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Ying Chen,1 Mengxia Yan,1 Haoyan Chen,1 Yanan Sheng,2 Zhenhua Wang,3 Bin Wu1 1Clinical Research Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 201112, People’s Republic of China; 2Medical Affairs, Takeda (China) International Trading Company, Beijing, 100006, People’s Republic of China; 3Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201112, People’s Republic of ChinaCorrespondence: Bin Wu, Tel/Fax +86-21-68383427, Email scilwsjtu-wb@yahoo.comPurpose: Understanding the quality of life and the factors that influence it for patients with short bowel syndrome (SBS) and their caregivers is of utmost importance in order to enhance their well-being. Therefore, This study aimed to provide a comprehensive understanding of the impact of SBS on patients and their caregivers, as well as its associated factors, by synthesizing the available evidence.Methods: A systematic review of the literature was done using PubMed, Embase databases, CNKI, and ISPOR conference papers. Included articles were manually searched to identify any other relevant studies. Quality was assessed using appropriate Joanna Briggs Institute critical appraisal tools.Results: This review included 16 studies, comprising 15 observational studies and 1 randomized controlled trial. The findings revealed that the QoL of patients with SBS was lower than that of the general population regarding physical functioning and psychological domain. Meanwhile, caregivers experienced challenges in maintaining their QoL. The QoL of SBS patients was found to be influenced by various factors such as treatment, age, sex, stoma, and small intestine length. Among them, the treatment is the most noteworthy factor that can be effectively improved through external interventions.Conclusion: While numerous studies have provided insights into the compromised QoL experienced by individuals with SBS and their caregivers, there remains a scarcity of large-sample quantitative investigations examining the determinants of QoL. The existing body of literature on caregivers is also notably deficient.Keywords: caregiver, malabsorption, quality of life, short bowel syndrome, stoma, age

Seismic velocities in rocks are highly sensitive to changes in permanent deformation and fluid content. The temporal variation of seismic velocity during the preparation phase of earthquakes has been well documented in laboratories but rarely observed in nature. It has been recently found that some anthropogenic, high-frequency (>1 Hz) seismic sources are powerful enough to generate body waves that travel down to a few kilometers and can be used to monitor fault zones at seismogenic depth. Anthropogenic seismic sources typically have fixed spatial distribution and provide new perspectives for velocity monitoring. In this work, we propose a systematic workflow to seek such powerful seismic sources in a rapid and straightforward manner. We tackle the problem from a statistical point of view, considering that persistent, powerful seismic sources yield highly coherent correlation functions (CFs) between pairs of seismic sensors. The algorithm is tested in California and Japan. Multiple sites close to fault zones show high-frequency CFs stable for an extended period of time. These findings have great potential for monitoring fault zones, including the San Jacinto Fault and the Ridgecrest area in Southern California, Napa in Northern California, and faults in central Japan. However, extra steps, such as beamforming or polarization analysis, are required to determine the dominant seismic sources and study the source characteristics, which are crucial to interpreting the velocity monitoring results. Train tremors identified by the present approach have been successfully used for seismic velocity monitoring of the San Jacinto Fault in previous studies.

Siyuan Zhou,1,2 Xiaojie Hu,1,2 Yunfei Wang,1,2 Wenting Fei,2 Yuqin Sheng,2 Huafa Que1,2 1Department of Traditional Chinese Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Longhua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Huafa Que, Department of Traditional Chinese Surgery, Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine, No. 725, Wanping South Road, Xuhui District, Shanghai, 200032, People’s Republic of China, Tel +86 18917763260, Email huafaque@126.comObjective: Diabetic foot ulcer (DFU) frequently leads to infections, with infected DFUs being a common cause of amputation. Infection by methicillin-resistant Staphylococcus aureus (MRSA) notably increases the necessity for amputation and surgical debridement in affected individuals. Consequently, determining the prevalence and trends of MRSA in patients with DFU is of critical importance. This study aimed to assess the global prevalence and to identify trends in the occurrence of MRSA in tissue or wound swab samples from DFU patients.Methods: We conducted a comprehensive literature search across PubMed, Embase, Scopus, and Ovid, spanning from the inception of these databases to July 2023, imposing no language restrictions. The inclusion criteria required that the studies report on 30 or more patients with DFU. Additionally, we categorized our analysis based on geographic region, publication date, and the economic status of the patient’s domicile. Our primary endpoint was to ascertain the prevalence of MRSA in DFUs. This systematic review has been registered at (https://www.crd.york.ac.uk/prospero/), with the identifier CRD 42023444360.Results: Our analysis encompassed 40 studies involving 12,924 patients across 20 countries. We found that the overall prevalence of MRSA in DFU was 17% (95% Confidence Interval [CI] 0.14– 0.20). Regional prevalence varied significantly: in South America, it was 61% (95% CI 0.46– 0.76), in North America 20% (95% CI 0.12– 0.27), in Europe 19% (95% CI 0.14– 0.25), in Africa 13% (95% CI 0.06– 0.20), and in other subgroups 11% (95% CI 0.08– 0.15). The prevalence of MRSA in DFUs also differed according to the economic status of the countries: 19% (95% CI 0.15– 0.23) in high-income countries, 24% (95% CI 0.1– 0.37) in upper-middle-income countries, 11% (95% CI 0.07– 0.15) in lower-middle-income countries, and 20% (95% CI 0.13– 0.27) in low-income countries. Notably, there has been a decline in MRSA prevalence, from 25% before 2010 to 9% thereafter.Conclusion: This meta-analysis reveals a decreasing yet still significant global prevalence of MRSA in DFUs. This trend has important implications for antimicrobial resistance and underscores the need for developing targeted programs focusing on infection prevention and exploring alternative therapeutic strategies.Keywords: diabetic foot ulcers, global prevalence, epidemiological trends, systematic review, meta-analysis

Yu-Yun Zhang,1 Wei Li,2 Yu Sheng,1 Qun Wang,3,&ast; Fang Zhao,4,&ast; Ying Wei4 1School of Nursing, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Endocrinology, Peking Union Medical College Hospital, Beijing, People’s Republic of China; 3Endocrinology and Metabolism Department, Peking University Third Hospital, Beijing, People’s Republic of China; 4Department of Endocrinology, China-Japan Friendship Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Sheng, School of Nursing, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 33 Badachu Road, Shijingshan District, Beijing, People’s Republic of China, Tel +86 138 1069 1298, Email shengyupumc2020@163.comPurpose: To address the prevalence of diabetes distress (DD) and its correlators in adults with type 2 diabetes.Patients and Methods: During 2021 and 2022, we conducted a cross-sectional study in three Class A tertiary comprehensive hospitals in China, and received 947 participants who completed a printed survey covering DD, demographic, diabetic, physiological, and psychosocial factors. We used Jonckheere-Terpstra, chi-square, and Fisher’s exact tests to assess intergroup differences between different levels of DD. We used ordinal logistic regression analysis to analyze correlators of DD further.Results: The prevalence of DD was 34.64%. In univariate analysis, those with lower satisfaction with financial status, longer durations of diabetes, more complications, higher glycemia, more severe insomnia, treatment by medications only, poorer lifestyle interventions, fewer self-care activities, more types and frequencies of insulin injections, and spending more money and time on treatment were susceptible to DD. Type D personality, negative illness perceptions, negative coping styles, and psychological effects of major life events were related to higher DD. Hope, self-efficacy, positive coping styles, and social support can reduce DD. In ordinal logistic regression analysis, hypoglycemic episode (β=− 1.118, p=0.019, “have hypoglycemic” as reference) and Brief Illness Perception Questionnaire (β=0.090, p< 0.001) were significant positive correlators for DD, while diet intervention (β=0.803, p=0.022, “have diet intervention” as reference), money spent on diabetes treatment (β

Yunjian Sheng,1,&ast; Yu Zeng,1,&ast; Wenling Luo,1 Xuemei Zhang,1 Hang Wang,2 Jiahuan Jiao3 1Department of Infectious Diseases, the Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2Department of Gastroenterology, Dazhou Hospital of Integrated Traditional and Western Medicine, Dazhou, Sichuan, People’s Republic of China; 3Department of Infectious Diseases, the People’s Hospital of Leshan, Leshan, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunjian Sheng, Department of Infectious Diseases, the Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Luzhou, Sichuan Province, People’s Republic of China, Email sheng200410@163.comBackground: Acute-on-chronic liver failure is a common clinical syndrome with high short-term mortality, and early assessment of its mortality risk is crucial, but the search for valid and accurate prognostic biomarkers is a challenging endeavor. The purpose of this study was to investigate the predictive value of the prothrombin time-international normalized ratio to albumin ratio (PTAR) for mortality in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF).Patients and methods: A total of 354 patients with HBV-ACLF were included in the retrospective study. Patients were divided into survival and non-survival groups based on 90-day follow-up. Cox regression analysis was used to explore the relationship between PTAR and 90-day mortality in patients with HBV-ACLF. The area under the receiver operating characteristic curve was used to evaluate the effectiveness of PTAR in predicting mortality.Results: PTAR was significantly higher in non-survivors than in survivors. The results of multivariate analysis showed that PTAR was a valid independent predictor of mortality in patients with HBV-ACLF. Its predictive ability for mortality was similar to that of the Child-Turcotte-Pugh score, the end-stage liver disease model (MELD) score, and the MELD-sodium score.Conclusion: PTAR may be a simple and effective tool for predicting the prognosis of patients with HBV-ACLF.Keywords: acute-on-chronic liver failure, hepatitis B virus, prothrombin time-international normalized ratio to albumin ratio, prognosis

Magnetic fluctuations is the leading candidate for pairing in cuprate, iron-based, and heavy fermion superconductors. This view is challenged by the recent discovery of nodeless superconductivity in CeCu2Si2, and calls for a detailed understanding of the corresponding magnetic fluctuations. Here, we mapped out the magnetic excitations in superconducting (S-type) CeCu2Si2 using inelastic neutron scattering, finding a strongly asymmetric dispersion for E ≲ 1.5 meV, which at higher energies evolves into broad columnar magnetic excitations that extend to E ≳ 5 meV. While low-energy magnetic excitations exhibit marked three-dimensional characteristics, the high-energy magnetic excitations in CeCu2Si2 are almost two-dimensional, reminiscent of paramagnons found in cuprate and iron-based superconductors. By comparing our experimental findings with calculations in the random-phase approximation,we find that the magnetic excitations in CeCu2Si2 arise from quasiparticles associated with its heavy electron band, which are also responsible for superconductivity. Our results provide a basis for understanding magnetism and superconductivity in CeCu2Si2, and demonstrate the utility of neutron scattering in probing band renormalization in heavy fermion metals.

Jihai Chen,1,2 Lijun Wei,2 Xiaoxia Zhu,2 Wenli Xu,2 Yuxin Zou,2 Xinyu Qi,2 Jia Fang,2 Xiaodong Wang,2 Xiaolan Shi,1 Yunlu Sheng,2 Guoxian Ding,2 Xiaojun Ouyang,1 Yu Duan2 1Department of Geriatric, Geriatric Hospital of Nanjing Medical University, Nanjing, 210024, People’s Republic of China; 2Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of ChinaCorrespondence: Yu Duan, Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People’s Republic of China, Email duanyujsph@163.com Xiaojun Ouyang, Department of Geriatric, Geriatric Hospital of Nanjing Medical University, Luojia Road 30, Nanjing, 210024, People’s Republic of China, Email xiaojun_ouyang@aliyun.comBackground and Aims: Sarcopenia is a common disease in the elderly, and the thyroid hormone (TH) might participate in the pathogenesis of sarcopenia. However, the results of previous studies were not completely consistent. We performed this study to investigate the association between THs and sarcopenia in a Chinese elderly euthyroid population.Subjects and Methods: A total of 309 Chinese elderly euthyroid subjects with an average age of 85.19 ± 7.8 years were enrolled. Participants were divided into four groups (non-sarcopenia, possible sarcopenia, sarcopenia and serve sarcopenia) according to the consensus update of AWGS in 2019. Serum levels of TT3, FT3, TT4, FT4, TSH, rT3 and TBG were measured. Muscle mass was measured by multifrequency bioelectrical impedance analysis, hand grip (HG) was represented by spring-type dynamometer, and gait speed (GS) was determined by 6-metre walk test. The FRAIL scale was used to assess frailty.Results: Compared to the non-sarcopenia group, the sarcopenia group showed a significant increase in age and FRIAL score, while FT3 and TT3 levels decreased significantly. Partial correlation analysis (adjusted by age, gender and the scores of FRIAL scale) indicated that FT3, TT3 and TSH had significant positive correlations with HG, and there also was a significant positive correlation between TT3 and GS. In addition, after adjusting for age, gender, BMI, ALT, sCr, and score on the FRAIL scale, the multivariate linear regression analysis showed that TT3 was positively associated with muscle strength and negatively associated with sarcopenia risk.Conclusion: There is an association between the low TT3 level and sarcopenia. Therefore, maintaining higher T3 concentrations within the normal range appears to be beneficial for sarcopenia in the elderly. In addition, due to the fluctuation of FT3, TT3 is a more stable and practical indicator to evaluate the relationship between sarcopenia and thyroid hormone in the elderly euthyroid population.Graphical Abstract: Keywords: sarcopenia, thyroid hormone, elderly, muscle strength

Xiaohui Zhang,1– 3 Da Zhen,4 Xuemei Li,1,2,5 Faling Yi,1,2,5 Zhanhao Zhang,1,2,5 Wei Yang,1,2,6 Xuguang Li,1,2,5 Yemeng Sheng,1,2,5 Xiaoli Liu,1,2,5 Tianbo Jin,1,2,5 Yongjun He1,2,5 1Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, People’s Republic of China; 2Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, People’s Republic of China; 3Department of Ultrasound, the Affiliated Hospital of Xizang Minzu University, Xianyang, People’s Republic of China; 4Department of Medical, Tibet Autonomous Region Maternity and Children’s Hospital, Lhasa, People’s Republic of China; 5School of Medicine, Xizang Minzu University, Xianyang, People’s Republic of China; 6Department of Emergency, the Affiliated Hospital of Xizang Minzu University, Xianyang, People’s Republic of ChinaCorrespondence: Tianbo Jin; Yongjun He, Xizang Minzu University, &num;6 East Wenhui Road, Xianyang, Shaanxi, 712082, People’s Republic of China, Email tianbo__jin@163.com; 545139647@qq.comBackground: Ventricular septal defect (VSD) is the most common congenital cardiac abnormality in children and the second most common in adults. This study aimed to explore the potentially causative genes in VSD patients in the Chinese Tibetan population, and to provide a theoretical basis for the genetic mechanism of VSD.Methods: Peripheral venous blood was collected from 20 VSD subjects, and whole-genome DNA was extracted. High-throughput sequencing was performed on qualified DNA samples using whole-exome sequencing (WES) technology. After filtering, detecting, and annotating qualified data, single nucleotide variations (SNVs) and insertion-deletion (InDel) markers were analyzed, and data processing software such as GATK, SIFT, Polyphen, and MutationTaster were used for comparative evaluation and prediction of pathogenic deleterious variants associated with VSD.Results: A total of 4793 variant loci, including 4168 SNVs, 557 InDels and 68 unknown loci and 2566 variant genes were obtained from 20 VSD subjects through bioinformatics analysis. According to the screening of the prediction software and database, the occurrence of VSD was predicted to be associated with five inherited pathogenic gene mutations, all of which were missense mutations, including NOTCH2 (c.1396C >A:p.Gln466Lys), ATIC (c.235C >T:p.Arg79Cys), MRI1 (c.629G >A:p.Arg210Gln), SLC6A13 (c.1138G >A:p.Gly380Arg), ATP13A2 (c.1363C >T:p.Arg455Trp).Conclusion: This study demonstrated that NOTCH2, ATIC, MRI1, SLC6A13, ATP13A2 gene variants were potentially associated with VSD in Chinese Tibetan population.Keywords: ventricular septal defect, genes, genetic variation, whole-exome sequencing

Background The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. It has been suggested that the adenosine pathway contributes to the ability of PDAC to evade the immune system and hence, its resistance to immuno-oncology therapies (IOT), by generating extracellular adenosine (eAdo).Methods Using genetically engineered allograft models of PDAC in syngeneic mice with defined and different immune infiltration and response to IOT and autochthonous tumors in KPC mice we investigated the impact of the adenosine pathway on the PDAC tumor microenvironment (TME). Flow cytometry and imaging mass cytometry (IMC) were used to characterize the subpopulation frequency and spatial distribution of tumor-infiltrating immune cells. Mass spectrometry imaging (MSI) was used to visualize adenosine compartmentalization in the PDAC tumors. RNA sequencing was used to evaluate the influence of the adenosine pathway on the shaping of the immune milieu and correlate our findings to published data sets in human PDAC.Results We demonstrated high expression of adenosine pathway components in tumor-infiltrating immune cells (particularly myeloid populations) in the murine models. MSI demonstrated that extracellular adenosine distribution is heterogeneous in tumors, with high concentrations in peri-necrotic, hypoxic regions, associated with rich myeloid infiltration, demonstrated using IMC. Protumorigenic M2 macrophages express high levels of the Adora2a receptor; particularly in the IOT resistant model. Blocking the in vivo formation and function of eAdo (Adoi), using a combination of anti-CD73 antibody and an Adora2a inhibitor slowed tumor growth and reduced metastatic burden. Additionally, blocking the adenosine pathway improved the efficacy of combinations of cytotoxic agents or immunotherapy. Adoi remodeled the TME, by reducing the infiltration of M2 macrophages and regulatory T cells. RNA sequencing analysis showed that genes related to immune modulation, hypoxia and tumor stroma were downregulated following Adoi and a specific adenosine signature derived from this is associated with a poorer prognosis in patients with PDAC.Conclusions The formation of eAdo promotes the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway may represent a strategy to modulate the PDAC immune milieu and improve therapy response in patients with PDAC.

AbstractThe Third Pole (TP) is experiencing rapid warming and is currently in its warmest period in the past 2,000 years. This paper reviews the latest development in multidisciplinary TP research associated with this warming. The rapid warming facilitates intense and broad glacier melt over most of the TP, although some glaciers in the northwest are advancing. By heating the atmosphere and reducing snow/ice albedo, aerosols also contribute to the glaciers melting. Glacier melt is accompanied by lake expansion and intensification of the water cycle over the TP. Precipitation has increased over the eastern and northwestern TP. Meanwhile, the TP is greening and most regions are experiencing advancing phenological trends, although over the southwest there is a spring phenological delay mainly in response to the recent decline in spring precipitation. Atmospheric and terrestrial thermal and dynamical processes over the TP affect the Asian monsoon at different scales. Recent evidence indicates substantial roles that mesoscale convective systems play in the TP’s precipitation as well as an association between soil moisture anomalies in the TP and the Indian monsoon. Moreover, an increase in geohazard events has been associated with recent environmental changes, some of which have had catastrophic consequences caused by glacial lake outbursts and landslides. Active debris flows are growing in both frequency of occurrences and spatial scale. Meanwhile, new types of disasters, such as the twin ice avalanches in Ali in 2016, are now appearing in the region. Adaptation and mitigation measures should be taken to help societies’ preparation for future environmental challenges. Some key issues for future TP studies are also discussed.

Semiconductive transition metal dichalcogenides (TMDs) have been considered as next generation semiconductors, but to date most device investigations are still based on microscale exfoliation with a low yield. Wafer scale growth of TMDs has been reported but effective doping approaches remain challenging due to their atomically thick nature. This work reports the synthesis of wafer-scale continuous few-layer PtSe2 films with effective doping in a controllable manner. Chemical component analyses confirm that both n-doping and p-doping can be effectively modulated through a controlled selenization process. The electrical properties of PtSe2 films have been systematically studied by fabricating top-gated field effect transistors (FETs). The device current on/off ratio is optimized in two-layer PtSe2 FETs, and four-terminal configuration displays a reasonably high effective field effect mobility (14 and 15 cm2 V−1 s−1 for p-type and n-type FETs, respectively) with a nearly symmetric p-type and n-type performance. Temperature dependent measurement reveals that the variable range hopping is dominant at low temperatures. To further establish feasible application based on controllable doping of PtSe2, a logic inverter and vertically stacked p–n junction arrays are demonstrated. These results validate that PtSe2 is a promising candidate among the family of TMDs for future functional electronic applications.

Cultural resources are often overlooked in climate change and resiliency planning, despite them being integral to community identity and the restoration of a sense of normalcy after significant weather events. This vulnerability assessment demonstrates how cultural resources can be included in planning efforts, and how they can be prioritized based on specific criteria. To complete this assessment, a working group with local land managers and cultural resource professionals was formed, and members employed a sophisticated Geo Tool, ACUNE (Adaptation of Coastal Urban and Natural Ecosystems) for climate adaptation, to predict how cultural resources throughout Collier County, Florida, would be impacted in two specific climate scenarios. The working group selected ten significant sites in the county and used ACUNE to prioritize action at these sites, using a matrix of hazard exposure, sensitivity, adaptive capacity, and the environmental, social, and economic consequences of the loss of these sites. Based on the results of our case study vulnerability assessment of cultural resources in Collier County, the next decade (2020 to 2030) has the potential to increase the number of sites at risk of storm flooding from 267 to 318, alerting managers that immediate action is needed for the sites of greatest value. The analysis of 10 case study sites is presented to demonstrate an approach for land managers and other cultural resource professionals to prioritize action at their own sites. [ABSTRACT FROM AUTHOR]

Yuzheng Xue,1,* Yao Zhong,1,* Tielong Wu,1 Yingyue Sheng,1 Yuanyuan Dai,1 Lingling Xu,1 Chuanqing Bao2 1Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi 214041, Jiangsu, People’s Republic of China; 2Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi 214041, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuzheng XueDepartment of Gastroenterology, Affiliated Hospital of Jiangnan University, No. 585, Xingyuan North Road, Wuxi 214041, Jiangsu, People’s Republic of ChinaEmail xueyz001@163.comPurpose: The expression of microRNA-125b (miR-125b) is low in a variety of cancers, including gastric, lung, bladder, thyroid, and esophageal cancers. However, its specific mechanism in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study is aimed to explore the role of miR-125b in PDAC.Methods: PDAC tissues and adjacent tissues were collected for miR-125b analysis by qRT-PCR. Different PDAC cell lines were cultured for miR-125b detection by qRT-PCR, and CAPAN1 cells were selected for the downstream experiments. Cell proliferation was characterized by methyl thiazolyl tetrazolium (MTT) and 5-bromo-2-deoxyUridine (BrdU) staining. Flow cytometry was utilized for apoptosis and cell cycle changes. Cell invasion was determined by the Transwell assay and the dual-luciferase assay was utilized for validating the target gene. Western blotting was used to detect apoptosis related and PI3K/AKT signaling proteins.Results: miR-125b was significantly down-regulated in human PDAC tissues and cell lines (P < 0.05). miR-125b inhibited the growth and invasion of CAPAN1 cells, facilitated apoptosis, and blocked the cell cycle at the G0/G1 phase. Furthermore, miR-125 directly targeted NEDD9. The high expression of NEDD9 impaired the anti-proliferative and anti-apoptotic activity of miR-125b. miR-125b also inhibited apoptosis-related proteins and PI3K/AKT signaling pathways via NEDD9.Conclusion: miR-125b decreased cell growth and invasion, and facilitated apoptosis in CAPAN1 cells through PI3K/AKT inhibition via targeting NEDD9.Keywords: miR-125b, pancreatic ductal adenocarcinoma, apoptosis, NEDD9, PI3K/AKT

Yanmei Wu,1 Yu Zhang,2 Hao Pi,1 Yuan Sheng1 1Department of Breast and Thyroid Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, People’s Republic of China; 2Medical Affairs, Pfizer Biopharmaceutical Group, Shanghai 200041, People’s Republic of ChinaCorrespondence: Yuan ShengDepartment of Breast and Thyroid Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, People’s Republic of ChinaEmail sheng528yuan@126.comAbstract: The clinical use of selective cyclin-dependent kinase (CDK) 4/6 inhibitors has significantly improved the prognosis of patients with hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer (ABC/mBC), which almost achieved the double progression-free survival (PFS) in combination with endocrine therapy (ET) compared with ET alone. To date, there are 3 CDK4/6 inhibitors (palbociclib, ribocilcib and abemaciclib) approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to treat patients with HR+/HER2-ABC/mBC in the first and later lines. The aim of this review is to summarize the current clinical use and ongoing clinical trials of CDK4/6 inhibitors, the published overall survival data, and the potential biomarkers and resistance to CDK4/6 inhibitors.Keywords: CDK4/6 inhibitor, breast cancer, mechanism, clinical efficacy, resistance

Ageing is associated with increased vulnerability to environmental cold exposure. Previously, we identified the role of the cold-sensitive transient receptor potential (TRP) A1, M8 receptors as vascular cold sensors in mouse skin. We hypothesised that this dynamic cold-sensor system may become dysfunctional in ageing. We show that behavioural and vascular responses to skin local environmental cooling are impaired with even moderate ageing, with reduced TRPM8 gene/protein expression especially. Pharmacological blockade of the residual TRPA1/TRPM8 component substantially diminished the response in aged, compared with young mice. This implies the reliance of the already reduced cold-induced vascular response in ageing mice on remaining TRP receptor activity. Moreover, sympathetic-induced vasoconstriction was reduced with downregulation of the α2c adrenoceptor expression in ageing. The cold-induced vascular response is important for sensing cold and retaining body heat and health. These findings reveal that cold sensors, essential for this neurovascular pathway, decline as ageing onsets.