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Zhan-He Sun,&ast; Cheng-Hong Yu,&ast; Xin Wang Department of Ultrasound, Tongxiang First People’s Hospital, Tongxiang, Zhejiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Wang, Email xings137@163.comObjective: This study aims to investigate the clinical application value of high-frequency ultrasound technology in diagnosing subcutaneous lipohypertrophy at insulin injection sites in diabetes patients.Methods: All diabetes patients treated in our hospital from January 2022 to January 2023 were selected as the study subjects. The incidence of subcutaneous lipohypertrophy was calculated at the end of the study period. All patients were screened, and those meeting the inclusion criteria were registered, and basic data were collected. Patients were screened for subcutaneous lipohypertrophy using conventional clinical examination (control group) and high-frequency ultrasound technology (study group).Results: The study found that the incidence of subcutaneous lipohypertrophy in diabetes patients receiving insulin injections in our hospital from January 2022 to January 2023 was 80.99%. The average longitudinal diameter of subcutaneous lipohypertrophy in these patients was 11.66 (7.56, 21.44) mm, the transverse diameter was 12.04 (8.96, 18.29) mm, depth was (5.62± 2.17) mm, and the area was 188.79 (76.85, 331.78) mm². The clinical detection rate in the study group was higher than that in the control group (P< 0.05). The quantity of detected sites was greater in the study group compared to the control group (P< 0.05).Conclusion: The incidence of subcutaneous lipohypertrophy in diabetes patients receiving insulin injections is relatively high clinically, and high-frequency ultrasound technology demonstrates significant potential in diagnosis. By providing high-resolution imaging and quantitative data, it effectively improves the clinical detection rate and clarifies symptoms. This technology is likely to become an important auxiliary tool in future diabetes treatment, providing more precise treatment plans for patients.Keywords: high-frequency ultrasound technology, diabetes, insulin injection, subcutaneous lipohypertrophy, diagnostic value

Zhi-Feng Liu,&ast; Yang Zhang,&ast; Jing Liu, Yu-Yan Wang, Mo Chen, Er-Yang Liu, Jun-Ming Guo, Yan-Hua Wang, Zhi-Wen Weng, Chang-Xin Liu, Chang-He Yu, Xi-You Wang Tuina and Pain Management Department, Beijing University of Chinese Medicine Affilliated Dongzhimen Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chang-He Yu; Xi-You Wang, Email yakno2@163.com; dwxy658@163.comAbstract: Knee osteoarthritis (KOA) stands as a degenerative ailment with a substantial and escalating prevalence. The practice of traditional Chinese non-pharmacological therapy has become a prevalent complementary and adjunctive approach. A mounting body of evidence suggests its efficacy in addressing KOA. Recent investigations have delved into its underlying mechanism, yielding some headway. Consequently, this comprehensive analysis seeks to encapsulate the clinical application and molecular mechanism of traditional Chinese non-pharmacological therapy in KOA treatment. The review reveals that various therapies, such as acupuncture, electroacupuncture, warm needle acupuncture, tuina, and acupotomy, primarily target localized knee components like cartilage, subchondral bone, and synovium. Moreover, their impact extends to the central nervous system and intestinal flora. More perfect experimental design and more comprehensive research remain a promising avenue in the future.Keywords: knee osteoarthritis, traditional Chinese non-pharmacological therapy, mechanism, acupuncture, tuina, acupotomy

Wen-Ying Yu,1,* Wei Cai,2,* Hua-Zhong Ying,1 Wen-You Zhang,1 Huan-Huan Zhang,1 Chen-Huan Yu1,3,4 1Zhejiang Key Laboratory of Experimental Animal and Safety Evaluation, Zhejiang Academy of Medical Sciences (Hangzhou Medical College), Hangzhou, People’s Republic of China; 2Department of Traditional Chinese Medicine, Zhejiang Pharmaceutical College, Ningbo, People’s Republic of China; 3Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, People’s Republic of China; 4Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chen-Huan YuInstitute of Cancer and Basic Medicine, Chinese Academy of Sciences, Dongfang Street 150, Hangzhou, Zhejiang, 310018, People’s Republic of ChinaEmail yuchenhuan2002@163.comPurpose: Plant-derived exogenous microRNAs (miRNAs) regulate human physiological functions by blocking the translation of target mRNAs. Although several computational approaches have been developed to elucidate the interactions of cross-species miRNAs and their targets in mammals, the number of verified plant miRNAs is still limited, and the biological roles of most exogenous plant miRNAs remain unknown.Methods: A miRNA mimic library-based phenotypic screening, which contained 8394 plant mature miRNAs published in the official database miRbase, was performed to identify more novel bioactive plant miRNAs for the prevention of hepatic fibrosis. Inhibition of candidates for the activation of hepatic stellate cells (HSCs) and the underlying mechanisms were evaluated in TGF-β 1- and PDGF-exposed HSC models. The protective effects of the candidates against CCl4-induced liver fibrosis were evaluated in a mouse model.Results: Among the 8394 plant mature miRNAs reported in the official database miRBase, five candidates were found to effectively inhibit the differentiation of HSCs. gma-miR-159a (miR159a) exerted the strongest inhibitory activities on both TGF-β 1- and PDGF-induced HSC activation and proliferation by inhibiting the GSK-3β-mediated NF-κB and TGF-β 1 pathways. Moreover, miR159a was mainly accumulated in the liver after intravenous injection, and it reduced CCl4-induced hepatic fibrosis and inflammation in mice.Conclusion: Results indicated that miR159a has the therapeutic potential for preventing hepatic fibrosis. This study provides a novel strategy for achieving natural nucleic acid drugs.Keywords: cross-kingdom regulation, miRNA library, GSK-3β, apoptosis, hepatic fibrosis, inflammation

Zhen-Hua Ying,1 Hui-Min Li,1 Wen-Ying Yu,2 Chen-Huan Yu2– 4 1Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, 310006, People’s Republic of China; 2Zhejiang Key Laboratory of Experimental Animal and Safety Evaluation, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China; 3Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, 310018, People’s Republic of China; 4Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, People’s Republic of ChinaCorrespondence: Chen-Huan YuInstitute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, 310018, People’s Republic of ChinaEmail yuchenhuan2002@163.comPurpose: Abnormal glycolysis of immune cells contributed to the development of inflammatory response. Inhibition of this Warburg phenotype could be a promising strategy for preventing various inflammatory diseases. Iridin (IRD) is a natural isoflavone, and exerts anticancer, antioxidant, and anti-inflammatory effects. However, the underlying mechanism of IRD on acute inflammation remains unknown. In this study, the protective effects of IRD against lipopolysaccharide (LPS)-induced inflammation were investigated in murine macrophage RAW264.7 cells and in mice.Methods: The inhibition of IRD on NO production in culture medium was detected by Griess assay while the levels of TNF-α, IL-1β, and MCP-1 were detected by ELISA assay. The effects of IRD on OCR and ECAR levels in LPS-treated macrophages were monitored by using Seahorse Analyzer. The apoptosis rate as well as the release of ROS and NO of RAW264.7 cells were analyzed by flow cytometric assay. The protective effects of IRD were investigated on LPS-induced inflammation in mice. The expressions of PKM2 and its downstream (p-JAK1, p-STAT1, p-STAT3, p-p65, iNOS, and COX2) in cells and in lung tissues were detected by Western blotting analysis.Results: IRD treatment at the concentrations of 12.5– 50 μM significantly inhibited the productions of TNF-α, IL-1β, MCP-1, and ROS, and suppressed the levels of glucose uptake and lactic acid in LPS-treated RAW264.7 cells. Oral administration with IRD (20– 80 mg/kg) inhibited LPS-induced acute lung injury as well as inflammatory cytokine production in mice. Moreover, IRD targeted pyruvate kinase isozyme type M2 (PKM2) and suppressed its downstream p-JAK1, p-STAT1, p-STAT3, p-p65, iNOS, and COX2, which could be abolished by PKM2 agonist DASA-58 and antioxidant N-acetyl-L-cysteine, but partly be reversed by NF-κB activator CUT129 and JAK1 activator RO8191.Conclusion: IRD alleviated LPS-induced inflammation through suppressing PKM2-mediated pathways, and could be a potential candidate for the prevention of inflammatory diseases.Keywords: isoflavone, glycolysis, Warburg effect, PKM2, JAK/STATs, NF-κB

Chin-Hsiu Yu,1 Ya-Ai Cheng,2 Ru-Yih Chen,3 Yu-Lung Wu,4 Min-Hsi Lin5 1Department of Information Engineering, I-Shou University, Kaohsiung, Taiwan; 2Department of Healthcare Administration, I-Shou University, Kaohsiung, Taiwan; 3Department of Family Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 4Department of Information Management, I-Shou University, Kaohsiung, Taiwan; 5Division of Chest Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, TaiwanCorrespondence: Ru-Yih Chen Department of Family MedicineKaohsiung Veterans General Hospital, No. 386, Dazhong 1st Road, Zuoying District, Kaohsiung City 813414, Taiwan (R.O.C.)Tel +886-7-346-8236Fax +886-7-342-2288Email louie0812@gmail.comPurpose: To explore whether antineoplastic treatment can improve overall survival (OS) in older patients with metastatic non-small-cell lung cancer (mNSCLC).Patients and Methods: Using the cancer registry database of a tertiary medical center in Taiwan, we followed patients 65 years old and above with pathologically proved mNSCLC. Chi-square test and Cox regression were used to analyze differences in clinical characteristics, the treatments they received, and factors predicting survival. Kaplan–Meier survival analysis was used to analyze OS differences.Results: A total of 542 older patients were diagnosed with mNSCLC from 2011 to 2017. Multivariate Cox regression showed that patients receiving targeted therapy (TT) alone, chemotherapy (CT) alone, and crossover (CO) treatment were at significantly less risk of short OS [hazard ratio (HR) 0.351, 95% confidence interval (CI), 0.257– 0.479; HR 0.517, CI 0.376– 0.711; and HR 0.544, CI 0.373– 0.792, respectively]. Patients at significantly increased risk of short OS were those aged ≥ 85 years and those assigned poorer Eastern Cooperative Oncology Group Performance Status (ECOG-PS) scores (HR 1.513, CI 1.135– 2.017, and HR 2.854, CI 2.188– 3.724, respectively). The result of Kaplan–Meier survival analysis of 418 patients with ECOG-PS scores 0– 2 suggested that patients who received antineoplastic treatments had a significantly better median OS than those receiving supportive care (SC), those receiving TT having the best result (SC, 4.00 months; TT, 21.17 months; CT, 12.83 months; CO, 15.83 months, P< 0.001).Conclusion: Antineoplastic treatments, especially TT, can improve OS for selected older patients with mNSCLC.Keywords: chemotherapy, targeted therapy, crossover treatment, stage IV lung cancer, older patient, survival

Wan-Wei Wang,1 Xi-Lei Zhou,1 Ying-Jian Song,2 Chang-Hua Yu,1 Wei-Guo Zhu,1 Yu-Suo Tong1 1Department of Radiation Oncology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu, China; 2Department of Respiratory Medicine, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu, China Purpose: Long noncoding RNAs (lncRNAs) are present in body fluids, but their potential as tumor biomarkers has never been investigated in malignant pleural effusion (MPE) caused by lung cancer. The aim of this study was to assess the clinical significance of lncRNAs in pleural effusion, which could potentially serve as diagnostic and predictive markers for lung cancer-associated MPE (LC-MPE). Patients and methods: RNAs from pleural effusion were extracted in 217 cases of LC-MPE and 132 cases of benign pleural effusion (BPE). Thirty-one lung cancer-associated lncRNAs were measured using quantitative real-time polymerase chain reaction (qRT-PCR). The level of carcinoembryonic antigen (CEA) was also determined. The receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were established to evaluate the sensitivity and specificity of the identified lncRNAs and other biomarkers. The correlations between baseline pleural effusion lncRNAs expression and response to chemotherapy were also analyzed. Results: Three lncRNAs (MALAT1, H19, and CUDR) were found to have potential as diagnostic markers in LC-MPE. The AUCs for MALAT1, H19, CUDR, and CEA were 0.891, 0.783, 0.824, and 0.826, respectively. Using a logistic model, the combination of MALAT1 and CEA (AUC, 0.924) provided higher sensitivity and accuracy in predicting LC-MPE than CEA (AUC, 0.826) alone. Moreover, baseline MALAT1 expression in pleural fluid was inversely correlated with chemotherapy response in patients with LC-MPE. Conclusion: Pleural effusion lncRNAs were effective in differentiating LC-MPE from BPE. The combination of MALAT1 and CEA was more effective for LC-MPE diagnosis. Keywords: malignant pleural effusion, lncRNA, MALAT1, lung cancer, diagnosis

Lu Che, Li Xu, Yuguang Huang, Chunhua Yu Department of Anesthesiology, Peking Union Medical College Hospital, Beijing, China Objectives: The revised Cardiac Risk Index (RCRI) is the most widely used risk prediction tool for postoperative cardiac adverse events. We aim to explore the predictive ability of the RCRI in older Chinese patients with coronary artery disease (CAD) undergoing noncardiac surgery, which has not been previously evaluated.Methods: We performed a multicenter, prospective study. We enrolled a total of 1,202 patients, aged >60 years, with a history of CAD who underwent noncardiac surgery. Perioperative data were extracted from an electronic database. The primary end point was defined as an occurrence of a postoperative major cardiac event (PoMCE) within 30 days. Logistic regression analysis was performed to evaluate the performance of the RCRI. A modified RCRI was created and compared with the original RCRI with regard to its ability to predict postoperative cardiac events.Results: Of the enrolled patients, 4.3% experienced PoMCE. Most components of the RCRI were not predictive of postoperative cardiac events with the exception of insulin-dependent diabetes mellitus (odds ratio =2.38, 95% CI: 1.11–5.11; P=0.03). The RCRI performed no better than chance (area under the curve =0.53; 95% CI: 0.45–0.61) in identifying patients’ cardiac risk. The modified score had a higher discriminatory ability toward PoMCE (c index, 0.69 versus 0.53; P

Catherine H Yu,1,2 Giuliana Guarna,1 Pamela Tsao,3 Jude R Jesuthasan,1 Adrian NC Lau,3,4 Ferhan S Siddiqi,1 Julie Anne Gilmour,3 Danyal Ladha,1 Henry Halapy,5 Andrew Advani1–3 1Li Ka Shing Knowledge Institute, St Michael’s Hospital, 2Division of Endocrinology and Metabolism, Department of Medicine, St Michael’s Hospital, University of Toronto, 3Department of Medicine, Faculty of Medicine, University of Toronto, 4Division of Endocrinology, Department of Medicine, University Health Network, 5Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada Purpose: For emerging adults with chronic medical diseases, the transition from pediatric to adult health care is often a time of great upheaval, commonly associated with unhealthy self-management choices, loss to follow-up, and adverse outcomes. We conducted a systematic review to examine the use of incentive strategies to promote positive health-related behaviors in young adults with chronic medical diseases.Methods: The Medline, CINAHL, Embase, PsycInfo, and Cochrane databases were searched through June 2014. Studies of any design where an incentive was used to achieve a target behavior or outcome in a pediatric or emerging adult population (age

Chuan-Hsun Yu,1 Ryouhei Ishii,2 Shun-Chieh Yu,1 Masatoshi Takeda2 1Yuli Hospital, Department of Health, Hualien, Taiwan; 2Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan Abstract: Schizophrenia is a debilitating psychotic mental disorder that affects almost the entire range of human mental function. The devastating effect of the illness is usually long-lasting and requires lifelong treatment. Despite an evolved psychopharmacological understanding, the overall therapeutic effect of antipsychotics is still not satisfactory. The choice of proper medication presents a clinical dilemma between efficacy and safety. As a result, searching for comparable treatment options with safer profiles is very important. Yokukansan (TJ-54), also called yi-gan san in Chinese, is a traditional herbal medicine with evident therapeutic effect for neuropsychiatric disorders. There are several open-label clinical studies upholding the possibility of using yokukansan to treat schizophrenia or schizophrenia-like psychosis. Evidence from animal studies and neurobiology also sheds light on the antipsychotic implications of yokukansan and its ingredients. Nevertheless, correlations between the experimental environment and clinical settings may be complicated by a number of confounders. Clinical trials with more sophisticated designs are required to fill the gap between the experimental environment and clinical settings. Keywords: herbal medicine, geissoschizine methyl ether, glycyrrhizin, antipsychotics, D2 receptor

Imperfections in analog-to-digital conversion (ADC) cannot be ignored when signal digitization requirements demand both wide dynamic range and high resolution, as is the case for the Majorana Demonstrator 76Ge neutrinoless double-beta decay search. Enabling the experiment's high-resolution spectral analysis and efficient pulse shape discrimination required careful measurement and correction of ADC nonlinearities. A simple measurement protocol was developed that did not require sophisticated equipment or lengthy data-taking campaigns. A slope-dependent hysteresis was observed and characterized. A correction applied to digitized waveforms prior to signal processing reduced the differential and integral nonlinearities by an order of magnitude, eliminating these as dominant contributions to the systematic energy uncertainty at the double-beta decay Q value.

The majorana demonstrator is a neutrinoless double-β decay search consisting of a low-background modular array of high-purity germanium detectors, ∼2/3 of which are enriched to 88% in Ge76. The experiment is also searching for double-beta decay of Ge76 to excited states (e.s.) in Se76. Ge76 can decay into three daughter states of Se76, with clear event signatures consisting of a ββ-decay followed by the prompt emission of one or two γ rays. This results with high probability in multi-detector coincidences. The granularity of the demonstrator detector array enables powerful discrimination of this event signature from backgrounds. Using 41.9 kg yr of isotopic exposure, the demonstrator has set world leading limits for each e.s. decay of Ge76, with 90% CL lower half-life limits in the range of (0.75-4.0)×1024 yr. In particular, for the 2ν transition to the first 0+ e.s. of Se76, a lower half-life limit of 7.5×1023 yr at 90% CL was achieved.

The MAJORANA DEMONSTRATOR is searching for double-beta decay of 76Ge to excited states (E.S.) in 76Se using a modular array of high purity Germanium detectors. 76Ge can decay into three E.S.s of 76Se. The E.S. decays have a clear event signature consisting of a ββ-decay with the prompt emission of one or two γ-rays, resulting in with high probability in a multi-site event. The granularity of the DEMONSTRATOR detector array enables powerful discrimination of this event signature from backgrounds. Using 21.3 kg-y of isotopic exposure, the DEMONSTRATOR has set world leading limits for each E.S. decay, with 90% CL lower half-life limits in the range of (0.56 2.1) ⋅ 1024 y. In particular, for the 2v transition to the first 0+ E.S. of 76Se, a lower half-life limit of 0.68 ⋅ 1024 at 90% CL was achieved.

The Majorana Collaboration has assembled an array of high purity Ge detectors to search for neutrinoless double-beta decay in 76Ge with the goal of establishing the required background and scalability of a Ge-based next-generation ton-scale experiment. The Majorana Demonstrator consists of 44 kg of high-purity Ge (HPGe) detectors (30 kg enriched in 76Ge) with a low-noise p-Type point contact (PPC) geometry. The detectors are split between two modules which are contained in a single lead and high-purity copper shield at the Sanford Underground Research Facility in Lead, South Dakota. Following a commissioning run that started in June 2015, the full detector array has been acquiring data since August 2016. We will discuss the status of the Majorana Demonstrator and initial results from the first physics run; including current background estimates, exotic low-energy physics searches, projections on the physics reach of the Demonstrator, and implications for a ton-scale Ge-based neutrinoless double-beta decay search.

The MAJORANA DEMONSTRATOR is an experiment constructed to search for neutrinoless double-beta decays in germanium-76 and to demonstrate the feasibility to deploy a ton-scale experiment in a phased and modular fashion. It consists of two modular arrays of natural and 76Ge-enriched germanium detectors totaling 44.1kg (29.7kg enriched detectors), located at the 4850' level of the Sanford Underground Research Facility in Lead, South Dakota, USA. Data taken with this setup since summer 2015 at different construction stages of the experiment show a clear reduction of the observed background index around the ROI for 0νββ-decay search due to improvements in shielding. We discuss the statistical approaches to search for a νββ-signal and derive the physics sensitivity for an expected exposure of 10kg• y from enriched detectors using a profile likelihood based hypothesis test in combination with toy Monte Carlo data.

The MAJORANA DEMONSTRATOR is a 76Ge-based neutrinoless double-beta decay (0νββ) experiment. Staged at the 4850 ft level of the Sanford Underground Research Facility, the DEMONSTRATOR operates an array of high-purity p-Type point contact Ge detectors deployed within a graded passive shield and an active muon veto system. The present work concerns the two-neutrino double-beta decay mode (2νββ) of 76Ge. For Ge detectors, having superior energy resolution (0.1%), this mode poses negligible background to the 0νββ mode, even for a ton-scale experiment. However, the measurement of the 2νββ mode allows for careful systematics checks of active detector mass, enrichment fraction, and pulse shape discrimination cuts related to both the 0νββ and 2νββ decay modes. A precision measurement of the 2νββ shape also allows searches for spectral distortions, possibly indicative of new physics, including 0νββχ. Work is underway to construct a full experimental background model enabling a Bayesian fit to the measured energy spectrum and extraction of a precise 2νββ spectrum and half-life.

The MAJORANA DEMONSTRATOR is an experiment constructed to search for neutrinoless double-beta decays in germanium-76 and to demonstrate the feasibility to deploy a ton-scale experiment in a phased and modular fashion. It consists of two modular arrays of natural and 76Ge-enriched germanium p-Type point contact detectors totaling 44.1 kg, located at the 4850' level of the Sanford Underground Research Facility in Lead, South Dakota, USA. The DEMONSTRATOR uses custom high voltage cables to bias the detectors, as well as custom signal cables and connectors to read out the charge deposited at each detectors point contact. These low-mass cables and connectors must meet stringent radiopurity requirements while being subjected to thermal and mechanical stress. A number of issues have been identified with the currently installed cables and connectors. An improved set of cables and connectors for the MAJORANA DEMONSTRATOR are being developed with the aim of increasing their overall reliability and connectivity. We will discuss some of the issues encountered with the current cables and connectors as well as our improved designs and their initial performance.

The MAJORANA DEMONSTRATOR is an experiment constructed to search for neutrinoless double-beta decays in germanium-76 and to demonstrate the feasibility to deploy a large-scale experiment in a phased and modular fashion. It consists of two modular arrays of natural and 76 Ge-enriched germanium detectors totalling 44.1 kg, located at the 4850' level of the Sanford Underground Research Facility in Lead, South Dakota, USA. Any neutrinoless double-beta decay search requires a thorough understanding of the background and the signal energy spectra. The various techniques employed to ensure the integrity of the measured spectra are discussed. Data collection is monitored with a thorough set of checks, and subsequent careful analysis is performed to qualify the data for higher level physics analysis. Instrumental background events are tagged for removal, and problematic channels are removed from consideration as necessary.

Neutrinoless double beta decay searches play a major role in determining neutrino properties, in particular the Majorana or Dirac nature of the neutrino and the absolute scale of the neutrino mass. The consequences of these searches go beyond neutrino physics, with implications for Grand Unification and leptogenesis. The Majorana Collaboration is assembling a low-background array of high purity Germanium (HPGe) detectors to search for neutrinoless double-beta decay in 76Ge. The Majorana Demonstrator, which is currently being constructed and commissioned at the Sanford Underground Research Facility in Lead, South Dakota, will contain 44 kg (30 kg enriched in 76Ge) of HPGe detectors. Its primary goal is to demonstrate the scalability and background required for a tonne-scale Ge experiment. This is accomplished via a modular design and projected background of less than 3 cnts/tonne-yr in the region of interest. The experiment is currently taking data with the first of its enriched detectors.

The Majorana Collaboration is operating an array of high-purity Ge detectors to search for the neutrinoless double-β decay of Ge76. The Majorana Demonstrator consists of 44.1 kg of Ge detectors (29.7 kg enriched to 88% in Ge76) split between two modules constructed from ultraclean materials. Both modules are contained in a low-background shield at the Sanford Underground Research Facility in Lead, South Dakota. We present updated results on the search for neutrinoless double-β decay in Ge76 with 26.0±0.5 kg yr of enriched exposure. With the Demonstrator's energy resolution of 2.53 keV FWHM at Qββ, which is the best among all neutrinoless double-β decay experiments, we observe one event in the region of interest with 0.65 events expected from the estimated background, resulting in a lower limit on the Ge76 neutrinoless double-β decay half-life of 2.7×1025 yr [90% confidence level (CL)] with a median sensitivity of 4.8×1025 yr (90% CL). Depending on the matrix elements used, a 90% CL upper limit on the effective Majorana neutrino mass in the range of 200-433 meV is obtained. The measured background in the configurations with full shielding and optimized grounding is 11.9±2.0 counts/(FWHM t yr).

The Majorana Demonstrator is searching for neutrinoless double-beta decay (0νββ) in Ge76 using arrays of point-contact germanium detectors operating at the Sanford Underground Research Facility. Background results in the 0νββ region of interest from data taken during construction, commissioning, and the start of full operations have been recently published. A pulse shape analysis cut applied to achieve this result, named AvsE, is described in this paper. This cut is developed to remove events whose waveforms are typical of multisite energy deposits while retaining (90±3.5)% of single-site events. This pulse shape discrimination is based on the relationship between the maximum current and energy, and tuned using Th228 calibration source data. The efficiency uncertainty accounts for variation across detectors, energy, and time, as well as for the position distribution difference between calibration and 0νββ events, established using simulations.

The Majorana Demonstrator is an ultra-low-background experiment searching for neutrinoless double-beta decay in Ge76. The heavily shielded array of germanium detectors, placed nearly a mile underground at the Sanford Underground Research Facility in Lead, South Dakota, also allows searches for new exotic physics. We present the first limits for trinucleon decay-specific modes and invisible decay modes for Ge isotopes. We find a half-life limit of 4.9×1025 yr for the decay Ge76(ppn)→Zn73 e+π+ and 4.7×1025 yr for the decay Ge76(ppp)→Cu73 e+π+π+. The half-life limit for the invisible triproton decay mode of Ge76 was found to be 7.5×1024 yr.

The MAJORANA DEMONSTRATOR is an experiment constructed to search for neutrinoless double-beta decay in 76Ge and to demonstrate the feasibility to deploy a large-scale experiment in a phased and modular fashion. It consists of two modules of natural and 76Ge-enriched germanium detectors totalling 44.1 kg, operating at the 4850' level of the Sanford Underground Research Facility in Lead, South Dakota, USA. Commissioning of the experiment began in June 2015, followed by data production with the full detector array in August 2016. The ultra-low background and record energy resolution achieved by the MAJORANA DEMONSTRATOR enable a sensitive neutrinoless double-beta decay search, as well as additional searches for physics beyond the Standard Model. I will discuss the design elements that enable these searches, along with the latest results, focusing on the neutrinoless double-beta decay search. I will also discuss the current status and the future plans of the MAJORANA DEMONSTRATOR, as well as the plans for a future tonne-scale 76Ge experiment.

The Majorana Collaboration is using an array of high-purity Ge detectors to search for neutrinoless double-beta decay in 76Ge. Searches for neutrinoless double-beta decay are understood to be the only viable experimental method for testing the Majorana nature of the neutrino. Observation of this decay would imply violation of lepton number, that neutrinos are Majorana in nature, and provide information on the neutrino mass. The Majorana Demonstrator comprises 44.1 kg of p-type point-contact Ge detectors (29.7 kg enriched in 76Ge) surrounded by a low-background shield system. The experiment achieved a high efficiency of converting raw Ge material to detectors and an unprecedented detector energy resolution of 2.5 keV FWHM at Qββ. The Majorana collaboration began taking physics data in 2016. This paper summarizes key construction aspects of the Demonstrator and shows preliminary results from initial data.

The Majorana Demonstrator is a neutrinoless double beta decay experiment utilizing enriched Ge-76 detectors in 2 separate modules inside of a common solid shield at the Sanford Underground Research Facility. The Demonstrator has utilized world leading assay sensitivities to develop clean materials and processes for producing ultra-pure copper and plastic components. This experiment is now operating, and initial data provide new insights into the success of cleaning and processing. Post production copper assays after the completion of Module 1 showed an increase in U and Th contamination in finished parts compared to starting bulk material. A revised cleaning method and additional round of surface contamination studies prior to Module 2 construction have provided evidence that more rigorous process control can reduce surface contamination. This article describes the assay results and discuss further studies to take advantage of assay capabilities for the purpose of maintaining ultra clean fabrication and process design.

The Majorana Collaboration is searching for the neutrinoless double-beta decay of the nucleus 76Ge. The Majorana Demonstrator is an array of germanium detectors deployed with the aim of implementing background reduction techniques suitable for a tonne scale 76Ge-based search (the LEGEND collaboration). In the Demonstrator, germanium detectors operate in an ultra-pure vacuum cryostat at 80 K. One special challenge of an ultra-pure environment is to develop reliable cables, connectors, and electronics that do not significantly contribute to the radioactive background of the experiment. This paper highlights the experimental requirements and how these requirements were met for the Majorana Demonstrator, including plans to upgrade the wiring for higher reliability in the summer of 2018. Also described are requirements for LEGEND R&D efforts underway to meet these additional requirements.

The MAJORANA DEMONSTRATOR is an array of point-contact Ge detectors fabricated from Ge isotopically enriched to 88% in 76Ge to search for neutrinoless double beta decay. The processing of Ge for germanium detectors is a well-known technology. However, because of the high cost of Ge enriched in 76Ge special procedures were required to maximize the yield of detector mass and to minimize exposure to cosmic rays. These procedures include careful accounting for the material; shielding it to reduce cosmogenic generation of radioactive isotopes; and development of special reprocessing techniques for contaminated solid germanium, shavings, grindings, acid etchant and cutting fluids from detector fabrication. Processing procedures were developed that resulted in a total yield in detector mass of 70%. However, none of the acid-etch solution and only 50% of the cutting fluids from detector fabrication were reprocessed. Had they been processed, the projections for the recovery yield would be between 80% and 85%. Maximizing yield is critical to justify a possible future ton-scale experiment. A process for recovery of germanium from the acid-etch solution was developed with yield of about 90%. All material was shielded or stored underground whenever possible to minimize the formation of 68Ge by cosmic rays, which contributes background in the double-beta decay region of interest and cannot be removed by zone refinement and crystal growth. Formation of 68Ge was reduced by a significant factor over that in natural abundance detectors not protected from cosmic rays.

The MAJORANA Collaboration is searching for the neutrinoless double-beta decay of the nucleus 76Ge. The MAJORANA DEMONSTRATOR is an array of germanium detectors deployed with the aim of implementing background reduction techniques suitable for a 1-ton 76Ge-based search. The ultra low-background conditions require regular calibrations to verify proper function of the detectors. Radioactive line sources can be deployed around the cryostats containing the detectors for regular energy calibrations. When measuring in low-background mode, these line sources have to be stored outside the shielding so they do not contribute to the background. The deployment and the retraction of the source are designed to be controlled by the data acquisition system and do not require any direct human interaction. In this paper, we detail the design requirements and implementation of the calibration apparatus, which provides the event rates needed to define the pulse-shape cuts and energy calibration used in the final analysis as well as data that can be compared to simulations.

Neutrinoless double-beta decay searches play a major role in determining the nature of neutrinos, the existence of a lepton violating process, and the effective Majorana neutrino mass. The Majorana Collaboration assembled an array of high purity Ge detectors to search for neutrinoless double-beta decay in 76Ge. The Majorana Demonstrator is comprised of 44.1 kg (29.7 kg enriched in 76Ge) of Ge detectors divided between two modules contained in a low-background shield at the Sanford Underground Research Facility in Lead, South Dakota, USA. The initial goals of the Demonstrator are to establish the required background and scalability of a Ge-based next-generation ton-scale experiment. Following a commissioning run that started in 2015, the first detector module started low-background data production in early 2016. The second detector module was added in August 2016 to begin operation of the entire array. We discuss results of the initial physics runs, as well as the status and physics reach of the full Majorana Demonstrator experiment.

Neutrinoless double-beta decay searches seek to determine the nature of neutrinos, the existence of a lepton violating process, and the effective Majorana neutrino mass. The Majorana Collaboration is assembling an array of high purity Ge detectors to search for neutrinoless double-beta decay in 76Ge. The Majorana Demonstrator is composed of 44.8 kg (29.7 kg enriched in 76Ge) of Ge detectors in total, split between two modules contained in a low background shield at the Sanford Underground Research Facility in Lead, South Dakota. The initial goals of the Demonstrator are to establish the required background and scalability of a Ge-based, next-generation, tonne-scale experiment. Following a commissioning run that began in 2015, the first detector module started physics data production in early 2016. We will discuss initial results of the Module 1 commissioning and first physics run, as well as the status and potential physics reach of the full Majorana Demonstrator experiment. The collaboration plans to complete the assembly of the second detector module by mid-2016 to begin full data production with the entire array.

We report the first measurement of the total muon flux underground at the Davis Campus of the Sanford Underground Research Facility at the 4850 ft level. Measurements were performed using the MAJORANA DEMONSTRATOR muon veto system arranged in two different configurations. The measured total flux is (5.31±0.17)×10−9μ/s/cm2.

The MAJORANA Collaboration is constructing the MAJORANA DEMONSTRATOR, an ultralow background, 40-kg modular high purity Ge (HPGe) detector array to search for neutrinoless double-beta decay (0νββ-decay) in 76Ge. The goal of the experiment is to demonstrate a background rate at or below 3 counts/(t-y) in the 4 keV region of interest (ROI) around the 2039 keV Q-value for 76Ge 0νββ-decay. In this paper, the status of the MAJORANA DEMONSTRATOR, including its design and measurements of properties of the HPGe crystals is presented.

A search for Pauli-exclusion-principle-violating Kα electron transitions was performed using 89.5 kg-d of data collected with a p-type point contact high-purity germanium detector operated at the Kimballton Underground Research Facility. A lower limit on the transition lifetime of 5.8 × 10 30 s at 90% C.L. was set by looking for a peak at 10.6 keV resulting from the X-ray and Auger electrons present following the transition. A similar analysis was done to look for the decay of atomic K-shell electrons into neutrinos, resulting in a lower limit of 6.8 × 10 30 s at 90% C.L. It is estimated that the Majorana Demonstrator, a 44 kg array of p-type point contact detectors that will search for the neutrinoless double-beta decay of 76Ge, could improve upon these exclusion limits by an order of magnitude after three years of operation.

The Majorana collaboration is constructing the Majorana Demonstrator at the Sanford Underground Research Facility at the Homestake gold mine, in Lead, SD. The apparatus will use Ge detectors, enriched in isotope 76Ge, to demonstrate the feasibility of a large-scale Ge detector experiment to search for neutrinoless double beta decay. The long half-life of this postulated process requires that the apparatus be extremely low in radioactive isotopes whose decays may produce backgrounds to the search. The radioassay program conducted by the collaboration to ensure that the materials comprising the apparatus are sufficiently pure is described. The resulting measurements from gamma-ray counting, neutron activation and mass spectroscopy of the radioactive-isotope contamination for the materials studied for use in the detector are reported. We interpret these numbers in the context of the expected background for the experiment.

The Majorana Collaboration is constructing the Majorana Demonstrator, an ultra-low background, 44-kg modular high-purity Ge (HPGe) detector array to search for neutrinoless double-beta decay in 76Ge. The phenomenon of surface micro-discharge induced by high-voltage has been studied in the context of the Majorana Demonstrator. This effect can damage the front-end electronics or mimic detector signals. To ensure the correct performance, every high-voltage cable and feedthrough must be capable of supplying HPGe detector operating voltages as high as 5 kV without exhibiting discharge. R&D measurements were carried out to understand the testing system and determine the optimum design configuration of the high-voltage path, including different improvements of the cable layout and feedthrough flange model selection. Every cable and feedthrough to be used at the Majorana Demonstrator was characterized and the micro-discharge effects during the Majorana Demonstrator commissioning phase were studied. A stable configuration has been achieved, and the cables and connectors can supply HPGe detector operating voltages without exhibiting discharge.

The Majorana Collaboration is constructing a system containing 40 kg of HPGedetectors to demonstrate the feasibility and potential of a future tonne-scaleexperiment capable of probing the neutrino mass scale in the inverted-hierarchyregion. To realize this, a major goal of the Majorana Demonstrator is todemonstrate a path forward to achieving a background rate at or below 1cnt/(ROI-t-y) in the 4 keV region of interest around the Q-value at 2039 keV.This goal is pursued through a combination of a significant reduction ofradioactive impurities in construction materials with analytical methods forbackground rejection, for example using powerful pulse shape analysistechniques profiting from the p-type point contact HPGe detectors technology.The effectiveness of these methods is assessed using simulations of thedifferent background components whose purity levels are constrained fromradioassay measurements.

The Majorana Demonstrator will search for the neutrinoless double-beta (β β 0 ) decay of the isotope Ge with a mixed array of enriched and natural germanium detectors. The observation of this rare decay would indicate that the neutrino is its own antiparticle, demonstrate that lepton number is not conserved, and provide information on the absolute mass scale of the neutrino. The Demonstrator is being assembled at the 4850-foot level of the Sanford Underground Research Facility in Lead, South Dakota. The array will be situated in a low-background environment and surrounded by passive and active shielding. Here we describe the science goals of the Demonstrator and the details of its design. © 2014 N. Abgrall et al.

A low-background, high-purity germanium detector has been used to search forevidence of low-energy, bremsstrahlung-generated solar axions. An upper boundof $1.36\times 10^{-11}$ $(95% CL)$ is placed on the direct coupling of DFSZmodel axions to electrons. The prospects for the sensitivity of the MajoranaDemonstrator array of point-contact germanium detectors to solar axions arediscussed in the context of the model-independent annual modulation due to theseasonal variation of the earth-sun distance.

A highly-deformed rotational band has been identified in the N = Z nucleus 36Ar. At high spin the band is observed to its presumed termination at Iπ = 16+, while at low spin it has been firmly linked to previously known states in 36Ar. Spins, parities, and absolute excitation energies have thus been determined throughout the band. Lifetime measurements establish a large low-spin quadrupole deformation (β2 = 0.46 ±0.03) and indicate a decreasing collectivity as the band termination is approached. With effectively complete spectroscopic information and a valence space large enough for significant collectivity to develop, yet small enough to be meaningfully approached from the shell model perspective, this rotational band in 36Ar provides many exciting opportunities to test and compare complementary models of collective motion in nuclei.

To reduce CO2 emissions from coal-fired power plants, the development of low-carbon or carbon-free fuel combustion technologies has become urgent. As a new zero-carbon fuel, ammonia (NH3) can be used to address the storage and transportation issues of hydrogen energy. Since it is not feasible to completely replace coal with ammonia in the short term, the development of ammonia–coal co-combustion technology at the current stage is a fast and feasible approach to reduce CO2 emissions from coal-fired power plants. This study focuses on modifying the boiler and installing two layers of eight pure-ammonia burners in a 300-MW coal-fired power plant to achieve ammonia–coal co-combustion at proportions ranging from 20% to 10% (by heat ratio) at loads of 180- to 300-MW, respectively. The results show that, during ammonia–coal co-combustion in a 300-MW coal-fired power plant, there was a more significant change in NOx emissions at the furnace outlet compared with that under pure-coal combustion as the boiler oxygen levels varied. Moreover, ammonia burners located in the middle part of the main combustion zone exhibited a better high-temperature reduction performance than those located in the upper part of the main combustion zone. Under all ammonia co-combustion conditions, the NH3 concentration at the furnace outlet remained below 1 parts per million (ppm). Compared with that under pure-coal conditions, the thermal efficiency of the boiler slightly decreased (by 0.12%–0.38%) under different loads when ammonia co-combustion reached 15 t·h−1. Ammonia co-combustion in coal-fired power plants is a potentially feasible technology route for carbon reduction.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a group of chronic interstitial pulmonary diseases characterized by myofibroblast proliferation and extracellular matrix (ECM) deposition. However, current treatments are not satisfactory. Therefore, more effective therapies need to be explored. Cepharanthine (CEP) is a naturally occurring alkaloid that has recently been reported to have multiple pharmacological effects, particularly in chronic inflammation. Methods For in vivo experiments, first, a pulmonary fibrosis murine model was generated via tracheal injection of bleomycin (BLM). Second, the clinical manifestations and histopathological changes of the mice were used to verify that treatment with CEP might significantly reduce BLM-induced fibrosis. Furthermore, flow cytometric analysis was used to analyze the changes in the number of M2 macrophages in the lung tissues before and after treatment with CEP to explore the relationship between macrophage M2 polarization and pulmonary fibrosis. In vitro, we constructed two co-culture systems (THP-1 and MRC5 cells, RAW264.7 and NIH 3T3 cells), and measured the expression of fibrosis-related proteins to explore whether CEP could reduce pulmonary fibrosis by regulating macrophage M2 polarization and fibroblast activation. Results The results showed that the intranasal treatment of CEP significantly attenuated the symptoms of pulmonary fibrosis induced by BLM in a murine model. Our findings also indicated that CEP treatment markedly reduced the expression of fibrosis markers, including TGF-β1, collagen I, fibronectin and α-SMA, in the mouse lung. Furthermore, in vitro studies demonstrated that CEP attenuated pulmonary fibrosis by inhibiting fibroblast activation through modulating macrophage M2 polarization and reducing TGF-β1 expression. Conclusions This study demonstrated the potential and efficacy of CEP in the treatment of pulmonary fibrosis. In particular, this study revealed a novel mechanism of CEP in inhibiting fibroblast activation by regulating macrophage M2 polarization and reducing the expression of fibrosis-associated factors. Our findings open a new direction for future research into the treatment of pulmonary fibrosis.

Abstract Background There has been no consensus on what power of radiofrequency energy can be used to produce the best surgical results in patients with atrial fibrillation. In addition, patients undergoing local anesthesia and fentanyl analgesia may experience pain when radiofrequency ablation is performed. This study investigated the effect of different power radiofrequency ablations in treatment and postoperative pain in patients with atrial fibrillation. Methods A retrospective study was performed with 60 patients who underwent radiofrequency ablation for atrial fibrillation between January and June 2023. Patients were divided into 2 groups according to the power of the radiofrequency ablation catheter used, with 30 patients in the conventional power group (35 W) and 30 patients in the high-power group (50 W). The cardiac electrophysiological indexes and postoperative pain of the 2 groups were compared. Results Most of the procedural key parameters between the 2 groups had no significant differences. However, the total application time during radiofrequency ablation and pulmonary vein isolation time in the high-power group were significantly shorter than those in the conventional power group (p

Abstract Astrocytes, the predominant glial cells in the central nervous system, play essential roles in maintaining brain function. Reprogramming induced pluripotent stem cells (iPSCs) to become astrocytes through overexpression of the transcription factors, NFIB and SOX9, is a rapid and efficient approach for studying human neurological diseases and identifying therapeutic targets. However, the precise differentiation path and molecular signatures of induced astrocytes remain incompletely understood. Accordingly, we performed single-cell RNA sequencing analysis on 64,736 cells to establish a comprehensive atlas of NFIB/SOX9-directed astrocyte differentiation from human iPSCs. Our dataset provides detailed information about the path of astrocyte differentiation, highlighting the stepwise molecular changes that occur throughout the differentiation process. This dataset serves as a valuable reference for dissecting uncharacterized transcriptomic features of NFIB/SOX9-induced astrocytes and investigating lineage progression during astrocyte differentiation. Moreover, these findings pave the way for future studies on neurological diseases using the NFIB/SOX9-induced astrocyte model.

Abstract Layered bismuth (Bi) has been focused on two Peierls distortion derivatives, i.e., bulk stable β-phase (A7 phase), black phosphorus-like α-phase (A17 phase), and their mutated structures. Metastable structures beyond Peierls distortion system are yet rarely accessible. Here, Bi in square symmetry ( $${C}_{4v}$$ C 4 v ), called s-Bi, was grown via physical vapor deposition. The co-existence of three 120°-associated s-Bi crystal grains was analyzed using transmission electron microscopy. 120°-oriented one-dimensional (1D) nuclei indicate s-Bi heteroepitaxy on six-fold symmetric ( $${C}_{6v}$$ C 6 v ) mica (001). A subsequent nanorod-like nuclei coalescing could promote a morphology evolution, resulting in triangular or hexagonal nanosheets with the unique triple s-Bi structure suitable for later β-Bi growth. Lattice misfit and strain calculations suggest a supercell match between $$4\times 7$$ 4 × 7 s-Bi and $$3\times 3$$ 3 × 3 mica (001). This work demonstrates the metastable s-Bi structure via anisotropic heteroepitaxy of $${C}_{4v}$$ C 4 v s-Bi on $${C}_{6v}$$ C 6 v mica.

Abstract Background Addressing the shortage of high-quality protein resources, this study was conducted to investigate the effects of replacing soybean meal (SBM) with different levels of enzymolysis-fermentation compound protein feed (EFCP) in the diets of growing-finishing pigs, focusing on growth performance, nutrients digestibility, carcass traits, and meat quality. Methods Sixty DLY (Duroc × Landrace × Yorkshire) pigs with an initial body weight of 42.76 ± 2.05 kg were assigned to 5 dietary treatments in a 2 × 2 + 1 factorial design. These dietary treatments included a corn-soybean meal diet (CON), untreated compound protein feed (UCP) substitution 50% (U50) and 100% SBM (U100) diets, and EFCP substitution 50% (EF50) and 100% SBM (EF100) diets. Each treatment had 6 pens (replicates) with 2 pigs per pen, and the experiment lasted 58 d, divided into phase I (1–28 d) and phase II (29–58 d). Following phase I, only the CON, U50, and EF50 groups were continued for phase II, each with 5 replicate pens. On d 59, a total of 15 pigs (1 pig/pen, 5 pens/treatment) were euthanized. Results During phase I, the EF50 group had a higher average daily gain (ADG) in pigs (P

Abstract Breast cancer (BC) stands as a predominant global malignancy, significantly contributing to female mortality. Recently uncovered, histone lysine lactylation (kla) has assumed a crucial role in cancer progression. However, the correlation with lncRNAs remains ambiguous. Scrutinizing lncRNAs associated with Kla not only improves clinical breast cancer management but also establishes a groundwork for antitumor drug development. We procured breast tissue samples, encompassing both normal and cancerous specimens, from The Cancer Genome Atlas (TCGA) database. Utilizing Cox regression and XGBoost methods, we developed a prognostic model using identified kla-related lncRNAs. The model's predictive efficacy underwent validation across training, testing, and the overall cohort. Functional analysis concerning kla-related lncRNAs ensued. We identified and screened 8 kla-related lncRNAs to formulate the risk model. Pathway analysis disclosed the connection between immune-related pathways and the risk model of kla-related lncRNAs. Significantly, the risk scores exhibited a correlation with both immune cell infiltration and immune function, indicating a clear association. Noteworthy is the observation that patients with elevated risk scores demonstrated an increased tumor mutation burden (TMB) and decreased tumor immune dysfunction and exclusion (TIDE) scores, suggesting heightened responses to immune checkpoint blockade. Our study uncovers a potential link between Kla-related lncRNAs and BC, providing innovative therapeutic guidelines for BC management.

Abstract Optical coherence tomography (OCT) can be used to image microstructures of human kidneys. However, current OCT probes exhibit inadequate field-of-view, leading to potentially biased kidney assessment. Here we present a robotic OCT system where the probe is integrated to a robot manipulator, enabling wider area (covers an area of 106.39 mm by 37.70 mm) spatially-resolved imaging. Our system comprehensively scans the kidney surface at the optimal altitude with preoperative path planning and OCT image-based feedback control scheme. It further parameterizes and visualizes microstructures of large area. We verified the system positioning accuracy on a phantom as 0.0762 ± 0.0727 mm and showed the clinical feasibility by scanning ex vivo kidneys. The parameterization reveals vasculatures beneath the kidney surface. Quantification on the proximal convoluted tubule of a human kidney yields clinical-relevant information. The system promises to assess kidney viability for transplantation after collecting a vast amount of whole-organ parameterization and patient outcomes data.

Abstract Background Colorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size. Methods This is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m2, d1) and irinotecan (180 mg/m2, d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety. Results A total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1–61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1–5.7) and median overall survival was 13.1 months (95% CI 12.2–15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths. Conclusions The combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients). Trial registration ClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017.

Abstract Background Premature rupture of the membranes (PROM) is a key cause of preterm birth and represents a major cause of neonatal mortality and morbidity. Natural products N-acetyl-d-galactosamine (GalNAc), which are basic building blocks of important polysaccharides in biological cells or tissues, such as chitin, glycoproteins, and glycolipids, may improve possible effects of wound healing. Methods An in vitro inflammation and oxidative stress model was constructed using tumor necrosis-α (TNF-α) and lipopolysaccharide (LPS) action on WISH cells. Human amniotic epithelial cells (hAECs) were primarily cultured by digestion to construct a wound model. The effects of GalNAc on anti-inflammatory and anti-oxidative stress, migration and proliferation, epithelial-mesenchymal transition (EMT), glycosaminoglycan (GAG)/hyaluronic acid (HA) production, and protein kinase B (Akt) pathway in hAECs and WISH cells were analyzed using the DCFH-DA fluorescent probe, ELISA, CCK-8, scratch, transwell migration, and western blot to determine the mechanism by which GalNAc promotes amniotic wound healing. Results GalNAc decreased IL-6 expression in TNF-α-stimulated WISH cells and ROS expression in LPS-stimulated WISH cells (P 0.05). GalNAc upregulated the expression of sGAG in WISH cells (P 0.05). Conclusions GalNAc might be a potential target for the prevention and treatment of PROM through the galectin pathway, including (i) inflammation; (ii) epithelial-mesenchymal transition; (iii) proliferation and migration; and (iv) regression, remodeling, and healing.

Abstract Background The incidence of comorbid depression and post-traumatic stress disorder (PTSD) symptoms is higher in snakebite victims. However, the present state and contributing factors of depression and PTSD among Chinese snakebite victims remain unclear. Methods A representative sample of 6837 snakebite victims were assessed with the Post-traumatic Stress Disorder Checklist (Civilian Version) and The Center for Epidemiologic Studies Depression Scale. Multivariate analyses, including network analysis, evaluated the contributing factors of PTSD and depression symptoms caused by snake bites, as well as the bridge symptoms of comorbidity networks. Results Among 6,837 snakebite victims, 79.5% reported PTSD symptoms and 81.4% reported depression symptoms. Comorbidity of PTSD and depression symptoms was found in 75.1%. Key factors included the presence sequelae after snakebite (ORPTSD = 2.31, ORDepression = 1.89), time to medical facilities (6–8 h: ORPTSD = 3.17, ORDepression = 2.46), and marital status (divorced/widowed: ORPTSD = 1.78, ORDepression = 1.76). Symptoms I1 ("Repeated disturbing memories") and D1 ("Bothered by things that don't usually bother me") bridged PTSD and depression networks. Conclusion The primary psychological challenges for snakebite victims in China are PTSD and depression symptoms, which is concerning. Standardized diagnosis and treatments, timely medical care, and stable marital relationships can reduce risks. Additional psychological support and management of negative memories, especially for those with severe bridge symptoms, can be beneficial. Further research should concentrate on understanding victims' psychological states and developing effective interventions.