bluuebunny/crossref_metadata_2025_split huggingface dataset:
OX40 Agonist BMS-986178 Alone or in Combination With Nivolumab and/or Ipilimumab in Patients With Advanced Solid Tumors
Authors: Gutierrez Martin , Moreno Victor , Heinhuis Kimberley M. , Olszanski Anthony J. , Spreafico Anna , Ong Michael , Chu Quincy , Carvajal Richard D. , Trigo José , Ochoa de Olza Maria , Provencio Mariano , De Vos Filip Yves , De Braud Filippo , Leong Stephen , Lathers Deanne , Wang Rui , Ravindran Palani , Feng Yan , Aanur Praveen , Melero Ignacio 
Published: November 2020

Abstract

Purpose:
This phase I/IIa study (NCT02737475) evaluated the safety and activity of BMS-986178, a fully human OX40 agonist IgG1 mAb, ± nivolumab and/or ipilimumab in patients with advanced solid tumors.

Patients and Methods:
Patients (with non–small cell lung, renal cell, bladder, other advanced cancers) received BMS-986178 (20–320 mg) ± nivolumab (240–480 mg) and/or ipilimumab (1–3 mg/kg). The primary endpoint was safety. Additional endpoints included immunogenicity, pharmacodynamics, pharmacokinetics, and antitumor activity per RECIST version 1.1.

Results:
Twenty patients received BMS-986178 monotherapy, and 145 received combination therapy in various regimens (including two patients receiving nivolumab monotherapy). With a follow-up of 1.1 to 103.6 weeks, the most common (≥5%) treatment-related adverse events (TRAEs) included fatigue, pruritus, rash, pyrexia, diarrhea, and infusion-related reactions. Overall, grade 3–4 TRAEs occurred in one of 20 patients (5%) receiving BMS-986178 monotherapy, six of 79 (8%) receiving BMS-986178 plus nivolumab, zero of two receiving nivolumab monotherapy, six of 41 (15%) receiving BMS-986178 plus ipilimumab, and three of 23 (13%) receiving BMS-986178 plus nivolumab plus ipilimumab. No deaths occurred. No dose-limiting toxicities were observed with monotherapy, and the MTD was not reached in either the monotherapy or the combination escalation cohorts. No objective responses were seen with BMS-986178 alone; objective response rates ranged from 0% to 13% across combination therapy cohorts.

Conclusions:
In this study, BMS-986178 ± nivolumab and/or ipilimumab appeared to have a manageable safety profile, but no clear efficacy signal was observed above that expected for nivolumab and/or ipilimumab.
Development of Highly Optimized Antibody–Drug Conjugates against CD33 and CD123 for Acute Myeloid Leukemia
Authors: Han Yoon-Chi , Kahler Jennifer , Piché-Nicholas Nicole , Hu Wenyue , Thibault Stephane , Jiang Fan , Leal Mauricio , Katragadda Madan , Maderna Andreas , Dushin Russell , Prashad Nadira , Charati Manoj B. , Clark Tracey , Tumey L. Nathan , Tan Xingzhi , Giannakou Andreas , Rosfjord Edward , Gerber Hans-Peter , Tchistiakova Lioudmila , Loganzo Frank , O'Donnell Christopher J. , Sapra Puja 
Published: November 2020

AbstractPurpose:Mortality due to acute myeloid leukemia (AML) remains high, and the management of relapsed or refractory AML continues to be therapeutically challenging. The reapproval of Mylotarg, an anti-CD33–calicheamicin antibody–drug conjugate (ADC), has provided a proof of concept for an ADC-based therapeutic for AML. Several other ADCs have since entered clinical development of AML, but have met with limited success. We sought to develop a next-generation ADC for AML with a wide therapeutic index (TI) that overcomes the shortcomings of previous generations of ADCs.Experimental Design:We compared the TI of our novel CD33-targeted ADC platform with other currently available CD33-targeted ADCs in preclinical models of AML. Next, using this next-generation ADC platform, we performed a head-to-head comparison of two attractive AML antigens, CD33 and CD123.Results:Our novel ADC platform offered improved safety and TI when compared with certain currently available ADC platforms in preclinical models of AML. Differentiation between the CD33- and CD123-targeted ADCs was observed in safety studies conducted in cynomolgus monkeys. The CD33-targeted ADC produced severe hematologic toxicity, whereas minimal hematologic toxicity was observed with the CD123-targeted ADC at the same doses and exposures. The improved toxicity profile of an ADC targeting CD123 over CD33 was consistent with the more restricted expression of CD123 in normal tissues.Conclusions:We optimized all components of ADC design (i.e., leukemia antigen, antibody, and linker-payload) to develop an ADC that has the potential to translate into an effective new therapy against AML.
PIPAC-OX: A Phase I Study of Oxaliplatin-Based Pressurized Intraperitoneal Aerosol Chemotherapy in Patients with Peritoneal Metastases
Authors: Kim Guowei , Tan Hon Lyn , Sundar Raghav , Lieske Bettina , Chee Cheng Ean , Ho Jingshan , Shabbir Asim , Babak Maria V. , Ang Wee Han , Goh Boon Cher , Yong Wei Peng , Wang Lingzhi , So Jimmy B.Y. 
Published: November 2020

Abstract

Purpose:
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel laparoscopic, intraperitoneal chemotherapy delivery technique aiming to improve drug distribution and tissue penetration to treat peritoneal metastases. Thus far, PIPAC oxaliplatin is conducted at an arbitrary dose of 92 mg/m2. We conducted a phase I study to establish safety and tolerability.

Patients and Methods:
We used a 3+3 dose-escalation design of PIPAC oxaliplatin for patients with peritoneal metastases from gastrointestinal tumors, after failure of at least first-line chemotherapy. Dose levels were planned at 45, 60, 90, and 120 mg/m2.

Results:
This study included 16 patients with 24 PIPAC procedures (8 gastric; 5 colorectal; and 1 gallbladder, pancreas, and appendix cancer each). Median age and peritoneal cancer index (PCI) score were 62 years and 17, respectively. Two patients developed pancreatitis (grade 2 and 3) at 45 mg/m2, necessitating cohort expansion. Another patient developed grade 2 pancreatitis at 90 mg/m2. There were no other dose-limiting toxicities, and the highest-dose cohort (120 mg/m2) tolerated PIPAC well. Pharmacokinetic analyses demonstrated good linearity between dose and maximum concentration (r2 = 0.95) and AUC (r2 = 0.99). On the basis of RECIST, 62.5% and 50% had stable disease after one and two PIPAC procedures, respectively. A total of 8 patients underwent two PIPAC procedures, with improvement of median PCI and peritoneal regression grade score from 15 to 12 and 2.5 to 2.0, respectively.

Conclusions:
The recommended phase II dose is 120 mg/m2. Future studies should further delineate the efficacy and role of PIPAC oxaliplatin for peritoneal metastases.
See related commentary by de Jong et al., p. 1830
Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients withPIK3CA-Mutant Cancers
Authors: Jhaveri Komal , Chang Matthew T. , Juric Dejan , Saura Cristina , Gambardella Valentina , Melnyk Anton , Patel Manish R. , Ribrag Vincent , Ma Cynthia X. , Aljumaily Raid , Bedard Philippe L. , Sachdev Jasgit C. , Dunn Lara , Won Helen , Bond John , Jones Surai , Savage Heidi M. , Scaltriti Maurizio , Wilson Timothy R. , Wei Michael C. , Hyman David M. 
Published: November 2020

AbstractPurpose:Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor taselisib.Patients and Methods:Patients were enrolled on the basis of local PIK3CA mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed.Results:A total of 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and postprogression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index.Conclusions:Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.
A Legislative History of Nonhuman Animal Fighting in the U.S. and Its Territories
Authors: Pacelle Wayne , Pacelle Richard L. 
Published: November 2020

Abstract
Nonhuman animal fighting is an ancient form of exploitation, still attracting millions of followers. While 19th-century proscriptions imposed in the U.S. succeeded in stigmatizing it, animal fighters adapted to these cultural and legal taboos and continued to operate, often clandestinely. Cockfighting thrived, operating as a quasi-legal enterprise until an incremental policy-making campaign succeeded in passing a raft of local, state, and federal laws to outlaw it everywhere in the U.S. Between 1998 and 2018, legal cockfighting was banned in the final five states; more than 40 other states reformed their laws; and Congress passed multiple reforms to ban animal fighting, including in the U.S. territories. The process of outlawing animal fighting faced fierce resistance, but these practices are now the most widely and severely criminalized forms of animal mistreatment in the U.S. Adherence to the law and enforcement are continuing challenges.
Revenge Pornography in Nigeria: A Call for Legal Response and Cyber-Censorship of Content by Internet Service Providers
Authors: Nwafor Ifeoma E. , Nwafor Ndubuisi , Alozie Josiah 
Published: November 2020

Abstract
Revenge pornography is the online distribution of sexually uncensored images or videos of another person without consent and to cause embarrassment or torment. Victims of revenge pornography suffer significant harm, including losing jobs and, in extreme cases, committing suicide. The public blames the victim for the role they played. Rather than victim-blaming, victims deserve a takedown order and criminal liability for uploaders of such images. This study adopts a doctrinal approach; it examines key statutes and their interpretation by Nigerian courts while juxtaposing it with the law and practice in the United Kingdom. The United Kingdom was undertaken as a case study because it has a developed jurisprudence which can provide lessons for Nigeria. This study found that the current state of laws in Nigeria is ill-equipped to tackle the menace of revenge pornography. The objective of this study is to offer insights on the prevalence of revenge pornography in Nigeria and suggest legal solutions to address this phenomenon. It canvasses for a non-consensual pornography provision that would criminalise the act of revenge pornography in Nigeria. It also makes a case for cyber-censorship of contents by internet service providers and the need for third-party liability.
National Security, Property Rights, and Development in Nigeria: How Should the Leviathan Resolve Herder-Farmer Conflict?
Authors: Nwankwo Chidebe Matthew 
Published: November 2020

Abstract
The spate of violent clashes between nomadic pastoralists and agrarian communities in Nigeria raises a number of legal and policy questions that had been long overlooked. Issues arising from the phenomenon range from questions over constitutionally guaranteed rights such as the right to own property, to questions over the inadequacies of Nigeria’s security apparatus as well as calls for land use reforms. Additionally, due to the groups affected and the scale of casualties, the topic has become a political molten magma. The constant conflicts between nomadic pastoralists who are majorly from the Fulani ethnic group, and agrarian communities from other parts of the country have reached unprecedented levels leading to accusations of coordinated attempts at land grab, ethnic cleansing, jihad and insurgency, threatening the country’s security and stability in the process. Fiscally, the destruction of lives and property and the state of insecurity emanating from the clashes stood at $16 billion in potential revenue as at 2018. In no small measure have these clashes been precipitated by climate change and the consequent drought in the Sahara region. This paper analyses the role of the Nigerian state in balancing the interests of affected groups in the clashes and promoting development. At its core, it seeks to identify legal and policy gaps that require filling to put a definite end to the lingering crisis.
Tropical and Extratropical Cyclone Detection Using Deep Learning
Authors: Kumler-Bonfanti Christina , Stewart Jebb , Hall David , Govett Mark 
Published: November 2020

AbstractExtracting valuable information from large sets of diverse meteorological data is a time-intensive process. Machine-learning methods can help to improve both speed and accuracy of this process. Specifically, deep-learning image-segmentation models using the U-Net structure perform faster and can identify areas that are missed by more restrictive approaches, such as expert hand-labeling and a priori heuristic methods. This paper discusses four different state-of-the-art U-Net models designed for detection of tropical and extratropical cyclone regions of interest (ROI) from two separate input sources: total precipitable water output from the Global Forecast System (GFS) model and water vapor radiance images from the Geostationary Operational Environmental Satellite (GOES). These models are referred to as International Best Track Archive for Climate Stewardship (IBTrACS)-GFS, Heuristic-GFS, IBTrACS-GOES, and Heuristic-GOES. All four U-Nets are fast information extraction tools and perform with an ROI detection accuracy ranging from 80% to 99%. These are additionally evaluated with the Dice and Tversky intersection-over-union (IoU) metrics, having Dice coefficient scores ranging from 0.51 to 0.76 and Tversky coefficients ranging from 0.56 to 0.74. The extratropical cyclone U-Net model performed 3 times as fast as the comparable heuristic model used to detect the same ROI. The U-Nets were specifically selected for their capabilities in detecting cyclone ROI beyond the scope of the training labels. These machine-learning models identified more ambiguous and active ROI missed by the heuristic model and hand-labeling methods that are commonly used in generating real-time weather alerts, having a potentially direct impact on public safety.
Acceptance of the disease and sexual functions of patients with heart failure
Authors: Wiśnicka Alicja , Uchmanowicz Izabella , Dyjakon Dorota , Cichoń Ewelina , Szczepanowski Remigiusz , Jankowska Ewa A 
Published: November 2020

Abstract

Background
Sexual activity is an important element of quality of life for many individuals suffering from heart failure.

Aims
The study investigated the influence of disease acceptance on sexual function in a population of male patients with chronic heart failure.

Methods
The study included 80 patients with chronic heart failure (mean age 63.3±9.2 years) who filled in the Mell–Krat Scale questionnaire to evaluate sexual needs and reactions. We also used the International Index of Erection Function (IIEF-5) inventory and the Acceptance of Illness Scale (AIS).

Results
The study showed that the acceptance of the illness was positively associated with all of the Mell–Krat components such as sexual need, F = (3.27), frequency of intercourse, F = (2.46), position and technique, F = (1.88). Also, according to the IIEF-5 questionnaire, 84.42% of respondents had erectile dysfunction. Taken together these indicated that psychological adjustments such as acceptance of disease increase quality of all aspects of sexual functions in heart failure patients, including their erectile functions.

Conclusions
Our findings suggest that psychological adjustments to feelings of loss associated with the onset of heart failure disease is the important determinant of quality of sexual life among male adults. Our research implicates that effects of AIS on sexual functioning give reasonable information to tailor sexual counselling for males suffering from heart failure.
Circulating microRNAs Is a Potential Prognostic Biomarker in Primary Central Nervous System Lymphoma
Authors: Ma Yan , Suolitiken Dina , Chen Bobin , Xu Xiaoping , Kang Hui , Zhiguang Lin 
Published: November 2020

Backgrounds and purposes Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin's lymphoma. The prognosis of PCNSL is poor and heterogeneous. MicroRNA is associated with prognosis of various cancers. Our study is the first time to compare circulating microRNAs of PCNSL patients with different prognosis using miRNA microarray scanning and find novel microRNAs associated with prognosis of PCNSL by further large-scale validation.
Materials and methods From a retrospective cohort, we collected the clinical data of patients who were diagnosed as PCNSL in Huashan Hospital between January 2007 and June 2016. We collected clinical data and blood samples from residual blood routine test of PCNSLs. First, we compared circulating microRNAs between patients with different overall survival (OS) using miRNA microarray scanning. Second, PCR assay was used for miRNAs quantification in blood sample from 6 patients that had long overall survival and other 6 patients that had short overall survival. Further miRNA validation was made by PCR assay in blood sample from 94 patients to validate prognostic value of miRNAs in PCNSLs. The Kruskal-Wallis and Mann-Whitney U tests were used for quantitative parameters and the χ2 square test was used for non-quantitative parameters. Univariate analysis was performed using log-rank test, and survival distributions were analyzed by the Kaplan-Meier curve and log-rank test. Multivariate analysis was done by Cox regression model.
Results A total of 90 differentially expressed miRNAs were identified, including 24 up-regulated miRNAs and 66 down-regulated miRNAs using miRNA microarray scanning. Then PCR assay was used for 10 differentially expressed miRNAs quantification in blood sample from 6 patients that had long overall survival and 6 patients that had short overall survival. Mir-21, mir-129-5p, mir-144-5, mir-363-5p, mir-409-3p, mir-1246, mir-1299 and mir-1825 showed no differences between 2 groups, while the expression of mir-455-3P and mir-940 between 2 groups are significantly different (P&lt;0.05). Further validation in 94 patients showed median OS in miR-940 overexpression group was 91 months and in miR-940 low-expression group was 28 months (P=0.0005), while median PFS in miR-940 overexpression group was 25 months and in miR-940 low-expression group was 16 months (P =0.0292). Multivariate analysis of COX model showed miR-940 was independent factors for OS and PFS.
Conclusion Circulating mir-940 had prognostic value in PCNSL and was an independent prognostic factor for PCNSL.
Figure 1

Disclosures
No relevant conflicts of interest to declare.
Mechanisms of Leukemia Stem Cell Plasticity Revealed By Single Cell Analysis
Authors: Rowe R. Grant , Daley George Q. , North Trista E. , Marion William , Pikman Yana , Harris Marian H. , Morris Vivian , Lummertz da rocha Edroaldo , Shalek Alex K. , Hughes Travis , Sensharma Prerana , Wang Dahai , Sousa Patricia , Ho Sui Shannan , Naumenko Sergey , Vinicius Da Silva Renan 
Published: November 2020

Leukemia stem cells (LSCs) are the subset of leukemic cells that drive leukemia progression, resist therapy, and remain latent to spark disease relapse. LSCs are quantified by efficiency of xenografting immunodeficient mice, a measurement that is predictive of leukemia outcome. Although LSCs have been previously thought to be rare and phenotypically primitive, recent data indicate that LSCs may actually be heterogeneous. Here, we use single-cell transcriptomics combined with limiting dilution xenotransplantation to dissect the ontogeny of MLL-rearranged B-lymphoblastic leukemia (MLL-r B-ALL), an aggressive form of childhood leukemia. Compared to acute myeloid leukemia (AML), LSCs are abundant in MLL-r B-ALL. Recapitulating the unique clinical behavior of this form of leukemia, MLL-r B-ALL cells undergo a B-lymphoid to myeloid lineage switch under chemotherapy pressure consistent with primitive, multipotent transcriptional programs present in LSCs. Although we identify rare, chemotherapy-resistant, primitive LSCs, we also observe LSCs emerging from more differentiated populations. These facultative LSCs self-renew and possess the capability to replenish the full cellular diversity of MLL-r B-ALL. Using CITE-seq, we find that stem cell programs can be fully uncoupled from immunophenotype in MLL-r B-ALL. In mechanistic studies, we find that the phenotypically differentiated LSCs that drive bottom-up reconstitution of the leukemic cellular ontogeny bear signatures of MYC activation and oxidative phosphorylation. We confirm recruitment of these pathways in actively reconstituting, phenotypically differentiated LSCs, and define a pathway by which MYC rewires metabolism in MLL-r B-ALL LSCs. We find that MYC is required for LSC plasticity in vitro and in vivo. Targeting oxidative metabolism impairs LSC engraftment, identifying a potential therapeutic intervention. We conclude that the high LSC content and dual lineage and LSC plasticities of MLL-r B-ALL contribute to its chemotherapy resistance and persistently poor outcomes.

Disclosures
Shalek: Honeycomb Biotechnologies: Consultancy, Current equity holder in publicly-traded company; Cellarity: Consultancy, Current equity holder in publicly-traded company; Repertoire Immune Medicines: Consultancy, Current equity holder in publicly-traded company; Merck: Consultancy; Orche Bio: Consultancy, Current equity holder in publicly-traded company; Dahlia Biosciences: Consultancy, Current equity holder in publicly-traded company.