tbuckley/cabot-search huggingface dataset:
Abstract 1249: MLN4924, a protein neddylation inhibitor, induces apoptosis via endoplasmic reticulum (ER)-stress in human cervical cancer
Authors: Kuan-Lin Kuo, Yeong-Shiau Pu, I-LIN Ho, Chen-Hsun Hsu, Ju-Ton Hsieh, Wei-Chou Lin, Chien-Tso Chou, Kuo-How Huang
Journal: Cancer Research (2015)

Abstract Cervical cancer is the second most common cancer among the women worldwide. The treatment of the cervical cancer includes the surgery, chemotherapy, external and intracavitary radiotherapy adjusted to the different cancer stage. Despite these treatments, a certain proportion of women still die of the cancer due to recurrent or chemoresistent disease. The toxicity and side effect of these therapies are substantial. Therefore, it is important to develop new drugs or combination treatments to improve patient survival and minimize side effect of the therapy. MLN4924 is an inhibitor of NEDD8 activating enzyme (NAE), has been reported to elicit anti-tumor response in various malignancies. In this study, we aim to investigate the anti-tumor effect of MLN4924 on human cervical cancer and underlying mechanism in vitro and in vivo. We used two different grade human bladder cervical cell lines: ME-180 and HeLa. After exposing to MLN4924, the cell viability and apoptosis were measured by MTT and flow cytometry with annexin V-FITC labeling. The efficacy of cell proliferation was determined by BrdU incorporation assay. The cell cycle regulators, cell death-related molecules, and ER stress-related proteins were examined by Western blotting. We also use Nu/Nu xenograft mice model to clarify the effect of MLN4924 on tumor growth in vivo. We demonstrated that MLN4924 effectively induces dose-dependent cytotoxicity, apoptosis and anti-tumor phenomenon in cervical cancer cells. MLN4924 also activate cleaved-Bid, phospho-histone H2A.X, caspases and PARP, decresed phospho-Bcl2, and cause cell cycle arrest. Furthermore, MLN4924 possessed the ability to activate ER stress-related moleculors caspase-4, and CCAAT/enhancer binding protein homologous protein (CHOP), which were involved in UC cell apoptosis, and other stress responses (JNK and c-Jun activations). Moreover, we confirmed MLN4924 inhibited tumor growth and induced ER-stress in a cervical cancer xenograft mice model. Taken together, we demonstrated that MLN4924 induces cytotoxicity and cell cycle retardation, as well as activation of ER stress responses in human cervical cancer. The anti-tumor effect of MLN4924 provides a novel implication in clinical treatment of cervical cancer. Citation Format: Kuan-Lin Kuo, Yeong-Shiau Pu, I-LIN Ho, Chen-Hsun Hsu, Ju-Ton Hsieh, Wei-Chou Lin, Chien-Tso Chou, Kuo-How Huang. MLN4924, a protein neddylation inhibitor, induces apoptosis via endoplasmic reticulum (ER)-stress in human cervical cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1249. doi:10.1158/1538-7445.AM2015-1249
Abstract 4455: Relapsed/refractory AML responds robustly to IACS-10759, a novel OXPHOS inhibitor
Authors: Marina Protopopova, Madhavi Bandi, Jennifer Bardenhagen, Christophor Bristow, Christopher Carroll, Edward Chang, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Marina Konopleva, Polina Matre, Zhijun Kang, Gang Liu, Florian Muller, Timothy Lofton, Timothy McAfoos, Jay Theroff, Yuting Sun, Yuanqiang Wu, Melinda Smith, Lynda Chin, Giulio Draetta, Philip Jones, Carlo Toniatti, M. Emilia Di Francesco, Joseph R. Marszalek
Journal: Cancer Research (2015)

Abstract Acute myeloid leukemia (AML) is a highly aggressive disease that is made up of several genetically and clinically diverse hematological malignancies that are characterized by clonal expansion of malignant stem/progenitor cells with limited ability to differentiate into mature blood cells. Standard of care for AML has progressed minimally in the past 30 years for relapse/refractory AML, with survival rates of &amp;lt;12% for those aged &amp;gt;65 years. Therefore, novel, highly effective therapeutics are needed for this population. Growing evidence suggests that in AML, metabolism is altered and that the tumor cells become highly dependent of mitochondria oxidative phosphorylation (OXPHOS) for their survival. We developed IACS-10759 as a novel small molecule inhibitor of complex I that potently inhibits oxygen consumption, eliminates hypoxia, and strongly inhibits the proliferation of cells grown in galactose medium with EC50 values between 1-10 nM. When AML cell lines as well as primary AML cells from relapsed/refractory patients were treated ex vivo with IACS-10759, apoptosis was robustly induced with EC50 values also ranging between 1-10 nM. It is noteworthy, that while apoptosis was induced in primary AML cells, normal patient-derived bone marrow cells were not sensitive. In AML orthotopic xenografts, daily oral dosing with 15 mg/kg IACS-10759 extended median survival to 70 days from 18 days in control animals. Taken together, the robust response in AML cell lines, primary AML samples ex vivo, and efficacy in orthotopic xenografts, IACS-10759 has entered IND enabling studies with first-in-human studies targeted for third quarter of 2015. Citation Format: Marina Protopopova, Madhavi Bandi, Jennifer Bardenhagen, Christophor Bristow, Christopher Carroll, Edward Chang, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Marina Konopleva, Polina Matre, Zhijun Kang, Gang Liu, Florian Muller, Timothy Lofton, Timothy McAfoos, Jay Theroff, Yuting Sun, Yuanqiang Wu, Melinda Smith, Lynda Chin, Giulio Draetta, Philip Jones, Carlo Toniatti, M. Emilia Di Francesco, Joseph R. Marszalek. Relapsed/refractory AML responds robustly to IACS-10759, a novel OXPHOS inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4455. doi:10.1158/1538-7445.AM2015-4455
Pulmonary Embolism, Pulmonary Hemorrhage and Pulmonary Infarction
Authors: James E. Dalen, Charles I. Haffajee, Joseph S. Alpert, John P. Howe, Ira S. Ockene, John A. Paraskos
Journal: New England Journal of Medicine (1977)

We compared 41 patients with angiographic proof of pulmonary embolism and clinical signs of pulmonary infarction (as evidenced by an infiltrate on x-ray study and pleuritic pain in the area of the embolus) with 24 patients with pulmonary embolism but without infarction. Only 18 of the 41 patients with pulmonary infarction had associated heart disease. Pulmonary infarction was uncommon when emboli obstructed central arteries but frequent when distal arteries were occluded. Follow-up x-ray examination showed that the infiltrates resolved in the patients with pulmonary infarction without heart disease, but persisted when heart disease was present. We suggest that obstruction of distal arteries results in pulmonary hemorrhage owing to an influx of bronchial arterial blood at systemic pressure. Hemorrhage causes symptoms and x-ray changes usually attributed to pulmonary infarction. However, hemorrhage resolves without infarction in patients without, but progresses to infarction in those with, heart disease.
Rocky Mountain Spotted Fever in the Eastern United States
Authors: Gerald W. Hazard, Robert N. Ganz, Robert W. Nevin, Alan H. Nauss, Ever Curtis, D. William J. Bell, Edward S. Murray
Journal: New England Journal of Medicine (1969)

The majority of 13 cases of Rocky Mountain spotted fever from an endemic focus of the disease in the Cape Cod area of Massachusetts were diagnosed late, and two patients died. However, earlier diagnosis, earlier initiation of specific therapy, and prevention of fatalities should have been possible. Clinical, epidemiologic and laboratory data highly suggestive of the disease were almost all available early in the first week of illness to help in the diagnosis. There was high fever, severe headache, toxicity, mental confusion and myalgia. A generalized measles-like rash involved the palms and soles in almost all cases. Cases occurred seasonally between April and September, sharply restricted geographically to a known endemic focus, and predominantly in children. Complement-fixing and Weil-Felix antibodies rose late in the second week and were of no help in early diagnosis. Thrombocytopenia was surprisingly frequent, occurring in seven of 11 patients tested.
Surgical Treatment of Lymph–Node Metastases
Authors: Grantley W. Taylor
Journal: New England Journal of Medicine (1951)

INTEREST in the problem of management of regional lymph-node metastases has greatly increased during the past ten years. Critical analysis of treatment of cancer has emphasized that failures are often attributable to regional recurrence rather than to widespread generalization of the disease and that a more radical eradication of the regional lymph-node drainage areas might have prevented recurrence.Basically, the problem of cancer treatment may be resolved into three phases. First, the primary focus of disease must be eradicated. The probability of spread to the regional lymph nodes must be evaluated in each case. When there is any significant probability, . . .
Hepatitis, Exfoliative Dermatitis and Abnormal Bone Marrow Occurring during Tridione Therapy
Authors: Samuel E. Leard, William E. R. Greer, I. Charles Kaufman
Journal: New England Journal of Medicine (1949)

SINCE 1944, when Everett and Richards1 described the anticonvulsive action of tridione (3, 5, 5-trimethyloxazolidine-2, 4-dione), the drug has been used in human beings to control epileptic attacks, especially petit mal seizures. Varying toxic reactions have been described, but to our knowledge this is the first case in which hepatic dysfunction, severe exfoliative dermatitis and leukemoid bone-marrow changes have been reported in the same patient.The first report on the clinical use of the drug made very little mention of toxic reactions or unpleasant side effects. In 1945 Lennox2 noted that in the majority of adolescent or adult patients, but . . .
Here Come the Women
Authors: Arnold S. Relman
Journal: New England Journal of Medicine (1980)

Until recently, the medical profession in this country has been a male preserve. Although the number of women had been rising slowly for some time, a decade ago they constituted less than 8 per cent of all practicing physicians and barely more than 9 per cent of all medical students. Then came the feminist revolution of the 1970's, and the sexual composition of medical-school classes began to change rapidly.Figure 1 tells the story. It shows the percentages of women among students applying and admitted to United States medical schools for the years 1950 to 1980. Applications are shown by the open . . .
Manifestations of Acute Leukemia in the Parenchyma of the Lung
Authors: Daniel J. Nathan, Martin Sanders
Journal: New England Journal of Medicine (1955)

ACUTE leukemia is characterized histologically by infiltration of the bone marrow with immature hematic cells and a variable degree of similar invasion of the other tissues of the hematopoietic system. Occasionally, however, in unusual situations a sufficient degree of infiltration occurs in other organs so that the presenting symptoms and clinical picture are highlighted by these concomitant sites of involvement.Infiltrations of the lung are not usually considered part of the clinical picture of acute leukemia. For this reason roentgenograms of the chest are not routinely taken in these cases, allowing this entity to go unrecognized. It is the purpose . . .
The Role of Reperfusion-Induced Injury in the Pathogenesis of the Crush Syndrome
Authors: M Odeh
Journal: New England Journal of Medicine (1991)

RHABDOMYOLYSIS is a common syndrome in which injury to skeletal muscle results in the leakage of the contents of myocytes into the plasma. It can be induced by numerous factors, including a crush injury to a limb, overuse of skeletal muscle, heat, alcoholism, viral infections, metabolic disorders, myopathies, drugs, toxins, and hypokalemia. Massive rhabdomyolysis can produce life-threatening myoglobinuric renal failure, hyperkalemia, disseminated intravascular coagulation, acute cardiomyopathy, and various other complications.1 2 3 Traumatic rhabdomyolysis, or the crush syndrome, is the consequence of prolonged continuous pressure on the limbs. It reflects the disintegration of muscle tissue and the influx of myoglobin, potassium, and . . .
S89 Hypersensitivity to Adenosine Triphosphate in Chronic Cough Patients
Authors: HE Fowles, AH Morice
Journal: Thorax (2015)

<h3>Introduction</h3> Recent studies have suggested a role for adenosine triphosphate (ATP) activated P2×3 receptors in the pathophysiology of chronic cough. ATP has previously been used as an inhalational challenge substance in asthmatics and COPD patients, with the main focus being on bronchospasm. We have considered whether chronic cough patients are hypersensitive to inhaled ATP compared to healthy volunteers. <h3>Method</h3> The recognised ERS standardised cough challenge using the Ko-Ko digidoser was performed with ATP and AMP as substrates. 20 Healthy volunteers and 20 chronic cough patients were randomised to the order of challenges. C5 (the concentration of substrate causing at least 5 coughs) was compared for ATP and AMP. Average cough response to ATP was compared between the 2 groups. <h3>Results</h3> 6 male and 14 female volunteers in each group were randomised to receive cough challenges. Hull Airways Reflux Questionnaire score range was 0–8 in healthy volunteers and 21–52 in chronic cough patients. 1 healthy volunteer had a mild hypersensitivity reaction to ATP with urticaria. 1 patient withdrew after their first challenge due to worsening cough. No other side effects were reported. 2/19 healthy volunteers coughed with AMP, neither achieved C5. 8/20 chronic cough patients coughed with AMP, 2 achieved C5. 18/20 healthy volunteers coughed with ATP with 15 achieving C5. 19/19 chronic cough patients coughed with ATP, 18 achieved C5. The chronic cough patients had a greater cough response at lower concentrations of ATP as demonstrated in Figure 1. <h3>Discussion</h3> Previous human ATP challenges have documented cough as a symptom but none have objectively measured the cough response in chronic cough patients. We present here the first results demonstrating that chronic cough patients have increased sensitivity to ATP compared to healthy volunteers. This supports a role for ATP driven receptors in the cough reflex arc and supports further research in this area as a target for treatments in chronic cough.
Newer Occupational Diseases
Authors: John B. Skinner
Journal: New England Journal of Medicine (1950)

MEMBERS of the staff of the Division of Occupational Hygiene have attempted to keep members of the Massachusetts Medical Society informed regarding current problems in occupational hygiene. Such attempts have included summaries of work in the field of industrial hygiene1 2 3 4 and reports regarding anthrax in Massachusetts5 , 6 and particularly the appearances of new clinical syndromes in workers exposed to beryllium compounds.7 This entity has received nationwide interest because of the varied uses of beryllium and its compounds and because various types of pneumonitis have been experienced almost everywhere this element or its compounds have been used. It is hoped that the . . .
Methylated tumor-specific DNA as a plasma biomarker in patients with glioma
Authors: K. D. Weaver, S. Grossman, J. Herman
Journal: Journal of Clinical Oncology (2004)

1527 Background: While patients without malignancy have <100μg/ml free DNA in plasma (Chang, J NC I 2002), patients with malignancy demonstrate substantial quantities of tumor-specific DNA in their plasma. Measurements of this DNA are being studied to develop plasma markers to correlate with tumor burden. This approach has not been explored in gliomas. Methods: This study assesses the presence of plasma tumor-specific DNA in gliomas using methylation specific polymerase chain reaction (MSP). With IRB approval, 30 ml venous blood was collected prior to craniotomy from 10 patients with presumed high grade glioma. After surgery, DNA was extracted and quantified from the tumor and plasma samples. The methylation status of p16, p73, RARβ, and MGMT gene promoters was assayed with MSP. The presence of tumor-specific DNA in the plasma was defined as identification of the same methylated promoter (MP) in both plasma and tumor. Results: Histology was: glioblastoma (N=6), anaplastic astrocytoma (2), anaplastic oligoastrocytoma (1), grade II oligodendroglioma (1). Total DNA concentration in plasma was grossly elevated (mean 6503 μg/ml, SEM 1400μg/ml). Surgical specimens revealed methylation of at least one promoter in 9/10 (90%) of patients. Six pts had 1 MP, 2 had 2 MP, and 1 had 3 MP. The one patient with no identified MP had glioblastoma. Of the 9 patients with MP, 6 (67%) had methylation of at least one of the same promoters in the plasma DNA. Five of these had 1 MP identified in the plasma and 1 had 2 MP. Overall, glioma-specific methylated DNA was present in plasma of 6/10 (60%) patients to date. Tumors with no plasma MP were 2 glioblastoma, 1 anaplastic astrocytoma and 1 oligodendroglioma. No positive markers were found in the plasma that were not also found in the intracranial tumor. Conclusions: Gliomas shed large amounts of DNA into the blood. Using MSP, we found that tumor-specific DNA can be identified in plasma of high grade glioma patients. This is likely to be quite specific as promoter methylation is not found in normal tissue. Isolation of tumor-specific plasma DNA in these patients represents the first step to developing a quantitative glioma plasma biomarker that could be used to monitor tumor status. No significant financial relationships to disclose.
Essential fatty acid supplementation in tardive dyskinesia
Authors: A Wolkin, B Jordan, E Peselow, M Rubinstein, J Rotrosen
Journal: American Journal of Psychiatry (1986)

Preclinical and clinical observations suggest that enhancement of prostaglandin activity inhibits catecholamine release and may have antidyskinetic effects. A double-blind therapeutic trial with prostaglandin precursor essential fatty acids was conducted in 16 patients with tardive dyskinesia. No beneficial effects were seen.
Development of a phase Ib/IIa proof-of-concept study of imalumab (BAX69), a first-in-class anti-macrophage migration inhibitory factor (MIF) antibody, as the 3<sup>rd</sup> or 4<sup>th</sup> line treatment in metastatic colorectal cancer (mCRC).
Authors: Xiaochun Liu, Deyaa Rafaat Adib, Hila Barak, Richard M. Goldberg, Salim Yazji
Journal: Journal of Clinical Oncology (2015)

TPS3633 Background: Patients with mCRC who fail 2 or 3 lines of treatment have few effective treatment options. MIF is dramatically upregulated in CRC tissue and its serum concentration positively correlates with increased tumor aggressiveness and risk of hepatic metastasis in CRC pts. MIF appears to contribute to cancer progression in tumor-associated anti-apoptosis, angiogenic growth factor expression, neovascularization and hypoxic adaptation. Imalumab is a novel recombinant, fully-human, monoclonal antibody specific for the pathogenic form of MIF (oxMIF). Imalumab showed preliminary antitumor activity with acceptable tolerability in a phase I study (NCT01765790) in patients with cancers, including mCRC. Imalumab has synergistic effects with chemotherapeutic agents in mCRC preclinical models independent of KRAS or p53 mutational status, leading us to evaluate imalumab-based combination regimens. Methods: We adopted a two-step approach for this trial. A safety run-in dose escalation phase will be conducted first with imalumab at 7.5mg/kg weekly in combination with 5-FU/LV or panitumumab in mCRC patients with or without KRAS/NRAS mutation, respectively. In the absence of dose limiting toxicities (DLTs), imalumab will be escalated to 10mg/kg weekly to evaluate DLT (primary endpoint) and determine the recommended phase II dose of imalumab combined with 5-FU/LV or panitumumab. Then, a randomized (2:1) phase II portion will investigate whether imalumab plus 5-FU/LV (KRAS/NRAS mut) or panitumumab (KRAS/NRAS wild type) is superior to standard of care at the 3rd or 4th line treatment setting in prolonging progression-free survival (primary endpoint) in mCRC patients. Secondary endpoints include safety and tolerability, overall survival and response rate, the pharmacokinetic (PK) profile of imalumab in combination with 5 FU/LV or panitumumab, quality of life, and biomarker association with treatment response. An accrual of 12-24 pts for the safety run-in phase and 66 pts for the randomized phase is planned. Eligibility includes diagnosis of mCRC and failure of 2-3 lines of therapies. Clinical trial information: pending.
Distal or proximal venous port device insertion: Results of a prospective randomized trial
Authors: P. Marcy, E. Chamorey, J. Macchiavello, R. Largillier, F. Peyrade, J. Ferrero, J. Hanoun-Levi, M. Poudenx, E. François, M. Frenay
Journal: Journal of Clinical Oncology (2009)

e20605 Background: Open, nonblinded, prospective, randomized, controlled trial comparing two techniques of venous port device insertion: percutaneous distal (phlebography-guided arm port- study technique- 2) vs proximal surgical (cephalic vein cutdown- control technique- 1) placement -To determine whether technique 1 is superior to technique 2. Methods: 230 eligible patients beginning a course of i.v. chemotherapy via a port device catheter with an expected duration of treatment of 3 months or longer were randomized (written informed consent). Eligibility criteria included adult patients with solid tissue malignancy (neuro oncology, gynecology, lung, abdominal, head§neck) beginning a course of I.V.chemotherapy, normal hemostatic parameters, no organ failure, a life expectancy &gt;3months, WHO status&lt;3. Exclusion criteria included current anticoagulant therapy, previous ipsilateral venous catheter/pacewires/surgical axillary node dissection/radiodermatitis, local tumor growth/sepsis, symptomatic brain metastasis, psychosis. The silicone rubber 7F catheter was connected to a 11mm port reservoir, and implanted under local anesthesia using either technique 1 or 2 after randomization. Outcome measurements included technical feasibility/procedure duration, port complications, quality of life (EORTC) questionnaires. Results: Median study duration was 12.2 vs 11.9 months (p: 0.9), median chemotherapy cycles were 6.0 in both groups. Patients groups differed significantly in venous access side (left access in group 2) and sex ratio (p=0.028). In group 2, technical success rate was higher (99 vs 91%, p&lt;0.02), procedure was shorter: 18.0min (10.0–90.0) vs 21min (15.0- 45.0)(p&lt;0.008), but global complication rate was higher (p&lt;0.05). Device complication related explantation rate was 11.9 vs 2.8% (p=0.022). Conclusions: Both techniques are safe and effective. Despite a higher technical success rate and a shorter procedure duration, arm port insertion has a lower complication-free duration. Distal (arm port) technique should be recommended in young female cancer patients (neckline cosmesis/discretion), head and neck cancer patients, obese patients (upright position) and in patients presenting with respiratory insufficiency or at high risk for pneumothorax. No significant financial relationships to disclose.