bluuebunny/crossref_metadata_2025 huggingface dataset:
SWIPT-Based Nonorthogonal Multiple Access under Arbitrary Nakagami-m Fading with Direct Links
Authors: Nguyen Thanh-Luan , Ha Duy-Hung , Tin Phu Tran , Vinh Nguyen Van
Published: December 2021

This paper studies the joint impact of simultaneous wireless information and power transfer (SWIPT) and nonorthogonal multiple access (NOMA) to the cooperative relay (CoR) network where direct links exist. Over Nakagami-m fading environments, the near users employ decode-and-forward (DF) and energy harvesting (EH) to assist the transmission from the source to the far users. Exploiting the time-switching protocol (TSP) and power-splitting protocol (PSP) to the CoR-based NOMA system, analytical results for the outage probability are derived, and the corresponding throughput is obtained. Comparative results show that the PSP outperforms the TSP at low transmit power, while at high-transmit-power regime, the TSP provides similar performance as the PSP.
Identification of Novel Biomarkers for Predicting Prognosis and Immunotherapy Response in Head and Neck Squamous Cell Carcinoma Based on ceRNA Network and Immune Infiltration Analysis
Authors: Guo Ya , Pan Wei Kang , Wang Zhong Wei , Su Wang Hui , Xu Kun , Jia Hui , Chen Jing
Published: December 2021

Objectives. Patients with head and neck squamous cell carcinoma (HNSCC) have poor prognosis and show poor responses to immune checkpoint (IC) inhibitor (ICI) therapy. Competing endogenous RNA (ceRNA) networks, tumor‐infiltrating immune cells (TIICs), and ICIs may influence tumor prognosis and response rates to ICI therapy. This study is aimed at identifying prognostic and IC‐related biomarkers and key TIIC signatures to improve prognosis and ICI therapy response in HNSCC patients. Methods and Results. Ninety‐five long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and 1746 mRNAs were identified using three independent methods. We constructed a ceRNA network and estimated the proportions of 22 immune cell subtypes. Ten ceRNAs were related to prognosis according to Kaplan–Meier analysis. Two risk signatures based, respectively, on nine ceRNAs (ANLN, CFL2, ITGA5, KDELC1, KIF23, NFIA, PTX3, RELT, and TMC7) and three immune cell types (naïve B cells, neutrophils, and regulatory T cells) via univariate Cox regression, least absolute shrinkage and selection operator, and multivariate Cox regression analyses could accurately and independently predict the prognosis of HNSCC patients. Key mRNAs in the ceRNA network were significantly correlated with naïve B cells and regulatory T cells and with stage, grade, and immune and molecular subtype. Eight IC genes exhibited higher expression in tumor tissues and were correlated with eight key mRNAs in the ceRNA network in HNSCC patients with different HPV statuses according to coexpression and TIMER 2.0 analyses. Most drugs were effective in association with expression of these key signatures (ANLN, CFL2, ITGA5, KIF23, NFIA, PTX3, RELT, and TMC7) based on GSCALite analysis. The prognostic value of key biomarkers and associations between key ceRNAs and IC genes were validated using online databases. Eight key ceRNAs were confirmed to predict response to ICI in other cancers based on TIDE analysis. Conclusions. We constructed two risk signatures to accurately predict prognosis in HNSCC. Key IC‐related signatures may be associated with response to ICI therapy. Combinations of ICIs with inhibitors of eight key mRNAs may improve survival outcomes of HNSCC patients.
The Number of Frames on ECG-Gated 18F-FDG Small Animal PET Has a Significant Impact on LV Systolic and Diastolic Functional Parameters
Authors: Eissler Christoph , Werner Rudolf A. , Arias-Loza Paula , Nose Naoko , Chen Xinyu , Pomper Martin G. , Rowe Steven P. , Lapa Constantin , Buck Andreas K. , Higuchi Takahiro
Published: December 2021

Objectives. This study is aimed at investigating the impact of frame numbers in preclinical electrocardiogram- (ECG-) gated 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) on systolic and diastolic left ventricular (LV) parameters in rats. Methods. 18F-FDG PET imaging using a dedicated small animal PET system with list mode data acquisition and continuous ECG recording was performed in diabetic and control rats. The list-mode data was sorted and reconstructed with different numbers of frames (4, 8, 12, and 16) per cardiac cycle into tomographic images. Using an automatic ventricular edge detection software, left ventricular (LV) functional parameters, including ejection fraction (EF), end-diastolic (EDV), and end-systolic volume (ESV), were calculated. Diastolic variables (time to peak filling (TPF), first third mean filling rate (1/3 FR), and peak filling rate (PFR)) were also assessed. Results. Significant differences in multiple parameters were observed among the reconstructions with different frames per cardiac cycle. EDV significantly increased by numbers of frames (353.8 ± 57.7  μl[Formula: see text], 380.8 ± 57.2  μl[Formula: see text], 398.0 ± 63.1  μl[Formula: see text], and 444.8 ± 75.3  μl at 4, 8, 12, and 16 frames, respectively; [Formula: see text] vs. 16 frames), while systolic (EF) and diastolic (TPF, 1/3 FR and PFR) parameters were not significantly different between 12 and 16 frames. In addition, significant differences between diabetic and control animals in 1/3 FR and PFR in 16 frames per cardiac cycle were observed ([Formula: see text]), but not for 4, 8, and 12 frames. Conclusions. Using ECG-gated PET in rats, measurements of cardiac function are significantly affected by the frames per cardiac cycle. Therefore, if you are going to compare those functional parameters, a consistent number of frames should be used.
Service-Based Hybrid Access Control Technology with Priority Level for the Internet of Vehicles under the Cloud Architecture
Authors: Xie Pengshou , Yang Haoxuan , Wang Liangxuan , Wang Shuai , Feng Tao , Yan Yan
Published: December 2021

The communication process of devices in IoV under cloud architecture needs to be protected by access control models. However, existing access control models have difficulty establishing the appropriate granularity of permissions in the face of large amounts of data in IoV. Moreover, the access control model may need to temporarily change user privileges to accommodate the dynamic nature of IoV scenarios, a requirement that is difficult to implement for traditional access control models. The unstable connection status of devices in IoV also creates problems for access control. The service (composed of role and attribute) based access control model (in IoV) S-RABAC (V), under the Cloud computing architecture, introduces a formal theoretical model. The model uses attribute grouping and prioritization mechanisms to form a hierarchical structure. The permission combination pattern in the hierarchical structure can avoid duplicate permissions and reduce the number of permissions while ensuring fine-grained permissions. Different layers in the model have different priorities, and when a user’s permission requires temporary changes, it can be adjusted to the corresponding layers according to the user’s priority. In addition, users are allowed to keep their assigned privileges for a period to avoid frequent access control because of unstable connections. We have implemented the proposed access control model in Alibaba Cloud Computing and given six example demonstrations. The experiment shows that this is an access control model that can protect IoV security more effectively. Various unique mechanisms in the model enable S-RABAC(V) to improve the overall access control efficiency. The model adds some extra features compared to ABAC and RBAC and can generate more access control decisions using the priority mechanism.
A Method for Quantitative Evaluation of Seismic Stability of Loess Slope Based on the Shaking Table Model Test
Authors: Xiaowu Pu , Lanmin Wang , Ping Wang , Shaofeng Chai , Shiyang Xu
Published: December 2021

The large‐scale shaking table model test, which can directly reproduce the process of slope instability and failure, is an important technical means for the prediction and evaluation of slope seismic stability. However, up to now, the systematic slope stability evaluation method based on the shaking table slope model test has not been established, which limits the application of the expensive shaking table model test in slope seismic design. Therefore, the slope stability evaluation method based on the model test needs to be developed and innovated. In this research, through three loess slope model tests with different rainfall, according to the change law of the peak value of transfer function spectrum, combined with the macrodestructive characteristics of the slope model, an accurate calculation method of the critical instability acceleration of the slope is proposed. Based on the behavior similarity theory, for the shaking table model test of slope whose soil cohesion cannot meet the similarity ratio, the reduction method of applying the critical instability acceleration obtained from the model test to prototype slope is proposed. Based on first‐order natural frequency and damping ratio extracted from the TF spectrum curve, a calculation method for the stability factor Fs of loess slope based on the shaking table model test is proposed, and the stability factors of loess slope under the action of different seismic ground motion would be quantitatively calculated. The above methods provide another effective way for qualitative prediction and evaluation of seismic stability of loess slope.
Traditional East Asian Herbal Medicine for Amyotrophic Lateral Sclerosis: A Scoping Review
Authors: Suh Won Joo , Seo Yuna , Jin Chul , Cho Seung-Yeon , Park Seong-Uk , Jung Woo-Sang , Moon Sang-Kwan , Park Jung-Mi , Ko Chang-Nam , Kwon Seungwon , Cho Ki-Ho
Published: December 2021

This study aimed to analyze and summarize the existing evidence regarding herbal medicine treatments for amyotrophic lateral sclerosis (ALS). Studies on herbal medicine treatment in patients with ALS were searched within English, Chinese, Japanese, and Korean databases up to July 31, 2021. In the selected studies, we collected the following information: the first author, year of publication, country, language, study methodology, sample size, demographic characteristics of the study participants, disease duration, diagnostic criteria, treatment method, treatment periods, evaluation tools, results, and side effects. The organized data were classified and analyzed narratively. This study included 59 studies. The first clinical study on the effect of herbal medicine was published in 1995; moreover, most studies were conducted in China. Among the 59 selected studies, 47.5% were observational studies, including case reports and case series. Moreover, there was one meta-analysis. The El Escorial criteria were the most commonly used diagnostic criterion for ALS; moreover, the ALS functional rating scale was the most common evaluation tool. Buzhongyiqitang, Sijunzitangjiawei, and Jianpiyifeitang were the most commonly used herbal medicines, with anti-inflammatory, protein aggregation, and anti-oxidant effects. There remain evidence of gaps in the effectiveness of herbal medicine for ALS. To allow effective treatment of patients with ALS using herbal medicine, large-scale and rigorously designed high-quality clinical studies should be performed.
Efficiency Evaluation of Energy in Northeastern China Based on Data Envelopment Analysis
Authors: Li Hongyan , Ma Zhiyu , Sun Jie
Published: December 2021

The development of the energy economy in Northeastern China is unbalanced. In this paper, some energy structures such as oil, coal, and electricity are chosen as input indexes, while per capita gross domestic product (GDP) and total retail sales of consumer goods are desirable output indexes. The main causes of haze are industrial waste gas emission, industrial wastewater discharge, and solid waste production, which are regarded as undesirable output indexes. Environmental variables include industrial structure, urbanization, per capita GDP, and government planning. The proportion of the tertiary industry’s output value to its total output value is one of the important indexes to measure economic development in one area. Therefore, industrial structure plays a vital role in a region’s economic development. The tertiary industry oriented by service sector is the main force to promote economic transformation. The development of the urban economy will change from high to low as the process of urbanization, which can be characterized by green coverage of the urban built-up area. The higher per capita GDP, the higher the economic development can be achieved. Government planning refers to the total number of construction projects and completed projects in the year the government takes measures to control pollution. It shows that the total factor productivity of energy green efficiency has been stable in the last decades but fluctuated wildly in special periods, in which technical progress has played a great role, as well as the increase of technical efficiency.
A Prediction Modeling Based on the Hospital for Special Surgery (HSS) Knee Score for Poor Postoperative Functional Prognosis of Elderly Patients with Patellar Fractures
Authors: Ying Chenting , Guo Chenyang , Wang Zhenlin , Chen Yiming , Sun Jiahui , Qi Xin , Chen Yisheng , Tao Jie
Published: December 2021

Background. The main aim of this study was to develop a nomogram prediction model for poor functional prognosis after patellar fracture surgery in the elderly based on the hospital for special surgery (HSS) knee score. Methods. A retrospective analysis of 168 elderly patients with patellar fractures was performed to collect demographic data, knee imaging, and functional prognosis preoperatively and during the 6‐month postoperative follow‐up period. Good functional prognosis of knee joint was defined as the percentage of HSS knee scores on the injured side relative to the uninjured side ≥ 80% at six‐month postoperative review. Multifactorial linear regression analysis and logistic regression analysis were then used to identify risk factors of functional prognosis and develop the nomogram prediction model. Furthermore, the validity and accuracy of the prediction model were evaluated using C‐index, area under the curve (AUC), and decision curve analyses. Results. The final screening from the 12 potential risk factors yielded three high‐risk factors which were included in the nomogram prediction model: advanced age (OR 0.28 (95% CI 0.11‐0.67), P = 0.005), sarcopenia (OR 0.11 (95% CI 0.05‐0.26), P < 0.001), and low albumin level (OR 1.14 (95% CI 1.02‐1.29), P = 0.025). The model had a good predictive ability with an AUC of 0.857 (95% CI (0.783‐0.929)) for the training group and a C‐index of 0.836 for the overall sample. In addition, the decision analysis curve indicated that the model had good clinical applicability. Conclusion. Our predictive model is effective in predicting the risk of poor functional prognosis after patellar fracture surgery in the elderly by assessing high‐risk factors such as advanced age, sarcopenia, and serum albumin levels. This prediction model can help clinicians to make individualized risk prediction, early identification of patients at high risk for poor functional outcome, and appropriate interventions.
Study on the Semiactive Control and Optimal Layout of a Hydropower House Based on Magnetorheological Dampers
Authors: Hu Shaopei , Su Chao , Yan Mingjiao , Yang Yang , Bai Jiawei , Cao Enhua
Published: December 2021

With the continuous development of hydropower stations, the capacities and the heads of hydro generator units are increasing, and the plant vibration problem is becoming more and more serious. A numerical simulation method for the vibration reduction control of magnetorheological (MR) dampers suitable for large-scale complex structures was proposed. The method is simple and easy to implement, and the semiactive control of the MR damper could be achieved by adjusting the current switch and size. On the basis of a numerical simulation, a mathematical model for the optimal layout of an MR damper device was established. The objective function was the vertical velocity and the vertical acceleration response of the generator floor. The results showed that the proposed semiactive control numerical simulation method could be applied to the vibration control of the hydropower plant structure, and the vertical velocity and vertical acceleration were reduced by 10.96% and 12.90%, respectively, compared with those without structural vibration control. At the same time, the proposed optimized layout method was effective and feasible, and the damping effect of the MR damper could be effectively improved through the optimized layout.
The Optimal Carrier-Secret Ratio for Wireless Covert Channels Based on Constellation Shaping Modulation
Authors: Qiao Sen , Liu Guangjie , Ji Xiaopeng , Liu Weiwei
Published: December 2021

Wireless covert communication is an emerging communication technique that prevents eavesdropping. This paper considers the bit error ratio (BER) problem of covert communication based on constellation shaping modulation (CSM). The impact of carrier-secret ratio (CSR) on BER is studied and the approximate solution of optimal CSR is obtained. Then, we extended the conclusion to typical communication scenarios with one and more relays where the undetectability and reliability were analyzed and inspected. It is proved that there also exists the optimal CSR in scenarios with relays. Additionally, it is found that the undetectability under the constraints of constant total power depends on the eavesdropper’s position, and we found an undetectability deterioration area (UDA) in the scenario of relays. Simulation results show the existence of optimal CSR and its impact on transmission performance.
Effect of Nb on
β
→

α

″

Martensitic Phase Transformation and Characterization of New Biomedical Ti-xNb-3Fe-9Zr Alloys
Authors: Jawed Syed Faraz , Rabadia Chirag Dhirajlal , Azim Fahad , Khan Saad Jawaid
Published: December 2021

A new generation of Ti-xNb-3Fe-9Zr (

x
=
15

, 20, 25, 30, 35 wt %) alloys have been designed using various theoretical approaches including DV-xα cluster, molybdenum equivalency, and electron to atom ratio. Afterward, designed alloys are fabricated using cold crucible levitation melting technique. The microstructure and mechanical performances of newly designed alloys are characterized in this work using scanning electron microscope and universal testing machine, respectively. Each alloy demonstrates monolithic

β

phase except Ti-35Nb-3Fe-9Zr alloy which display dual

α

″

+
β

phases. Typically, niobium acts as an isomorphous beta stabilizer. However, in this work, formation of martensitic

α

″

phases occurs at 35 wt % of niobium among the series of newly designed alloys. Furthermore, none of the alloys fail till the maximum load capacity of machine, i.e., 100 KN except Ti-35Nb-3Fe-9Zr alloy. Moreover, the Vickers hardness test is carried out on Ti-xNb-3Fe-9Zr alloys which demonstrate slip bands around the indentation for each alloy. Notably, the deformation bands and cracks around the indentations of each alloy have been observed using optical microscopy; Ti-35Nb-3Fe-9Zr demonstrates some cracks along with slip bands around its indentation. The Ti-25Nb-3Fe-9Zr alloy shows the highest yield strength of

1043
±
20
 
MPa

, large plasticity of

32
±
0.5
%

, and adequate hardness of

152
±
3.90
 
Hv

among the investigated alloys. The Ti-25Nb-3Fe-9Zr alloy demonstrates good blend of strength and malleability. Therefore, Ti-25Nb-3Fe-9Zr can be used effectively for the biomedical applications.
Successful Treatment of Invasive Mucormycosis in Orthotopic Liver Transplant Population
Authors: Eubank Taryn A. , Mobley Constance M. , Moaddab Mozhgon , Hobeika Mark J. , O’Neal Melissa , Musick William L. , Knight Joshua M. , Galati Joseph S. , Kodali Sudha , Shetty Akshay , Victor David W. , Saharia Ashish , Ghobrial R. Mark , Grimes Kevin A.
Published: December 2021

Mucormycosis is caused by ubiquitous fungi and encompasses a variety of different opportunistic syndromes in humans that disproportionately affect immunocompromised patients. Mortality has been documented to range between 50 and 100%; however, location of infection greatly dictates likelihood of survival. Treatment of mucormycosis involves aggressive surgical intervention and combination therapy of antifungal agents. In solid organ transplant recipients, immunosuppressive agents used to prevent rejection of the transplanted organ pose additional obstacles in the treatment of invasive fungal infections. We report on 3 high models for end-stage liver disease (MELD-Na) score orthotopic liver transplant (OLT) recipients who all were diagnosed with Rhizopus spp. infections with positive, 1-year outcomes after aggressive, individualized treatment.
Hepatoprotective Screening of Seriphidium kurramense (Qazilb.) Y.R. Ling
Authors: Ali Maroof , Hussain Hidayat , Hussain Amjad , Rauf Abdur , Hussain Wahid , Ullah Manzoor , Abbas Safdar , Al-Awthan Yahya S. , Bahattab Omar , Khan Muhammad , Olatunde Ahmed , Almarhoon Zainab M. , Mabkhot Yahia N. , Alshehri Mohammed M. , Daştan Sevgi Durna , Ramadan Mohamed Fawzy , Sharifi-Rad Javad
Published: December 2021

Investigation on medicinal plants’ therapeutic potential has gained substantial importance in the discovery of novel effective and safe therapeutic agents. The present study is aimed at investigating the hepatoprotective potential of Seriphidium kurramense methanolic extract (SKM) against carbon tetrachloride‐ (CCl4‐) induced hepatotoxicity in rats. S. kurramense is one of the most imperative plants for its various pharmacological activities. Therefore, this study was aimed at evaluating the hepatoprotective potential against CCl4‐induced liver toxicity. The serum samples were analyzed for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) together with the oxidative stress mediator levels as nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), reduced glutathione (GSH), and superoxide dismutase (SOD) as well as peroxidation and H2O2 activity. CCl4 administration resulted in an elevated free radical generation, altered liver marker (AST and ALT) enzymes, reduced antioxidant enzyme, and increased DNA damage. Methanolic extract of S. kurramense decreased CCl4‐induced hepatotoxicity by increasing the antioxidant status and reducing H2O2 and nitrate content generation as well as reducing DNA damage. Additionally, SKM reversed the morphological alterations induced by CCl4 in the SKM‐treated groups. These results demonstrated that SKM displayed hepatoprotective activity against CCl4‐induced hepatic damage in experimental rats.
Security and Privacy for Edge-Assisted Internet of Things Security Proof for the SKKE Protocol
Authors: Wang Xiangyang , Gu Chunxiang , Wei Fushan , Lu Siqi
Published: December 2021

As an Internet of things (IoT) technology, the ZigBee has a wide range of applications in home automation, smart energy, commercial building automation, personal, home and hospital care, telecom, and wireless sensor. The ZigBee standard has the advantage of high reliability, which is based on the security of authentication key agreement protocol, namely, the SKKE protocol. In the ZigBee standard, this protocol based on shared symmetric-key is applied on the security protocol level. It is a full symmetric-key key agreement with key confirmation scheme, while the key confirmation mechanism is provided by a message authentication coding mechanism. In this paper, we consider the security of the SKKE protocol. In the random Oracle model, we reduce the security of the SKKE protocol to the collision of the hash function and the HMAC function and the indistinguishability between the output of the random Oracle and a random number. We also give a theoretical proof with the game-based method. To our knowledge, there is no research on the provable security of the ZigBee protocol at this stage, so it is helpful to promote further research of the ZigBee protocol security.
Efficacy and Safety of Oral Herbal Drugs Used as Adjunctive Therapy for Melasma: A Systematic Review and Meta-Analysis of Randomised Controlled Trials
Authors: Tang Qingti , Yang Hongjie , Liu Xiarong , Zou Yu , Lv Xintong , Chen Kai
Published: December 2021

Background. Melasma is an acquired disorder of facial pigmentation. Its etiology is multifactorial; thus, the management is usually challenging. As a complementary therapy, herbal drugs are often used in the management of melasma. This work was aimed to investigate the efficacy and safety of herbal drugs on melasma in female patients. Methods. This study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was conducted, and all randomised controlled trials (RCTs) on the use of oral herbal drugs as complementary therapy for melasma in female patients were included. A meta-analysis was conducted according to the guidelines of the Cochrane Collaboration using Review Manager 5.4. Results. Ten eligible trials, with 1015 female melasma patients, were included. All of the included RCTs had some concerns for risk of bias for different reasons, especially for that most of included trials were unblinded. Pooled data suggested phytotherapy plus routine therapy had significantly better efficacy on melasma than routine therapy, in terms of response rate (OR: 4.49, 95% CI: 3.25 to 6.20,

p
<
0.00001

), reduction of skin lesion score (SMD: −0.56, 95% CI: −0.79 to −0.33,

p
<
0.00001

), and improvement of serum E2 levels (SMD: −1.58, 95% CI: −2.62 to −0.55, p 0.003). In addition, there was no significant difference in the incidence of AEs between phytotherapy plus routine therapy and routine therapy (OR: 0.92, 95% CI: 0.53 to 1.58; p 0.76). Overall, herbal drugs used as an adjunct to routine therapy significantly enhanced the efficacy for the treatment of melasma but with a comparable safety profile. Conclusion. These findings have implications for recommending herbal drugs as a viable complementary treatment option for melasma.
Comparing Emergent and Elective Colectomy Outcomes in Elderly Patients: A NSQIP Study
Authors: El Edelbi Mostapha , Abdallah Ibrahim , Jaafar Rola F. , Tamim Hani , Deeba Samer , Doughan Samer
Published: December 2021

Introduction. With the increasing prevalence of colorectal cancer (CRC) worldwide, especially in the elderly, and the variability between physiological and chronological age and its impact on functional status, acute symptoms leading to emergent surgery due to colorectal malignancy may lead to increased morbidity and mortality. The aim of this study is to identify the outcome differences of elective vs. emergent open colectomy in patients above 80 years. Methods. The National Surgical Quality Improvement Program (NSQIP) database was reviewed from 2010 to 2014 for open colectomy based on CPT codes. Comparison between groups was done based on the clinical context at presentation as elective or emergent surgery. Data were analyzed using SAS. Results. Elective colectomies were performed in 8289 (70.8%) vs. emergent colectomies in 3409 (29.1%). Emergent colectomy patients had higher American Society of Anesthesiologists (ASA) preoperative classification III-IV, 1429 (42.0%) and 224 (6.6%), vs. 1238 (14.9%) and 21 (0.2%) in elective colectomy patients

p
<
0.0001

. Emergent colectomy patients had more comorbidities such as chronic obstructive pulmonary disorder (493 (14.5%) vs. 796 (9.6%)), congestive heart failure (206 (6.0%) vs. 310 (3.8%)), dialysis (106 (3.1%) vs. 56 (0.7%)), and acute renal failure (166 (4.9%) vs. 46 (0.6%))

p
<
0.0001

, respectively. Postoperative morbidity and mortality were significantly higher in emergent colectomy (1651 (48.4%) and 872 (25.6%)) vs. elective colectomy (1859 (22.4%) and 567 (6.8%))

p
<
0.0001

, respectively. Conclusion. Emergent open colectomy in elderly patients carries a higher risk of morbidity and mortality when compared to elective open colectomy with risk factors being higher ASA classification and more comorbidities.
A Phase I Study of Autologous Dendritic Cell Vaccine Pulsed with Allogeneic Stem-like Cell Line Lysate in Patients with Newly Diagnosed or Recurrent Glioblastoma
Authors: Hu Jethro L. , Omofoye Oluwaseun A. , Rudnick Jeremy D. , Kim Sungjin , Tighiouart Mourad , Phuphanich Surasak , Wang Hongqiang , Mazer Mia , Ganaway Toni , Chu Ray M. , Patil Chirag G. , Black Keith L. , Shiao Stephen L. , Wang Rongfu , Yu John S.
Published: December 2021

Purpose:

Glioblastoma (GBM) is a heterogeneous malignancy with multiple subpopulations of cancer cells present within any tumor. We present the results of a phase I clinical trial using an autologous dendritic cell (DC) vaccine pulsed with lysate derived from a GBM stem-like cell line.

Patients and Methods:

Patients with newly diagnosed and recurrent GBM were enrolled as separate cohorts. Eligibility criteria included a qualifying surgical resection or minimal tumor size, ≤ 4-mg dexamethasone daily dose, and Karnofsky score ≥70. Vaccine treatment consisted of two phases: an induction phase with vaccine given weekly for 4 weeks, and a maintenance phase with vaccines administered every 8 weeks until depletion of supply or disease progression. Patients with newly diagnosed GBM also received standard-of-care radiation and temozolomide. The primary objective for this open-label, single-institution trial was to assess the safety and tolerability of the autologous DC vaccine.

Results:

For the 11 patients with newly diagnosed GBM, median progression-free survival (PFS) was 8.75 months, and median overall survival was 20.36 months. For the 25 patients with recurrent GBM, median PFS was 3.23 months, 6-month PFS was 24%, and median survival was 11.97 months. A subset of patients developed a cytotoxic T-cell response as determined by an IFNγ ELISpot assay.

Conclusions:

In this trial, treatment of newly diagnosed and recurrent GBM with autologous DC vaccine pulsed with lysate derived from an allogeneic stem-like cell line was safe and well tolerated. Clinical outcomes add to the body of evidence suggesting that immunotherapy plays a role in the treatment of GBM.
Abstract CC01-01: The landscape of precision cancer combination therapy: A single-cell perspective
Authors: Ahmadi Saba , Sukprasert Pattara , Vegesna Rahulsimham , Sinha Sanju , Schischlik Fiorella , Artzi Natalie , Khuller Samir , Schäffer Alejandro A. , Ruppin Eytan
Published: December 2021

The availability of single-cell transcriptomics data opens new opportunities for rational design of combination cancer treatments in a systematic manner. Mining such data, we employed combinatorial optimization techniques to explore the landscape of optimal combination therapies in solid tumors, including brain, head and neck, melanoma, lung, breast and colon cancers. We assume that each individual therapy can target any one of 1269 genes encoding cell surface receptors, which may be targets of CAR-T, conjugated antibodies or coated nanoparticle therapies. In most cancer types, personalized combinations composed of at most four targets are sufficient to kill at least 80% of the tumor cells while killing at most 10% of the non-tumor cells in each patient. The number of distinct targets needed to do that for all patients in 8 of the 9 cohorts we studied is at most 11, while one larger melanoma cohort requires over 30 distinct targets. Further requiring that the target genes be lowly expressed across many different healthy tissues uncovers qualitatively similar trends. However, as one requires either more stringent killing thresholds or more stringent sparing of non-cancerous tissues beyond these baseline values, the number of targets needed rises rapidly. Emerging promising targets include the gene PTPRZ1, which is frequently found in the optimal combinations for brain and head and neck cancers, and EGFR, a recurring target in multiple tumor types. In sum, this is the first systematic single-cell based characterization of the landscape of combinatorial receptor-mediated cancer treatments, identifying promising targets for future development.

Citation Format: Saba Ahmadi, Pattara Sukprasert, Rahulsimham Vegesna, Sanju Sinha, Fiorella Schischlik, Natalie Artzi, Samir Khuller, Alejandro A. Schäffer, Eytan Ruppin. The landscape of precision cancer combination therapy: A single-cell perspective [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr CC01-01.
Abstract IACC0103: Predicting outcomes of Phase III oncology trials with Bayesian mediation modeling
Authors: Hobbs Brian P.
Published: December 2021

Pivotal cancer trials often fail to yield evidence in support of new therapies thought to offer promising alternatives to standards-of-care. Conducting RCTs in oncology tends to be more expensive than studies of other diseases with comparable sample size. Moreover, phase III trial design often takes place with a paucity of survival data for experimental therapies. Experts have explained the failures on the basis of design flaws which produce studies with unrealistic expectations. This article presents a framework for predicting outcomes of phase III oncology trials using Bayesian mediation models. Predictions, which arise from interim analyses, derive from multivariate modeling of the relationships among treatment, tumor response, and their conjoint effects on survival. Acting as a safeguard against inaccurate pre-trial design assumptions, the methodology may better facilitate rapid closure of negative studies.

Additionally the models can be used to inform re-estimations of sample size for under-powered trials that demonstrate survival benefit via tumor response mediation. The methods are applied to predict the outcomes of three colorectal cancer RCTs.

Citation Format: Brian P. Hobbs. Predicting outcomes of Phase III oncology trials with Bayesian mediation modeling [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr IACC0103.
Abstract IACC0601: Radiopharmaceuticals and their future in cancer care
Authors: Kunos Charles A.
Published: December 2021

Radiopharmaceutical agents have been an appealing treatment approach since the use of 131I to treat thyroid malignancies. Advances in cancer radiobiology and radiochemistry have brought radiopharmaceuticals forward to the cutting edge of oncology clinical research. The National Cancer Institute (NCI) and its partnering academic and clinical research networks monitor radiopharmaceutical discoveries that might be incorporated into cancer treatment strategies for patients with unmet therapeutic needs. Such endeavors happen through leveraged partnerships between NCI's Cancer Therapy Evaluation Program (CTEP), its Radiation Research Program (RRP), and academic institutions in the Experimental Therapeutics Clinical Trials Network (ETCTN). If innovative discoveries are made, NCI supports clinician scientists to plan new and original radiopharmaceutical phase I and II monotherapy or combination trials. The clinical trial infrastructure needs, such as radiopharmaceutical dosimetry and treatment planning, are now available in government workflow and regulatory oversight. This presentation introduces a modern approach to the clinical development of radiopharmaceutical agents in an era of molecular targets and personalized cancer therapeutics.

Citation Format: Charles A. Kunos. Radiopharmaceuticals and their future in cancer care [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr IACC0601.
Abstract LBA012: Engineered mini-livers for high-throughput tumor organoid screening of prodrugs
Authors: Tebon Peyton J , Soragni Alice
Published: December 2021

Several anti-cancer compounds, including chemotherapy and targeted agents such as ifosfamide, cyclophosphamide, and imatinib, are administered as prodrugs which are metabolized to become pharmacologically active. Prodrugs are particularly difficult to study in vitro or ex vivo as many are activated in the liver by Cytochrome P450 enzymes. Preclinical studies of these compounds are restricted to in vivo models, as cancer cells typically do not express the enzymes required to transform prodrugs into their active form. While animal models effectively recapitulate the complexity of systemic drug metabolism and distribution, in vivo studies are time-consuming, expensive, and unsuitable for high-throughput drug screening studies. In previous work, we have developed a platform for screening patient-derived tumor organoids that yields results within a week of surgery (Phan et al, Commun Biol 2, 78, 2019; Nguyen and Soragni, STAR Protoc 1, 2, 2020; Al Shihabi et al, bioRxiv, 2021). Tumor organoids are promising pre-clinical models as they closely recapitulate features of the parent tumor, including drug responses. Here, we expand the physiological relevance of tumor organoid screenings by including mini-livers to metabolize prodrugs of interest. To retain the ability to perform automated, high-throughput screenings, we engineered a miniature liver insert (MLI). The MLI is a removable system that facilitates the addition of liver organoids to specific wells of 96-well plates in which prodrugs are tested. The MLI is designed to integrate with our existing tumor organoid screening platform (Phan et al, Commun Biol 2, 78, 2019; Nguyen and Soragni, STAR Protoc 1, 2, 2020; Al Shihabi et al, bioRxiv, 2021), and allows for simultaneous monitoring of tumor organoids and hepatocytes with brightfield and fluorescent imaging. Hepatocytes seeded in the MLI are viable and maintain their expression of the key Cytochrome P450 enzymes responsible for the metabolism of many clinically used prodrugs. Finally, we demonstrate that incorporating the MLI into prodrug screening experiments sensitizes tumor organoids to treatment with chemotherapeutic and targeted agents. Due to the facile integration with existing screening protocols, the MLI is a simple and effective system for studying anti-cancer prodrugs ex vivo. The MLI is a novel tool that facilitates the co-culture of functional liver organoids with clinically relevant tumor organoid models for drug discovery studies and precision medicine applications.

Citation Format: Peyton J Tebon, Alice Soragni. Engineered mini-livers for high-throughput tumor organoid screening of prodrugs [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA012.
Abstract LBA024: IL-36γ induces immune infiltration and suppresses tumor growth in a syngeneic mouse model for pancreatic cancer
Authors: Halder Kuntal , Von Hoff Daniel D , Han Haiyong
Published: December 2021

Pancreatic cancer (PC) is one of the most aggressive and lethal types of cancer. It is the third leading cause of cancer-related mortality in U.S., accounting for 6% of annual death. Immunotherapeutic strategies such as immune checkpoint inhibitors have shown great success in a number of tumor types, but only with limited activity in patients with PC. Pancreatic tumor is characterized by the presence of dense stromal tissue which primarily consists of immune-suppressive fibroblasts. The immune microenvironment remains dysfunctional due to the lack of tumor infiltrating lymphocytes (TILs) and immune stimulatory molecules. Proinflammatory cytokines play a pivotal role in regulating tumor immunogenicity and antitumor immunity. Elucidating the role of proinflammatory host mediators can contribute to the development of new therapies for PC. IL-36γ, a proinflammatory mediator is important for the IL-23/IL-17-dominated inflammation and induces Th1 immune responses. The role of IL-36γ in pancreatic tumor immunity has not been well studied. In this study, we examined the expression and functional regulation of IL-36γ in PC cells and found that IL-36γ cytokine treatment induces immune infiltration and suppresses tumor growth in a murine PC model. Immunohistochemical (IHC) analysis of pancreatic ductal adenocarcinoma (PDAC) specimens showed minimal IL-36γ positive staining, thus indicating very low expression of IL-36γ in PDAC. Intratumoral treatment with recombinant IL-36γ in a syngeneic mouse model of PDAC significantly inhibited tumor growth (57.8% inhibition after two weeks of treatment) without any significant animal weight loss compared to the vehicle control. Flow cytometry analysis showed increased infiltration of lymphocyte subsets (CD45+ and CD3+ cells) in tumors derived from the IL-36γ treated mice. Further studies are ongoing to investigate the effect of IL-36γ treatment on dendritic cells and macrophages in PDAC tumors. Our study establishes the potential role of IL-36γ in promoting antitumor immune responses and lay the foundation for clinical application in PC (This work was supported by TGen’s Women Philanthropy Council).

Citation Format: Kuntal Halder, Daniel D Von Hoff, Haiyong Han. IL-36γ induces immune infiltration and suppresses tumor growth in a syngeneic mouse model for pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA024.
Abstract LBA027: Mechanistic insights on the effects of the lead next generation galeterone analog, VNPP433-3β in castration resistant prostate cancer
Authors: Thomas Elizabeth , Thankan Retheesh S , Purushottamachar Puranik , Njar Vincent C.O.
Published: December 2021

Introduction Metastatic castration-resistant prostate cancer (mCRPC) remains the second leading cause of cancer-related death in men in the United States and the second most frequently diagnosed cancer among males worldwide. Dysregulated androgen receptor (AR) is associated with nearly all known cases of prostate cancer (PCa) and its expression level has been correlated with poor survival. This study describes the mechanism of action of VNPP433-3β, a next generation galeterone analog (NGGA) in inhibiting PCa. Methods PCa cell lines CWR22Rv1 and LNCaP were treated with VNPP433-3β and followed up using cellular thermal shift assay (CETSA), RNA seq, mRNA 5’ cap-binding assay, translation and proteasome inhibition assays. Co-immunoprecipitation, molecular docking and fluorescence spectroscopy were used to study the interactions. Results VNPP433-3β, the lead next generation galeterone analog (NGGA) directly interacts with AR and inhibits metastatic castration resistant PCa (mCRPC) by enhancing degradation of full-length AR (fAR) and its splice variant AR-V7 in a dose-dependent manner. Moreover, VNPP433-3β drives the proteasomal degradation of fAR and AR-V7 by augmenting the interaction between AR and E3 ligases MDM2 & CHIP but disrupting HSP90 binding to AR. VNPP433-3β also impedes eIF4E phosphorylation by depleting MNK1/2 besides disrupting binding of eIF4E and eIF4G to mRNA 5’ cap thereby impeding translational activity of the cancer cells. Finally, the transcriptome analyses by RNA-seq reveal that VNPP433-3β modulates transcription of several genes and activates more than 20 cellular pathways, each of which synergistically contribute to PCa inhibition. Hence, VNPP433-3β obstructs PCa by invoking 1) transcriptional regulation of AR-responsive oncogenes via degrading AR, 2) translational regulation by depleting MNK1/2 thereby impeding phosphorylation of eIF4E and subsequent mRNA 5’cap-dependent translation initiation and 3) affecting AR half-life through enhanced proteasomal degradation. Conclusion As VNPP433-3β promotes degradation of fAR and AR-V7, concurrently depletes Mnk1/2, prevents eIF4E phosphorylation and modulates several cellular pathways to halt PCa, it could potentially be developed for clinical trials in mCRPC patients.

Citation Format: Elizabeth Thomas, Retheesh S Thankan, Puranik Purushottamachar, Vincent C.O. Njar. Mechanistic insights on the effects of the lead next generation galeterone analog, VNPP433-3β in castration resistant prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA027.
Abstract LBA042: Male Sex is an Independent Predictor of Recurrence-Free Survival in Middle Eastern Papillary Thyroid Carcinoma
Authors: AL-KURAYA KHAWLA S. , Parvathareddy Sandeep Kumar , Siraj Abdul K , De Vera Felisa , Annaiyappanaidu Padmanaban , Ahmed Saeeda O. , Al-Sobhi Saif S. , Al-Dayel Fouad
Published: December 2021

Background: Disparity between sexes with regards to incidence, disease aggressiveness, and prognosis has been documented in several cancers. Although various reports have documented the association between male sex and aggressive papillary thyroid carcinoma (PTC), the prognostic impact of sex on PTC has been inconsistent. The role of sex in PTC aggressiveness and outcome in Middle Eastern PTC remains unknown. Therefore, our study retrospectively analyzed the data of a large cohort of Middle Eastern PTC patients to address this issue. Methods: We compared men and women with respect to clinico-pathological characteristics, disease persistence, structural recurrence, risk stratification and prognosis. We included 1430 patient - 1085 (75.9%) women and 345 (24.1%) men. Results: The median follow up was 9.5 years. At diagnosis, 27% (93/345) of men were ≥ 55 years, compared with 17.8% (193/1085) of women (p = 0.0003). Men had significantly more advanced disease at presentation: higher stage (p = 0.0074), larger tumor size (p = 0.0069), higher rates of lymphovascular invasion (p = 0.0129), extrathyroidal extension (p = 0.0086), regional lymph node metastasis (p = 0.0279), and distant metastasis (p = 0.0101). There was a higher rate of recurrence (p < 0.0001) and TERT mutations (p = 0.0003) in male PTC patients than in female patients. Additionally, radioiodine refractoriness was higher in male PTC patients (p = 0.0014). In multivariate analysis, male sex was an independent prognostic factor for poor recurrence-free survival (RFS) (Hazard ratio = 1.59; 95% Confidence interval = 1.21 – 2.07; p = 0.0010). Conclusions: Men with PTC are more likely to present with more advanced and aggressive diseases. Importantly, male sex was an independent prognostic factor for RFS. Thus, men may benefit from more aggressive management and therapeutic interventions.

Citation Format: KHAWLA S. AL-KURAYA, Sandeep Kumar Parvathareddy, Abdul K Siraj, Felisa De Vera, Padmanaban Annaiyappanaidu, Saeeda O. Ahmed, Saif S. Al-Sobhi, Fouad Al-Dayel. Male Sex is an Independent Predictor of Recurrence-Free Survival in Middle Eastern Papillary Thyroid Carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA042.