tbuckley/cabot-search huggingface dataset:
Iron restriction in sickle cell anemia: Time for controlled clinical studies
Authors: Oswaldo Castro, Gregory J. Kato
Journal: American Journal of Hematology (2015)

In 1973, Lincoln et al. 1 hypothesized that induction of iron deficiency, by lowering erythrocyte mean corpuscular hemoglobin concentration (MCHC), should also decrease Hb S polymerization and thereby improve the clinical course of sickle cell anemia. They wrote: "The net effect would be to replace an anaemia characterised by excessive red-cell destruction by a less detrimental microcytic hypochromic anaemia." The polymerization of HbS is very sensitive to its concentration in erythrocytes. Even small decrements in MCHC have a marked inhibitory effect on HbS polymerization, which is dependent on the 30th power of the deoxy-Hb S concentration 2. This principle is supported also by the natural occurrence of α-thalassemia in some patients with sickle cell anemia, which results in lower MCHC, less hemolysis, and less severe anemia 3. A paper just published by Das et al. now shows that in a sickle mouse model, iron restriction not only lowers hemolysis but also improves the anemia 4. During the four decades elapsed since the Lincoln et al. paper, a few case reports and case series suggested that naturally occurring or experimental iron restriction decreases pain events and/or lowers hemolysis in sickle cell disease patients 5-10. These observations, while interesting, were uncontrolled and did not lead to the implementation of clinical studies. It is probable that the theoretical benefit of iron restriction was insufficient to overcome a reluctance to add iron deficiency to the anemia of sickle cell patients. Furthermore, phlebotomies were used to induce iron restriction in these clinical reports, and phlebotomies seem counterintuitive in anemic patients. We believe, however, that the recently demonstrated reduction of hemolysis and improvement of anemia in iron-restricted sickle mice not only represent "proof of principle" for iron restriction as sickle cell disease therapy, but have also lowered the risk/benefit ratio of this intervention as experimental treatment. Hence we also believe it is time for carefully controlled clinical studies to determine whether iron restriction can become a new therapeutic option for sickle cell patients. Questions that could be initially addressed include: (a) the safety of regular phlebotomies in sickle patients, (b) whether hepcidin administration or iron chelation could eliminate or decrease the need for phlebotomies to lower MCHC and hemolytic rate, (c) whether iron restriction effects are additive in sickle patients also being treated with hydroxyurea, and (d) whether iron restriction is beneficial in leg ulcers and SC retinopathy, complications not typically treated with hydroxyurea. Oswaldo Castro1* Gregory J. Kato2 1Department of Medicine, Center for Sickle Cell Disease, Howard University College of Medicine, Washington, DC, 2Division of Hematology-Oncology, Department of Medicine, Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
Looking to the Future From the Past: Take Home Lessons From Japanese World War II Medical Atrocities
Authors: Rael D. Strous, Ari Z. Zivotofsky
Journal: The American Journal of Bioethics (2015)

The injustices and atrocities of Nazi medicine were of catastrophic proportions. It is now well known that Nazi physicians during the Nazi era not only participated willingly in many of the inhuman...
Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia.
Authors: A Osterborg, M J Dyer, D Bunjes, G A Pangalis, Y Bastion, D Catovsky, H Mellstedt
Journal: Journal of Clinical Oncology (1997)

PURPOSE CAMPATH-1H is a human immunoglobulin G1 (IgG1) anti-CD52 monoclonal antibody (MAb) that binds to nearly all B- and T-cell lymphomas and leukemias. We report the results of a multicenter phase II trial that used CAMPATH-1H in previously chemotherapy-treated patients with chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS Twenty-nine patients who had relapsed after an initial response (n = 8) or were refractory (n = 21) to chemotherapy were treated with CAMPATH-1H administered as a 30-mg 2-hour intravenous (IV) infusion thrice weekly for a maximum period of 12 weeks. RESULTS Eleven patients (38%) achieved a partial remission (PR) and one (4%) a complete remission (CR) (response rate, 42%; 95% confidence interval [CI], 23% to 61%). Three of eight patients (38%) with a relapse and nine of 21 refractory patients (43%) responded to CAMPATH-1H therapy. CLL cells were rapidly eliminated from blood in 28 of 29 patients (97%). CR in the bone marrow was obtained in 36% and splenomegaly resolved completely in 32%. Lymphadenopathy was normalized in only two patients (7%). The median response duration was 12 months (range, 6 to 25+). World Health Organization (WHO) grade IV neutropenia and thrombocytopenia developed in three (10%) and two patients (7%), respectively. Neutropenia and thrombocytopenia recovered in most responding patients during continued CAMPATH-1H treatment. Lymphopenia (&lt; 0.5 x 10(9)/L) occurred in all patients. Two patients had opportunistic infections and four had bacterial septicemia. CONCLUSION CAMPATH-1H had significant activity in patients with advanced and chemotherapy-resistant CLL. The most pronounced effects were noted in blood, bone marrow, and spleen. Preferential clearance of blood may allow harvesting of uncontaminated blood stem cells for use in high-dose chemotherapy protocols.
Diffuse female hair loss: are androgens necessary?
Authors: None Orme, None Cullen, None Messenger
Journal: British Journal of Dermatology (1999)

Diffuse hair loss in women is generally regarded as the female equivalent of male balding and is often referred to as female androgenetic alopecia. In this article we report the case of a young woman with hypopituitarism who presented with the clinical and histological features of female androgenetic alopecia in the absence of detectable levels of circulating androgens or other signs of postpubertal androgenization, showing that this pattern of hair loss is not necessarily androgen dependent.
The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl‐DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis
Authors: Andreas Keil, Manuela Frese‐Schaper, Selina K. Steiner, Meike Körner, Ralph A. Schmid, Steffen Frese
Journal: Arthritis & Rheumatology (2015)

The treatment of lupus nephritis is still an unmet medical need requiring new therapeutic approaches. Our group found recently that irinotecan, an inhibitor of topoisomerase I (topo I), reversed proteinuria and prolonged survival in mice with advanced lupus nephritis. While irinotecan is known to stabilize the complex of topo I and DNA, the enzyme tyrosyl-DNA phosphodiesterase 1 (TDP-1) functions in an opposing manner by releasing topo I from DNA. Therefore, we undertook this study to test whether the TDP-1 inhibitor furamidine has an additional effect on lupus nephritis when used in combination with irinotecan. NZB/NZW mice were treated with low-dose irinotecan and furamidine either alone or in combination beginning at age 26 weeks. DNA relaxation was visualized using gel electrophoresis. Binding of anti-double-stranded DNA (anti-dsDNA) antibodies to DNA modified by topo I, TDP-1, and the topo I inhibitor camptothecin was determined by enzyme-linked immunosorbent assay. Compared to treatment with either agent alone, simultaneous treatment with low-dose irinotecan and furamidine significantly improved survival of NZB/NZW mice. Similar to what has been previously shown for irinotecan alone, the combination treatment did not change the levels of anti-dsDNA antibodies. In vitro, recombinant TDP-1 increased topo I-mediated DNA relaxation, resulting in enhanced binding of anti-dsDNA antibodies. In combination with topo I and camptothecin, TDP-1 reversed the inhibitory effects of camptothecin on DNA relaxation and anti-dsDNA binding. Affecting DNA relaxation by the enzymes topo I and TDP-1 and their inhibitors may be a promising approach for the development of new targeted therapies for systemic lupus erythematosus.
Down-regulation of BRCA1-BARD1 Ubiquitin Ligase by CDK2
Authors: Ryosuke Hayami, Ko Sato, Wenwen Wu, Toru Nishikawa, Junya Hiroi, Ritsuko Ohtani-Kaneko, Mamoru Fukuda, Tomohiko Ohta
Journal: Cancer Research (2005)

Abstract BRCA1, a breast and ovarian tumor suppressor, is a phosphoprotein whose cellular expression level is regulated in a cell cycle–dependent manner. BRCA1 interacts with BARD1 to generate significant ubiquitin ligase activity which catalyzes nontraditional Lys-6-linked polyubiquitin chains. However, it is not clear how the activity is regulated and how this affects BRCA1's multiple cellular functions. Here we show that the ubiquitin ligase activity of BRCA1-BARD1 is down-regulated by CDK2. During the cell cycle, BARD1 expression can largely be categorized into three patterns: moderately expressed in a predominantly unphosphorylated form in early G1 phase, expressed at low levels in both phosphorylated and unphosphorylated forms during late G1 and S phases, and highly expressed in its phosphorylated form during mitosis coinciding with BRCA1 expression. CDK2-cyclin A1/E1 and CDK1-cyclin B1 phosphorylate BARD1 on its NH2 terminus in vivo and in vitro. Intriguingly, the BRCA1-BARD1–mediated in vivo ubiquitination of nucleophosmin/B23 (NPM) and autoubiquitination of BRCA1 are dramatically disrupted by coexpression of CDK2-cyclin A1/E1, but not by CDK1-cyclin B1. The inhibition of ubiquitin ligase activity is not due to the direct effect of the kinases on BARD1 because an unphosphorylatable mutant of BARD1, S148A/S251A/S288A/T299A, is still inhibited by CDK2-cyclin E1. Alternatively, BRCA1 and BARD1 are likely exported to the cytoplasm and their expressions are remarkably reduced by CDK2-cyclin E1 coexpression. Recognizing the importance of cyclin E1 overexpression in breast cancer development, these results suggest a CDK2-BRCA1-NPM pathway that coordinately functions in cell growth and tumor progression pathways.
Serum antibodies against Panton–Valentine leukocidin in a normal population and during Staphylococcus aureus infection
Authors: M. Croze, O. Dauwalder, O. Dumitrescu, C. Badiou, Y. Gillet, A.-L. Genestier, F. Vandenesch, J. Etienne, G. Lina
Journal: Clinical Microbiology and Infection (2009)
Abstract 16390: Long-Term Clinical Outcomes in NYHA I-II Patients After Cardiac Resynchronization Therapy: Sub-Group Analysis From CUBIC Registry
Authors: Kenji Ando, Satoshi Shizuta, Satoki Fujii, Kouichi Inoue, Natsuhiko Ehara, Takeshi Arita, Kazuaki Kaitani, Takeshi Kimura, Takaaki Isshiki, Masakiyo Nobuyoshi, Cubic Investigators
Journal: Circulation (2011)

Background: Long term clinical outcomes of mild heart failure patients (pts) after cardiac resynchronization therapy (CRT) is not well known. Methods: We investigated 651 pts from CUBIC study which...
Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.
Authors: S M Swain, F S Whaley, M C Gerber, S Weisberg, M York, D Spicer, S E Jones, S Wadler, A Desai, C Vogel, J Speyer, A Mittelman, S Reddy, K Pendergrass, E Velez-Garcia, M S Ewer, J R Bianchine, R A Gams
Journal: Journal of Clinical Oncology (1997)

PURPOSE To determine the cardioprotective effect of dexrazoxane (DZR) used in a doxorubicin-based combination therapy in advanced breast cancer. PATIENTS AND METHODS Between November 1988 and January 1991, 534 patients with advanced breast cancer were randomized to two multicenter, double-blind studies (088001 and 088006). Patients received fluorouracil, doxorubicin, and cyclophosphamide (FAC) with either DZR (DZR-to-doxorubicin ratio, 10:1) or placebo (PLA) every 3 weeks and were monitored with serial multiplegated acquisition (MUGA) scans. RESULTS The hazards ratio (HR) of PLA to DZR for a cardiac event, which was predefined ejection fraction changes or congestive heart failure (CHF), was 2.63 (95% confidence interval [CI], 1.61 to 4.27; P &lt; .001) for 088001 and 2.00 (95% CI, 1.01 to 3.96; P = .038) for 088006. The objective response rates for 088001 were 46.8% for DZR and 60.5% for PLA, a difference of 14% (95% CI, -25% to -2%; P = .019), and for 088006 were 53.7% for DZR and 49.3% for PLA, a difference of 4% (95% CI, -13% to 22%; P = .63). Time to progression and survival were not significantly different between treatment arms in either study. Toxicities on the DZR arms included lower granulocyte and platelet counts at nadir (P = .009 and P = .004, respectively) and more pain on injection (P = .001), with no difference in the rates of fever, infection, or hemorrhage. CONCLUSION DZR had a significant cardioprotective effect as measured by noninvasive testing and clinical CHF. One of the two studies (088001) showed a lower response rate with DZR, but time to progression and survival were not significantly different. DZR is the first agent shown to reduce cardiotoxicity from doxorubicin.
Toxicity assessment of spark-generated, airborne copper oxide nanoparticles in lung epithelial cells
Authors: Peter Thorne, Xuefang Jing, Jae Hong Park, Andrea Adamcakova-Dodd, Thomas Peters, Sarah Perry
Journal: European Respiratory Journal (2014)

Background: Copper oxide nanoparticles (CuONPs) are of great interest in nanotoxicology due to widespread use and significant toxicity.The aim of this study was to evaluate and compare the toxicity of CuONPs in human primary cells and in a commonly-employed cancer cell line. We investigated the consequences of CuONPs exposure using an in vitro air-liquid interface system.

Methods: Human Bronchial Epithelial Cells (HBEC) and A549 cells were exposed to clean air or spark-generated CuONPs for 2 or 4 h. Cellular doses of Cu were assessed by inductively coupled plasma mass spectrometry. Outcome measures included cell viability, cytotoxicity (lactate dehydrogenase [LDH]), oxidative stress (reactive oxygen species [ROS]) and inflammation (interleukin [IL]-8).

Results: The number median diameterand concentration of CuONPswere 9.2 nm and 3.5×107 particles/cm3. Compared with control, CuONPs significantly reduced cell viability, increased LDH release and elevated levels of ROS and IL-8 in a dose dependent manner. 4 hr exposure to CuONPs resulted in 63% loss of viability, 1.9-fold increase of ROS and 290% LDH release over controls in A549 cells; whereas HBEC had 15% viability loss, 2.7-fold ROS increase and 165% LDH release (all p<0.001 compared with A549); IL-8 was comparable in two cell types. N -acetylcysteine reduced the cell viability loss from 63% to 16% (p<0.001) and decreased ROS level from 190% to 132% (p<0.001).

Conclusion: Spark-generated CuONPs exposure induced cytotoxicity, oxidative stress and inflammation in both cell types in a dose dependent manner. A549 cells were more susceptible to CuONPs effects than primary HBEC. Antioxidant treatment reduced CuONPs-induced cytotoxicity.
The Population Impact of Severe Mental Illness on Violent Crime
Authors: Seena Fazel, Martin Grann
Journal: American Journal of Psychiatry (2006)

Objective: This study aimed to determine the population impact of patients with severe mental illness on violent crime. Method: Sweden possesses high-quality national registers for all hospital admissions and criminal convictions. All individuals discharged from the hospital with ICD diagnoses of schizophrenia and other psychoses (N=98,082) were linked to the crime register to determine the population-attributable risk of patients with severe mental illness to violent crime. The attributable risk was calculated by gender, three age bands (15–24, 25–39, and 40 years and over), and offense type. Results: Over a 13-year period, there were 45 violent crimes committed per 1,000 inhabitants. Of these, 2.4 were attributable to patients with severe mental illness. This corresponds to a population-attributable risk fraction of 5.2%. This attributable risk fraction was higher in women than men across all age bands. In women ages 25–39, it was 14.0%, and in women over 40, it was 19.0%. The attributable risk fractions were lowest in those ages 15–24 (2.3% for male patients and 2.9% for female patients). Conclusions: The population impact of patients with severe mental illness on violent crime, estimated by calculating the population-attributable risk, varies by gender and age. Overall, the population-attributable risk fraction of patients was 5%, suggesting that patients with severe mental illness commit one in 20 violent crimes.
Carcinogenicity of Tannin and Tannin-Free Extracts of Bracken Fern (&lt;italic&gt;Pteridium aquilinum&lt;/italic&gt;) in Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN4"&gt;4&lt;/xref&gt;
Authors: A M Pamukcu, C Y Wang, J Hatcher, G T Bryan
Journal: JNCI Journal of the National Cancer Institute (1980)

F344 inbred and Sprague-Dawley noninbred rats were fed a basic diet (groups 1 and 7) or a basic diet supplemented with 0.1% (later, 0.2 and 0.4%) tannin (group 2) isolated from bracken fern (Pteridium aquilinum) (BF), 33% BF (groups 3 and 6), 2% chloroform fraction of BF (group 4), or 4% tannin-free fraction of BF (group 5). The following incidences of intestinal or bladder tumors were observed: group 1, intestinal and bladder, 0/16; group 2, 0/21; group 7, 0/16; groups 4 and 5, intestinal, 7/15, bladder, 0/15; group 3, intestinal, 19/20, bladder, 12/20; and group 6, intestinal, 22/30, bladder, 15/30. The chloroform-methanol fraction prepared from urine of rats fed BF, chloroform fraction of BF, or tannin-free fraction of BF demonstrated mutagenicity for Salmonella typhimurium TA 100 but not for TA 98. No mutagenicity was detected in other prepared fractions. F344 rats in group 8 received weekly sc injections of tannin solution (0.1 g/kg body wt) for 38 weeks, and 16/20 developed palpable tumors that were malignant fibrous histiocytomas at the injection site. No tumor was present in any rat of control group 9.
Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial
Authors: Alistair Nichol, Craig French, Lorraine Little, Samir Haddad, Jeffrey Presneill, Yaseen Arabi, Michael Bailey, D James Cooper, Jacques Duranteau, Olivier Huet, Anne Mak, Colin McArthur, Ville Pettilä, Markus Skrifvars, Shirley Vallance, Dinesh Varma, Judy Wills, Rinaldo Bellomo
Journal: The Lancet (2015)
Aerosol Delivery and Modern Mechanical Ventilation
Authors: Dorisanne D. Miller, Mohammad M. Amin, Lucy B. Palmer, Akbar R. Shah, Gerald C. Smaldone
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Aerosol delivery via a mechanical ventilator remains unregulated with no standards for drug delivery to intubated patients. Bench models predicting drug delivery have not been validated in vivo. For modern ventilator designs, we chose to identify, on the bench, the most important variables affecting aerosol delivery and to correlate in vitro predictions of aerosol delivery with in vivo end points independent of patient response. Test aerosols of albuterol and antibiotics were compared. Bench measurements of inhaled mass (percentage of nebulizer charge, mean +/- SEM) ranged from 5.7 +/- 0.5% to 37.4 +/- 1.6%, with breath-actuated nebulization and humidity identified as the most important factors determining aerosol delivery. In patients, sputum levels of deposited antibiotics varied from 1.10 to 19.6 microg/ml/mg. Variation in sputum levels correlated with predictions from the in vitro model. Aerosol delivery in ventilated patients can be efficient and reproducible only if defined ventilator parameters are tightly controlled. Key parameters can be determined via in vitro bench testing defining delivery standards for clinical trials of drugs with narrow therapeutic/toxicity ratios.
Laboratory based low dose combination chemotherapy + bevacizumab for recurrent refractory and unresectable gastric cancer
Authors: H. W. Bruckner, V. R. Hrehorovich, P. Degregorio
Journal: Journal of Clinical Oncology (2006)

14133 Twenty consecutive prospectively registered patients with refractory or Stage IV gastric cancer were treated with GFLIP (Bruckner el al ASCO 2002;2005). The last 10 upon relapse were treated with GFL[OX]T and Bevacizumab, substituting oxaliplatin (OX) 30→40 mg/M 2 , taxotere (T) 30→40 mg/M 2 for cisplatin in the q2wk schedule. One or both regimens produced; objective responses for 15 patients including 5 complete (radiologic, tumor markers, PET responses) and 2 surgical downstaging resulting in resection or successful completion surgery; 3 patients had stable disease greater than 4 months with subjective benefit, gemcitabine was given at 400→500 mg/M 2 as tolerated (→), 2 failed both regimens. One-year actuarial survival was 75%, two-year survival was 25%. All 20 lived more than six months. The level of activity, multiple crossover responses, responses with both regimens, a number of long remissions (long survival after 5FU cisplatin and GFLIP failed) and clinical downstaging allowing further surgery identify both regimens either individually or in sequence as deserving systematic investigation. The utility of low doses (responses), unusual clinical benefits, quality of life and safety offer possible advantages compared to standard dose regimens.This strategy appears to reduce and delay the limiting toxicity of the irinotecan (I) 80 mg/M 2 , cisplatin (P) 40 mg/M 2 OX/T which are conventionally treatment limiting drugs. The regimens were designed based on laboratory evidence of low dose drug interaction including reversal of resistance to conventional drugs (applicable to both pancreatic and gastric cancer (Janat et al, Amer Asso Cancer Res 1999). After clinical demonstrations of high response rates and reversal of resistance against refractory pancreatic cancer (Bruckner et al, AntiCancer Res and ASCO 2005). The regimens were offered to patients with recurrent previously treated and refractory gastric cancer and then based on initial exceptional responses to high risk patients with poor prognosis due to clinical complications of their gastric cancer. No significant financial relationships to disclose.
Prevalence of nontuberculous mycobacteria in diffuse panbronchiolitis
Authors: Takahiro Tsuji, Eisaku Tanaka, Seishu Hashimoto, Takashi Hajiro, Yoshio Taguchi
Journal: European Respiratory Journal (2012)

[Background]  Nontuberculous mycobacterial (NTM) lung disease secondary to cystic fibrosis is often reported, but prevalence of NTM in other chronic respiratory tract infection is still unknown.  [objectives]  We retrospectively investigated prevalence of NTM in diffuse panbronchiolitis (DPB), notorious chronic respiratory tract infection with severe obstruction seen in Japan, and clinical characteritics of DPB with NTM patients.  [Methods]  We reviewed Mycobacterial culture of 32 DPB patients who regularly visited our hospital (local central hospital with 872 beds) from Jan. 2000 to Dec. 2011. Prevalence was defined as subjects having at least one positive NTM culture. Age, sex, BMI, result of pulmonary function test, immunocompromised state, and time from DPB diagnosis to the first positive result of NTM culture was also investigated.  [Result]  Of 32 patients, mean age was 51.3 (95% CI 45.9-56.7), follow-up time was 153.8 months (95% CI 107.9-199.6). The overall prevalence of NTM in sputum was 12.5% (4 patients). Of the 4 patients, 4 had positive culture of MAC and 2 had positive culture more than twice. No patients needed treatment for NTM. Mean time from DPB diagnosis to the first positive result was 166.2 months. DPB with NTM patients tended to have smaller BMI and smaller %FEV1 (table 1). The CT findings showed bronchiectasis and multiple nodules.  [Conclusion]  NTM infection sometimes occurs secondary to DPB. The CT findings were similar to those of primary nodular/bronchiectatic MAC disease.