tbuckley/cabot-search huggingface dataset:
Signal Transduction–Directed Cancer Treatments
Authors: Edward A. Sausville, Yusri Elsayed, Manish Monga, George Kim
Journal: The Annual Review of Pharmacology and Toxicology (2003)

The pathogenic mechanisms giving rise to cancer frequently involve altered signal transduction pathways. Therefore therapeutic agents that directly address signal transduction molecules are being explored as cancer treatments. Inhibitors of protein tyrosine and threonine kinases including STI-571, ZD-1839, OSI-774, and flavopiridol are ATP-site antagonists that have completed initial phase I and phase II evaluations. Herceptin and C225 are monoclonal antibodies also directed against signaling targets. Numerous other kinase antagonists are in clinical evaluation, including UCN-01 and PD184352. Alternative strategies to downmodulate kinase-driven signaling include 17-allyl-amino-17-demethoxygeldanamycin and rapamycin derivatives, and phospholipase-directed signaling may be modulated by alkylphospholipids. Farnesyltransferase inhibitors were originally developed as inhibitors of ras-driven signals but may have activity by affecting other or additional targets. Signal transduction will remain a fertile basis for suggesting cancer treatments of the future, the evaluation of which should include monitoring effects of the drugs on their intended target signaling molecules in preclinical and early clinical studies.
The Challenges and Promise of Neuroimaging in Psychiatry
Authors: David E.J. Linden
Journal: Neuron (2012)

Neuroimaging is central to the quest for a biological foundation of psychiatric diagnosis but so far has not yielded clinically relevant biomarkers for mental disorders. This review addresses potential reasons for this limitation and discusses refinements of paradigms and analytic techniques that may yield improved diagnostic and prognostic accuracy. Neuroimaging can also be used to probe genetically defined biological pathways underlying mental disorders, for example through the genetic imaging of variants discovered in genome-wide association studies. These approaches may ultimately reveal mechanisms through which genes contribute to psychiatric symptoms and how pharmacological and psychological interventions exert their effects.
A Comparison of Apnea–Hypopnea Indices Derived from Different Definitions of Hypopnea
Authors: WILLIS H. TSAI, W. WARD FLEMONS, WILLIAM A. WHITELAW, JOHN E. REMMERS
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

We examined the effects of arousal- and desaturation-based scoring criteria on the apnea–hypopnea index (AHI) and on the measured prevalence of obstructive sleep apnea (OSA). Ninety-four randomly selected patients underwent overnight polysomnography. Studies were scored according to three different criteria for hypopnea, as defined by a ⩾ 10 s discernible reduction in thoracoabdominal movement associated with: (1) ⩾ 4% decrease in oxygen saturation (SaO2 ) (Type A); (2) either a ⩾ 4% decrease in SaO2 or an arousal (Type B); or (3) electroencephalographically based arousal alone (Type C). Excellent correlation existed between AHI-A, AHI-B, and the oxygen desaturation index (ODI) (r > 0.98). AHI-A and AHI-B differed by only 2.04 ± 1.72/h (2 SD). AHI-A and AHI-B differed from the ODI by 1.04 ± 4.07/h and 3.07 ± 4.30/h, respectively. Despite these small differences, use of the Type B rather than Type A definition resulted in an extra case of OSA being diagnosed for every 14 to 31 patients tested, depending on the definition of OSA (AHI: ⩾ 5, 10, 15, or 20/h). The addition of arousal-based scoring criteria for hypopnea causes only small changes in the AHI, but if OSA is defined solely by an AHI value, the measured prevalence of OSA will increase.
Induction Docetaxel, Cisplatin, and Cetuximab Followed by Concurrent Radiotherapy, Cisplatin, and Cetuximab and Maintenance Cetuximab in Patients With Locally Advanced Head and Neck Cancer
Authors: Athanassios Argiris, Dwight E. Heron, Ryan P. Smith, Seungwon Kim, Michael K. Gibson, Stephen Y. Lai, Barton F. Branstetter, Donna M. Posluszny, Lin Wang, Raja R. Seethala, Sanja Dacic, William Gooding, Jennifer R. Grandis, Jonas T. Johnson, Robert L. Ferris
Journal: Journal of Clinical Oncology (2010)

Purpose We incorporated cetuximab, a chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR), into the induction therapy and subsequent chemoradiotherapy of head and neck cancer (HNC). Patients and Methods Patients with locally advanced HNC, including squamous and undifferentiated histologies, were treated with docetaxel 75 mg/m 2 day 1, cisplatin 75 mg/m 2 day 1, and cetuximab 250 mg/m 2 days 1, 8, and 15 (after an initial loading dose of 400 mg/m 2 ), termed TPE, repeated every 21 days for three cycles, followed by radiotherapy with concurrent cisplatin 30 mg/m 2 and cetuximab weekly (XPE), and maintenance cetuximab for 6 months. Quality of life (QOL) was assessed using Functional Assessment of Cancer Therapy–Head and Neck. In situ hybridization (ISH) for human papillomavirus (HPV), immunohistochemistry for p16, and fluorescence ISH for EGFR gene copy number were performed on tissue microarrays. Results Of 39 enrolled patients, 36 had stage IV disease and 23 an oropharyngeal primary. Acute toxicities during TPE included neutropenic fever (10%) and during XPE, grade 3 or 4 oral mucositis (54%) and hypomagnesemia (39%). With a median follow-up of 36 months, 3-year progression-free survival and overall survival were 70% and 74%, respectively. Eight patients progressed in locoregional sites, three in distant, and one in both. HPV positivity was not associated with treatment efficacy. No progression-free patient remained G-tube dependent. The H&amp;N subscale QOL scores showed a significant decrement at 3 months after XPE, which normalized at 1 year. Conclusion This cetuximab-containing regimen resulted in excellent long-term survival and safety, and warrants further evaluation in both HPV-positive and -negative HNC.
Use of Mefenamic Acid in the Treatment of Primary Dysmenorrhea
Authors: Penny Wise Budoff
Journal: JAMA (1979)

Mefenamic acid (Ponstel), 250 mg four times a day, and placebo were compared in a double-blind, crossover study conducted in 46 women with primary spasmodic dysmenorrhea. When compared with placebo, treatment with mefenamic acid resulted in significant decreases in the frequency and severity of the symptoms, and significantly reduced the need for additional analgesic medication. Mefenamic acid was well tolerated. No changes in clinical laboratory values were associated with its use. (<i>JAMA</i>241:2713-2716, 1979)
Randomized Trial of Radiotherapy Versus Concurrent Chemoradiotherapy Followed by Adjuvant Chemotherapy in Patients With American Joint Committee on Cancer/International Union Against Cancer Stage III and IV Nasopharyngeal Cancer of the Endemic Variety
Authors: Joseph Wee, Eng Huat Tan, Bee Choo Tai, Hwee Bee Wong, Swan Swan Leong, Terence Tan, Eu Tiong Chua, Edward Yang, Khai Mun Lee, Kam Weng Fong, Hoon Seng Khoo Tan, Kim Shang Lee, Susan Loong, Vijay Sethi, Eu Jin Chua, David Machin
Journal: Journal of Clinical Oncology (2005)

The Intergroup 00-99 Trial for nasopharyngeal cancer (NPC) showed a benefit of adding chemotherapy to radiotherapy. However, there were controversies regarding the applicability of the results to patients in endemic regions. This study aims to confirm the findings of the 00-99 Trial and its applicability to patients with endemic NPC.Between September 1997 and May 2003, 221 patients were randomly assigned to receive radiotherapy (RT) alone (n = 110) or chemoradiotherapy (CRT; n = 111). Patients in both arms received 70 Gy in 7 weeks using standard RT portals and techniques. Patients on CRT received concurrent cisplatin (25 mg/m2 on days 1 to 4) on weeks 1, 4, and 7 of RT and adjuvant cisplatin (20 mg/m2 on days 1 to 4) and fluorouracil (1,000 mg/m2 on days 1 to 4) every 4 weeks (weeks 11, 15, and 19) for three cycles after completion of RT. All patients were analyzed by intent-to-treat analysis. The median follow-up time was 3.2 years.Distant metastasis occurred in 38 patients on RT alone and 18 patients on CRT. The difference in 2-year cumulative incidence was 17% (95% CI, 14% to 20%; P = .0029). The hazard ratio (HR) for disease-free survival was 0.57 (95% CI, 0.38 to 0.87; P = .0093). The 2- and 3-year overall survival (OS) rates were 78% and 85% and 65% and 80% for RT alone and CRT, respectively. The HR for OS was 0.51 (95% CI, 0.31 to 0.81; P = .0061).This report confirms the findings of the Intergroup 00-99 Trial and demonstrates its applicability to endemic NPC. This study also confirms that chemotherapy improves the distant metastasis control rate in NPC.
Comparison of Injectable Haloperidol and Chlorpromazine
Authors: ROBERT M. RITTER, DAVID E. DAVIDSON, THOMAS A. ROBINSON
Journal: American Journal of Psychiatry (1972)

The effectiveness of injectable chlorpromazine was compared with the effectiveness of injectable haloperidol with highly agitated, acute psychotic patients and chronic patients with acute exacerbations. While both groups improved, haloperidol effected a significantly greater improvement in patients 40 years of age or older than did chlorpromazine. This result is consistent with those reported in other studies.
Classification of Proliferative Pulmonary Lesions of the Mouse
Authors: Alexander Yu. Nikitin, Ana Alcaraz, Miriam R. Anver, Roderick T. Bronson, Robert D. Cardiff, Darlene Dixon, Armando E. Fraire, Edward W. Gabrielson, William T. Gunning, Diana C. Haines, Matthew H. Kaufman, R. Ilona Linnoila, Robert R. Maronpot, Alan S. Rabson, Robert L. Reddick, Sabine Rehm, Nora Rozengurt, Hildegard M. Schuller, Elena N. Shmidt, William D. Travis, Jerrold M. Ward, Tyler Jacks
Journal: Cancer Research (2004)

Rapid advances in generating new mouse genetic models for lung neoplasia provide a continuous challenge for pathologists and investigators. Frequently, phenotypes of new models either have no precedents or are arbitrarily attributed according to incongruent human and mouse classifications. Thus, comparative characterization and validation of novel models can be difficult. To address these issues, a series of discussions was initiated by a panel of human, veterinary, and experimental pathologists during the Mouse Models of Human Cancers Consortium (NIH/National Cancer Institute) workshop on mouse models of lung cancer held in Boston on June 20-22, 2001. The panel performed a comparative evaluation of 78 cases of mouse and human lung proliferative lesions, and recommended development of a new practical classification scheme that would (a) allow easier comparison between human and mouse lung neoplasms, (b) accommodate newly emerging mouse neoplasms, and (c) address the interpretation of benign and preinvasive lesions of the mouse lung. Subsequent discussions with additional experts in pulmonary pathology resulted in the current proposal of a new classification. It is anticipated that this classification, as well as the complementary digital atlas of virtual histological slides, will help investigators and pathologists in their characterization of new mouse models, as well as stimulate further research aimed at a better understanding of proliferative lesions of the lung.
Identification of EP4 as a Potential Target for the Treatment of Castration-Resistant Prostate Cancer Using a Novel Xenograft Model
Authors: Naoki Terada, Yosuke Shimizu, Tomomi Kamba, Takahiro Inoue, Atsushi Maeno, Takashi Kobayashi, Eijiro Nakamura, Toshiyuki Kamoto, Toshiya Kanaji, Takayuki Maruyama, Yoshiki Mikami, Yoshinobu Toda, Toshiyuki Matsuoka, Yasushi Okuno, Gozoh Tsujimoto, Shuh Narumiya, Osamu Ogawa
Journal: Cancer Research (2010)

More effective therapeutic approaches for castration-resistant prostate cancer (CRPC) are urgently needed, thus reinforcing the need to understand how prostate tumors progress to castration resistance. We have established a novel mouse xenograft model of prostate cancer, KUCaP-2, which expresses the wild-type androgen receptor (AR) and which produces the prostate-specific antigen (PSA). In this model, tumors regress soon after castration, but then reproducibly restore their ability to proliferate after 1 to 2 months without AR mutation, mimicking the clinical behavior of CRPC. In the present study, we used this model to identify novel therapeutic targets for CRPC. Evaluating tumor tissues at various stages by gene expression profiling, we discovered that the prostaglandin E receptor EP4 subtype (EP4) was significantly upregulated during progression to castration resistance. Immunohistochemical results of human prostate cancer tissues confirmed that EP4 expression was higher in CRPC compared with hormone-naïve prostate cancer. Ectopic overexpression of EP4 in LNCaP cells (LNCaP-EP4 cells) drove proliferation and PSA production in the absence of androgen supplementation in vitro and in vivo. Androgen-independent proliferation of LNCaP-EP4 cells was suppressed when AR expression was attenuated by RNA interference. Treatment of LNCaP-EP4 cells with a specific EP4 antagonist, ONO-AE3-208, decreased intracellular cyclic AMP levels, suppressed PSA production in vitro, and inhibited castration-resistant growth of LNCaP-EP4 or KUCaP-2 tumors in vivo. Our findings reveal that EP4 overexpression, via AR activation, supports an important mechanism for castration-resistant progression of prostate cancer. Furthermore, they prompt further evaluation of EP4 antagonists as a novel therapeutic modality to treat CRPC.
Biomarkers in IBS: when will they replace symptoms for diagnosis and management?
Authors: G. Barbara, V. Stanghellini
Journal: Gut (2009)

Biomarkers are objectively measurable indicators of normal or pathological processes or pharmacological responses to a therapeutic intervention.1 Examples of biomarkers that unquestionably help physicians in their daily clinical practice include simple physiological indicators, like the assessment of blood pressure or heart rate, and more advanced markers, like anti-endomysial antibodies for celiac disease. The identification of reliable biomarkers represents a major step forward in the management of a disease because they can elucidate the aetiology, define the diagnosis, and predict the prognosis. Biomarkers may also speed up different phases of drug development and reduce disease-related costs. Thus, biomarkers are generating considerable interest in the pharmaceutical industry. A disease biomarker should be characterised by high sensitivity (ie, discriminate well between health and disease) and specificity (ie, be able to distinguish the disease from other pathological conditions). Biomarkers should also be reproducible, ideally non-invasive, and inexpensive to allow screening large numbers of patients in clinical or trial settings. For these reasons, biomarker discovery represents a significant challenge to basic and clinical researchers and has been a major initiative in the roadmaps of the European Medicines Agency (http://www.emea.europa.eu) and the U.S. Food and Drug Administration (http://www.fda.gov).

Abdominal pain, diarrhoea, constipation, bloating, nausea, and vomiting are common gastrointestinal complaints in the general population. Usually, patients seeking medical attention experience severe symptoms, have an impaired daily life, or worry that “it might be something serious”. Disappointingly, efforts to identify metabolic, biochemical, infectious, degenerative or neoplastic causes fail in a significant percentage of patients. This leads to a diagnosis of “functional bowel disorders”, among which, irritable bowel syndrome (IBS) is the most common. These diagnoses vanquish the patients’ expectations of finding a “cause” for their symptoms and generate frustration. Symptom-based criteria and Bristol stool score, in the absence of red flags, have been developed as …
A family of serine proteases expressed exclusively in myelo-monocytic cells specifically processes the nuclear factor-kappa B subunit p65 in vitro and may impair human immunodeficiency virus replication in these cells.
Authors: G Franzoso, P Biswas, G Poli, L M Carlson, K D Brown, M Tomita-Yamaguchi, A S Fauci, U K Siebenlist
Journal: The Journal of Experimental Medicine (1994)

Two groups of U937 promonocytic cells were obtained by limiting dilution cloning which differed strikingly in their ability to support human immunodeficiency virus 1 (HIV-1) replication. "Plus" clones replicated the virus efficiently, whereas "minus" clones did not. We examined these clones for differences in nuclear factor (NF)-kappa B activity which might account for the observed phenomenon. Stimulation of plus clones liberated the classical p50-p65 complex from cytoplasmic pools, whereas minus clones produced an apparently novel, faster-migrating complex, as judged by electrophoretic mobility shift assays. It is surprising that the faster-migrating complex was composed also of p50 and p65. However, the p65 subunit was COOH-terminally truncated, as shown by immunoprecipitation. The truncation resulted from limited proteolysis of p65 during cellular extraction which released particular lysosomal serine proteases, such as elastase, cathepsin G, and proteinase 3. These specific proteases are coordinately expressed and were present exclusively in the minus U937 clones, but not in the plus clones, as demonstrated in the case of cathepsin G. In addition, these proteases were detected in certain subclones of THP-1 and HL-60 cells and in primary monocytes, in each case correlating with the truncated from of p65. We demonstrate in vitro cleavage of p65 by purified elastase and cathepsin G. It is possible that particular serine proteases may have inhibiting effects on the replication of HIV-1 in myelo-monocytic cells. The data also demonstrate that special precautions must be taken when making extracts from myelo-monocytic cells.
Atrial Natriuretic Peptide Induces Mitogen-Activated Protein Kinase Phosphatase-1 in Human Endothelial Cells via Rac1 and NAD(P)H Oxidase/Nox2-Activation
Authors: Robert Fürst, Corinna Brueckl, Wolfgang M. Kuebler, Stefan Zahler, Florian Krötz, Agnes Görlach, Angelika M. Vollmar, Alexandra K. Kiemer
Journal: Circulation Research (2004)

The cardiovascular hormone atrial natriuretic peptide (ANP) exerts anti-inflammatory effects on tumor necrosis factor-alpha-activated endothelial cells by inducing mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1). The underlying mechanisms are as yet unknown. We aimed to elucidate the signaling pathways leading to an induction of MKP-1 by ANP in primary human endothelial cells. By using antioxidants, generation of reactive oxygen species (ROS) was shown to be crucially involved in MKP-1 upregulation. ANP was found to increase ROS formation in cultured cells as well as in the endothelium of intact rat lung vessels. We applied NAD(P)H oxidase (Nox) inhibitors (apocynin and gp91ds-tat) and revealed this enzyme complex to be crucial for superoxide generation and MKP-1 expression. Moreover, by performing Nox2/4 antisense experiments, we identified Nox2 as the critically involved Nox homologue. Pull-down assays and confocal microscopy showed that ANP activates the small Rho-GTPase Rac1. Transfection of a dominant-negative (RacN17) and constitutively active Rac1 mutant (RacV12) indicated that ANP-induced superoxide generation and MKP-1 expression are mediated via Rac1 activation. ANP-evoked production of superoxide was found to activate c-Jun N-terminal kinase (JNK). Using specific inhibitors, we linked ANP-induced JNK activation to MKP-1 expression and excluded an involvement of protein kinase C, extracellular signal-regulated kinase, and p38 MAPK. MKP-1 induction was shown to depend on activation of the transcription factor activator protein-1 (AP-1) by using electrophoretic mobility shift assay and AP-1 decoys. In summary, our work provides insights into the mechanisms by which ANP induces MKP-1 and shows that ANP is a novel endogenous activator of endothelial Rac1 and Nox/Nox2.
Combination of Trastuzumab and Tanespimycin (17-AAG, KOS-953) Is Safe and Active in Trastuzumab-Refractory HER-2–Overexpressing Breast Cancer: A Phase I Dose-Escalation Study
Authors: Shanu Modi, Alison T. Stopeck, Michael S. Gordon, David Mendelson, David B. Solit, Rochelle Bagatell, Weining Ma, Jennifer Wheler, Neal Rosen, Larry Norton, Gillian F. Cropp, Robert G. Johnson, Alison L. Hannah, Clifford A. Hudis
Journal: Journal of Clinical Oncology (2007)

This phase I study examined whether a heat shock protein (Hsp) 90 inhibitor tanespimycin (17-AAG; KOS-953) could be administered safely in combination with trastuzumab at a dose that inhibits Hsp90 function in vivo in lymphocytes.Patients with an advanced solid tumor progressing during standard therapy were eligible. Patients were treated with weekly trastuzumab followed by intravenous tanespimycin, assessed in escalating dose levels.Twenty-five patients were enrolled onto four tanespimycin dose levels: 225 (n = 4), 300 (n = 3), 375 (n = 8), and 450 mg/m2 (n = 10). Dose-limiting toxicity (DLT) was observed at the third and fourth cohort (1 patient each): more than 2-week delay for grade 4 fatigue/grade 2 nausea and anorexia (375 mg/m2); more than 2-week delay for thrombocytopenia (450 mg/m2). Drug-related grade 3 toxicity included emesis, increased ALT, hypersensitivity reactions (two patients each), and drug-induced thrombocytopenia (n = 1). Common mild to moderate toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT, and anorexia. Pharmacokinetic analysis demonstrated no difference in tanespimycin kinetics with or without trastuzumab. Pharmacodynamic testing showed reactive induction of Hsp70 (a marker of Hsp90 inhibition) in lymphocytes at all dose levels. Antitumor activity was noted (partial response, n = 1; minor response, n = 4; stable disease > or = 4 months, n = 4). Tumor regressions were seen only in patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer.Tanespimycin plus trastuzumab is well tolerated and has antitumor activity in patients with HER-2+ breast cancer whose tumors have progressed during treatment with trastuzumab. These data suggest that Hsp90 function can be inhibited in vivo to a degree sufficient to cause inhibition of tumor growth.
The Interface of Genetics and Public Health: Research and Educational Challenges
Authors: Melissa A. Austin, Patricia A. Peyser, Muin J. Khoury
Journal: Annual Review of Public Health (2000)

▪ Abstract As the target date for the sequencing of the human genome approaches, there is growing recognition that public health practice, research, and education will be impacted by new genetic technologies and information and that a multidisciplinary approach is required. Research in the emerging field of public health genetics encompasses a broad range of disciplines and will increasingly involve the interactions among the investigators in these fields. An overview of these areas of research is provided, with illustrative examples. Education in public health genetics needs to address a variety of audiences, including public health graduate students and practitioners, students from related disciplines, and health care professionals. Two new graduate programs at the Universities of Michigan and Washington and training opportunities for public health professionals are described. These educational efforts must be ongoing so that the potential of genetic technology and information can be appropriately used to benefit the health of all.