bluuebunny/crossref_metadata_2025_split huggingface dataset:
HER2 Expression in Gastric Cancer: Rare, Heterogeneous and of No Prognostic Value – Conclusions from 924 Cases of Two Independent Series
Authors: Grabsch Heike , Sivakumar Shivan , Gray Sally , Gabbert Helmut E. , Müller Wolfram 
Published: January 2021

Background: Patients with gastric cancer (GC) have a poor survival and biologicals such as Trastuzumab have not been used routinely in these patients. Existing data on HER2 expression and its clinical relevance in GC are still limited and controversial.Methods: HER2 expression was investigated by immunohistochemistry in 418 GC from Germany and 506 GC from England. Results were compared to clinicopathological parameters and patient survival.Results: Less than 10% of all GC showed HER2 expression in more than 5% of tumour cells and 91% of these were intestinal type GC. In both series, no relationship was found between HER2 expression, patient survival or TNM stage. Marked intratumoural heterogeneity was noted.Conclusions: This is the largest study to date demonstrating in two independent series that HER2 expression is not related to gastric cancer patient prognosis and that only a very small subgroup of intestinal type GC may potentially respond to HER2 targeting therapy. Due to prominent intratumoural heterogeneity of HER2 expression in GC, HER2 testing in endoscopic biopsies before treatment will be prone to false negative results.
PIDDosome Expression and the Role of Caspase-2 Activation for Chemotherapy-Induced Apoptosis in RCCs
Authors: Heikaus Sebastian , Pejin Igor , Gabbert Helmut Erich , Ramp Uwe , Mahotka Csaba 
Published: January 2021

Background: The importance of caspase-2 activation for mediating apoptosis in cancer is not clear and seems to differ between different tumour types. Furthermore, only few data have been obtained concerning the expression of caspase-2, which can be alternatively spliced into caspase-2L and caspase-2S, and the other PIDDosome members PIDD and RAIDD in human tumours in vivo. We, therefore, investigated their expression in renal cell carcinomas (RCCs) of the clear cell type in vivo and analysed the role of caspase-2 in chemotherapy-induced apoptosis in RCCs in vitro.Methods: The analyses were performed by semiquantitative real-time PCR, Western Blot and Caspase-2 Assay.Results: Our in vivo results showed an overall decrease in proapoptotic caspase-2L expression during tumour progression due to an increase in the relative share of caspase-2S mRNA in total caspase-2 mRNA expression. Furthermore, an increase in the expression of PIDD and RAIDD could be observed. In contrast, antiapoptotic BCL-2 expression increased only during early tumour stages, whereas expression decreased in pT3 RCCs. In vitro, caspase-2 activation in RCC cell lines coincidenced with sensitivity of tumour cells towards Topotecan-induced apoptosis. However, inhibition of caspase-2 could not prevent Topotecan-induced apoptosis. Interestingly, Topotecan-resistance could be overcome by the apoptosis-sensitizing drug HA14-1.Conclusions: Our study confirms the concept of a shift towards a more antiapoptotic transcriptional context during tumour progression in RCCs. Furthermore, it shows that caspase-2 participates in chemotherapy-induced apoptosis in RCCs although it is not mandatory for it. Additionally, inhibition of antiapoptotic BCL-2 family members might provide a possible way to overcome chemotherapy resistance of RCCs.
Attenuation of SRC Kinase Activity Augments PARP Inhibitor–mediated Synthetic Lethality in BRCA2-altered Prostate Tumors
Authors: Chakraborty Goutam , Patail Nabeela Khan , Hirani Rahim , Nandakumar Subhiksha , Mazzu Ying Z. , Yoshikawa Yuki , Atiq Mohammad , Jehane Lina E. , Stopsack Konrad H. , Lee Gwo-Shu Mary , Abida Wassim , Morris Michael J. , Mucci Lorelei A. , Danila Daniel , Kantoff Philip W. 
Published: January 2021

Abstract

Purpose:
Alterations in DNA damage repair (DDR) pathway genes occur in 20%–25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although PARP inhibitors (PARPis) have been shown to benefit men with mCRPC harboring DDR defects due to mutations in BRCA1/2 and ATM, additional treatments are necessary because the effects are not durable.

Experimental Design:
We performed transcriptomic analysis of publicly available mCRPC cases, comparing BRCA2 null with BRCA2 wild-type. We generated BRCA2-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPis and SRC inhibitors. We also assessed the antiproliferative effects of combination treatment in 3D prostate cancer organoids.

Results:
We observed significant enrichment of the SRC signaling pathway in BRCA2-altered mCRPC. BRCA2-null prostate cancer cell lines had increased SRC phosphorylation and higher sensitivity to SRC inhibitors (e.g., dasatinib, bosutinib, and saracatinib) relative to wild-type cells. Combination treatment with PARPis and SRC inhibitors was antiproliferative and had a synergistic effect in BRCA2-null prostate cancer cells, mCRPC organoids, and Trp53/Rb1-null prostate cancer cells. Inhibition of SRC signaling by dasatinib augmented DNA damage in BRCA2-null prostate cancer cells. Moreover, SRC knockdown increased PARPi sensitivity in BRCA2-null prostate cancer cells.

Conclusions:
This work suggests that SRC activation may be a potential mechanism of PARPi resistance and that treatment with SRC inhibitors may overcome this resistance. Our preclinical study demonstrates that combining PARPis and SRC inhibitors may be a promising therapeutic strategy for patients with BRCA2-null mCRPC.
COMP (Cartilage Oligomeric Matrix Protein) Neoepitope
Authors: Sandstedt Joakim , Vargmar Karin , Björkman Kristina , Ruetschi Ulla , Bergström Göran , Hultén Lillemor Mattsson , Skiöldebrand Eva 
Published: January 2021

Objective:
COMP (cartilage oligomeric matrix protein) is abundantly expressed in the cardiovascular system, cartilage, and atherosclerotic plaques. We investigated if the total COMP (COMPtotal) and COMP neoepitope (COMPneo) with other cardiovascular markers and clinical parameters could identify symptomatic carotid stenosis.

Approach and Results:
Blood samples were collected from patients with symptomatic carotid stenosis (stenosis, n=50), patients with stroke without carotid stenosis but small plaques (plaque, n=50), and control subjects (n=50). COMPtotal and COMPneo were measured using an ELISA. Ninety-two cardiovascular disease markers were measured by the Olink CVD kit. The presence of native COMP and COMPneo was determined by immunohistochemistry. The concentration of COMPneo was higher and COMPtotal was lower in the stenosis group. When the concentration was compared between the stenosis and control groups, IL-1ra (interleukin-1 receptor antagonist protein), IL6 (interleukin-6), REN (Renin), MMP1 (matrix metalloproteinase-1), TRAIL-R2 (tumor necrosis factor-related apoptosis-inducing ligand receptor 2), ITGB1BP2 (integrin beta 1 binding protein 2), and COMPneo were predictive of stenosis. Conversely, KLK6 (kallikrein-6), COMPtotal, NEMO (nuclear factor-kappa-B essential modulator), SRC (Proto-oncogene tyrosine-protein kinase Src), SIRT2 (SIR2-like protein), CD40 (cluster of differentiation 40), TF (tissue factor), MP (myoglobin), and RAGE (receptor for advanced glycation end-products) were predictive of the control group. Model reproducibility was good with the receiver operating characteristic plot area under the curve being 0.86. When comparing the plaque group and stenosis group, COMPneo, GAL (galanin), and PTX3 (pentraxin-related protein PTX3) were predictive of stenosis. Model reproducibility was excellent (receiver operating characteristic plot area under the curve 0.92). COMPneo was detected in smooth muscle-, endothelial-, and foam-cells in carotid stenosis.

Conclusions:
Degradation of COMP may be associated with atherosclerosis progression and generation of a specific COMP fragment—COMPneo. This may represent a novel biomarker that together with COMPtotal and other risk-markers could be used to identify symptomatic carotid stenosis.

Graphic Abstract:
A graphic abstract is available for this article.
Statin Effects on Vascular Calcification
Authors: Xian Joshua Zhaojun , Lu Mimi , Fong Felicia , Qiao Rong , Patel Nikhil Rajesh , Abeydeera Dishan , Iriana Sidney , Demer Linda L. , Tintut Yin 
Published: January 2021

Objective:
Statins lower cardiovascular event risk, yet, they paradoxically increase coronary artery calcification, a marker consistently associated with increased cardiovascular risks. As calcium deposits influence rupture risk due to stress from compliance mismatch at their surfaces, we hypothesized that statins may lower cardiovascular risk by altering the microarchitecture of calcium deposits. Thus, using mice with preexisting vascular calcification, we tested whether pravastatin reduces the mineral surface area of calcium deposits.

Approach and Results:

Aged
Apoe
−/−
mice were treated with pravastatin or vehicle for 20 weeks. Aortic calcification was assessed by in vivo micro-computed tomography/micro-positron emission tomography using fluorine-18-labeled sodium fluoride at weeks 0, 10, and 20 and by histomorphometry at euthanasia. Micro-computed tomography analysis showed that, in both groups, the amount of vascular calcification increased significantly over the 20-week period, but pravastatin treatment did not augment over the controls. In contrast, the micro-positron emission tomography analysis showed that, at week 10, the pravastatin group had less
18
F uptake, suggesting reduced surface area of actively mineralizing deposits, but this decrease was not sustained at week 20. However, a significant difference in the mineral deposit size was found by histomorphometry. The pravastatin group had significantly more aortic microcalcium deposits (<50 µm in diameter) than the controls. The pravastatin group also had more vascular cells positive for alkaline phosphatase activity than the controls. The amount of collagen and osteopontin, additional osteoblastic markers, were not significantly different between the 2 groups.

Conclusions:
These results suggest that pravastatin treatment alters the microarchitecture of aortic calcium deposits with potential effects on plaque stability.
Inhibition of T-Cells by Cyclosporine A Reduces Macrophage Accumulation to Regulate Venous Adaptive Remodeling and Increase Arteriovenous Fistula Maturation
Authors: Matsubara Yutaka , Kiwan Gathe , Liu Jia , Gonzalez Luis , Langford John , Gao Mingjie , Gao Xixiang , Taniguchi Ryosuke , Yatsula Bogdan , Furuyama Tadashi , Matsumoto Takuya , Komori Kimihiro , Dardik Alan 
Published: January 2021

Objective:
Arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis, but the primary success rate of AVF remains poor. Successful AVF maturation requires vascular wall thickening and outward remodeling. A key factor determining successful AVF maturation is inflammation that is characterized by accumulation of both T-cells and macrophages. We have previously shown that anti-inflammatory (M2) macrophages are critically important for vascular wall thickening during venous remodeling; therefore, regulation of macrophage accumulation may be an important mechanism promoting AVF maturation. Since CD4+ T-cells such as T-helper type 1 cells, T-helper type 2 cells, and regulatory T-cells can induce macrophage migration, proliferation, and polarization, we hypothesized that CD4+ T-cells regulate macrophage accumulation to promote AVF maturation.

Approach and Results:
In a mouse aortocaval fistula model, T-cells temporally precede macrophages in the remodeling AVF wall. CsA (cyclosporine A; 5 mg/kg, sq, daily) or vehicle (5% dimethyl sulfoxide) was administered to inhibit T-cell function during venous remodeling. CsA reduced the numbers of T-helper type 1 cells, T-helper type 2, and regulatory T-cells, as well as M1- and M2-macrophage accumulation in the wall of the remodeling fistula; these effects were associated with reduced vascular wall thickening and increased outward remodeling in wild-type mice. However, these effects were eliminated in nude mice, showing that the effects of CsA on macrophage accumulation and adaptive venous remodeling are T-cell-dependent.

Conclusions:
T-cells regulate macrophage accumulation in the maturing venous wall to control adaptive remodeling. Regulation of T-cells during AVF maturation may be a strategy that can improve AVF maturation.

Graphic Abstract:
A graphic abstract is available for this article.
Contemporary Reevaluation of Race and Ethnicity With Outcomes in Heart Failure
Authors: Savitz Samuel T. , Leong Thomas , Sung Sue Hee , Lee Keane , Rana Jamal S. , Tabada Grace , Go Alan S. 
Published: January 2021

Background
Variation in outcomes by race/ethnicity in adults with heart failure (HF) has been previously observed. Identifying factors contributing to these variations could help target interventions. We evaluated the association of race/ethnicity with HF outcomes and potentially contributing factors within a contemporary HF cohort.

Methods and Results
We identified members of Kaiser Permanente Northern California, a large integrated healthcare delivery system, who were diagnosed with HF between 2012 and 2016 and had at least 1 year of prior continuous membership and left ventricular ejection fraction data. We used Cox regression with time‐dependent covariates to evaluate the association of self‐identified race/ethnicity with HF or all‐cause hospitalization and all‐cause death, with backward selection for potential explanatory variables. Among 34 621 patients with HF, compared with White patients, Black patients had a higher rate of HF hospitalization (adjusted hazard ratio [HR], 1.28; 95% CI, 1.18–1.38) but a lower rate of death (adjusted HR, 0.78; 95% CI, 0.72–0.85). In contrast, Asian/Pacific Islander patients had similar rates of HF hospitalization, but lower rates of all‐cause hospitalization (adjusted HR, 0.89; 95% CI, 0.85–0.93) and death (adjusted HR, 0.75; 95% CI, 0.69–0.80). Hispanic patients also had a lower rate of death (adjusted HR, 0.85; 95% CI, 0.80–0.91). Sensitivity analyses showed that effect sizes for Black patients were larger among patients with reduced ejection fraction.

Conclusions
In a contemporary and diverse population with HF, Black patients experienced a higher rate of HF hospitalization and a lower rate of death compared with White patients. In contrast, selected outcomes for Asian/Pacific Islander and Hispanic patients were more favorable compared with White patients. The observed differences were not explained by measured potentially modifiable factors, including pharmacological treatment. Future research is needed to identify explanatory mechanisms underlying ongoing racial/ethnic variation to target potential interventions.
Cortical Tracking of Speech: Toward Collaboration between the Fields of Signal and Sentence Processing
Authors: Beier Eleonora J. , Chantavarin Suphasiree , Rehrig Gwendolyn , Ferreira Fernanda , Miller Lee M. 
Published: January 2021

Abstract
In recent years, a growing number of studies have used cortical tracking methods to investigate auditory language processing. Although most studies that employ cortical tracking stem from the field of auditory signal processing, this approach should also be of interest to psycholinguistics—particularly the subfield of sentence processing—given its potential to provide insight into dynamic language comprehension processes. However, there has been limited collaboration between these fields, which we suggest is partly because of differences in theoretical background and methodological constraints, some mutually exclusive. In this paper, we first review the theories and methodological constraints that have historically been prioritized in each field and provide concrete examples of how some of these constraints may be reconciled. We then elaborate on how further collaboration between the two fields could be mutually beneficial. Specifically, we argue that the use of cortical tracking methods may help resolve long-standing debates in the field of sentence processing that commonly used behavioral and neural measures (e.g., ERPs) have failed to adjudicate. Similarly, signal processing researchers who use cortical tracking may be able to reduce noise in the neural data and broaden the impact of their results by controlling for linguistic features of their stimuli and by using simple comprehension tasks. Overall, we argue that a balance between the methodological constraints of the two fields will lead to an overall improved understanding of language processing as well as greater clarity on what mechanisms cortical tracking of speech reflects. Increased collaboration will help resolve debates in both fields and will lead to new and exciting avenues for research.
Methods and Roles of Experience in Christian Wolff’s “Deutsche Metaphysik”
Authors: Engelhard Kristina 
Published: January 2021

Abstract
The main thesis of this article is that in Christian Wolff’s Deutsche Metaphysik, empirical sources of knowledge play important if not foundational roles and that inductive methods of reasoning are extensively applied. It is argued that experiential self-awareness plays a foundational role and that empirical evidence, phenomena, and scientific theories from the empirical sciences of Wolff’s time are used for inferential purposes. Wolff also makes use of inductive reasoning, i.e., abduction to hidden causes of empirical phenomena, and inferences to the best or to the only possible explanation. Wolff’s Deutsche Metaphysik is therefore a prefiguration and an interesting case of inductive metaphysics in the contemporary sense. From this contemporary perspective, Wolff draws the distinction between valid and speculative abductions in a different way – but it is also different from that of his more empirically oriented contemporaries.
Application of Practice Oriented–Peer Review for Prosthodontics (PRO-PReP)—A Qualitative Study
Authors: Murthy Varsha , Sethuraman KR , Choudhury Sunayana , Shakila R 
Published: January 2021

Objective Communication skills diminish with time and must be applied and updated frequently. Due to various professional constraints, the dentists may not be able to attend training programs to sharpen their skills. During patient interactions, dentists may face difficult situations which they may be unable to handle and, consequently, make them overreact. Therefore, there is a need to provide a platform to freely discuss their feelings, ideas, and take opinion from peers. Methods Training in communication skills customized for dealing with complete denture patients was conducted for the prosthodontic postgraduates. Based on feedback obtained, it was decided to have periodic meetings and the concept of Practice-Oriented–Peer Review for Prosthodontics (PrO-PReP) was introduced. This novel concept is a combination of the Relationship building, exploring Reactions, exploring Content, and Coaching (R2C2) model of residency education and the Balint method. The meetings were scheduled every one or two months based on the available caseload of the patients treated by the postgraduates. Results The thematic analysis of the postgraduates’ self-reflection during the sessions and the video recorded observations (assessed using the Kalamazoo scale) revealed that these sessions were effective in positively engaging the postgraduates to discuss their experiences, reflect on their performances, practice their newly gained skills, and learn from peer sharing. Conclusion The postgraduates felt that they have changed in their working style and were more confident to manage patients. They found such sessions very useful for being updated with the already-learned skills.
Efficacy and safety of laparoscopic pyelolithotomy versus percutaneous nephrolithotomy for treatment of large renal stones: a meta-analysis
Authors: Mao Tie , Wei Na , Yu Jing , Lu Yinghui 
Published: January 2021

Background We aimed to compare the efficacy and safety of laparoscopic pyelolithotomy (LPL) versus percutaneous nephrolithotomy (PCNL) for treating renal stones larger than 2 cm. Methods We searched the PubMed, Embase, Web of Science, SinoMed, and Chinese National Knowledge Infrastructure databases for studies that compared the surgical outcomes of LPL and PCNL. We conducted a meta-analysis of the retrieved studies, expressed as weighted mean difference or risk ratios with 95% confidence intervals. Results We included 25 studies (1831 patients). LPL was associated with a significantly higher stone-free rate, lower rates of blood loss, complementary treatment, blood transfusion, and complications, and less reduction in hemoglobin level compared with PCNL. LPL and PCNL were similar in terms of duration of hospital stay, conversion rate, changes in glomerular filtration rate and creatinine level, and mean time of postoperative analgesia. However, LPL was associated with a longer operation time than PCNL. Conclusion LPL appears to be more effective and safer than PCNL in patients with large renal stones, by increasing the stone-free rate and reducing blood loss, complementary treatment, blood transfusion, and complications compared with PCNL. LPL may thus be a useful modality for treating patients with large renal stones.
Differences in perioperative cardiovascular outcomes in elderly male and female patients undergoing intra-abdominal surgery: a retrospective cohort study
Authors: Chu Song-Yun , Li Pei-Wen , Han Xiao-Ning , Liu Lin , Ye Xiao-Jin , Wang Jie , Zhao Jing , Ding Wen-Hui 
Published: January 2021

Objective Perioperative cardiovascular events constitute the majority of complications in noncardiac surgery. Older and female patients have been less investigated. We aimed to evaluate differences in perioperative cardiovascular outcomes by age and sex. Methods We enrolled 1079 patients (57.5 ± 17.0 years, 42.6% women) undergoing intra-abdominal surgery from July 2007 to June 2008 and compared occurrence of perioperative cardiac events by age (≥65 vs. <65 years) and sex. Multivariable logistic regression was used to investigate associations between age, sex, and outcomes. Results Age ≥65 years was associated with perioperative myocardial infarction (MI) (odds ratio [OR] 2.9, 95% confidence interval [CI]: 1.3–6.6) and total cardiovascular events (OR 2.4, 95% CI: 1.3–4.2). Age ≥65 years was associated with higher perioperative MI risks in men (OR 4.7, 95% CI: 1.3–17.6) than in women (OR 3.1, 95% CI: 1.2–8.3). Advanced age was associated with heart failure in women (OR 13.9, 95% CI: 1.7–110.5). Female sex was a risk factor for heart failure in elderly patients (OR 4.2, 95% CI: 1.1–15.7). Conclusions Advanced age appeared to be associated with increased perioperative cardiac risk but differed by sex. Tailored strategies should be considered with respect to the patient’s sex.
Dietary chlorogenic acid ameliorates oxidative stress and improves endothelial function in diabetic mice via Nrf2 activation
Authors: Wang Dan , Hou Jixin , Wan Jindong , Yang Yi , Liu Sen , Li Xiaoqing , Li Wenzhang , Dai Xiaozhen , Zhou Peng , Liu Weihua , Wang Peijian 
Published: January 2021

Objectives Chlorogenic acid (CGA) is an antioxidant dietary factor. We investigated the effects of CGA on endothelial cell dysfunction in diabetic mice and the mechanistic role of nuclear factor erythroid-related factor 2 (Nrf2) in the antioxidant effect of CGA. Methods Diabetic (db/db) mice were fed normal chow or chow containing 0.02% CGA for 12 weeks. Human umbilical vein endothelial cells (HUVECs) and mouse aortas were treated with normal or high glucose. Results CGA treatment induced upregulation of Nrf2 in HUVECs in a dose-dependent manner. CGA pretreatment prevented reactive oxygen species generation and preserved nitric oxide bioavailability in HUVECs and aortas from wild-type but not Nrf2−/− mice. CGA improved endothelium-dependent relaxation in high glucose-treated aortas from wild-type and db/db mice, but not Nrf2−/− mice. Dietary CGA improved endothelium-dependent relaxation in db/db mice. Conclusions CGA ameliorates endothelial dysfunction in diabetic mice through activation of the Nrf2 anti-oxidative pathway.