus University Hospital between 2000 and 2018 ( n = 27) and 81 singleton pregnant women with type 1 diabetes, matched 1:3 on maternal age and year of delivery. Nine women had repeat pregnancies with twin and singleton pregnancies.

Clinical data, insulin doses, and hemoglobin A1c (HbA1c) values were recorded. During the study period, guidelines for handling pregnant women with type 1 diabetes remained essentially unchanged. Data collection was approved by the regional health data …
Transcriptome analysis by cDNA microarray demonstrating the dichontomy in molecular pathways leading to cancer development in lateral and ventral lobes of rat prostate induced by testosterone and 17β-estradiol / diethylstibestrol
Authors: Yuksing R. Cheng, Neville N. Tam, Y. K. Leung, Shukmei Ho
Journal: Cancer Research (2004)

1661  Exposure of Noble rats to combined testosterone (T) and 17β-estradiol (E2) induces extensive multifocal dysplasia and invasive adenocarcinoma exclusively in the lateral lobe (LP) of prostate gland, whereas treatment of rats with T and diethylstibestrol (DES), a xenoestrogen, causes the development of atypical hyperplasia or dysplasia in a vacuolarized epithelium and carcinoma in situ (or adenoma) in the ventral lobe (VP) but not other lobes of prostate gland. At present, it remains unclear as to why these two estrogens, under the same exogenous androgen support, would target different prostatic lobes and produce different types of epithelial lesions. We used a cDNA array containing 3800 rat known transcripts to identify distinctive transcriptomes of prostate gland treated with T+E2 or T +DES. From our non-supervised learning data analysis approach, we are able to distinguish the hormone-treated groups with cancer induction (T+E2 LP and T+DES VP) from untreated control or hormone-treated groups with no cancer induced (T+E2 VP and T+DES LP). Hundred and thirteen genes in the T+E2- treated LP and hundred and thirty-three genes in T+DES- treated VP were identified as key gene sets by stringent data filtering. And only sixteen genes were found common in both key gene sets, demonstrating the dichontomous natures of cancer-specific transcriptomes between LP and VP. The cancer-specific differentially expressed gene fell into several functional clusters: oncogene/tumor suppressor genes, cancer-associated genes, neuronal growth and development and cytoskeleton/structural protein related genes. This study provided valuable information regarding the early development of the malignant tissue. The gene(s) identified form the study could be a potential cancer prevention target. *This study is supported by NIH grant No. CA15776, DK61084 & CA 62269