bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective evaluation of the “Stop the Bleed” program in Japanese participants
Authors: Ito Kaori , Morishita Koji , Tsunoyama Taichiro , Nagao Tsuyoshi , Tomonaga Ayumi , Hondo Kenichi , Yagi Masayuki , Kato Nagisa , Miyake Yasufumi , Sakamoto Tetsuya
Published: August 2020

Background

The Stop the Bleed (STB) program was developed to bring military bleeding control techniques into wider use among American civilians. It was introduced in Japan in case of mass casualty events during the Tokyo Olympic/Paralympic Games in 2021, and its effectiveness was prospectively evaluated.

Methods

Japanese physicians certified as STB instructors held bleeding control basic training courses from April to July 2019. Participants’ knowledge was assessed using pre-training and post-training tests comprising five questions. One point was awarded for each correct answer, giving a maximum total score of 5. (Q1) What is the most common preventable trauma death?; (Q2) Which actions should be prioritized for bleeding victims?; (Q3) Which patients should be transferred to hospital first?; (Q4) How should a tourniquet be applied?; (Q5) How should pain associated with a tourniquet be managed?

Results

The study involved 157 participants (20 physicians/nurses, 82 medical students, 33 emergency services personnel, 22 police officers/security personnel). The mean±SD scores were 2.1±1.1 before training and 3.2±1.0 after training (p<0.01). The respective percentages of correct answers before and after training were 58% and 75% for Q1, 10% and 13% for Q2, 38% and 55% for Q3, 73% and 89% for Q4, and 33% and 91% for Q5. Q2 had the lowest percentage of correct answers and the poorest improvement.

Discussion

The STB program improved tourniquet knowledge. However, it was less effective in improving knowledge about which actions to prioritize for bleeding victims. This may be because the participants were well trained in basic life support and therefore expected to immediately commence cardiopulmonary resuscitation for patients in shock. The STB program is valuable in preparing Japanese people for mass casualty events during the Tokyo Olympic/Paralympic Games in 2021.

Level of evidence

IV.

Study type

Therapeutic.
Revisiting the evolution of the North American tetraploid treefrog (Hyla versicolor)
Authors: Bogart James P. , Burgess Patrick , Fu Jinzhong
Published: August 2020

Hyla chrysoscelis and H. versicolor are common treefrogs in eastern North America and are a cryptic diploid–tetraploid species pair. They are morphologically identical but H. versicolor is a tetraploid. They can be identified acoustically by the male’s advertisement mating call, which has a pulse repetition rate that has twice as many pulses per second in the diploid species, H. chrysoscelis. We used isozymes, microsatellite DNA alleles, and mitochondrial cytochrome b sequences to test the hypothesis that gene exchange occurs between the diploid and tetraploid species in sympatric populations. Each method provided results that are best explained by occasional hybridization of female H. versicolor and male H. chrysoscelis. We propose that H. versicolor first arose from an autotriploid H. chrysoscelis female that produced unreduced triploid eggs. After H. versicolor became established, genes could be passed from H. chrysoscelis to H. versicolor in sympatric populations when these species hybridize. Their F1female progeny produce unreduced triploid eggs that are fertilized by haploid H. chrysoscelis sperm to reconstitute H. versicolor. Genes can be passed from diploid H. chrysoscelis to tetraploid H. versicolor in sympatric populations.
Response to Discussion on “Improved Overlap-Based Undersampling for Imbalanced Dataset Classification with Application to Epilepsy and Parkinson’s Disease,”
Authors: Vuttipittayamongkol Pattaramon , Elyan Eyad
Published: August 2020

In the paper Improved Overlap-Based Undersampling for Imbalanced Dataset Classification with Application to Epilepsy and Parkinson’s Disease, the authors introduced two new methods that address the class overlap problem in imbalanced datasets. The methods involve identification and removal of potentially overlapped majority class instances. Extensive evaluations were carried out using 136 datasets and compared against several state-of-the-art methods. Results showed competitive performance with those methods, and statistical tests proved significant improvement in classification results. The discussion on the paper related to the behavioral analysis of class overlap and method validation was raised by Fernández. In this article, the response to the discussion is delivered. Detailed clarification and supporting evidence to answer all the points raised are provided.
Similarities and exact solutions of transonic gas flow model
Authors: Pinar Zehra
Published: August 2020

In this work, one of the important models in nonlinear wave theory and also in nonlinear acoustic, the Lin–Reissner–Tsien (LRT) equation is considered. For the homogeneous form of LRT equation, the exact solutions are obtained. For steady and non-steady state forms of the LRT equation with force terms, similarity reductions are obtained via the classical symmetry analysis method. Both of the considered problems are not seen in the literature. The results obtained in this paper are new solutions and believed to have a major role in the development of the model.
Yangians versus minimal W-algebras: A surprising coincidence
Authors: Kac Victor G. , Frajria Pierluigi Möseneder , Papi Paolo
Published: August 2020

We prove that the singularities of the [Formula: see text]-matrix [Formula: see text] of the minimal quantization of the adjoint representation of the Yangian [Formula: see text] of a finite dimensional simple Lie algebra [Formula: see text] are the opposite of the roots of the monic polynomial [Formula: see text] entering in the OPE expansions of quantum fields of conformal weight [Formula: see text] of the universal minimal affine [Formula: see text]-algebra at level [Formula: see text] attached to [Formula: see text].
Bilateral Ramanujan-like series for 1/πk and their congruences
Authors: Guillera Jesús
Published: August 2020

We prove a kind of bilateral series that terminates to one side (left or right) related to Ramanujan-like series for negative powers of [Formula: see text], and conjecture a type of supercongruences associated with them. We support this conjecture by checking all the cases for many primes. In addition, we are able to prove a few of them from some terminating hypergeometric identities. Finally, we make an intriguing observation.
Maintenance of endothelial function following acute resistance exercise in females is associated with a tempered blood pressure response
Authors: Morishima Takuma , Padilla Jaume , Tsuchiya Yosuke , Ochi Eisuke
Published: August 2020

The present data demonstrate for the first time that acute resistance exercise impairs endothelial function in young, healthy male but not female subjects. In addition, we show that the preservation of endothelial function in females is associated with a mitigated blood pressure response during resistance exercise. Accordingly, this work portrays a sexual dimorphism in the barostress response, and ensuing vascular effects, to resistance exercise.
The Effect of Genetically Modified Food on Infertility Indices: A Systematic Review Study
Authors: Keshani Parisa , Sharifi Mohammad Hossein , Heydari Mohammad Reza , Joulaei Hassan
Published: August 2020

Background and Objectives. With the increase in the growth of genetically modified (GM) crops, concerns as to the adverse effects of GM crops have risen in the community. The present systematic review seeks to assess the GM plants’ potential impacts on the sperm parameters, including sperm head, sperm motility, sperm abnormality, and fertility index. Materials and Methods. A structured literature search was independently performed by three authors on Scopus, Web of Science, PubMed, and Embase in January 2019. A total of 1467 publications were obtained by the search strategy after eliminating the duplicates. Moreover, the review only included articles written in English language. Other pertinent peer-reviewed publications were chosen (“snowballing”) from the reference lists in the selected publications. To assess the GM crop effects on infertility, experimental studies designed with the control group were selected. On the basis of abstract screening and full-text reviewing, 39 relevant publications were selected, seven of which were used in our review. To access the quality of articles, we used the Cochrane checklist. The collected articles were scored independently by three authors, and the publications with the eligibility criteria were included in our review. No article was excluded due to quality assessment. Results and Conclusion. Our findings indicated that GM products had no adverse effects on infertility indices such as the sperm head, sperm motility, sperm abnormality, and fertility indices. Long-term research still seems to be strongly necessary to ensure that the use of GM plants does not cause any harm to consumers, especially in infertility area.
Multiscale Study on the Modification Mechanism of Red Mud Modified Asphalt
Authors: Fu Tao , Wei JianHui , Bao Huiming , Liang Junlin
Published: August 2020

Red mud, a waste residue of aluminium industry, was used as modified asphalt material to prepare red mud modified asphalt and red mud modified asphalt under freeze‐thaw cycles. The matrix asphalt (MA), red mud modified asphalt (RMMA), and red mud modified asphalt under freeze‐thaw cycles (RMMAFC) were studied by scanning electron microscopy (SEM), Fourier transform infrared spectrometry (FTIR), atomic force microscopy (AFM), and differential scanning calorimetry (DSC). Microscopic experiments were conducted to investigate the modification performance and mechanism. The modification mechanism of red mud modified asphalt was investigated using molecular dynamics simulation in this study. The results show that red mud can form a uniform and stable blending system with base asphalt after adding base asphalt. The structure of asphalt after adding red mud and adding red mud and freezing‐thawing cycles does not change. The bee‐structure decreases obviously with the addition of red mud by atomic force microscopy (AFM). Density decreases gradually, but bee‐structure height increases obviously; bee‐structure of red mud modified asphalt is destroyed after freeze‐thaw cycles. Through differential scanning calorimetry (DSC), after adding red mud, heat absorption decreases. Freeze‐thaw cycles greatly reduce heat absorption of red mud modified asphalt. Constructing molecular model of major components of red mud (Fe2O3, Al2O3) and asphaltene, simulation results show that the interfacial energy between asphaltene and red mud’s main components Fe2O3 and Al2O3 at −10°C, 25°C, and 170°C is stronger than that of Fe2O3. The results of calculating the interfacial energy of asphaltene on the chemical composition surface of red mud are negative. It can be seen that there are adsorption effects on the surface of asphaltene and red mud. Therefore, increasing the content of Al2O3 or decreasing the content of Fe2O3 in red mud is beneficial to the adsorption of asphaltene.
Pharmacokinetics of Bismuth following Oral Administration of Wei Bi Mei in Healthy Chinese Volunteers
Authors: Zhang Lingye , Liu Juan , Meng Fandong , Guan Yingying , Wang Yongjun , Zhu Shengtao , Liu Yaqiong , Xie Qing , Yu Junxian , Zhang Shutian
Published: August 2020

Background. Bismuth‐containing quadruple therapy achieves higher eradication rate of Helicobacter pylori. High level of bismuth in blood may result in damage of many organs. Wei Bi Mei is a new bismuth‐containing drug combining chemicals and Chinese medicine portions. The present research is to study the pharmacokinetics of bismuth to evaluate the safety and rational use of Wei Bi Mei granules. Material and Methods. Seven healthy Chinese adult subjects were enrolled in this research, which included a single‐dose study and a multiple‐dose study. Wei Bi Mei granules were administered orally to the subjects at corresponding time. Blood and urine were collected. All samples were analyzed by inductively coupled plasma mass spectrometry (ICP‐MS). Results. For single‐dose Wei Bi Mei granules administration, the mean time to peak concentration (tmax) of bismuth was 2.29 ± 0.76 h, and the mean peak concentration (Cmax) of bismuth was 0.85 ± 0.55 ng/mL. For multiple‐dose Wei Bi Mei granules administration, the Cmax was 2.25 ± 1.18 ng/mL at day two, and the volume of distribution (Vd) was (22.97 ± 9.82) × 103 L. The urinary excretion of bismuth was the fastest during the first two days, with a mean excretion rate of 3.84 ± 1.23 ng/h. The bismuth concentration in urine was significantly reduced at day 16. Conclusion. Bismuth has a washout period of approximately two months. The concentration of bismuth in blood was far less than the “safe level.” Thus, Wei Bi Mei is a highly safe therapeutic medicine, with a good clinical application value. Wei Bi Mei should be recommended more widely for use in bismuth‐containing quadruple therapy for the treatment of Helicobacter pylori infection.
The Effect of Electroacupuncture on Dynamic Balance during Stair Climbing for Elderly Patients with Knee Osteoarthritis
Authors: Hou Meijin , Wang Xiangbin , Yu Jiao , Fu Shengxing , Yang Fengjiao , Li Zhenhui , Zhang Yanxin , Tao Jing
Published: August 2020

Background. Poor balance is one of the risk factors for falls in patients with knee osteoarthritis (KOA), which is related to the symptoms. Electroacupuncture (EA) is one of the traditional Chinese conservative methods commonly used to improve the symptoms in patients with KOA. Objective. To assess whether EA increases the dynamic balance during stair negotiation among patients with KOA. Methods. A total of 40 KOA patients were assigned to two groups randomly (true electroacupuncture vs. mock electroacupuncture). Acupoints around the knee were selected in the true electroacupuncture (TEA) group with electrical stimulation (2 Hz). In the mock electroacupuncture (MEA) group, about 2 cm next to the above acupoints, the needles were inserted superficially without electrical stimulation. All the participants received 11 sessions of stimulation treatment in three weeks. The primary outcome was margin of stability (MOS). Secondary outcomes included hip kinematics and kinetics as well as pain. Results. There was no significant difference between the two groups for self‐reported pain (p = 0.585). During ascent, there was no difference between groups in MOS value in both directions, which was the anterior‐posterior (A/P) direction and medial‐lateral (M/L) direction at initial contact and toe‐off as well as the midstance in the gait cycle, and no difference for the hip kinematics and kinetics between the groups was detected (p > 0.05). For descent, at the toe‐off event, the TEA group was more unstable as compared to the MEA group in the A/P direction (p = 0.029) but not in the M/L direction, and the hip showed a larger internal rotator moment (p = 0.049); at the midstance, the TEA group showed a lower abductor moment than the MEA group (p = 0.003). Conclusions. Based on the assessment results from the chosen patients with KOA, the TEA did not demonstrate a significant effect in improving the dynamic balance during stair negotiation in comparison with the MEA. This finding does not support EA as a conservative treatment to improve the dynamic balance in such patients.
A Study of the Pattern of Admissions to the Accident and Emergency (A&E) Department of a Tertiary Care Hospital in Sri Lanka
Authors: Jayasekera Priyamali , Dassanayake Gayani , Bandara Kasthuri , Jayawardhena Lakmali , Malkanthi K. M. S.
Published: August 2020

Introduction. The latest national healthcare reform policies of Sri Lanka include the development of accident and emergency (A&E) departments in all major hospitals. Provincial General Hospital Kurunegala (PGHK) is a home to the first established A&E department in Sri Lanka. PGHK provides services to a population of 2.4 million spread out in the North Western Province and part of the Sabaragamuwa Province. This study was carried out to identify the pattern of all admissions to the A&E department of PGHK.Methods. The prospective observational study was carried out from July 1, 2016, to June 30, 2017 (one year) to identify the pattern of admissions to the A&E department.Results. There were 49,213 admissions to PGHK’s A&E department during the study period. The average number of admissions was 135 (±17.9) per day. The percentage of deaths in the A&E department was 0.21%. The mean age of admitted patients was 46.7 (±21.7) years. A further 62% of admitted patients were males. The number of medical, surgical, paediatric, and gynaecological and obstetrical admissions was 55%, 42%, 3.5%, and 0.22%, respectively. Among the common emergency medical presentations, 34% were chest pain, 11% patients presented with unilateral weakness and/or slurring of speech, 10% covered dyspnoea, and 9% complained of dizziness/giddiness. Among emergency surgical presentations, 83% were trauma due to accidents, of which 27% were road-traffic-related accidents (RTAs).Discussion. The A&E department of PGHK provides services to a significantly high number of health emergencies every day. The majority of these admissions was due to chest pain and trauma related to accidents. The lower recorded number of paediatric and gynaecological and obstetrical emergencies presented to the A&E department is a result of a government policy mandating the admission of these types of patients directly to their respective wards. Further infrastructure development, staff recruitment, and training have to be planned and implemented to address the significantly high number of admissions to the A&E Department of PGHK.
Nonlinear Dynamics Modeling and Subharmonic Resonances Analysis of a Laminated Composite Plate
Authors: Ma Ting , Song Xiao Juan , Lu Shu Feng
Published: August 2020

The nonlinear subharmonic resonance of an orthotropic rectangular laminated composite plate is studied. Based on the theory of high-order shear laminates, von Karman's geometric relation for the large deformation of plates, and Hamilton's principle, the nonlinear dynamic equations of a rectangular, orthotropic composite laminated plate subjected to the transverse harmonic excitation are established. According to the displacement boundary conditions, the modal functions that satisfy the boundary conditions of the rectangular plate are selected. The two-degree-of-freedom ordinary differential equations that describe the vibration of the rectangular plate are obtained by the Galerkin method. The multiscale method is used to obtain an approximate solution to the resonance problem. Both the amplitude-frequency equation and the average equations in the Cartesian coordinate form are obtained. The amplitude-frequency curves, bifurcation diagrams, phase diagrams, and time history diagrams of the rectangular plate under different parameters are obtained numerically. The influence of relevant parameters, such as excitation amplitude, tuning parameter, and damping coefficient, on the nonlinear dynamic response of the system is analyzed.
Elevated Levels of Activated and Pathogenic Eosinophils Characterize Moderate-Severe House Dust Mite Allergic Rhinitis
Authors: Chen Yang , Yang Meng , Deng Jie , Wang Kanghua , Shi Jianbo , Sun Yueqi
Published: August 2020

Eosinophils play a critical role in the pathogenesis of allergic airway inflammation. However, the relative importance of eosinophil activation and pathogenicity in driving the progression of disease severity of allergic rhinitis (AR) remains to be defined. We aimed to assess the relation of activated and pathogenic eosinophils with disease severity of patients with AR. Peripheral blood and nasal samples were collected from patients with mild (n=10) and moderate-severe (n=21) house dust mite AR and healthy control subjects (n=10) recruited prospectively. Expressions of activation and pathogenic markers on eosinophils in the blood and nose were analyzed by flow cytometry. The eosinophilic cation protein- (ECP-) releasing potential and the pro-Th2 function of blood eosinophils were compared between the mild and moderate-severe patients and healthy controls. Our results showed that the numbers of activated (CD44+ and CD69+) and pathogenic (CD101+CD274+) eosinophils in the blood and nose as well as blood eosinophil progenitors were increased in moderate-severe AR compared with the mild patients and healthy controls. In addition, the levels of activated and pathogenic eosinophils in the blood were positively correlated with the total nasal symptom score and serum ECP and eosinophil peroxidase (EPX) levels in patients with AR. Furthermore, the blood eosinophils obtained from the moderate-severe patients exhibited a higher potential of releasing ECP and EPX induced by CCL11 and of promoting Th2 responses than those from the mild patients and healthy controls. In conclusion, patients with moderate-severe AR are characterized by elevated levels of activated and pathogenic eosinophils, which are associated with higher production of ECP, EPX, and IL-4 in the peripheral blood.
Isolated Large Glenoid Fracture in Acute Glenohumeral Dislocation in the Elderly: A Novel Indication for Reverse Shoulder Arthroplasty
Authors: Smith Tyler , D’Alonzo Joseph , Arevalo Alfonso , Kazanjian Jack
Published: August 2020

Case. Two elderly males presented with traumatic shoulder dislocation and bony Bankart fracture consisting of greater than 25% of the glenoid width. Due to several concomitant factors such as polytrauma, activity level, rotator cuff pathology, optimization of comorbidities, risk of complications, and potential for revision surgery, the patients were treated with reverse shoulder arthroplasty (RSA). Conclusion. RSA may be a satisfactory treatment option for isolated, large glenoid fractures associated with anterior glenohumeral instability in the elderly. These patients are susceptible to rapid deconditioning with prolonged immobilization and may not be medically suited to undergo the prolonged recovery period associated with open reduction internal fixation or potentially undergo revision operations.
A Case of Diabetic Ketoacidosis in a Patient on an SGLT2 Inhibitor and a Ketogenic Diet: A Critical Trio Not to Be Missed
Authors: Steinmetz-Wood Samantha , Gilbert Matthew , Menson Katherine
Published: August 2020

Results from major clinical trials have shown significant cardiorenal-protective benefits of SGLT2 inhibitors in patients with type 2 diabetes (T2DM), leading to increased popularity. A rare but serious side effect of SGLT2 inhibitors is euglycemic diabetic ketoacidosis (EDKA), which presents more covertly but has been described. Identification and report of modifiable risk factors would be an important step in helping clinicians appropriately counsel patients. In this case report, we present DKA in a patient on an SGLT2 inhibitor and ketogenic diet (KD). A 47-year-old male with a history of poorly controlled T2DM on metformin and empagliflozin presented to the emergency department (ED) with several days of pharyngitis, dyspnea, emesis, abdominal pain, and anorexia. Of note, one month prior to this event, he presented to the ED with malaise and was found to have an anion gap of 21, a bicarbonate level of 13 mmol/L, a pH level of 7.22, 3+ ketonuria, and a glucose level of 7 mmol/L (127 mg/dl). Additional workup was negative, and findings were attributed to his KD. His use of empagliflozin was not identified on his medication list. At second presentation, the patient was tachypneic and tachycardic and had mild abdominal tenderness. Labs revealed anion gap 28, bicarbonate 5 mmol/l, pH 6.94, 3+ ketonuria, glucose 14.9 mmol/L (269 mg/dl), and beta-hydroxybutyrate 8.9 mmol/L. The patient was diagnosed with DKA and was treated accordingly. With closure of anion gap, the patient was transitioned to insulin and metformin, and his empagliflozin was discontinued indefinitely. Before prescribing this medication class, physicians should inquire about low-carbohydrate diets given the higher risk for DKA, though knowledge of this risk is still not widespread.
Preparation and Performance Characterization of Warm‐Mix Rejuvenated Bioasphalt
Authors: Zhang Zhu , Li Jiusu , Duan Zhenjun , Zhang Shuaipeng , Lou Menglei
Published: August 2020

Reclaimed asphalt pavement (RAP) material is generally under a large amount of aged asphalt coated on the surface of the aggregates, which often limits its (RAP) wide application. Bioasphalt is a renewable material with constituent components that are comparable to regular petroleum asphalt and has the potential to rejuvenate the performance of the aged asphalt in RAP materials. In this laboratory study, the optimum bioasphalt dosage for rejuvenating and optimizing warm‐mix rejuvenated bioasphalt (WBA) performance, in the presence of styrene‐butadiene‐styrene (SBS) and naphthenic oil additives, was investigated. The laboratory test results of the single‐factor and orthogonal experiment indicated that the optimal dosage of bioasphalt in WBA was 30% at 4% SBS and 10% naphthenic oil, respectively. The test results further indicated that the WBA’s ductility properties were highly responsive to the bioasphalt dosage. Naphthenic oil, on the other hand, had the greatest impact on the WBA fluidity. Likewise, the Brookfield viscosity experimentation showed that the fluidity of WBA and aged asphalt with different contents at 30%, 40%, 50%, 60%, and 70%, respectively, satisfactorily met the Chinese construction requirements. The adhesion test indicated excellent adhesion and good moisture stability properties for WBA. The resultant PG grades of WBA blended with 40% and 70% aged asphalt were PG 64‐34 and PG 70‐22, respectively. Microstructure and surface morphology analysis showed carbonyl absorption peaks with high rejuvenation and surface‐crack repair potential for the WBA over the control asphalt that was evaluated in the study.
Body Composition, Metabolic Health, and Functional Impairment among Adults Treated for Abdominal and Pelvic Tumors during Childhood
Authors: Wilson Carmen L. , Liu Wei , Chemaitilly Wassim , Howell Carrie R. , Srivastava Deo Kumar , Howell Rebecca M. , Hudson Melissa M. , Robison Leslie L. , Ness Kirsten K.
Published: August 2020

Background:

We aimed to characterize body composition, metabolic impairments, and physical performance among survivors of pediatric abdominal and pelvic solid tumors.

Methods:

Participants included 431 survivors of abdominal or pelvic tumors [median attained age = 29.9 (range: 18.7–55.1) years]. Relative lean mass and fat mass were assessed with dual X-ray absorptiometry. Metabolic outcomes [insulin resistance (IR), high-density lipoprotein (HDL), low-density lipoprotein, and triglycerides] were based on laboratory values and medication usage. General linear regression evaluated associations between treatment and lifestyle with body composition; binomial regression evaluated associations between body composition and metabolic outcomes and physical performance.

Results:

Lean mass was lower than values from the National Health and Nutrition Examination Survey (NHANES) in males (Z-score = −0.67 ± 1.27; P < 0.001) and females (Z-score = −0.72 ± 1.28; P < 0.001). Higher cumulative abdominal and pelvic radiation doses were associated with lower lean mass among males [abdominal: β = −0.22 (SE) ± 0.07; P = 0.002 and pelvic: β = −0.23 ± 0.07; P = 0.002] and females (abdominal: β = −0.30 ± 0.09; P = 0.001 and pelvic: β = −0.16 ± 0.08; P = 0.037). Prevalence of IR (40.6% vs. 33.8%; P = 0.006), low HDL (28.9% vs. 33.5%; P = 0.046), and high triglycerides (18.4% vs. 10.0%; P < 0.001) was increased among survivors relative to NHANES. Compared with survivors with normal/high lean mass and normal/low fat mass, survivors with normal/high lean mass and high fat mass had an increased risk of IR (P < 0.001), low HDL (P < 0.001), reduced quadriceps strength at 60°/second (P < 0.001) and 300°/second (P < 0.001), and reduced distance covered in the 6-minute walk (P < 0.01).

Conclusions:

Abdominal/pelvic radiotherapy is associated with body composition changes that can adversely influence metabolic outcomes and performance status among survivors.

Impact:

Interventions targeting body composition may facilitate management of cardiovascular disease risk in this population.
Abstract A09: Photoimmunotherapy (PIT) for treatment of bladder cancer
Authors: Railkar Reema , Siddiqui Mohammad Rashid , Sanford Thomas , Kobayashi Hisataka , Choyke Peter L. , Agarwal Piyush K.
Published: August 2020

Introduction: The use of light as a means of therapy for bladder cancer (BC) has a long history but has been hampered by a lack of tumor specificity and therefore, damage to the normal bladder mucosa. Here, we describe a targeted form of phototherapy called photoimmunotherapy (PIT). To begin with, anti-EGFR antibody panitumumab (pan) was labeled with the photo-absorber (PA), IRDye 700Dx (IR700), to create pan IR700, an antibody-PA conjugate that is activated by near-infrared radiation (NIR). However, PIT may be less effective when a tumor lacks “overwhelming” expression of a single target such as EGFR. Hence, a combinatorial PIT approach for targeting BC expressing EGFR and HER2, using PA-labeled pan and trastuzumab (tra), respectively.

Methods: Human BC tissue microarray (TMAs) and BC cell lines were analyzed for expression of EGFR and HER2. Mechanism of PIT-induced cell death was studied using proliferation assays, transmission electron microscopy (TEM), and production of reactive and singlet oxygen species (ROS/SOS). Finally, efficacy of PA-labeled antibodies singly and in combination was analyzed in vitro and in vivo.

Results: Most BC tissues have some expression of EGFR, but squamous cell carcinoma (SCC) of bladder has maximum EGFR expression. About 45% of BC tissues stain for both EGFR and HER2. Pan IR700 activated by NIR light rapidly killed UMUC-5 cells, a bladder SCC line. Pan alone, pan IR700 without NIR, or NIR alone had no effect on cells. TEM demonstrated that cell death is due to necrosis. Singlet oxygen species (SOS) had a substantially larger contribution towards cell death than reactive oxygen species (ROS). NIR-PIT with pan IR700 demonstrated reduced growth compared to only pan IR700-treated UMUC-5 xenograft tumors. In non-SCC BCs we used a combinatorial PIT approach using pan IR700 and tra IR700 to target EGFR and HER2, respectively. In vitro, PIT in the presence of combination pan IR700 and tra IR700 was more efficacious than either agent alone with lethal dose 50 (LD50) of 28.66 J/cm2 for combination PIT compared to 71.55 J/cm2 for the PanIR700 alone. In vivo, tumor xenografts treated with combination PIT showed significant tumor growth retardation compared to single-agent therapy.

Conclusion: PIT is a new targeted treatment for BC. Our data demonstrate that pan IR700-induced PIT selectively kills EGFR-expressing bladder cancer. Combination PIT is a promising approach for treating BC by selectively inducing death in BC cells with low/moderate expression of surface receptors.

Citation Format: Reema Railkar, Mohammad Rashid Siddiqui, Thomas Sanford, Hisataka Kobayashi, Peter L. Choyke, Piyush K. Agarwal. Photoimmunotherapy (PIT) for treatment of bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A09.
Abstract IA20: Intravesical versus systemic therapy: Win, lose, or draw—the future is now for multidisciplinary NMIBC drug development
Authors: Hahn Noah M.
Published: August 2020

In recent years, we have witnessed an explosion in both therapeutic drug development and our understanding of the key biologic drivers and targets in bladder cancer. While new drug approvals have thus far been confined to metastatic patients, several promising agents have fully accrued key FDA registration studies in the BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) population. Initial early-response data in the carcinoma in situ (CIS) populations demonstrate clear signals of activity with long-term follow-up ongoing to assess response durability. Agents administered by either intravesical or systemic routes are among those being assessed. While urologists, medical oncologists, and radiation oncologists have long worked together in the care of muscle-invasive bladder cancer (MIBC) and metastatic bladder cancer patients, an established template of multidisciplinary collaboration in the care of NMIBC patients is lacking. This unknown frontier creates both challenges and immense opportunities. True lasting, impactful progress rarely happens in isolation. This session will utilize data and example cases to illustrate specialty-specific skills and perceptions that define us, must be acknowledged for the biases they create, and ultimately should be embraced as a vehicle to establish functional and collaborative multidisciplinary drug development and clinical care models for NIMIBC patients.

Citation Format: Noah M. Hahn. Intravesical versus systemic therapy: Win, lose, or draw—the future is now for multidisciplinary NMIBC drug development [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA20.
Abstract IA21: Intravesical gene therapy for NMIBC
Authors: Mokkapati Sharada , Duplisea Jon , Metcalfe Michael , Lim Amy , Narayan Vikram , Plote Devin , Sundi Debashish , Furguson James E. , Parker Nigel R. , Yla-Herttuala Seppo , McConkey David , Shluns Kimberly S. , Dinney Colin P.N.
Published: August 2020

BCG is our most effective therapy for treating NMIBC, but over time, most patients will eventually recur. Alternative therapies to avoid cystectomy are needed as to date, only valrubicin, with a CR approaching 10% at 12 months in BCG-refractory CIS, has been FDA approved. Significant unmet need thus remains for an effective second-line therapy for patients facing cystectomy. The elucidation of a pathway for registration of new agents for BCG-unresponsive NMIBC has drawn the attention of pharma, and a variety of new approaches are under evaluation. Gene therapy is a promising approach for the management of BCG-unresponsive NMIBC. Effective gene transfer across the urothelium has been accomplished, and several agents are being evaluated in ongoing clinical trials. Coldgenesys reported a 47% CR at 6 months for BCG-unresponsive NMIBC using a replication-competent oncolytic adenovirus. The SUO CTC reported a 35% RFS at 12 months for patients treated with rAd-IFNα2b/Syn3 gene therapy in a phase II trial. The RFS for patients with papillary disease was 50% and the CR for patients with CIS was 30%. The SUO-CTC have recently completed recruitment for the phase III trial and further preclinical work has progressed to elucidate rAd-IFN/Syn3 treatment efficacy via predictive efficacy biomarkers for patient selection, vectors that might improve transduction efficiency and the design of novel therapeutic combination strategies to take advantage of rAd-IFN's immunologic activity.

Citation Format: Sharada Mokkapati, Jon Duplisea, Michael Metcalfe, Amy Lim, Vikram Narayan, Devin Plote, Debashish Sundi, James E. Furguson III, Nigel R. Parker, Seppo Yla-Herttuala, David McConkey, Kimberly S. Shluns, Colin P.N. Dinney. Intravesical gene therapy for NMIBC [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA21.
Abstract PR09: Gene expression profiling in wild-type and mutant FGFR3 metastatic urothelial cancer treated with combination therapy with vofatamab and pembrolizumab
Authors: Choi Woonyoung , McConkey David , Lee I-ling , Currie Graeme , Abella Steve , Kelly William , Siefker-Radtke Arlene
Published: August 2020

Background: FGFR3 mutations (mutFGFR3) are present in up to 20-35% of metastatic bladder (mUC) and upper tract urothelial cancer, respectively. Early data suggest that these tumors respond better to FGFR inhibition as compared with immunotherapy.

Methods: Patients who failed prior treatment for mUC were treated with vofatamab, an antibody targeting both wild-type (wtFGFR3) and mutFGFR3. Patients were treated with a loading dose of vofatamab 25 mg/kg with a biopsy pre- and post-treatment, followed by combination therapy with pembrolizumab to cohorts of patients with and without mutFGFR3. We performed gene expression profiling on paired biopsies from patients enrolled to date.

Results: We performed whole-transcriptome RNAseq on 17 matched tumors. The responses to the therapy were 7 partial responses (PR), 4 stable disease (SD), 5 progressed disease (PD), and 1 unknown. Surprisingly, we did not observe any relationships between FGFR3 mutation status and clinical response (ORR:1/3 mutant and 6/14 wild-type). Unsupervised cluster analysis of 17 matched tumors revealed the presence of two clusters: cluster 1 was enriched for responders (6 PR, 1 SD, and 1 PD), compared with cluster 2 (1 PD, 3 SD, and 4 PD). The significantly differentially expressed genes comparing cluster 1 and 2 were extracted and analyzed by Ingenuity Pathway Analysis (Sigma). Immune cell trafficking pathways, including migration of lymphocytes/T cells and phagocytes, were significantly upregulated in cluster 2 (p<0.001). We then used BASE47 (47 gene signature for basal and luminal subtypes) to assign 17 paired tumors to the molecular subtypes. Of the responding tumors, 6 were luminal and 1 was basal. To further explore sensitivity/resistance mechanisms, the differentially expressed genes between pre- and post-treated PR tumors were extracted and were used to perform IPA analysis. Upstream regulators (CEBPA and RXRA) that control luminal biology were significantly activated after treatment (p<0.001, Z score >2).

Conclusions: Luminal biology may sensitize to combination of vofatamab with pembrolizumab regardless of presence of mutFGFR3, suggesting a role for this combination in wtFGFR3 mUC. Larger cohorts are needed to confirm these results.

This abstract is also being presented as Poster B25.

Citation Format: Woonyoung Choi, David McConkey, I-ling Lee, Graeme Currie, Steve Abella, William Kelly, Arlene Siefker-Radtke. Gene expression profiling in wild-type and mutant FGFR3 metastatic urothelial cancer treated with combination therapy with vofatamab and pembrolizumab [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr PR09.
Relative Cerebellum Size Is Not Sexually Dimorphic across Primates
Authors: DeCasien Alex R. , Higham James P.
Published: August 2020

Background/Aims: Substantive sex differences in behavior and cognition are found in humans and other primates. However, potential sex differences in primate neuroanatomy remain largely unexplored. Here, we investigate sex differences in the relative size of the cerebellum, a region that has played a major role in primate brain evolution and that has been associated with cognitive abilities that may be subject to sexual selection in primates. Methods: We compiled individual volumetric and sex data from published data sources and used MCMC generalized linear mixed models to test for sex effects in relative cerebellar volume while controlling for phylogenetic relationships between species. Given that the cerebellum is a functionally heterogeneous structure involved in multiple complex cognitive processes that may be under selection in males or females within certain species, and that sexual selection pressures vary so greatly across primate species, we predicted there would be no sex difference in the relative size of the cerebellum across primates. Results: Our results support our prediction, suggesting there is no consistent sex difference in relative cerebellum size. Conclusion: This work suggests that the potential for sex differences in relative cerebellum size has been subject to either developmental constraint or lack of consistent selection pressures, and highlights the need for more individual-level primate neuroanatomical data to facilitate intra- and inter-specific study of brain sexual dimorphism.
Analysis of Cannabidiol, Δ9-Tetrahydrocannabinol, and Their Acids in CBD Oil/Hemp Oil Products
Authors: ElSohly Mahmoud A. , Murphy Timothy P. , Khan Ikhlas , Walker Larry W. , Gul Waseem
Published: August 2020

Hemp products are readily available and are aggressively marketed for their health and medicinal benefits. Most consumers of these products are interested because of cannabidiol (CBD), which has taken the natural products industry by storm. The CBD and Δ9-tetrahydrocannabinol (Δ9-THC) concentrations in these products are often absent, and even where labeled, the accuracy of the label amounts is often questionable. In order to gain a better understanding of the CBD content, fifty hemp products were analyzed by gas chromatography coupled with mass spectrometry (GC-MS) for CBD, Δ9-THC, tetrahydrocannabinolic acid (Δ9-THCAA), and cannabidiolic acid (CBDA). Δ9-THCAA and CBDA are the natural precursors of Δ9-THC and CBD in the plant material. Decarboxylation to Δ9-THC and CBD is essential to get the total benefit of the neutral cannabinoids. Therefore, analysis for the neutral and acid cannabinoids is important to get a complete picture of the chemical profile of the products. The GC-MS method used for the analysis of these products was developed and validated. A 10-m × 0.18-mm DB-1 (0.4 μ film) column was used for the analysis. The majority of the hemp products were oils, one of the products was hemp butter, one was a concentrated hemp powder capsule, and another was a hemp extract capsule. Most of the products contained less than 0.1% CBD and less than 0.01% Δ9-THC. Three products contained 0.1–1% CBD, and 2 products contained 0.1–0.9% Δ9-THC. All of the samples appeared to be decarboxylated since the CBDA and Δ9-THCAA results were less than 0.001%. The developed method is simple, sensitive, and reproducible for the detection of Δ9-THC, Δ9-THCAA, CBD, and CBDA in CBD oil/hemp products.
Clinical Experience of Steroid Switch from Prednisone to Dexamethasone in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone Acetate
Authors: Fang Wan-Yun , Wang Pai-Fu , Fan Yen-Chun , Shih Hung-Jen
Published: August 2020

Objective: To evaluate the therapeutic efficacy of a steroid switch from prednisone to dexamethasone in Asians with metastatic castration-resistant prostate cancer (mCRPC) that progressed after docetaxel chemotherapy. Methods: This study included postdocetaxel patients with mCRPC treated with abiraterone acetate combined with prednisone (AA + P) who had experienced prostate-specific antigen (PSA) progression. All patients underwent a steroid switch from prednisone (10 mg/day) to dexamethasone (1 mg/day). The PSA level and clinical symptoms were recorded. Moreover, follow-up was conducted until patients were either lost to follow-up or death. Results: This study included 11 patients from a single center in Taiwan. The median follow-up time starting from AA + P treatment was 19.47 months. Seven patients (63.64%) had >30% PSA decline, and 6 patients (54.55%) had >50% PSA decline. The median percentage of PSA decline was 83.6%. The median time until PSA progression after the steroid switch was 11.38 months. No adverse events greater than grade 3 were noted. Conclusions: Steroid switching is a feasible and effective therapy in docetaxel-treated Asian patients with mCRPC.
Association of Coronavirus Disease 2019 and Stroke: A Rising Concern
Authors: Kolikonda Murali Krishnan , Jandrasupalli Kranthi Kumar , Lippmann Steven
Published: August 2020

The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) causes the coronavirus disease 2019 (COVID-19). It quickly became pandemic, and so did a new concern about COVID-19 infections increasing the risk for cerebrovascular diseases. There is an association between COVID-19 illness in people and acute stroke. Several chemical, mechanical, and/or inflammatory central nervous system pathologies are proposed to explain how this viral infection might induce acute cerebrovascular disease. Timely available evaluation and/or intervention is imperative for patients with concerns about acute cerebrovascular issues.
Loss of Down Syndrome Critical Region-1 Mediated-Hypercholesterolemia Accelerates Corneal Opacity Via Pathological Neovessel Formation
Authors: Muramatsu Masashi , Nakagawa Suguru , Osawa Tsuyoshi , Toyono Tetsuya , Uemura Akiyoshi , Kidoya Hiroyasu , Takakura Nobuyuki , Usui Tomohiko , Ryeom Sandra , Minami Takashi
Published: August 2020

Objective:

The calcineurin-NFAT (nuclear factor for activated T cells)-DSCR (Down syndrome critical region)-1 pathway plays a crucial role as the downstream effector of VEGF (vascular endothelial growth factor)-mediated tumor angiogenesis in endothelial cells. A role for DSCR-1 in different organ microenvironment such as the cornea and its role in ocular diseases is not well understood. Corneal changes can be indicators of various disease states and are easily detected through ocular examinations.

Approach and Results:

The presentation of a corneal arcus or a corneal opacity due to lipid deposition in the cornea often indicates hyperlipidemia and in most cases, hypercholesterolemia. Although the loss of Apo (apolipoprotein) E has been well characterized and is known to lead to elevated serum cholesterol levels, there are few corneal changes observed in
ApoE
−/−
mice. In this study, we show that the combined loss of ApoE and DSCR-1 leads to a dramatic increase in serum cholesterol levels and severe corneal opacity with complete penetrance. The cornea is normally maintained in an avascular state; however, loss of
Dscr-1
is sufficient to induce hyper-inflammatory and -oxidative condition, increased corneal neovascularization, and lymphangiogenesis. Furthermore, immunohistological analysis and genome-wide screening revealed that loss of
Dscr-1
in mice triggers increased immune cell infiltration and upregulation of SDF (stromal derived factor)-1 and its receptor, CXCR4 (C-X-C motif chemokine ligand receptor-4), potentiating this signaling axis in the cornea, thereby contributing to pathological corneal angiogenesis and opacity.

Conclusions:

This study is the first demonstration of the critical role for the endogenous inhibitor of calcineurin, DSCR-1, and pathological corneal angiogenesis in hypercholesterolemia induced corneal opacity.