tbuckley/cabot-search huggingface dataset:
Multitargeted Antifolate LY231514 as First-Line Chemotherapy for Patients With Advanced Non–Small-Cell Lung Cancer: A Phase II Study
Authors: James J. Rusthoven, Elizabeth Eisenhauer, Charles Butts, Richard Gregg, Janet Dancey, Bryn Fisher, Jose Iglesias
Journal: Journal of Clinical Oncology (1999)

To evaluate the efficacy and safety of the multitargeted antifolate LY231514 (MTA) in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC).Patients with measurable, advanced NSCLC who had not received previous chemotherapy for advanced disease were considered for this study. Eligible patients who gave written informed consent initially received MTA 600 mg/m(2) intravenously (IV) for 10 minutes every 3 weeks. After three patients received treatment at this dose, the dose was reduced to 500 mg/m(2) IV at the same infusion time and frequency because of toxicity seen in this study and another Canadian MTA trial in colorectal cancer. Patients received up to four cycles after complete or partial remission or six cycles after stable disease was documented.Thirty-three patients were accrued onto the study. All were assessable for toxicity, and 30 patients were assessable for response. All but one patient had an Eastern Cooperative Oncology Group performance status score of 0 or 1, 18 patients (55%) had adenocarcinoma, and nine patients (27%) had squamous cell carcinoma. Twenty-five patients (76%) had stage IV disease, and the remainder had stage IIIB disease at trial entry. Seven patients experienced a confirmed partial response and no complete responses were seen; thus, the overall response rate was 23.3% (95% confidence interval, 9.9% to 42.3%). The median duration of response was 3.1 months (range, 2. 3 to 13.5 months) after a median follow-up period of 7.9 months. Four (67%) of six patients with stage IIIB disease and three (12.5%) of 24 with stage IV disease responded to treatment. Four patients (13.3%) experienced febrile neutropenia and 13 (39%) experienced grade 3 or 4 neutropenia, whereas only one patient (3%) developed grade 4 thrombocytopenia. Nonhematologic toxicity was generally mild or moderate, but 39% of patients developed a grade 3 skin rash. Most other toxicities comprised grade 1 or 2 stomatitis, diarrhea, lethargy, and anorexia. Ten patients stopped protocol therapy because of toxicity.MTA seems to have clinically meaningful activity as a single agent against advanced NSCLC. Toxicity is generally mild and tolerable. Further study of this agent in combination with cisplatin and other active drugs is warranted in this disease.
New Strategies in Sarcoma Therapy: Linking Biology and Novel Agents
Authors: Katherine A. Janeway, Robert G. Maki
Journal: Clinical Cancer Research (2012)

Abstract The ability to better interrogate the genetic state of a given cancer is giving rise to a new paradigm in cancer therapeutics in which the specific genetic alterations that give rise to the cancer inform the therapeutic decision-making for that specific patient. Sarcomas of soft tissue and bone represent model diseases that underscore this paradigm. However, many barriers prevent linkage of one of the 75 or more different types of sarcoma to novel therapeutic agents. In the present perspective, the authors outline key therapeutic opportunities and hurdles in clinical sarcoma research, focusing on specific examples of sarcomas that are on the verge of new breakthroughs, as well as those in which promise has not lived up to expectations. Focused clinical trial design, ideally with several biomarker or histology-specific arms, is one means to be simultaneously parsimonious and inclusive. Clin Cancer Res; 18(21); 5837–44. ©2012 AACR.
Fat fights inflammation
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

CD103 spurs on suppressorsAn integrin expressed by gut dendritic cells (DCs) gives regulatory T (T reg) cells the green light for suppression, according to a study on page 1051.Annacker and colleagues show that DCs expressing the integrin CD103 are required for T reg cells to subdue gutattacking effector T cells in a mouse model of inflammatory bowel disease (IBD).Naturally occurring T reg cells help protect against autoimmunity and exces- IBD in mice (right) is suppressed by T reg cells only if dendritic cells express CD103.which is released from vagus nerve endings upon stimulation.Acetylcholine binds to nicotinic receptors on macrophages, thus inhibiting the synthesis and release of inflammatory cytokines such as TNF and interleukin (IL)-6.Luyer et al. now show that the antiinflammatory effect of fat consumption in the rat model of hemorrhagic shock requires both CCK and the vagus nerve, as blocking CCK or severing the vagus nerve abolished this effect.With the vagus nerve intact, fatinduced CCK inhibited the production of circulating TNF and IL-6 and reduced gut permeability.Blocking nicotinic receptors also eliminated the antiinflammatory effects of dietary fat, thus solidifying the connection between fat-induced CCK and the cholinergic antiinflammatory pathway.The authors think that this pathway might be important in suppressing gut inflammation in response to food proteins and normal gut bacteria, which immune cells might otherwise regard as foreign invaders.They also suggest that this pathway could potentially be targeted in patients as a way to reduce inflammatory complications after surgery. Fat fights inflammationDietary fat triggers the cholinergic antiinflammatory pathway via the vagus nerve.
Buffering Hypercapnic Acidosis Worsens Acute Lung Injury
Authors: JOHN G. LAFFEY, DOREEN ENGELBERTS, BRIAN P. KAVANAGH
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Hypoventilation, associated with hypercapnic acidosis (HCA), may improve outcome in acute lung injury (ALI). We have recently reported that HCA per se protects against ALI. The current study explored whether the mechanisms of protection with HCA were related to acidosis versus hypercapnia. Because CO2 equilibrates rapidly across cell membranes, we hypothesized that (1) HCA would afford greater protection than metabolic acidosis. We further hypothesized that (2) buffering HCA would attenuate its protection. Forty isolated perfused rabbit lung preparations were randomized to: control (normal pH, Pco 2); HCA; metabolic acidosis; or buffered hypercapnia. After ischemia-reperfusion (IR) injury wet:dry ratio was greatest with control and buffered hypercapnia, and rank order of capillary filtration coefficient was: control ≈ buffered hypercapnia > metabolic acidosis > HCA. Isogravimetric pressure reduction was greatest with buffered hypercapnia. Despite comparable injury, pulmonary artery pressure elevation was less with buffered hypercapnia versus control. In vitro xanthine oxidase (XO) activity depended on pH, not Pco 2. We conclude that: (1) HCA and metabolic acidosis are protective, but HCA is the most protective; (2) buffering HCA attenuates its protection; (3) buffering HCA causes pulmonary vasodilation; (4) because metabolic acidosis and HCA similarly inhibit in vitro XO activity, the differential effects cannot be explained solely on the basis of extracellular XO activity. Laffey JG, Engelberts D, Kavanagh BP. Buffering hypercapnic acidosis worsens acute lung injury.
Functional foods: health boon or quackery?
Authors: M. F Jacobson, B. Silverglade
Journal: BMJ (1999)

The dividing line between foods and drugs is becoming increasingly blurred In the United States a canned split pea soup features the herb St John's Wort to “give your mood a natural lift,” and a chewing gum with phosphatidyl serine claims it “improves concentration.” In Japan a soft drink named VegitaBeta is fortified with β carotene “to support a healthy lifestyle.” And in the United Kingdom, MD Foods claimed that its butter-like spread made with fish oil would benefit the heart. What is our food supply turning into?

The driving forces behind foods that claim drug-like effects are evidence suggesting beneficial effects of phytochemicals and other substances and the public's great interest in alternative health remedies. Those factors, coupled with weak government regulation, attract marketers who see big profits in “functional foods.”

In some cases adding substances to foods offers real …
Autoimmune Thrombocytopenia and Primary Biliary Cirrhosis with Hypoglycemia and Insulin Receptor Autoantibodies
Authors: SHARON SELINGER
Journal: Annals of Internal Medicine (1987)

A 43-year-old woman with spontaneous episodes of neuroglycopenic hypoglycemia was found to have immune-mediated thrombocytopenic purpura and primary biliary cirrhosis. Hypoglycemia along with hyperinsulinemia suggested insulinoma. Serum c-peptide levels were disproportionately low, raising the possibility of factitious hypoglycemia. The patient's plasma contained circulating insulin receptor autoantibodies, thought to cause hypoglycemia by their insulin-like actions. With prednisone therapy, her other autoimmune features improved, and the hypoglycemia eventually resolved. Hypoglycemia mediated by insulin receptor autoantibodies should be considered in patients with fasting hypoglycemia and features suggesting an underlying autoimmune disorder before pursuing more invasive procedures. High-dose steroids may be lifesaving in this disorder.
Radial endobronchial ultrasound images for ground-glass opacity pulmonary lesions
Authors: Takehiro Izumo, Shinji Sasada, Christine Chavez, Yuji Matsumoto, Takaaki Tsuchida
Journal: European Respiratory Journal (2015)

Radial endobronchial ultrasound (R-EBUS) is a useful tool for precise localisation of peripheral pulmonary lesions, but there have been no detailed reports about the use of R-EBUS images for ground-glass opacity (GGO). The R-EBUS images of 116 patients with GGO, who were diagnosed as having adenocarcinoma by R-EBUS with a guide sheath (EBUS-GS), were compared with the respective chest computed tomography findings. In 103 patients, R-EBUS images were correlated with the histological surgical specimens. R-EBUS images of GGO were identified based on the internal structure of the lesion and classified into two groups. Blizzard showed an enlarged, diffuse hyperintense acoustic shadow. Mixed blizzard showed a combination of blizzard and some diffuse heterogeneity with several hyperechoic dots and vessels. All pure GGO lesions (nine out of nine) were blizzard on R-EBUS. For part-solid GGOs, the percentage of mixed blizzard was inversely related to the amount of the GGO component. Histological findings from surgery revealed that all blizzard lesions were on the spectrum of adenocarcinoma in situ to well differentiated adenocarcinoma while majority (33 out of 64) of mixed blizzard lesions were moderately to poorly differentiated adenocarcinoma. R-EBUS types are important to locate GGOs prior to transbronchial sampling with EBUS-GS.
Dose-response and pharmacokinetic study with almitrine bismesylate after single oral administrations in COPD patients
Authors: T Bury, J P Jeannot, J C Ansquer, M Radermecker
Journal: European Respiratory Journal (1989)

To better define the dose-effect relationship and the pharmacokinetics of almitrine, sixteen stable hypoxaemic COPD patients received random single oral administrations of almitrine bismesylate 50, 100 and 150 mg or placebo at two-week intervals in a double-blind manner. Resting ventilation, arterial blood gases and plasma almitrine levels were measured. No significant changes were seen after placebo administration. Almitrine 50 and 100 mg caused a significant dose-related improvement in arterial oxygen tension (PaO2) in thirteen of the sixteen patients. Almitrine 150 mg caused little if any additional PaO2 increment. PaO2 returned to near basal values after 24 h. Two patients responded to almitrine 100 and 150 mg only, whereas one patient did not respond at all. Mean PaO2 increases in the sixteen patients were 0.9 kPa (7 mmHg), 1.5 kPa (11 mmHg) and 1.6 kPa (12 mmHg) 3 h after 50, 100 and 150 mg, respectively. A significant mean 0.9 kPa (7 mmHg) decrease in arterial carbon dioxide tension (PaCO2) and a l.min-1 increase in ventilation were observed after almitrine 150 mg. Mean maximum almitrine plasma concentration and area under the curve correlated linearly with dose. The relationship between mean PaO2 improvement and mean almitrine plasma level was curvilinear with a flattening of the curve over plasma levels of 150 ng.ml-1. Almitrine plasma half-life was found to be 116-140 h.
Results of Induction Chemotherapy in Children Older Than 1 Year With a Stage 4 Neuroblastoma Treated With the NB 97 French Society of Pediatric Oncology (SFOP) Protocol
Authors: Dominique Valteau-Couanet, Jean Michon, Andrée Boneu, Chantal Rodary, Yves Perel, Christophe Bergeron, Hervé Rubie, Carole Coze, Dominique Plantaz, Frédéric Bernard, Pascal Chastagner, Jeannine Bouzy, Olivier Hartmann
Journal: Journal of Clinical Oncology (2005)

Purpose To test the metastatic response rate in stage 4 neuroblastoma, using dose-intensive induction chemotherapy in a multi-institutional setting. Patients and Methods From 1998 to 1999, 47 consecutive children were treated according to N7 protocol. Children received cyclophosphamide 140 mg/kg, doxorubicin 75 mg/m 2 , and vincristine 0.066 mg/kg (CAV) in cycles 1, 2, 4, and 6, and cisplatinum 200 mg/m 2 and etoposide 600 mg/m 2 (P/VP) in cycles 3, 5, and 7. The International Neuroblastoma Staging system was used with an emphasis on skeletal evaluation by 123-iodine-metaiodobenzylguanidine (MIBG) scintigraphy. A phase II study evaluating the metastasis complete response rate after induction chemotherapy was conducted in patients who had positive metastatic sites on MIBG scans at diagnosis. Results Forty-six patients were assessable for toxicity. Hematologic toxicity was the main toxicity observed. Neutropenia was more frequent after CAV than after P/VP (P &lt; .001). A higher rate of thrombocytopenia was observed after P/VP (P = .03). Forty patients with positive MIBG were assessable for metastatic response, and complete regression of metastases was achieved in 17 patients (ie, 43%; 95% CI, 27% to 59%). Of all 47 patients, 21 achieved complete metastatic response. Conclusion The N7 induction chemotherapy protocol was feasible in a multicentric setting. The observed metastasis complete response rate was similar to that obtained in our previous studies and significantly lower than that published in a previous series using the same regimen. In our hands, escalating doses of cyclophosphamide and prolonging conventional chemotherapy with the same drugs failed to improve the metastasis complete response rate.
Necrotizing pulmonary aspergillosis
Authors: W. P. U. Kennedy, D. N. Malone, W. Blyth
Journal: Thorax (1970)

Necrotizing or invasive aspergillary infection of the lungs has previously been considered a rare condition affecting only the debilitated or seriously ill. Four patients with necrotizing pulmonary aspergillosis are described, and the mycological and histopathological findings are discussed. The diagnosis in the first patient was not made until necropsy, following death from fulminating pulmonary infection. Of three patients treated with natamycin, two made a satisfactory recovery; the other died later from bronchial carcinoma. Previous multiple antibiotic therapy in each case may have been a contributory factor to infection with <i>Aspergillus fumigatus.</i> We suggest that fungal infection of the lungs should be actively sought in patients with pulmonary disease, especially in those receiving multiple antibiotic or corticosteroid therapy.
The role of thrombosis in severe pulmonary hypertension
Authors: A Chaouat, E Weitzenblum, T Higenbottam
Journal: European Respiratory Journal (1996)

Considering the important surface in pulmonary circulation where blood can interact with the endothelium, the maintenance of blood fluidity through the lung, by antithrombotic pathways and products of the endothelium, is essential. This function appears to be ineffective in primary pulmonary hypertension and in severe secondary pulmonary hypertension. Thrombotic lesions are frequently found in pulmonary arteries in these diseases. Thrombin activity appears to be increased in severe pulmonary hypertension. Antithrombotic pathway disorders may account for this abnormality, particularly in chronic thromboembolic pulmonary hypertension and primary pulmonary hypertension. Injured endothelium, a constant feature in severe pulmonary hypertension, either primary or secondary, enhances thrombus formation in pulmonary vessels. This is probably related to thrombomodulin and tissue factor imbalance, impairment of prostacyclin and nitric oxide release, as well as inefficiency of fibrinolysis. Moreover, platelets appear to be activated in the pulmonary circulation of these patients. They release several mediators acting on vascular tone and as mitogenic agents, and may also contribute to thrombin and clot generation. Long-term oral anticoagulant and continuous infusion of prostacyclin, treatments which impede thrombosis, are known to improve the survival rate in patients with primary pulmonary hypertension. These are the strongest arguments, so far, in favour of the role of thrombosis in severe pulmonary hypertension. However, we do not know whether these abnormalities result from a previous vascular injury or represent the primary disturbance.
Bronchial reactivity to methacholine after combined heart-lung transplantation.
Authors: N R Banner, R Heaton, L Hollingshead, A Guz, M H Yacoub
Journal: Thorax (1988)

The operation of combined heart-lung transplantation results in acute denervation of the heart, lungs, and airways below the level of the trachea. The bronchoconstrictor response to inhaled methacholine of 12 recipients of heart-lung transplants was compared with that of 12 recipients of heart transplants having similar medication and 12 normal subjects. The median dose of methacholine that produced a reduction of at least 20% in the FEV1 (PC20) for the recipients of heart-lung transplants (8 mg/ml) was significantly lower than that for the recipients of heart transplants (64 mg/ml) and normal subjects (greater than 64 mg/ml). The increased airway reactivity may be related to the effects of chronic pulmonary denervation or subclinical inflammation in the airways. The effect of denervation on the response to full inspiration during bronchoconstriction was studied in six patients with heart-lung transplants by means of partial and maximal forced expiratory manoeuvres. Four showed bronchodilation after a deep breath, indicating that this response can occur after extrinsic pulmonary denervation in man. The patients with heart-lung transplants described a "tight" sensation in the anterior chest during bronchoconstriction, indicating that this sensation is not dependent on pulmonary innervation.
Seizure control following radiotherapy in patients with diffuse gliomas: a retrospective study
Authors: R. Ruda, U. Magliola, L. Bertero, E. Trevisan, C. Bosa, C. Mantovani, U. Ricardi, A. Castiglione, C. Monagheddu, R. Soffietti
Journal: Neuro-Oncology (2013)

Little information is available regarding the effect of conventional radiotherapy on glioma-related seizures. In this retrospective study, we analyzed the seizure response and outcome following conventional radiotherapy in a cohort of 43 patients with glioma (33 grade II, 10 grade III) and medically intractable epilepsy. At 3 months after radiotherapy, seizure reduction was significant (≥50% reduction of frequency compared with baseline) in 31/43 patients (72%) of the whole series and in 25/33 patients (76%) with grade II gliomas, whereas at 12 months seizure reduction was significant in 26/34 (76%) and in 19/25 (76%) patients, respectively. Seizure reduction was observed more often among patients displaying an objective tumor response on MRI, but patients with no change on MRI also had a significant seizure reduction. Seizure freedom (Engel class I) was achieved at 12 months in 32% of all patients and in 38% of patients with grade II tumors. Timing of radiotherapy and duration of seizures prior to radiotherapy were significantly associated with seizure reduction. This study showed that a high proportion of patients with medically intractable epilepsy from diffuse gliomas derive a significant and durable benefit from radiotherapy in terms of epilepsy control and that this positive effect is not strictly associated with tumor shrinkage as shown on MRI. Radiotherapy at tumor progression seems as effective as early radiotherapy after surgery. Prospective studies must confirm and better characterize the response to radiotherapy.
Discriminant function analysis as decision support system for the diagnosis of acute leukemia with a minimal four color screening panel and multiparameter flow cytometry immunophenotyping
Authors: R Ratei, L Karawajew, F Lacombe, K Jagoda, G D Poeta, J Kraan, M De Santiago, J Kappelmayer, E Björklund, W-D Ludwig, J W Gratama, A Orfao
Journal: Leukemia (2007)
Anti-immunoglobulin-induced histamine secretion by rat peritoneal mast cells studied by immunoferritin electron microscopy.
Authors: D Lawson, C Fewtrell, B Gomperts, M Raff
Journal: The Journal of Experimental Medicine (1975)

We have used ferritin-conjugated divalent and monovalent anti-Ig antibodies to study simultaneously, histamine secretion and the ultrastructural distribution and redistribution of Ig receptors on rat peritoneal mast cells. We conclude that (a) divalent anti-Ig is required for both receptor redistribution and for calcium-dependent degranulation and histamine release, (b) divalent anti-Ig induces patching and pinocytosis but not capping of Ig molecules, (c) neither capping nor pinocytosis are required for triggering and if clustering is necessary, then less than 10 Ig molecules are required per cluster, and (d) degranulation (and histamine release) is not an all or none response of the mast cell.
Identification of Insulin-Like Growth Factor Binding Protein-3 as a Farnesyl Transferase Inhibitor SCH66336-Induced Negative Regulator of Angiogenesis in Head and Neck Squamous Cell Carcinoma
Authors: Seung-Hyun Oh, Woo-Young Kim, Jai-Hyun Kim, Maher N. Younes, Adel K. El-Naggar, Jeffrey N. Myers, Merril Kies, Pinchas Cohen, Fadlo Khuri, Waun K. Hong, Ho-Young Lee
Journal: Clinical Cancer Research (2006)

Abstract The farnesyl transferase inhibitor (FTI) SCH66336 has been shown to have antitumor activities in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. However, its mechanism of action has not been well defined. Here, we report that the insulin-like growth factor (IGF) binding protein (IGFBP)-3 mediates antitumor activities of SCH66336 in HNSCC by inhibiting angiogenesis. SCH66336 significantly suppressed HNSCC tumor growth and angiogenesis via mechanisms that are independent of H-Ras and RhoB. By inducing IGFBP-3 secretion from HNSCC cells, this compound suppresses angiogenic activities of endothelial cells, including vessel formation in chorioallantoic membranes of chick, endothelial cell sprouting from chick aorta, and capillary tube formation of human umbilical vascular endothelial cells (HUVEC). Knockdown of IGFBP-3 expression in HNSCC cells by RNA interference or depletion of IGFBP-3 in HUVECs by neutralizing antibody effectively blocked the effects of IGFBP-3 secreted from SCH66336-treated HNSCC cells on HUVECs. These findings suggest that IGFBP-3 could be a primary target for antitumor activities of FTIs and that IGFBP-3 is an effective therapeutic approach against angiogenesis in HNSCC.
Pemphigus, Bullous Impetigo, and the Staphylococcal Scalded-Skin Syndrome
Authors: John R. Stanley, Masayuki Amagai
Journal: New England Journal of Medicine (2006)

This review discusses the autoantibodies in pemphigus vulgaris and pemphigus foliaceus and the clinical and pathological similarities among these forms of pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome.