tbuckley/cabot-search huggingface dataset:
Histone deacetylase inhibitor (HDACi) LBH589 interference with androgen receptor expression transcriptional activity in prostate cancer cells.
Authors: Paul Thelen, Rolf-Hermann Ringert, Arne Strauß
Journal: Journal of Clinical Oncology (2012)

e15156 Background: Development of incurable castration resistant prostate cancer (CRPC) is intrinsically tied to androgen receptor (AR) deregulation. Our previous research demonstrated that the estrogen receptor-β regulates AR transcriptional activity when relieved from epigenetic repression by HDACi treatments. Here we investigated the HDACi LBH589 established clinically in cancer treatments for its therapeutic function in CRPC. Methods: LBH589 (obtained from Novartis, Switzerland) was used (1 through 100µM) to treat representative CRPC-cell models i.e. LNCaP with an AR mutation and VCaP featuring AR overexpression. We investigated tumor cell proliferation with a BrdU-test and investigated AR including AR splice variants, PSA, PCA3,TMPRSS2-ERG, IGF-axis genes and ERβ expression by real-time RT-PCR, ELISA and Western blots. Results: LBH589 treatment even at low concentrations of 1µM reduced excessively AR expression in LNCaP and diminished even overexpressed AR to moderate levels in VCaP. Accordingly, tumor cell proliferation and the expression of androgen regulated genes PSA, PCA-3 and TMPRSS2-ERG (in VCaP) decreased. Furthermore, the expression of IGF-1 receptor and IGF-1 was reduced. Whereas, the expression of pro-apoptotic, anti-proliferative IGFBP-3 and the expression of tumor suppressor ERβ were increased, even at highest LBH589 concentrations. Conclusions: The main target in CRPC therapy is the AR equipped with resurgent activity by gain of function and overexpression. HDACi treatments with LBH 589 while restoring ERβ expression directly intervenes with this AR surge resulting in reduced tumor cell proliferation and tumor cells adopt a less malignant phenotype. Such measures in the core of CRPC deregulations alone or in combination with further anti-androgen treatments might reduce the potential of escape mechanisms of CRPC-tumors in future therapy approaches.
Novel retrieval basket for the extraction of choledocholithiasis
Authors: Srinivas Ramireddy, Tomas R. DaVee, Ricardo Badillo, Nirav Thosani
Journal: Endoscopy (2019)

The management of choledocholithiasis can be a challenging problem depending on the number, size, and location of the stones. Therapeutic endoscopic retrograde cholangiopancreatography (ERCP) has been the standard of care for decades. Various tools and techniques have been used during ERCP including, but not limited to, sphincteroplasty, extraction balloon, mechanical lithotripsy with trapezoid basket, extracorporeal shockwave lithotripsy, and direct cholangioscopy with lithotripsy. Residual stones may remain even after adequate balloon sweeps and negative occlusion cholangiogram, especially if the bile duct is dilated and stones are small, escaping the balloon sweeps [1]. Direct cholangioscopy has proven to be a useful tool in directly visualizing the ducts for any residual stones in order to achieve complete clearance [2] [3].
DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance
Authors: Katsuhiro Togami, Timothy Pastika, Jason Stephansky, Mahmoud Ghandi, Amanda L. Christie, Kristen L. Jones, Carl A. Johnson, Ross W. Lindsay, Christopher L. Brooks, Anthony Letai, Jeffrey W. Craig, Olga Pozdnyakova, David M. Weinstock, Joan Montero, Jon C. Aster, Cory M. Johannessen, Andrew A. Lane
Journal: Journal of Clinical Investigation (2019)

The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp's ability to ADP-ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drug-dependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myeloid malignancies.
Dengue vascular leak syndrome: insights into potentially new treatment modalities
Authors: Anna P. Durbin
Journal: Journal of Clinical Investigation (2019)

Dengue viruses (DENV) are the most common cause of mosquito-borne viral illness in the world, affecting approximately 400 million people annually. Symptomatic illness ranges from a mild, self-limiting febrile illness to one manifested by plasma leakage that can lead to vascular collapse and death. In this issue of the JCI, Rathore et al. report that DENV can cause mast cell degranulation independently of mast cell infection, resulting in the release of the vasoactive mediators chymase and tryptase. The authors showed that recombinant chymase and tryptase increased endothelial permeability in a dose-dependent manner in human microvascular endothelial cells. They went on to evaluate the tryptase inhibitor nafamostat mesylate in a mouse model for severe DENV viremia. Strikingly, the potential therapeutic prevented and reversed the tryptase-induced vascular permeability. As there are currently no licensed drugs for the treatment of dengue, these findings present a possible treatment modality for severe disease.
Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule
Authors: Fei Deng, Isha Sharma, Yingbo Dai, Ming Yang, Yashpal S. Kanwar
Journal: Journal of Clinical Investigation (2019)

Overexpression of myo-inositol oxygenase (MIOX), a proximal tubular enzyme, exacerbates cellular redox injury in acute kidney injury (AKI). Ferroptosis, a newly coined term associated with lipid hydroperoxidation, plays a critical role in the pathogenesis of AKI. Whether or not MIOX exacerbates tubular damage by accelerating ferroptosis in cisplatin-induced AKI remains elusive. Cisplatin-treated HK-2 cells exhibited notable cell death, which was reduced by ferroptosis inhibitors. Also, alterations in various ferroptosis metabolic sensors, including lipid hydroperoxidation, glutathione peroxidase 4 (GPX4) activity, NADPH and reduced glutathione (GSH) levels, and ferritinophagy, were observed. These perturbations were accentuated by MIOX overexpression, while ameliorated by MIOX knockdown. Likewise, cisplatin-treated CD1 mice exhibited tubular damage and derangement of renal physiological parameters, which were alleviated by ferrostatin-1, a ferroptosis inhibitor. To investigate the relevance of MIOX to ferroptosis, WT mice, MIOX-overexpressing transgenic (MIOX-Tg) mice, and MIOX-KO mice were subjected to cisplatin treatment. In comparison with cisplatin-treated WT mice, cisplatin-treated MIOX-Tg mice had more severe renal pathological changes and perturbations in ferroptosis metabolic sensors, which were minimal in cisplatin-treated MIOX-KO mice. In conclusion, these findings indicate that ferroptosis, an integral process in the pathogenesis of cisplatin-induced AKI, is modulated by the expression profile of MIOX.
Novel small molecule retrograde transport blocker confers post-exposure protection against ricin intoxication
Authors: Xu Zhao, Haixia Li, Jia Li, Kunlu Liu, Bo Wang, Yuxia Wang, Xingzhou Li, Wu Zhong
Journal: Acta Pharmaceutica Sinica B (2019)

Ricin is a highly toxic type 2 ribosome-inactivating protein (RIP) which is extracted from the seeds of castor beans. Ricin is considered a potential bioterror agent and no effective antidote for ricin exists so far. In this study, by structural modification of a retrograde transport blocker Retro-2cycl, a series of novel compounds were obtained. The primary screen revealed that compound 27 has an improved anti-ricin activity compare to positive control. In vitro pre-exposure evaluation in Madin–Darby Canine Kidney (MDCK) cells demonstrated that 27 is a powerful anti-ricin compound with an EC50 of 41.05 nmol/L against one LC (lethal concentration, 5.56 ng/mL) of ricin. Further studies surprisingly indicated that 27 confers post-exposure activity against ricin intoxication. An in vivo study showed that 1 h post-exposure administration of 27 can improve the survival rate as well as delay the death of ricin-intoxicated mice. A drug combination of 27 with monoclonal antibody mAb4C13 rescued mice from one LD (lethal dose) ricin challenge and the survival rate of tested animals is 100%. These results represent, for the first time, indication that small molecule retrograde transport blocker confers both in vitro and in vivo post-exposure protection against ricin and therefore provides a promising candidate for the development of anti-ricin medicines.
Gynecologic cancers in pregnancy: guidelines based on a third international consensus meeting
Authors: F. Amant, P. Berveiller, I.A. Boere, E. Cardonick, R. Fruscio, M. Fumagalli, M.J. Halaska, A. Hasenburg, A.L.V. Johansson, M. Lambertini, C.A.R. Lok, C. Maggen, P. Morice, F. Peccatori, P. Poortmans, K. Van Calsteren, T. Vandenbroucke, M. van Gerwen, M. van den Heuvel-Eibrink, F. Zagouri, I. Zapardiel
Journal: Annals of Oncology (2019)

We aimed to provide comprehensive protocols and promote effective management of pregnant women with gynecological cancers. New insights and more experience have been gained since the previous guidelines were published in 2014. Members of the International Network on Cancer, Infertility and Pregnancy (INCIP), in collaboration with other international experts, reviewed existing literature on their respective areas of expertise. Summaries were subsequently merged into a manuscript that served as a basis for discussion during the consensus meeting. Treatment of gynecological cancers during pregnancy is attainable if management is achieved by collaboration of a multidisciplinary team of health care providers. This allows further optimization of maternal treatment, while considering fetal development and providing psychological support and long-term follow-up of the infants. Nonionizing imaging procedures are preferred diagnostic procedures, but limited ionizing imaging methods can be allowed if indispensable for treatment plans. In contrast to other cancers, standard surgery for gynecological cancers often needs to be adapted according to cancer type and gestational age. Most standard regimens of chemotherapy can be administered after 14 weeks gestational age but are not recommended beyond 35 weeks. C-section is recommended for most cervical and vulvar cancers, whereas vaginal delivery is allowed in most ovarian cancers. Breast-feeding should be avoided with ongoing chemotherapeutic, endocrine or targeted treatment. More studies that focus on the long-term toxic effects of gynecologic cancer treatments are needed to provide a full understanding of their fetal impact. In particular, data on targeted therapies that are becoming standard of care in certain gynecological malignancies is still limited. Furthermore, more studies aimed at the definition of the exact prognosis of patients after antenatal cancer treatment are warranted. Participation in existing registries (www.cancerinpregnancy.org) and the creation of national tumor boards with multidisciplinary teams of care providers (supplementary Box S1, available at Annals of Oncology online) is encouraged.
Histone Methyltransferases G9a and GLP; Identification and Validation of Novel Therapeutic Targets for Multiple Myeloma Treatment
Authors: Eva De Smedt, Julie Devin, Hui Liu, Anke Maes, Ken Maes, Kim De Veirman, Eline Menu, Karin Vanderkerken, Jerome Moreaux, Elke De Bruyne
Journal: Blood (2017)
Dissecting the Regulation of Human Hematopoiesis at Single-Cell and Single-Variant Resolution
Authors: Erik L. Bao, Jacob C. Ulirsch, Caleb A. Lareau, Leif S. Ludwig, Michael H. Guo, Christian Benner, Ansuman T. Satpathy, Vinay K. Kartha, Rany M. Salem, Joel N. Hirschhorn, Hilary K. Finucane, Martin J. Aryee, Jason D. Buenrostro, Vijay G. Sankaran
Journal: Blood (2018)
The immunohistological profile of membranous nephropathy associated with chronic Schistosoma mansoni infection reveals a glomerulopathy with primary features
Authors: Stanley de Almeida Araújo, Precil Diego Miranda de Menezes Neves, David Campos Wanderley, Marlene Antônia dos Reis, Cristiane Bitencourt Dias, Denise Maria Avancini Costa Malheiros, Luiz Fernando Onuchic
Journal: Kidney International (2019)

Schistosoma mansoni infection has been associated with glomerulonephritis for decades.1 Among the patients who present with hepatic fibrosis, 10%–15% develop glomerular disorders.2 Several types of glomerulopathy, including membranous nephropathy (MN),3 have been observed. Immunopathologic data were gathered from 12 patients with MN from Brazilian academic institutions (Figure 1). The patients had a mean age of 47.8 ± 13.7 years, and 75% were male. Median proteinuria was 5.2 g/24 h (varying between 2.0 and 6.9 g/24 h) with a mean serum creatinine of 1.06 ± 0.39 mg/dl.
Addressing Limitations in Case-Control Study of Patients Undergoing Resuscitative Endovascular Balloon Occlusion of the Aorta
Authors: Christopher A. Guidry, Allan B. Peetz, Mayur B. Patel
Journal: JAMA Surgery (2019)

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Abstract 12060: Tolvaptan Inhibits Aldosterone Production and Blood Pressure Elevation Induced by Angiotensin II in Hypertensive Rat Model
Authors: Yusuf Ali, Kaoru Dohi, Ryuji Okamoto, Kan Katayama, Masaaki Ito
Journal: Circulation (2018)

Introduction: Tolvaptan (Tolv), a selective vasopressin type 2 receptor (V2R) antagonist, therapy avoids stimulation of aldosterone production despite its strong diuretic effect. However, its influ...
OP0089 Association between tnf -308a and systemic lupus erythematosus in relation to hla-dr3 and six microsatellite markers on the short arm of chromosome vi
Authors: MW Van der Linden, A Van der Slik, E Pieterman, E Zanelli, MJ Giphart, FC Breedveld, RG Westendorp, TW Huizinga
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Allelic imbalance at polymorphic loci within the human HLA-DRB1 and TNF genes has been observed in association with increased susceptibility to systemic lupus erythematosus. <h3>Objectives</h3> We investigated whether the association of HLA-DRB1*0301 (HLA-DR3) and TNF-308A with SLE could be attributed to linkage to six polymorphic microsatellites between HLA-DRB1 and HLA-C. <h3>Methods</h3> Ninety-one consecutive Caucasian patients with SLE and 253 controls (organ donors) were typed for HLA-DRB1, D6S1014, D6S273, TNFa, MIB, C-1–2–5 and C-1–3–2 and for TNF promoter polymorphisms. Independent contribution of alleles to disease susceptibility was estimated by crosstabulation and multivariate regression. <h3>Results</h3> Carriership of TNF-308A was associated with susceptibility to SLE (odds ratio [95% confidence interval], 3.70 [2.24–6.11]). This remained present after stratification on carriership of HLA-DR3 (pooled odds ratio, 2.53 [1.37–4.70]). Stratification further revealed a possible association of carriership of C-1–2–5*192 with protection from SLE beyond the effects of HLA-DR3 and TNF-308A. Gene dose effect was observed for -308A only (homozygotes, 7.75 [3.01–20.0], heterozygotes, 3.15 [1.85–5.37]). In multivariate analysis, the association between HLA-DR3, TNF-308A, and C-1–2–5*192 remained independently associated with susceptibility to SLE (2.58 [1.29–5.18], 2.76 [1.43–5.31], and 0.26 [0.10–0.66], respectively). <h3>Conclusion</h3> An association of carriership of TNF-308A with susceptibility to SLE can not be attributed to linkage to HLA-DR3, nor to other polymorphic markers in the vicinity of the TNF gene. Further loci that are independently associated with SLE might be located in the vicinity of marker C-1–2–5.
Detection of mutations in the EGFR tyrosine kinase domain by DNA sequencing
Authors: M. Da Silva, K. E. Flynn, P. Choppa, Z. Zhou, D. W. Bell, A. J. Iafrate, R. J. Paler, B. A. Allitto, E. M. Rohlfs
Journal: Journal of Clinical Oncology (2006)

10060 Background: The presence of sequence alterations in the tyrosine kinase domain of the epidermal growth factor receptor gene (EGFR) have been documented as gefitinib/erlotinib sensitizing mutations and serve as indicators for targeted (Iressa/Tarceva) therapy in patients with non-small-cell lung carcinoma (NSCLC). We report results obtained from the development and validation of a sequencing-based assay for the detection of these somatic mutations. Methods: Specimens tested included4 DNA samples with known EGFR mutations and 59 formalin-fixed primary or metastatic lung carcinomas, 22 which had known EGFR genotypes and 37 which were untested. Forty-one were adenocarcinomas. The most tumor-rich area of the section was micro-dissected to minimize amplification of non-tumor cells. DNA was extracted following treatment to deparaffinize and dehydrate the tissue section. A quantitative EGFR PCR was used to determine if the quantity of isolated DNA was sufficient for sequence analysis. A first-round multiplex amplification was followed by four semi-nested PCR amplifications targeting EGFR exons 18–21 and the flanking splice sites. These products were then subjected to sequencing reactions and evaluated for alterations as compared to the wild type sequence. Results: All of the specimens met the minimum quantity of 750pg of EGFR DNA required for the analysis. Thirty-one of the 37 anonymous specimens showed no sequence alterations in exons 18–21. Four of the five specimens with sequence alterations had known sensitizing mutations; three were L858R and one was 2235–2249del15. One specimen had a novel W817X mutation in exon 20. One specimen failed analysis for three of the exons. The percent tumor in the area selected for analysis varied from 5–30% in the specimens with sequence alterations. Twenty-five of the 26 samples with known genotypes were correctly identified by this method. In one sample a reported mutation was not detected, possibly due to selection of a different tumor nodule for testing. Resequencing of the sample by an outside lab confirmed the negative result. Conclusions: We have developed a highly sensitive and accurate sequencing-based assay capable of detecting somatic mutations in EGFR exons 18–21 which is important in the treatment and management of patients with NSCLC. [Table: see text]
Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma
Authors: Ann-Kathrin Desch, Kristin Hartung, Ante Botzen, Alexander Brobeil, Mathias Rummel, Lars Kurch, Thomas Georgi, Theresa Jox, Stefan Bielack, Stefan Burdach, Carl Friedrich Classen, Alexander Claviez, Klaus-Michael Debatin, Martin Ebinger, Angelika Eggert, Jörg Faber, Christian Flotho, Michael Frühwald, Norbert Graf, Norbert Jorch, Udo Kontny, Christof Kramm, Andreas Kulozik, Joachim Kühr, Karl-Walter Sykora, Markus Metzler, Hermann L. Müller, Michaela Nathrath, Thomas Nüßlein, Michael Paulussen, Arnulf Pekrun, Dirk Reinhardt, Harald Reinhard, Claudia Rössig, Axel Sauerbrey, Paul-Gerhardt Schlegel, Dominik T. Schneider, Wolfram Scheurlen, Lothar Schweigerer, Thorsten Simon, Meinolf Suttorp, Peter Vorwerk, Roland Schmitz, Regine Kluge, Christine Mauz-Körholz, Dieter Körholz, Stefan Gattenlöhner, Andreas Bräuninger
Journal: Leukemia (2019)
USPSTF Recommendations for <i>BRCA1</i> and <i>BRCA2</i> Testing in the Context of a Transformative National Cancer Control Plan
Authors: Padma Sheila Rajagopal, Sarah Nielsen, Olufunmilayo I. Olopade
Journal: JAMA Network Open (2019)

USPSTF Breast Cancer Recommendation Statement on Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer
Long-term response in a patient with urothelial cancer (UC) treated with AEZS-108.
Authors: Gustavo L. Fernandez, Andrew V. Schally, Tulay Koru-Sengul, Merce Jorda, Jaime R. Merchan, Aurea M. Flores, Norman L. Block, Murugesan Manoharan, Juergen Engel
Journal: Journal of Clinical Oncology (2013)

e15596 Background: AEZS-108 (AN-152, zoptarelin doxorubicin) is an LHRH-cytotoxic hybrid drug consisting of a Luteinizing Hormone Releasing Hormone (LHRH) agonist coupled to the cytotoxic radical, doxorubicin. The binding permits AEZS-108 to accumulate on the surface of cells expressing LHRH receptors (LHRH-R) thus allowing drug uptake. This approach exploits LHRH-R to gain access to the targeted tumor cells. Once internalized, the cytotoxic properties of doxorubicin induce the anti-tumor response. Methods: This is a case report of a 66 year old male with a superficial bladder cancer history who was diagnosed in May 2009 with metastatic UC from the prostatic urethra. He presented with pelvic and retroperitoneal lymph nodes (LN). Patient had a partial response to cisplatin based chemotherapy and underwent radical cystoprostatectomy in Oct 2009. No residual UC in bladder or prostate was seen on pathology's examination. However he did have 11/24 removed LN positive for UC. The patient showed increased retroperitoneal LN by December 2009. He received 2 further lines of chemotherapy with no response and developed severe back pain, cervical LN, extensive liver metastases and a bulky retroperitoneal mass. The patient entered a Phase I clinical trial of AEZS-108, for “locally advanced unresectable or metastatic LHRH-R positive UC patients who failed platinum based chemotherapy“. He received AEZS-108 every 3 weeks for 9 cycles from May to October, 2011. Results: After 2 cycles of the investigational drug all pain and palpable lymph neck nodes disappeared; he stopped all narcotics and tolerated treatment very well. Mostly grade1-2 with few grade 3 toxicities were seen. CT scan pretreatment, and at 8, 22, 75 weeks post-treatment showed dramatic response at all disease sites. Twenty months after treatment start, the patient is symptom- free with no evidence of disease. Conclusions: This is the first case of a patient with LHRH-R positive Urothelial Carcinoma treated with AEZS-108 that is being reported. Considering the generally poor outcome of progressive UC and the short survival of these patients, the effect of this drug in this patient has been remarkable. The phase one study is ongoing.