bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Swine Gastrointestinal Parasites in Nyagatare District, Rwanda
Authors: Tumusiime M. , Ntampaka P. , Niragire F. , Sindikubwabo T. , Habineza F.
Published: December 2020

While pig farming has been growing rapidly in Rwanda, its potential contribution to the prevalence of zoonotic infections is not well known. Pig production is usually affected by gastrointestinal parasites, some of which are zoonotic and can threaten human health. The knowledge about the status of such infections is essential for policy decisions and interventions. We aimed to investigate the prevalence of swine gastrointestinal parasites in Nyagatare district, Rwanda. A cross-sectional study involved collecting 104 faecal samples from apparently healthy pigs. The floatation technique was used to identify the parasites and frequency distribution analysis, and Pearson chi-square tests of association were conducted for this study data. Overall, the prevalence of swine gastrointestinal parasites was 84.6%, and the predominant species were Strongyle-type helminths representing 70.2%, followed by coccidia (55.8%), Strongyloides ransomi (39.4%), and Ascaris suum (10.6%). Of all parasitized pigs (

n
=
88

), 84.1% developed coinfections involving 2, 3, or 4 different parasite species. The results showed a statistically significant correlation between the location of pigs and parasitic infections and that some prevalent parasites are zoonotic. Interventions among pig farmers in Nyagatare should aim to improve awareness and to provide information on the negative impacts of swine gastrointestinal parasites on pig production and human health.
Do Not Huff, Puff, or Vape That Stuff: Interstitial Airspace Disease in a Teenager
Authors: Amin Amee A. , Haught Erica , Mousattat Youmna
Published: December 2020

A 17-year-old previously healthy male was admitted to the hospital for intractable and persistent vomiting, fever, cough, abdominal pain, and intermittent diarrhea and dehydration. He presented with severe chest pain and O2 desaturations up to 80% on room air. An infectious (including a nasopharyngeal swab), GI, and cardiac workup was completed and was negative except for elevated inflammatory markers with a C-reactive protein (CRP) level of 261 mg/L, erythrocyte sedimentation rate (ESR) of 53 mm/hr, and a D-dimer level of 0.93 mcg/ml. Chest X-ray showed diffuse multifocal infiltrates. The patient was treated with ceftriaxone and azithromycin initially for a suspected pneumonia. He was also started on 4L of nasal cannula O2 supplementation. Due to persistent hypoxic respiratory failure, worsening respiratory distress clinically, with tachypnea and retractions, and lab findings of elevated D-dimer, a chest CT was performed to rule out a pulmonary embolism (PE). Computed tomography (CT) findings were negative for PE but notable for diffuse airspace opacities, primarily within the lower lobes, with a ground-glass appearance concerning for ARDS. Upon further investigation of the social history, the patient admitted to vaping nicotine products for the past 4 years and tetrahydrocannabinol (THC) products within the last several months. He was immediately started on prednisone 30 mg BID for a diagnosis of e-cigarette or vaping product use-associated lung injury (EVALI) and started showing clinical improvement. The patient was able to be weaned off of supplemental oxygen to room air, and clinical symptoms of respiratory distress began to improve over the next 24 hours.
Numerical Simulation of Split‐Hopkinson Pressure Bar Tests for the Combined Coal‐Rock by Using the Holmquist–Johnson–Cook Model and Case Analysis of Outburst
Authors: Xie Beijing , Chen Dongxin , Ding Hao , Wang Guangyu , Yan Zheng
Published: December 2020

In the coal and rock dynamic disasters, such as the rock burst, dynamic load damage often acts simultaneously on the combined coal and rock mass. Based on the split‐Hopkinson pressure bar (SHPB) test of the combined coal and rock with a bullet velocity of 4.590–8.791 m/s, the numerical model of four kinds of combined coal and rock with different sandstone‐coal‐sandstone ratios, including 1 : 1 : 1, 2 : 1 : 1, 1 : 1 : 2, and 1 : 2 : 1, is investigated. A finite element software (LS‐DYNA) and the Holmquist–Johnson–Cook (HJC) constitutive model of rock are employed in these regards. The stress waveform, the oscillation phenomenon of stress wave, and the damage process of the specimen in the impact test of the composite coal and rock are studied. The obtained results show that the compression‐shear failure is the main failure mode of the coal body and the tensile failure of the sandstone along the axial direction in the composite coal‐rock specimens. Moreover, it is found that combination of coal and rock samples is mainly destroyed by the coal body, which has no correlation with the impact speed and combination mode. Finally, numerical simulation about Hongling coalmine extralarge tunnel malfunction is carried out. Obtained results showed the protruding and stress change processes of the coal seam of the tunnel exposing. It is found that the simulation results are in an excellent agreement with those from the field investigation. The present study may provide a reference for further understanding the mechanism of the coal and rock dynamic disasters, such as the rock burst.
Modified Password Guessing Methods Based on TarGuess-I
Authors: Xie Zhijie , Zhang Min , Guo Yuqi , Li Zhenhan , Wang Hongjun
Published: December 2020

TarGuess
−
I

is a leading online targeted password guessing model using users’ personally identifiable information (PII) proposed at ACM CCS 2016 by Wang et al. It has attracted widespread attention in password security owing to its superior guessing performance. Yet, after analyzing the users’ vulnerable behaviors of using popular passwords and constructing passwords with users’ PII, we find that this model does not take into account popular passwords, keyboard patterns, and the special strings. The special strings are the strings related to users but do not appear in the users’ demographic information. Thus, we propose

TarGuess
−

I

+
K
P
X

, a modified password guessing model with three semantic methods, including (1) identifying popular passwords by generating top-300 lists from similar websites, (2) recognizing keyboard patterns by relative position, and (3) catching the special strings by extracting continuous characters from user-generated PII. We conduct a series of evaluations on six large-scale real-world leaked password datasets. The experimental results show that our modified model outperforms

TarGuess
−
I

by 2.62% within

100

guesses.
How to Determine the Early Warning Threshold Value of Meteorological Factors on Influenza through Big Data Analysis and Machine Learning
Authors: Ge Hui , Fan Debao , Wan Ming , Jin Lizhu , Wang Xiaofeng , Du Xuejie , Yang Xu
Published: December 2020

Infectious diseases are a major health challenge for the worldwide population. Since their rapid spread can cause great distress to the real world, in addition to taking appropriate measures to curb the spread of infectious diseases in the event of an outbreak, proper prediction and early warning before the outbreak of the threat of infectious diseases can provide an important basis for early and reasonable response by the government health sector, reduce morbidity and mortality, and greatly reduce national losses. However, if only traditional medical data is involved, it may be too late or too difficult to implement prediction and early warning of an infectious outbreak. Recently, medical big data has become a research hotspot and has played an increasingly important role in public health, precision medicine, and disease prediction. In this paper, we focus on exploring a prediction and early warning method for influenza with the help of medical big data. It is well known that meteorological conditions have an influence on influenza outbreaks. So, we try to find a way to determine the early warning threshold value of influenza outbreaks through big data analysis concerning meteorological factors. Results show that, based on analysis of meteorological conditions combined with influenza outbreak history data, the early warning threshold of influenza outbreaks could be established with reasonable high accuracy.
Sleep Pattern and Problems in Young Children Visiting Outpatient Department of a Tertiary Level Hospital in Kathmandu, Nepal
Authors: Pandey Shrijana , Bhattarai Shristi , Bhatta Anwesh
Published: December 2020

Background. Sleep is an important parameter of a child’s growth and development. The pattern and duration of sleep varies with age. Sleep problems are a common occurrence during childhood days, and these problems that establish in childhood are presumed to continue later in life. Many times, parental concerns regarding their child’s sleep problems like difficulty in putting to sleep, frequent night time awakening, and waking up early are overlooked during their visits to the hospital. Objective. The aim of this study was to find out the sleep patterns and problems of children aged six to thirty-six months. Methodology. A cross-sectional study was conducted at the pediatric outpatient department of Kathmandu Medical College Teaching Hospital from October, 2019 till March, 2020. Two hundred and forty-nine respondents were chosen purposively and were given questionnaires to be filled out. Research instrument was a standard, Nepali version of a structured questionnaire called Brief Infant Sleep Questionnaire (BISQ) which contained questions related to sleep parameters and sleep problems existing among young children of 6-36 months. Mean, standard deviation, frequencies, and Kruskal Wallis test were used for statistical analysis. Results. The mean duration of total sleep was

12.12
±
2.00

hours, while that of night sleep was

9.22
±
1.19

hours and mean daytime nap was

2.90
±
1.66

hours. Most of the children (96%) coslept with their parents, and 55% of the children had feeding as a bedtime ritual. Overall, 19.6% of the children had sleep problems as identified by BISQ although only 5.6% of the parents perceived that their children had it. Conclusions. Sleep problems were present among young Nepalese children included in our study, and sleep assessment should be a part of every health checkup for children.
Growth and Yield Responses of Cowpea and Groundnut to Five Rhizobial Inoculant Strains in the Guinea Savanna Zone of Ghana
Authors: Mintah F. , Mohammed Y. Z. , Lamptey S. , Ahiabor B. D. K.
Published: December 2020

Inoculating groundnut and cowpea with highly effective and competitive rhizobial strain improves nodulation. A field experiment was carried out at the experimental field of the Faculty of Agriculture, University for Development Studies, Nyankpala, to evaluate the growth and yield responses of cowpea and groundnut to five rhizobial inoculant strains in the Guinea Savanna zone. The experiment was laid out in a randomized complete block design (RCBD) with eight (8) treatments replicated four (4) times. The treatments included five rhizobial inoculant strains (NC 92, KNUST 1002, KNUST 1003, KNUST 1006, and BR 3267), two N fertilizer levels (20 kg·N/ha and 40 kg·N/ha), and a control. The results showed that rhizobial inoculation and N fertilizer application increased nodulation, biomass yield, pod number, pod weight, hundred seed weight, nodule dry weight, and pod yield of groundnut compared with the control. Rhizobial inoculation averagely increased the nodulation and yield by 63 and 67%, respectively, compared with the control. Mineral N fertilizer (20 kg N/ha) on average increased the nodulation and yield by 24 and 25%, respectively, compared with the control plots. It can be recommended from this study that, in the absence of highly competitive rhizobial strains such as KNUST 1006 and NC 92 as biofertilizers for increasing the nodulation and yield of cowpea and groundnut, 20 kg·N/ha can be used for the purpose. Further research is recommended using these rhizobial strains in combination with lower rates of N fertilizers (<20 kg·ha−1).
SIR Meta Distribution in the Heterogeneous and Hybrid Networks
Authors: Sun Yuhong , Liu Qinghai , Wang Hua
Published: December 2020

With the development of the technology, the wireless systems are becoming more heterogeneous with the introduction of various power nodes including femtocells, relays, or distributed antennas. Among the research of wireless network performance, the meta distribution of the signal-to-interference ratio (SIR) has attracted significant attention. Compared to the standard success (coverage) probability, the meta distribution provides much more fine-grained information about the network performance. In this paper, we analyze the meta distribution of the SIR in the multi-tier heterogeneous and hybrid networks, where each tier is based on a homogeneous independent Poisson point process model. For the open tiers (the users can associate with any tier) and the closed tiers (the users can only associate with a certain tier), we study the

b

th moment of the conditional success probability for the typical user and give the beta approximation of the meta distribution from analysis and simulations. Furthermore, we analyze the per-link rate control for open tiers and closed tiers, which answers the question: “how to set the SIR threshold to meet a target reliability?”. We give the approximate value of the SIR threshold to meet a target reliability and show how the value is related to the path loss exponent and densities.
Life Cycle Assessment of Environmental Impact of Steelmaking Process
Authors: Liu Huimin , Li Qiqiang , Li Guanguan , Ding Ran
Published: December 2020

The steel industry is facing problems such as serious environmental pollution and high resource consumption. At the same time, it lacks effective methods to quantify potential environmental impacts. The purpose of this work is to conduct a specific environmental analysis of steelmaking production in steel plants. The ultimate goal is to discover the main pollution of steelmaking and identify potential options for improving the environment. This paper uses life cycle assessment method to carry out inventory and quantitative analysis on the environmental impact of steelmaking system. Through analysis, the hazards are divided into four major categories, which are human health, climate change, ecosystem quality, and resources. The results show that molten iron has the greatest impact on human health, followed by the greatest impact on resources. The impact of scrap steel on human health ranks third. Molten iron is a key process that affects human health, climate change, ecosystems quality, and resources. In addition, processes such as fuels, working fluids, and auxiliary materials also cause certain environmental damage, accounting for a relatively small proportion. Optimizing the utilization of scrap steel and molten iron resources and improving the utilization efficiency of resources and energy are helpful to reduce the environmental hazards of steelmaking system.
Exploring the Antihyperglycemic Chemical Composition and Mechanisms of Tea Using Molecular Docking
Authors: Sun Yue , Wang Lufei , Shaughnessy Lily K. , Lin Yan , Xu Qingliang , Shi Xueping , Zhang Liang , Yu Rilei , Xiao Hang , Wan Xiaochun , Wu Xian
Published: December 2020

Tea, a widely consumed beverage, has long been utilized for promoting human health with a close correlation to hyperglycemia. The Tea Metabolome Database (TMDB), the most complete and comprehensive curated collection of tea compounds data containing 1271 identified small molecule compounds from the tea plant (Camellia sinensis), was established previously by our research team. More recently, our studies have found that various tea types possess an antihyperglycemic effect in mice. However, the bioactive ingredients from tea have potential antihyperglycemic activity and their underlying molecular mechanisms remain unclear. In this study, we used a molecular docking approach to investigate the potential interactions between a selected 747 constituents contained in tea and 11 key protein targets of clinical antihyperglycemic drugs. According to our results, the main antihyperglycemic targets of tea composition were consistent with those of the drug rosiglitazone. The screening results showed that GCG, ECG3’Me, TMDB‐01443, and CG had great target binding capacity. The results indicated that these chemicals of tea might affect hyperglycemia by acting on protein targets of rosiglitazone.
Chemical Evaluation of Trace Elements in Bottled Water
Authors: Gautam Bikram
Published: December 2020

Sales of bottled water have been increasing around the globe. This study was carried out to assess the trace elements present in bottled water. For the study of bottled water, a total of 100 samples of different volumes (20 L and 1 L) were selected. The physicochemical assessments were performed as per the methods described in the American Public Health Association, 2005. Average values of pH, electrical conductivity, total dissolved solids, and turbidity were found to be 5.96 ± 0.54, 59.97 ± 58.65, 4.42 ± 3.69, and 0.408 ± 0.19, respectively. Likewise, average values of total hardness (as CaCO3), calcium (as CaCO3), magnesium (as CaCO3), chlorine, iron, copper, cobalt, nickel, fluoride, sodium, and potassium were found to be 14.78 ± 8.43, 3.26 ± 1.55, 11.51 ± 7.92, 7.51 ± 3.21, 0.0032 ± 0.0017, 0.0091 ± 0.0116, 0.2520 ± 0.0127, 0.0080 ± 0.0082, 0.047 ± 0.0139, 12.65 ± 10.90, and 1.41 ± 2.00, respectively; meanwhile residual chlorine, zinc, silver, cadmium, and lead were below detection limit. All the physicochemical characteristics of bottled water were found to be within International Bottled Water Association (IBWA) guidelines. From the physicochemical aspects, the bottled water was found to be within the permissible value set by IBWA. Pearson’s correlation revealed significant association between trace elements. Levene’s test for equity of variances indicated that the majority (iron, copper, cobalt, nickel, fluoride, sodium, and potassium) of trace elements and seasons (monsoon and postmonsoon) demonstrated a statistically significant distribution (at 95% confidence interval). At elevated concentrations, some elements can be harmful to human health and can cause morphological abnormalities, mutagenic effects, reduced growth, and increased morbidity and mortality in humans but it all depends upon a person’s metabolic factors, genetic factors, and ability to excrete trace elements through different routes, etc. Water could have percolated down from the surface to the ground water and as such the difference in concentration of trace elements in monsoon and postmonsoon seasons could be noticeable.
A Study on Spatial Accessibility of the Urban Tourism Attraction Emergency Response under the Flood Disaster Scenario
Authors: Shi Yong , Wen Jiahong , Xi Jianchao , Xu Hui , Shan Xinmeng , Yao Qian
Published: December 2020

With the ultrahigh-speed, large-scale development of tourism and the increasing frequency, intensity, and scope of extreme natural hazards in the context of climate warming, tourism has entered a high-risk era. Based on the central urban area within the outer ring of Shanghai as the research area and the tourism attraction as the research object, this paper takes the flood scenario simulation combined with GIS network analysis to evaluate the spatial accessibility of the emergency response of urban key public service departments (120) under current and future river flood scenarios in different return periods. The results of the study show that, (1) under the current and future flood scenarios, the submergence range is mainly distributed within 2 ∼ 3 km along the banks of the Huangpu River, and it tends to increase from north to south; (2) there are 6, 9, and 21 tourism attractions in the emergency blind area under the once-in-a-century floods in 2010, 2030, and 2050 and 98, 105, and 112 tourism attractions in the emergency blind area under the once-in-a-millennium floods in 2010, 2030, and 2050, respectively; (3) in the flood scene, local road traffic in the inundation area is interrupted by water, and 120 first aid cannot get or be delayed to some tourist attraction (blind area); and (4) in 2030, under the normal and flooding scenarios, 120 first aid in the downtown area of Shanghai has the fastest route to tourism attractions according to the speed of S1, S2, S3, and S4. The flooding intensity (range and water depth), road traffic conditions (vehicle flow speed), and the number and location of key public service departments jointly determine the service scope and response time of medical emergency in urban floods. Since the flood control area of the central city in Shanghai is mainly distributed in the 2 ∼ 3 km area on both banks of the Huangpu River, the impact of flood on the emergency medical service in the entire central city is limited, mainly in some hospitals in the riverside area, where 120 emergency vehicles are unable or delayed to reach some tourism attractions. The research indicates that the quantitative assessment method of spatial accessibility of the emergency response under flood scenario simulation has important scientific value and practical significance, which can provide decision-making basis for emergency management of tourism in China’s urban flood disaster.
Critical Evaluation of the Interaction of Reactive Oxygen and Nitrogen Species with Blood to Inform the Clinical Translation of Nonthermal Plasma Therapy
Authors: Lin Abraham , Biscop Eline , Breen Colum , Butler Stephen J. , Smits Evelien , Bogaerts Annemie
Published: December 2020

Non-thermal plasma (NTP), an ionized gas generated at ambient pressure and temperature, has been an emerging technology for medical applications. Through controlled delivery of reactive oxygen and nitrogen species (ROS/RNS), NTP can elicit hormetic cellular responses, thus stimulating broad therapeutic effects. To enable clinical translation of the promising preclinical research into NTP therapy, a deeper understanding of NTP interactions with clinical substrates is profoundly needed. Since NTP-generated ROS/RNS will inevitably interact with blood in several clinical contexts, understanding their stability in this system is crucial. In this study, two medically relevant NTP delivery modalities were used to assess the stability of NTP-generated ROS/RNS in three aqueous solutions with increasing organic complexities: phosphate-buffered saline (PBS), blood plasma (BP), and processed whole blood. NTP-generated RNS collectively (NO2−, ONOO−), H2O2, and ONOO− exclusively were analyzed over time. We demonstrated that NTP-generated RNS and H2O2 were stable in PBS but scavenged by different components of the blood. While RNS remained stable in BP after initial scavenging effects, it was completely reduced in processed whole blood. On the other hand, H2O2 was completely scavenged in both liquids over time. Our previously developed luminescent probe europium(III) was used for precision measurement of ONOO− concentration. NTP-generated ONOO− was detected in all three liquids for up to at least 30 seconds, thus highlighting its therapeutic potential. Based on our results, we discussed the necessary considerations to choose the most optimal NTP modality for delivery of ROS/RNS to and via blood in the clinical context.
AZD0364 Is a Potent and Selective ERK1/2 Inhibitor That Enhances Antitumor Activity inKRAS-Mutant Tumor Models when Combined with the MEK Inhibitor, Selumetinib
Authors: Flemington Vikki , Davies Emma J. , Robinson David , Sandin Linda C. , Delpuech Oona , Zhang Pei , Hanson Lyndsey , Farrington Paul , Bell Sigourney , Falenta Katarzyna , Gibbons Francis D. , Lindsay Nicola , Smith Aaron , Wilson Joanne , Roberts Karen , Tonge Michael , Hopcroft Philip , Willis Sophie E. , Roudier Martine P. , Rooney Claire , Coker Elizabeth A. , Jaaks Patricia , Garnett Mathew J. , Fawell Stephen E. , Jones Clifford D. , Ward Richard A. , Simpson Iain , Cosulich Sabina C. , Pease J. Elizabeth , Smith Paul D.
Published: December 2020

The RAS-regulated RAF–MEK1/2–ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF-mutant melanoma, with limited effect of single-agent pathway inhibitors in KRAS-mutant tumors. Combined inhibition of multiple nodes within this pathway, such as MEK1/2 and ERK1/2, may be necessary to effectively suppress pathway signaling in KRAS-mutant tumors and achieve meaningful clinical benefit. Here, we report the discovery and characterization of AZD0364, a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and kinase selectivity. In vitro, AZD0364 treatment resulted in inhibition of proximal and distal biomarkers and reduced proliferation in sensitive BRAF-mutant and KRAS-mutant cell lines. In multiple in vivo xenograft models, AZD0364 showed dose- and time-dependent modulation of ERK1/2-dependent signaling biomarkers resulting in tumor regression in sensitive BRAF- and KRAS-mutant xenografts. We demonstrate that AZD0364 in combination with the MEK1/2 inhibitor, selumetinib (AZD6244 and ARRY142886), enhances efficacy in KRAS-mutant preclinical models that are moderately sensitive or resistant to MEK1/2 inhibition. This combination results in deeper and more durable suppression of the RAS/MAPK signaling pathway that is not achievable with single-agent treatment. The AZD0364 and selumetinib combination also results in significant tumor regressions in multiple KRAS-mutant xenograft models. The combination of ERK1/2 and MEK1/2 inhibition thereby represents a viable clinical approach to target KRAS-mutant tumors.
The HPV and p63 Status in Penile Cancer Are Linked with the Infiltration and Therapeutic Availability of Neutrophils
Authors: Bernhard Muriel Charlotte , Zwick Anabel , Mohr Tobias , Gasparoni Gilles , Khalmurzaev Oybek , Matveev Vsevolod Borisovich , Loertzer Philine , Pryalukhin Alexey , Hartmann Arndt , Geppert Carol-Immanuel , Loertzer Hagen , Wunderlich Heiko , Naumann Carsten Maik , Kalthoff Holger , Junker Kerstin , Smola Sigrun , Lohse Stefan
Published: December 2020

Squamous penile cancer displays a rare human papillomavirus (HPV)–associated tumor entity. Investigations on the molecular pathogenesis of HPV-driven penile cancer are impaired by the rareness of clinical specimens and, in particular, are missing relevant cell culture models. Here, we identified in HPV-positive penile cancer cell lines that HPV16 oncoproteins control TP63 expression by modulating critical regulators, while integration into the TP63 open reading frame facilitates oncogene expression. The resulting feed-forward loop leads to elevated p63 levels that in turn enhance the release of the neutrophil-recruiting chemokine CXCL8. Remarkably, elevated CXCL8 amounts lead to the increased surface exposition of the Fc receptor of human IgA antibodies, FcαRI, on neutrophils and correlated with a higher susceptibility to antibody-dependent neutrophil-mediated cytotoxicity (ADCC) using an EGFR-specific IgA2 antibody. IHC staining of tissue microarrays proved that elevated expression of p63 together with neutrophil infiltration were significantly more frequent in HPV-positive penile cancer displaying a higher tumor grade. In summary, we identified a promising marker profile of patients with penile cancer at higher risk for worse prognosis. However, these patients may benefit from immunotherapeutic approaches efficiently engaging neutrophils for tumor cell killing.
Development of Novel Antibody–Camptothecin Conjugates
Authors: Lyski Ryan D. , Bou Lauren B. , Lau Uland Y. , Meyer David W. , Cochran Julia H. , Okeley Nicole M. , Emmerton Kim K. , Zapata Francisco , Simmons Jessica K. , Trueblood Esther S. , Ortiz David J. , Zaval Margo C. , Snead Katie M. , Jin Steven , Farr Lauren M. , Ryan Maureen C. , Senter Peter D. , Jeffrey Scott C.
Published: December 2020

We have developed a highly active and well-tolerated camptothecin (CPT) drug-linker designed for antibody-mediated drug delivery in which the lead molecule consists of a 7-aminomethyl-10,11-methylenedioxy CPT (CPT1) derivative payload attached to a novel hydrophilic protease-cleavable valine–lysine–glycine tripeptide linker. A defined polyethylene glycol stretcher was included to improve the properties of the drug-linker, facilitating high antibody–drug conjugate (ADC) drug loading, while reducing the propensity for aggregation. A CPT1 ADC with 8 drug-linkers/mAb displayed a pharmacokinetic profile coincident with parental unconjugated antibody and had high serum stability. The ADCs were broadly active against cancer cells in vitro and in mouse xenograft models, giving tumor regressions and complete responses at low (≤3 mg/kg, single administration) doses. Pronounced activities were obtained in both solid and hematologic tumor models and in models of bystander killing activity and multidrug resistance. Payload release studies demonstrated that two CPTs, CPT1 and the corresponding glycine analog (CPT2), were released from a cAC10 ADC by tumor cells. An ADC containing this drug-linker was well tolerated in rats at 60 mg/kg, given weekly four times. Thus, ADCs comprised of this valine–lysine–glycine linker with CPT drug payloads have promise in targeted drug delivery.
Abstract IA02: Host microbiome interactions in health and disease
Authors: Elinav Eran
Published: December 2020

The mammalian intestine contains trillions of microbes, a community that is dominated by members of the domain Bacteria but also includes members of Archaea, Eukarya, and viruses. The vast repertoire of this microbiome functions in ways that benefit the host. The mucosal immune system coevolves with the microbiota beginning at birth, acquiring the capacity to tolerate components of the community while maintaining the capacity to respond to invading pathogens. The gut microbiota is shaped and regulated by multiple factors including our genomic composition, the local intestinal niche, and multiple environmental factors including our nutritional repertoire and biogeographic location. Moreover, it has been recently highlighted that dysregulation of these genetic or environmental factors leads to aberrant host-microbiome interactions, ultimately predisposing to pathologies ranging from chronic inflammation, obesity, the metabolic syndrome, and even cancer. We have identified various possible mechanisms participating in the reciprocal regulation between the host and the intestinal microbial ecosystem and demonstrate that disruption of these factors, in mice and humans, lead to dysbiosis and susceptibility to common multifactorial disease. Understanding the molecular basis of host-microbiome interactions may lead to development of new microbiome-targeting treatments.

Citation Format: Eran Elinav. Host microbiome interactions in health and disease [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA02.
Abstract IA23: Impact of metastatic prostate cancer on human bone marrow
Authors: Baryawno Ninib , Kfoury Youmna , Severe Nicolas , Mei Shenglin , Gustafsson Karin , Hirz Taghreed , Brouse Thomas , Scadden Elizabeth W. , Igolkina Anna A. , Choi Bryan D. , Barkas Nikolas , Shin John H. , Saylor Philip J. , Scadden David T. , Sykes David B. , Kharchenko Peter V.
Published: December 2020

Cancer-related mortality due to solid tumor malignancies is overwhelmingly due to the development and progression of metastases. In advanced prostate cancer, metastases most often involve the bone and generally represent incurable disease. It remains unclear what aspects of the bone marrow microenvironment make it hospitable to metastatic dissemination. Similarly, the impact of the metastatic tumor on hematopoiesis and the marrow immune response is poorly understood. We took advantage of rare spinal cord decompression surgeries to profile marrow and metastatic tumors from men with advanced prostate cancer at single-cell resolution. Our analysis contrasts the cellular composition and transcriptional states in matched samples of tumor and liquid bone marrow collected at adjacent vertebral body levels, as well as bone marrow of orthopedic patients without malignancy. Metastatic prostate cancer was associated with hematopoietic suppression and multifaceted immune distortion. There was exhaustion of specific T cell subsets, appearance of inflammatory monocytes and macrophages, and alteration of cytokine profiles. Computational analysis showed association between the presence of specific myeloid subsets and the level of T lymphocyte dysfunction in the tumor fraction. We screened for potential signaling axes that may underlie this interaction. Among them was chemokine CCL20, notably overexpressed by myeloid cells, as was its cognate CCR6 receptor, expressed on T cells. We developed a syngeneic mouse model of bone-metastatic prostate cancer to explore this observation, and demonstrated that disruption of the CCL20-CCR6 axis from either side resulted in significant prolongation of survival. Our results further indicated that this dual overexpression was associated with repressed immune responses. Overall, comparative high-resolution analysis of bone marrow reveals distinct alterations associated with prostate cancer bone metastases that may be amenable to therapeutic targeting with the goal of altering cancer progression.

Citation Format: Ninib Baryawno, Youmna Kfoury, Nicolas Severe, Shenglin Mei, Karin Gustafsson, Taghreed Hirz, Thomas Brouse, Elizabeth W. Scadden, Anna A. Igolkina, Bryan D. Choi, Nikolas Barkas, John H. Shin, Philip J. Saylor, David T. Scadden, David B. Sykes, Peter V. Kharchenko, as part of the Boston Bone Metastasis Consortium. Impact of metastatic prostate cancer on human bone marrow [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA23.
Abstract PO-120: MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate
Authors: Ireland Abbie S. , Micinski Alexi M. , Kastner David W. , Guo Bingqian , Wait Sarah J. , Spainhower Kyle B. , Conley Christopher C. , Chen Opal S. , Guthrie Matthew R. , Soltero Danny , Qiao Yi , Huang Xiaomeng , Tarapcsak Szabolcs , Devarakonda Siddhartha , Chalishazar Milind D. , Gertz Jason , Moser Justin C. , Marth Gabor , Puri Sonam , Witt Benjamin L. , Spike Benjamin T. , Oliver Trudy G.
Published: December 2020

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor that is treated clinically as a single disease with poor outcomes. However, SCLC is recently recognized to comprise multiple molecular subsets with unique therapeutic vulnerabilities. Four distinct subtypes of SCLC have been defined based on expression of lineage-related transcription factors: ASCL1, NEUROD1, POU2F3 or YAP1. The origins of these subtypes remain unknown. We use mouse and human SCLC models with a time-series analysis of single-cell transcriptome profiling to reveal that the oncogene MYC drives the dynamic evolution of SCLC subtypes by activation of Notch signaling. MYC cooperates with Notch signaling to promote a temporal shift from an ASCL1-to-NEUROD1-to-YAP1-positive state from a neuroendocrine cell of origin, whereas MYC promotes POU2F3+ tumors from a distinct cell type. SCLC molecular subtypes are therefore not distinct, but rather represent dynamic stages of MYC-driven tumor evolution. Treatment-naive human SCLC exhibits intratumoral heterogeneity in SCLC subtypes, suggesting this dynamic evolution occurs in patient tumors. These findings demonstrate that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype. Given the reported unique therapeutic vulnerabilities of each subtype, we postulate that SCLC tumors represent a “moving therapeutic target” that may require more general, combinatorial, or plasticity-directed therapeutic approaches to combat this transcriptional flexibility. We anticipate that molecular subsets of other cancer types may also represent dynamic stages of tumor evolution.

Citation Format: Abbie S. Ireland, Alexi M. Micinski, David W. Kastner, Bingqian Guo, Sarah J. Wait, Kyle B. Spainhower, Christopher C. Conley, Opal S. Chen, Matthew R. Guthrie, Danny Soltero, Yi Qiao, Xiaomeng Huang, Szabolcs Tarapcsak, Siddhartha Devarakonda, Milind D. Chalishazar, Jason Gertz, Justin C. Moser, Gabor Marth, Sonam Puri, Benjamin L. Witt, Benjamin T. Spike, Trudy G. Oliver. MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-120.
Abstract PO-016: Putting their money where their mouths are: A review of the literature concerning health research and grant funding organizations and the recruitment of Black women to breast cancer clinical trials
Authors: Ridley-Merriweather Katherine E.
Published: December 2020

Numerous clinical trials exist that focus on addressing treatments that might help improve racial disparities, but the outcomes can be significantly compromised by deficiencies in sample diversity. There is little doubt that increasing the number of Black women represented in clinical trials could positively affect well known adverse racial health statistics. Due to several factors, however, recruiting these women into clinical trials can be a challenging prospect. This review primarily focuses on how Black women are recruited into breast cancer clinical trials and/or treatment protocols, paying particular attention to public and private health organizations and grant-funding agencies that ultimately determine which studies receive funding.

Gaps clearly exist in the literature surrounding the use of communication vehicles and channels to deliver messages these women themselves say they want to hear. This work examines the recruitment of Black women to breast cancer research, identifying themes in the literature where gaps exist. Through illuminating a critical exemplar of the importance of highlighting the needs for increased cross-sectional literature in the fields of communication and psychology, a significant case study is presented as an illustration. Next, some of the industrial/organizational psychology literature on influencing the recruitment of women and racial/ethnic minorities is examined, while suggesting this field may yield some crossover methods (such as incorporating research on identity threat and safety) that may be helpful for addressing the recognized gaps. Finally, suggestions for future applied research opportunities for increasing the participation of Black women in breast cancer research are offered.

Citation Format: Katherine E. Ridley-Merriweather. Putting their money where their mouths are: A review of the literature concerning health research and grant funding organizations and the recruitment of Black women to breast cancer clinical trials [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-016.
Abstract PO-229: Rural disparities in surgical care from gynecologic oncologists among Midwestern ovarian cancer patients
Authors: Weeks Kristin S. , Lynch Charles F. , West Michele , Carnahan Ryan , O'Rorke Michael , Oleson Jacob , McDonald Megan , Stewart Sherri L. ,   Ovarian Cancer Treatment Study Group, Charlton Mary
Published: December 2020

Objective Up to one-third of women with ovarian cancer in the United States do not receive surgical care from a gynecologic oncology specialist despite guideline recommendations. There is a critical need to investigate the contributing barriers.

We aim to investigate the impact of rurality on receiving surgical care from a specialist, referral to a specialist, and specialist surgery after referral, and the consequences of specialist care. Methods We utilized a retrospective cohort created through extension of standard state cancer surveillance in three Midwestern states. Multivariable adjusted logistic regression was utilized to assess gynecologic oncologist treatment of women 18-89 years old, who were diagnosed with primary, histologically confirmed, malignant ovarian cancer in 2010-2012 in Kansas, Missouri and Iowa by rurality. As well, factors associated with surgical care were assessed among women living in urban and rural residences at the time of cancer diagnosis.

Results Rural women were significantly less likely to receive surgical care from a gynecologic oncologist specialist (adjusted odds ratio (OR) 0.37, 95% confidence interval (CI) 0.24-0.58) and referral to a specialist (OR 0.37, 95% CI 0.23-0.59) compared to urban women. There was no significant difference in specialist surgery after a referral (OR 0.56, 95% CI 0.26-1.20). Rural women treated surgically by a gynecologic oncologist versus non-specialist were more likely to receive cytoreduction and more complete tumor removal to ≤ 1cm, but experienced a greater time from diagnosis-to-surgery (mean: 19 days versus 9 days, p value 0.022). Conclusion There is a large urban-rural difference in receipt of ovarian cancer surgery from a gynecologic oncologist specialist (versus a non-specialist). Disparities in referral rates contribute to the urban-rural difference. Further research is needed into the causes of referral disparities, as well as promising strategies to address them.

Citation Format: Kristin S. Weeks, Charles F. Lynch, Michele West, Ryan Carnahan, Michael O'Rorke, Jacob Oleson, Megan McDonald, Sherri L. Stewart, Ovarian Cancer Treatment Study Group, Mary Charlton. Rural disparities in surgical care from gynecologic oncologists among Midwestern ovarian cancer patients [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-229.
Abstract PO-267: Does primary care providers' implicit and explicit bias impact cervical cancer screening recommendations for lesbian women?
Authors: Aleshire Mollie E. , Fallin-Bennett Amanda , Rayens Mary Kay , Fallin-Bennett Keisa , Hatcher Jennifer
Published: December 2020

Background: Lesbian women are 25% less likely to receive cervical cancer screening than other women which contributes to lesbian women’s higher risk for cervical cancer. The purposes of this study were to measure primary care providers' (PCPs) bias toward lesbian women and to assess the association of PCPs’ implicit and explicit bias toward lesbian women with PCPs’ recommendations for cervical cancer screening in this population. Methods: In this cross-sectional study, 182 PCPs in Kentucky completed a web-based survey that included a clinical vignette, an Implicit Association Test (IAT), and explicit bias measures. PCP’s bias was analyzed descriptively. Two-sample t-tests compared bias scores between PCPs who recommended and did not recommend cervical cancer screening for a lesbian woman. Multiple linear regression determined demographic predictors of implicit and explicit bias. Results: The PCP participants average IAT score (possible score range -2.00 to +2.00) was 0.34 with positive scores indicating preferences for heterosexual women and negative scores indicating preferences for lesbian women. There was no association between IAT scores and PCPs’ cervical cancer screening recommendations for lesbian women (p = .15). PCPs who supported same sex marriage (p < .001) and same-sex partners’ adoption of children (p < .02) and those who were less religious (p < 0.1) had significantly lower IAT scores. Characteristics such as type of PCP, age, and years in practice were not significantly associated with PCPs’ implicit and explicit bias. Conclusions: PCPs’ implicit and explicit bias was not associated with their cervical cancer screening recommendations for lesbian women in this study; however, the PCPs’ had implicit bias toward lesbian women. While not uncommon, this finding supports the need for identification of implicit bias and for implicit bias training to mitigate of PCPs’ bias toward lesbian women to prevent the potential negative effects of PCPs’ implicit bias on cervical cancer screening and other health outcomes for lesbian women.

Citation Format: Mollie E. Aleshire, Amanda Fallin-Bennett, Mary Kay Rayens, Keisa Fallin-Bennett, Jennifer Hatcher. Does primary care providers' implicit and explicit bias impact cervical cancer screening recommendations for lesbian women? [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-267.
Differential Effects of Clinically Relevant N- versus C-Terminal Truncating CDKN1A Mutations on Cisplatin Sensitivity in Bladder Cancer
Authors: Sikder Rahmat K. , Ellithi Moataz , Uzzo Robert N. , Weader David J. , Metz Alexander L. , Behbahani Ali , McKenzie Erica R. , El-Deiry Wafik S. , Abbosh Philip H.
Published: December 2020

Muscle-invasive bladder cancer (MIBC) frequently harbors mutations in the CDKN1A gene, which encodes the tumor suppressor protein p21, with the majority of alterations truncating the peptide. The effect of these mutations is poorly understood. We hypothesized that after DNA-damaging events, cells deficient in p21 would be unable to halt the cell cycle and efficiently repair DNA damage, thus proceeding down the apoptotic pathway. We used synthetic CRISPR guide RNAs to ablate the whole peptide (sg12, targeting the 12th amino acid) or the C-terminal proliferating cell nuclear antigen (PCNA)-binding domain (sg109) to mimic different p21-truncating mutations compared with a negative control (sgGFP) in bladder cancer cell lines. Loss of detectable p21 and a stable truncated p21 peptide were identified in sg12 and sg109 single-cell clones, respectively. We found that p21-deficient cells (sg12) were sensitized to cisplatin, while cells harboring distally truncated p21 (sg12 clones) demonstrated enhanced cisplatin resistance. p21-deficient sg12 clones demonstrated less repair of DNA-platinum adducts and increased γ-H2AX foci after cisplatin exposure, suggesting there was persistent DNA damage after p21 loss. p21-deficient sg12 clones were also unable to prevent the activation of CDK1 after DNA damage, and therefore, continued through the cell cycle, resulting in replication fork collapse, potentially explaining the observed cisplatin sensitization. sg109 clones were neither unable to sequester PCNA nor localize p21 to the nucleus after DNA damage, potentially explaining the chemoresistant phenotype. Our findings suggest that different CDKN1A truncations have different and perhaps disparate biology, and that there may be a duality of effect on cisplatin sensitivity depending on mutation context.

Implications:

Some truncating CDKN1A mutations generate a retained peptide that may have neomorphic functions and affect cisplatin sensitivity in patients with bladder cancer.