bluuebunny/crossref_metadata_2025 huggingface dataset:
A Hybrid Short-Term Traffic Flow Multistep Prediction Method Based on Variational Mode Decomposition and Long Short-Term Memory Model
Authors: Bing Qichun , Shen Fuxin , Chen Xiufeng , Zhang Weijian , Hu Yanran , Qu Dayi
Published: October 2021

Timely and accurate traffic prediction information is essential for advanced traffic management system (ATMS) and advanced traveler information system (ATIS). Because of the characteristics of nonlinearity, nonstationarity, and randomness, short-term traffic flow prediction could be still a challenging task. In this study, a hybrid short-term traffic flow multistep prediction method is proposed by combining the variational mode decomposition (VMD) algorithm and long short-term memory (LSTM) model. Firstly, the VMD algorithm is employed to decompose the original traffic flow data into a series of intrinsic mode function (IMF) components. Secondly, different LSTM models are established to predict different IMF components. For each prediction model, one-step to three-step predictions are carried out. Finally, the component prediction results are aggregated to obtain the final traffic flow multistep prediction values. The prediction performance of the proposed hybrid model is investigated using inductive loop data measured from the north-south viaduct expressway in Shanghai. The experiment results show that (1) VMD algorithm could effectively avoid the problems of endpoint effects and modal aliasing, and the decomposition effect is better than empirical mode decomposition algorithm and wavelet decomposition algorithm; (2) among all the involved methods, the proposed hybrid model is more effective and robust in extracting the trend information, which has the best multistep prediction performance.
Analysis Using High‐Precision Airborne LiDAR Data to Survey Potential Collapse Geological Hazards
Authors: She Jinxing , Mabi Awei , Liu Zhongming , Sheng Mingqiang , Dong Xiujun , Liu Fei , Wang Shiyang
Published: October 2021

On August 8, 2017, an earthquake of magnitude 7.0 on the Richter scale occurred in Jiuzhaigou, Sichuan, causing significant damage to both life and property. Traditional geological hazard investigation is difficult in Jiuzhaigou because of the high altitude, the high‐altitude canyons, and the vegetation‐covered seismic areas. This study explores the technical advantages of using airborne LiDAR technology to penetrate vegetation and gather information directly from the surface, rapidly acquiring airborne 3D point cloud data in difficult areas. Through the preprocessing of data, the high‐precision digital terrain and landform results were obtained. Comparative research found that the DEM obtained by high‐precision airborne LiDAR technology has significant advantages in terms of the accuracy, details, and microgeomorphology of the data collected. The results can be directly used in the early identification of disasters, such as during the initial collapse or for disaster management. Studies have shown that airborne LiDAR has the technical advantage of penetrating vegetation to the surface and can, therefore, be used to guide the early identification and management of geological disasters in similar areas in the future.
Forecasting Confirmed Malaria Cases in Northwestern Province of Zambia: A Time Series Analysis Using 2014–2020 Routine Data
Authors: Menda Dhally M. , Nawa Mukumbuta , Zimba Rosemary K. , Mulikita Catherine M. , Mwandia Jim , Mwaba Henry , Sichinga Karen
Published: October 2021

Background. Malaria remains a significant public health problem, especially in resource-poor settings. We aimed to forecast the year 2021 monthly confirmed malaria cases in the northwestern province of Zambia. Methods. The total number of confirmed monthly malaria cases recorded at health facilities over the past 7-years period (January 2014 to December 2020) was taken from the District Health Information System version 2 (DHIS.2) database. Box–Jenkins autoregressive integrated moving average (ARIMA) was used to forecast monthly confirmed malaria cases for 2021. STATA software version 16 was used for analyzing the time series data. Results. Between 2014 and 2020, there were 3,795,541 confirmed malaria cases in the northwestern province with a monthly mean of 45,185 cases. ARIMA (2, 1, 2) (0, 1, 1)12 was the best fit and the most parsimonious model. The forecasted mean monthly confirmed malaria cases were 60,284 (95%CI 30,969–121,944), and the total forecasted confirmed malaria cases were 723,413 (95%CI 371,626–1,463,322) for the year 2021. Conclusion. The forecasted confirmed malaria cases suggest that there will be an increase in the number of confirmed malaria cases for the year 2021 in the northwestern province. Therefore, there is a need for concerted efforts to prevent and eliminate the disease if the goal to eliminate malaria in Zambia by 2030 is to be realized.
Inversion Analysis of Seepage Parameters Based on Improved Shuffled Frog Leaping Algorithm
Authors: Xu Li Qun , Li Ling
Published: October 2021

Aiming at overcoming the defects such as slow searching speed and easily trapping into local extremum at anaphase of the shuffled frog leaping algorithm (SFLA), based on the Evolutionary Exploration strategy, a more effective shuffled frog leaping algorithm, Improved Shuffled Frog Leaping Algorithm (ISFLA), which can be applied to the inverse analysis of seepage parameters to dams, is proposed. With the introduction of the threshold value selection in the local search of the original initial population to improve the best frogs in memeplex, the improved algorithm overcomes the shortcomings of traditional SFLA which can easily fall into a local optimum. By comparative analysis between the laboratory test and numerical simulation, the effectiveness and accuracy of ISFLA are demonstrated by the application to the inversion analysis of seepage parameters of earth dams. Furthermore, the inversion analysis of seepage parameters to the earth dam in Lianyungang China is studied by the ISFLA. Moreover, the seepage characteristics of the dam are evaluated; thus, the suggestion that the dam should be reinforced is put forward. All the results show that ISFLA in an inverse analysis of seepage parameters of dams has excellent value to hydropower engineering.
Experimental Investigation of an RC Slab Culvert Rehabilitated with Grouted CSPs
Authors: Li Bai-Jian , Fu Wen-Qiang , He Yu-Ting , Fu Xin-Sha
Published: October 2021

The rehabilitation of an existing culvert with corrugated steel plates (CSPs) has been an emerging technology in recent years, but engineers and researchers are not particularly clear about the working principle of the rehabilitated structure. To investigate the mechanical properties of reinforced concrete (RC) slabs rehabilitated with CSPs, laboratory tests were carried out to explore the calculation method and influencing factors of load‐carrying capacity of RC slab culverts rehabilitated with grouted CSPs. The results revealed the following: the flexural failure of the prerehabilitated RC slab has little influence on the test‐loading capacity of the rehabilitated system; shear failure will occur in the RC slab and grout, and an arch effect will be formed in the CSP and grout after rehabilitation; the higher the shear strength of the concrete of the RC slab and grout, the greater the test‐loading capacity of the rehabilitated system: the RC slab and grout greatly contribute to the test‐loading capacity of the rehabilitated system; CSP changes the ductility of the rehabilitated system at the failure stage. It was found that the estimation method for the test‐loading capacity of the rehabilitated system based on the shear capacities of the RC slab and grout and the flexural capacity of the CSP is reasonable; the maximum difference between the theoretical and experimental results was less than 30%, and the minimum difference between them was 0%.
The Application of Magnetic-Controlled Capsule Gastroscopy in Patients Refusing C-EGD: A Single-Center 5-Year Observational Study
Authors: Zhou Lihan , Wang Sijia , Li Jian , Zhong Jie , Zhang Ling , Shen Ruizhe , Kouken Bielike , Zhou Chunhua , Wang Qi , Qian Yuting , Zou Duowu , Chu Ye
Published: October 2021

Background and Aims. Screening for gastric diseases in symptomatic outpatients with conventional esophagogastroduodenoscopy (C-EGD) is expensive and has poor compliance. We aimed to explore the efficiency and safety of magnetic-controlled capsule gastroscopy (MCCG) in symptomatic outpatients who refused C-EGD. Methods. We performed a retrospective study of 76794 consecutive symptomatic outpatients from January 2014 to October 2019. A total of 2318 adults (

F
/
M
=
1064
/
1254

) in the MCCG group who refused C-EGD were matched with adults in the C-EGD group using propensity-score matching (PSM). The detection rates of abnormalities were analyzed to explore the application of MCCG in symptomatic patients. Results. Our study demonstrated a prevalence of gastric ulcers (GUs) in patients with functional dyspepsia- (FD-) like symptoms of 8.14%. The detection rate of esophagitis and Barrett’s esophagus was higher in patients with typical gastroesophageal reflux disease (GERD) symptoms than in patients in the other four groups (

P
<
0.01

). The detection rates of gastric ulcers in the five groups (abdominal pain, bloating, heartburn, follow-up, and bleeding) were significantly different (

P
=
0.015

). The total detection rate of gastric ulcers in symptomatic patients was 9.7%. A total of 7 advanced carcinomas were detected by MCCG and confirmed by endoscopic or surgical biopsy. The advanced gastric cancer detection rate was not significantly different between the MCCG group and the C-EGD matched group in terms of nonhematemesis GI bleeding (2 vs. 2,

P
=
1.00

). In addition, the overall focal lesion detection rate in the MCCG group was superior to that in the C-EGD matched group (224 vs. 184,

P
=
0.038

). MCCG gained a clinically meaningful small bowel diagnostic yield of 54.8% (17/31) out of 31 cases of suspected small bowel bleeding. No patient reported capsule retention at the two-week follow-up. Conclusion. MCCG is well tolerated, safe, and technically feasible and has a considerable diagnostic yield. The overall gastric diagnostic yield of gastric focal lesions with MCCG was comparable to that with C-EGD. MCCG offered a supplementary diagnosis in patients who had a previously undiagnostic C-EGD, indicating that MCCG could play an important role in the routine monitoring and follow-up of outpatient. MCCG shows its safety and efficiency in symptomatic outpatient applications.
Unsupervised Anomaly Detection Based on Deep Autoencoding and Clustering
Authors: Zhang Chuanlei , Liu Jiangtao , Chen Wei , Shi Jinyuan , Yao Minda , Yan Xiaoning , Xu Nenghua , Chen Dufeng
Published: October 2021

The unsupervised anomaly detection task based on high-dimensional or multidimensional data occupies a very important position in the field of machine learning and industrial applications; especially in the aspect of network security, the anomaly detection of network data is particularly important. The key to anomaly detection is density estimation. Although the methods of dimension reduction and density estimation have made great progress in recent years, most dimension reduction methods are difficult to retain the key information of original data or multidimensional data. Recent studies have shown that the deep autoencoder (DAE) can solve this problem well. In order to improve the performance of unsupervised anomaly detection, we propose an anomaly detection scheme based on a deep autoencoder (DAE) and clustering methods. The deep autoencoder is trained to learn the compressed representation of the input data and then feed it to clustering approach. This scheme makes full use of the advantages of the deep autoencoder (DAE) to generate low-dimensional representation and reconstruction errors for the input high-dimensional or multidimensional data and uses them to reconstruct the input samples. The proposed scheme could eliminate redundant information contained in the data, improve performance of clustering methods in identifying abnormal samples, and reduce the amount of calculation. To verify the effectiveness of the proposed scheme, massive comparison experiments have been conducted with traditional dimension reduction algorithms and clustering methods. The results of experiments demonstrate that, in most cases, the proposed scheme outperforms the traditional dimension reduction algorithms with different clustering methods.
Collagen Family Genes Associated with Risk of Recurrence after Radiation Therapy for Vestibular Schwannoma and Pan-Cancer Analysis
Authors: Shi Qingyuan , Yan Xiaojun , Wang Jiyun , Zhang Xiangbao
Published: October 2021

Background. The safety of radiotherapy techniques in the treatment of vestibular schwannoma (VS) shows a high rate of tumor control with few side effects. Neuropeptide Y (NPY) may have a potential relevance to the recurrence of VS. Further research is still needed on the key genes that determine the sensitivity of VS to radiation therapy. Materials and Methods. Transcriptional microarray data and clinical information data from VS patients were downloaded from GSE141801, and vascular-related genes associated with recurrence after radiation therapy for VS were obtained by combining information from MSigDB. Logistics regression was applied to construct a column line graph prediction model for recurrence status after radiation therapy. Pan-cancer analysis was also performed to investigate the cooccurrence of these genes in tumorigenesis. Results. We identified eight VS recurrence-related genes from the GSE141801 dataset. All of these genes were highly expressed in the VS recurrence samples. Four collagen family genes (COL5A1, COL3A1, COL4A1, and COL15A1) were further screened, and a model was constructed to predict the risk of recurrence of VS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that these four collagen family genes play important roles in a variety of biological functions and cellular pathways. Pan-cancer analysis further revealed that the expression of these genes was significantly heterogeneous across immune phenotypes and significantly associated with immune infiltration. Finally, Neuropeptide Y (NPY) was found to be significantly and negatively correlated with the expression of COL5A1, COL3A1, and COL4A1. Conclusions. Four collagen family genes have been identified as possible predictors of recurrence after radiation therapy for VS. Pan-cancer analysis reveals potential associations between the pathogenesis of VS and other tumorigenic factors. The relevance of NPY to VS was also revealed for the first time.
Asymptotic Distributions for Power Variations of the Solution to the Spatially Colored Stochastic Heat Equation
Authors: Wang Wensheng , Chang Xiaoying , Liao Wang
Published: October 2021

Let

u

α
,
d

=

u

α
,
d

t
,
x

,
 
t
∈

0
,
T

,
x
∈

ℝ

d

be the solution to the stochastic heat equations (SHEs) with spatially colored noise. We study the realized power variations for the process

u

α
,
d

, in time, having infinite quadratic variation and dimension-dependent Gaussian asymptotic distributions. We use the underlying explicit kernels and spectral/harmonic analysis, yielding temporal central limit theorems for SHEs with spatially colored noise. This work builds on the recent works on delicate analysis of variations of general Gaussian processes and SHEs driven by space-time white noise.
A Lightweight Modulation Classification Network Resisting White Box Gradient Attacks
Authors: Zhang Sicheng , Lin Yun , Bao Zhida , Fu Jiangzhi
Published: October 2021

Improving the attack resistance of the modulation classification model is an important means to improve the security of the physical layer of the Internet of Things (IoT). In this paper, a binary modulation classification defense network (BMCDN) was proposed, which has the advantages of small model scale and strong immunity to white box gradient attacks. Specifically, an end-to-end modulation signal recognition network that directly recognizes the form of the signal sequence is constructed, and its parameters are quantized to 1 bit to obtain the advantages of low memory usage and fast calculation speed. The gradient of the quantized parameter is directly transferred to the original parameter to realize the gradient concealment and achieve the effect of effectively defending against the white box gradient attack. Experimental results show that BMCDN obtains significant immune performance against white box gradient attacks while achieving a scale reduction of 6 times.
Characteristics Evolution of Multiscale Structures in Deep Coal under Liquid Nitrogen Freeze-Thaw Cycles
Authors: Sun Yingfeng , Zhao Yixin , Li Yulin , Danesh Nima Noraei , Zhang Zetian
Published: October 2021

Liquid nitrogen freeze-thaw fracturing has attracted more and more attention in improving the coal reservoir permeability. In order to reveal the impact of liquid nitrogen freeze-thaw on the multiscale structure of deep coal, the multiscale structure evolution law of deep and shallow coal samples from the same seam in the Qinshui coalfield during the liquid nitrogen freeze-thaw cycling was investigated using NMR

T

2

spectrum, NMRI, and SEM. The connectivity between mesopores and macropores in deep and shallow coal is improved after liquid nitrogen freeze-thaw cycles. The influence of liquid nitrogen freeze-thaw cycles on the structure evolution of deep and shallow coal is the formation and expansion of microscopic fractures. The initial NMR porosity of deep coal is lower than that of shallow coal from the same coalfield and coal seam. The NMR porosity of both the deep and shallow coal samples increases with the increase of the number of freeze-thaw cycles, and the NMR porosity growth rate of the deep sample is lower than that of the shallow sample.
An Image Encryption Algorithm Based on the Improved Sine-Tent Map
Authors: Gao Zijing , Liu Zeyu , Wang Lichan
Published: October 2021

This paper makes use of the characteristics of initial sensitivity and randomness of the chaotic map to design an image encryption algorithm based on the sine map and the tent map. The sine map is used to improve the tent map; then, the improved sine-tent map is proposed. The traditional tent map proposed in this paper has an expanded control parameter range and better chaos. In this algorithm, bit rearrangement is adopted to further improve the improved sine-tent map, which can reconstruct the output value and expand the chaotic characteristics of the map. In this algorithm, the image parameters are connected with the algorithm to generate the key. In the encryption step, a method of replacing the most significant bit and scrambling-diffusion algorithm is designed to encrypt the plaintext image. Finally, the algorithm is simulated with the experiment and evaluated with analysis; then, the experimental results are given. The evaluation results show that the ciphertext of the algorithm has high randomness, strong robustness, and better resistance to differential attacks after comparison. The correlation of the ciphertext image pixels is very low, and the algorithm is highly secure as a conclusion.
Supraphysiologic Testosterone Induces Ferroptosis and Activates Immune Pathways through Nucleophagy in Prostate Cancer
Authors: Kumar Rajendra , Mendonca Janet , Owoyemi Olutosin , Boyapati Kavya , Thomas Naiju , Kanacharoen Suthicha , Coffey Max , Topiwala Deven , Gomes Carolina , Ozbek Busra , Jones Tracy , Rosen Marc , Dong Liang , Wiens Sadie , Brennen W. Nathaniel , Isaacs John T. , De Marzo Angelo M. , Markowski Mark C. , Antonarakis Emmanuel S. , Qian David Z. , Pienta Kenneth J. , Pardoll Drew M. , Carducci Michael A. , Denmeade Samuel R. , Kachhap Sushant K.
Published: October 2021

The discovery that androgens play an important role in the progression of prostate cancer led to the development of androgen deprivation therapy (ADT) as a first line of treatment. However, paradoxical growth inhibition has been observed in a subset of prostate cancer upon administration of supraphysiologic levels of testosterone (SupraT), both experimentally and clinically. Here we report that SupraT activates cytoplasmic nucleic acid sensors and induces growth inhibition of SupraT-sensitive prostate cancer cells. This was initiated by the induction of two parallel autophagy-mediated processes, namely, ferritinophagy and nucleophagy. Consequently, autophagosomal DNA activated nucleic acid sensors converge on NFκB to drive immune signaling pathways. Chemokines and cytokines secreted by the tumor cells in response to SupraT resulted in increased migration of cytotoxic immune cells to tumor beds in xenograft models and patient tumors. Collectively, these findings indicate that SupraT may inhibit a subset of prostate cancer by activating nucleic acid sensors and downstream immune signaling.

Significance:

This study demonstrates that supraphysiologic testosterone induces two parallel autophagy-mediated processes, ferritinophagy and nucleophagy, which then activate nucleic acid sensors to drive immune signaling pathways in prostate cancer.
Targeting KDM6A Suppresses SREBP1c-Dependent Lipid Metabolism and Prostate Tumorigenesis
Authors: Tang Donge , Dai Yong , Xu Songhui
Published: October 2021

The histone demethylase KDM6A controls gene expression by the epigenetic regulation of H3K27 methylation and functions in diverse processes, including differentiation, development, and cancer. Here, we investigated the role of KDM6A in prostate cancer. Specific deletion of KDM6A in the adult mouse prostate epithelium strongly inhibited tumor progression initiated by the loss of PTEN. Mechanistically, KDM6A promoted prostate tumorigenesis and lipid metabolism by binding to the SREBP1c promoter to increase SREBP1c transcription. USP7 deubiquitinated KDM6A to increase its expression. KDM6A was significantly upregulated in prostate cancer and positively associated with USP7 expression. Furthermore, targeting KDM6A stability by inhibiting USP7 in conditional knockout mice and xenograft models markedly suppressed prostate cancer growth and significantly enhanced KDM6A inhibitor efficacy. Collectively, these findings indicate that KDM6A regulates prostate lipid metabolism and is essential for prostate tumorigenesis initiated by PTEN loss. Targeting USP7/KDM6A could be a valuable strategy to ameliorate prostate cancer progression and therapeutic resistance.

Significance:

These findings show that KDM6A supports prostate tumorigenesis by promoting SREBP1c-mediated lipid metabolism, proposing targeting the USP7/KDM6A axis as a therapeutic strategy for treating prostate cancer.
ANGPTL4-Mediated Promotion of Glycolysis Facilitates the Colonization ofFusobacterium nucleatumin Colorectal Cancer
Authors: Zheng Xin , Liu Rui , Zhou Chenchen , Yu Haopeng , Luo Wanyi , Zhu Jianhui , Liu Jiaxin , Zhang Zhe , Xie Na , Peng Xian , Xu Xin , Cheng Lei , Yuan Quan , Huang Canhua , Zhou Xuedong
Published: October 2021

Colorectal cancer is a severe health problem worldwide, and accumulating evidence supports the contribution of Fusobacterium nucleatum (F. nucleatum) to colorectal cancer development, metastasis, and chemoresistance. However, the mechanisms underlying the colonization of F. nucleatum in colorectal cancer tissue are not yet clarified. Here we demonstrate that F. nucleatum infection mediated elevation of angiopoietin-like 4 (ANGPTL4) expression. Upregulated ANGPTL4 promoted glucose uptake and glycolysis activity in colorectal cancer cells in vitro and in vivo, which are necessary for the colonization of F. nucleatum. Furthermore, overall increased acetylation of histone H3 lysine 27 was observed in F. nucleatum–infected colorectal cancer cells and patient tumors, which was responsible for the corresponding transcriptional upregulation of ANGPTL4. These data indicate that the metabolic reprogramming of cancer cells induced by F. nucleatum is essential for its enrichment and persistence in colorectal cancer, providing a novel potential target for the clinical intervention of F. nucleatum–related colorectal cancer.

Significance:

F. nucleatum colonization in colorectal cancer is regulated by ANGPTL4-mediated glycolysis, suggesting that this axis could be targeted for combined repression of F. nucleatum and cancer progression.
Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer: An Open-Label, Four-Arm, Phase II Study
Authors: Moore Kathleen N. , Chambers Setsuko K. , Hamilton Erika P. , Chen Lee-may , Oza Amit M. , Ghamande Sharad A. , Konecny Gottfried E. , Plaxe Steven C. , Spitz Daniel L. , Geenen Jill J.J. , Troso-Sandoval Tiffany A. , Cragun Janiel M. , Rodrigo Imedio Esteban , Kumar Sanjeev , Mugundu Ganesh M. , Lai Zhongwu , Chmielecki Juliann , Jones Suzanne F. , Spigel David R. , Cadoo Karen A.
Published: October 2021

Purpose:

This study assessed the efficacy, safety, and pharmacokinetics of adavosertib in combination with four chemotherapy agents commonly used in patients with primary platinum-resistant ovarian cancer.

Patients and Methods:

Women with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled between January 2015 and January 2018 in this open-label, four-arm, multicenter, phase II study. Patients received adavosertib (oral capsules, 2 days on/5 days off or 3 days on/4 days off) in six cohorts from 175 mg once daily to 225 mg twice daily combined with gemcitabine, paclitaxel, carboplatin, or pegylated liposomal doxorubicin. The primary outcome measurement was overall response rate.

Results:

Three percent of patients (3/94) had confirmed complete response and 29% (27/94) had confirmed partial response. The response rate was highest with carboplatin plus weekly adavosertib, at 66.7%, with 100% disease control rate, and median progression-free survival of 12.0 months. The longest median duration of response was in the paclitaxel cohort (12.0 months). The most common grade ≥3 adverse events across all cohorts were neutropenia [45/94 (47.9%) patients], anemia [31/94 (33.0%)], thrombocytopenia [30/94 (31.9%)], and diarrhea and vomiting [10/94 (10.6%) each].

Conclusions:

Adavosertib showed preliminary efficacy when combined with chemotherapy. The most promising treatment combination was adavosertib 225 mg twice daily on days 1–3, 8–10, and 15–17 plus carboplatin every 21 days. However, hematologic toxicity was more frequent than would be expected for carboplatin monotherapy, and the combination requires further study to optimize the dose, schedule, and supportive medications.
Biomarkers of Response and Resistance to Palbociclib Plus Letrozole in Patients With ER+/HER2− Breast Cancer
Authors: Dowsett Mitch , Kilburn Lucy , Rimawi Mothaffar F. , Osborne C. Kent , Pogue-Geile Katherine , Liu Yuan , Jacobs Samuel A. , Finnigan Melanie , Puhalla Shannon , Dodson Andrew , Martins Vera , Cheang Maggie , Perry Sophie , Holcombe Chris , Turner Nick , Swift Claire , Bliss Judith M. , Johnston Stephen ,   on behalf of the PALLET trialists
Published: October 2021

Purpose:

To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER+/HER2− breast cancer; and (ii) the pharmacodynamic effect of the agents on the biomarkers.

Experimental Design:

307 postmenopausal women with ER+/HER2− primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib. Immunohistochemical analyses were conducted for Ki67, c-PARP, ER, PgR, RB1, CCNE1, and CCND1.

Results:

Higher baselines ER and PgR were significantly associated with a greater chance of complete cell-cycle arrest (CCCA: Ki67 <2.7%) at 14 weeks and higher baseline Ki67, c-PARP, and CCNE1 with a lower chance. The interaction with treatment was significant only for c-PARP. CCND1 levels were decreased c.20% by letrozole at 2 and 14 weeks but showed a tendency to increase with palbociclib. CCNE1 levels fell 82% (median) in tumors showing CCCA but were unchanged in those with no CCCA. Only 2/9 tumors showed CCCA 3–9 days after stopping palbociclib. ESR1 mutations were found in 2/4 tumors for which surgery took place ≥6 months after starting treatment.

Conclusions:

High CCNE1 levels were confirmed as a biomarker of resistance to letrozole+palbociclib. Ki67 recovery within 3–9 days of discontinuing palbociclib indicates incomplete suppression of proliferation during the “off” week of its schedule.
Phase Ib/II Study of Cetuximab plus Pembrolizumab in Patients with Advanced RAS Wild-Type Colorectal Cancer
Authors: Fountzilas Christos , Bajor David L. , Mukherjee Sarbajit , Saltzman Joel , Witkiewicz Agnieszka K. , Maguire Orla , Minderman Hans , Nambiar Ram , Rosenheck Hanna R. , Knudsen Erik S. , Muhitch Jason B. , Abrams Scott I. , Wang Chong , Hutson Alan D. , Attwood Kristopher , Hicks Karen A. , Jurcevic Jennifer A. , Kalinski Pawel , Iyer Renuka , Boland Patrick M.
Published: October 2021

Purpose:

We evaluated the antitumor efficacy of cetuximab in combination with pembrolizumab in patients with RAS wild-type (RASwt), metastatic colorectal adenocarcinoma (mCRC).

Patients and Methods:

In this phase Ib/II study, cetuximab was combined with pembrolizumab in patients with RASwt mCRC with ≥ one prior line of therapy for advanced disease. We analyzed baseline on-treatment tumor tissues for changes in the tumor microenvironment (TME), using flow cytometry and multispectral immunofluorescence.

Results:

Forty-four patients were evaluable for efficacy. The study was negative for the primary efficacy endpoint [overall response rate: 2.6%, 6-month progression-free survival (PFS): 31%; P = 0.52]. Median PFS was 4.1 months [95% confidence interval (CI): 3.9–5.5 months]. No increase in adverse effects was identified. We observed favorable immunomodulation with 47% increase in the number of intratumoral CTLs posttreatment (P = 0.035). These changes were more pronounced in patients with tumor shrinkage (P = 0.05). The TME was characterized by high numbers of TIM3+ and CTLA4+ cells; there were few activated OX40+ cells. PD-L1 expression was higher in pretreatment tumor cells from metastatic sites versus primary tumor samples (P < 0.05). Higher numbers of PD-L1+ tumor cells at baseline were associated with tumor shrinkage (P = 0.04). Analysis of immune populations in the blood demonstrated decreases in PD-1+ memory effector cells (P = 0.04) and granulocytic myeloid-derived suppressor cells (P = 0.03), with simultaneous increases in CD4+/CTLA4+ cells (P = 0.01).

Conclusions:

The combination of cetuximab and pembrolizumab is inactive in patients with RASwt mCRC, despite its partial local immunologic efficacy. Further development of immuno-oncology combinations with enhanced efficacy and/or targeting additional or alternative immune checkpoints merits investigation.
S-Adenosylmethionine Supplementation May Reduce Cancer-Related Fatigue: A Prospective Evaluation Using the FACIT-F Questionnaire in Colon Cancer Patients Undergoing Oxaliplatin-Based Chemotherapy Regimens
Authors: Onorato Angelo , Napolitano Andrea , Spoto Silvia , Incorvaia Lorena , Russo Antonio , Santini Daniele , Tonini Giuseppe , Vincenzi Bruno
Published: October 2021

Background: Fatigue is a common distressing symptom for patients living with chronic or acute diseases, including liver disorders and cancer (Cancer-Related Fatigue, CRF). Its etiology is multifactorial, and some hypotheses regarding the pathogenesis are summarized, with possible shared mechanisms both in cancer and in chronic liver diseases. A deal of work has investigated the role of a multifunctional molecule in improving symptoms and outcomes in different liver dysfunctions and associated symptoms, including chronic fatigue: S-adenosylmethionine (SAM; AdoMet). The aim of this work is actually to consider its role also in oncologic settings. Patients and Methods: Between January 2006 and December 2009, at the University Campus Bio-Medico of Rome, 145 patients affected by colorectal cancer in adjuvant (n = 91) or metastatic (n = 54; n = 40 with liver metastases) setting and treated with oxaliplatin-based regimen (FOLFOX for adjuvant and bevacizumab + XELOX for metastatic ones), 76 of which with the supplementation of S-adenosylmethionine (AdoMet; 400 mg b.i.d.) (57% of adjuvant patients and 44% of metastatic ones) and 69 without AdoMet supplementation, were evaluated for fatigue prevalence using the Functional Assessment of Chronic Illnesses Therapy-Fatigue (FACIT-F) questionnaire, at 3 and 6 months after the beginning of oncologic treatment. Notably, the number of patients with liver metastases was well balanced between the group of patients treated with AdoMet and those who were not. Results: Among patients receiving oxaliplatin-based chemotherapy, both in adjuvant and in metastatic settings, after just 3 months from the beginning of chemotherapy, mean scores from questionnaire domains like FACIT-F subscale (7.9 vs. 3.1, p = 0.006), FACIT physical (6.25 vs. 3.32, p = 0.020), FACIT emotional (4.65 vs. 2.19, p = 0.045), and FACIT-F total score (16.5 vs. 8.27, p = 0.021) were higher in those receiving supplementation of AdoMet, resulting in reduced fatigue; a significant difference was maintained even after 6 months of treatment. Discussion and Conclusions: Mechanisms and strategies for managing CRF are not fully understood. This work aimed at investigating the possible role of S-adenosylmethionine supplementation in improving fatigue scores in a specific setting of cancer patients, using a FACIT-F questionnaire, a well-validated quality of life instrument widely used for the assessment of CRF in clinical trials.
Physical and Chemical Compatibility of Etomidate and Propofol Injectable Emulsions
Authors: Wang Chunling , Wang Shengnan , Wu Cuishuan , Lei Li , Wang Dong-Xin , Zhang Qiang
Published: October 2021

Introduction: The mixture of etomidate and propofol is widely used in clinical practice to improve efficacy of general anesthesia and to minimize side effects. As a thermodynamically unstable system, emulsion is prone to destabilization through mechanisms including coalescence, flocculation, and creaming. Such unwanted phenomenon can induce fat embolism after intravenous administration. This study was aimed to investigate the physical and chemical stability of the mixture of etomidate and propofol in the dosage form of emulsion. Methods: This compatibility study focused on the critical quality attributes (CQAs) of drug-containing emulsions, such as appearance, pH, particle size and distribution, zeta potential, the observation under centrifugation, and drug content and impurity. Results: As the results, there were no significant changes in the CQAs of the mixed emulsions up to 24 h after mixing at refrigeration temperature (4°C), room temperature (25°C), and body temperature (37°C). Conclusions: These results demonstrate that etomidate emulsion is physically and chemically compatible with propofol emulsions up to 24 h at 4°C, 25°C, and 37°C, suggesting that etomidate and propofol can be administrated in mixture without adversely affecting product characteristics, at least in vitro.
Primary Adrenal Glomus Tumor: The First Case Report
Authors: Hu Yuqi , He Xianglei , Zhang Qi , Zhang Dahong , Zhao Ming
Published: October 2021

We report a unique case of a 25-year-old man who was incidentally identified to have a mass in the left adrenal gland region by computerized tomography scan. The image revealed a 1.8 × 1.6 cm, well-defined adrenal mass with moderately homogeneous enhancement. The mass was laparoscopically completely removed, and the diagnosis of a solid variant glomus tumor of the adrenal gland was rendered. There were no histologic features indicating atypia or malignance and no primary tumors anywhere else. The patient was free of disease at the 6-month follow-up. To our knowledge, this is the first case of primary adrenal glomus tumor described in the literature.
Outpatient visit among elderly in Indonesia
Authors: Idris Haerawati , Nurafni Nurafni
Published: October 2021

Population aging has become an important issue mostly discussed in many countries in the world. The proportion of the older population is getting better in both developed and developing countries. Elderly tend to need more health care as they are more susceptible to chronic diseases. The purpose of this study was to determine the factors affecting outpatient visit among elderly in Indonesia. This study employed a cross-sectional study design with a sample of ≥60-year-old individual with a total sample of 5,325 elderly. The data used to be analyzed were from the Indonesian Family Life Survey 2014 representing 83% of the population in Indonesia. The theory used was Andersen health service utilization model. In analyzing the data, bivariate analysis were used, with Chi-square and multivariate test using multiple logistic regression test prediction model. Elderly who utilize health service for outpatient was 18.6%. Variables that have significant relationships with outpatient utilization on elderly were female, high education, formal job, Java and Bali, urban, health insurance ownership, economic status, the perception of ill, smoking habit, history of chronic disease, fat, and obesity. Predictor for the most dominant outpatient utilization is influenced by chronic disesase after controlled by other variables. Chronic disesase greatly affect the elderly in utilizing health services for outpatient. To overcome this, the government is expected to provide policies on health facilities to better emphasize promotive and preventive efforts among the elderly.
Knowledge, attitude, and practice towards COVID-19 among university students in Indonesia: A cross-sectional study
Authors: Sulistyawati Sulistyawati , Hidayat Syamsu , Wijayanti Siwi Pramatama Mars , Sukesi Tri Wahyuni , Hastuti Siti Kurnia Widi , Mulasari Surahma Asti , Tentama Fatwa , Rokhmayanti Rokhmayanti , Putra Ulinnuha Yudiansa , Djannah Sitti Nur
Published: October 2021

The presence of asymptomatic people exacerbates the widespread Coronavirus disease (COVID-19) transmission. The majority of them come from young people. This study aimed to explore the knowledge, attitude, and practice related to COVID-19 among university students in Indonesia, and the potential factor influenced their knowledge. A cross-sectional study involved 1,427 university students were carried out using an online survey from March 28 to April 10, 2020. A structured questionnaire consist of six sections focuses on knowledge, attitude, and preventive measure related to COVID-19 was used to collect the data. The analysis was performed using descriptive, Mann-Whitney, and Kruskal-Wallis tests. Results of the analysis indicated a significant difference in terms of mean between males and females regarding knowledge about preventing and protect others from COVID-19, the risk factor of getting COVID-19 infection, and knowledge that COVID-19 is curable. Knowledge total score among the respondent, there was a significant difference within the research group. This study demonstrates that the respondent has a basic knowledge about COVID-19 and the proper attitude, but it seems they are not consistent on practice in a particular measure.
Abordagem sobre o ensino interdisciplinar e interprofissional em uma Faculdade de Medicina Brasileira
Authors: Souza Mariana Passos de , USP Grupo PET Medicina , Alves Ana Carolina Bonetti , Pinto Maria Paula Panuncio , Riberto Marcelo
Published: October 2021

A Educação Interprofissional (EIP) é uma tendência internacional, contemplada pelas Diretrizes Curriculares Nacionais (DNCs) dos cursos de saúde, presente também nas DCNs do curso médico de 2014, ao incluir interprofissionalidade como meio de atender as múltiplas dimensões das necessidades dos usuários do sistema de saúde. A Faculdade de Medicina de Ribeirão Preto da USP abriga seis cursos de graduação em saúde além de Medicina, podendo ser um campo para efetiva formação que enfatize o trabalho em equipe. Objetivo: o objetivo desse estudo foi avaliar de que forma as experiências de interação multiprofissional e interdisciplinaridade (ID/MP) são oferecidas nas disciplinas para os estudantes de graduação em Medicina da FMRP. Método: Levantamento documental das palavras multiprofissional, interprofissional, multidisciplinar e interdisciplinar nos objetivos, roteiros de aulas e atividades, avaliação e bibliografia. Os achados foram tabulados em planilhas e classificados de acordo com o ano de oferecimento da disciplina no ciclo básico (primeiros dois anos), clínico (dois anos intermediários) e internato (dois anos finais). Resultados: Os termos relacionados da ID/MP foram identificados em 11 (13,9%) das 79 disciplinas do currículo obrigatório do curso de Medicina, sendo mais frequentes no internato. Quatro das 109 disciplinas optativas oferecidas entre o 1° e 5° ano em 2017 apresentaram os termos procurados. Conclusão: A oferta formal e planejada de experiência em atuação ID/MP foi pequena, apesar de crescente ao longo do curso de Medicina.
Systems of Care for ST-Segment–Elevation Myocardial Infarction: A Policy Statement From the American Heart Association
Authors: Jacobs Alice K. , Ali Murtuza J. , Best Patricia J. , Bieniarz Mark C. , Bufalino Vincent J. , French William J. , Henry Timothy D. , Hollowell Lori , Jauch Edward C. , Kurz Michael C. , Levy Michael , Patel Puja , Spier Travis , Stone R. Harper , Tataris Katie L. , Thomas Randal J. , Zègre-Hemsey Jessica K. ,   on behalf of the American Heart Association Advocacy Coordinating Committee
Published: October 2021

The introduction of Mission: Lifeline significantly increased timely access to percutaneous coronary intervention for patients with ST-segment–elevation myocardial infarction (STEMI). In the years since, morbidity and mortality rates have declined, and research has led to significant developments that have broadened our concept of the STEMI system of care. However, significant barriers and opportunities remain. From community education to 9-1-1 activation and emergency medical services triage and from emergency department and interfacility transfer protocols to postacute care, each critical juncture presents unique challenges for the optimal care of patients with STEMI. This policy statement sets forth recommendations for how the ideal STEMI system of care should be designed and implemented to ensure that patients with STEMI receive the best evidence-based care at each stage in their illness.
Myofilament Phosphorylation in Stem Cell Treated Diastolic Heart Failure
Authors: Soetkamp Daniel , Gallet Romain , Parker Sarah J. , Holewinski Ronald , Venkatraman Vidya , Peck Kiel , Goldhaber Joshua I. , Marbán Eduardo , Van Eyk Jennifer E.
Published: October 2021

Rationale:

Phosphorylation of sarcomeric proteins has been implicated in heart failure with preserved ejection fraction (HFpEF); such changes may contribute to diastolic dysfunction by altering contractility, cardiac stiffness, Ca
2+
-sensitivity, and mechanosensing. Treatment with cardiosphere-derived cells (CDCs) restores normal diastolic function, attenuates fibrosis and inflammation, and improves survival in a rat HFpEF model.

Objective:

Phosphorylation changes that underlie HFpEF and those reversed by CDC therapy, with a focus on the sarcomeric subproteome were analyzed.

Methods and Results:

Dahl salt–sensitive rats fed a high-salt diet, with echocardiographically verified diastolic dysfunction, were randomly assigned to either intracoronary CDCs or placebo. Dahl salt–sensitive rats receiving low salt diet served as controls. Protein and phosphorylated Ser, Thr, and Tyr residues from left ventricular tissue were quantified by mass spectrometry. HFpEF hearts exhibited extensive hyperphosphorylation with 98% of the 529 significantly changed phospho-sites increased compared with control. Of those, 39% were located within the sarcomeric subproteome, with a large group of proteins located or associated with the Z-disk. CDC treatment partially reverted the hyperphosphorylation, with 85% of the significantly altered 76 residues hypophosphorylated. Bioinformatic upstream analysis of the differentially phosphorylated protein residues revealed PKC as the dominant putative regulatory kinase. PKC isoform analysis indicated increases in PKC α, β, and δ concentration, whereas CDC treatment led to a reversion of PKCβ. Use of PKC isoform specific inhibition and overexpression of various PKC isoforms strongly suggests that PKCβ is the dominant kinase involved in hyperphosphorylation in HFpEF and is altered with CDC treatment.

Conclusions:

Increased protein phosphorylation at the Z-disk is associated with diastolic dysfunction, with PKC isoforms driving most quantified phosphorylation changes. Because CDCs reverse the key abnormalities in HFpEF and selectively reverse PKCβ upregulation, PKCβ merits being classified as a potential therapeutic target in HFpEF, a disease notoriously refractory to medical intervention.
Post-GDPR survey of data protection officers in research and non-research institutions in Croatia
Authors: Mladinić Anamarija , Puljak Livia , Koporc Zvonimir
Published: October 2021

General Data Protection Regulation (GDPR) focuses on important elements of data ethics, including protecting people’s privacy, accountability and transparency. According to the GDPR, certain public institutions are obliged to appoint a Data Protection Officer (DPO). However, there is little publicly available data from national EU surveys on DPOs. This study aimed to examine the scope of work, type of work, and education of DPOs in institutions in Croatia.
During 2020-2021, this cross-sectional study surveyed DPOs appointed in Croatia. The survey had 35 items. The questions referred to their appointment, work methods, number and type of cases handled by DPOs, the sources of information they use, their experience and education, level of work independence, contacts with ethics committees, problems experienced, knowledge, suggestions for improvement of their work, changes caused by the GDPR, and sociodemographic information.
Out of 5671 invited DPOs, 732 (13%) participated in the study. The majority (91%) indicated that they could perform their job independently; they did not have prior experience in data protection before being appointed as DPOs (54%) and that they need additional education in data protection (82%).
Most DPOs indicated that they had none or minimal prior experience in data protection when they were appointed as DPO, that they would benefit from further education on data protection, and exhibited insufficient knowledge on basic concepts of personal data protection. Requirements for DPO appointments should be clarified; mandatory education and certification of DPOs could be introduced and DPOs encouraged to engage in continuous education.