tbuckley/cabot-search huggingface dataset:
Dynamin–Related Protein 1 Deficiency Improves Mitochondrial Fitness and Protects against Progression of Diabetic Nephropathy
Authors: Bernard A. Ayanga, Shawn S. Badal, Yin Wang, Daniel L. Galvan, Benny H. Chang, Paul T. Schumacker, Farhad R. Danesh
Journal: Journal of the American Society of Nephrology (2016)

Mitochondrial fission has been linked to the pathogenesis of diabetic nephropathy (DN). However, how mitochondrial fission affects progression of DN in vivo is unknown. Here, we report the effect of conditional podocyte–specific deletion of dynamin-related protein 1 (Drp1), an essential component of mitochondrial fission, on the pathogenesis and progression of DN. Inducible podocyte–specific deletion of Drp1 in diabetic mice decreased albuminuria and improved mesangial matrix expansion and podocyte morphology. Ultrastructure analysis revealed a significant increase in fragmented mitochondria in the podocytes of wild–type diabetic mice but a marked improvement in mitochondrial structure in Drp1-null podocytes of diabetic mice. When isolated from diabetic mice and cultured in high glucose, Drp1-null podocytes had more elongated mitochondria and better mitochondrial fitness associated with enhanced oxygen consumption and ATP production than wild-type podocytes. Furthermore, administration of a pharmacologic inhibitor of Drp1, Mdivi1, significantly blunted mitochondrial fission and rescued key pathologic features of DN in mice. Taken together, these results provide novel correlations between mitochondrial morphology and the progression of DN and point to Drp1 as a potential therapeutic target in DN.
Phase II induction cetuximab (C225), paclitaxel (P), and carboplatin (C) followed by chemoradiation with C225, P, C, and RT 68-72Gy for stage III/IV head and neck squamous cancer: Primary site organ preservation and disease control at 2 years (ECOG, E2303).
Authors: H. J. Wanebo, M. S. Ghebremichael, B. Burtness, J. A. Ridge, S. Spencer, F. R. Rosen, M. R. Hancock, K. A. Tolba, A. A. Forastiere
Journal: Journal of Clinical Oncology (2010)

5513 Background: C225 plus RT improved survival vs. RT alone (Bonner, 2009). E2303 evaluated C225 with induction CT plus C225 and RT (CRT) in stage III/IV head and neck SCC with focus on event free survival, pathologic complete response (pCR) and toxicity. Restaging biopsy showed high pCR after C225/CRT 50 Gy w/ low toxicity. We now report 2-yr disease control and organ preservation rates. Methods: IRB consented resectable stage III/IV (21/42) patients (pts) sites- (oropharynx, 61%, larynx 22% other 16%) had triple endoscopy, gastrostomy, CT/MRI. Induction CT was C225 (400mg/m2 wk1, then 250mg/m2), P 90mg/m2, C (AUC=2)/ wk × 6. Restaging primary site (PS) biopsy (bx) was done wk 8, if the pt had a clinical CR and at wk 14 if disease persisted after CRT (C225 250mg/m2, P 30mg/m2, C (AUC=1) wkly × 6, 50 Gy). If PS bx was negative wk 14 pts completed CRT (68-72 Gy); If positive, the pt had surgery. Results: Of 74 enrolled pts, 70 had induction and 68 pts CRT. (13% < 70 Gy, 87% ≥70Gy ): 63 pts were eligible for analysis. Of 41 pts (59%) with clinical CR after induction, PS bx was neg. in 24 (59% pCR); Re-bx at wk 14 after chemo-RT (50Gy) in 34 pts (15 previous bx'd and 19 initial non-responders) was neg in 33 pts (97%). Thus 57 of 60 (95%) re biopsied pts and 91% of all eligible 63 pts had pCR. Neck dissection (n=34) was positive in 11 pts (32%). Pattern of failure was noted as: Local recurrence 11 (17.5%), regional 5 (8%), distant 5 (8%). Primary disease control at 2yr was 83%. Overall survival (OS): 1yr 97%, 2yr 82%; progression free survival (PFS) was 1yr 82%, 2 yr 66%. 2 yr PFS in stage III was 62%; in stage IV it was 68%. Conclusions: Induction C225 and CT followed by C225 plus CRT induces a 95% primary site path CR in biopsied pts and 91% response in eligible pts with a 2 yr OS of 82%, and PFS of 66%. This therapy and management approach produced promising local control, organ site preservation, and 2-yr survival. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, GenMab AACR, ASCO, IMER, NCCN, Pfizer Amgen, Bristol-Myers Squibb
P148 Once-daily tiotropium Respimat® add-on to at least ICS maintenance therapy reduces exacerbation risk in patients with uncontrolled symptomatic asthma: Abstract P148 Table 1
Authors: D Halpin, ED Bateman, P Paggiaro, ER Bleecker, M Engel, P Moroni-Zentgraf, H Schmidt, HAM Kerstjens
Journal: Thorax (2015)

<h3>Background</h3> A reduction in the risk of asthma exacerbation may provide improvements in clinical burden, patient experience and healthcare costs. In Phase III trials, once-daily tiotropium Respimat® add-on to at least ICS improved lung function in patients with symptomatic asthma. We investigated exacerbation risk in each trial. <h3>Methods</h3> Five Phase III, double-blind, placebo-controlled, parallel-group trials in patients with symptomatic asthma. Patients received tiotropium Respimat® 5 µg or placebo Respimat® each as add-on to at least ICS maintenance therapy (Table 1). Pre-planned co-primary or secondary end points were time to first severe exacerbation and time to any asthma worsening. <h3>Results</h3> Mean baseline% of predicted FEV<sub>1</sub>, ACQ-7 score and ICS dose (µg) were: 56.0 ± 13.1, 2.6 ± 0.7 and 1198 ± 539 in PrimoTinA-asthma® (two replicate trials); 75.1 ± 11.5, 2.2 ± 0.5 and 660 ± 213 in MezzoTinA-asthma® (two replicate trials); and 77.7 ± 11.9, 2.1 ± 0.4 and 381 ± 78 in GraziaTinA-asthma®. Tiotropium Respimat® 5 µg reduced risk of severe asthma exacerbation by at least 21% in all three severity cohorts (Table 1) and risk of asthma worsening versus placebo Respimat® in all trials, with a statistically significant reduction in PrimoTinA-asthma®. <h3>Conclusion</h3> Once-daily tiotropium Respimat® 5 µg add-on to at least ICS maintenance therapy consistently reduced exacerbations across asthma severities and so may be a beneficial add-on option to reduce current and future exacerbation risk.
Clinical Evaluation of Nafcillin in Patients with Severe Staphylococcal Disease
Authors: Theodore C. Eickhoff, Jay Ward Kislak, Maxwell Finland
Journal: New England Journal of Medicine (1965)

NAFCILLIN, 6-(2-ethoxy-1-naphthamido) penicillin,1 is one of the semisynthetic, penicillinase-resistant penicillins that has been introduced since the isolation of 6-aminopenicillanic acid.2 Each of the newer penicillins in this series — namely, oxacillin, diphenicillin and nafcillin — has several readily apparent advantages over methicillin,3 the first one to become available for clinical use. Most important of these advantages are acid stability, permitting absorption of the drug when it is administered orally, and greater in vitro activity against both penicillinase-producing and nonpenicillinase-producing staphylococci. In addition, some data suggest that nafcillin may have greater therapeutic activity than methicillin or oxacillin in experimental infections in . . .
An Arntl2-Driven Secretome Enables Lung Adenocarcinoma Metastatic Self-Sufficiency
Authors: Jennifer J. Brady, Chen-Hua Chuang, Peyton G. Greenside, Zoë N. Rogers, Christopher W. Murray, Deborah R. Caswell, Ursula Hartmann, Andrew J. Connolly, E. Alejandro Sweet-Cordero, Anshul Kundaje, Monte M. Winslow
Journal: Cancer Cell (2016)
Apoprotein A-I Synthesis in Normal Intestinal Mucosa and in Tangier Disease
Authors: Robert M. Glickman, Peter H. R. Green, Robert S. Lees, Alan Tall
Journal: New England Journal of Medicine (1978)

To determine whether human small intestine synthesizes apoA-I, the major apoprotein of plasma high-density lipoproteins, we used immunofluorescence technics and monospecific antiserums to visualize apoA-I within intestinal epithelial cells from four normal subjects and one patient with Tangier disease. Biopsies from all subjects during fasting showed limited fluorescence. After lipid feeding intracellular apoA-I markedly increased in both normal subjects and the patient. During alimentary lipemia, mean plasma apoA-I levels (milligrams per deciliter) increased in four normal subjects from 161 +/- 12 (+/- S.E.M.) to 180 +/- 15 (P less than 0.05) and in the patient from 1.9 to 6.8. Normal plasma chylomicrons contained apoB, apoE and the C peptides but not apoA-I. The patient's chylomicrons contained ap0A-I. Normal and Tangier-disease intestinal-mucosa cells increase their content of apoA-I during chylomicron formation and subsequently contribute to plasma apoA-I levels. The low levels of apoA-I in Tangier disease are not due to a failure of intestinal synthesis but might be due to abnormal metabolism of chylomicron apoproteins.
Case 40-2000
Authors: Christopher L. Carpenter, Eva D. Patalas
Journal: New England Journal of Medicine (2000)

Presentation of CaseA 38-year-old woman was admitted to the hospital because of a tumor at the gastroesophageal junction.The patient had been in excellent health until six and a half weeks earlier, when she began to have a fever with a cough productive of green sputum. At about the same time, she also felt a “sticking” sensation on swallowing solid foods, even after thorough chewing; liquids were swallowed adequately. Lansoprazole was prescribed, without improvement. Two and a half weeks before admission, esophagogastroduodenoscopic examination at another hospital revealed a tumor, 7 by 4 cm, in the proximal portion of the . . .
Release of Prostaglandins and Thromboxane into the Coronary Circulation in Patients with Ischemic Heart Disease
Authors: Paul D. Hirsh, L. David Hillis, William B. Campbell, Brian G. Firth, James T. Willerson
Journal: New England Journal of Medicine (1981)

Endogenous modulators of platelet aggregability and vascular tone may play a part in coronary-artery disease. We therefore measured the release of prostaglandins and thromboxane into the coronary circulation in patients with various kinds of cardiac disease. Simultaneous coronary-sinus (CS) and ascending-aortic (AO) blood samples were obtained from 60 patients for measurement of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha, a prostaglandin I2 metabolite) and of thromboxane B2 (TxB2). Samples from 45 of these patients were also tested for prostaglandin E2 (PGE2) and lactate. Patients with unstable angina pectoris who reported chest pain within 24 hours of study had higher TxB2 CS/AO ratios (5.8 +/- 2.8, mean +/- S.D.) than patients whose most recent anginal pain was more than 96 hours before study (1.3 +/- 0.6; P less than 0.05), than those with nonischemic chest pain (1.2 +/- 0.4; P less than 0.05), or with valvular or congenital nonischemic heart disease (1.2 +/- 0.6; P less than 0.05). Those whose most recent anginal pain occurred 24 to 96 hours before study were distributed bimodally: the majority had low TxB2 CS/AO ratios (range, 0.5 to 2.1) like the patients in the three aforementioned groups, whereas a few had markedly elevated values (range, 10.5 to 46.6). The 6-keto-PGF1 alpha and PGE2 CS/AO ratios and myocardial lactate extraction were not significantly different among the five groups. These data suggest that local thromboxane release is associated with recent episodes of angina in patients with unstable angina pectoris, but whether this release is a cause or an effect is not yet known.
DDEL-01EVALUATION OF A MULTIFUNCTIONAL NANOVESICLE IN A MPNST MOUSE MODEL
Authors: Achutha Madhankumar, Becky Slagle-Webb, Elias Rizk, Russell Payne, Kimberly Harbaugh, James Connor
Journal: Neuro-Oncology (2015)

Peripheral nerve sheath tumors are benign tumors that have the potential to transform to malignant peripheral nerve sheath tumor (MPNST). In our initial study we found that majority of the MPNST cells and tissues express IL13Rα2 receptor, which could be a potential target for therapy. We have also observed earlier that the IL13 conjugated liposomal doxorubicin was effectively endocytosed by established MPNST cells like ST88-14 and sNF96.2 and induces cytotocity. To determine the in vivo efficacy, sciatic nerve tumor mouse model was developed by injecting the luciferase transfected STS26T cells in the sciatic nerve. The tumor progression was monitored following the injection of luciferin intraperitoneally and imaging with intravital imaging spectroscopy (IVIS). All the mice developed tumor in 2 weeks after implantation of tumor cells in the sciatic nerve as evidenced by IVIS imaging. Once the tumor was visualized the mice were treated with IL-13 conjugated and non-conjugated liposomal doxorubicin for 7 weeks at a low dose of 4 mg/kg body weight weekly once. Similarly the tumor sections from the mice which were treated with liposomes were analyzed for apoptotic markers like Caspase 3. The tumor volume, weight of the mice and the serum chemistry were recorded. Although the tumor progression was controlled initially, the efficacy was reduced with increasing tumor volume. So currently we are adopting a more frequent dosage regimen instead of weekly once strategy. Furthermore, as Ras activation has also been reported to promote the Schwann cell to MPNST transformation, we combined the doxorubicin with farnesyl thiosalicylic acid (FTS, a Ras inhibitor) in the liposome formulation to study their tumor regression property in such models. In conclusion we developed a successful MPNST animal model to monitor the tumor progression by non-invasive method and currently utilizing this model for investigating the therapeutic efficacy of multifunctional nanovesicles.
PWE-305 Nqo1 is a predictive biomarker and therapaeutic target in metastatic colorectal cancer
Authors: PA Sutton, J Evans, R Jones, C Goldring, D Palmer, N Kitteringham, H Malik, D Vimalachandran
Journal: Gut (2015)

<h3>Introduction</h3> A knowledge of the biological phenotype of colorectal liver metastases would be invaluable to inform clinical decision making; however, deriving this information from the metastatic lesions is not feasible until after resection. We aimed to use proteomic analysis to identify biomarkers in the primary tumour which predict response to neoadjuvant chemotherapy in liver metastases. <h3>Method</h3> Fresh tissue from both primary colorectal tumour and liver metastases from 17 patients was subjected to proteomic analysis using isobaric tagging for relative quantification, with stratification of patients into those showing low or high response to chemotherapy permitting the identification of potential predictive biomarkers. These markers were subsequently validated by immunohistochemistry on a tissue microarray of 57 patients and further investigated in an <i><i>in vitro</i></i>model. <h3>Results</h3> We identified 5768 discrete proteins, 5 of which predicted histopathological response to fluorouracil-based chemotherapy regimens. Immunostaining of NQO1 in the metastases was lower in those responding to chemotherapy (p = 0.041), with a significant correlation between primary and metastatic disease sites (r = 0.44, p = 0.001). Knockdown of NQO1 with small interfering RNA followed by treatment with irinotecan and 5FU reduced the IC50 from 100.1µM to 49.8µM and from 200.1µM to 25.0µM respectively. Pre-treating cells with dicoumarol (a known competitive inhibitor) prior to incubation in irinotecan and 5FU reduced the IC50 from 100.0µM to 50.0µM and from 183.7µM to 49.9µM respectively. <h3>Conclusion</h3> These results show that proteomic sequencing of matched metastatic colorectal cancer samples is feasible, with high protein coverage. The high degree of similarity between the primary and secondary proteomes suggests that primary tissue is predictive of the metastatic phenotype. NQO1 expression in the primary tumour predicts response to neoadjuvant chemotherapy in the liver metastases, and inhibition of this protein at both genetic and functional levels improves chemosensitivity. Further validation in an <i><i>in vivo</i></i>model is planned. <h3>Disclosure of interest</h3> P. Sutton Grant/ Research Support from: Cancer Research UK, J. Evans: None Declared, R. Jones: None Declared, C. Goldring: None Declared, D. Palmer: None Declared, N. Kitteringham: None Declared, H. Malik: None Declared, D. Vimalachandran: None Declared.
NIMG-38MULTIMODAL IMAGING OF SPATIAL PATTERNS OF POST-TREATMENT GLIOBLASTOMA PROGRESSION
Authors: Edit Bosnyak, David Kamson, Natasha Robinette, Geoffrey Barger, Sandeep Mittal, Csaba Juhasz
Journal: Neuro-Oncology (2015)

BACKGROUND: Amino acid PET can accurately detect recurrent gliomas. In high-grade gliomas, increased amino acid uptake is often observed not only in the tumor mass but also outside the contrast-enhancing tumor region, in tumor-infiltrated brain. In this study, we evaluated if high uptake of the PET radiotracer alpha-[11C]-methyl-L-tryptophan (AMT) in non-enhancing brain regions could predict subsequent MRI progression in previously treated glioblastomas. METHODS: AMT-PET scanning was performed in 12 patients (mean age: 61 years) who showed a contrast-enhancing area suspicious for glioblastoma recurrence on MRI. Brain regions showing increased AMT uptake within and outside the contrast-enhancing volume were objectively delineated using a previously defined uptake threshold (Kamson et al., Neuro-Oncol, 2014;16:1373-83), consistent with glioma infiltration, using the 3D Slicer software. Volume and AMT uptake of non-enhancing regions with high AMT uptake were compared to the areas showing progressive MRI contrast-enhancement on subsequent serial MRIs performed in 1-2-month intervals. RESULTS: The volume of increased AMT uptake outside the contrast-enhancing region varied widely across patients (0.6-37 cm3; median: 4.5 cm3) and extended up to 24 mm from the edge of MRI contrast enhancement. Ten patients showed clear subsequent progression of the contrast-enhancing lesion, with new areas of enhancement preferentially encompassing and, in 6 cases, extending beyond the PET-positive brain volume. In two patients, where high AMT uptake did not extend beyond the initial contrast enhancement, MRI remained stable during a 2-year follow-up. Higher maximum AMT uptake in non-enhancing brain was associated with shorter time to subsequent MRI progression (r = -0.69, p = 0.014). CONCLUSIONS: Increased amino acid uptake, detected by PET, beyond contrast-enhancing lesions can help predict the location and timing of subsequent tumor progression. This could support decisions for surgical intervention or other targeted therapies for recurrent glioblastomas.
Predictors of a true complete response in colorectal liver metastases that disappear radiographically following chemotherapy
Authors: R. A. Taylor, R. R. White, N. Kemeny, W. R. Jarnagin, R. P. DeMatteo, Y. Fong, L. H. Blumgart, M. D’Angelica
Journal: Journal of Clinical Oncology (2007)

4058 Background: During chemotherapy for colorectal liver metastases (LM), some lesions disappear by CT scan. This may represent a true complete response (CR) with eradication of tumor or a reduced sensitivity of imaging due to chemotherapy induced hepatic steatosis. This study aimed to determine the significance of radiologic disappearance of LM treated with chemotherapy and factors predictive of a true CR. Methods: Between 2000 and 2003, 435 patients evaluated by a hepatobiliary surgeon were treated with neoadjuvant chemotherapy for LM. Inclusion criteria were fewer than 12 LM initially, disappearance of one or more LM by CT scan and a clinical follow-up of at least 1 year after disappearance. A pathologic CR (pCR) was defined as the absence of a LM in the resected specimen, a durable clinical CR (cCR) was defined as a LM that did not reappear during follow-up imaging. A LM was defined as found if it was detected by other imaging (MRI), at resection, or if it recurred during follow-up. LM that were found were compared to pCR and durable cCR to determine factors predictive of a true CR. Results: During chemotherapy, 39 (9%) patients had a total of 117 LM disappear by follow-up CT scan. The outcome is shown in the Table . Treatment with hepatic arterial infusion (HAI) chemotherapy (n=22) was associated with a significantly higher rate of pCR or durable cCR (42% vs. 14%, p&lt;0.001). LM were also significantly more likely to represent a pCR or durable cCR when the surrounding liver did not demonstrate steatosis (p&lt;0.001), when the patient’s BMI was &lt;30 kg/m 2 (p=0.002), and when a preoperative MRI was performed (p=0.01). Conclusions: Among disappearing LM, a pCR occurs in 37% and a durable cCR in 26%, yielding a true CR rate of 63%. The disappearing LM in patients treated with HAI chemotherapy were more likely to a represent true CR when compared to systemic chemotherapy alone. Hepatic steatosis and obesity impaired the ability to detect lesions by CT scan and MRI improved the preoperative detection rate of disappearing LM. [Table: see text] No significant financial relationships to disclose.
NTCT-12UPDATED SAFETY ANALYSIS OF BEVACIZUMAB PLUS ALTERNATING ELECTRIC FIELDS THERAPY IN PATIENTS WITH RECURRENT MALIGNANT GLIOMAS
Authors: Eric T. Wong, Melissa Phung, Loretta Barron, Edwin Lok
Journal: Neuro-Oncology (2015)

BACKGROUND: Bevacizumab and NovoTTF Therapy are treatments approved by the FDA for recurrent glioblastoma. We updated our single-institution experience in using this combination for patients with recurrent malignant gliomas. METHODS: We identified from January 2012 to May 2015 the side effects experienced by patients while on bevacizumab and NovoTTF Therapy, together with their dexamethasone usage. Overall survival (OS) was also tabulated. RESULTS: Out of 53 patients in the cohort, there were 25 men and 13 women who received both treatments. Their median age was 54 (range 29-76). All had Karnofsky Performance Score of 60 or above. The median on-treatment time was 3.3 (range 0.2-31.7) months. Adverse events include minor scalp rash (9), electric shock sensations (5), liquefied hydrogels from high ambient temperature (5), array removal during sleep (3), vivid dreams (2), scalp ulcers (2), confusion with connector ports (2), scalp pruritis (1) and meningitis from contemporaneous craniotomy (1). Seven (18%) required treatment interruption, but only one grade 3 scalp rash (3%) and one grade 4 meningitis (3%) resulted in prolonged treatment interruption or cessation. No hemorrhagic complication or thromboembolism was seen. The concurrent use of bevacizumab enabled a majority to lower dexamethasone usage below 4 mg/day and the median on-treatment duration was 4.2 months in patients who used  4 mg/day, respectively (P = 0.05). CONCLUSIONS: No additive or synergistic side effects were observed and the addition of bevacizumab helped to lower dexamethasone requirement among patients treated with NovoTTF Therapy. Future prospective evaluation will be needed to assess both side effects and efficacy of this treatment combination.
Observations on the Use of Cortisone and ACTH in Rheumatoid Arthritis
Authors: William S. Clark, Henrick O. Tonning, J. Peter Kulka, Walter Bauer
Journal: New England Journal of Medicine (1953)

CORTISONE and ACTH have favorable effects on the clinical, laboratory and histologic manifestations of rheumatoid arthritis. However, neither of these agents is curative or specific, and both are capable of inducing the disturbing biochemical and pathologic changes of Cushing's syndrome.1 2 3 4 5 6 7 It is too early to determine their effects on the ultimate course of this unpredictable, chronic disease, but cumulative experience permits certain general conclusions regarding their ameliorative properties. "Improvement" in rheumatoid arthritis embraces a variety of changes in its manifestations, ranging from remissions in articular and systemic inflammatory processes to purely functional or subjective changes. Accordingly, it is difficult to . . .