bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of complement 3 in renin generation during the differentiation of mesenchymal stem cells to smooth muscle cells
Authors: Chen Lan , Fukuda Noboru , Shimizu Shoichi , Kobayashi Hiroki , Tanaka Sho , Nakamura Yoshihiro , Matsumoto Taro , Abe Masanori
Published: March 2020

We showed that increased expression of complement 3 (C3) induces dedifferentiation of mesenchymal cells and epithelial mesenchymal transition, which activate the local renin-angiotensin system (RAS) that contributes to cardiovascular and renal remodeling in spontaneously hypertensive rats (SHRs). In the present study, to investigate contributions of C3 to the development of the pathogenesis of hypertension, we evaluated the formation of renin-producing cells and roles of C3 in renin generation during differentiation of primary bone marrow-mesenchymal stem cells (MSCs) from C57BL/6 mice, Wistar-Kyoto (WKY) rats, and SHRs to smooth muscle cells (SMCs) with transforming growth factor-β1. The expression of renin transiently increased with increases in transcription factor liver X receptor α (LXRα), and expression of C3 and Krüppel -like factor 5 (KLF5) increased during differentiation of MSCs from C57BL/6 mice, WKY rats, and SHRs to SMCs. Exogenous C3a stimulated renin and LXRα expression accompanied by nuclear translocation of LXRα. C3a receptor antagonist SB290157 suppressed renin and LXRα expression, with inhibition of nuclear translocation of LXRα during the differentiation of mouse MSCs to SMCs. The expression of C3 and KLF5 was significantly higher in the differentiated cells from SHRs compared with the cells from WKY rats during differentiation. Renin-producing cells were formed during differentiation of MSCs to SMCs, and renin generation was observed in undifferentiated SMCs, in which transient expression of renin in the differentiated cells with lower differentiation stage was stronger from SHRs than that from WKY rats. Expression and nuclear localization of LXRα in the differentiated cells from SHRs were stronger than that from WKY rats. C3 was important in forming and maintaining this undifferentiated state of SMCs from MSCs to generate renin with increases in transcription factor LXRα and KLF5. Increases in C3 expression maintain the undifferentiated state of SMCs from MSCs to generate renin that activates RAS and contributes to the pathogenesis of hypertension in SHRs.
Neurocognitive Complications after Ventricular Neuroendoscopy: A Systematic Review
Authors: Soleman Jehuda , Guzman Raphael
Published: March 2020

In recent years, neuroendoscopic treatment of hydrocephalus and various ventricular pathologies has become increasingly popular. It is considered by many as the first-choice treatment for the majority of these cases. However, neurocognitive complications following ventricular neuroendoscopic procedures may occur leading mostly to amnesia, which might have a grave effect on the patient’s quality of life. Studies assessing neurocognitive complications after ventricular neuroendoscopic procedures are sparse. Therefore, we conducted a systematic review assessing the available literature of neurocognitive complications and outcome after ventricular neuroendoscopy. Of 1216 articles screened, 46 were included in this systematic review. Transient and permanent neurocognitive complications in 2804 ventricular neuroendoscopic procedures occurred in 2.0% (n=55) and 1.04% (n=28) of the patients, respectively. Most complications described are memory impairment, followed by psychiatric symptoms (psychosyndrome), cognitive impairment not further specified, declined executive function, and confusion. However, only in 20% of the series describing neurocognitive complications or outcome (n=40) was neurocognition assessed by a trained neuropsychologist in a systematic manner. While in most of these series only a part of the included patients underwent neuropsychological testing, neurocognitive assessment was seldom done pre- and postoperatively, long-term follow up was rare, and patient’s cohorts were small. A paucity of studies analyzing neurocognitive complications and outcome, through systematic neuropsychological testing, and the correlation with intraoperative lesions of neuronal structures (e.g., fornix) exists in the literature. Therefore, the neurocognitive and emotional morbidity after ventricular neuroendoscopic procedures might be underestimated and warrants further research.
Perspectives in HPV Secondary Screening and Personalized Therapy Basing on Our Understanding of HPV-Related Carcinogenesis Pathways
Authors: Celewicz Aleksander , Celewicz Marta , Michalczyk Michał , Rzepka Rafał
Published: March 2020

As cervical cancer is one of the most common malignancies in women worldwide even with present screening methods, the incidence in most developed countries is not decreasing for the last 15-20 years. A shift has been observed in the age of diagnosis in favour of younger women, and treatment of already developed cervical cancer is a challenge for surgeons. It is imperative to find new diagnostic methods for accurately pointing out patients at high risk of developing malignant disease and developing personalized treatment. Since cervical cancer is almost exclusively associated with HPV infection, understanding changes happening in an infected cell may prove invaluable for search of such methods, but it may also prove helpful in the diagnosis and treatment of other anogenital and nasopharyngeal region cancers. This review follows HPV-related changes in infected cell biology to point what potential markers and targets for therapy are in option when dealing with HPV-related diseases.
Pain Relieving Effect of Intraoperative Chemical Splanchnicectomy of Celiac Ganglions in Patients with Resectable Pancreatic or Gastric Masses: A Randomized Clinical Trial
Authors: Vahedian Jalal , Saraee Amir , Baghai Wadji Massoud , Safari Saeed , Chavoshi Khamneh Abdolhamid
Published: March 2020

Background. Trials of intraoperative chemical splanchnicectomy during resection of pancreatic and gastric masses resulted in significant difference in a patient’s postoperative pain. This study aims to determine if splanchnicectomy by alcohol neurolysis can relieve postoperative pain after gastrectomy and Whipple surgery. The study explores differences in outcomes at first four months after surgery. Methods. Fifty-eight patients with gastric and 60 patients with pancreatic resectable masses were included (28 were lost to follow-up). Each randomized in control and intervention subgroups. Intervention subgroups underwent chemical blockage of celiac ganglions by ethanol injection at both sides of suprapancreatic aorta. Participants were asked to report their pain intensity according to the Visual Analogue Scale (VAS) at specific times. Result. The overall postoperative pain of injected Whipple and gastrectomy subgroups was lower than the noninjected Whipple and gastrectomy subgroups (p<0.001). The pain-modifying effect of the injection was not different between Whipple and gastrectomy groups (p=0.125) Conclusion. Splanchnicectomy is recommended for pain reduction after abdominal operations. Perspective. This article presents positive effect of intraoperative chemical splanchnicectomy during resection of pancreatic and gastric masses on postoperative pain. This is an easy, effective, safe, and inexpensive procedure recommended for all operable gastric or pancreatic masses to palliate the pain degree.
The Prevalence and Correlates of Social Anxiety Symptoms among People with Schizophrenia in Ethiopia: An Institution-Based Cross-Sectional Study
Authors: Kibru Boki , Tesfaw Getachew , Demilew Demeke , Salelew Endalamaw
Published: March 2020

Background. The comorbidity of social anxiety disorder is very common in schizophrenia patients and affects almost all age groups. This social anxiety disorder negatively impacts the quality of life, medication adherence, and treatment outcomes of people with schizophrenia. It is not well recognized in clinical settings. Therefore, assessing social anxiety symptoms and its associated factors was significant to early intervention and management of schizophrenia patients in Ethiopia. Methods. An institution-based cross-sectional study was conducted at Amanuel Mental Specialized Hospital in Addis Ababa, Ethiopia. Data collectors randomly recruited 423 schizophrenic patients by using the systematic sampling technique. A face-to-face interviewer-administered questionnaire was used to collect data. The standardized Liebowitz Social Anxiety Scale (LSAS) was employed to assess individual social anxiety symptoms. We computed bivariate and multivariate binary logistic regressions to identify factors associated with social anxiety symptoms. Statistical significance was declared at p<0.05. Results. The prevalence of social anxiety symptoms was 36.2% (95% CI: 31.50, 40.80). Male sex (AOR=2.03, 95% CI: 1.20, 3.44), age of onset of schizophrenia (AOR=1.91, 95% CI:1.17, 3.12), positive symptoms (AOR=0.75, 95% CI:0.67, 0.83), depression/anxiety symptoms (AOR=1.29, 95% CI: 1.18, 1.41), number of hospitalizations (AOR=2.80, 95% CI:1.32, 5.80), and suicidal ideation (AOR=0.44, 95% CI: 0.26, 0.74) were factors significantly associated with social anxiety symptoms at p<0.001, whereas poor social support (AOR=5.23, 95% CI:2.03, 14.70) and suicide attempts (AOR=1.93, 95% CI: 1.14, 3.26) were statistically associated with social anxiety symptoms at p<0.01. Conclusion. The prevalence of social anxiety symptoms among schizophrenia patients was found to be high. Timely treatment of positive and depression/anxiety symptoms and suicide risk assessments and interventions need to be done to manage the problems.
Association between Resting Energy Expenditure and Heat Pattern in Traditional Medicine
Authors: Mun Sujeong , Bae Kwang-Ho , Park Kihyun , Lee Siwoo
Published: March 2020

Many symptoms of heat pattern (HP) in traditional medicine are related to thermoregulation; however, research on the association between energy expenditure characteristics and HP is limited. We aimed to study the association between HP and resting energy expenditure (REE). A total of 109 participants were divided into the HP and non‐HP groups based on a self‐administered questionnaire and their REE was measured using an indirect calorimeter. Multiple logistic regression models were used to calculate the odds ratio (OR) of HP according to the level of REE. No significant differences in age, anthropometric, and body composition characteristics were observed between the HP and the non‐HP groups. The likelihood of having an HP significantly increased with higher REE after adjustment for fat‐free mass (OR 1.22 [95% CI 1.03–1.46]) and also after additional adjustment for sex and age (OR 1.21 [95% CI 1.01–1.46]). These results suggest that increased REE could be a biological characteristic of HP. Future studies are necessary to investigate the underlying mechanisms associated with the differing energy expenditure in HP.
Adaptive Fault Compensation and Disturbance Suppression Design for Nonlinear Systems with an Aircraft Control Application
Authors: Yao X. , Yang Y.
Published: March 2020

A comprehensive adaptive compensation control strategy based on feedback linearization design is proposed for multivariable nonlinear systems with uncertain actuator fault and unknown mismatched disturbances. Firstly, the linear dynamic system is obtained through nonlinear feedback linearization, and the dynamic model of the mismatched disturbances as well as its relevance to the nonlinear system is given. The effect of disturbances on the system output is suppressed with the basic controller of the linearized system. Then, a direct adaptive controller is developed for the multiple uncertain actuator faults. Finally, an integrated algorithm based on adaptive weighted fusion could provide an effective compensation for the effect of multiple uncertain faults and mismatched disturbances. Thus, the stability and asymptotic tracking performance of the closed-loop system are ensured. The feasibility and performance of the proposed control strategy are validated by the numerical simulation results.
Laboratory Evaluation and Construction of Fully Recycled Low‐Temperature Asphalt for Low‐Volume Roads
Authors: Raab Christiane , Partl Manfred N.
Published: March 2020

Growing economy and increasing pollution evoke the need for more environmentally friendly road construction techniques and the saving of natural resources. In this context, cold recycling plays an important role since, on the one hand, it allows to reduce CO2 emissions drastically and, on the other hand, it offers a variety of opportunities for high percentages of recycling. Inspired by experience in Sweden, the international project “Optimal Recycling of Reclaimed Asphalts for low‐traffic Pavement” (ORRAP) for low‐volume roads in the Upper Rhine region aims to develop and establish a new strategy for 100% reclaimed asphalt pavement (RAP) at ambient temperature (20°C) without adding virgin bituminous binders or rejuvenators. The still ongoing research project involves laboratory experiments as well as in situ test sections. The link between small‐scale laboratory experiments and in situ testing is provided by medium‐scale traffic simulation in the laboratory. This paper describes results from medium‐scale compaction in the laboratory using different methods as well as traffic simulation with a medium‐scale mobile traffic load simulator. The results show that compaction in the laboratory at ambient temperature (20°) is very difficult to achieve. Nevertheless, it was found that compaction at a temperature of 60°C appears possible and provides promising results regarding stability and rutting enabling the in situ construction. The in situ pavement construction at ambient temperature on a low‐volume road in Switzerland resulted in a visibly well‐compacted and stable base course which was covered by a hot mix asphalt surface course the day after. The test section will be monitored closely over the next 12 months.
Bone Mineral Density and Risk of Osteoporotic Fractures in Women with Parkinson’s Disease
Authors: Bystrytska Maryna , Povoroznyuk Vladyslav , Grygorieva Nataliia , Karaban Iryna , Karasevich Nina
Published: March 2020

Osteoporosis and Parkinson’s disease (PD) are two important age-related diseases, which have an influence on pain, physical activity, disability, and mortality. The aim of this research was to study the parameters of bone mineral density (BMD), frequency, and 10-year probability of osteoporotic fractures (OFs) in females with Parkinson’s disease (PD). We have examined 113 postmenopausal women aged 50–74 years old which were divided into 2 groups (I, control group (CG), n = 53 and II, subjects with PD, n = 60). Bone mineral density of lumbar spine, femoral neck, distal radius, and total body were measured, and quantity and localization of vertebral deformities were performed by the vertebral fracture assessment (VFA). Ten-year probability of OFs was assessed by Ukrainian version of FRAX®. It was established that BMD of lumbar spine, femoral neck, distal radius, and total body in PD women was reliably lower compared to CG. The frequency of OFs in PD subjects was higher compared to CG (51.7 and 11.3%, respectively) with prevalence of vertebral fractures (VFs) in women with PD (52.6% among all fractures). 47.4% of the females had combined VFs: 74.2% of VFs were in thoracic part of the spine and 73.7% were wedge ones. Ten-year probability of major OFs and hip fracture were higher in PD women compared to CG with and without BMD measurements. Inclusion of PD in the FRAX calculation increased the requirement of antiosteoporotic treatment from 5 to 28% (without additional examination) and increased the need of additional BMD measurement from 50 to 68%. Anterior/posterior vertebral height ratios (Th8-Th11) measured by VFA in PD females without confirmed vertebral deformities were lower compared to indices of CG. In conclusion, women with PD have lower BMD indices, higher rate of osteoporosis, and risk of future low-energy fractures that should be taken into account in the assessment of their osteoporosis risk and clinical management.
Synchronization Analysis of Complex Dynamical Networks Subject to Delayed Impulsive Disturbances
Authors: Li Mingyue , Chen Huanzhen , Li Xiaodi
Published: March 2020

This paper studies the problem of leader-following synchronization for complex networks subject to delayed impulsive disturbances, where two kinds of time delays considered exist in internal complex networks and impulsive disturbances. Some delay-dependent sufficient criteria are derived in terms of linear matrix inequalities (LMIs) by using the delayed impulsive differential inequality method. Moreover, a feedback controller is designed to realize desired synchronization via the established LMIs. Our proposed results show that the requirements of impulse intervals and impulse sizes are dropped, and delayed impulses and large scale impulses are allowed to coexist. Finally, some examples are given to show the effectiveness of the obtained results.
Orbital Cavernous Hemangioma Presenting with a Dome-Shaped Maculopathy-Like Appearance on Swept-Source Optical Tomography Imaging
Authors: Bekdemir Şükran , Gündüz Ahmet Kaan , Ersöz Cevriye Cansız
Published: March 2020

A 43-year-old patient presented with painless proptosis, limited upgaze, and vision loss in the right eye. Funduscopic examination revealed right optic disc edema and subtle macular compression. Swept-source optical coherence tomography (SS-OCT) revealed a smooth contoured elevation of the posterior pole without any distortion of retinal structures, an appearance closely simulating dome-shaped maculopathy. Swept-source optical coherence tomography angiography (SS-OCTA) revealed normal retinal and choroidal vasculature. Orbital magnetic resonance imaging demonstrated a well-circumscribed intraconal mass compressing the globe and optic nerve in the right orbit. An anterior orbitotomy was performed, whereby the tumor was totally excised and diagnosed histopathologically as cavernous hemangioma. This case represents an orbital cavernous hemangioma touching the eyeball and producing compression of the posterior pole presenting with a dome-shaped maculopathy-like appearance on SS-OCT. SS-OCT and SS-OCTA are important noninvasive tools for evaluating the retinal and choroidal effects in orbital tumors.
Multiobjective Particle Swarm Optimization for Microgrids Pareto Optimization Dispatch
Authors: Zhang Qian , Ding Jinjin , Shen Weixiang , Ma Jinhui , Li Guoli
Published: March 2020

Multiobjective optimization (MOO) dispatch for microgrids (MGs) can achieve many benefits, such as minimized operation cost, greenhouse gas emission reduction, and enhanced reliability of service. In this paper, a MG with the PV-battery-diesel system is introduced to establish its characteristic and economic models. Based on the models and three objectives, the constrained MOO problem is formulated. Then, an advanced multiobjective particle swarm optimization (MOPSO) algorithm is proposed to obtain Pareto optimization dispatch for MGs. The combination of archive maintenance and Pareto selection enables the MOPSO algorithm to maintain enough nondominated solutions and seek Pareto frontiers. The final trade-off solutions are decided based on the fuzzy set. The benchmark function tests and simulation results demonstrate that the proposed MOPSO algorithm has better searching ability than nondominated sorting genetic algorithm-II (NSGA-II), which is widely used in generation dispatch for MGs. The proposed method can efficiently offer more Pareto solutions and find a trade-off one to simultaneously achieve three benefits: minimized operation cost, reduced environmental cost, and maximized reliability of service.
Change in Viability and Function of Pancreatic Islets after Coculture with Mesenchymal Stromal Cells: A Systemic Review and Meta-Analysis
Authors: Li Xiaohang , Lang Hongxin , Li Baifeng , Zhang Chengshuo , Sun Ning , Lin Jianzhen , Zhang Jialin
Published: March 2020

Background. There is no clear consensus on the effect of coculture of islets with mesenchymal stem cells (MSCs) on islet function and viability.Methods. We conducted a meta-analysis of relevant studies to evaluate the effect of coculture of islets with MSCs on the function and viability of islets, bothin vitroandin vivo. We searched PubMed, Embase, and Web of Science databases for all relevant studies that compared the effect of coculture of islets with MSCs on the function and viability of islets (language of publication: English; reference period: January 2000–May 2019). Data pertaining to islet function and viability, concentrations of some cytokines, andin vivoexperimental outcomes were extracted and compared.Results. Twenty-four articles were included in the meta-analysis. In comparison to islets cultured alone, coculture of islets with MSCs was associated with a significantly higher islet viability [weighted mean difference (WMD), -15.59; -22.34 to -8.83;P<0.00001], insulin level (WMD, -5.74; -9.29 to -2.19;P=0.002), insulin secretion index (WMD, -2.45; -3.70 to -1.21;P=0.0001), and higher concentrations of interleukin-6 (WMD, -1225.66; -2044.47 to -406.86;P=0.003) and vascular endothelial growth factor (WMD, -1.19; -2.25 to -0.14;P=0.03). Direct coculture of islets and MSCs significantly increased islet viability (WMD, -19.82; -26.56 to -13.07;P<0.00001). In thein vivoexperiments, coculture of islets with MSCs induced lower fasting blood glucose level (on postoperative days 21 and 28, WMD, 102.60; 27.14 to 178.05;P=0.008and WMD, 121.19; 49.56 to 192.82;P=0.0009) and better glucose tolerance (blood glucose at 30 minutes after intraperitoneal injection of glucose, WMD, 85.92; 5.33 to 166.51;P=0.04).Conclusion. Coculture of islets with MSCs improves insulin secretory function of islets and enhances islet viability. Direct coculture of two cells significantly increased islet viability. MSC-based strategy may be beneficial for clinical islet transplantation for type 1 diabetes in the future.
Effects of Aromatherapy with Lavender and Peppermint Essential Oils on the Sleep Quality of Cancer Patients: A Randomized Controlled Trial
Authors: Hamzeh Sahar , Safari-Faramani Roya , Khatony Alireza
Published: March 2020

One of the problems of cancer patients is sleep disorder. Given the absence of studies on comparing the effect of inhalation aromatherapy with lavender and peppermint on the sleep quality of the cancer patients, this study was performed to compare the effect of inhalation aromatherapy with lavender and peppermint essential oils on the sleep quality of cancer patients. For this purpose, 120 patients were randomly allocated to three groups of lavender, peppermint, and control. The intervention groups received three drops of the essential oil for 7 days. In the control group, aromatic distilled water was used instead. Pittsburgh Sleep Quality Inventory (PSQI) was used. Before the intervention, no significant difference was observed between the mean PSQI scores of three groups, while the difference was statistically significant after the intervention. The mean PSQI scores were lower in lavender and peppermint groups than in the control group. Aromatherapy can improve the sleep quality of cancer patients. To confirm the findings, more studies should be done.
Impact of Single and Combined Faults Composed of Rotor Eccentricity and Stator Interturn Short Circuit on Electromagnetic Torque Ripples in Synchronous Generator
Authors: He Yu-Ling , Zhang Zhi-Jie , Wang Xiao-Long , Gao Peng , Gerada David , Gerada Chris , Vakil Gaurang
Published: March 2020

In order to comprehensively study and identify the electromagnetic torque (EMT) difference among the single static air-gap eccentricity (SAGE) fault, the single stator interturn short circuit fault (SISC), and the combined fault composed of these two, this article investigates the EMT ripple properties due to the mentioned three faults. Different from other studies, this paper considers not only the effect of the single fault types but also the impact of the single fault combinations on the EMT ripple characteristics. Detailed EMT expressions for each fault are firstly derived on the basis of the magnetic flux density (MFD) analysis. Then, finite element calculation and experimental study on a CS-5 prototype generator with two poles at 3000 rpm, which is specifically designed and manufactured ourselves, are carried out to validate the analysis result. It is found that the three faults will induce different ripple components in EMT. The combined faults have the most intensive impact sensitivity on the EMT ripples, while the single SAGE fault ranks the last in the impact effect.
Critical Care Admission of an HIV Patient with Diabetic Ketoacidosis Secondary to Pembrolizumab
Authors: Cuenca John A. , Laserna Andres , Reyes María P. , Nates Joseph L. , Botz Gregory H.
Published: March 2020

Background. Pembrolizumab is a checkpoint inhibitor that targets the programmed cell death-1 receptor (PD-1) and has shown to be effective against several malignancies, including lung cancer. However, life-threatening immune-related adverse events can result from these immunotherapy treatments. Case presentation. A 62-year-old man with HIV, metastatic adenocarcinoma of the lung, and no previous history of diabetes presented to the emergency department with new-onset nausea, vomiting, and generalized weakness. Glucose was 1191 mg/dl, hemoglobin A1c 11%, and potassium 6.9 mEq/L. He had metabolic acidosis with a lactate of 6.6 mmol/L and anion gap of 38 mEq/L, and ketones were detected on the urinalysis. Severe diabetic ketoacidosis was diagnosed, and the patient was admitted to the intensive care unit. Additional investigations showed low C-peptide and negative anti-glutamic acid decarboxylase antibody, anti-insulin antibody, and anti-islet-antigen 2Ab antibody. After ruling out other possible etiologies, pembrolizumab was considered to be the cause of the diabetes and ketoacidosis. Conclusions. Life-threatening adverse drug events associated with checkpoint inhibitors such as pembrolizumab are on the rise. We recommend to closely follow and monitor patients receiving these immunotherapies. This strategy could lead to early detection and prevention, as well as reduction of more serious life-threatening complications requiring intensive care.
Melioidosis with Septic Shock and Disseminated Infection in a Neutropenic Patient Receiving Chemotherapy
Authors: Sukauichai Sitthi , Pattarowas Chantana
Published: March 2020

Melioidosis is a bacterial infection, caused by Gram-negative bacillus, Burkholderia pseudomallei, widespread in Southeast Asia and the northern part of Australia, resulting in a high mortality rate in severe infection. However, it has rarely been reported in patients with chemotherapy-induced neutropenia. The authors described a case of melioidosis in a neutropenic patient presenting with septic shock after receiving chemotherapy. Blood and urine cultures were positive for Burkholderia pseudomallei, and CT scan showed multiple pulmonary nodules and hepatosplenic abscesses. The patient was successfully treated with antibiotics for the infection and with combined modalities for a malignancy.
Loss of Apc Rapidly Impairs DNA Methylation Programs and Cell Fate Decisions in Lgr5+ Intestinal Stem Cells
Authors: Bruschi Marco , Garnier Laure , Cleroux Elouan , Giordano Alicia , Dumas Michael , Bardet Anaïs F. , Kergrohen Thomas , Quesada Stanislas , Cesses Pierre , Weber Michael , Gerbe François , Jay Philippe
Published: March 2020

Colorectal cancer initiation and progression result from the accumulation of genetic and epigenetic alterations. Although aberrant gene expression and DNA methylation profiles are considered hallmarks of colorectal cancer development, the precise timing at which these are produced during tumor establishment remains elusive. Here we investigated the early transcriptional and epigenetic changes induced by adenomatous polyposis coli (Apc) inactivation in intestinal crypts. Hyperactivation of the Wnt pathway via Apc inactivation in crypt base columnar intestinal stem cells (ISC) led to their rapid accumulation driven by an impaired molecular commitment to differentiation, which was associated with discrete alterations in DNA methylation. Importantly, inhibiting the enzymes responsible for de novo DNA methylation restored the responsiveness of Apc-deficient intestinal organoids to stimuli regulating the proliferation-to-differentiation transition in ISC. This work reveals that early DNA methylation changes play critical roles in the establishment of the impaired fate decision program consecutive to Apc loss of function.

Significance:

This study demonstrates the functional impact of changes in DNA methylation to determine the colorectal cancer cell phenotype following loss of Apc function.
PSF Promotes ER-Positive Breast Cancer Progression via Posttranscriptional Regulation of ESR1 and SCFD2
Authors: Mitobe Yuichi , Iino Kaori , Takayama Ken-ichi , Ikeda Kazuhiro , Suzuki Takashi , Aogi Kenjiro , Kawabata Hidetaka , Suzuki Yutaka , Horie-Inoue Kuniko , Inoue Satoshi
Published: March 2020

Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer, yet long-term treatment often causes acquired resistance, which results in recurrence and metastasis. Recent studies have revealed that RNA-binding proteins (RBP) are involved in tumorigenesis. Here, we demonstrate that PSF/SFPQ is an RBP that potentially predicts poor prognosis of patients with ER-positive breast cancer by posttranscriptionally regulating ERα (ESR1) mRNA expression. Strong PSF immunoreactivity correlated with shorter overall survival in patients with ER-positive breast cancer. PSF was predominantly expressed in a model of tamoxifen-resistant breast cancer cells, and depletion of PSF attenuated proliferation of cultured cells and xenografted tumors. PSF expression was significantly associated with estrogen signaling. PSF siRNA downregulated ESR1 mRNA by inhibiting nuclear export of the RNA. Integrative analyses of microarray and RNA immunoprecipitation sequencing also identified SCFD2, TRA2B, and ASPM as targets of PSF. Among the PSF targets, SCFD2 was a poor prognostic indicator of breast cancer and SCFD2 knockdown significantly suppressed breast cancer cell proliferation. Collectively, this study shows that PSF plays a pathophysiologic role in ER-positive breast cancer by posttranscriptionally regulating expression of its target genes such as ESR1 and SCFD2. Overall, PSF and SCFD2 could be potential diagnostic and therapeutic targets for primary and hormone-refractory breast cancers.

Significance:

This study defines oncogenic roles of RNA-binding protein PSF, which exhibits posttranscriptional regulation in ER-positive breast cancer.
Consumption of the Fish Oil High-Fat Diet Uncouples Obesity and Mammary Tumor Growth through Induction of Reactive Oxygen Species in Protumor Macrophages
Authors: Liu Lianliang , Jin Rong , Hao Jiaqing , Zeng Jun , Yin Di , Yi Yanmei , Zhu Mingming , Mandal Anita , Hua Yuan , Ng Chin K. , Egilmez Nejat K. , Sauter Edward R. , Li Bing
Published: March 2020

Obesity is associated with increased risk of many types of cancer and can be induced by various high-fat diets (HFD) from different fat sources. It remains unknown whether fatty acid composition in different HFD influences obesity-associated tumor development. Here we report that consumption of either a cocoa butter or fish oil HFD induced similar obesity in mouse models. While obesity induced by the cocoa butter HFD was associated with accelerated mammary tumor growth, consumption of the fish oil HFD uncoupled obesity from increased mammary tumor growth and exhibited a decrease in protumor macrophages. Compared with fatty acid (FA) components in both HFDs, n-3 FA rich in the fish oil HFD induced significant production of reactive oxygen species (ROS) and macrophage death. Moreover, A-FABP expression in the protumor macrophages facilitated intracellular transportation of n-3 FA and oxidation of mitochondrial FA. A-FABP deficiency diminished n-3 FA–mediated ROS production and macrophage death in vitro and in vivo. Together, our results demonstrate a novel mechanism by which n-3 FA induce ROS-mediated protumor macrophage death in an A-FABP–dependent manner.

Significance:

This study provides mechanistic insight into dietary supplementation with fish oil for breast cancer prevention and advances a new concept that not all HFDs leading to obesity are tumorigenic.
Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors
Authors: Tsurutani Junji , Iwata Hiroji , Krop Ian , Jänne Pasi A. , Doi Toshihiko , Takahashi Shunji , Park Haeseong , Redfern Charles , Tamura Kenji , Wise-Draper Trisha M. , Saito Kaku , Sugihara Masahiro , Singh Jasmeet , Jikoh Takahiro , Gallant Gilles , Li Bob T.
Published: March 2020

HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8–11.1] months. In HER2-mutant non–small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1–14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors.

Significance:

T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially HER2-mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention. Further research of T-DXd is warranted to address these unmet medical needs.

See related commentary by Rolfo and Russo, p. 643.

This article is highlighted in the In This Issue feature, p. 627
Poor Renal and Cardiovascular Outcomes in Patients with Biopsy-Proven Diabetic Nephropathy
Authors: Wang Yiyun , Zhou Ting , Zhang Qiming , Fei Yang , Li Ze , Li Shiqi , He Li , Zhang Qunzi , Dong Yang , Fan Ying , Wang Niansong
Published: March 2020

Background: Despite the high mortality of cardiovascular disease (CVD) in diabetic patients with renal injury, few studies have compared cardiovascular characteristics and outcomes between patients with diabetic nephropathy (DN) and non-diabetic renal disease (NDRD). Methods: A total of 326 type 2 diabetes mellitus patients with renal biopsy were assigned to DN and NDRD groups. Echocardiography and Doppler ultrasound were performed to evaluate left ventricular hypertrophy (LVH) and peripheral atherosclerosis disease (PAD). Renal and cardiovascular survival rates were compared between the DN and NDRD groups by Kaplan-Meier analysis. Risk factors for renal and cardiovascular events in DN patients were identified by a Cox proportional hazards model. Results: In total, 179 patients entered the DN group (54.9%) and 147 made up the NDRD group (45.1%). The presence of diabetic retinopathy, family history of diabetes, and dependence on insulin therapy were associated with the presence of DN. DN patients had more CVD with more severe LVH and PAD. Poorer renal (log-rank χ2 = 26.534, p < 0.001) and cardiovascular (log-rank χ2 = 16.257, p < 0.001) prognoses were seen in the DN group. DR (HR 1.539, 95% CI 1.332–1.842), eGFR (HR 0.943, 95% CI 0.919–0.961), and 24-h proteinuria (HR 1.211, 95% CI 1.132–1.387) were identified as risk factors for renal endpoints. Age (HR 1.672, 95% CI 1.487–1.821), HbA1C (HR 1.398, 95% CI 1.197–1.876), and 24-h proteinuria (HR 1.453, 95% CI 1.289–1.672) were associated with cardiovascular endpoints. Conclusion: Patients with DN had more severe CVD along with poorer renal and cardiovascular prognoses than those with NDRD.
White Matter Hyperintensities and Cognitive Impairment in Healthy and Pathological Aging: A Quantified Brain MRI Study
Authors: Kaskikallio Alar , Karrasch Mira , Koikkalainen Juha , Lötjönen Jyrki , Rinne Juha O. , Tuokkola Terhi , Parkkola Riitta , Grönholm-Nyman Petra
Published: March 2020

Background: Brain changes involving the white matter (WM), often an indication of cerebrovascular pathology, are frequently seen in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). Few studies have examined possible cognitive domain- or group-specific cognitive effects of WM pathology in old age, MCI, and AD. Objective: Our purpose was to examine the relationship between WM hyperintensities (WMH), a typical marker for WM pathology, and cognitive functioning in healthy old age and pathological aging using quantified MRI data. Methods: We utilized multidomain neuropsychological data and quantified MRI data from a sample of 42 cognitively healthy older adults and 44 patients with MCI/AD (total n = 86). Results: After controlling for age and education, WMH in the temporal and parieto-occipital lobes was associated with impairments in processing speed and parieto-occipital pathology with verbal memory impairment in the whole sample. Additionally, temporal WMH was associated with impaired processing speed in the patient group specifically. Conclusions: WM pathology is strongly associated with impaired processing speed, and our results indicate that these impairments arise from WMH in the temporal and parieto-occipital regions. In MCI and AD patients with temporal WMH, processing speed impairments are especially prominent. The results of this study increase our knowledge of cognitive repercussions stemming from temporal and/or parieto-occipital WM pathology in healthy and pathological aging.
Lumbar Facet Cyst as a Rare Cause of L5 Radiculopathy: A Case Report
Authors: AL Habsi Salim , AL Ghafri Khalifa , Elsaid Mansour , AL Subhi Abdulrahman , AL Kindi Hunaina , AL Baccouche Kaouthar
Published: March 2020

Lumbar facet cysts arise from zygapophyseal joints and are commonly associated with spondylosis. They are a rare cause of symptomatic nerve root compression. We are presenting a rare case of L4/5 lumbar facet cyst compressing the nerve root in a patient presenting with L5 radiculopathy. The clinical picture of a facet cyst in this case is similar to intervertebral disc disease.
A Case of Diffuse Large B Cell Lymphoma of the Breast with Predominantly High-Level Internal Echoes
Authors: Tomita Masafumi , Oura Shoji , Nishiguchi Haruka , Makimoto Shinichiro
Published: March 2020

A 70-year-old woman had a large mass in her right breast. Mammography displayed focal asymmetrical density in the scattered areas of fibroglandular density. Ultrasonography showed the tumor to have predominantly high-level internal echoes. Histological examination showed that the tumor was composed of CD20-positive atypical cells with a large nucleus, scant cytoplasm, and abundant mitoses accompanied by a lot of fat cell interspersion and the diagnosis of diffuse large B cell lymphoma was made. We considered that the massive back scattering generated by the heterogeneity of acoustic impedance between fat cells and tumor cells brought about the high-level internal echoes. The patient had undergone chemotherapy followed by radiotherapy to the breast and regional nodes and has been well without lymphoma recurrence for more than 6 years. Although breast malignant lymphoma generally shows very low-level internal echoes, it could have high-level internal echoes especially in case of a non-dense breast.
How Often Are Patient-Important Outcomes Represented in Neonatal Randomized Controlled Trials? An Analysis of Cochrane Neonatal Reviews
Authors: Lai Nai Ming , Leom Denise Yin Xian , Chow Wen Li , Chen Kee-Hsin , Lin Pu-Hong , Chaiyakunapruk Nathorn , Ovelman Colleen , Soll Roger
Published: March 2020

Background: Research findings based on patient-important outcomes (PIOs) provide more useful conclusions than those that are based on surrogate outcomes. It is unclear to what extent PIOs are represented in neonatal randomized controlled trials (RCTs). Objectives: We determined the proportion of PIOs in neonatal RCTs included in Cochrane Neonatal reviews. Methods: We extracted up to 5 outcomes from each RCT included in Cochrane Neonatal reviews published until January 2018, with independent determination of PIOs among authors followed by a discussion leading to a consensus. We defined PIOs as outcomes that matter to patient care, such as clinical events or physiological or laboratory parameters that are widely used to guide management. Results: Among 6,832 outcomes extracted from 1,874 RCTs included in 276 reviews, 5,349 (78.3%) were considered PIOs; 461 studies (24.5%) included 5 or more PIOs, 1,278 (68.2%) included 1–4 PIOs, while 135 (7.2%) had no PIO included. PIOs were observed more often among dichotomous than among continuous outcomes (94.9 vs. 61.5%; RR: 1.54; 95% CI: 1.50–1.58), and more among subjective than among objective outcomes (95.9 vs. 76.8%; RR: 1.25; 95% CI: 1.22–1.28). Newer studies were more likely to have a greater number of PIOs (adjusted OR: 1.033 [95% CI: 1.025–1.041] with each publication year). Conclusions: The large and increasing representation of PIOs over the years suggests an improving awareness by neonatal trialists of the need to incorporate important outcomes in order to justify the utilization of resources. Further research should explore the reasons for non-inclusion or non-reporting of PIOs in a small proportion of RCTs.
Effect of Cataract Extraction on Retinal Sensitivity Measurements
Authors: Palkovits Stefan , Hirnschall Nino , Georgiev Stefan , Leisser Christoph , Findl Oliver
Published: March 2020

Introduction: Central and paracentral retinal function is often compromised in various retinal diseases. In these conditions, microperimetry is an important tool for assessing retinal sensitivity values. As retinal diseases are prevalent among the elderly, cataract often coexists. This study investigates the effect of cataract surgery on retinal sensitivity in patients with cataract without retinal disease. Material and Methods: A total of 30 patients already scheduled for cataract surgery were enrolled and microperimetry and visual acuity evaluation was performed before and after cataract extraction. The patients were allocated to 1 of 3 study groups in accordance with the main cataract subtype: nuclear, cortical, or posterior subcapsular (PSC) cataract. Results: Visual acuity increased significantly after cataract surgery (from 0.34 to 0.00 logMar, p < 0.001, paired t test). Similarly, median retinal sensitivity increased significantly from 23 dB (IQR 21–25 dB) to 27 dB (IQR 25.75–28 dB) (p < 0.001, Wilcoxon test). The increase of retinal sensitivity after cataract surgery was highest in the PSC cataract group. Conclusion: This study showed an increase in retinal sensitivity values after cataract removal, especially in the PSC group. Therefore, coexisting cataract should be considered when interpreting microperimetry results.
Typical and Atypical Symptoms of Acute Coronary Syndrome: Time to Retire the Terms?
Authors: DeVon Holli A. , Mirzaei Sahereh , Zègre‐Hemsey Jessica
Published: March 2020

Studies indicate that symptoms labeled as “atypical” are more common in women evaluated for myocardial infarction (MI) and may contribute to the lower likelihood of a diagnosis and delayed treatment and result in poorer outcomes compared with men with MI. Atypical pain is frequently defined as epigastric or back pain or pain that is described as burning, stabbing, or characteristic of indigestion. Typical symptoms usually include chest, arm, or jaw pain described as dull, heavy, tight, or crushing. In a recent article published in the
Journal of the American Heart Association
(
JAHA
), Ferry and colleagues addressed presenting symptoms in men and women diagnosed with MI and reported that typical symptoms in women were more predictive of a diagnosis of MI than for men. A critical question is, are there really typical or atypical symptoms, and if so, who is the reference group? We propose that researchers and clinicians either discontinue using the terms
typical
and
atypical
or provide the reference group to which the terms apply (eg, men versus women). We believe it is past time to standardize the symptom assessment for MI so that proper and rapid diagnostic testing can be undertaken; however, we cannot standardize the symptom experience. When we do this, we are at risk of having study results, such as those of Ferry and colleagues, that vary from prior evidence and could lead to what the authors hope to avoid: disadvantaging women in receiving expeditious diagnostic testing and treatment for acute coronary syndrome.
Dabigatran Reversal Before Intravenous Tenecteplase in Acute Ischemic Stroke
Authors: Beharry James , Waters Michael J. , Drew Roy , Fink John N. , Wilson Duncan , Campbell Bruce C.V. , Parsons Mark W. , Kleinig Timothy J. , Wu Teddy Y.
Published: March 2020

Background and Purpose—

Reversal of dabigatran before intravenous thrombolysis in patients with acute ischemic stroke has been well described using alteplase but experience with intravenous tenecteplase is limited. Tenecteplase seems at least noninferior to alteplase in patients with intracranial large vessel occlusion. We report on the experience of dabigatran reversal before tenecteplase thrombolysis for acute ischemic stroke.

Methods—

We included consecutive patients with ischemic stroke receiving dabigatran prestroke treated with intravenous tenecteplase after receiving idarucizumab. Patients were from 2 centers in New Zealand and Australia. We reported the clinical, laboratory, and radiological characteristics and their functional outcome.

Results—

We identified 13 patients receiving intravenous tenecteplase after dabigatran reversal. Nine (69%) were male, median age was 79 (interquartile range, 69–85) and median baseline National Institutes of Health Stroke Scale score was 6 (interquartile range, 4–21). Atrial fibrillation was the indication for dabigatran therapy in all patients. All patients had a prolonged thrombin clotting time (median, 80 seconds [interquartile range, 57–113]). Seven patients with large vessel occlusion were referred for endovascular thrombectomy, 2 of these patients (29%) had early recanalization with tenecteplase abrogating thrombectomy. No patients had parenchymal hemorrhage or symptomatic hemorrhagic transformation. Favorable functional outcome (modified Rankin Scale score, 0–2) occurred in 8 (62%) patients. Two deaths occurred from large territory infarction.

Conclusions—

Our experience suggests intravenous thrombolysis with tenecteplase following dabigatran reversal using idarucizumab may be safe in selected patients with acute ischemic stroke. Further studies are required to more precisely estimate the efficacy and risk of clinically significant hemorrhage.