bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concentration-dependent Early Antivascular and Antitumor Effects of Itraconazole in Non–Small Cell Lung Cancer
Authors: Gerber David E. , Putnam William C. , Fattah Farjana J. , Kernstine Kemp H. , Brekken Rolf A. , Pedrosa Ivan , Skelton Rachael , Saltarski Jessica M. , Lenkinski Robert E. , Leff Richard D. , Ahn Chul , Padmanabhan Chyndhri , Chembukar Vaidehi , Kasiri Sahba , Kallem Raja Reddy , Subramaniyan Indhumathy , Yuan Qing , Do Quyen N. , Xi Yin , Reznik Scott I. , Pelosof Lorraine , Faubert Brandon , DeBerardinis Ralph J. , Kim James 
Published: August 2020

Abstract

Purpose:
Itraconazole has been repurposed as an anticancer therapeutic agent for multiple malignancies. In preclinical models, itraconazole has antiangiogenic properties and inhibits Hedgehog pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients.

Experimental Design:
Patients with non–small cell lung cancer (NSCLC) who had planned for surgical resection were administered with itraconazole 300 mg orally twice daily for 10–14 days. Patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic and pharmacodynamic analyses. Tissues from pretreatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyitraconazole concentration, and vascular and Hedgehog pathway biomarkers.

Results:
Thirteen patients were enrolled in this study. Itraconazole was well-tolerated. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole demonstrated a 6-fold difference across patients. Tumor itraconazole concentrations trended with and exceeded those of plasma. Greater itraconazole levels were significantly and meaningfully associated with reduction in tumor volume (Spearman correlation, −0.71; P = 0.05) and tumor perfusion (Ktrans; Spearman correlation, −0.71; P = 0.01), decrease in the proangiogenic cytokines IL1b (Spearman correlation, −0.73; P = 0.01) and GM-CSF (Spearman correlation, −1.00; P &lt; 0.001), and reduction in tumor microvessel density (Spearman correlation, −0.69; P = 0.03). Itraconazole-treated tumors also demonstrated distinct metabolic profiles. Itraconazole treatment did not alter transcription of GLI1 and PTCH1 mRNA. Patient size, renal function, and hepatic function did not predict itraconazole concentrations.

Conclusions:
Itraconazole demonstrates concentration-dependent early antivascular, metabolic, and antitumor effects in patients with NSCLC. As the number of fixed dose cancer therapies increases, attention to interpatient pharmacokinetics and pharmacodynamics differences may be warranted.
Calcium Channel Blockers Impair the Antitumor Activity of Anti-CD20 Monoclonal Antibodies by Blocking EGR-1 Induction
Authors: Spasevska Ivana , Matera Eva Laure , Chettab Kamel , Ville Jade , Potier-Cartereau Marie , Jordheim Lars Petter , Thieblemont Catherine , Sahin Denis , Klein Christian , Dumontet Charles 
Published: August 2020

AbstractDirect cell death induction, in addition to immune-effector cell-mediated mechanisms, is one of the key mechanisms of action of anti-CD20 antibodies, and yet the signaling pathways implicated remain poorly investigated. Here we show that the transcription factor EGR-1 is rapidly induced by anti-CD20 antibodies and is a key mediator for CD20-induced cell death. EGR-1 induction results from an increased calcium influx induced by anti-CD20 antibodies. We show that both rituximab and obinutuzumab induce calcium influx, albeit through different mechanisms, and this influx is crucial for cell death induction. Inhibition of the calcium flux with calcium channel blockers (CCB) abolished EGR-1 induction and impaired the efficacy of anti-CD20 antibodies in preclinical in vitro and in vivo models. Finally, we investigated the impact of CCBs in patients treated with anti-CD20 antibodies included in the clinical trials GOYA and REMARC, and found that patients simultaneously receiving CCBs and anti-CD20 therapy have a shorter progression-free survival and overall survival. These results reveal EGR-1 as a key mediator of the direct cytotoxic activity of anti-CD20 antibodies and provide a rationale to evaluate EGR-1 expression as a new biomarker to predict response to anti-CD20 treatment. In addition, our findings show that calcium influx is required for anti-CD20–mediated tumor cell death and suggest that simultaneous administration of calcium channel blocking agents could be deleterious in patients receiving anti-CD20–based immunotherapy.
Dysregulation of EAAT2 and VGLUT2 Spinal Glutamate Transports via Histone Deacetylase 2 (HDAC2) Contributes to Paclitaxel-induced Painful Neuropathy
Authors: Wang Xiao-Min , Gu Pan , Saligan Leorey , Iadarola Michael , Wong Stanley Sau Ching , Ti Lian Kah , Cheung Chi Wai 
Published: August 2020

Abstract
Effective treatments for chemotherapy-induced peripheral neuropathy (CIPN) remain unavailable. Given the significance of spinal cord glutamate transporters in neuronal plasticity and central sensitization, this study investigated the role of excitatory amino acid transporter 2 (EAAT2) and vesicular-glutamate transporter 2 (VGLUT2) in the development of paclitaxel-induced painful neuropathy. Paclitaxel (2 mg/kg, i.p., cumulative dose 8 mg/kg) induced long-lasting mechanical allodynia (&gt;28 days) with increased glutamate concentration and decreased EAAT2 expression with no changes in GABA/glycine or VGAT (vesicular GABA transporter) in rat spinal dorsal horn. VGLUT2 expression was upregulated and coexpressed with enhanced synaptophysin, characterizing nociceptive afferent sprouting and new synapse formation of glutamatergic neurons in the spinal cord dorsal horn. HDAC2 and transcription factor YY1 were also upregulated, and their interaction and colocalization were confirmed following paclitaxel treatment using co-immunoprecipitation. Inhibition or knockdown of HDAC2 expression by valproic acid, BRD6688, or HDAC2 siRNA not only attenuated paclitaxel-induced mechanical allodynia but also suppressed HDAC2 upregulation, glutamate accumulation, and the corresponding changes in EAAT2/VGLUT/synaptophysin expression and HDAC2/YY1 interaction. These findings indicate that loss of the balance between glutamate release and reuptake due to dysregulation EAAT2/VGLUT2/synaptophysin cascade in the spinal dorsal horn plays an important role in the development of paclitaxel-induced neuropathic pain. HDAC2/YY1 interaction as a complex appears essential in regulating this pathway, which can potentially be a therapeutic target to relieve CIPN by reversing central sensitization of spinal nociceptive neurons.
Concurrent Targeting of Potential Cancer Stem Cells Regulating Pathways Sensitizes Lung Adenocarcinoma to Standard Chemotherapy
Authors: Shibata Masahiro , Ooki Akira , Inokawa Yoshikuni , Sadhukhan Pritam , Ugurlu M. Talha , Izumchenko Evgeny , Munari Enrico , Bogina Giuseppe , Rudin Charles M. , Gabrielson Edward , Singh Anju , Hoque Mohammad O. 
Published: August 2020

Abstract
Cancer stem cells (CSC) are highly resistant to conventional chemotherapeutic drugs. YAP1 and STAT3 are the two transcription factors that facilitate the therapeutic resistance and expansion of CSCs. The objective of this study was to understand the cross-talk between YAP1 and STAT3 activities and to determine the therapeutic efficacy of targeting dual CSC-regulating pathways (YAP1 and STAT3) combined with chemotherapy in lung adenocarcinoma. Here, we showed that YAP1 contributes to CSC regulation and enhances tumor formation while suppressing apoptosis. Mechanistically, YAP1 promotes phosphorylation of STAT3 by upregulating IL6. In lung adenocarcinoma clinical specimens, YAP1 expression correlated with that of IL6 (P &lt; 0.01). More importantly, YAP1 and phosphorylated STAT3 (pSTAT3) protein expressions were significantly correlated (P &lt; 0.0001) in primary lung adenocarcinoma as determined by IHC. Immunoblotting of 13 lung adenocarcinoma patient-derived xenografts (PDX) showed that all YAP1-expressing PDXs also exhibited pSTAT3. Additional investigations revealed that chemotherapy resistance and malignant stemness were influenced by upregulating NANOG, OCT4, and SOX2, and the expression of these targets significantly attenuated by genetically and pharmacologically hindering the activities of YAP1 and STAT3 in vivo and in vitro. Therapeutically, the dual inhibition of YAP1 and STAT3 elicits a long-lasting therapeutic response by limiting CSC expansion following chemotherapy in cell line xenograft and PDX models of lung adenocarcinoma. Collectively, these findings provide a conceptual framework to target the YAP1 and STAT3 pathways concurrently with systemic chemotherapy to improve the clinical management of lung adenocarcinoma, based on evidence that these two pathways expand CSC populations that mediate resistance to chemotherapy.
Dual Epitope Targeting and Enhanced Hexamerization by DR5 Antibodies as a Novel Approach to Induce Potent Antitumor Activity Through DR5 Agonism
Authors: Overdijk Marije B. , Strumane Kristin , Beurskens Frank J. , Ortiz Buijsse Antonio , Vermot-Desroches Claudine , Vuillermoz Boris S. , Kroes Thessa , de Jong Bart , Hoevenaars Naomi , Hibbert Richard G. , Lingnau Andreas , Forssmann Ulf , Schuurman Janine , Parren Paul W.H.I. , de Jong Rob N. , Breij Esther C.W. 
Published: August 2020

Abstract
Higher-order death receptor 5 (DR5) clustering can induce tumor cell death; however, therapeutic compounds targeting DR5 have achieved limited clinical efficacy. We describe HexaBody-DR5/DR5, an equimolar mixture of two DR5-specific IgG1 antibodies with an Fc-domain mutation that augments antibody hexamerization after cell surface target binding. The two antibodies do not compete for binding to DR5 as demonstrated using binding competition studies, and binding to distinct epitopes in the DR5 extracellular domain was confirmed by crystallography. The unique combination of dual epitope targeting and increased IgG hexamerization resulted in potent DR5 agonist activity by inducing efficient DR5 outside-in signaling and caspase-mediated cell death. Preclinical studies in vitro and in vivo demonstrated that maximal DR5 agonist activity could be achieved independent of Fc gamma receptor–mediated antibody crosslinking. Most optimal agonism was observed in the presence of complement complex C1, although without inducing complement-dependent cytotoxicity. It is hypothesized that C1 may stabilize IgG hexamers that are formed after binding of HexaBody-DR5/DR5 to DR5 on the plasma membrane, thereby strengthening DR5 clustering and subsequent outside-in signaling. We observed potent antitumor activity in vitro and in vivo in large panels of patient-derived xenograft models representing various solid cancers. The results of our preclinical studies provided the basis for an ongoing clinical trial exploring the activity of HexaBody-DR5/DR5 (GEN1029) in patients with malignant solid tumors.
Retargeted and Stealth-Modified Oncolytic Measles Viruses for Systemic Cancer Therapy in Measles Immune Patients
Authors: Bah Eugene S. , Nace Rebecca A. , Peng Kah Whye , Muñoz-Alía Miguel Ángel , Russell Stephen J. 
Published: August 2020

Abstract
Measles viruses (MV) are rapidly inactivated by anti-measles neutralizing antibodies, which has limited their clinical performance as oncolytic agents. Here, by substituting the H and F surface glycoproteins of MV with those from the homologous canine distemper virus (CDV) and engineering the CDV H attachment protein to target EGFR or CD38, we generated a fully retargeted MV capable of resisting neutralization by measles-immune human serum. The resultant recombinant MVs encoding retargeted CDV envelope glycoproteins had similar growth kinetics as the control MV, showed the expected engineered receptor specificities for cell entry, intercellular fusion, and target cell killing, and were blind to native CDV receptors. In contrast to the control MV, recombinant MVs incorporating CDV F and H glycoproteins retained full infectivity when exposed to high concentrations of pooled measles-immune human serum. Comparing viruses bearing MV or CDV glycoproteins in the SKOV3ip.1 model, only the virus bearing an EGFR-retargeted CDV envelope glycoprotein complex was capable of limiting tumor growth and extending the survival in measles immune mice. MV, “stealthed” and retargeted using engineered CDV surface glycoproteins, may be a promising platform to advance for systemic cancer therapy in measles immune patients.
Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody–Drug Conjugate
Authors: Anderson Mark G. , Falls Hugh D. , Mitten Michael J. , Oleksijew Anatol , Vaidya Kedar S. , Boghaert Erwin R. , Gao Wenqing , Palma Joann P. , Cao Diana , Chia Puey-Ling , John Thomas , Gan Hui K. , Scott Andrew M. , Reilly Edward B. 
Published: August 2020

Abstract
ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody–drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window. Potency of the PBD dimer, combined with increased binding of AM1 to EGFR-positive tumor cells, opens the possibility to target a wide array of tumors beyond those with high levels of EGFR overexpression or amplification, including those insensitive to auristatin-based ADCs. ABBV-321 exhibits potent antitumor activity in cellular and in vivo studies including xenograft cell line and patient-derived xenograft glioblastoma, colorectal, lung, head and neck, and malignant mesothelioma tumor models that are less sensitive to depatux-m or ABBV-221. Combination studies with ABBV-321 and depatux-m suggest a promising treatment option permitting suboptimal, and potentially better tolerated, doses of both ADCs while providing improved potency. Collectively, these data suggest that ABBV-321 may offer an extended breadth of efficacy relative to other EGFR ADCs while extending utility to multiple EGFR-expressing tumor indications. Despite its highly potent PBD dimer payload, the tumor selectivity of ABBV-321, coupled with its pharmacology, toxicology, and pharmacokinetic profiles, support continuation of ongoing phase I clinical trials in patients with advanced EGFR-expressing malignancies.
Phase I, Pharmacogenomic, Drug Interaction Study of Sorafenib and Bevacizumab in Combination with Paclitaxel in Patients with Advanced Refractory Solid Tumors
Authors: Chiorean E. Gabriela , Perkins Susan M. , Strother R. Matthew , Younger Anne , Funke Jennifer M. , Shahda Safi G. , Hahn Noah M. , Sandrasegaran Kumar , Jones David R. , Skaar Todd C. , Schneider Bryan P. , Sweeney Christopher J. , Matei Daniela E. 
Published: August 2020

Abstract
VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a “3 + 3” design, using paclitaxel 80 mg/m2 every week for 3 weeks, in every 4 week cycles, bevacizumab 5 mg/kg every 2 weeks, and sorafenib 200 or 400 mg twice a day, 5 or 7 days/week (5/7, 7/7). The MTD cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg twice a day 5/7, 200 mg twice a day 7/7, and 400 mg twice a day 5/7. DLTs were grade 3 neutropenia &gt;7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand–foot skin reaction (HFSR; cohort 3, 2). MTD was sorafenib 200 mg twice a day 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay &gt;7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia &gt;7 days (1). RP2D was sorafenib 200 mg twice a day 5/7. Most patients (62%) dose reduced sorafenib to 200 mg daily 5/7 after a median 3 (range, 2–17) cycles. Response rates were 48% overall (27) and 64% for ovarian cancers (14). VEGF-A-1154AA and -7TT recessive homozygous genotypes conferred worse overall survival versus alternative genotypes (7 vs. 22 months). Intermittent, low-dose sorafenib (200 mg twice a day 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in patients with refractory cancer (NCT00572078).
An IL6–Adenosine Positive Feedback Loop between CD73+ γδTregs and CAFs Promotes Tumor Progression in Human Breast Cancer
Authors: Hu Guoming , Cheng Pu , Pan Jun , Wang Shimin , Ding Qiannan , Jiang Zhou , Cheng Lu , Shao Xuan , Huang Liming , Huang Jian 
Published: August 2020

Abstract
The tumor microenvironment induces immunosuppression via recruiting and expanding suppressive immune cells such as regulatory T cells (Treg) to promote cancer progression. In this study, we documented that tumor-infiltrating CD73+ γδTregs were the predominant Tregs in human breast cancer and exerted more potent immunosuppressive activity than CD4+ or CD8+ Tregs. We further demonstrated that cancer-associated fibroblast (CAF)–derived IL6, rather than TGFβ1, induced CD73+ γδTreg differentiation from paired normal breast tissues via the IL6/STAT3 pathway to produce more adenosine and become potent immunosuppressive T cells. CD73+ γδTregs could in turn promote IL6 secretion by CAFs through adenosine/A2BR/p38MAPK signaling, thereby forming an IL6–adenosine positive feedback loop. CD73+ γδTreg infiltration also impaired the tumoricidal functions of CD8+ T cells and significantly correlated with worse prognosis of patients. The data indicate that the IL6–adenosine loop between CD73+ γδTregs and CAFs is important to promote immunosuppression and tumor progression in human breast cancer, which may be critical for tumor immunotherapy.
Spatial aggregation and specificity of incidents with wildlife make tea plantations in southern India potential buffers with protected areas
Authors: Kalam Tamanna , Puttaveeraswamy Tejesvini A. , Srivastava Rajeev K. , Puyravaud Jean-Philippe , Davidar Priya 
Published: August 2020

Abstract: Many wildlife species survive in human-modified landscapes and understanding the opinions of those who share space with wildlife will aid conservation efforts. Using a questionnaire, we assessed the presence of 12 mammal species in 78 tea plantations in the Nilgiris, southern India. We obtained data on (i) plantation size, location, and elevation, (ii) species presence over a year, (iii) type and number of wildlife incidents caused, (iv) financial cost of wildlife damage, and (v) support for wildlife conservation. We used a generalized linear model to assess whether the distance to protected areas, elevation, and plantation size influenced species presence and the effect of these variables and wildlife incidents on support for conservation. Among all species reported, Bonnet Macaque, Wild Boar, and Porcupine were the most widespread, and the former two and the Gaur reportedly caused >50% of damages. Crop damage was the most frequent (74%, n = 244), whereas livestock predation, attacks on people, and infrastructure damage constituted <10% of incidents reported. The cost of wildlife damage was negligible for 72 estates and significant for six. The number of species increased with proximity to protected areas, with increasing elevation and plantation area. Plantation management (62%) supported wildlife conservation, and support increased with decreasing plantation size, increasing distance to protected areas, and with a higher number of species reported, but decreased with increasing incidents of wildlife damage. Mitigating impacts of a few widely distributed species that cause disproportionate damage and compensating those that incur disproportionately high costs could increase support for conservation. Education and awareness programs for the plantation community can further help increase support and participation in wildlife conservation activities. Plantations can thus serve as supplementary habitats for wildlife in regions where hard boundaries between protected areas and human settlements prevail.
Innovative way of human-elephant competition mitigation
Authors: Sanjit Kumar Saha  
Published: August 2020

Abstract: The negative interaction between humans and elephants is often referred to as conflict, however it is also seen as competition. Human-elephant competition (HEC) is a major protection threat in the fringe villages of the Jaldapara National Park (JPNP) of West Bengal, India. JPNP is facing challenges from the highly populated fringe villages, which exist in elephant corridors. Between 2015 and 2018 there were 12 elephant deaths. During the same period elephants caused 34 human deaths. As per data, most of the elephant interactions occurred in the fringe villages of Madarihat and Jaldapara North Range. Per reports of human deaths, Chekamari and Khairbari villages of Madarihat Range are in the most vulnerable list. Most of the human deaths occurred in the early morning (05.00–06.00 h) and in the evening, when people are going outside for open defecation (OD). On a pilot basis Chekamari and Khairbari villages of Madarihat Range were selected for a door to door household survey with the objective to develop an innovative strategy as a mitigation measure of HEC. The results of the survey show that both villages are tribal and minority population, the socio-economic condition of the people is very poor, on an average 5–6 members are in each household, the source of drinking water is a community well for most of the households, and 50 households are devoid of toilet facilities so automatically the members of those households go outside for OD. Out of the total human deaths, 16 occurred in the Madarihat area; out of these 16 cases, six were from the Chekamari and Khairbari villages. For this reason, between April 2019 to September 2019, with available funds 20 toilets with tube-well were built in the 20 neediest households of these two villages. Due to the communication with the community, behavioural changes were made and their participation for 100% usage of those toilets was assured. After the construction of the toilets until now, no human death cases have been reported.
First record of a morphologically abnormal and highly metal-contaminated Spotback Skate Atlantoraja castelnaui (Rajiformes: Arhynchobatidae) from southeastern Rio de Janeiro, Brazil
Authors: Rachel Ann Hauser-Davis  , Márcio L.V. Barbosa-Filho  , Lucia Helena S. de S. Pereira  , Catarina A. Lopes  , Sérgio C. Moreira  , Rafael C.C. Rocha  , Tatiana D. Saint’Pierre  , Paula Baldassin  , Salvatore Siciliano  
Published: August 2020

This paper reports the first record of a morphologically abnormal and highly metal-contaminated Spotback Skate Atlantoraja castelnaui (Ribeiro, 1907) (Elasmobranchii, Rajidae) in Rio de Janeiro, Brazil. Incomplete fusion of the right pectoral fin with the head was observed, while a radiography indicated muscle sheaf discontinuity near the rostrum. Extremely high contamination by several elements, including teratogenic As, Hg and Cd in the individual was detected. The observed morphological deformity may be due to high concentrations of teratogenic elements in the environment, possibly playing a role in abnormal embryonic development in egg cases exposed to high environmental concentrations of these contaminants. Atlantoraja castelnaui is the least biologically understood member of the genus Atlantoraja, and this paper furthers both morphological observations and ecotoxicological assessments on this species.