tbuckley/cabot-search huggingface dataset:
Abstract 990: Saxifragifolin D induces autophagy via activating IRE1α/ JNK pathway in breast cancer cells
Authors: Liang-Liang Bai, Jun-Min Shi, Min-Feng Chen, Dong-Mei Zhang, Ying Wang, Wen-Cai Ye
Journal: Cancer Research (2015)

Abstract Background and Objective: Saxifragifolin D (SD) was isolated from Androsace umbellata by our group. It has been reported to inhibit some types of cancer cells, such as Hep3B, HepG2, SK-OV-3, A549, HCT-115 and multidrug resistante cell line HepG2/ADM. However, the growth inhibitory effect of SD on breast cancer cells and the mechanisms is still unclear. In this study, we explored the underlying molecular mechanisms of SD-induced autophagy in breast cancer cells. Methods and Results: The autophagosomes, double membrane vacuolar structures, were observed in SD-treated MCF-7 and MDA-MB-231 cells by transmission electronic microscopy. And the autophagic vacuoles labeled by MDC were also increased in a time-dependent manner significantly. Besides, the autophagic ratio, quantified by using Cyto-ID® detection kit, was enhanced in a dose-dependent manner in these two cells. What's more, the marker of autophagy, LC3, was activated in MCF-7 and MDA-MB-231 cells treated with SD showed by western blot assay, further confirmed autophagy induced by SD. We also found that IRE1α which associated with endoplasmic reticulum (ER) stress was activated, and the JNK and Bcl-2 were phosphorylated in SD-treated MCF-7 and MDA-MB-231 cells by western blot assay. Accordingly, the up-regulation of Beclin1, Vps34, Atg5 and Atg16L were also detected in these two cells. Furthermore, suppression of autophagy by pretreating with Beclin1 siRNA or bafilomycin A1 decreased apoptosis and cell death, and resulted in decreases in expression of LC3- II and cleaved PARP. It's worth noting that inhibition of ER stress by IRE1α siRNA or TUDCA suppress autophagy and apoptosis, and the down-expression of LC3- II and cleaved PARP were measured. Conclusion: SD induces autophagy associated with IRE1α/ JNK pathway in breast cancer cells and these findings will provide molecular bases for molecular mechanistic studies of SD-treated breast cancer cells. Key words: Saxifragifolin D, autophagy, breast cancer. Citation Format: Liang-Liang Bai, Jun-Min Shi, Min-Feng Chen, Dong-Mei Zhang, Ying Wang, Wen-Cai Ye. Saxifragifolin D induces autophagy via activating IRE1α/ JNK pathway in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 990. doi:10.1158/1538-7445.AM2015-990
Identification Of Leukemia Suppressive Genes By Inducible Overexpression Of The DNA Methyltransferase DNMT3B During Leukemogenesis In Mice
Authors: Isabell Schulze, Petra Tschanter, Christian Rohde, Annika Krause, Heinz Linhart, Katja Hebestreit, Martin Dugas, Frank Rosenbauer, Wolfgang E. Berdel, Carsten Müller-Tidow
Journal: Blood (2013)
Immunologic activity of an activating anti-CD27 antibody (CDX-1127) in patients (pts) with solid tumors.
Authors: Jeffrey R. Infante, Howard A. Burris, Stephen Maxted Ansell, John J. Nemunaitis, Geoffrey R. Weiss, Victor Manuel Villalobos, Branimir I. Sikic, Matthew Hiram Taylor, Donald W. Northfelt, William Edgar Carson, Lana Pilja, Thomas R. Hawthorne, Thomas A. Davis, Michael Jay Yellin, Tibor Keler, Timothy Bullock
Journal: Journal of Clinical Oncology (2014)

3027 Background: CD27 is a co-stimulatory molecule that regulates T cell activation, survival, and memory responses through interaction with a tightly regulated ligand, CD70. CDX-1127 is an anti-CD27 antibody shown to activate T cells when combined with T cell receptor stimulation, and mediate anti-tumor activity in human CD27 transgenic mice challenged with syngeneic tumors. Methods: In a 3+3 dose-escalation (DE), 25 pts with advanced solid tumors received a single dose of CDX-1127 (0.1, 0.3, 1.0, 3.0 or 10 mg/kg IV) with 28-day observation, followed by up to 5 treatment cycles (4 weekly doses / Day 85 restaging), until progression. 16 melanoma and 11 renal cell carcinoma (RCC) pts have been enrolled in expansion (EX) cohorts (target n=15 each). Pharmacokinetic (PK) and immune parameters were assessed on serum and PBMC collected during study. Results: DE completed at 10 mg/kg with one dose-limiting toxicity, grade 3 transient asymptomatic hyponatremia, at 1.0 mg/kg. Treatment-related toxicity, generally grade 1-2, included fatigue, rash, nausea, decreased appetite and headache. 3 mg/kg was selected for EX based on DE immunological activity, PK and preclinical modeling. Stable disease has been seen in 4/25 DE pts (3.0, 3.8, 5.7 and 16.8+ months duration); 3/14 evaluable melanoma EX pts (2.6+, 3.1+, 5.7+ months); and 2/6 evaluable RCC EX pts (2.8+, 2.9+ months). In DE, sustained serum CDX-1127 levels were consistent with expected PK profile and correlated with binding to circulating lymphocytes; rapid and transient increases in serum IP-10 (mean [pg/ml]: Day 1 = 215, peak (6 hours post) = 731 [p<0.0001]); lesser increases in IL-6 and MCP-1; a significant reduction in regulatory T cells (mean [% of lymphocytes]: Day 1 = 1.66, Day 85 = 0.68 [p = 0.01]) and increase in NK cells. Ex vivo analysis demonstrated an increase in T cells responding to melanoma antigens in select melanoma pts. Gene expression analysis of RNA from PBMC is ongoing. Conclusions: In pts with solid tumors, CDX-1127 is well tolerated and induces immune activation consistent with CD27 co-stimulation. These results support combination studies with both conventional and immune-based therapies, which have shown synergistic activity in preclinical models. Clinical trial information: NCT01460134.
Phase II study of oxaliplatin (O) and bevacizumab (B) chemotherapy in refractory germ cell tumors (GCT).
Authors: R. Ramasubbaiah, J. Brames, E. L. Johnston, L. H. Einhorn, D. J.aughn, S. M. Perkins
Journal: Journal of Clinical Oncology (2010)

e15054 Background: Approximately 80% of patients (pts) with metastatic GCT are cured with first line cisplatin based chemotherapy or subsequent salvage therapy. However, there remains a cohort of pts with incurable refractory and late relapse disease. Single agent O has demonstrated response rate of 13-19% in this setting. VEGF overexpression appears to have a role in GCT progression, and there may be synergy between anti-VEGF therapy and certain cytotoxic agents. This is the first clinical study evaluating B in refractory GCT. Methods: Eligibility required prior cisplatin combination chemotherapy, salvage therapy with high dose chemotherapy (HDC) and prior paclitaxel and gemcitabine. Pts with late relapse or primary mediastinal nonseminomatous GCT (PMNGCT) required failure of at least one prior salvage chemotherapy regimen. Pts received O 85mg/m2 IV and B 10mg/kg IV on a q2wk cycle for up to 14 cycles. Toxicity, response (including serologic) and duration of remission were evaluated. Tumor response was evaluated by RECIST criteria. Serologic response was defined as normalization of markers > 4 wks (CR) and 1 log reduction in hCG or 50% reduction in AFP lasting > 4 wks (PR). Results: Since 11/2006, 19 pts have been enrolled, 18 are evaluable and enrollment continues. Median age was 42y (range 21-55). 2 women with PMNGCT were entered. Median number of prior treatments was 3.5 (range 2-6). There were 8 pts with late relapse and 8 had prior salvage HDC. Therapy was well tolerated. The most common all grade toxicities were nausea (66.7%), sensory neuropathy (61%) and fatigue (55.6%). G3/4 toxicities (seen in late relapse only) were fatigue (11%), pulmonary HTN and laryngitis (6% each). 16 pts were evaluated for serologic response; there were 3 CRs (16.7%) and 3 PRs (16.7%). 10 pts had measurable disease for RECIST evaluation, and no CRs were seen. 1 pt had PR per RECIST and serologic criteria (6%). Median duration of response was 29.3 wks (95% CI 10-36.9). 5 of 8 pts (62.5%) with late relapse responded (3 CR, 2PR). Conclusions: The combination of O+B is well tolerated in a heavily pretreated pt population. The response rate is encouraging when compared to previous trials with O alone. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Biogen Idec, GlaxoSmithKline
Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint
Authors: Tineke Cantaert, Jean-Nicolas Schickel, Jason M. Bannock, Yen-Shing Ng, Christopher Massad, Fabien R. Delmotte, Natsuko Yamakawa, Salome Glauzy, Nicolas Chamberlain, Tuure Kinnunen, Laurence Menard, Aubert Lavoie, Jolan E. Walter, Luigi D. Notarangelo, Julie Bruneau, Waleed Al-Herz, Sara Sebnem Kilic, Hans D. Ochs, Charlotte Cunningham-Rundles, Mirjam van der Burg, Taco W. Kuijpers, Sven Kracker, Hideo Kaneko, Yujin Sekinaka, Shigeaki Nonoyama, Anne Durandy, Eric Meffre
Journal: Journal of Clinical Investigation (2016)

Patients with mutations in AICDA, which encodes activation-induced cytidine deaminase (AID), display an impaired peripheral B cell tolerance. AID mediates class-switch recombination (CSR) and somatic hypermutation (SHM) in B cells, but the mechanism by which AID prevents the accumulation of autoreactive B cells in blood is unclear. Here, we analyzed B cell tolerance in AID-deficient patients, patients with autosomal dominant AID mutations (AD-AID), asymptomatic AICDA heterozygotes (AID+/–), and patients with uracil N-glycosylase (UNG) deficiency, which impairs CSR but not SHM. The low frequency of autoreactive mature naive B cells in UNG-deficient patients resembled that of healthy subjects, revealing that impaired CSR does not interfere with the peripheral B cell tolerance checkpoint. In contrast, we observed decreased frequencies of SHM in memory B cells from AD-AID patients and AID+/– subjects, who were unable to prevent the accumulation of autoreactive mature naive B cells. In addition, the individuals with AICDA mutations, but not UNG-deficient patients, displayed Tregs with defective suppressive capacity that correlated with increases in circulating T follicular helper cells and enhanced cytokine production. We conclude that SHM, but not CSR, regulates peripheral B cell tolerance through the production of mutated antibodies that clear antigens and prevent sustained interleukin secretions that interfere with Treg function.
In Vivo Role of Neutrophil Extracellular Traps in Antiphospholipid Antibody–Mediated Venous Thrombosis
Authors: He Meng, Srilakshmi Yalavarthi, Yogendra Kanthi, Levi F. Mazza, Megan A. Elfline, Catherine E. Luke, David J. Pinsky, Peter K. Henke, Jason S. Knight
Journal: Arthritis & Rheumatology (2016)

Antiphospholipid syndrome (APS) is a leading acquired cause of thrombotic events. Although antiphospholipid antibodies have been shown to promote thrombosis in mice, the role of neutrophils has not been explicitly studied. The aim of this study was to characterize neutrophils in the context of a new model of antiphospholipid antibody-mediated venous thrombosis.Mice were administered fractions of IgG obtained from patients with APS. At the same time, blood flow through the inferior vena cava was reduced by induction of stenosis. Resulting thrombi were characterized for size and neutrophil content. Circulating factors and the vessel wall were also assessed.As measured by both thrombus weight and thrombosis frequency, mice treated with IgG from patients with APS (APS IgG) demonstrated exaggerated thrombosis as compared with control IgG-treated mice. Thrombi in mice treated with APS IgG were enriched for citrullinated histone H3 (a marker of neutrophil extracellular traps [NETs]). APS IgG-treated mice also demonstrated elevated levels of circulating cell-free DNA and human IgG bound to the neutrophil surface. In contrast, circulating neutrophil numbers and markers of vessel wall activation were not appreciably different between APS IgG-treated mice and control mice. Treatment with either DNase (which dissolves NETs) or a neutrophil-depleting antibody reduced thrombosis in APS IgG-treated mice to the level in control mice.These data support a mechanism whereby circulating neutrophils are primed by antiphospholipid antibodies to accelerate thrombosis. This line of investigation suggests new, immunomodulatory approaches for the treatment of APS.
Age-related deterioration in the mechanical function of human dermal fibrillin microfibrils
Authors: M J Sherratt, J Y Bastrilles, J J Bowden, R E Watson, C E Griffiths
Journal: British Journal of Dermatology (2006)

Annual Meeting of the British-Society-for-Investigative-Dermatology APR 10-12, 2006 Manchester, ENGLAND
First-In-Man Phase I Study of Tpcs2a-Based Photochemical Internalisation (PCI) of Bleomycin in Locally Recurrent or Advanced/Metastatic, Cutaneous or Subcutaneous Malignancies
Authors: M. Forster, A. Sultan, W. Jerjes, C. Simeon, S. Morley, D. Carnell, C. Hopper
Journal: Annals of Oncology (2012)
Expression of Proliferation Related Genes in Myelodysplastic Syndromes (MDS) and Secondary Acute Myeloid Leukemia (AML) Patients with Resistance to Low Dose Vidaza and Thalidomide.
Authors: Naomi Galili, Benjamin L. Ebert, Peter Westervelt, Jessica Wasserman, Daniel Lee, Fatima Z. Raza, Todd R. Golub, Azra Raza
Journal: Blood (2006)
Metronomic capecitabine in advanced well or moderately differentiated neuroendocrine carcinomas.
Authors: M. Squadroni, G. Di Meglio, F. Spada, S. Terzi, K. Lorizzo, F. G. De Braud, V. Formica, A. Goldhirsch, N. Fazio
Journal: Journal of Clinical Oncology (2010)

e13130 Background: Conventional chemotherapy is not a standard of care for well or moderately differentiated neuroendocrine carcinomas (NECs). 5-fluorouracil (5FU) as a protracted venous infusion (PVI) showed some activity in this setting. Metronomic capecitabine (MC) is the oral alternative to PVI 5FU, avoiding a central venous device and elastomeric pump. We report our experience with MC in patients with advanced NECs. Methods: We retrospectively reviewed the clinical records of 23 patients with metastatic well or moderately differentiated NECs treated with MC at the European Institute of Oncology from Milan, between July 2005 and August 2009. Results: M/F ratio was 13/10, median age 56 years (range: 30-77). Seventeen patients (73%) had well- differentiated NECs, 1 had typical and 5 atypical PCs. Primary sites of tumor were pancreas/ileum/thyroid/lung/unknown in 48%, 9%, 4%, 26%, and 13% of patients, respectively. The Ki-67 was < 2% in 2 patients (9%), 3-19% in 16 (70%), and not performed in the other cases (22%). Twenty-two patients (96%) were pretreated. Baseline status of tumor was progression of disease (PD) in 16 (69%) patients, and stable disease (SD) in 7 (31%). MC was orally administered at 1,000-2,000 mg daily, continuously. Median duration of therapy was 7 months (range 3 days-31 months). In 11 patients (48%) a SD was observed, in 7 (30%) PD, and 5 (22%) were not evaluable. Median time to progression was 19 months (range: 2-31). Study treatment was discontinued due to PD in 9 patients (39%), and toxicity in 2 patients (9%). Twelve patients (52%) are currently on study treatment. Toxicity included 1 very early coronary spasm in a patient with a negative cardiac history, one grade 3 neutropenia, one grade 2 skin toxicity. After a 24 months median follow-up (range: 2-31) 5 patients (22%) died. Conclusions: Metronomic capecitabine is well tolerated and moderately active in patients with advanced well/moderately differentiated NECs. Cardiac toxicity seems to be independent from the drug dose and underlying cardiac status of the patient. Combination studies with biologic agents or other metronomic therapies are warranted. No significant financial relationships to disclose.
No Summer Vacation From Diabetes: Glycemic Control in Pediatric Participants in the T1D Exchange Registry Based on Time of Year
Authors: Jennifer L. Sherr, Claire T. Boyle, Kellee M. Miller, Roy W. Beck, William V. Tamborlane
Journal: Diabetes Care (2016)

Seasonal variation in glycemic control has been postulated to occur in school-aged children with type 1 diabetes, with higher HbA1c levels during summer months than during the school year because of lack of structure and less stringent adherence to a prescribed medical regimen during summer vacation (1). To address this question, we used data obtained in 1,972 youth with type 1 diabetes enrolled in the T1D Exchange (T1DX) at 56 clinical centers in the U.S. between 2010 and 2012 (2).

To be included in these analyses, participants had to be 8 to  3 years to minimize the influence of changes in residual endogenous insulin secretion over time, and have HbA1c measurements in each of three predefined periods: prior to the start of summer (March, April, May), end of summer vacation (August and September), and back in school (November and December). HbA1c values …
Anti-β2 Microglobulin Monoclonal Antibodies Overcome Bortezomib-Induced Drug Resistance In Multiple Myeloma By Inhibition Of Autophagy
Authors: Mingjun Zhang, Jin He, Yong Lu, Yuhuan Zheng, Bangxing Hong, Haiyan Li, Zhiqiang Liu, Jingda Xu, Huan Liu, Jianfei Qian, Qing Yi, Jing Yang
Journal: Blood (2013)
Urothelial carcinoma of donor origin in a kidney transplant patient
Authors: Rosa M. Michel Ortega, Daynna J. Wolff, Cynthia A. Schandl, Harry A. Drabkin
Journal: Journal for ImmunoTherapy of Cancer (2016)

Malignancy after transplantation is an uncommon multifactorial occurrence. Immunosuppression to prevent graft rejection is described as a major risk factor in malignancy development in the post-transplant state. Donor-derived malignancy is a rare reported complication. Herein, we review our patient history and discuss diagnostic strategies and the implications of immunosuppression for donor-derived malignancy.This is a 69-year-old man with post-renal-transplant urothelial carcinoma determined to be of donor origin. His course was complicated by BK virus at six years post-transplant; urothelial carcinoma was identified nine years post-transplant. Cystectomy was performed, but because of immunosuppression and underlying chronic kidney disease, the patient was considered ineligible for adjuvant chemotherapy. Two years after resection, screening MRI demonstrated retroperitoneal lymphadenopathy and a right upper pole mass in the transplanted kidney. Urine cytology confirmed the presence of malignant cells; FISH showed 2-8 copies of the X chromosome and no Y chromosome consistent with female origin of the malignant cells. CT-guided renal mass and paraaortic lymph node biopsies demonstrated that about 50 % of cells had an XY complement, while the remainder showed a XX genotype by chromosomal SNP microarray analysis. Immunosuppression was discontinued and the donor kidney removed. X/Y FISH of the urothelial carcinoma identified in the explanted kidney confirmed that the malignant cells were of female donor origin. Follow-up at 3, 6 and 12 months after discontinuation of immunosuppression and surgery demonstrated normalization of the lymphadenopathy and absence of new lesions.Immunosuppression is a major risk factor for development of malignancy in transplant recipients. Donor-derived malignancy can arise and current molecular studies allow an accurate diagnosis. Withdrawal of immunosuppression and surgical resection of the transplant kidney proved an effective treatment in our case.
Child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency: a cohort study of the French national registry for thrombotic microangiopathy
Authors: Bérangère S Joly, Alain Stepanian, Thierry Leblanc, David Hajage, Hervé Chambost, Jérôme Harambat, Fanny Fouyssac, Vincent Guigonis, Guy Leverger, Tim Ulinski, Thérésa Kwon, Chantal Loirat, Paul Coppo, Agnès Veyradier
Journal: The Lancet Haematology (2016)
Accuracy of preoperative imaging diagnosis as a possible new staging system in advanced ovarian, tubal, and peritoneal cancer: Using data from Japan Clinical Oncology Group study JCOG0602.
Authors: Takashi Onda, Yumiko Tanaka, Mitsuya Ishikawa, Yoko Hasumi, Satomi Kitai, Tomoko Manabe, Toyomi Satoh, Toshiaki Saito, Takahiro Kasamatsu, Tohru Nakanishi, Kaichiro Yamamoto, Hiroyuki Seki, Taro Shibata, Kenichi Miyamoto, Ikuo Konishi, Nobuo Yegashi, Hiroyuki Yoshikawa
Journal: Journal of Clinical Oncology (2016)

e17074 Background: We need a new staging system by preoperative imaging diagnosis when neoadjuvant chemotherapy (NAC) setting treatment becomes a standard treatment for advanced ovarian, tubal and peritoneal cancers. The purpose is to know whether we can accurately diagnose the origin and stage of cancer without diagnostic surgery before NAC. Methods: Preoperative institutional imaging diagnosis (IDx) for origin and tumor spread were compared with surgical or pathological findings in primary debulking surgery (PDS) in randomized controlled trial comparing between PDS and NAC arms in stage III/IV ovarian, tubal and peritoneal cancers (JCOG0602). These cancers were diagnosed preoperatively by 1) imaging studies (CT and/or MRI), 2) cytology of ascites, pleural effusions or fluids obtained by tumor centesis, and 3) CA125 > 200 U/ml and CEA < 20 ng/ml. Accuracy of IDx to diagnose extra-pelvic peritoneal tumor (EPT) and retroperitoneal lymph node metastasis (LNM), and to distinguish between ≤ 2cm and > 2cm EPT were analyzed. Dx by diagnostic radiology central review (DRCR) was also analyzed. Results: In total 149/301 patients (Pts) were allocated to PDS arm in JCOG0602 from 2006-2011. Two Pts did not undergo PDS, and DRCR was not performed in 1 Pt due to missing image films. Pathological Dx of the disease included 1 Pt with gastric cancer. Accuracy of IDx for target disease (ovary, tube, or peritoneum) was 99%. Positive predictive value (PPV) of IDx for EPT and LNM was 99% and 91%. In combination, PPV of IDx for stage III disease (T3 or N1) was 99%, while PPV of DRCR was 99%. Contrary, PPV of IDx for ≤ 2cm EPT was only 53%. Conclusions: We can diagnose the origin and stage III disease of ovarian, tubal and peritoneal cancers accurately by preoperative IDx using cytology and tumor markers together. However, we cannot distinguish between ≤ 2 cm and > 2 cm EPT. Clinical trial information: UMIN000000523.IDx Sensitivity(%) Specificity(%) PPV(%) NPV(%) Stage III disease 99 33 99 33 1. EPT overall 95 71 99 41 Rt subphrenic 60 89 94 44 Lt subphrenic 43 93 84 65 Omentum 90 80 97 55 Intestine 55 76 85 40 Paracolic gutter 52 88 84 60 Parietal peritoneum 58 78 75 61 2. LNM overall 66 78 91 41 Pelvic LNM 44 94 95 41 Aortic LNM 65 78 83 56