tbuckley/cabot-search huggingface dataset:
Abstract 2915: Penfluridol suppresses glioblastoma tumor growth by inhibiting sonic hedgehog signaling
Authors: Alok Ranjan, Sanjay K. Srivastava
Journal: Cancer Research (2016)

Abstract Glioblastoma (GBM) is the most common brain tumor with poor survival rate. The main obstacle in the treatment of glioblastoma patients is the presence of blood brain barrier, which restricts the movement of the drugs to reach the brain. Penfluridol (PF) is known to cross blood brain barrier and is a clinically approved drug for schizophrenia patients. It is demonstrated and established by us that penfluridol suppresses the growth of metastasized breast cancer cells in brain giving us the rationale to evaluate it against glioblastoma (Alok Ranjan, Parul Gupta and Sanjay Srivastava, Cancer Research 2015). Penfluridol significantly reduced the viability of U87-MG, T98G and U251 MG glioblastoma cells with an IC50 of 6μM, 5.5μM and 9μM respectively after 24 h of treatment and induced apoptosis as exhibited by FITC/Annexin assay and cleavage of caspase 3 as well as PARP. It has been shown that GLI1, a transcription factor belonging to sonic hedgehog signaling is overexpressed in GBM and responsible for tumor progression. Our results demonstrated that penfluridol treatment reduced the expression of GLI1 in U87MG, T98G and U251 MG cells in concentration-dependent manner. In addition, overexpression of MGMT, a DNA repair enzyme has been linked to temozolomide (TMZ) resistance in GBM therapy. Combination of PF and TMZ induced more apoptosis and reduced the expression of GLI1 and MGMT as compared to PF or TMZ treatment alone. Our results further demonstrated that oral administration of PF inhibited the growth of GBM tumors by 66% and 72% in subcutaneous and intracranial GBM tumor model respectively. Immunohistochemical analysis of tumor tissue and western blot analysis of tumor lysate indicated down regulation of GLI1, MGMT and increase in cleavage of caspase 3, confirming in vitro finding. Apoptosis induction effect of PF treatment in tumor tissues was further confirmed by Tunel staining. Taken together, these results indicate that overall GBM tumor growth suppression by penfluridol was associated with inhibition of Gli1 and induction of apoptosis Citation Format: Alok Ranjan, Sanjay K. Srivastava. Penfluridol suppresses glioblastoma tumor growth by inhibiting sonic hedgehog signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2915.
Exosome-mediated Delivery of Hydrophobically Modified siRNA for Huntingtin mRNA Silencing
Authors: Marie-Cécile Didiot, Lauren M Hall, Andrew H Coles, Reka A Haraszti, Bruno MDC Godinho, Kathryn Chase, Ellen Sapp, Socheata Ly, Julia F Alterman, Matthew R Hassler, Dimas Echeverria, Lakshmi Raj, David V Morrissey, Marian DiFiglia, Neil Aronin, Anastasia Khvorova
Journal: Molecular Therapy (2016)

Delivery represents a significant barrier to the clinical advancement of oligonucleotide therapeutics for the treatment of neurological disorders, such as Huntington's disease. Small, endogenous vesicles known as exosomes have the potential to act as oligonucleotide delivery vehicles, but robust and scalable methods for loading RNA therapeutic cargo into exosomes are lacking. Here, we show that hydrophobically modified small interfering RNAs (hsiRNAs) efficiently load into exosomes upon co-incubation, without altering vesicle size distribution or integrity. Exosomes loaded with hsiRNAs targeting Huntingtin mRNA were efficiently internalized by mouse primary cortical neurons and promoted dose-dependent silencing of Huntingtin mRNA and protein. Unilateral infusion of hsiRNA-loaded exosomes, but not hsiRNAs alone, into mouse striatum resulted in bilateral oligonucleotide distribution and statistically significant bilateral silencing of up to 35% of Huntingtin mRNA. The broad distribution and efficacy of hsiRNA-loaded exosomes delivered to brain is expected to advance the development of therapies for the treatment of Huntington's disease and other neurodegenerative disorders. Delivery represents a significant barrier to the clinical advancement of oligonucleotide therapeutics for the treatment of neurological disorders, such as Huntington's disease. Small, endogenous vesicles known as exosomes have the potential to act as oligonucleotide delivery vehicles, but robust and scalable methods for loading RNA therapeutic cargo into exosomes are lacking. Here, we show that hydrophobically modified small interfering RNAs (hsiRNAs) efficiently load into exosomes upon co-incubation, without altering vesicle size distribution or integrity. Exosomes loaded with hsiRNAs targeting Huntingtin mRNA were efficiently internalized by mouse primary cortical neurons and promoted dose-dependent silencing of Huntingtin mRNA and protein. Unilateral infusion of hsiRNA-loaded exosomes, but not hsiRNAs alone, into mouse striatum resulted in bilateral oligonucleotide distribution and statistically significant bilateral silencing of up to 35% of Huntingtin mRNA. The broad distribution and efficacy of hsiRNA-loaded exosomes delivered to brain is expected to advance the development of therapies for the treatment of Huntington's disease and other neurodegenerative disorders.
TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy
Authors: Han Zhang, Zheng Chen, Roberto N. Miranda, L. Jeffrey Medeiros, Nami McCarty
Journal: Cancer Research (2016)

Expression of the transglutaminase TG2 has been linked to constitutive activation of NF-κB and chemotherapy resistance in mantle cell lymphoma (MCL) cells. TG2 forms complexes with NF-κB components, but mechanistic insights that could be used to leverage therapeutic responses has been lacking. In the current study, we address this issue with the discovery of an unexpected role for TG2 in triggering autophagy in drug-resistant MCL cells through induction of IL6. CRISPR-mediated silencing of TG2 delayed apoptosis while overexpressing TG2 enhanced tumor progression. Under stress, TG2 and IL6 mediate enhanced autophagy formation to promote MCL cell survival. Interestingly, the autophagy product ATG5 involved in autophagosome elongation positively regulated TG2/NF-κB/IL6 signaling, suggesting a positive feedback loop. Our results uncover an interconnected network of TG2/NF-κB and IL6/STAT3 signaling with autophagy regulation in MCL cells, the disruption of which may offer a promising therapeutic strategy. Cancer Res; 76(21); 6410-23. ©2016 AACR.
Abstract 30: Kras mediates amino acid metabolism during nutrient stress
Authors: Dana Gwinn, Alejandro Sweet-Cordero
Journal: Cancer Research (2016)

Abstract Kras is a small GTPase that functions in the transmission of extracellular mitogenic stimuli, and is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC). Previously, Kras has been demonstrated to play a role in tumor metabolism in certain cell types and cancers, but this has yet to be analyzed in the context of NSCLC. We have analyzed how Kras changes metabolic gene expression by expressing a doxycycline-inducible hairpin against Kras in 4 NSCLC cell lines. One of the most regulated metabolism genes is asparagine synthetase (Asns), which transfers the γ-amino group of glutamine to aspartate, yielding glutamate and asparagine. We find elevated levels of Asns in Kras mutant tumors, and that expression of Asns correlates with poor patient outcome. Knockdown of Asns in the absence of exogenous asparagine in the media results in inhibition of cell growth and induction of apoptosis that is rescued by addition of asparagine. Additionally, under conditions of low glutamine levels, knockdown of Asns sensitizes cells to apoptosis, and overexpression of Asns is protective under these conditions. We also find a role for the glutaminase-activity of Asns in glutamine-mediated anapleurosis of the TCA cycle. These observations suggest Asns may be an interesting therapeutic target for NSCLC tumors with mutations in Kras. Citation Format: Dana Gwinn, Alejandro Sweet-Cordero. Kras mediates amino acid metabolism during nutrient stress. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 30.
Abstract 26: Long-term Blood Pressure Variability though Young Adulthood and Cognitive Function in Midlife; The Coronary Artery Risk Development in Young Adults (CARDIA)Study
Authors: Yuichiro Yano, Hongyan Ning, Norrina Allen, Jared P. Reis, Kiang Liu, Philip Greenland, Donald Lloyd-Jones
Journal: Circulation (2014)

Background: Blood pressure variability (BPV) consists of short-term BPV (e.g., diurnal BPV) and long-term BPV (e.g., visit-to-visit BPV). The prospective association of long-term BPV though young adulthood with cognition in midlife is unknown. Methods: CARDIA is a multicenter community-based study that included participants (ppts) aged 18 to 30 years at baseline (Year 0: Y 0 ) in 1985-86 with follow-up examinations at Y 2 , Y 5 , Y 7 , Y 10 , Y 15 , Y 20 , and Y 25 . BP was measured at each exam, and visit-to-visit BPV was assessed by standard deviation (SD), coefficient of variation (CV), maximum minus minimum BP difference (MMD), and average real variability (ARV) across 7 visits (Y 0-20 ). Cognitive function was assessed at Y 25 by the Digit Symbol Substitution Test (DSST, a measure of psychomotor speed; n=2,318), the Rey Auditory Verbal Learning Test (RAVLT, a measure of short-term verbal memory; n=2,321), and the modified Stroop test (executive function; n=2,307). We performed separate multivariable-adjusted linear regression models, and also adjusted for baseline BP (Y 0 ), change of BP (Y 20 -Y 0 ), or cumulative BP from Y 0 to Y 20 (mmHg х year) to determine whether BPV is associated with cognition independent of long-term BP level. Results: At the Y 25 examination, included ppts had a mean age of 50 years, 57% were women and 43% were black. BPV measured by higher SD and ARV in both systolic and diastolic BP was significantly associated with lower DSST and lower RAVLT. SD and ARV remained significant even after further adjustment for baseline BP, change of BP, or cumulative BP (Table). Measures of BPV were not associated with the Stroop test. Associations between the CV and MMD measures of BPV with cognitive function were similar to those of SD (not shown). Conclusions: Long-term BPV over 20-years through young adulthood is associated with worse psychomotor speed and verbal memory in midlife, independent of BP levels. These results may have implications for understanding the pathogenesis of cognitive dysfunction in older adults.
Community-acquired pneumonia in children: what to do when there is no response to standard empirical treatment?
Authors: Shivanthan Shanthikumar, Amelia Clifford, John Massie, Theresa Cole, Andrew Steer, Michael Marks, Amanda Gwee
Journal: Thorax (2016)

A 5-year-old female presents to a tertiary paediatric hospital in Australia with a 2-day history of fever, vomiting and abdominal pain. Her past history consists of three episodes of otitis media in the preceding 12 months, all resulting in tympanic membrane perforation. Her parents report an ‘innocent heart murmur’ diagnosed by a paediatric cardiologist. There is no history of travel or animal exposure. With regard to family history, she is the child of non-consanguineous Caucasian parents, and her father has Crohn's disease. On examination, she is febrile (40.0°C) and tachypnoeic (45 breaths/min) with normal oxygen saturations (99% room air). Bronchial breath sounds are auscultated posteriorly in the left lower zone. She has a 3/6 systolic murmur heard at the apex and lower left sternal edge with no radiation. Her first full blood examination showed a neutrophilia (13.9×109/L, normal  2.0×109/L) which resolved. Her C-reactive protein (CRP) is elevated at 157 mg/L (normal  39.0°C). Blood cultures on two occasions are negative.



Figure 1 
(A) A chest radiograph (CXR) showing left lower lobe consolidation with suggestion of abscess; (B). Repeat CXR showing worsening left lower lobe consolidation and tracheal deviation; (C). CT scan showing left lower lobe consolidation, bilateral lung nodules and some areas of ground-glass opacification.



The initial presentation with fever and abdominal pain is not uncommon in patients with pneumonia. Tachypnoea is a sensitive and specific sign of pneumonia, and CXR is the most appropriate initial diagnostic investigation.1 The presence of fever, …
Addressing the High Costs of Pancreaticoduodenectomy at Safety-Net Hospitals
Authors: Derek E. Go, Daniel E. Abbott, Koffi Wima, Dennis J. Hanseman, Audrey E. Ertel, Alex L. Chang, Shimul A. Shah, Richard S. Hoehn
Journal: JAMA Surgery (2016)

Safety-net hospitals care for vulnerable patients, providing complex surgery at increased costs. These hospitals are at risk due to changing health care reimbursement policies and demand for better value in surgical care.To model different techniques for reducing the cost of complex surgery performed at safety-net hospitals.Hospitals performing pancreaticoduodenectomy (PD) were queried from the University HealthSystem Consortium database (January 1, 2009, to December 31, 2013) and grouped according to safety-net burden. A decision analytic model was constructed and populated with clinical and cost data. Sensitivity analyses were then conducted to determine how changes in the management or redistribution of patients between hospital groups affected cost.Overall cost per patient after PD.During the 5 years of the study, 15 090 patients underwent PD. Among safety-net hospitals, low-burden hospitals (LBHs), medium-burden hospitals (MBHs), and high-burden hospitals (HBHs) treated 4220 (28.0%), 9505 (63.0%), and 1365 (9.0%) patients, respectively. High-burden hospitals had higher rates of complications or comorbidities and more patients with increased severity of illness. Perioperative mortality was twice as high at HBHs (3.7%) than at LBHs (1.6%) and MBHs (1.7%) (P < .001). In the base case, when all clinical and cost data were considered, PD at HBHs cost $35 303 per patient, 30.1% and 36.2% higher than at MBHs ($27 130) and LBHs ($25 916), respectively. Reducing perioperative complications or comorbidities by 50% resulted in a cost reduction of up to $4607 for HBH patients, while reducing mortality rates had a negligible effect. However, redistribution of HBH patients to LBHs and MBHs resulted in significantly more cost savings of $9155 per HBH patient, or $699 per patient overall.Safety-net hospitals performing PD have inferior outcomes and higher costs, and improving perioperative outcomes may have a nominal effect on reducing these costs. Redirecting patients away from safety-net hospitals for complex surgery may represent the best option for reducing costs, but the implementation of such a policy will undoubtedly meet significant challenges.
PR1 Peptide Vaccine-Induced Immune Response Is Associated with Better Event-Free Survival in Patients with Myeloid Leukemia.
Authors: Muzaffar H. Qazilbash, Eric D. Wieder, Peter F. Thall, Xuemei Wang, Rosa L. Rios, Sijie Lu, Shreya Kant, Sergio Giralt, Elihu H. Estey, Jorge Cortes, Krishna Komanduri, Richard E. Champlin, Jeffrey J. Molldrem
Journal: Blood (2007)
Lenalidomide (LEN) in patients with transformed lymphoma: Results from a large international phase II study (NHL-003).
Authors: C. B. Reeder, J. Vose, T. E. Witzig, P. L. Zinzani, R. Buckstein, J. Polikoff, J. Li, D. Pietronigro, A. L. Ervin-Haynes, M. S. Czuczman
Journal: Journal of Clinical Oncology (2010)

8037 Background: From time of diagnosis, patients with indolent lymphoma have a 10-year 30% risk of transformation to an aggressive non-Hodgkin's lymphoma (aNHL) (Al-Tourah. JCO. 2008). Patients with transformed disease have an aggressive disease course with poorer outcomes than patients with untransformed disease, and fewer effective therapies than those with DLBCL. An analysis of 600 patients with FL showed a 10-yr OS of 36% for patients with transformed lymphoma (TL) vs 75% for non-transformed patients (P<0.001); median OS for patients with TL was 1.7 yrs, despite increased use of high-dose chemotherapy and SCT. The few trials that include patients with TL show limited activity with treatments used for other NHLs. Here we report results for patients with TL enrolled in an international phase 2 trial of LEN monotherapy in patients with relapsed/refractory (rel/ref) aNHL. Methods: Patients had to have rel/ref aNHL after ≥1 prior therapies and ≥1 measurable lesion ≥2 cm. Oral LEN 25 mg/day was given on days 1–21 of a 28-day cycle, and continued until progression or unacceptable toxicity. Results: Of 217 patients enrolled on study 33 (15%) had TL; 23 had transformed FL (tFL), 7 had transformed CLL/SLL (tCLL/SLL), and 3 were other. Median age was 66 yrs (42–84), 58% of patients were stage IV, patients had a median of 4 (1–12) prior therapies, and 24.2% had prior SCT. LEN induced responses in 45% of patients with TL, which included 21% of patients with a CR/unconfirmed CR. Responses were observed in 13/23 (57%) patients with tFL, and in 0/7 patients with tCLL/SLL. Median PFS was 5.4 mos. At a median follow-up of 5.6 mos median response duration was 12.8 mos. The most common Gr 4/3 side effect was reversible myelosuppression, including neutropenia (15% gr 4; 33% gr 3) and thrombocytopenia (3%; 12%), which is consistent with results from other studies of LEN in NHL. Conclusions: LEN has promising clinical activity and achieves durable responses in patients with TL. Also, it may be necessary to consider the original histology when setting a course of therapy for patients with TL. Further studies are needed in this hard-to-treat population. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene Celgene Celgene
The volume regulated anion channel inhibitor NS3728 to enhance the cytotoxic effects of SN-38 in human colorectal cancer cells grown in vitro.
Authors: Jan Stenvang, Thiago Lima, Signe Lykke Nielsen, Jorgen Drejer, Nils Brunner, Palle Christophersen
Journal: Journal of Clinical Oncology (2016)

e23170 Background: Drug resistance represents the main cause of cancer related deaths. Identification of new drugs for treatment of drug resistant cancer thus constitute a highly unmet medical need. The activity of ion channels is involved in regulation of cancer progression Thus, ion channel modulators are important compounds to investigate for their potential as targeted anti-cancer therapy. Methods: We applied the ion channel inhibitor NS3728, which is a blocker of the Volume Regulated Anion Channels (VRAC). We used human colorectal cancer (CRC) cell lines grown in culture (HT-29wt and HT-29SN38R : (this cell line has acquired SN3-8 resistance (SN-38 is the active metabolite of irinotecan) and HT-29OXR (this cell line has acquired resistance to oxaliplatin). In the HT-29wt and HT-29SN38R cell lines NS3728 was administred either alone or in combination with SN-38. In the HT-29wt and HT-29OXR cell lines NS3728 was administred either alone or in combination with oxaliplatin. Inhibition of cell viability was determined by MTT assays. Results: We applied 50 µM NS3728 to slightly inhibit both the HT-29wt and HT-29SN38 CRC cells typically to 70-80% of control treated cells. SN-38 was applied at 0.16 µM and caused inhibition in the HT-29wt and HT-29SN38 CRC cells to approximately 50-60% and 80-90%, respectively. However, when combining 50 µM NS3728 with 0,16 µM SN-38 a significant inhibition of cell growth was observed exceeding that of each of the drugs (p < 0.0003) in both cell lines suggesting that NS3728 sensitize and re-sensitize cells to SN-38. There were no re-sensitizing effects of NS3728 in the oxaliplatin resistant HT-29OXR cells (p > 0.05). Conclusions: These preclinical studies demonstrate that the VRAC inhibitor NS3728 can enhance the effect of certain types of chemotherapy on human CRC cells. Of particular interest is that NS3728 also enhanced the effect of SN-38 in cancer cells with acquired SN-38 resistance. SNS3728 has already passed clinical phase 1 testing and a potential clinical development plan could start with a phase 2 study enrolling metastatic CRC patients who have failed irinotecan treatment and then re-exposing the patients to irinotecan plus NS3728.
Therapeutic challenges: Cancer and pregnancy.
Authors: K. A. Cadoo, D. M. Graham, D. N. Carney
Journal: Journal of Clinical Oncology (2010)

e19668 Background: The incidence of cancer in pregnancy is rising. We report the outcome of 15 women treated at our institution over a 20-year period. Methods: Cases were identified and records reviewed. Results: Median age at diagnosis was 35 years (25–42), with median gestational age at presentation of 10 weeks (3–25). 3 (20%) had chemotherapy deferred- 2 had node negative, ER positive breast cancers who had surgery at diagnosis, with CMF post delivery, 1 patient with early stage Hodgkin's disease presented in the second trimester and received ABVD postpartum. 12 (80%) received chemotherapy while pregnant. 1 woman had Ewing sarcoma, 1 had limited stage small cell cancer of cervix, and 1 had stage 1c ovarian cancer. The other 9 women had large (mean 4 cm), high grade (89% gr III), high risk (67% node +) breast cancers, 8 of these women had surgery at diagnosis with adjuvant chemotherapy, 1 was locally advanced and received neoadjuvant chemotherapy. All 12 women received doxorubicin/cyclophosphamide q 21 days whilst pregnant. None were treated prior to 2nd trimester. A total of 54 cycles of chemotherapy were administered during pregnancy. The mean gestational age at delivery was 36 weeks (30–40). There were no spontaneous abortions or fetal malformations. 1 baby was born neutropenic but was well and recovered counts quickly. Postpartum, all women received further chemotherapy with or without radiotherapy as appropriate for their disease site and stage. At median follow-up 35 months (5–219), all 15 women are alive and clinically well; 14 (93%) are disease free. 1 patient with breast cancer had bone metastases on postpartum bone scan; she continues on zolendronic acid and is well at 3 years. There have been no developmental abnormalities reported in the children to date. Conclusions: Doxorubicin/cyclophosphamide can be safely administered beyond the first trimester. Although a heterogeneous group, there has been no apparent compromise of maternal oncologic outcome. Long-term follow up of these children for potential late toxicities is required. No significant financial relationships to disclose.