tbuckley/cabot-search huggingface dataset:
Waldenström macroglobulinemia: 2013 update on diagnosis, risk stratification, and management
Authors: Morie A. Gertz
Journal: American Journal of Hematology (2013)

Disease Overview Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy. Diagnosis The presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. Risk Stratification Age, hemoglobin level, platelet count, β2 microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. Risk-Adapted Therapy Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-based therapy is used in virtually all US patients with WM and can be combined with alkylating agent or purine nucleoside analog (or both). The preferred Mayo Clinic nonstudy therapeutic induction is rituximab, cyclophosphamide, and dexamethasone. Future stem cell transplantation should be considered in induction therapy selection. Management of Refractory Disease Bortezomib, thalidomide, everolimus, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials. Am. J. Hematol. 88:703–711, 2013. © 2013 Wiley Periodicals, Inc.
Protective effects of Dengzhanshengmai capsules on bleomycin-induced pulmonary fibrosis in mice
Authors: Yaxia Tan, Qiang Zeng, Hong Sun, Dan Xiao
Journal: European Respiratory Journal (2014)

Objective : To evaluate the effects of Dengzhanshengmai (DZSM) capsules, traditional chinese medicin, on bleomycin-induced murine lung fibrosis.

Methods: Female mice were divided into three groups averagely and randomly: saline, bleomycin and DZSM group. Pulmonary fibrosis models were generated by intratracheally instilled of bleomycin and then treated with saline and DZSM solution for 21 days respectively. The body weight was recorded every two days. After the last treatment, the lung resistance was tested using Buxco invasive lung mechanics machine. Lung tissues were collected after the mice were killed and observed following staining with H&E solution or Masson's solution to estimate the inflammatory level and fibrosis degree respectively. BALF were collected for inflammatory cytokines assay. Hydroxyproline levels were also detected to estimate fibrosis degree.

Results: The body weights was significantly decreased after giving bleomycin. DZSM solution (222 mg•kg-1•day-1) could retard the loss of body weights and improve the lung resistance significantly ( P < 0.05). The inflammatory cytokines such as TGF-β,TNF-α,IL-1β in BALF and the hydroxyproline level in lung tissue were also significantly down-regulated ( P < 0.05). Furthermore, the inflammatory state and fibrosis level were also relieved in pathological specimens.

Conclusions: DZSM capsules could improve the weakness in bleomycin-induced pulmonary fibrosis mouse models, lower the lung resistance, inhibit the inflammatory statement, decrease the hydroxyproline levels and inflammatory cytokines levels and relieve fibrosis.
Phenotypic Expression of Drug Resistance in Cell Cultures&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Morgan Harris
Journal: JNCI Journal of the National Cancer Institute (1967)

Clonal lines of pig kidney cells were used to analyze factors affecting the expression of puromycin resistance at the population level. Nominal mutation rates for the transition from sensitivity to resistance were estimated by two modifications of the Luria-Delbrück fluctuation test. Discrepancies in these data suggest that the incidence of spontaneous variation was obscured by nongenetic resistance which increased in proportion to population density. Large colonies or aggregates of sensitive cells grew progressively in puromycin at concentrations which destroyed the same populations completely when present in dispersed form. These findings indicate that response to puromycin is conditioned by cellular interactions as well as by genetic susceptibility. Under such conditions, the incidence of mutant cells cannot be determined by one-step selection with inhibitor media, as assumed by previous investigators. It follows that estimates of mutation rates based on drug resistance in somatic cells are of questionable validity, unless a clear distinction can be drawn between heritable alterations in resistance and refractory responses by sensitive cells in the system used.
Compound GW506U78 in refractory hematologic malignancies: relationship between cellular pharmacokinetics and clinical response.
Authors: V Gandhi, W Plunkett, C O Rodriguez, B J Nowak, M Du, M Ayres, D F Kisor, B S Mitchell, J Kurtzberg, M J Keating
Journal: Journal of Clinical Oncology (1998)

PURPOSE In vitro investigations with arabinosylguanine (ara-G) demonstrated potent cytotoxicity to T-lymphoblastoid cell lines. The goals of the present study were to evaluate GW506U78, a prodrug of ara-G, against human hematologic malignancies and to determine its pharmacokinetics in plasma and cells. PATIENTS AND METHODS During a phase I multicenter trial of GW506U78, 26 patients were treated at M.D. Anderson Cancer Center (MDACC). Daily doses between 20 and 60 mg/kg were administered for 5 days. Parallel plasma and cellular pharmacokinetic studies were conducted. RESULTS Complete (n=5) or partial remission (n=5) was achieved in T-cell acute lymphoblastic leukemia (T-ALL), T-lymphoid blast crisis, T-lymphoma, and B-cell chronic lymphocytic leukemia (B-CLL) (n=13). In contrast, patients with B-ALL, B-lymphoma, acute myelogenous leukemia (AMI), or T-CLL did not respond. Peak plasma concentrations of GW506U78 and ara-G were dose-dependent. The elimination of GW506U78 (half-life [t1/2]=17 minutes) was faster than the elimination of ara-G (t1/2=3.7 hours). Median peak concentrations of ara-GTP were 23, 42, 85, and 93 micromol/L at 20, 30, 40, and 60 mg/kg, respectively. T-lymphoblasts accumulated significantly (P=.0008) higher peak arabinsylguanosine triphosphate (ara-GTP) (median, 140 micromol/L; n=7) compared with other diagnoses (median, 50 micromol/L; n=9) and normal mononuclear cells (n=3). The ara-GTP elimination was slow in all diagnoses (median, &gt; 24 hours). Responders accumulated significantly (P=.0005) higher levels of ara-GTP (median, 157 micromol/L) compared with patients who failed to respond (median, 44 micromol/L). CONCLUSION GW506U78 is an effective prodrug and a potent agent for hematologic malignancies with major efficacy in T-cell diseases. The pharmacokinetics of ara-GTP in leukemia cells are strongly correlated with clinical responses to GW506U78.
Loss of Mitochondrial Pyruvate Carrier 2 in the Liver Leads to Defects in Gluconeogenesis and Compensation via Pyruvate-Alanine Cycling
Authors: Kyle S. McCommis, Zhouji Chen, Xiaorong Fu, William G. McDonald, Jerry R. Colca, Rolf F. Kletzien, Shawn C. Burgess, Brian N. Finck
Journal: Cell Metabolism (2015)
The subclinical atherosclerosis and its association to clinical features of stable COPD
Authors: Ozlem Salman Sever, Isik Conkbayir, Melike Yuce Ege, Serap Akcali, Hikmet Firat, Tugba Kaplan, Sadik Ardic
Journal: European Respiratory Journal (2011)

The link between COPD and atheroscleros (AS) has been speculated but such information at clinical features of COPD and its relation to AS is limited. To evaluate subclinic AS in patients with COPD 33 male COPD patients and 15 healthy male control subjects included the study. Subjects with exacerbation, DM, chronic renal failure, cardiac diseases excluded. All the subject underwent spirometry, blood sampling, carotid artery USG,24 hour oxygen saturation recording via a holteroxymeter. We determined carotid artery intima-media thickness (CAIMT) as indicator of subclinical AS.

Mean CAIMT was greater in COPD group (p=0.005)

View this table:

Table 1. Subject characteristics





View this table:

Table 2. Pearson's corralation of all subjects forCAIMT and other variables





Multivariate stepwise analysis showed significant associations between CAIMT and decreased % FEV1 (p=0.018) and between systolic BP (p=0.004) independent of age, BMI, duration of illness, diastolic BP, % FVC, CRP, T90%. Although the duration of COPD, T90% and CRP correlated with CAIMT, impaired lung function and severity of systolic blood pressure the predict CAIMT.
Proto-oncogene abnormalities in human breast cancer: correlations with anatomic features and clinical course of disease.
Authors: M J Cline, H Battifora, J Yokota
Journal: Journal of Clinical Oncology (1987)

DNAs from fifty-three primary breast cancers were hybridized with 16 different proto-oncogene or oncogene probes. Abnormalities of one or more of five proto-oncogenes were found in fifty-eight percent of tumors at the time of mastectomy. Amplification of c-myc and c-erbB-2, and allelic deletions of c-ras-Ha and c-myb were the most common abnormalities. The presence of altered proto-oncogenes correlated with clinical stage of the cancers. Fifteen of 43 evaluable tumors of stages I to III recurred, and four of five evaluable stage IV tumors progressed within 16 to 24 months of surgery. All but one of the cancers that recurred or progressed had detectably altered proto-oncogenes (P less than .001). Analysis of proto-oncogenes may have prognostic value in breast cancer.
Injurious Loading of Articular Cartilage Compromises Chondrocyte Respiratory Function
Authors: Mitchell C. Coleman, Prem S. Ramakrishnan, Marc J. Brouillette, James A. Martin
Journal: Arthritis & Rheumatology (2015)

Objective To determine whether repeatedly overloading healthy cartilage disrupts mitochondrial function in a manner similar to that associated with osteoarthritis (OA) pathogenesis. Methods We exposed normal articular cartilage on bovine osteochondral explants to 1 day or 7 consecutive days of cyclic axial compression (0.25 MPa or 1.0 MPa at 0.5 Hz for 3 hours) and evaluated the effects on chondrocyte viability, ATP concentration, reactive oxygen species (ROS) production, indicators of oxidative stress, respiration, and mitochondrial membrane potential. Results Neither 0.25 MPa nor 1.0 MPa of cyclic compression caused extensive chondrocyte death, macroscopic tissue damage, or overt changes in stress–strain behavior. After 1 day of loading, differences in respiratory activities between the 0.25 MPa and 1.0 MPa groups were minimal; however, after 7 days of loading, respiratory activity and ATP levels were suppressed in the 1.0 MPa group relative to the 0.25 MPa group, an effect prevented by pretreatment with 10 m M N ‐acetylcysteine. These changes were accompanied by increased proton leakage and decreased mitochondrial membrane potential, as well as by increased ROS formation, as indicated by dihydroethidium staining and glutathione oxidation. Conclusion Repeated overloading leads to chondrocyte oxidant‐dependent mitochondrial dysfunction. This mitochondrial dysfunction may contribute to destabilization of cartilage during various stages of OA in distinct ways by disrupting chondrocyte anabolic responses to mechanical stimuli.
Are All 5-HT3 Receptor Antagonists the Same?
Authors: Robert McNulty
Journal: Journal of the National Comprehensive Cancer Network (2007)

The 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists have become the cornerstone for preventing and treating chemotherapy-induced nausea and vomiting. Four 5-HT3 antagonists are commercially available in the United States, and numerous reports have been published comparing 2 or more agents. The studies ranged from randomized, double-blinded to open-label or retrospective trials; included chemotherapy-naïve and -non-naïve patients; and covered a range of doses and routes of administration with and without concomitant steroids, for preventing and treating nausea and vomiting after highly and moderately high emetogenic chemotherapy. With few exceptions, the studies uniformly show an equivalent efficacy rate and side effect profile among the various agents at equivalent doses. This article reviews the pharmacology of the class for insight into minor differences among the agents that could possibly influence drug selection for certain patients, and considers data on the absorption, half-life, metabolism, and receptor activity. Clinical trials support the claim of various guidelines that the 5-HT3 receptor antagonists are therapeutically similar in safety and efficacy, particularly because the current best practice for preventing nausea and vomiting after highly and moderately high emetogenic chemotherapy is a combination of a 5-HT3 antagonist, steroids, and aprepitant.
Biologic Markers as Predictors of Clinical Outcome From Systemic Therapy for Primary Operable Breast Cancer
Authors: J. Chang, T. J. Powles, D. C. Allred, S. E. Ashley, G. M. Clark, A. Makris, L. Assersohn, R. K. Gregory, C. K. Osborne, M. Dowsett
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To determine whether pretreatment clinical features and molecular markers, together with changes in these factors, can predict treatment response and survival in patients with primary operable breast cancer who receive neoadjuvant therapy. PATIENTS AND METHODS: Mitoxantrone, methotrexate (with or without mitomycin), and tamoxifen chemoendocrine therapy was administered to 158 patients before surgery. Clinical response was assessed after four cycles of treatment. Fine-needle aspiration cytology for estrogen receptor (ER), progesterone receptor (PgR), c-erbB-2, p53, bcl-2, Ki67, S-phase fraction (SPF), and ploidy were performed pretreatment and repeated on day 10 or day 21 after the first cycle of treatment. RESULTS: Good clinical response (GCR, defined as complete response or minimal residual disease) was achieved in 31% of patients (49 of 158). Tumor size, nodal disease, response, ER, PgR, c-erbB-2, p53, bcl-2, Ki67, SPF, and ploidy were analyzed as predictors of survival. By univariate analysis, node-positive disease (P = .05), lack of ER (P &lt; .05) and PgR (P &lt; .05), and failure to attain GCR (P = .008) were associated with a significantly increased risk of relapse. A significantly increased risk of death was associated with node-positive disease (P = .02), lack of ER expression (P = .04), and failure to attain GCR. By multivariate analysis, GCR was an independent predictor for survival (P = .05). ER expression (P = .03), absence of c-erbB-2 (P = .03), and a decrease in Ki67 on day 10 or day 21 of the first cycle (P &lt; .05) significantly predicted for subsequent GCR. CONCLUSION: Molecular markers may be used to predict the likelihood of achieving GCR, which seems to be a valid surrogate marker for survival.
The diagnostic accuracy of allergen-specific IgE and its relation to exhaled nitric oxide in children
Authors: Bjørg Evjenth, Tonje Elisabeth Hansen, Ole-Lars Brekke, Jan Holt
Journal: European Respiratory Journal (2014)

Background: Cut-off values for serum allergen-specific IgE (sIgE) using the Siemens IMMULITE®2000 system to diagnose allergic rhinoconjunctivitis have not been established in children. Likewise the relation between sgE, total IgE and fraction exhaled nitric oxide (FENO) has not been fully elucidated in a subarctic children population.

Aims: We aimed to determine cut-off levels of sIgE for ten common inhalant allergens and to study the relationship between sIgE, total IgE and FENO.

Methods: We enrolled 243 schoolchildren including 164 with allergic rhinoconjunctivitis. Parental interview, skin prick test, sIgE, total IgE, FENO measurements, spirometry and exercise treadmill tests were performed.

Results: Cut-off values with the best combined sensitivity and specificity were above the detection limit of the assay for seven of ten allergens (0.23-1.1 kU/L). The overall accuracy of IMMULITE® in detecting allergic rhinoconjunctivitis was good. sIgE was superior to total IgE and FENO in predicting allergic rhinoconjunctivitis to timothy, birch, mugwort, cat, dog and house dust mite. FENO was elevated in children with allergic rhinoconjunctivitis, irrespective of asthma. FENO was highest in children with current allergic asthma 29.7 (23.3-37.7) ppb.

Conclusions: Cut-off values for sIgE were dependent on the allergic phenotype and were above the IMMULITE® detection limit for seven of ten inhalant allergens. Consequently, using the detection limit for sIgE as the decision point would result in over-diagnosing allergic rhinoconjunctivitis. When measuring elevated FENO in children, allergic rhinoconjunctivitis should be suspected.

The manuscript has been submitted to ACTA Paediatrica.
Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis
Authors: Hiromi I. Wettersten, A. Ari Hakimi, Dexter Morin, Cristina Bianchi, Megan E. Johnstone, Dallas R. Donohoe, Josephine F. Trott, Omran Abu Aboud, Steven Stirdivant, Bruce Neri, Robert Wolfert, Benjamin Stewart, Roberto Perego, James J. Hsieh, Robert H. Weiss
Journal: Cancer Research (2015)

Kidney cancer [or renal cell carcinoma (RCC)] is known as "the internist's tumor" because it has protean systemic manifestations, suggesting that it utilizes complex, nonphysiologic metabolic pathways. Given the increasing incidence of this cancer and its lack of effective therapeutic targets, we undertook an extensive analysis of human RCC tissue employing combined grade-dependent proteomics and metabolomics analysis to determine how metabolic reprogramming occurring in this disease allows it to escape available therapeutic approaches. After validation experiments in RCC cell lines that were wild-type or mutant for the Von Hippel-Lindau tumor suppressor, in characterizing higher-grade tumors, we found that the Warburg effect is relatively more prominent at the expense of the tricarboxylic acid cycle and oxidative metabolism in general. Further, we found that the glutamine metabolism pathway acts to inhibit reactive oxygen species, as evidenced by an upregulated glutathione pathway, whereas the β-oxidation pathway is inhibited, leading to increased fatty acylcarnitines. In support of findings from previous urine metabolomics analyses, we also documented tryptophan catabolism associated with immune suppression, which was highly represented in RCC compared with other metabolic pathways. Together, our results offer a rationale to evaluate novel antimetabolic treatment strategies being developed in other disease settings as therapeutic strategies in RCC.
Molecular basis of hypotrichosis with juvenile macular dystrophy in two siblings
Authors: M. Indelman, R. Leibu, A. Jammal, R. Bergman, E. Sprecher
Journal: British Journal of Dermatology (2005)

Background Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive disorder characterized by sparse and short scalp hair from birth, followed within a few years by progressive macular degeneration leading to blindness. HJMD was shown to result from mutations in CDH3 encoding P-cadherin. Objectives In the present study, we attempted to identify the molecular basis of abnormal hair growth in two siblings of Arab Muslim origin with hypotrichosis but no visual symptoms. Methods Mutation analysis was performed using direct sequencing and polymerase chain reaction–restriction fragment length polymorphism analysis. Results Patients displayed sparse and short hair since birth. Significant macular degenerative pigmentary changes were noticed in the face of normal visual acuity. Despite the fact that a single CDH3 mutation had previously been described in several families of Israeli Arab Muslim origin, the two affected patients were found to be homozygous carriers of a novel nonsense mutation (Y615X) predicted to result in premature termination of P-cadherin translation. Conclusions The present results indicate that all patients with congenital hypotrichosis should undergo thorough fundus examination, which, when revealing pigmentary macular changes, can be considered as indicative of an underlying CDH3 causative mutation.
The prevalence of symptoms suggestive of COPD amongst patients attending an illicit drug misuse clinic
Authors: Andreas Tridimas, Thomas Archer, Sandra Olebaum, Hassan Burhan
Journal: European Respiratory Journal (2013)

Background:  Illicit drug use such as crack cocaine and heroin smoking contribute to a range of respiratory conditions. A significant proportion of drug users also smoke tobacco. For a wide range of social, psychological and economic reasons, respiratory conditions within this population may often go undiagnosed for many years.  Methods:  Drug users referred to an inner city drug treatment centre in Liverpool through the criminal justice have their medical and prescribed drug histories documented. Patients attending this clinic were asked to fill in an anonymous questionnaire to assess whether they had symptoms suggestive of COPD. Uptake was low and the questionnaire was eventually administered over several visits by staff at the centre and from the Royal Liverpool University Hospital.  Results  Questionnaires were completed by 62 patients (19 female, mean age 40). 44 (71%) of patients were current or ex smokers of tobacco (mean 23.5 pack year history) 40 (65%) were or had smoked marijuana, 54 (87%) crack, and 57 (92%) heroin. 43 (66%) reported dyspnoea and 34 (54%) reported a cough. The mean MRC Dyspnoea score was 2 on a 9good9 day and 3 on a 9bad9 day. 35 (56%) patients were or had been on inhaled treatment. 13 (21%) patients had been to a chest clinic and 19 (31%) patients had been admitted to hospital with respiratory problems in the past. Only 14 (23%) patients had been told they had COPD.  Conclusions  Respiratory symptoms suggestive of COPD are common in patients who are current or ex drug smokers attending an illicit drug treatment centre. Few patients have been diagnosed and this may reflect difficult access to healthcare for spirometric assessment when stable.
Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia
Authors: Evert de Jonge, Pascale E. P. Dekkers, Abla A. Creasey, C. Erik Hack, Susan K. Paulson, Aziz Karim, Jozef Kesecioglu, Marcel Levi, Sander J. H. van Deventer, Tom van der Poll
Journal: Blood (2000)