bluuebunny/crossref_metadata_2025 huggingface dataset:
PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells
Authors: Kaarbø Mari , Mikkelsen Øyvind Løveseter , Malerød Lene , Qu Su , Lobert Viola H. , Akgul Gulcan , Halvorsen Thomas , Mælandsmo Gunhild M. , Saatcioglu Fahri
Published: January 2021

Background: Androgen receptor (AR) and the phosphatidylinositol-3 kinase (PI3K) signaling are two of the most important pathways implicated in prostate cancer. Previous work has shown that there is crosstalk between these two pathways; however, there are conflicting findings and the molecular mechanisms are not clear. Here we studied the AR–PI3K pathway crosstalk in prostate cancer cells in vitro as well as in vivo.

Methods: Quantitative PCR, Western analysis, reporter assays, and proliferation analyses in vitro and in vivo were used to evaluate the effect of PI3K pathway inhibition on AR signaling and cell growth.

Results: Transcriptional activity of AR was increased when the PI3K pathway was inhibited at different levels. In the androgen responsive prostate cancer cell line LNCaP, androgen and the mTOR inhibitor rapamycin synergistically activated androgen target genes. Despite increased androgen signaling, rapamycin treatment reduced LNCaP cell growth; the AR antagonist bicalutamide potentiated this effect. Furthermore, the rapamycin derivative CCI-779 reduced the growth of CWR22 prostate cancer xenografts while increasing AR target gene expression.

Conclusions: These findings suggest that inhibition of the PI3K pathway activates AR signaling. Despite the increase in AR signaling which has proliferative effects, the result of PI3K pathway inhibition is antiproliferative. These findings suggest that the PI3K pathway is dominant over AR signaling in prostate cancer cells which should be considered in developing novel therapeutic strategies for prostate cancer.
Expression Profile of Tyrosine Phosphatases in HER2 Breast Cancer Cells and Tumors
Authors: Lucci Maria Antonietta , Orlandi Rosaria , Triulzi Tiziana , Tagliabue Elda , Balsari Andrea , Villa-Moruzzi Emma
Published: January 2021

Background: HER2-overexpression promotes malignancy by modulating signalling molecules, which include PTPs/DSPs (protein tyrosine and dual-specificity phosphatases). Our aim was to identify PTPs/DSPs displaying HER2-associated expression alterations.

Methods: HER2 activity was modulated in MDA-MB-453 cells and PTPs/DSPs expression was analysed with a DNA oligoarray, by RT-PCR and immunoblotting. Two public breast tumor datasets were analysed to identify PTPs/DSPs differentially expressed in HER2-positive tumors.

Results: In cells (1) HER2-inhibition up-regulated 4 PTPs (PTPRA, PTPRK, PTPN11, PTPN18) and 11 DSPs (7 MKPs [MAP Kinase Phosphatases], 2 PTP4, 2 MTMRs [Myotubularin related phosphatases]) and down-regulated 7 DSPs (2 MKPs, 2 MTMRs, CDKN3, PTEN, CDC25C); (2) HER2-activation with EGF affected 10 DSPs (5 MKPs, 2 MTMRs, PTP4A1, CDKN3, CDC25B) and PTPN13; 8 DSPs were found in both groups. Furthermore, 7 PTPs/DSPs displayed also altered protein level. Analysis of 2 breast cancer datasets identified 6 differentially expressed DSPs: DUSP6, strongly up-regulated in both datasets; DUSP10 and CDC25B, up-regulated; PTP4A2, CDC14A and MTMR11 down-regulated in one dataset.

Conclusions: Several DSPs, mainly MKPs and, unexpectedly, MTMRs, were altered following HER2-modulation in cells and 3 DSPs (DUSP6, CDC25B and MTMR11) were altered in both cells and tumors. Among these, DUSP6, strongly up-regulated in HER2-positive tumors, would deserve further investigation as tumor marker or potential therapy target.
The Pan-Deacetylase Inhibitor Panobinostat Inhibits Growth of Hepatocellular Carcinoma Models by Alternative Pathways of Apoptosis
Authors: Di Fazio Pietro , Schneider-Stock Regine , Neureiter Daniel , Okamoto Kinya , Wissniowski Till , Gahr Susanne , Quint Karl , Meissnitzer Matthias , Alinger Beate , Montalbano Roberta , Sass Gabriele , Hohenstein Bernd , Hahn Eckhart G. , Ocker Matthias
Published: January 2021

Inhibition of deacetylases represents a new treatment option for human cancer diseases. We applied the novel and potent pan-deacetylase inhibitor panobinostat (LBH589) to human hepatocellular carcinoma models and investigated by which pathways tumor cell survival is influenced.

HepG2 (p53wt) and Hep3B (p53null) responded to panobinostat treatment with a reduction of cell proliferation and a significant increase in apoptotic cell death at low micromolar concentrations. Apoptosis was neither mediated by the extrinsic nor the intrinsic pathway but quantitative RT-PCR showed an upregulation of CHOP, a marker of the unfolded protein response and endoplasmic reticulum stress with subsequent activation of caspase 12. Dependent on the p53 status, a transcriptional upregulation of p21cip1/waf1, an increased phosphorylation of H2AX, and an activation of the MAPK pathway were observed. In a subcutaneous xenograft model, daily i.p. injections of 10 mg/kg panobinostat lead to a significant growth delay with prolonged overall survival, mediated by reduced tumor cell proliferation, increased apoptosis and reduced angiogenesis in tumor xenografts. Panobinostat increased the acetylation of histones H3 and H4.

Panobinostat is a well tolerated new treatment option for HCC that activates alternative pathways of apoptosis, also in p53-deficient tumors.
Numerical Modeling of Water and Gas Transport in Compacted GMZ Bentonite under Constant Volume Condition
Authors: Liu Jiang-Feng , Cao Xu-Lou , Ni Hong-Yang , Zhang Kai , Ma Zhi-Xiao , Ma Li-Ke , Pu Hai
Published: January 2021

During deep geological disposal of high-level and long-lived radioactive waste, underground water erosion into buffer materials, such as bentonite, and gas production around the canister are unavoidable. Therefore, understanding water and gas migration into buffer materials is important when it comes to determining the sealing ability of engineered barriers in deep geological repositories. The main aim of our study is to provide insights into the water/gas transport in a compacted bentonite sample under constant volume conditions. The results of our study indicate that water saturation is obtained after 450 hours, which is similar to experimental results. Gas migration testing shows that the degree of water saturation in the samples is very sensitive to the gas pressure. As soon as 2 MPa or higher gas pressure was applied, the water saturation degree decreased quickly. Laboratory experiments indicate that gas breakthrough occurs at 4 MPa, with water being expelled from the downstream side. This indicates that gas pressure has a significant effect on the sealing ability of Gaomizozi (GMZ) bentonite.
Chaos Synchronization of a Finance Chaotic System with an Integral Sliding Mode Controller
Authors: Wang Jingjing , Yang Chunzhi
Published: January 2021

In this paper, an integral sliding mode controller is proposed to realize the synchroniza-tion of a class of finance chaotic systems. First, an integral sliding surface with tanh function is designed. Then, fuzzy logic systems are used to estimate unknown functions, and then based on the Lyapunov stability theorem, the proposed control method can quickly drive the synchroniza-tion error into a small neighborhood of zero, and the range of this neighborhood can be estimated. The simulation results verify that the proposed method in this paper is better than the traditional method.
A Semidynamic Bidirectional Clustering Algorithm for Downlink Cell‐Free Massive Distributed Antenna System
Authors: Qian Panpan , Zhao Huan , Zhu Yanmin , Sun Qiang
Published: January 2021

Cell‐free massive distributed antenna system (CF‐MDAS) can further reduce the access distance between mobile stations (MSs) and remote access points (RAPs), which brings a lower propagation loss and higher multiplexing gain. However, the interference caused by the overlapping coverage areas of distributed RAPs will severely degrade the system performance in terms of the sum‐rate. Since that clustering RAPs can mitigate the interference, in this paper, we investigate a novel clustering algorithm for a downlink CF‐MDAS with the limited‐capacity backhaul. To reduce the backhaul burden and mitigate interference effectively, a semidynamic bidirectional clustering algorithm based on the long‐term channel state information (CSI) is proposed, which has a low computational complexity. Simulation results show that the proposed algorithm can efficiently achieve a higher sum‐rate than that of the static clustering one, which is close to the curve obtained by dynamic clustering algorithm using the short‐term CSI. Furthermore, the proposed algorithm always reveals a significant performance gain regardless of the size of the networks.
[18F]PARPi Imaging Is Not Affected by HPV Status In Vitro
Authors: Guru Navjot , Demétrio De Souza França Paula , Pirovano Giacomo , Huang Cien , Patel Snehal G. , Reiner Thomas
Published: January 2021

Background. Human papillomavirus- (HPV-) associated oropharyngeal squamous cell carcinomas (OPSCCs) are clinically and pathologically distinct from HPV-negative tumors. Here, we explore whether HPV affects functional biomarkers, including γH2AX, RAD51, and PARP1. Moreover, the role of [18F]PARPi as a broadly applicable imaging tool for head and neck carcinomas is investigated. Methods. HPV-positive and HPV-negative cell lines were used to evaluate the γH2AX, RAD51, and PARP1 expression with immunoblotting and immunofluorescence. Effects of external beam ionizing radiation were investigated in vitro, and survival was investigated via colony-formation assay. [18F]PARPi uptake experiments were performed on HPV-negative and HPV-positive cell lines to quantify PARP1 expression. PARP1 IHC and γH2AX foci were quantified using patient-derived oropharyngeal tumor specimens. Results. Differences in DNA repair were detected, showing higher RAD51 and γH2AX expression in HPV-positive cell lines. Clonogenic assays confirm HPV-positive cell lines to be significantly more radiosensitive. PARP1 expression levels were similar, irrespective of HPV status. Consequently, [18F]PARPi uptake assays demonstrated that this tracer is internalized in cell lines independently from their HPV status. Conclusion. The HPV status, often used clinically to stratify patients, did not affect PARP1 levels, suggesting that PARP imaging can be performed in both HPV-positive and HPV-negative patients. This study confirms that the PET imaging agent [18F]PARPi could serve as a general clinical tool for oropharyngeal cancer patients.
Nasogastric Tube Feeding in Older Patients: A Review of Current Practice and Challenges Faced
Authors: Chauhan Devkishan , Varma Surabhi , Dani Melanie , Fertleman Michael B. , Koizia Louis J.
Published: January 2021

Nasogastric tube feeding is an essential way of delivering enteral nutrition when the oral route is insufficient or unsafe. Malnutrition is recognised as a reversible factor for sarcopenia and frailty. It is therefore crucial that malnutrition is treated in older inpatients who have dysphagia and require enteral nutrition. Despite five National Patient Safety Alerts since 2005, “Never Events” related to nasogastric feeding persist. In addition to placement errors, current practice often leads to delays in feeding, which subsequently result in worse patient outcomes. It is crucial that tube placement is confirmed accurately and in a timely way. Medical advancements in this area have been slow to find a solution which meets this need. In this paper, we provide an updated review on the current use of feeding nasogastric tubes in the older population, the issues associated with confirming correct placement, and innovative solutions for improving safety and outcomes in older patients.
The Preference, Effect, and Prognosis of Intra‐Aortic Balloon Counterpulsation in Acute Myocardial Infarction Complicated by Cardiogenic Shock Patients: A Retrospective Cohort Study
Authors: Wang Wenjun , Yang Feifei , Lin Xixiang , Zhong Qin , Li Zongren , Chen Xu , Wang Junfeng , He Kunlun
Published: January 2021

Backgrounds. Intra‐aortic balloon counterpulsation is increasingly used in acute myocardial infarction complicated by cardiogenic shock. The aim of this study was to explore the preference, effect, and prognosis of intra‐aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock patients. Methods. Data of acute myocardial infarction complicated by cardiogenic shock patients at the Fourth Medical Center of PLA General Hospital were collected retrospectively. A propensity score was calculated with a logistic regression which contained clinically meaningful variables and variables selected by Lasso and then used to match the control group. The cumulative incidence curve and Gray’s test were employed to analyse the effect and prognosis of intra‐aortic balloon counterpulsation on mortality. Results. A total of 1962 acute myocardial infarction cases admitted between May 2015 and November 2018 were identified, and 223 cases with acute myocardial infarction complicated by cardiogenic shock were included as the study cohort, which contained 34 cases that received IABP and 189 cases that did not receive IABP. Patients with higher alanine aminotransferase (OR = 1.93, 95% CI 1.29‐2.98), higher triglyceride (OR = 3.71, 95% CI 1.87‐7.95), and higher blood glucose (OR = 1.08, 95% CI 0.99‐1.18) had a higher probability of receiving intra‐aortic balloon counterpulsation. In the propensity score matching analysis, 34 cases received intra‐aortic balloon counterpulsation and 102 matched controls were included in the comparison. By comparing the cumulative incidence of in‐hospital mortality, there was no statistically significant difference between the intra‐aortic balloon counterpulsation group and matched control group (P = 0.454). Conclusion. The use of intra‐aortic balloon counterpulsation may not improve the prognosis of the acute myocardial infarction complicated by cardiogenic shock patients.
The Effect of Hydraulic-Natural Fracture Networks on the Waterflooding Development in a Multilayer Tight Reservoir: Case Study
Authors: Hui Gang , Chen Shengnan , Wang Youjing , Gu Fei
Published: January 2021

An integrated hydraulic fracturing followed by waterflooding was conducted in a heterogeneous sandstone formation in the Northern Shanxi Slop of Ordos Basin in Western China. Water breakthrough quickly occurred, and the underlying mechanism of water breakthrough has not been well understood. Such mechanism needs to be investigated comprehensively from the spatial connectivity of multilayer sand bodies and characterization of hydraulic-natural fracture networks. Here, an integrated approach is proposed to tap the remaining oil in the individual sand layer during the late-stage development of tight sandstone reservoirs. A case study is utilized to demonstrate the applicability of the integrated method. It is found that the six sand layers could be further divided within the target oil layers. These sand layers have a variety of physical and mechanical properties, leading to the asymmetric spatial distribution of hydraulic fractures after performing the integrated fracturing of whole oil layers. The spatial difference of sand bodies conforms to the features of the multiperiod superimposed channel in the sedimentary environment of fan delta front. The natural fractures were generated from the tectonic movement in the Mesozoic period with a dominant orientation of approximately NE 67°. The asymmetric hydraulic fractures propagated and connected with the preexisting natural fractures, forming the intricate natural-hydraulic fracture networks. The water breakthrough pattern in each sand layer is primarily ascribed to the spatial distribution of the hydraulic-natural fracture networks and sedimentary microfacies. The refracturing operations based on the remaining oil distribution in sand layers are proven to be effective in further developing the formation. The average oil production of related wells increased from 0.61 t/d to 2.18 t/d. This practical development strategy provides insights for further development of likewise heterogeneous tight sandstone reservoirs.
Dynamic Large‐Scale Server Scheduling for IVF Queuing Network in Cloud Healthcare System
Authors: Li Yafei , Wang Hongfeng , Li Li , Fu Yaping
Published: January 2021

As one of the most effective medical technologies for the infertile patients, in vitro fertilization (IVF) has been more and more widely developed in recent years. However, prolonged waiting for IVF procedures has become a problem of great concern, since this technology is only mastered by the large general hospitals. To deal with the insufficiency of IVF service capacity, this paper studies an IVF queuing network in an integrated cloud healthcare system, where the two key medical services, that is, egg retrieval and transplantation, are assigned to accomplish in the general hospital, while the routine medical tests are assigned into the community hospital. Based on continuous‐time Markov procedure, a dynamic large‐scale server scheduling problem in this complicated service network is modeled with consideration of different arrival rates of multiple type of patients and different service capacities of multiple servers that can be defined as doctors of the general hospital. To solve this model, a reinforcement learning (RL) algorithm is proposed, where the reward functions are designed for four conflicting subcosts: setup cost, patient waiting cost, penalty cost for unsatisfied patient personal preferences, and medical cost of patient. The experimental results show that the optimal service rule of each server’s queue obtained by the RL method is significantly superior to the traditional service rule.
Experimental Study on Shear Failure Characteristics of Jointed Rock Mass Based on Direct Shear Tests and Digital Image Correction Techniques
Authors: Ren Fenhua , Zhang Liwei , Wu Xinghui , Liu Wensheng
Published: January 2021

The instability of rock engineering is normally dominated by the shear failure of rock mass. The dip angle of discontinuous planes widely existing in rock mass is a key parameter affecting the shear strength and failure mode of jointed rock. This paper aims to investigate the influence of discontinuous joints on the shear failure of rock. Direct shear tests are carried out on rock‐like specimens with discontinuous joints in different dip angles. During the shear tests, the strain field is monitored in real‐time by digital image correction (DIC) technology. Experimental results show that the shear strength, shear strain evolution, and failure mode for the jointed specimens are affected by the dip angles of the discontinuous joints. The maximum shear strain of specimens with joint angles of 45° and 75° increases gradually with the increase of shear loading. The maximum shear strain for the specimens with joint angles of 0°, 15°, 30°, 60°, and 90° increases sharply after the shear load reaches 80% of the peak load. When the joint inclination angle is less than 45°, the crack begins to expand from the joint tip and is interconnected to form a penetrating fracture. When the joint dip angle is greater than 45°, the cracks initiate at the joint tip and then propagate at different paths resulting in multistage shearing and crushing failure.
Online Monitoring and Early Warning of Subsynchronous Oscillation Using Levenberg–Marquardt and Backpropagation Algorithm Combined with Sensitivity Analysis and Principal Component Analysis
Authors: Wu Lingjie , Zhou Ming , Wang Yanwen , Wang Le , Tian Xu
Published: January 2021

Over the past few years, with the access of large-scale new energy sources, the problem of subsynchronous oscillation (SSO) in power systems has presented a novel multisource and multitransformation form, which may be significantly threatening. Conventional control and protection methods primarily give rise to device protection actions in the presence of severe oscillation. On the whole, online monitoring only identifies the frequency and amplitude, whereas it cannot identify the attenuation factor. Moreover, the determination of the warning threshold is more dependent on human experience, so the reliability and rapidity of the early warning cannot be ensured. This study conducts an in-depth investigation of the wind-thermal power bundling and extreme high-voltage alternating current- (AC-) direct current (DC) hybrid transmission system. The major factors of SSO using this system are unclear, which brings difficulties to effective monitoring. Given the mentioned problems, a method combining Levenberg–Marquardt- (LM-) Backpropagation (BP) machine learning and Sensitivity Analysis (SA) and principal component analysis (PCA) is developed. First, the sensitivity analysis of each factor in the system is conducted to identify the major factors of SSO. Subsequently, the historical sample data are reduced with the principal component analysis to reduce the redundancy, which is adopted to train the regression model to determine the attenuation factor and frequency and then send them to the classifier for classification to complete the task of the assessment model. When a novel data signal is uploaded, the assessment model identifies the attenuation factor and frequency and subsequently determines the presence of SSO. Accordingly, an early warning is conducted. The system's refined simulation model and machine learning model verify the effectiveness of the method.
Right/Left-Handed Leaky Rectangular Waveguide with Broadside Radiation Property
Authors: Huo Xingying , Li Zheng
Published: January 2021

When a leaky rectangular waveguide is used to realize the coverage of radio wave in the small confined spaces, there will be a shadow region, which influences the coverage performance. In this paper, the traditional leaky rectangular waveguide is improved according to the principle of the equivalent circuit, by cutting interdigital slots in the upper wall and adding uniserial metal vias between the upper and lower walls of the rectangular waveguide. Thus, the right/left-handed transmission line property is introduced to the periodic leaky-waveguide (LWG), realizing the broadside radiation with relatively high gain (15.7 dBi), good cross polarization (−50 dB), and narrow half-power beamwidth (10.9°) at 6.97 GHz and providing a method for a uniform coverage of the radio wave in rooms without a shadow region.
Characteristics of Obstetric and Iatrogenic Urogenital Fistulas in Burkina Faso: A Cross-Sectional Study
Authors: Kabore Fasnéwindé Aristide , Nama Stéphanie Dominique Amida , Ouedraogo Boureima , Kabore Moussa , Ouattara Adama , Kirakoya Brahima , Karsenty Gilles
Published: January 2021

Objective. To compare the sociodemographic, clinical, and therapeutic characteristics of obstetric urogenital fistulas (OF) and iatrogenic urogenital fistulas (IF) treated in seven centers in Burkina Faso. Material and Methods. We carried out a cross-sectional study over a seven years’ period (January 1, 2010 to December 31, 2016). We considered as iatrogenic all urogenital fistulas (UGF) occurred after elective caesarean section, gynecologic surgery (hysterectomy, myomectomy, and prolapse repair), or induced abortion. UGF following vaginal delivery after prolonged labor without obstetric maneuvers or caesarean section were considered as obstetric. UGF caused by other mechanisms (emergency caesarian section, congenital, and traumatic) were excluded from this study. The statistical analysis was carried out using version 14 of the STATA software. A logistic regression model was used to compare the two groups. Results. 310 cases of UGF were included. IF accounted for 25.8% (n = 80) versus 74.2% (n = 230) for OF. The median age was 35 years for IF and 35.38 years for OF. The vesicovaginal fistulas were predominant (74.5%) in the two groups. All circumferential fistulas were found in the OF group. OF were frequently associated with residence in rural areas (OR = 1.8; CI = [1.05–3.1]), low level of education (OR = 5.4; CI = [2.3–12.9]), and a height under 158 cm (OR = 3.4 CI = [1.7–6.6]). Vaginal sclerosis was less common among IF (OR = 2.2; CI = [1–4.6]). The failure of surgical treatment after 3 months was more associated with OF (OR = 4.7; CI = [1.1–20.5]). Conclusion. OF were the most common, frequently affecting short women living in rural area and with low level of schooling. Fistulas were also more severe in the OF group. IF gave better results after surgical repair.
Surgical Treatment of Severe Idiopathic Flexible Flatfoot by Evans–Mosca Technique in Adolescent Patients: A Long-Term Follow-Up Study
Authors: De Luna Vincenzo , De Maio Fernando , Caterini Alessandro , Marsiolo Martina , Petrungaro Lidio , Ippolito Ernesto , Farsetti Pasquale
Published: January 2021

Flexible idiopathic flatfoot is very common in growing age and rarely causes pain or disability. Surgery is indicated only in severe symptomatic cases that are resistant to conservative treatment, and numerous surgical procedures have been proposed. Lateral column calcaneal lengthening as described by Evans and modified by Mosca is a widely used surgical technique for the correction of severe symptomatic flexible flatfoot. In the present study, we report the long-term clinical and radiographic results in 14 adolescent patients (mean age: 12.8 years) affected by severe symptomatic flexible flatfoot, surgically treated by Evans–Mosca procedure, for a total of 26 treated feet (12 cases bilateral and 2 unilateral). In all cases, surgery was indicated for the presence of significant symptoms resistant to nonsurgical management. Clinical evaluation was made according to the American Orthopedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale, the Foot and Ankle Disability Index (FADI) Score, and Yoo et al.’s criteria. Radiographic evaluation was made using anteroposterior and lateral weight-bearing radiographs of the feet to evaluate Meary’s angle and Costa–Bertani’s angle and to evaluate possible osteoarthritic changes in the midtarsal joints. At follow-up (mean: 7 years and 7 months), we observed a satisfactory result in all patients. The mean average score of the AOFAS Ankle-Hindfoot Scale improved from 60.03 points to 95.26; the mean FADI score improved from 71.41 to 97.44; and according to Yoo et al.’s criteria, the average clinical outcome score was 10.96. At radiographic examination, nonunion of the calcaneal osteotomy was never observed. Meary’s angle improved from an average preoperative value of 25° to 1.38° at follow-up; Costa–Bertani’s angle improved from an average preoperative value of 154.2° to 130.9° at follow-up. In no case, significant radiographic signs of midtarsal joint arthritis were observed. According to our results, we believe that Evans–Mosca technique is a valid option of surgical treatment for severe idiopathic flexible flatfoot and allows a satisfactory correction of the deformity with a low rate of complications.
Four-Rooted Maxillary First Molars: A Systematic Review and Meta-Analysis
Authors: Magnucki Gabriel , Mietling Sven V. K.
Published: January 2021

Objectives. The majority of human maxillary first molars is usually described as having three roots, but different morphologies were documented in several studies and case reports. One very rare and less investigated anatomical anomaly is the occurrence of four radicular structures in the upper first molars. This communication aimed to define the prevalence of four-rooted maxillary first molars on a meta-analytical basis. The external and internal morphology of these teeth was described by the collection of published case reports. Materials and Methods. Six electronic databases were accessed to collect case reports dealing with four-rooted maxillary first molars, as well as population-based cone-beam computed tomography (CBCT) studies. Afterward, the publications were selected according to predefined inclusion/exclusion criteria and evaluated using the Joanna Briggs Institute Critical Appraisal tool. The teeth of the chosen case reports were then independently analyzed by two dental professionals according to different dental classifications. Furthermore, the population studies were meta-analyzed to calculate the global and regional prevalence of four-rooted maxillary molars. Results. Included were forty-nine population-based CBCT studies containing 26663 maxillary first molars. Upon these data, the global incidence of four-rooted maxillary molars was meta-analytically determined as 0.047% (95%-CI:0.011–0.103%). In combination with the case reports, it was pointed out that this anomaly is distributed worldwide. Furthermore, forty-eight case reports were included containing fifty-three maxillary molars with four roots. The analyzed teeth exhibited Versiani´s pulpal chamber floor Types A and B. The majority of four-rooted maxillary first molars were classified as Type I regarding Christie's configuration. But, also 7.54% of the altered teeth could not be described by this classification. 62.34% exhibited four root canals, but also variations with five, six, or seven canals were identified. Furthermore, a significant difference was found in the occurrence rate between male and female patients. Conclusion. Due to the worldwide occurrence, dental professionals should be aware of this rare anomaly to avoid treatment errors, especially during endodontic or surgical therapies.
Simvastatin Inhibits CYR61 Expression in Orbital Fibroblasts in Graves’ Ophthalmopathy through the Regulation of FoxO3a Signaling
Authors: Wei Yi-Hsuan , Liao Shu-Lang , Wang Chia-Chun , Wang Sen-Hsu , Tang Wan-Chun , Yang Chang-Hao
Published: January 2021

Graves’ ophthalmopathy (GO), which is characterized by orbital tissue inflammation, expansion, and fibrosis, is the ocular manifestation in 25% to 50% of patients with Graves’ disease. As the pathology of GO is driven by autoimmune inflammation, many proinflammatory cytokines/chemokines, including TNF-α, IL-1β, IL-6, and CCL20, are crucial in the pathogenesis of GO to activate the orbital fibroblasts. Cysteine-rich protein 61 (CYR61), which is known to regulate cell proliferation, adhesion, and migration, plays a proinflammatory role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis. CYR61 was considered a potential biomarker of GO in recent studies. Statins, which are cholesterol-lowering drugs, were found to reduce the risk of GO, probably through their anti-inflammatory and immunomodulatory effects. In this study, we established a link between CYR61 and statins in the pathogenesis and potential treatment for GO. Firstly, our data showed the overexpression of CYR61 in the orbital tissue (

n
=
4

) and serum specimens (

n
=
6

) obtained from the patients with inactive GO. CYR61 could induce the production of IL-6 and CCL20 in cultured GO orbital fibroblasts. The expression of CYR61 in cultured GO orbital fibroblasts was upregulated via TNF-α stimulation. Secondly, we pretreated cultured GO orbital fibroblasts using simvastatin, a statin, followed by TNF-α stimulation. The data revealed that simvastatin could inhibit TNF-α-induced CYR61 expression by modulating the activity of transcription factor FoxO3a. Our results provided insights into some cellular mechanisms that may explain the possible protective effects of simvastatin against the development of GO.
Translational Regulation of Cancer Metastasis
Authors: Micalizzi Douglas S. , Ebright Richard Y. , Haber Daniel A. , Maheswaran Shyamala
Published: January 2021

Deregulation of the mRNA translational process has been observed during tumorigenesis. However, recent findings have shown that deregulation of translation also contributes specifically to cancer cell spread. During metastasis, cancer cells undergo changes in cellular state, permitting the acquisition of features necessary for cell survival, dissemination, and outgrowth. In addition, metastatic cells respond to external cues, allowing for their persistence under significant cellular and microenvironmental stresses. Recent work has revealed the importance of mRNA translation to these dynamic changes, including regulation of cell states through epithelial-to-mesenchymal transition and tumor dormancy and as a response to external stresses such as hypoxia and immune surveillance. In this review, we focus on examples of altered translation underlying these phenotypic changes and responses to external cues and explore how they contribute to metastatic progression. We also highlight the therapeutic opportunities presented by aberrant mRNA translation, suggesting novel ways to target metastatic tumor cells.
The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas
Authors: Makohon-Moore Alvin P. , Lipson Evan J. , Hooper Jody E. , Zucker Amanda , Hong Jungeui , Bielski Craig M. , Hayashi Akimasa , Tokheim Collin , Baez Priscilla , Kappagantula Rajya , Kohutek Zachary , Makarov Vladimir , Riaz Nadeem , Postow Michael A. , Chapman Paul B. , Karchin Rachel , Socci Nicholas D. , Solit David B. , Chan Timothy A. , Taylor Barry S. , Topalian Suzanne L. , Iacobuzio-Donahue Christine A.
Published: January 2021

Purpose:

Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (n = 3), uveal (n = 2), and acral (n = 2) melanoma subtypes.

Experimental Design:

Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression.

Results:

For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance.

Conclusions:

In 4 patients who received immunotherapy, we found 1–3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective.
Point of Care Ultrasonography for Objective Assessment of Heart Failure: Integration of Cardiac, Vascular, and Extravascular Determinants of Volume Status
Authors: Koratala Abhilash , Kazory Amir
Published: January 2021

Background: Lingering congestion portends poor outcomes in patients with heart failure (HF) and is a key target in their management. Studies have shown that physical exam has low yield in this setting and conventional methods for more precise assessment and monitoring of volume status (e.g., body weight, natriuretic peptides, and chest radiography) have significant inherent shortcomings. Summary: Point of care ultrasonography (POCUS) is a noninvasive versatile bedside diagnostic tool that enhances the sensitivity of conventional physical examination to gauge congestion in these patients. It also aids in monitoring the efficacy of decongestive therapy and bears prognostic significance. In this narrative review, we discuss the role of focused sonographic assessment of the heart, venous system, and extravascular lung water/ascites (i.e., the pump, pipes, and the leaks) in objective assessment of fluid volume status. Key Messages: Since each of the discussed components of POCUS has its limitations, a combinational ultrasound evaluation guided by the main clinical features would be the key to reliable assessment and effective management of congestion in patients with HF.
Anti-N-Methyl-D-Aspartate Receptor Encephalitis with Decrease in Blood Flow in Cerebellum
Authors: Obara Koji , Ono Tomoko , Toyoshima Itaru
Published: January 2021

In anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, progressive cerebellar atrophy potentially leads to severe sequelae. We encountered a patient with anti-NMDAR antibody encephalitis who showed a decrease of blood flow in the cerebellum. A 15-year-old girl presented with consciousness disturbance. Influenza encephalopathy was suspected, and she was treated with glucocorticoid pulse therapy, high-dose intravenous immunoglobulins, and plasma exchange sequentially. She subsequently underwent left oophorectomy due to the presence of anti-NMDAR antibodies and a left ovarian teratoma. In spite of the surgery, her neuropsychiatric symptoms persisted, and she recovered slowly after the introduction of oral methotrexate (MTX). Sequential cerebral blood flow monitoring with single-photon emission computed tomography showed marked cerebellar hypoperfusion. Although mild impairments including working memory and verbal fluency persisted, she eventually returned to high school 3 years after onset. Profound cerebellar hypoperfusion including lobules VI and VII may be the reason for her working memory impairment and speaking problems. Oral MTX may be a promising alternative treatment for some refractory cases of anti-NMDAR encephalitis.
Clinical and Histopathological Features of Corneal Primary Acquired Melanosis and Melanoma
Authors: Yeung Aaron , Uner Ogul E. , Wells Jill R. , Grossniklaus Hans E.
Published: January 2021

Aim: The aim of this study is to describe the clinical and pathologic features of corneal primary acquired melanosis (PAM) and melanoma. Methods: We describe 3 cases in total: two cases of corneal melanomas and 1 case of corneal PAM. The eyes were processed routinely for histopathological examination. Clinical histories, treatments, and outcomes were reviewed. Results: Corneal melanomas arose from recurrence of conjunctival melanoma or conjunctival PAM at the limbus. One patient had a recurrence after excision of a limbal melanoma, another had a de novo corneal melanoma, and the last patient had corneal PAM in the setting of conjunctival PAM with atypia. All lesions were excised with adjuvant alcohol debridement and cryotherapy with no recurrence ranging from 1 week to 8 years. Conclusions: Corneal melanomas arise at the limbus from corneal PAM or conjunctival atypia. They can appear after excisional removal of a conjunctival melanoma. Surgical excision with alcohol debridement and adjuvant cryotherapy is successful.
Adalimumab in the Management of Isotretinoin-Induced Acne Fulminans: Report of a Case
Authors: Marasca Claudio , Fabbrocini Gabriella , Abategiovanni Luisa , Camela Elisa , Nocerino Mariateresa , Di Guida Adriana , De Fata Salvatores Gaia
Published: January 2021

Acne fulminans (AF) is a rare, acute, and severe form of acne vulgaris often associated with systemic symptoms. Its treatment is challenging and controversial. We report a case of isotretinoin-induced AF (IIAF) in a 12-year-old boy resistant to traditional therapies (oral steroids and isotretinoin). The patient was successfully treated with adalimumab that can be considered an effective off-label option in the treatment of resistant IIAF in children.
2021 European Thyroid Association Guideline on Thyroid Disorders prior to and during Assisted Reproduction
Authors: Poppe Kris , Bisschop Peter , Fugazzola Laura , Minziori Gesthimani , Unuane David , Weghofer Andrea
Published: January 2021

Severe thyroid dysfunction may lead to menstrual disorders and subfertility. Fertility problems may persist even after restoring normal thyroid function, and then an assisted reproductive technology (ART) may be a solution. Prior to an ART treatment, ovarian stimulation is performed, leading to high oestradiol levels, which may lead to hypothyroidism in women with thyroid autoimmunity (TAI), necessitating levothyroxine (LT4) supplements before pregnancy. Moreover, women with the polycystic ovarian syndrome and idiopathic subfertility have a higher prevalence of TAI. Women with hypothyroidism treated with LT4 prior to ART should have a serum TSH level <2.5 mIU/L. Subfertile women with hyperthyroidism planning an ART procedure should be informed of the increased risk of maternal and foetal complications, and euthyroidism should be restored and maintained for several months prior to an ART treatment. Fertilisation rates and embryo quality may be impaired in women with TSH >4.0 mIU/L and improved with LT4 therapy. In meta-analyses that mainly included women with TSH levels >4.0 mIU/L, LT4 treatment increased live birth rates, but that was not the case in 2 recent interventional studies in euthyroid women with TAI. The importance of the increased use of intracytoplasmic sperm injection as a type of ART on pregnancy outcomes in women with TAI deserves more investigation. For all of the above reasons, women of subfertile couples should be screened routinely for the presence of thyroid disorders.
The Effect of Reflexology on Lactation in Women Who Had Cesarean Section: A Randomized Controlled Pilot Study
Authors: Aksu Sevde , Palas Karaca Pelin
Published: January 2021

Aim: The research was conducted as a randomized controlled pilot study to evaluate the effects of reflexology on lactation in mothers who delivered by cesarean section (CS). Methods: A single-blind randomized controlled experimental study was conducted with a total of 60 postpartum women in the reflexology application (n = 30) and control groups (n = 30). After the CS, the mothers in the control group were given approximately 3-h routine nursing care after recovering from the effects of anesthesia; the introductory information form was applied, and the Breastfeeding Charting System and Documentation Tool (LATCH) and visual analog scale (VAS) for the signs of the onset of lactation were implemented on the first and second days. Reflexology was applied to the women in the intervention group after an average of 3 h following the mother’s condition had become stable and she had recovered from the effects of anesthesia. Reflexology was applied a total of 20 min – 10 min for the right foot, 10 min for the left foot – twice a day with 8-h intervals on the first and second days after CS. After the last reflexology application, the LATCH and VAS for the signs of the onset of lactation were applied. Results: Of the women, 70% breastfed their babies within 60 min after delivery; 46.7% of the mothers received breastfeeding training and 81.7% needed support for breastfeeding after the CS. The LATCH breastfeeding scores of the women in the intervention group on both days were significantly higher compared to those of the women in the control group (p < 0.001). On the first day after the CS, apart from breast pain, there was no significant difference between the two groups in terms of breast heat and breast tension (p > 0.05). On the second day after the CS, apart from breast tension, there was no significant difference between the groups in terms of breast heat and breast pain (p < 0.05). In the study, women in the intervention group were found to have higher scores in terms of all three symptoms compared to the control group (p < 0.05). Conclusions: In the study, it was determined that LATCH scores and signs of the onset of breastfeeding increased in the mothers who received reflexology after CS.
Geeignete Messzeitpunkte in der Psychotherapieevaluation: Ein Vorschlag
Authors: Geissner Edgar , Ivert Petra Maria , Schmitt Manfred
Published: January 2021

Untersucht man Therapieverläufe nicht nur zwischen unmittelbarem Beginn und Beendigung, können Fortschritte be­reits zwischen Anmeldung und Beginn, noch ohne Intervention, aufgezeigt werden. Diese t0-t1-Veränderungen werden anhand eigener Befunde diskutiert: Ist der Vergleich Beginn (t1) – Ende der Therapie (t2) bzw. Katamnese (t3) sinnvoll, oder erfordert die angemessene Erfolgsbeurteilung nicht gerade Anmeldezeitpunkt t0? Wir plädieren für t0. (1) Anmeldung (t0) impliziert eine ausgeprägte, realistische Symptomschilde­rung, (2) positive Erwartungen zur erfolgreichen Behandlung verbessern Messwerte zu t1 (Aufnahme), (3) Aufnahmezeitpunkt t1 ist durch Sicherheitssignale der Klinik/der Behandler beeinflusst, Patientenratings – z.B. bei Angst – sind geringer (Kontextfaktoren), (4) Regression zur Mitte relativiert die Aussagekraft eines Einzelmesszeitpunkts: Hohe Messwerte dort fallen zu einem zweiten Zeitpunkt geringer aus. Um dies zu kontrollieren, müssen zu t0 (in geringem Abstand) 2 Messungen durchgeführt werden, nämlich t01 und t02. In der Praxis dient das Intervall t02–t2 zur geeigneten Erfolgsbeurteilung, aber auch t02–t3 sollte, wenn möglich, Auswertungsroutine sein. Einzelfallbeurteilungen erfordern die Berücksichtigung kritischer Differenzen, um messfehlerbereinigte Unterschiede zu sichern (Beispielerläuterung). Die Möglichkeit erweiterter Auswertung mittels Ausschluß nichtpathologischer Werte, der vereinfachten Auswertung mittels Cutoff-Bestimmung und einige Praxishinweise komplettieren die Arbeit. Unspezifische t0–t1-Veränderungen bedeuten keine Relativierung der Ergebnisse aktiver Intervention (t1–t2), sind vielmehr Bestandteil der Gesamttherapie.
Development and Validation of a Simplified Probability Assessment Score Integrated With Age‐Adjusted
d
‐Dimer for Diagnosis of Acute Aortic Syndromes
Authors: Morello Fulvio , Bima Paolo , Pivetta Emanuele , Santoro Marco , Catini Elisabetta , Casanova Barbara , Leidel Bernd A. , de Matos Soeiro Alexandre , Nestelberger Thomas , Mueller Christian , Grifoni Stefano , Lupia Enrico , Nazerian Peiman
Published: January 2021

Background

When acute aortic syndromes (AASs) are suspected, pretest clinical probability assessment and
d
‐dimer (DD) testing are diagnostic options allowing standardized care. Guidelines suggest use of a 12‐item/3‐category score (aortic dissection detection) and a DD cutoff of 500 ng/mL. However, a simplified assessment tool and a more specific DD cutoff could be advantageous.

Methods and Results

In a prospective derivation cohort (n=1848), 6 items identified by logistic regression (thoracic aortic aneurysm, severe pain, sudden pain, pulse deficit, neurologic deficit, hypotension), composed a simplified score (AORTAs) assigning 2 points to hypotension and 1 to the other items. AORTAs≤1 and ≥2 defined low and high clinical probability, respectively. Age‐adjusted DD was calculated as years/age × 10 ng/mL (minimum 500). The AORTAs score and AORTAs≤1/age‐adjusted DD rule were validated in 2 patient cohorts: a high‐prevalence retrospective cohort (n=1035; 22% AASs) and a low‐prevalence prospective cohort (n=447; 11% AASs) subjected to 30‐day follow‐up. The AUC of the AORTAs score was 0.729 versus 0.697 of the aortic dissection detection score (
P
=0.005). AORTAs score assessment reclassified 16.6% to 25.1% of patients, with significant net reclassification improvement of 10.3% to 32.7% for AASs and −8.6 to −17% for alternative diagnoses. In both cohorts, AORTAs≥2 had superior sensitivity and slightly lower specificity than aortic dissection detection ≥2. In the prospective validation cohort, AORTAs≤1/age‐adjusted DD had a sensitivity of 100%, a specificity of 48.6%, and an efficiency of 43.3%.

Conclusions

AORTAs is a simplified score with increased sensitivity, improved AAS classification, and minor trade‐off in specificity, amenable to integration with age‐adjusted DD for diagnostic rule‐out.