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Mengru Lai1 ,* Yuqing Ge2 ,* Meng Chen,1 Siya Sun,1 Jianzhen Chen,1 Rubin Cheng1 1College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, People’s Republic of China; 2First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuqing GeFirst Affiliated Hospital, Zhejiang Chinese Medical University, 54 Youdian Road, Hangzhou, Zhejiang Province 310006, People’s Republic of ChinaTel +86-571-8662-0280Email geyuqing@hotmail.comRubin ChengCollege of Pharmaceutical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, Zhejiang Province 310053, People’s Republic of ChinaTel +86-571-6176-8180Email biothcheng@hotmail.comIntroduction: Pancreatic cancer remains one of the most lethal malignancies and has few treatment options. Saikosaponin D (SSD), a major bioactive triterpene saponin isolated from Bupleurum chinense, has been reported to exert cytotoxicity properties toward many cancer cells. However, the effects of SSD on pancreatic cancer have been little scrutinized.Methods: Here, we investigated the effect of SSD on the proliferation and apoptosis of human pancreatic cancer BxPC3 and PANC1 cells and the mouse pancreatic cancer cell line Pan02. Cell viability was determined by MTT assays and cell apoptosis analyzed by DAPI staining and flow cytometry. Expression levels of apoptosis-regulating markers and activity of the MKK4–JNK signaling pathway were determined by Western blotting. The inhibitor SP600125 was applied to confirm the role of the JNK pathway in SSD efficiency.Results: SSD significantly inhibited the proliferation of BxPC3, PANC1, and Pan02 cells in a concentration- and time-dependent manner. Flow-cytometry analysis indicated obvious apoptosis induction after SSD exposure. Furthermore, SSD significantly triggered cleavage of caspase 3 and caspase 9 proteins and increased the expression of FoxO3a. In addition, activity of the MKK4–JNK pathway was dramatically increased after treatment with SSD in BxPC3 cells. SSD obviously stimulated phosphorylation of JNK, cJun, and SEK1/MKK4 proteins within 30 minutes. The addition of SP600125 blocked the activation of SSD on the MKK4–JNK regulatory pathway and reversed the effects of SSD on proliferation inhibition and apoptosis induction in BxPC3 cells.Conclusion: These results revealed that SSD was capable of suppressing tumor growth and promoting apoptosis of pancreatic cancer cells via targeting the MKK4–JNK signaling pathway, indicating the possibility of further developing SSD as a potential therapeutic candidate for pancreatic cancer.Keywords: saikosaponin D, pancreatic cancer, proliferation inhibition, apoptosis induction, MKK4–JNK pathway

Xicheng Wang,1 Jianfeng Zhou,2 Yan Li,1 Yuping Ge,2 Yanping Zhou,2 Chunmei Bai,2 Lin Shen1 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China; 2Department of Oncology, Peking Union Medical College Hospital, Beijing 100032, People’s Republic of ChinaCorrespondence: Lin ShenKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, No. 52, Fu Cheng Road, Hai Dian District, Beijing, People’s Republic of ChinaTel +86-010-88156175Fax +86-010-88196561Email linshenpku@163.comChunmei BaiDepartment of Oncology, Peking Union Medical College Hospital, No. 41, Da Mu Cang Hutong, Xi Cheng District, Beijing, People’s Republic of ChinaTel/ Fax +86-010-69158315Email baichunmei1964@163.comPurpose: Trifluridine/tipiracil (FTD/TPI) is approved in Japan, the United States (US), and Europe for metastatic colorectal cancer (mCRC) refractory to standard therapies. This Phase 1b open-label study focused on the pharmacokinetic (PK) and toxicity profiles of FTD/TPI in Chinese patients with solid tumors.Methods: Patients with definitive histologically or cytologically confirmed advanced/metastatic solid tumors refractory to standard treatments were enrolled. FTD/TPI (35 mg/m2) was administered orally twice daily for five consecutive days, followed by a 2-day recovery. Treatment was repeated for five consecutive days, followed by a 16-day recovery. The primary objective was to assess PK characteristics of FTD, 5-trifluoromethyl-2,4 (1H,3H)-pyrimidinedione (FTY; an inactive form of FTD), and TPI, calculated from plasma concentrations. Additionally, these PK values were compared with those from similar Phase 1 studies in patients from Japan and the US, using Tukey–Kramer’s honestly significant difference (HSD) multiple comparison tests. Safety and preliminary efficacy of FTD/TPI were assessed.Results: Fifteen patients (12 males, three females) were enrolled, most with CRC (87%). Geometric mean analysis showed that maximum plasma concentration (Cmax) of FTD increased after multiple administration (from day 1 [3019.5 ng/mL] to day 12 [3693.1 ng/mL]), and the exposure (AUC0-t) increased 2.4-fold (day 1:7796.6 ng/mL•h; day 12:18,181.3 ng/mL•h). There was no meaningful change in the exposure to FTY and TPI throughout the study. HSD tests showed comparable PK for FTD, FTY, and TPI between Chinese and Japanese patients, and comparable exposure to FTD between Chinese and US patients. Eight patients (53.3%) experienced Grade 3 treatment-emergent adverse events, most frequently anemia and fatigue (13.3%, two events each). Median progression-free survival was 1.9 months.Conclusion: FTD/TPI had an acceptable safety and efficacy profile and PK characteristics were comparable between Chinese, Japanese, and US patients, suggesting that this treatment may be suitable for Chinese patients with refractory mCRC.Trial Registration: This trial was registered at clinicaltrials.gov as NCT02261532.Keywords: Chinese, colorectal cancer, pharmacokinetics, safety, trifluridine/tipiracil

Yonghao Feng, 1,* Ying Ge, 2,* Men Wu, 1 Yangmei Xie, 3 Ming Wang, 3 Yinghui Chen, 3 Xiaohong Shi 1 1Department of Endocrinology, Jinshan Hospital, Fudan University, Shanghai 201508, People’s Republic of China; 2Department of General Medicine, Community Health Service Center of Shanghai Jinshan Industrial Zone, Shanghai 201506, People’s Republic of China; 3Department of Neurology, Jinshan Hospital, Fudan University, Shanghai 201508, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaohong ShiDepartment of Endocrinology, Jinshan Hospital, Fudan University, No. 1508 Longhang Road, Shanghai 201508, People’s Republic of ChinaTel +86 21-34189990Fax +86 21-57039502Email xiaohongshi@fudan.edu.cnYinghui ChenDepartment of Neurology, Jinshan Hospital, Fudan University, No. 1508, Longhang Road, Shanghai 201508, People’s Republic of ChinaTel +86 21-34189990Fax +86 21-57039502Email yinghuichen@fudan.edu.cnBackground: Long non-coding RNAs (lncRNAs), as competing endogenous RNAs (ceRNAs), can regulate various pathophysiological processes by binding competitively to microRNAs at the post-transcription level. Our previous work demonstrated that miR-146a-5p was lowly expressed in diabetic peripheral neuropathy (DPN) rats. However, the ceRNA network in DPN mediated by lncRNAs and miR-146a-5p remains to be explored.Methods: Two groups of rats (n=4 per group), a type 2 diabetes (T2DM) group and a DPN group, were used in this study. Sciatic nerve conduction velocity (NCV) of each rat was determined at the 6th and the 12th week. LncRNA microarray analysis was performed in the sciatic nerve of DPN and T2DM rats. Based on the TargetScan algorithm and the miRanda database, we determined the differentially expressed (DE) lncRNAs bound to miR-146a-5p. Furthermore, we verified the DE lncRNAs potentially bound to miR-146a-5p by qRT-PCR. The genes targeted by miR-146a-5p were identified by bioinformatics prediction and experimental techniques.Results: We found 413 DE lncRNAs between DPN and T2DM rats (|log2FC| ≥ 2 and adjust P ≤ 0.05). Eight DE lncRNAs were predicted to bind to miR-146a-5p by both algorithms, of which four were verified by qRT-PCR. TRAF6, IRAK1, and SMAD4 were identified as miR-146a-5p targeted genes and were predominantly enriched in the inflammatory signaling pathway.Conclusion: LncRNAs may contribute to the pathogenesis of DPN by regulating inflammation through functioning as ceRNAs of miR-146a-5p.Keywords: diabetic peripheral neuropathy, long non-coding RNA, MicroRNA, inflammation

How do we learn the sound systems of different languages from the complex speech input around us? One influential perspective is that listeners can track the statistical distribution of acoustic features in speech to promote learning. However, although str ong evidence has been found for the role of input statistics in phonological development, the underlying learning mechanisms that drive statistical learningHow do we learn the sound systems of different languages from the complex speech input around us? One influential perspective is that listeners can track the statistical distribution of acoustic features in speech to promote learning. However, although str ong evidence has been found for the role of input statistics in phonological development, the underlying learning mechanisms that drive statistical learning remain unclear. The current study investigates this issue under a discriminative model of language learning originated from animal learning research, which suggests that learning is driven by prediction error and cue competition. Specifically, the model proposes that a learning environment that allows for predictions to be made on the basis of the avail able linguistic cues leads to better learning, since learners can compare their predictions with actual outcomes and if there are discrepancies between the two, they can learn from the prediction error. The predictions of the discriminative learning mode l are tested in two artificial language learning experiments with adult native speakers of Chinese. The artificial language was designed to contain a geminate consonant cue which is used contrastively (e.g. fato and fatto have different meanings) but is non native (and hence less salient) to Chinese speakers, as well as a tonal cue that Chinese speakers are familiar with but is not used to contrast lexical meanings. Subjects learned words in the artificial language either in a discriminative (cue outcome) o rder or a non discriminative (outcome cue) order. In the discriminative order, learners heard words immediately before seeing the referents, which enables them to make predictions about the referent (the outcome) on the basis of the acoustic features of the words (the cues). This further allows learners to adjust their expectations when a predicted referent does not occur after particular cues and learn from such prediction error. On the other hand, the non discriminative order had referents being viewed before hearing the words, and hence there is no opportunity to make predictions about referents and participants cannot learn from cue competition and prediction error. The referents and participants cannot learn from cue competition and prediction error. The predicted benefit of the discriminative order was not found in any tests of Experimenpredicted benefit of the discriminative order was not found in any tests of Experiment t 1, however in this experiment there was limited exposure during training. Experiment 1, however in this experiment there was limited exposure during training. Experiment 2 thus replicated the first experiment with increased exposure. There was tentative 2 thus replicated the first experiment with increased exposure. There was tentative evidence in the generalization test that learners in the discriminative order conditievidence in the generalization test that learners in the discriminative order condition on had learned that tones were uninformative in the language, which is in line with the had learned that tones were uninformative in the language, which is in line with the predictions, but no evidence that learners had learned the geminate consonant cue. predictions, but no evidence that learners had learned the geminate consonant cue. Taken together, this study generally supports the discriminative approach to speech Taken together, this study generally supports the discriminative approach to speech ssound learning with adult learners. It suggests potential directions for future ound learning with adult learners. It suggests potential directions for future theoretical language learning research which may have further implications for the theoretical language learning research which may have further implications for the design of language teaching programs. design of language teaching programs. remain unclear. The current study investigates this issue under a discriminative model of language learning originated from animal learning research, which suggests that learning is driven by prediction error and cue competition. Specifically, the model proposes that a learning environment that allows for predictions to be made on the basis of the avail able linguistic cues leads to better learning, since learners can compare their predictions with actual outcomes and if there are discrepancies between the two, they can learn from the prediction error. The predictions of the discriminative learning mode l are tested in two artificial language learning experiments with adult native speakers of Chinese. The artificial language was designed to contain a geminate consonant cue which is used contrastively (e.g. fato and fatto have different meanings) but is no n native (and hence less salient) to Chinese speakers, as well as a tonal cue that Chinese speakers are familiar with but is not used to contrast lexical meanings. Subjects learned words in the artificial language either in a discriminative (cue outcome) o rder or a non discriminative (outcome cue) order. In the discriminative order, learners heard words immediately before seeing the referents, which enables them to make predictions about the referent (the outcome) on the basis of the acoustic features of th e words (the cues). This further allows learners to adjust their expectations when a predicted referent does not occur after particular cues and learn from such prediction error. On the other hand, the non discriminative order had referents being viewed be fore hearing the words, and hence there is no opportunity to make predictions about referents and participants cannot learn from cue competition and prediction error. The referents and participants cannot learn from cue competition and prediction error. The predicted benefit of the discriminative order was not found in any tests of Experimenpredicted benefit of the discriminative order was not found in any tests of Experiment t 1, however in this experiment there was limited exposure during training. Experiment 1, however in this experiment there was limited exposure during training. Experiment 2 thus replicated the first experiment with increased exposure. There was tentative 2 thus replicated the first experiment with increased exposure. There was tentative evidence in the generalization test that learners in the discriminative order conditievidence in the generalization test that learners in the discriminative order condition on had learned that tones were uninformative in the language, which is in line with the had learned that tones were uninformative in the language, which is in line with the predictions, but no evidence that learners had learned the geminate consonant cue. predictions, but no evidence that learners had learned the geminate consonant cue. Taken together, this study generally supports the discriminative approach to speech Taken together, this study generally supports the discriminative approach to speech ssound learning with adult learners. It suggests potential directions for future ound learning with adult learners. It suggests potential directions for future theoretical language learning research which may have further implications for the theoretical language learning research which may have further implications for the design of language teaching programs. design of language teaching programs.

Objectives: The aim of this study was to compare the costs of a noninvasive cardiac magnetic resonance (CMR)–guided strategy versus 2 invasive strategies with and without fractional flow reserve (FFR). Background: Coronary artery disease (CAD) is a major contributor to the public health burden. Stress perfusion CMR has excellent accuracy to detect CAD. International guidelines recommend as a first step noninvasive testing of patients in stable condition with known or suspected CAD. However, nonadherence in routine clinical practice is high. Methods: In the EuroCMR (European Cardiovascular Magnetic Resonance) registry (n = 3,647, 59 centers, 18 countries) and the U.S.-based SPINS (Stress-CMR Perfusion Imaging in the United States) registry (n = 2,349, 13 centers, 11 states), costs were calculated for 12 health care systems (8 in Europe, the United States, 2 in Latin America, and 1 in Asia). Costs included diagnostic examinations (CMR and x-ray coronary angiography [CXA] with and without FFR), revascularizations, and complications during 1-year follow-up. Seven subgroup analyses covered low- to high-risk cohorts. Patients with ischemia-positive CMR underwent CXA and revascularization at the treating physician's discretion (CMR+CXA strategy). In the hypothetical invasive CXA+FFR strategy, costs were calculated for initial CXA and FFR in vessels with ≥50% stenoses, assuming the same proportion of revascularizations and complications as with the CMR+CXA strategy and FFR-positive rates as given in the published research. In the CXA-only strategy, costs included CXA and revascularizations of ≥50% stenoses. Results: Consistent cost savings were observed for the CMR+CXA strategy compared with the CXA+FFR strategy in all 12 health care systems, ranging from 42% ± 20% and 52% ± 15% in low-risk EuroCMR and SPINS patients with atypical chest pain, respectively, to 31% ± 16% in high-risk SPINS patients with known CAD (P < 0.0001 vs 0 in all groups). Cost savings were even higher compared with CXA only, at 63% ± 11%, 73% ± 6%, and 52% ± 9%, respectively (P < 0.0001 vs 0 in all groups). Conclusions: In 12 health care systems, a CMR+CXA strategy yielded consistent moderate to high cost savings compared with a hypothetical CXA+FFR strategy over the entire spectrum of risk. Cost savings were consistently high compared with CXA only for all risk groups. © 2022 The Authors

Thesis for an academic degree «Master» specialty 1-25 80 01 «Economics». Scientific advisеr : candidate of philosophical sciences, ass. professor Boretskaya V. K.

Материалы XXII Междунар. науч.-техн. конф. студентов, аспирантов и молодых ученых, Гомель, 28–29 апр. 2022 г.

Martensitic transformations are important for many materials exhibiting magneto-, elasto- and barcaloric effects and often the functional properties benefit from additional magnetic transformations. For caloric applications, thin films are of particular interest due to their fast heat exchange, which promises a high cooling power. In particular epitaxial films are a model system to understand the formation of the martensitic microstructure.[1] However, commonly transformations from austenite to martensite only occur during cooling. The recent observation of a so-called reentrant transformation obtained much interest, as an additional transformation from martensite to austenite was observed during further cooling.[2,3] A reentrant transition increases both, the number of new physical effects and the possible applications. However, reports are currently very few and only on bulk materials. Will this phenomenon occur also in thin films? Will the martensitic transformation and microstructure differ when induced by heating or cooling? Also for caloric applications, reentrant martensite is interesting as it may enable bidirectional caloric effects driven by deformation and recovery of the ferromagnetic shape memory alloys (FSMA) through both, heating and cooling. As a model system, epitaxial Co-Cr-Ga-Si ferromagnetic shape memory thin films were grown by DC magnetron sputtering. To obtain epitaxial growth, films were deposited on different substrates as well as orientations. We identify MgO(100) as the optimum substrate. Films were grown at different deposition temperatures and the influence of an additional postannealing process was examined to understand the influence on elemental composition, structure, microstructure and the transformation behavior. As a kind of summary, Fig.1-a depicts a phase diagram of all samples prepared. Under optimum conditions, we obtain epitaxial growth, as evident from pole figure measurements of an austenitic film (Fig. 1-b). When films are subjected to an additional heat treatment at 800°C, films are martensitic at room temperature, which is evident the peak splitting in pole figure measurements (Fig. 2-a) and agree well with pole figures calculated by the phenomenological theory of martensite with a c/a ratio of 1.37 (Fig. 2-b). Furthermore, the microstructure becomes granular and twin boundaries become visible. Though annealing improves the martensitic transformation, we observe a degradation of the ferromagnetic transition. To sum up, we could demonstrate epitaxial growth of Co-Cr-Ga-Si films, which are martensitic and ferromagnetic at room temperature. This is a key step to utilize the additional possibilities of reentrant martensite also for thin films.

Complete supplemental material for manuscript, includes 4 tables and 3 figures

The heart is innervated by the autonomic nervous system, which can be divided into sympathetic and parasympathetic parts. The balance between cardiac sympathetic and parasympathetic innervation is critical for maintaining normal cardiac function. After myocardial infarction, sympathetic hyperinnervation has been discovered in patients as well as in animal models, which has raised growing awareness in relation to arrhythmogenesis. However the mechanism is not clear yet. In this thesis, we hypothesize a role for epicardium-derived cells (EPDCs) in this process. In addition, we aimed to study ganglia remodeling after myocardial infarction. We explored: i) the role of EPDCs in promoting cardiac sympathetic re-/hyperinnervation after cardiac damage in vitro, ii) the impact of sex of EPDCs on cardiac innervation, iii) the generation of inducible proliferative human EPDCs (iEPDCs), iv) neuronal remodeling of superior cervical ganglia after myocardial infarction and v) the molecular signature of SCG revealed by single nucleus RNA sequencing.

OBJECTIVES The authors investigated the incremental prognostic value of entropy, a novel measure of myocardial tissue heterogeneity by cardiac magnetic resonance (CMR) imaging in patients presenting with ventricular arrhythmias (VAs). BACKGROUND CMR can characterize myocardial areas serving as arrhythmogenic substrate. METHODS Consecutive patients undergoing CMR imaging for VAs were followed for major adverse cardiac events (MACEs) defined by all-cause death, incident VAs requiring therapy, or heart failure hospitalization. Entropy was derived from the probability distribution of pixel signal intensities of the left ventricular (LV) myocardium. RESULTS A total of 583 patients (age 54 +/- 15 years, female 39%, left ventricular ejection fraction [LVEF] 54 +/- 13%) were followed for a median of 4.4 years and experienced 141 MACEs. Entropy showed strong unadjusted association with MACE (HR: 1.88; 95% CI: 1.63-2.17; P < 0.001). In a multivariable model including LVEF, QRS duration, late gadolinium enhancement, and presenting arrhythmia, entropy maintained independent association with MACE (HR: 1.61; 95% CI: 1.32-1.96; P < 0.001). Entropy was further significantly associated with MACE in patients without myocardial scar (HR: 2.43; 95% CI: 1.55-3.82; P < 0.001) and in those presenting with nonsustained VAs (HR: 2.16; 95% CI: 1.43-3.25; P < 0.001). Addition of LV entropy to the baseline multivariable model significantly improved model performance (C-statistic improvement: 0.725 to 0.754; P 1/4 0.003) and risk reclassification. CONCLUSIONS In patients with VAs, CMR-assessed LV entropy was independently associated with MACE and provided incremental prognostic value, on top of LVEF and late gadolinium enhancement. LV entropy assessment may help risk stratification in patients with absence of myocardial scar or with nonsustained VAs.(C) 2022 by the American College of Cardiology Foundation.