tbuckley/cabot-search huggingface dataset:
Generation of leukemia-reactive cytotoxic T lymphocyte clones from the HLA-identical bone marrow donor of a patient with leukemia.
Authors: L M Faber, S A van Luxemburg-Heijs, R Willemze, J H Falkenburg
Journal: The Journal of Experimental Medicine (1992)

Allogeneic bone marrow transplantation (BMT) has been associated with a graft-vs.-leukemia (GVL) reactivity. Since T cell depletion of the bone marrow graft has decreased the risk of graft-vs.-host disease (GVHD), but has been associated with higher rates of leukemia relapse, GVL reactivity is probably caused by donor-derived T lymphocytes. Previously, we demonstrated that minor histocompatibility (mH) antigen-specific cytotoxic T lymphocyte (CTL) clones, generated from patients after BMT, are capable of major histocompatibility complex-(MHC) restricted lysis of (clonogenic) myeloid leukemic cells. Here, we investigated whether donor-derived leukemia-specific CTL clones can be generated in vitro, before BMT, using irradiated leukemic cells from a patient with acute myeloid leukemia as stimulator cells, and peripheral blood or bone marrow from the HLA genotypically identical sibling donor as responder cells. Several CTL lines were generated that showed specific lysis (&amp;gt; 50%) of the recipient leukemic cells in a 51Cr-release assay. Two of these CTL lines were cloned by limiting dilution in the presence of the irradiated recipient cells. Multiple leukemia-reactive, HLA class I and II-restricted clones with various specificities could be established. These alloreactive, antileukemic CTL clones may cause GVL reactivity after BMT, and may be used as adjuvant immunotherapy in the treatment of leukemia.
Inhibition of DNA Double-Strand Break Repair by the Dual PI3K/mTOR Inhibitor NVP-BEZ235 as a Strategy for Radiosensitization of Glioblastoma
Authors: Carlos Rodrigo Gil del Alcazar, Molly Catherine Hardebeck, Bipasha Mukherjee, Nozomi Tomimatsu, Xiaohuan Gao, Jingsheng Yan, Xian-Jin Xie, Robert Bachoo, Li Li, Amyn A. Habib, Sandeep Burma
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Inhibitors of the DNA damage response (DDR) have great potential for radiosensitization of numerous cancers, including glioblastomas, which are extremely radio- and chemoresistant brain tumors. Currently, there are no DNA double-strand break (DSB) repair inhibitors that have been successful in treating glioblastoma. Our laboratory previously demonstrated that the dual phosphoinositide 3-kinase/mTOR inhibitor NVP-BEZ235 can potently inhibit the two central DDR kinases, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia-telangiectasia mutated (ATM), in vitro. Here, we tested whether NVP-BEZ235 could also inhibit ATM and DNA-PKcs in tumors in vivo and assessed its potential as a radio- and chemosensitizer in preclinical mouse glioblastoma models. Experimental Design: The radiosensitizing effect of NVP-BEZ235 was tested by following tumor growth in subcutaneous and orthotopic glioblastoma models. Tumors were generated using the radioresistant U87-vIII glioma cell line and GBM9 neurospheres in nude mice. These tumors were then treated with ionizing radiation and/or NVP-BEZ235 and analyzed for DNA-PKcs and ATM activation, DSB repair inhibition, and attenuation of growth. Results: NVP-BEZ235 potently inhibited both DNA-PKcs and ATM kinases and attenuated the repair of ionizing radiation–induced DNA damage in tumors. This resulted in striking tumor radiosensitization, which extended the survival of brain tumor–bearing mice. Notably, tumors displayed a higher DSB-load when compared with normal brain tissue. NVP-BEZ235 also sensitized a subset of subcutaneous tumors to temozolomide, a drug routinely used concurrently with ionizing radiation for the treatment of glioblastoma. Conclusions: These results demonstrate that it may be possible to significantly improve glioblastoma therapy by combining ionizing radiation with potent and bioavailable DNA repair inhibitors such as NVP-BEZ235. Clin Cancer Res; 20(5); 1235–48. ©2013 AACR.
Macroalbuminuria and Renal Pathology in First Nation Youth With Type 2 Diabetes
Authors: Elizabeth A.C. Sellers, Tom D. Blydt-Hansen, Heather J. Dean, Ian W. Gibson, Patricia E. Birk, Malcolm Ogborn
Journal: Diabetes Care (2009)

OBJECTIVE To determine the prevalence of macroalbuminuria and to describe the clinical and renal pathological changes associated with macroalbuminuria in a population of Canadian First Nation children and adolescents with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted a retrospective chart review at a single tertiary care pediatric diabetes center, and a case series was constructed. We collected data on microalbuminuria (≥3 mg/mmol creatinine [26.5 mg/g]) and macroalbuminuria (≥28 mg/mmol creatinine [247.5 mg/g]), estimated glomerular filtration rate, renal pathology, and aggravating risk factors (poor glycemic control, obesity, hypertension, glomerular hyperfiltration, hypercholesterolemia, smoking, and exposure to diabetes in utero). RESULTS We reviewed 90 charts of children and adolescents with type 2 diabetes. A total of 53% had at least one random urine albumin-to-creatinine ratio ≥3 mg/mmol (26.5 mg/g). There were 14 of 90 (16%) who had persistent macroalbuminuria at or within 8 years of diagnosis of diabetes. Of these 14 subjects, 1 had orthostatic albuminuria and 3 had spontaneous resolution of albuminuria. A total of 10 had renal biopsies performed. There were 9 of 10 who exhibited immune complex disease or glomerulosclerosis, and none had classic diabetic nephropathy. CONCLUSIONS This study suggests that the diagnosis of renal disease in children with type 2 diabetes cannot be reliably determined by clinical and laboratory findings alone. Renal biopsy is necessary for accurate diagnosis of renal disease in children and adolescents with type 2 diabetes and macroalbuminuria. The additional burden of nondiabetic kidney disease may explain the high rate of progression to end-stage kidney failure in this population.
Tumor Stage After Neoadjuvant Chemotherapy Determines Survival After Surgery for Adenocarcinoma of the Esophagus and Esophagogastric Junction
Authors: Andrew R. Davies, James A. Gossage, Janine Zylstra, Fredrik Mattsson, Jesper Lagergren, Nick Maisey, Elizabeth C. Smyth, David Cunningham, William H. Allum, Robert C. Mason
Journal: Journal of Clinical Oncology (2014)

Neoadjuvant chemotherapy is established in the management of most resectable esophageal and esophagogastric junction adenocarcinomas. However, assessing the downstaging effects of chemotherapy and predicting response to treatment remain challenging, and the relative importance of tumor stage before and after chemotherapy is debatable.We analyzed consecutive resections for esophageal or esophagogastric junction adenocarcinomas performed at two high-volume cancer centers in London between 2000 and 2010. After standard investigations and multidisciplinary team consensus, all patients were allocated a clinical tumor stage before treatment, which was compared with pathologic stage after surgical resection. Survival analysis was conducted using Kaplan-Meier analysis and Cox regression analysis.Among 584 included patients, 400 patients (68%) received neoadjuvant chemotherapy. Patients with downstaged tumors after neoadjuvant chemotherapy experienced improved survival compared with patients without response (P < .001), and such downstaging (hazard ratio, 0.43; 95% CI, 0.31 to 0.59) was the strongest independent predictor of survival after adjusting for patient age, tumor grade, clinical tumor stage, lymphovascular invasion, resection margin status, and surgical resection type. Patients downstaged by chemotherapy, compared with patients with no response, experienced lower rates of local recurrence (6% v. 13%, respectively; P = .030) and systemic recurrence (19% v. 29%, respectively; P = .027) and improved Mandard tumor regression scores (P = .001). Survival was strongly dictated by stage after neoadjuvant chemotherapy, rather than clinical stage at presentation.The stage of esophageal or esophagogastric junction adenocarcinoma after neoadjuvant chemotherapy determines prognosis rather than the clinical stage before neoadjuvant chemotherapy, indicating the importance of focusing on postchemotherapy staging to more accurately predict outcome and eligibility for surgery. Patients who are downstaged by neoadjuvant chemotherapy benefit from reduced rates of local and systemic recurrence.
Hyperfractionated Accelerated Radiotherapy in the Milan Strategy for Metastatic Medulloblastoma
Authors: Lorenza Gandola, Maura Massimino, Graziella Cefalo, Carlo Solero, Filippo Spreafico, Emilia Pecori, Daria Riva, Paola Collini, Emanuele Pignoli, Felice Giangaspero, Roberto Luksch, Serena Berretta, Geraldina Poggi, Veronica Biassoni, Andrea Ferrari, Bianca Pollo, Claudio Favre, Iacopo Sardi, Monica Terenziani, Franca Fossati-Bellani
Journal: Journal of Clinical Oncology (2008)

With a view to improving the prognosis for patients with metastatic medulloblastoma, we tested the efficacy and toxicity of a hyperfractionated accelerated radiotherapy (HART) regimen delivered after intensive sequential chemotherapy.Between 1998 and 2007, 33 consecutive patients received postoperative methotrexate (8 g/m(2)), etoposide (2.4 g/m(2)), cyclophosphamide (4 g/m(2)), and carboplatin (0.8 g/m(2)) in a 2-month schedule, then HART with a maximal dose to the neuraxis of 39 Gy (1.3 Gy/fraction, 2 fractions/d) and a posterior fossa boost up to 60 Gy (1.5 Gy/fraction,2 fractions/d). Patients with persistent disseminated disease before HART were consolidated with two myeloablative courses and circulating progenitor cell rescue.Patients were classified as having M1 (n = 9), M2 (n = 6), M3 (n = 17), and M4 (n = 1) disease. Seven patients younger than 10 years old who achieved complete response after chemotherapy received a lower dose to the neuraxis (31.2 Gy). Twenty-two of the 32 assessable patients responded to chemotherapy; disease was stable in five patients and progressed in five patients. One septic death occurred before radiotherapy. Eight patients experienced relapse after a median of 12 months. Fourteen of the 33 patients underwent consolidation therapy after HART. With a median 82-month survivor follow-up, the 5-year event-free, progression-free, and overall survival rates were 70%, 72%, and 73%, respectively. No severe clinical complications of HART have emerged so far.HART after intensive postoperative chemotherapy, followed by myeloablative chemotherapy in selected cases, proved feasible in children with metastatic medulloblastoma. The results of our treatment compare favorably with other series treated using conventional therapies.
Severe asthmatic attack with cardiac arrest suspected to be induced by sulbactam sodium
Authors: Wei Zheng, Yu Chen, Li Zhao
Journal: European Respiratory Journal (2014)

We reported one case of severe asthmatic attack with cardiac arrest suspected to be induced by sulbactam sodium. A 74-year-old female received intravenous administration of mezlocillin sodium/sulbactam sodium for pulmonary infection complicated by bronchial asthma. After infusion of about 10 ml, the patient suddenly developed severe asthmatic attack and palpitations, then apnea and cardiac arrest. The patient was successfully rescued by glucocorticoids treatment and cardiopulmonary resuscitation. The above symptoms were considered to be caused by mezlocillin sodium/sulbactam sodium. Detailed investigation showed that the patient9s past allergy history was significant for allergy to cefoperazone/sulbactam sodium. However, she was ever administered cefoperazone, penicillin, piperacillin/tazobactam intravenously without allergic reaction. We suspected the patient was allergic to sulbactam sodium. After the patient recovered completely, the intracutaneous susceptibility test of 0.9% sodium chloride, penicillin, sulbactam sodium was performed. The result of the former two agents was negative, but that of sulbactam sodium was positive. To our knowledge, this is the first report of life-threatening allergy probably induced by sulbactam sodium. Clinicians are usually cautious of allergy to penicillin and cephalosporins but ignore allergy to β-lactamase inhibitors. If a patient has a past history of allergy to compound antimicrobial agents, possible allergy to β-lactamase inhibitors should also be considered. In such a patient, the intracutaneous susceptibility test of the two preparations should be performed respectively for fear of possible serious outcomes.
MicroRNA-29a Promotion of Nephrin Acetylation Ameliorates Hyperglycemia-Induced Podocyte Dysfunction
Authors: Chun-Liang Lin, Pei-Hsien Lee, Yung-Chien Hsu, Chen-Chou Lei, Jih-Yang Ko, Pei-Chin Chuang, Yu-Ting Huang, Shao-Yu Wang, Shin-Long Wu, Yu-Shan Chen, Wen-Chih Chiang, Jochen Reiser, Feng-Sheng Wang
Journal: Journal of the American Society of Nephrology (2014)

Podocyte dysfunction is a detrimental feature in diabetic nephropathy, with loss of nephrin integrity contributing to diabetic podocytopathy. MicroRNAs (miRs) reportedly modulate the hyperglycemia-induced perturbation of renal tissue homeostasis. This study investigated whether regulation of histone deacetylase (HDAC) actions and nephrin acetylation by miR-29 contributes to podocyte homeostasis and renal function in diabetic kidneys. Hyperglycemia accelerated podocyte injury and reduced nephrin, acetylated nephrin, and miR-29a levels in primary renal glomeruli from streptozotocin-induced diabetic mice. Diabetic miR-29a transgenic mice had better nephrin levels, podocyte viability, and renal function and less glomerular fibrosis and inflammation reaction compared with diabetic wild-type mice. Overexpression of miR-29a attenuated the promotion of HDAC4 signaling, nephrin ubiquitination, and urinary nephrin excretion associated with diabetes and restored nephrin acetylation. Knockdown of miR-29a by antisense oligonucleotides promoted HDAC4 action, nephrin loss, podocyte apoptosis, and proteinuria in nondiabetic mice. In vitro, interruption of HDAC4 signaling alleviated the high glucose–induced apoptosis and inhibition of nephrin acetylation in podocyte cultures. Furthermore, HDAC4 interference increased the acetylation status of histone H3 at lysine 9 (H3K9Ac), the enrichment of H3K9Ac in miR-29a proximal promoter, and miR-29a transcription in high glucose–stressed podocytes. In conclusion, hyperglycemia impairs miR-29a signaling to intensify HDAC4 actions that contribute to podocyte protein deacetylation and degradation as well as renal dysfunction. HDAC4, via epigenetic H3K9 hypoacetylation, reduces miR-29a transcription. The renoprotective effects of miR-29a in diabetes-induced loss of podocyte integrity and renal homeostasis highlights the importance of post-translational acetylation reactions in podocyte microenvironments. Increasing miR-29a action may protect against diabetic podocytopathy.
Potential risk factors for recurrence of pulmonary tuberculosis
Authors: O. Jolobe
Journal: Thorax (2011)

However, the principal finding remains: while we agree that the presence of airway eosinophilia is a reliable predictor of steroid responsiveness, the absence of eosinophilia does not accurately predict steroid unresponsiveness.Whether intentionally or not, these authors imply that only patients with demonstrable sputum eosinophilia are steroid responsive.This is not the case.
Defective insulin secretion in pancreatic β cells lacking type 1 IGF receptor
Authors: Shouhong Xuan, Tadahiro Kitamura, Jun Nakae, Katerina Politi, Yoshiaki Kido, Peter E. Fisher, Manrico Morroni, Saverio Cinti, Morris F. White, Pedro L. Herrera, Domenico Accili, Argiris Efstratiadis
Journal: Journal of Clinical Investigation (2002)

Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase of β cell mass and impaired glucose-dependent insulin release. β cell proliferation and secretion are thought to be regulated by signaling through receptor tyrosine kinases. In this regard, we sought to examine the potential proliferative and/or antiapoptotic role of IGFs in β cells by tissue-specific conditional mutagenesis ablating type 1 IGF receptor (IGF1R) signaling. Unexpectedly, lack of functional IGF1R did not affect β cell mass, but resulted in age-dependent impairment of glucose tolerance, associated with a decrease of glucose- and arginine-dependent insulin release. These observations reveal a requirement of IGF1R-mediated signaling for insulin secretion.
Reading numbers aloud: a measure of the limiting effect of breathlessness in patients with cancer
Authors: A. Wilcock, V. Crosby, D. Clarke, R. Corcoran, A. Tattersfield
Journal: Thorax (1999)

Progress in the treatment of breathlessness at rest or on minimum exertion in patients with cancer requires a practical and valid method of measuring symptoms. A study was undertaken to explore the practicality, repeatability, and sensitivity of reading numbers as a form of exercise test in this group of patients.Thirty patients with cancer and 30 age matched healthy subjects read numbers aloud as quickly and clearly as they could for 60 seconds. After five readings the maximum number of numbers read and the number read per breath was noted. This procedure was carried out twice in one day and one week later to assess within and between day repeatability. The sensitivity of the test was assessed by making measurements in 13 patients with cancer before and after drainage of their pleural effusion.The concept was easily understood by all subjects. Twelve patients were unable to complete five readings in all tests due to tiredness. Compared with control subjects patients read fewer numbers in the three tests (87-89% of control) and fewer numbers per breath (59-60% of control). Repeatability was good both within and between days. After drainage of their effusion all patients were less breathless and there was an increase in both the maximum number of numbers read (23%) and the number read per breath (60%).The number of numbers read and the number read per breath over 60 seconds was practical, easy to carry out, showed good repeatability within and between days and was sensitive to the improvement seen following drainage of a pleural effusion. It may be a useful measure of the limiting effect of breathlessness in this group of patients.
Vitamin A in skin and serum—studies of acne vulgaris, atopic dermatitis, ichthyosis vulgaris and lichen planus
Authors: OLA ROLLMAN, A. VAHLQUIST
Journal: British Journal of Dermatology (1985)

The concentrations of vitamin A and total carotenoids were measured in serum and skin of 61 patients with acne vulgaris, atopic dermatitis, ichthyosis vulgaris or lichen planus, and compared with those in 37 healthy subjects. The mean serum concentrations of retinol and retinol-binding protein were significantly decreased in patients with acne (P<0.01) and slightly increased in those with ichthyosis (P<0.05), but were otherwise normal. Serum carotenoid levels did not differ between patients and controls. Superficial shave biopsies from both involved and uninvolved skin were examined for the presence of retinol (vitamin A1), dehydroretinol (vitamin A2) and total carotenoids. The mean retinol concentration was increased in lichen planus lesions (P<0.05) and decreased in both acne skin (involved and uninvolved) and in lesions of atopic dermatitis (P<0.05). The mean dehydroretinol concentration was markedly increased in lesions of atopic dermatitis and lichen planus (P<0.01). No consistent abnormalities were found in skin of patients with ichthyosis vulgaris. The mean carotenoid concentration in the patients' skin did not differ significantly from that in the controls. The reduced retinol level in the skin of acne patients is probably explained by diminished supply of vitamin A from the blood. The abnormal ratio of retinol to dehydroretinol in lesions of lichen planus and atopic dermatitis is possibly due to changes in cutaneous vitamin A metabolism associated with epidermal hyperproliferation and inflammation.
Navigated transcranial magnetic stimulation: another tool for preoperative planning for patients with motor-eloquent brain tumors
Authors: R. L. Jensen
Journal: Neuro-Oncology (2014)

Dr Frey and his group are to be congratulated on the successful demonstration of the use of navigated transcranial magnetic stimulation (nTMS) as an aid in the resection of brain tumors in motor-eloquent locations. They correctly state that one of the dilemmas of brain tumor surgery in eloquent cortex is how to gain benefit for the patient in terms of extended survival, maintenance or even improvement of function, and quality of life while at the same time not risking new neurological deficits. The authors point out that the natural history of the disease must be weighed against the risk generated by the intervention itself. This is especially true in the realm of low-grade gliomas, where the natural history can be relatively benign, but postoperative complications can have great impact on the patient’s overall outcome. On the other hand, there is a body of emerging literature that indicates that the extent of resection of a given glioma is positively correlated with patient survival. 1,2 When counseling patients on the best course of action in the preoperative setting, one must walk a delicate balance between aggressive treatment and the potential for complications. Thus, any tool that allows for preoperative assessment of critical brain function in relationship to the location of a given lesion is highly valuable. The authors of this paper observe that there is an inherent problem with preoperative tests that “lead to improper restraint in surgical indication” and thus undertreat a given patient. In this study, the authors compared 2 groups: patients treated over 2 years without nTMS and patients treated over a subsequent 5 years with nTMS. Unfortunately, this study design complicates interpretation, as the authors have certainly improved their technique and judgment during these time frames. Nevertheless, there are some solid findings from this study. First, this report confirms that nTMS is well tolerated by patients without any induced seizure activity. The authors also report increased extent of resection and fewer biopsy-only cases in the nTMS group. Progression-free survival (PFS) was improved but overall survival (OS) remained unchanged. The improved PFS might be explained in part by a much lower number of “biopsy-only” cases. We also are unaware of the mix of patient molecular profiles between the 2 groups (methylguanine methyltransferase promoter methylation, isodehydrogenase-1 mutation, 1p19q deletion, etc), which could impact PFS or OS. It is also important to note that measurement of PFS in gliomas can be technically problematic given the reliance on imaging and the timing of imaging as well as definitions of “progression.” Nevertheless, PFS is used more and more frequently in clinical trials to evaluate outcomes for patients with gliomas. 3 Therefore, the improved PFS in the nTMS group is even