tbuckley/cabot-search huggingface dataset:
Telomerase-Specific Virotheranostics for Human Head and Neck Cancer
Authors: Yuji Kurihara, Yuichi Watanabe, Hideki Onimatsu, Toru Kojima, Tatsuo Shirota, Masashi Hatori, Dong Liu, Satoru Kyo, Hiroyuki Mizuguchi, Yasuo Urata, Satoru Shintani, Toshiyoshi Fujiwara
Journal: Clinical Cancer Research (2009)

Long-term outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) remain unsatisfactory despite advances in combination of treatment modalities. SCCHN is characterized by locoregional spread and it is clinically accessible, making it an attractive target for intratumoral biological therapies.OBP-301 is a type 5 adenovirus that contains the replication cassette in which the human telomerase reverse transcriptase promoter drives expression of the E1 genes. OBP-401 contained the replication cassette and the green fluorescent protein (GFP) gene. The antitumor effects of OBP-301 were evaluated in vitro by the sodium 30-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate assay and in vivo in an orthotopic xenograft model. Virus spread into the lymphatics was also orthotopically assessed by using OBP-401.Intratumoral injection of OBP-301 resulted in the shrinkage of human SCCHN tumors orthotopically implanted into the tongues of BALB/c nu/nu mice and significantly recovered weight loss by enabling oral ingestion. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Moreover, whole-body fluorescent imaging revealed that intratumorally injected OBP-401 could visualize the metastatic lymph nodes, indicating the ability of the virus to traffic to the regional lymphatic area and to selectively replicate in neoplastic lesions, resulting in GFP expression and cell death in metastatic lymph nodes.These results illustrate the potential of telomerase-specific oncolytic viruses for a novel therapeutic and diagnostic approach, termed theranostics, for human SCCHN.
Predicting Sensitivity of Non-Small-Cell Lung Cancer to Gefitinib: Is There a Role for P-Akt?
Authors: W. Pao, V. A. Miller, E. Venkatraman, M. G. Kris
Journal: JNCI Journal of the National Cancer Institute (2004)

The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor of the ErbB family that is abnormally activated in epithelial tumors (1). Receptor activation leads to recruitment and phosphorylation of downstream intracellular substrates. Multiple pathways are activated, including the phosphatidylinositol 3–kinase/Akt (PI3K/Akt) cascade implicated in cell survival and the RAS/RAF/mitogen-activated protein kinase (MAPK) cascade associated with cell proliferation (2,3). Aberrant signaling through EGFR can lead to tumor-promoting cellular activities. EGFR is the target for cancer therapies such as gefitinib (4-quinazolinamine, N-[3-chloro-4-fluorophenylamino]-7methoxy6-[3-(4-morpholinyl) propoxy]) (4,5), which inhibits the tyrosine kinase activity of EGFR by reversibly competing with adenosine triphosphate (ATP) at the ATP-binding site within the EGFR protein. Gefitinib selectively inhibits EGFR when tested against several other kinases in vitro (6). In phase I trials, gefitinib induced responses in 10 of 100 unselected patients with non–small-cell lung cancer (NSCLC). Subsequently, in two phase II trials, radiographic regression of NSCLC was observed in 28% of patients enrolled in a study from Japan (7) and in 10% of patients enrolled in a study from Europe and the United States (8). On the basis of these two studies, regulatory authorities approved gefitinib for the treatment of patients with NSCLC after other chemotherapies had failed.
Rare diseases bullet 1: Lymphangioleiomyomatosis: clinical features, management and basic mechanisms
Authors: S. Johnson
Journal: Thorax (1999)

Lymphangioleiomyomatosis, a rare disease of unknown aetiology, affects women only. It mainly involves the lungs where, as its name suggests, lymphatics ( lymph ), blood vessels ( angio ), and airways are surrounded by smooth muscle ( leiomyo ) proliferation. It is characterised by progressive dyspnoea, haemoptysis, pneumothorax, and chylous pleural effusions and runs a variable course culminating usually in respiratory failure.1 2 Lymph nodes in the abdomen and pelvis may be involved and up to half the patients have renal angiomyolipomas. The disease usually arises spontaneously although it also occurs in some patients with tuberous sclerosis.3 

Much of our knowledge of this unusual disorder is anecdotal, coming from case reports and reviews of patients attending tertiary referral centres, which may not represent the full spectrum of the disease. This will change over the next few years as patient registries are being compiled for research purposes in the United Kingdom, United States, and France. This approach, coupled with recent advances in the cell biology of lymphangioleiomyomatosis, will it is hoped improve management and the outcome for patients. This article will cover the clinical features and natural history of isolated lymphangioleiomyomatosis, discuss issues in diagnosis and management, and finally review what is known of the aetiology and cell biology of the disease.

### INCIDENCE AND DEMOGRAPHIC FEATURES

The reported prevalence of lymphangioleiomyomatosis is around one per million in the United Kingdom,4 France,5and the United States, although the true prevalence is likely to be greater. The disease is well described in Asia6 although data on prevalence are not available.

Lymphangioleiomyomatosis is exclusively confined to women, the mean age of onset being 34 years.1 2 6-8 Presentation after the menopause is very unusual, occurring in only eight of 186 patients in the larger series,1 2 4 6-8 six of whom were taking oestrogen containing hormone replacement …
Idiopathic Osteo-Arthritis of the Hip
Authors: J. R. Pearson, D. M. Riddell
Journal: Annals of the Rheumatic Diseases (1962)

We have studied the disease from the clinical aspect.All patients with osteo-arthritis of the hip seen in the Robert Jones and Agnes Hunt Ortho- paedic Hospital, Oswestry, in the last 15 years have been reviewed.We have excluded all those in whom insufficient information was available, and all those in whom the osteo-arthritis was considered to be secondary to a previous disorder of the hip joint, such as congenital dislocation of the hip, slipped upper femoral epiphysis, and rheumatoid arthritis.Patients in all stages of the disease were seen, and we were able to follow the progress of the disorder for periods of from 4 to 15 years.From the data so collected we have been able to divide osteoarthritic hips into two clinical and radiological groups.
Endothelin Receptor Antagonism Ameliorates Mast Cell Infiltration, Vascular Hypertrophy, and Epidermal Growth Factor Expression in Experimental Diabetes
Authors: Richard E. Gilbert, Jonathan R. Rumble, Zemin Cao, Alison J. Cox, Pauline van Eeden, Terri J. Allen, Darren J. Kelly, Mark E. Cooper
Journal: Circulation Research (2000)

Abstract —Vascular hypertrophy, a feature of experimental and human diabetes, has been implicated in the pathogenesis of the microvascular and macrovascular complications of the disease. In the present study, we sought to examine the role of endogenous endothelin and its relation to vascular growth factors in the mediation of vascular hypertrophy in experimental diabetes and to examine the contribution of mast cells to this process. Vessel morphology, endothelin, growth factor gene expression, and matrix deposition were studied in the mesenteric arteries of control and streptozotocin-induced diabetic Sprague-Dawley rats treated with or without the dual endothelin A/B receptor antagonist bosentan (100 mg · kg −1 · d −1 ) during a 3-week period. Compared with control animals, diabetic animals had significant increases in vessel weight, wall-to-lumen ratio, mast cell infiltration, extracellular matrix deposition, and gene expression of epidermal growth factor (EGF) and transforming growth factor-β 1 . In diabetic, but not control, vessels, not only were EGF mRNA and endothelin present in endothelial cells, but also their expression was observed in adventitial mast cells. Immunoreactive endothelin was present in the media of mesenteric vessels of diabetic, but not control, animals. Bosentan treatment significantly reduced mesenteric weight, wall-to-lumen ratio, mast cell infiltration, matrix deposition, and EGF mRNA but did not prevent the overexpression of transforming growth factor-β 1 mRNA in diabetic rats. These findings suggest that endogenous endothelin and EGF may play a role in diabetes-induced vascular hypertrophy and that mast cells may be pathogenetically involved in this process.
PP2A inhibition overcomes acquired resistance to HER2 targeted therapy
Authors: Martina S J McDermott, Brigid C Browne, Neil T Conlon, Neil A O’Brien, Dennis J Slamon, Michael Henry, Paula Meleady, Martin Clynes, Paul Dowling, John Crown, Norma O’Donovan
Journal: Molecular Cancer (2014)

HER2 targeted therapies including trastuzumab and more recently lapatinib have significantly improved the prognosis for HER2 positive breast cancer patients. However, resistance to these agents is a significant clinical problem. Although several mechanisms have been proposed for resistance to trastuzumab, the mechanisms of lapatinib resistance remain largely unknown. In this study we generated new models of acquired resistance to HER2 targeted therapy and investigated mechanisms of resistance using phospho-proteomic profiling.Long-term continuous exposure of SKBR3 cells to low dose lapatinib established a cell line, SKBR3-L, which is resistant to both lapatinib and trastuzumab. Phospho-proteomic profiling and immunoblotting revealed significant alterations in phospho-proteins involved in key signaling pathways and molecular events. In particular, phosphorylation of eukaryotic elongation factor 2 (eEF2), which inactivates eEF2, was significantly decreased in SKBR3-L cells compared to the parental SKBR3 cells. SKBR3-L cells exhibited significantly increased activity of protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates eEF2. SKBR3-L cells showed increased sensitivity to PP2A inhibition, with okadaic acid, compared to SKBR3 cells. PP2A inhibition significantly enhanced response to lapatinib in both the SKBR3 and SKBR3-L cells. Furthermore, treatment of SKBR3 parental cells with the PP2A activator, FTY720, decreased sensitivity to lapatinib. The alteration in eEF2 phosphorylation, PP2A activity and sensitivity to okadaic acid were also observed in a second HER2 positive cell line model of acquired lapatinib resistance, HCC1954-L.Our data suggests that decreased eEF2 phosphorylation, mediated by increased PP2A activity, contributes to resistance to HER2 inhibition and may provide novel targets for therapeutic intervention in HER2 positive breast cancer which is resistant to HER2 targeted therapies.
Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma
Authors: S. Kunwar, S. Chang, M. Westphal, M. Vogelbaum, J. Sampson, G. Barnett, M. Shaffrey, Z. Ram, J. Piepmeier, M. Prados, D. Croteau, C. Pedain, P. Leland, S. R. Husain, B. H. Joshi, R. K. Puri
Journal: Neuro-Oncology (2010)

Convection-enhanced delivery (CED) of cintredekin besudotox (CB) was compared with Gliadel wafers (GW) in adult patients with glioblastoma multiforme (GBM) at first recurrence. Patients were randomized 2:1 to receive CB or GW. CB (0.5 µg/mL; total flow rate 0.75 mL/h) was administered over 96 hours via 2–4 intraparenchymal catheters placed after tumor resection. GW (3.85%/7.7 mg carmustine per wafer; maximum 8 wafers) were placed immediately after tumor resection. The primary endpoint was overall survival from the time of randomization. Prestated interim analyses were built into the study design. Secondary and tertiary endpoints were safety and health-related quality-of-life assessments. From March 2004 to December 2005, 296 patients were enrolled at 52 centers. Demographic and baseline characteristics were balanced between the 2 treatment arms. Median survival was 36.4 weeks (9.1 months) for CB and 35.3 weeks (8.8 months) for GW (P = .476). For the efficacy evaluable population, the median survival was 45.3 weeks (11.3 months) for CB and 39.8 weeks (10 months) for GW (P = .310). The adverse-events profile was similar in both arms, except that pulmonary embolism was higher in the CB arm (8% vs 1%, P = .014). This is the first randomized phase III evaluation of an agent administered via CED and the first with an active comparator in GBM patients. There was no survival difference between CB administered via CED and GW. Drug distribution was not assessed and may be crucial for evaluating future CED-based therapeutics.
The expression of p53, p21, Bax and induction of apoptosis in normal volunteers in response to different doses of ultraviolet radiation
Authors: M. Murphy, M.J.E.M.F. Mabruk, P. Lenane, A. Liew, P. Mccann, A. Buckley, P. Billet, M. Leader, E. Kay, G.M. Murphy
Journal: British Journal of Dermatology (2002)

Summary Background Ultraviolet radiation (UVR) damages keratinocytes. Direct DNA damage may undergo enzymatic repair followed by resumption of the normal cell cycle. Cells may also be eliminated without inflammation by the error-free process of programmed cell death or apoptosis. Necrosis of cells can occur after overwhelming damage. Failure of apoptosis leads to retention of cells with persistent mutations. Objectives This study investigates p53-dependent apoptotic responses in normal skin following solar-simulated radiation (SSR). Methods Sun-protected buttock skin from normal volunteers with no history or clinical evidence of skin cancer was exposed to graded doses of SSR, 0·5, 1, 2 and 3 times the minimal erythema dose (MED). Biopsies taken at a range of time points (4·5, 9, 24, 33, 48 and 72 h) after UVR, quantified the time course and dose–response of apoptosis and the expression of the relevant proteins, p53, p21waf1/Cip1 and Bax, by single and double labelling techniques. Results Apoptosis was upregulated in a dose-dependent manner as was the expression of p53, p21waf1/Cip1 and Bax in response to SSR. Following exposure to 3 MEDs it was found that: (i) the maximum number of apoptotic cells occurred at 48 h; (ii) p53 protein expression was upregulated from 4 to 72 h preceding peak p21waf1/Cip1 protein expression (9–48 h) and peak Bax protein expression (33 h). Conclusions These results suggest that, following SSR, normal human skin induces apoptosis by the p53, p21waf1/Cip1, Bax pathway in vivo. In addition, induction of apoptosis and expression of p53, p21waf1/Cip1 and Bax occurs in a dose-dependent manner.
Human herpes virus 8 (Kaposi’s sarcoma herpes virus) and malignant lymphoproliferations in France: a molecular study of 250 cases including two AIDS-associated body cavity based lymphomas
Authors: A Gessain, J Brière, C Angelin-Duclos, F Valensi, H Merle Béral, F Davi, M-A Nicola, A Sudaka, N Fouchard, J Gabarre, X Troussard, E Dulmet, J Audouin, J Diebold, G de Thé
Journal: Leukemia (1997)
Oestrogens promote tumorigenesis in a mouse model for colitis-associated cancer
Authors: Jarom Heijmans, Mattheus C B Wielenga, Sanne Liesbeth Rosekrans, Jooske F van Lidth de Jeude, Joris Roelofs, Patrick Groothuis, Antwan Ederveen, Eveline S M de Jonge-Muller, Izak Biemond, James C H Hardwick, Geert D'Haens, Daniel W Hommes, Vanesa Muncan, Gijs R van den Brink
Journal: Gut (2013)

<h3>Background</h3> Hormone replacement therapy increases the risk of developing ulcerative colitis in postmenopausal women. Chronic intestinal inflammation predisposes to colon cancer development, but effects of female hormones on colitis-associated cancer development have not been examined. <h3>Aim</h3> To investigate the role of female hormones in the dextran sodium sulfate (DSS)-azoxymethane (AOM) mouse model for colitis-associated cancer. <h3>Design</h3> We performed ovariectomies, or sham operations, on mice, and supplemented these animals with indicated hormones. Additionally, we used <i>oestrogen receptor α</i> or <i>β</i> (<i>Erα or Erβ</i>) mutant mice. To study colitis or colitis-associated cancer, we used DSS only, or DSS and AOM, respectively. <h3>Results</h3> Ovariectomy protects female mice against colitis-associated tumour development. Hormone replacement in ovariectomised mice with either oestradiol (E2), medroxyprogesterone acetate or a combination of both suggests that oestrogens are the ovary-derived factor that promotes tumour development in the context of inflammatory damage. E2-treated animals showed increased clinical symptoms and Il-6 production upon DSS-induced colitis and enhanced epithelial proliferation. Treatment with E2 markedly increased the numbers of polyps in ovariectomised mice and also strongly promoted tumour progression with all E2-treated animals developing at least one invasive adenocarcinoma, whereas, placebo-treated animals developed adenomas only. Using <i>Er</i> mutant mice, we find that the protumorigenic effect of oestrogen depends on both Erα and Erβ. <h3>Conclusions</h3> Our results suggest that oestrogens promote inflammation-associated cancer development by impairing the mucosal response to inflammatory damage.
Neoplastic Disease: Hormone-Producing or Hormone-Dependent Tumors
Authors: O H Pearson, A G Pazianos, J M Dominguez
Journal: Annual Review of Medicine (1960)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Early-Onset Insulin-Resistant Diabetes in Obese Caucasians Has Features of Typical Type 2 Diabetes, but 3 Decades Earlier
Authors: Siobhan McQuaid, Donal J. O’Gorman, Obada Yousif, Toh Peng Yeow, Yusof Rahman, Declan Gasparro, Giovanni Pacini, John J Nolan
Journal: Diabetes Care (2005)

Obesity has dramatically increased in Irish adolescents and young adults and is related to changes in physical activity and diet (1,2). Severe obesity is associated with a much earlier presentation of type 2 diabetes (3—6), as noted in Irish Caucasian patients (7). Most studies of early-onset type 2 diabetes have been in minority populations with higher risk of type 2 diabetes than Caucasians (4—6). The potential for diabetes complications in these young individuals has immediate implications for diagnosis and treatment and longer-term implications for public health. We measured insulin resistance, insulin secretion, and a range of cardiovascular risk markers in an obese group of young Irish subjects with type 2 diabetes and compared them with a matched group of obese nondiabetic subjects and a representative group of older subjects with type 2 diabetes. All of the subjects were from the same clinic, and all were matched for obesity and duration of diabetes.

Eleven subjects with early-onset (age  40 years) type 2 diabetes were recruited, as well as 13 nondiabetic control subjects who were age and obesity matched to the young type 2 diabetic group. The protocol had ethical approval, and written informed consent was obtained. An oral glucose tolerance test was used to confirm glucose tolerance.

### Intravenous glucose tolerance test

An insulin-modified frequently sampled intravenous glucose tolerance test was performed (8,9). Oral hypoglycemic agents were withheld for 7 days before the …
Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation.
Authors: T Kavanagh, M H Yacoub, D J Mertens, J Kennedy, R B Campbell, P Sawyer
Journal: Circulation (1988)

We have tested the feasibility and effectiveness of a 2 year (average 16 +/- 7 months) walk/jog exercise program on 36 male orthotopic cardiac transplant patients (21 to 57 years old) seen initially 2 to 23 months after surgery. Comparison of initial exercise test results with those in 45 age-matched normal men showed the patients to have a lesser lean body mass (56 +/- 7 vs 63 +/- 8 kg, p less than .001), with a higher resting heart rate (104 +/- 12 vs 77 +/- 14 beats/min, p less than .001) and systolic (138 +/- 16 vs 129 +/- 17 mm Hg, p less than .001) and diastolic (95 +/- 14 vs 84 +/- 10 mm Hg, p less than .001) blood pressures. Peak power output was less than normal (101 +/- 27 vs 219 +/- 41 W, p less than .001), as was peak heart rate (136 +/- 15 vs 176 +/- 13 beats/min, p less than .001), peak oxygen intake (VO2max) (22 +/- 5 vs 34 +/- 6 ml.kg.min-1, p less than .001), and absolute anaerobic threshold (1.18 +/- 0.40 vs 2.04 +/- 0.40 liters.min-1, p less than .001). Peak ventilatory equivalent was higher (48 +/- 9 vs 37 +/- 61.1-1, p less than .001). Cardiac output (Q), as estimated by the CO2 rebreathing method, was slightly above normal at rest (p less than .01), but below normal at two submaximal work rates. The group's average weekly training distance was 24 km, with eight highly compliant patients progressing to 32 km or more weekly. After training, lean tissue increased (+2.4 +/- 3.1 kg, p less than .001), and resting values were reduced for heart rate (-4 +/- 11 beats/min, p less than .05), systolic (-13 +/- 20 mm Hg, p less than .001), and diastolic (-9 +/- 17 mm Hg, p less than .001) blood pressures. There were significant reductions in submaximal values for minute ventilation (VE), ratings of perceived exertion, and diastolic blood pressure at equivalent workloads. Peak values increased for power output (+49 +/- 34 W, p less than .001), VO2max (+4.0 +/- 6.0 ml.kg.min-1, p less than .001), VE (+20 +/- 20 l.min-1, p less than .001), and heart rate (+13 +/- 17 beats/min, p less than .001), and decreased for diastolic blood pressure (-8 +/- 15 mm Hg, p less than .001).(ABSTRACT TRUNCATED AT 400 WORDS)
Association of Epidermal Growth Factor Receptor Polymorphism, Skin Toxicity, and Outcome in Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab-Docetaxel Treatment
Authors: Konrad Klinghammer, Maren Knödler, Alexander Schmittel, Volker Budach, Ulrich Keilholz, Ingeborg Tinhofer
Journal: Clinical Cancer Research (2009)

Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), has shown clinical efficacy in squamous cell carcinoma of the head and neck with prolonged progression-free (PFS) and overall survival (OS). In this study, we analyzed whether cetuximab-induced skin rash was correlated with distinct polymorphisms within the EGFR gene known to modulate EGFR expression, ligand binding, or signaling activity.Fifty-one patients enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck with cetuximab/docetaxel were genotyped for two genetic variations in the EGFR gene, a point substitution G-->A in exon 13 resulting in an amino acid substitution in position 521 (EGFR-R521K) and a CA repeat (CA-SSR) polymorphism in intron 1. Association between genotypes and incidence/grade of skin rash was determined by Fisher's exact test. The predictive value of genotypes for PFS and OS was determined using the log-rank test.Overall, 21 patients (41%) developed skin rash with grade >1 within 6 weeks of treatment. The common EGFR-R521K genotype (G/G) was significantly associated with increased skin toxicity (P = 0.024) and showed a trend toward reduced risk of tumor progression (hazard ratio, 0.55; 95% confidence interval, 0.27-1.08; P = 0.08), whereas no correlation of the EGFR-R521K genotype with OS could be observed (P = 0.20). No significant interaction between CA-SSR polymorphism and skin toxicity, PFS, or OS could be detected.Our study revealed an influence of the EGFR-R521K genotype on skin toxicity and suggested its relation to clinical activity of cetuximab/docetaxel treatment.