bluuebunny/crossref_metadata_2025 huggingface dataset:
Construction of Regional Logistics Weighted Network Model and Its Robust optimization: Evidence from China
Authors: Yan Lizhao , Wen Yi , Teo Kok Lay , Liu Jian , Xu Fei
Published: September 2020

In this paper, we construct a regional logistics model from a macroperspective. First, based on the gravity model, the index of logistics attraction between cities is established as the weight of the model, and hence the regional logistics weighted model is constructed. Next, we use the social network analysis method to analyze its structure and make specific recommendations for the construction of logistics networks. Finally, we analyze the model’s response to random attacks and deliberate attacks. From our study, it is found that when the failure nodes or edges reach a certain percentage, the regional logistics network will collapse on a large scale. Therefore, it is important to optimization the threshold of the regional logistics network. This clearly provides a new perspective for the study of the regional logistics networks.
Analysing and Data-Driven Modelling the Handling Performance of Rugby Balls under Wet Conditions
Authors: Liu Jiaojiao , Liu Yunan , Wang Ya , Liu Chao
Published: September 2020

This paper studies the effect of moisture on the handling performance of rugby balls, where different moisture conditions will cause a change in skin friction between finger pads and rugby balls. In this study, a set of rugby ball passing tests was performed under wet conditions to test the effect of skin hydration on the performance of ball handling. A comprehensive analysis was then conducted to assess skin frictional properties at various moisture levels. It was observed that skin moisture is strongly associated with the handling performance of rugby balls. Based on the collected experimental data, intelligent data-driven models were finally developed, including a neural network and a fuzzy rule-based system. These models will likely enhance the anticipation of the handling performance of rugby players, which helps in designing specific training programmes and better preparing for rugby games to cope with wet conditions.
Synthesis, Spectroscopic Characterization, Structural Studies, and In Vitro Antitumor Activities of Pyridine-3-carbaldehyde Thiosemicarbazone Derivatives
Authors: Hernández Wilfredo , Carrasco Fernando , Vaisberg Abraham , Spodine Evgenia , Manzur Jorge , Icker Maik , Krautscheid Harald , Beyer Lothar
Published: September 2020

Eight new thiosemicarbazone derivatives, 6-(1-trifluoroethoxy)pyridine-3-carbaldehyde thiosemicarbazone (1), 6-(4′-fluorophenyl)pyridine-3-carbaldehyde thiosemicarbazone (2), 5-chloro-pyridine-3-carbaldehyde thiosemicarbazone (3), 2-chloro-5-bromo-pyridine-3-carbaldehyde thiosemicarbazone (4), 6-(3′,4′-dimethoxyphenyl)pyridine-3-carbaldehyde thiosemicarbazone (5), 2-chloro-5-fluor-pyridine-3-carbaldehyde thiosemicarbazone, (6), 5-iodo-pyridine-3-carbaldehyde thiosemicarbazone (7), and 6-(3′,5′-dichlorophenyl)pyridine-3-carbaldehyde thiosemicarbazone (8) were synthesized, from the reaction of the corresponding pyridine-3-carbaldehyde with thiosemicarbazide. The synthesized compounds were characterized by ESI-Mass, UV-Vis, IR, and NMR (1H, 13C, 19F) spectroscopic techniques. Molar mass values and spectroscopic data are consistent with the proposed structural formulas. The molecular structure of 7 has been also confirmed by single crystal X-ray diffraction. In the solid state 7 exists in the E conformation about the N2-N3 bond; 7 also presents the E conformation in solution, as evidenced by 1H NMR spectroscopy. The in vitro antitumor activity of the synthesized compounds was studied on six human tumor cell lines: H460 (lung large cell carcinoma), HuTu80 (duodenum adenocarcinoma), DU145 (prostate carcinoma), MCF-7 (breast adenocarcinoma), M-14 (amelanotic melanoma), and HT-29 (colon adenocarcinoma). Furthermore, toxicity studies in 3T3 normal cells were carried out for the prepared compounds. The results were expressed as IC50 and the selectivity index (SI) was calculated. Biological studies revealed that 1 (IC50 = 3.36 to 21.35 μM) displayed the highest antiproliferative activity, as compared to the other tested thiosemicarbazones (IC50 = 40.00 to >582.26 μM) against different types of human tumor cell lines. 1 was found to be about twice as cytotoxic (SI = 1.82) than 5-fluorouracile (5-FU) against the M14 cell line, indicating its efficiency in inhibiting the cell growth even at low concentrations. A slightly less efficient activity was shown by 1 towards the HuTu80 and MCF7 tumor cell lines, as compared to that of 5-FU. Therefore, 1 can be considered as a promising candidate to be used as a pharmacological agent, since it presents significant activity and was found to be more innocuous than the 5-FU anticancer drug against the 3T3 mouse embryo fibroblast cells.
Attack-Defense Game between Malicious Programs and Energy-Harvesting Wireless Sensor Networks Based on Epidemic Modeling
Authors: Liu Guiyun , Peng Baihao , Zhong Xiaojing , Cheng Lefeng , Li Zhifu
Published: September 2020

As energy-harvesting wireless sensor networks (EHWSNs) are increasingly integrated with all walks of life, their security problems have gradually become hot issues. As an attack means, malicious programs often attack sensor nodes in critical locations in the networks to cause paralysis and information leakage of the networks, resulting in security risks. Based on the previous works and the introduction of solar charging, we proposed a novel model, namely, Susceptible-Infected-Low (energy)-Recovered-Dead (SILRD) with solar energy harvesters. Meanwhile, this paper takes Logistic Growth as the drop rate of sensor nodes and the infection rate of multitype malicious programs under nonlinear condition into consideration. Finally, an Λ-Susceptible-Infected-Low (energy)-Recovered-Dead (ΛSILRD) model is proposed. Based on the Pontryagin Maximum Principle, this paper proposes the optimal strategies based on the SILRD with solar energy harvesters and the ΛSILRD. The effectiveness of SILRD with solar energy harvesters was demonstrated by comparison with the general epidemic model. At the same time, by analyzing different charging strategies, we conclude that solar charging is highly efficient. Moreover, we further analyze the influence of controllable and uncontrollable input and various node degrees on ΛSILRD model.
Deep-Learning Prediction Model with Serial Two-Level Decomposition Based on Bayesian Optimization
Authors: Jin Xue-Bo , Wang Hong-Xing , Wang Xiao-Yi , Bai Yu-Ting , Su Ting-Li , Kong Jian-Lei
Published: September 2020

The power load prediction is significant in a sustainable power system, which is the key to the energy system’s economic operation. An accurate prediction of the power load can provide a reliable decision for power system planning. However, it is challenging to predict the power load with a single model, especially for multistep prediction, because the time series load data have multiple periods. This paper presents a deep hybrid model with a serial two‐level decomposition structure. First, the power load data are decomposed into components; then, the gated recurrent unit (GRU) network, with the Bayesian optimization parameters, is used as the subpredictor for each component. Last, the predictions of different components are fused to achieve the final predictions. The power load data of American Electric Power (AEP) were used to verify the proposed predictor. The results showed that the proposed prediction method could effectively improve the accuracy of power load prediction.
Leptomeningeal Metastases in a Patient with Castration-Resistant Prostate Cancer
Authors: Koie Takuya , Hashimoto Yasuhiro , Suzuki Yuichiro , Hatayama Yoshiomi , Kimura Futoshi
Published: September 2020

A 42-year-old man visited a community hospital with chief complaints of lumbago and dyschesia. Computed tomography (CT) showed multiple lung, lymph node, and bone metastases and the irregular enlarged prostate with urinary bladder invasion. Serum prostate-specific antigen (PSA) was 544.0 ng/mL. Histological evaluation showed adenocarcinoma with the Gleason score 5+4, and the clinical stage was T4N1M1c as an initial diagnosis. Although androgen deprivation therapy was performed immediately, he had castration-resistant PCa after 3 months. Therefore, he received 6 courses of docetaxel chemotherapy every 3 weeks. Serum PSA was decreased to 0.2 ng/mL, and multiple metastases and prostate size were obviously reduced based on CT. He underwent robot-assisted radical prostatectomy and radiation therapy for prostatic fossa and multiple metastases. Although serum PSA level remained low, CT showed multiple liver metastases after 3 years from surgery. He received the combination therapy of cisplatin and etoposide (PE) every 4 weeks. Liver metastases had complete response. However, he visited our hospital with complaint of vomiting and a right drooping eyelid after 6 weeks from withdrawal of PE therapy. T2-weighted magnetic resonance imaging revealed multiple leptomeningeal metastases (LM). He received RT for the brain and was administered amrubicin. However, he died of PCa after 6 weeks from the diagnosis of LM.
Clinical Features and Correlates of Poor Nighttime Sleepiness in Patients with Parkinson’s Disease
Authors: Qin Xiaoling , Li Xue , Chen Gang , Chen Xu , Shi Mingyu , Liu Xue-kui , Li Zai-li , Xin Zai-e , Gao Dianshuai
Published: September 2020

Objective. The present study investigated the clinical features and correlates of poor nighttime sleepiness (PNS) in patients with Parkinson’s disease (PD). Methods. One hundred ten patients with PD (divided into PD-PNS group and PD-nPNS group) and forty-seven controls (nPD-PNS group) were enrolled in this study. Demographic information was collected. Patients were assessed according to the unified Parkinson’s disease rating scale (UPDRS) and Hoehn–Yahr (H&Y) stage scale. Patients were also evaluated according to the Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS), rapid eye movement sleep behavior disorder screening questionnaire (RBD-SQ), restless leg syndrome (RLS) diagnosis, Hamilton’s depression scale (HAMD), and Hamilton’s anxiety scale (HAMA). Results. The prevalence of PNS was 55.45% (61/110) in patients with PD. The PD-PNS group tended to have a longer duration of disease, higher UPDRS-I and UPDRS-III scores, a higher percentage of RLS patients, and higher HAMA and HAMD scores than those of the PD-nPNS group. The PD-PNS group tended to have a higher percentage of RBD and RLS patients and higher HAMA and HAMD scores than those of the nPD-PNS group. Analysis of the PSQI components and PSQI impact factors showed that the PD-PNS group had worse subjective sleep quality (χ2 = −2.267, P = 0.023), shorter sleep latency (χ2 = −2.262, P = 0.024), fewer sleep medications (χ2 = −4.170, P ≤ 0.001), worse daytime functioning (χ2 = −2.347, P = 0.019), and an even higher prevalence of increased nocturia (χ2 = 4.447, P = 0.035), nightmares (χ2 = 7.887, P = 0.005), and pain (χ2 = 9.604, P = 0.002) than those of the nPD-PNS group. Analysis also indicated that the PSQI global score positively correlated with BMI (r = 0.216, P < 0.05), H&Y stage (r = 0.223, P < 0.05), UPDRS-I (r = 0.501, P < 0.01), UPDRS-III (r = 0.425, P < 0.01), ESS (r = −0.296, P < 0.01), RBD (r = 0.227, P < 0.05), RLS (r = 0.254, P < 0.01), HAMA (r = 0.329, P < 0.01), and HAMD (r = 0.466, P < 0.01). In the final model, H&Y stage, RLS, UPDRS-III, and HAMD remained associated with the PQSI score (P ≤ 0.001, P ≤ 0.001, P = 0.049, P ≤ 0.001, respectively). Conclusions. Our data showed that PNS was common in patients with PD. H&Y stage, UPDRS-III, HAMD, and RLS were positively associated with PNS. Attention to the management of motor symptoms, RLS, and depression may be beneficial to nighttime sleep quality in patients with PD.
Strategies of Haze Risk Reduction Using the Tripartite Game Model
Authors: Zheng Chaoyu , Peng Benhong , XinSheng  , Elahi Ehsan , Wan Anxia
Published: September 2020

Although haze risk management is mainly under government control, willingness of stakeholders is compulsory to determine. Therefore, this study constructs a tripartite game model of government, public, and enterprises and determines the haze risk evolution model considering the initial willingness of stakeholders. Moreover, numerical simulation analysis was also conducted. The results revealed that stakeholders were affected by the change due to initial willingness to participate in and reach the equilibrium at different speeds. It is found that if subsidy coefficient of the government is big, it will reach equilibrium faster. The bigger the penalty coefficient is, the better the pollution reduction effect of pollutant discharge enterprises. It is found that, at the final equilibrium stage, the government will eventually choose to withdraw from supervision, but the speed of withdrawing varies with different regulatory intentions. Study results stress that the government should actively participate in supervision to reduce environmental pollution.
Scheduling on a Single Machine and Parallel Machines with Batch Deliveries and Potential Disruption
Authors: Gong Hua , Zhang Yuyan , Yuan Puyu
Published: September 2020

In this paper, we study several coordinated production-delivery scheduling problems with potential disruption motivated by a supply chain in the manufacturing industry. Both single-machine environment and identical parallel-machine environment are considered in the production part. The jobs finished on the machines are delivered to the same customer in batches. Each delivery batch has a capacity and incurs a delivery cost. There is a situation that a possible disruption in the production part may occur at some particular time and will last for a period of time with a probability. We consider both resumable case and nonresumable case where a job does not need (needs) to restart if it is disrupted for a resumable (nonresumable) case. The objective is to find a coordinated schedule of production and delivery that minimizes the expected total flow times plus the delivery costs. We first present some properties and analyze the NP-hard complexity for four various problems. For the corresponding single-machine and parallel-machine scheduling problems, pseudo-polynomial-time algorithms and fully polynomial-time approximation schemes (FPTASs) are presented in this paper, respectively.
A Review of Nutrients and Compounds, Which Promote or Inhibit Intestinal Iron Absorption: Making a Platform for Dietary Measures That Can Reduce Iron Uptake in Patients with Genetic Haemochromatosis
Authors: Milman Nils Thorm
Published: September 2020

Objective. To provide an overview of nutrients and compounds, which influence human intestinal iron absorption, thereby making a platform for elaboration of dietary recommendations that can reduce iron uptake in patients with genetic haemochromatosis. Design. Review. Setting. A literature search in PubMed and Google Scholar of papers dealing with iron absorption. Results. The most important promoters of iron absorption in foods are ascorbic acid, lactic acid (produced by fermentation), meat factors in animal meat, the presence of heme iron, and alcohol which stimulate iron uptake by inhibition of hepcidin expression. The most important inhibitors of iron uptake are phytic acid/phytates, polyphenols/tannins, proteins from soya beans, milk, eggs, and calcium. Oxalic acid/oxalate does not seem to influence iron uptake. Turmeric/curcumin may stimulate iron uptake through a decrease in hepcidin expression and inhibit uptake by complex formation with iron, but the net effect has not been clarified. Conclusions. In haemochromatosis, iron absorption is enhanced due to a decreased expression of hepcidin. Dietary modifications that lower iron intake and decrease iron bioavailability may provide additional measures to reduce iron uptake from the foods. This could stimulate the patients’ active cooperation in the treatment of their disorder and reduce the number of phlebotomies.
Quantitation of Phenolic Compounds Related to Antioxidant and Antiosteoporosis Activities in Ripe and Unripe Maesil (Prunus mume)
Authors: Cho Chong Woon , Park Young Sik , Yan Xi-Tao , Kim Hyun June , Kim Young Ho , Kim Kyung Tae , Men Chu Van , Kang Jong Seong
Published: September 2020

The fruits of Prunus mume, maesil (Rosaceae), have been widely used as a valuable source of foods and herbal medicines from ancient times in Northeast Asia. Specially, phenolic compounds of main compounds in maesil were reported to have various activities. This study aims to develop the simultaneous analytical method of nine phenolic compounds in maesil and to evaluate these compound contents in samples during the ripeness. Twenty-one species of samples and nine phenolic compounds were used for this study. In results, compounds 1–9 contents in unripe fruits were 0.16∼1.81 mg/g. However, these compounds in ripe samples were 0.09∼1.66 mg/g. Compounds 1–9 contents in ripe fruits were generally reduced rather than those in unripe fruits. Otherwise, the contents of compounds 2, 5, 8, and 9 in seed part were relatively higher than those in flesh part. In contrast, contents of compounds 1, 3, and 7 in flesh part were relatively higher than those in seed part. Generally, the contents of compounds 1–9 in unripe fruits were higher than those in ripe fruits. However, the contents of compounds 1–9 in each part (seed and fresh) of fruits were different according to species of compounds. It indicates that the selection of harvesting time and process part of fruits as the source of foods and medicines is important.
Analytical Multiloop Control for Multivariable Systems with Time Delays
Authors: Wang Zhiguo , Wei Peng
Published: September 2020

In this paper, a new design method with performance improvements of multiloop controllers for multivariable systems is proposed. Precise expression is developed to show the relationship between the dynamic- and steady-state characteristics of the multiloop control system and its parameters. First, an equivalent transfer function (ETF) is introduced to decompose the multivariable system, based on which the multiloop controller parameters are calculated. According to the ETF matrix property, an analytical expression for the PI controller for multivariable systems is derived in terms of substituting the ETF matrix for the inverse open-loop transfer function. In the proposed controller design method, no approximation of the inverse of the process model is needed, implying that this method can be applied to some multivariable systems with high dimensions. The simulation results obtained from several examples demonstrate the effectiveness of the proposed method.
Prediction and Aerodynamic Analysis of Interior Noise and Wind Drag Generated by the Outside Rear-View Mirror for Commercial Vehicles
Authors: Hu Binfei , Lu Zengjun , Cui Qiming , Tang Rongjiang , Feng Zhe , Bi Daokun
Published: September 2020

The outside rear-view mirror (OSRVM) is installed on the vehicle’s surface, which causes unwanted aerodynamic noise and wind drag during driving. It is important to use simulation methods to predict the performance of aerodynamic noise and wind drag of commercial vehicles due to the OSRVM. Considering the wind drag of the OSRVM, a combinational simulation strategy is employed to calculate external flow and interior acoustic fields of commercial vehicles, respectively. The flow field is computed a priori with an incompressible flow solver. The acoustic field was then computed based on the information extracted from the CFD solver. To obtain the interior noise level at the driver’s ears, a vibroacoustic model is used to calculate the response of the window glass structure and interior cavities, where the unsteady aerodynamic pressure loading on the two side windows’ surface is treated as the acoustic source field. The paper provides flow field and acoustic simulations for three OSRVM configuration models. The results are compared to data obtained in road sliding test measurement on the commercial vehicle. The accuracy of the hybrid simulation method is proved, and the comparative analyses verify that the OSRVM B model dramatically reduces the interior noise and wind drag of commercial vehicles.
Association of Pathologic Complete Response with Long-Term Survival Outcomes in Triple-Negative Breast Cancer: A Meta-Analysis
Authors: Huang Min , O'Shaughnessy Joyce , Zhao Jing , Haiderali Amin , Cortés Javier , Ramsey Scott D. , Briggs Andrew , Hu Peter , Karantza Vassiliki , Aktan Gursel , Qi Cynthia Z. , Gu Chenyang , Xie Jipan , Yuan Muhan , Cook John , Untch Michael , Schmid Peter , Fasching Peter A.
Published: September 2020

Pathologic complete response (pCR) following neoadjuvant therapy has been associated with improved event-free survival (EFS) and overall survival (OS) in early-stage breast cancer. The magnitude of this association varies by breast cancer subtype, yet further research focusing on subtype-specific populations is limited. Here we provide an updated and comprehensive evaluation of the association between pCR and survival outcomes in triple-negative breast cancer (TNBC). A literature review identified neoadjuvant studies, including clinical trials, real-world cohort studies, and studies that pooled multiple trials or cohorts, which reported EFS/OS results by pCR in patients with early-stage TNBC. Meta-analyses were performed to evaluate the association between pCR and EFS/OS and to predict long-term survival outcomes based on pCR status. Sensitivity analyses were conducted to assess the impact of cross-study variations. Twenty-five studies with over 4,000 patients with TNBC were identified. A synthesis of evidence from these studies suggested substantial improvement in EFS and OS for pCR versus non-pCR [EFS HR (95% confidence interval): 0.24 (0.20–0.29); OS: 0.19 (0.15–0.24)]; consistent results were reported in sensitivity analyses. Collectively, our findings suggest that adjuvant therapy is associated with improved EFS/OS in patients with TNBC who received neoadjuvant therapy, regardless of pCR status.
Steroid Sulfatase Stimulates Intracrine Androgen Synthesis and is a Therapeutic Target for Advanced Prostate Cancer
Authors: Armstrong Cameron M. , Liu Chengfei , Liu Liangren , Yang Joy C. , Lou Wei , Zhao Ruining , Ning Shu , Lombard Alan P. , Zhao Jinge , D'Abronzo Leandro S. , Evans Christopher P. , Li Pui-Kai , Gao Allen C.
Published: September 2020

Purpose:

Most patients with prostate cancer receiving enzalutamide or abiraterone develop resistance. Clinical evidence indicates that serum levels of dehydroepiandrosterone sulfate (DHEAS) and biologically active DHEA remain in the high range despite antiandrogen treatment. The conversion of DHEAS into DHEA by steroid sulfatase (STS) may contribute to sustained intracrine androgen synthesis. Here, we determine the contribution of STS to treatment resistance and explore the potential of targeting STS to overcome resistance in prostate cancer.

Experimental Design:

STS expression was examined in patients and cell lines. In vitro, STS activity and expression were modulated using STS-specific siRNA or novel STS inhibitors (STSi). Cell growth, colony formation, androgen production, and gene expression were examined. RNA-sequencing analysis was conducted on VCaP cells treated with STSi. Mice were treated with STSis with or without enzalutamide to determine their effects in vivo.

Results:

STS is overexpressed in patients with castration-resistant prostate cancer (CRPC) and resistant cells. STS overexpression increases intracrine androgen synthesis, cell proliferation, and confers resistance to enzalutamide and abiraterone. Inhibition of STS using siRNA suppresses prostate cancer cell growth. Targeting STS activity using STSi inhibits STS activity, suppresses androgen receptor transcriptional activity, and reduces the growth of resistant C4-2B and VCaP prostate cancer cells. STSis significantly suppress resistant VCaP tumor growth, decrease serum PSA levels, and enhance enzalutamide treatment in vitro and in vivo.

Conclusions:

These studies suggest that STS drives intracrine androgen synthesis and prostate cancer proliferation. Targeting STS represents a therapeutic strategy to treat CRPC and improve second-generation antiandrogen therapy.
The Capacity of the Ovarian Cancer Tumor Microenvironment to Integrate Inflammation Signaling Conveys a Shorter Disease-free Interval
Authors: Jordan Kimberly R. , Sikora Matthew J. , Slansky Jill E. , Minic Angela , Richer Jennifer K. , Moroney Marisa R. , Hu Junxiao , Wolsky Rebecca J. , Watson Zachary L. , Yamamoto Tomomi M. , Costello James C. , Clauset Aaron , Behbakht Kian , Kumar T. Rajendra , Bitler Benjamin G.
Published: September 2020

Purpose:

Ovarian cancer has one of the highest deaths to incidence ratios across all cancers. Initial chemotherapy is effective, but most patients develop chemoresistant disease. Mechanisms driving clinical chemo-response or -resistance are not well-understood. However, achieving optimal surgical cytoreduction improves survival, and cytoreduction is improved by neoadjuvant chemotherapy (NACT). NACT offers a window to profile pre- versus post-NACT tumors, which we used to identify chemotherapy-induced changes to the tumor microenvironment.

Experimental Design:

We obtained matched pre- and post-NACT archival tumor tissues from patients with high-grade serous ovarian cancer (patient, n = 6). We measured mRNA levels of 770 genes (756 genes/14 housekeeping genes, NanoString Technologies), and performed reverse phase protein array (RPPA) on a subset of matched tumors. We examined cytokine levels in pre-NACT ascites samples (n = 39) by ELISAs. A tissue microarray with 128 annotated ovarian tumors expanded the transcriptional, RPPA, and cytokine data by multispectral IHC.

Results:

The most upregulated gene post-NACT was IL6 (16.79-fold). RPPA data were concordant with mRNA, consistent with elevated immune infiltration. Elevated IL6 in pre-NACT ascites specimens correlated with a shorter time to recurrence. Integrating NanoString (n = 12), RPPA (n = 4), and cytokine (n = 39) studies identified an activated inflammatory signaling network and induced IL6 and IER3 (immediate early response 3) post-NACT, associated with poor chemo-response and time to recurrence.

Conclusions:

Multiomics profiling of ovarian tumor samples pre- and post-NACT provides unique insight into chemo-induced changes to the tumor microenvironment. We identified a novel IL6/IER3 signaling axis that may drive chemoresistance and disease recurrence.
Immunomodulation in Pomalidomide, Dexamethasone, and Daratumumab-Treated Patients with Relapsed/Refractory Multiple Myeloma
Authors: Pierceall William E. , Amatangelo Michael D. , Bahlis Nizar J. , Siegel David S. , Rahman Adeeb , Van Oekelen Oliver , Neri Paola , Young Mary , Chung Weiyuan , Serbina Natalya , Parekh Samir , Agarwal Amit , Thakurta Anjan
Published: September 2020

Purpose:

Addition of daratumumab to pomalidomide and low-dose dexamethasone (LoDEX) is a safe and effective combination for relapsed/refractory multiple myeloma treatment. We sought to better understand immune combinational benefit of pomalidomide and daratumumab with LoDEX.

Patients and Methods:

Immunophenotypic changes were analyzed in peripheral blood from longitudinal sampling of patients treated with this triplet regimen from cohort B of the CC4047-MM-014 phase II trial (NCT01946477).

Results:

Consistent with the daratumumab mechanism, treatment led to decreased natural killer (NK) and B cells. In contrast, pronounced increases occurred in activated and proliferating NK and T cells, appreciably in CD8+ T cells, along with reduction in naïve and expansion of effector memory compartments. Timing of T-cell changes correlated with pomalidomide dosing schedule. Enhanced activation/differentiation did not result in increased exhausted T-cell phenotypes or increases in regulatory T cells. Similar immune enhancements were also observed in patients previously refractory to lenalidomide.

Conclusions:

These data support a potential mechanism for enhanced immune-mediated cytotoxicity in which daratumumab-mediated NK-cell diminution is partially offset by pomalidomide effects on the remaining NK-cell pool. Furthermore, daratumumab antimyeloma activity and elimination of CD38+ T cells (regulatory/activated) provide a rationale for therapeutic combination with direct tumoricidal activity and immunomodulation of pomalidomide-directed T-cell enhancements. These data highlight enhancements in immune subpopulations for the combination of daratumumab with pomalidomide and potentially with next-generation cereblon-targeting agents.
β2-adrenoreceptor Signaling Increases Therapy Resistance in Prostate Cancer by Upregulating MCL1
Authors: Hassan Sazzad , Pullikuth Ashok , Nelson Kyle C. , Flores Anabel , Karpova Yelena , Baiz Daniele , Zhu Sinan , Sui Guangchao , Huang Yue , Choi Young A. , D'Agostino Ralph , Hemal Ashok , von Holzen Urs , Debinski Waldemar , Kulik George
Published: September 2020

There is accumulating evidence that continuous activation of the sympathetic nervous system due to psychosocial stress increases resistance to therapy and accelerates tumor growth via β2-adrenoreceptor signaling (ADRB2). However, the effector mechanisms appear to be specific to tumor type. Here we show that activation of ADRB2 by epinephrine, increased in response to immobilization stress, delays the loss of MCL1 apoptosis regulator (MCL1) protein expression induced by cytotoxic drugs in prostate cancer cells; and thus, increases resistance of prostate cancer xenografts to cytotoxic therapies. The effect of epinephrine on MCL1 protein depended on protein kinase A (PKA) activity, but was independent from androgen receptor expression. Furthermore, elevated blood epinephrine levels correlated positively with an increased MCL1 protein expression in human prostate biopsies. In summary, we demonstrate that stress triggers an androgen-independent antiapoptotic signaling via the ADRB2/PKA/MCL1 pathway in prostate cancer cells.

Implications:

Presented results justify clinical studies of ADRB2 blockers as therapeutics and of MCL1 protein expression as potential biomarker predicting efficacy of apoptosis-targeting drugs in prostate cancer.
High Activation of the AKT Pathway in Human Multicystic Renal Dysplasia
Authors: Apostolou Alexia , Poreau Brice , Delrieu Loris , Thévenon Julien , Jouk Pierre-Simon , Lallemand Guillaume , Emadali Anouk , Sartelet Herve
Published: September 2020

Multicystic renal dysplasia is a congenital cystic anomaly of the kidney caused by abnormal metanephric differentiation with immature tubules. It is surrounded by mesenchymal collars and islands of immature mesenchyma present between the cysts. The PI3K-AKT-mTOR signaling pathway is a key regulator involved in cell growth, proliferation, motility, survival, and apoptosis. Activation of the PI3K-AKT-mTOR pathway results in the survival and proliferation of tumor cells in many cancers. The aim of this study is to analyze the topographic expression of phospho-AKT, phospho-mTOR, and phospho-70S6K in renal development and in the multicystic dysplastic kidney (MCDK). A total of 17 fetal kidneys of development age from the first to the third trimester and 13 cases of pathological kidneys with MCDK were analyzed by immunohistochemistry in order to evaluate the expression of phospho-AKT (S473), phospho-mTOR, and phospho-70S6K. Phospho-AKT and phospho-mTOR were expressed early in renal development and in an identical manner for every structure derived from the ureteric bud, such as collecting ducts and urothelium. Phospho-p70S6K was expressed early in the urothelium and in glomerular mesangial cells. Later, their expressions differed according to the needs of cell proliferation and differentiation over time by becoming more selective. In MCDK, phospho-AKT, phospho-mTOR, and phospho-70S6K have the same profile: a high cytoplasmic expression in cystic epithelium, loose mesenchyma, and primitive tubes. This study demonstrates the essential and specific role of the PI3K-AKT-mTOR pathway in the formation of cysts in multicystic renal dysplasia.
Genotype-Guided Hydralazine Therapy
Authors: Collins Kimberly S. , Raviele Anthony L.J. , Elchynski Amanda L. , Woodcock Alexander M. , Zhao Yang , Cooper-DeHoff Rhonda M. , Eadon Michael T.
Published: September 2020

Background: Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity. Summary: There is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. Key Messages: NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension.
Gut Microbiota Profile Identifies Transition From Compensated Cardiac Hypertrophy to Heart Failure in Hypertensive Rats
Authors: Gutiérrez-Calabrés Elena , Ortega-Hernández Adriana , Modrego Javier , Gómez-Gordo Rubén , Caro-Vadillo Alicia , Rodríguez-Bobada Cruz , González Pablo , Gómez-Garre Dulcenombre
Published: September 2020

Microcirculatory alterations displayed by patients with heart failure (HF) induce structural and functional intestinal changes that may affect normal gut microbial community. At the same time, gut microbiota can influence pathological mechanisms implicated in HF progression. However, it is unknown whether gut microbiota dysbiosis can precede the development of cardiac alterations in HF or it is only a mere consequence. Our aim was to investigate the potential relationship between gut microbiota composition and HF development by comparing spontaneously hypertensive heart failure and spontaneously hypertensive rat models. Gut microbiota from spontaneously hypertensive heart failure, spontaneously hypertensive rat, and normotensive Wistar Kyoto rats at 9 and 19 months of age was analyzed by sequencing the 16S ribosomal RNA gene, and KEGG metabolic pathways associated to 16S profiles were predicted. Beta diversity,
Firmicutes
/
Bacteroidetes
ratio, taxonomic abundances, and potential metabolic functions of gut microbiota were significantly different in spontaneously hypertensive heart failure with respect to spontaneously hypertensive rat before (9 months) and after (19 months) cardiac differences were presented. Nine-month-old spontaneously hypertensive heart failure showed a significant increase in the genera
Paraprevotella, Oscillospira, Prevotella 9, Faecalitalea, Faecalibacterium, Ruminiclostridium 6, Phascolarctobacterium, Butyrivibrio, Parasutterella, and Parabacteroides
compared with both Wistar Kyoto and spontaneously hypertensive rat, while
Ruminiclostridium 9
,
Oscillibacter
,
Ruminiclostridium
,
Mucispirillum, Intestinimonas
, and
Akkermansia
were diminished. Of them,
Akkermansia, Prevotella 9
,
Paraprevotella
, and
Phascolarctobaterium
were associated to changes in cardiac structure and function. Our results demonstrate an association between specific changes in gut microbiota and the development of HF in a hypertensive model of HF and further support the intervention to restore gut microbiota as an innovative therapeutic strategy for preventing HF.
Evidence and Recommendations on the Use of Telemedicine for the Management of Arterial Hypertension
Authors: Omboni Stefano , McManus Richard J. , Bosworth Hayden B. , Chappell Lucy C. , Green Beverly B. , Kario Kazuomi , Logan Alexander G. , Magid David J. , Mckinstry Brian , Margolis Karen L. , Parati Gianfranco , Wakefield Bonnie J.
Published: September 2020

Telemedicine allows the remote exchange of medical data between patients and healthcare professionals. It is used to increase patients’ access to care and provide effective healthcare services at a distance. During the recent coronavirus disease 2019 (COVID-19) pandemic, telemedicine has thrived and emerged worldwide as an indispensable resource to improve the management of isolated patients due to lockdown or shielding, including those with hypertension. The best proposed healthcare model for telemedicine in hypertension management should include remote monitoring and transmission of vital signs (notably blood pressure) and medication adherence plus education on lifestyle and risk factors, with video consultation as an option. The use of mixed automated feedback services with supervision of a multidisciplinary clinical team (physician, nurse, or pharmacist) is the ideal approach. The indications include screening for suspected hypertension, management of older adults, medically underserved people, high-risk hypertensive patients, patients with multiple diseases, and those isolated due to pandemics or national emergencies.
Risk of Paradoxical Embolism (RoPE)–Estimated Attributable Fraction Correlates With the Benefit of Patent Foramen Ovale Closure
Authors: Kent David M. , Saver Jeffrey L. , Ruthazer Robin , Furlan Anthony J. , Reisman Mark , Carroll John D. , Smalling Richard W. , Jüni Peter , Mattle Heinrich P. , Meier Bernhard , Thaler David E.
Published: September 2020

Background and Purpose:

In patients with cryptogenic stroke and patent foramen ovale (PFO), the Risk of Paradoxical Embolism (RoPE) Score has been proposed as a method to estimate a patient-specific “PFO-attributable fraction”—the probability that a documented PFO is causally-related to the stroke, rather than an incidental finding. The objective of this research is to examine the relationship between this RoPE-estimated PFO-attributable fraction and the effect of closure in 3 randomized trials.

Methods:

We pooled data from the CLOSURE-I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale), RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment), and PC (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale [PFO] Using the Amplatzer PFO Occluder With Medical Treatment in Patients With Cryptogenic Embolism) trials. We examine the treatment effect of closure in high RoPE score (≥7) versus low RoPE score (<7) patients. We also estimated the relative risk reduction associated with PFO closure across each level of the RoPE score using Cox proportional hazard analysis. We estimated a patient-specific attributable fraction using a PC trial–compatible (9-point) RoPE equation (omitting the neuroradiology variable), as well as a 2-trial analysis using the original (10-point) RoPE equation. We examined the Pearson correlation between the estimated attributable fraction and the relative risk reduction across RoPE strata.

Results:

In the low RoPE score group (<7, n=912), the rate of recurrent strokes per 100 person-years was 1.37 in the device arm versus 1.68 in the medical arm (hazard ratio, 0.82 [0.42–1.59]
P
=0.56) compared with 0.30 versus 1.03 (hazard ratio, 0.31 [0.11–0.85]
P
=0.02) in the high RoPE score group (≥7, n=1221); treatment-by-RoPE score group interaction,
P
=0.12. The RoPE score estimated attributable fraction anticipated the relative risk reduction across all levels of the RoPE score, in both the 3-trial (
r
=0.95,
P
<0.001) and 2-trial (
r
=0.92,
P
<0.001) analyses.

Conclusions:

The RoPE score estimated attributable fraction is highly correlated to the relative risk reduction of device versus medical therapy. This observation suggests the RoPE score identifies patients with cryptogenic stroke who are likely to have a PFO that is pathogenic rather than incidental.
Deep Listening to the Amazon Rainforest through Sonic Architectures
Authors: Forcucci Luca
Published: September 2020

De Rerum Natura is an electroacoustic composition by the author, based on field recordings from the Brazilian Amazon rainforest. The piece is part of wider research from the author that explores the act of listening, associated visual mental imagery and dynamic subjective links between the composer's experience of listening to/recording experience of the original material and the audience's perception of the final composition as it is performed. This article focuses on the author's process of developing De Rerum Natura, based on Deep Listening. De Rerum Natura also examines the merging of the composition with the acoustics of the performance space.
Study in three phases: An Adaptive Sound Installation
Authors: Panariello Claudio
Published: September 2020

Study in three phases is an adaptive site-specific sound installation that includes 22 solenoids placed on metallic arches that surround visitors and react to environmental perturbations, creating a self-regulating soundscape of metallic hits that serves to renew the visitors’ acoustic perspective. Adaptivity is a crucial aspect of the work: Similar perturbations will not generally cause similar reactions from the installation based on past interactions, thus allowing evolution over time to play a key role artistically and technically. This article discusses the author's position on adaptivity in music interaction and composition and reports on the technical and artistic aspects of the installation.
The Role of Upper-Level Coupling on Great Plains Low-Level Jet Structure and Variability
Authors: Burrows D. Alex , Ferguson Craig R. , Bosart Lance F.
Published: September 2020

The Great Plains (GP) southerly nocturnal low-level jet (GPLLJ) is a dominant contributor to the region’s warm-season (May–September) mean and extreme precipitation, wind energy generation, and severe weather outbreaks—including mesoscale convective systems. The spatiotemporal structure, variability, and impact of individual GPLLJ events are closely related to their degree of upper-level synoptic coupling, which varies from strong coupling in synoptic trough–ridge environments to weak coupling in quiescent, synoptic ridge environments. Here, we apply an objective dynamic classification of GPLLJ upper-level coupling and fully characterize strongly coupled (C) and relatively uncoupled (UC) GPLLJs from the perspective of the ground-based observer. Through composite analyses of C and UC GPLLJ event samples taken from the European Centre for Medium-Range Weather Forecasts’ Coupled Earth Reanalysis of the twentieth century (CERA-20C), we address how the frequency of these jet types, as well as their inherent weather- and climate-relevant characteristics—including wind speed, direction, and shear; atmospheric stability; and precipitation—vary on diurnal and monthly time scales across the southern, central, and northern subregions of the GP. It is shown that C and UC GPLLJ events have similar diurnal phasing, but the diurnal amplitude is much greater for UC GPLLJs. C GPLLJs tend to have a faster and more elevated jet nose, less low-level wind shear, and enhanced CAPE and precipitation. UC GPLLJs undergo a larger inertial oscillation (Blackadar mechanism) for all subregions, and C GPLLJs have greater geostrophic forcing (Holton mechanism) in the southern and northern GP. The results underscore the need to differentiate between C and UC GPLLJs in future seasonal forecast and climate prediction activities.
Doing Time in “The Devil’s Chair:” Evaluating Nonjudicial Administrative Decisions to Isolate and Restrain Prisoners and Detainees With Mental Health Disabilities in Jails and Prisons
Authors: Dorfman Deborah A.
Published: September 2020

I address the therapeutic jurisprudence implications of nonjudicial/administrative determinations to impose restrictive behavioral interventions on individuals with mental health disabilities in the jail and prison context. Such restrictive interventions include involuntarily medications, segregation, seclusion and restraints, and other related restrictive measures. I explain why our current policies violate the basic precepts of therapeutic jurisprudence and discuss the value of introducing therapeutic jurisprudence into this process.
Examination of Decision Making and Botched Lethal Injection Executions in Texas
Authors: Harmon Talia Roitberg , Cassidy Michael , Kloch Richelle
Published: September 2020

This research examines the influence of lethal injection drug shortages on Texas criminal justice officials’ decision to change the state’s three-drug lethal injection protocol to the use of pentobarbital as a single drug protocol, without judicial oversight. We analyze data collected under the three- and one-drug protocols from 1982 through 2020 and compare differences in the length of time the lethal injection took, and complications reported by media witnesses. Findings suggest a higher rate of botched executions under the one-drug protocol than the three-drug protocol. We discuss the role compounding pharmacies may play in our results, the impact of this work on the U.S. Supreme Court’s death penalty jurisprudence, and implications concerning the unilateral decision making by Texas state officials.