Background Manganese is an essential trace element for the human body and maintains normal development of many organs including the brain. However, long-term exposure to a high manganese environment or excessive manganese intake will lead to manganese poisoning and result in neurological diseases, and currently no effective treatment plan is available. Objective To develop an animal model for subchronic manganese exposure and assess the impact of Dendrobium nobile Lindl. alkaloids (DNLA) on manganese associated behavioral and hippocampal effects in rats. Methods Fifty male SPF SD rats were randomly allocated into a control group (0.9% normal saline by intraperitoneal injection), two experimental groups [7.5 mg·kg⁻¹ (low) or 15 mg·kg⁻¹ (high) of MnCl₂·4H₂O by intraperitoneal injection], and two DNLA antagonistic groups [15 mg·kg⁻¹ MnCl₂·4H₂O by intraperitoneal injection then either 20 mg·kg⁻¹ (low) or 40 mg·kg⁻¹ (high) DNLA by oral administration]. All groups of rats were adminaistered 5 d per wek, once a day, for consecutive 13 weeks. Following modeling, neurobehavioral assessments were conducted using open field, Morris water maze, and Y maze. Inductively coupled plasma mass spectrometry (ICP-MS) was utilized to measure manganese levels in the blood and brain tissues of the rats, and hematoxylin-eosin (HE) staining was employed to examine neuronal morphological changes in the hippocampal tissues of the rats. Results The neurobehavioral tests revealed that the manganese-exposed rats exhibited decreased total movement distance, prolonged central zone dwelling time, and reduced motor activity in the open field test, indicating tendencies toward depression and anxiety (P<0.05). In the Y-maze test, the mean exploration distance in the novel arm, the number of entries into the novel arm, and the time spent in the novel arm of the managanses-exposed rats were all reduced, while the latency period increased, suggesting impaired spatial exploration and learning-memory functions (P<0.05). In the Morris water maze navigation test, the escape latency was significantly longer in the manganese-exposed rats compared to the control group, and the number of platform crossings decreased in the spatial probe test, indicating a significant decline in spatial learning and memory (P<0.05). The ICP-MS analysis showed elevated manganese concentrations in the blood and hippocampus of the exposed rats (P<0.05), and the histopathological observation revealed hippocampal damage. Following the DNLA intervention, the manganese-exposed rats showed increased total movement distance and reduced central zone dwelling time in the open field test (P<0.05). In the Y-maze test, the mean exploration distance in the novel arm, the number of entries into the novel arm, and the time spent in the novel arm increased, while the latency period decreased, suggesting alleviation of anxiety and improved exploratory behavior (P<0.05). In the Morris water maze test, the escape latency gradually shortened, and both the number of platform crossings and the percentage of time spent in the target quadrant increased, indicating improved spatial learning and memory (P<0.05). Additionally, the manganese levels in the blood and hippocampus decreased (P<0.05), and the hippocampal pathological changes were partially restored. Conclusion DNLA demonstrates the ability to counteract multiple neurotoxic effects following the elevation of manganese levels in the blood and hippocampal tissues of rats induced by subchronic manganese exposure. Specifically, DNLA is shown to ameliorate the behavioral alterations observed in rats after manganese exposure, and mitigate the hippocampal damage in manganese-exposed rats.

For patients with locally advanced head and neck squamous cell carcinoma(LA-HNSCC),multi-disciplinary combination therapy based on radical surgery is still the best treatment modality.In recent years,immune checkpoint inhibitors(ICIs)have been successfully applied in the adjuvant therapy of LA-HNSCC,which has aroused great interest in exploring the efficacy and safety of their use in the neoadjuvant therapy.Numerous studies have shown that the application of ICIs in neoadjuvant therapy can increase the major pathological response(MPR)and improve the quality of life without delaying the surgery or increasing the difficulty of surgery and downgrade the subsequent adjuvant therapy.Compared with immune monotherapy,immune combination therapy further increases the pathological remission rate and promotes pathological down-staging with controllable side effects.But the efficacy of the therapy may be affected by various factors such as HPV+/-,tumor microenvironment(TME).Therefore,how to select more suitable biomarkers for patients among the many neoadjuvant immunotherapy regimens is an urgent clinical problem need to be solved.Predictive biomarkers may be one of the bases for developing individualized treatment regimens for LA-HNSCC.Therefore,this article briefly describes the progress of exploratory studies on the optimal sequence of neoadjuvant immunotherapy alone or combinative in LA-HNSCC,and the predictive biomarkers of immunotherapeutic response.

Objective To conduct a scoping review of studies on the use of virtual reality(VR)in cancer-related cognitive impairment(CRCI),and to generalize and summarize the current state of the art of VR use in CRCI.Methods The computerized retrieval of PubMed,Embase,Web of Science,the Cochrane Library,WanFang Data,CNKI and VIP databases was carried out.Studies were collected from the database establishment to July 2023.3 researchers independently screened the literature,extracted data,and evaluated the risk of bias in the included studies.Results A total of 9 studies were included.VR was used for CRCI assessment and intervention.The assessment included visual and auditory memory,executive function and verbal fluency.The intervention content involved common cognitive impairment dimensions of CRCI,including memory,executive ability,attention,information processing speed and language fluency.The intervention frequency ranged from 3 to 5 times/week,15 to 60 min/time,and the duration was 2 to 8 weeks.The intervention frequency and intensity were dynamically adjusted based on the patient performance,game type and complexity.VR has shown good validity and benefits in CRCI assessments and interventions,while improving patients'sleep quality and ability to perform daily living,with higher patient acceptance and no VR related adverse events being reported,but its role in improving mental health remains controversial.Conclusion VR shows good validity and benefits in CRCI assessment and intervention,and has good safety and high acceptance.In the future,it is still necessary to conduct large-sample,randomized controlled studies,attach importance to the role of patient needs in the formulation of VR cognitive intervention programs,and increase CRCI-related objective indicators to further verify the effect of VR intervention on CRCI.At the same time,longitudinal evaluation and follow-up programs may be considered to determine progressive changes in CRCI from VR interventions.

LIN28 is an RNA binding protein with important roles in early embryo development, stem cell differentiation/reprogramming, tumorigenesis and metabolism. Previous studies have focused mainly on its role in the cytosol where it interacts with Let-7 microRNA precursors or mRNAs, and few have addressed LIN28's role within the nucleus. Here, we show that LIN28 displays dynamic temporal and spatial expression during murine embryo development. Maternal LIN28 expression drops upon exit from the 2-cell stage, and zygotic LIN28 protein is induced at the forming nucleolus during 4-cell to blastocyst stage development, to become dominantly expressed in the cytosol after implantation. In cultured pluripotent stem cells (PSCs), loss of LIN28 led to nucleolar stress and activation of a 2-cell/4-cell-like transcriptional program characterized by the expression of endogenous retrovirus genes. Mechanistically, LIN28 binds to small nucleolar RNAs and rRNA to maintain nucleolar integrity, and its loss leads to nucleolar phase separation defects, ribosomal stress and activation of P53 which in turn binds to and activates 2C transcription factor Dux. LIN28 also resides in a complex containing the nucleolar factor Nucleolin (NCL) and the transcriptional repressor TRIM28, and LIN28 loss leads to reduced occupancy of the NCL/TRIM28 complex on the Dux and rDNA loci, and thus de-repressed Dux and reduced rRNA expression. Lin28 knockout cells with nucleolar stress are more likely to assume a slowly cycling, translationally inert and anabolically inactive state, which is a part of previously unappreciated 2C-like transcriptional program. These findings elucidate novel roles for nucleolar LIN28 in PSCs, and a new mechanism linking 2C program and nucleolar functions in PSCs and early embryo development.
Animals ; Cell Differentiation ; Embryo, Mammalian/metabolism* ; Embryonic Development ; Mice ; Pluripotent Stem Cells/metabolism* ; RNA, Messenger/genetics* ; RNA, Ribosomal ; RNA-Binding Proteins/metabolism* ; Transcription Factors/metabolism* ; Zygote/metabolism*

Objective:To investigate the risk factors associated with failure of trial of labor in primiparous women with preeclampsia (PE) and to establish a risk prediction model.Methods:Primiparae with PE who underwent trial of labor in the Department of Obstetrics of Suzhou Ninth People's Hospital from February 2018 to July 2020 were retrospectively selected as the modeling set, and divided into two groups: the success group and the failure group. Various parameters were compared between the two groups and those data with statistically significant difference were analyzed with multivariate logistic regression analysis. Those factors related to vaginal delivery failure in primiparous women with PE were identified. Based on the results, a risk prediction model was established using R language. Its performance was assessed with receiver operating characteristic (ROC) curve and goodness-of-fit test. This study also retrospectively enrolled primiparae with PE who underwent trial of labor in the same hospital from August 2020 to December 2021 as the validation set. Bootstrap method was used for verification and a calibration chart was created.Results:A total of 312 PE patients were selected as the modeling set with 89 in the failure group and 223 in the success group. Another 146 primiparae with PE were selected as the validation set. Logistic regression analysis showed that older age ( OR=1.609, 95% CI: 1.251-2.483), higher body fat rate in early pregnancy ( OR=1.456, 95% CI: 1.209-2.159) and higher ratio of umbilical artery systolic to diastolic flow velocity within a week before delivery ( OR=1.799, 95% CI: 1.372-2.794) were risk factors for vaginal delivery failure in primiparae with PE, while more maternal education during pregnancy ( OR=0.233, 95% CI: 0.054-0.672) and higher Bishop score ( OR=0.395, 95% CI: 0.258-0.756) were protective factors. A nomogram model to predict the risks of vaginal delivery failure was constructed based on the above five factors. The area under the ROC curve (AUC) of the modeling set was 0.921 (95% CI: 0.847-0.963) with the cut-off value of 0.213, and the corresponding sensitivity and specificity were 0.871 and 0.852, respectively;goodness-of-fit test showed that the observed values matched with those expected ( χ2=7.69, P=0.464); and the calibration curve indicated that the consistency of the prediction model was good. The AUC of the validation set was 0.903 (95% CI: 0.835-0.942) with the sensitivity and specificity of 0.892 and 0.796, respectively; the discrepancy between the observed values and those expected was not significant as indicated by goodness-of-fit test ( χ2=6.82, P=0.512); calibration curve of the validation set showed that the predicted values of the model was consistent with the actual values. Conclusions:The failure of vaginal delivery in primiparae with PE is associated with maternal age, prenatal body fat percentage, ratio of fetal umbilical artery systolic to diastolic flow velocity within a week before delivery, maternal education during pregnancy and Bishop score. The nomogram model based on these five risk factors for prediction of vaginal delivery failure performs well.

Objective:To verify the value of whole genomic copy number variation (WGCNV) detection and scoring system in the diagnosis and prognosis of lung adenocarcinoma.Methods:Seventy-six lung adenocarcinoma specimens including ninety-one tumor samples and twenty adjacent non-tumor lung tissue samples were collected using Laser capture microdissection (LCM). Whole genomic amplification (WGA) was used to enrich DNA and construct a sequencing library for next generation sequencing (NGS). Changes of larger than 5Mb CNV in this study were analyzed and scored. The nuclear grading and score of tumor cells in the surgery and pleural effusion cytology of lung adenocarcinoma specimens were evaluated separately. For each case, we evaluated (1) nuclear size, (2) mitotic counts, (3) nuclear atypia, (4) atypical mitoses. The data of disease-free survive (DFS) and overall survive (OS) were collected for assessing the prognostic value of WGCNV score. Meanwhile, receiver operating characteristic (ROC) and area under curve (AUC) were used to define a cut-off value and evaluate the diagnostic significance in lung adenocarcinoma.Results:The WGCNV scores of twenty adjacent non-tumor lung tissue samples were treated as normal control and all of WGCNV scores of tumor samples range from 0 to 9.95, the median score was 2.7. The WGCNV scores were divided into three groups: low score group <1.74, medium score grade 1.74~4.23, high score grade >4.23. The WGCNV score was positively associated with the nuclear grade scoring ( r=0.780 90, P<0.001). The result for evaluation of prognostic value of the WGCNV scores showed that comparing with low WGCNV score group, Hazard Ratio (HR) of medium score group was 4.11 (95% CI=0.72~23.57) and high score group was 2.07 (95% CI=0.30~14.12). These results suggested that the risks of the medium and high WGCNV score group elevated. According to the analysis results of ROC curve, when the cut off value was 0.01, the sensitivity and specificity for lung adenocarcinoma diagnosis were 97.8% and 95.0% respectively, the positive predictive value (PPV) and negative predictive value (NPV) were 99.0% and 90.1%, respectively, the AUC was 0.981. In the differentiation of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) group and invasive adenocarcinoma group, when the cut off value was 1.8, the sensitivity and specificity between the two groups were 78.1% and 94.4%, and the PPV and NPV were 98.0% and 52.0%, respectively, the AUC was 0.896. Conclusion:This study verifies that WGCNV scoring system has a potential diagnostic and prognostic value in lung adenocarcinoma.

Objective:To verify the value of whole genomic copy number variation (WGCNV) detection and scoring system in the diagnosis and prognosis of lung adenocarcinoma.Methods:Seventy-six lung adenocarcinoma specimens including ninety-one tumor samples and twenty adjacent non-tumor lung tissue samples were collected using Laser capture microdissection (LCM). Whole genomic amplification (WGA) was used to enrich DNA and construct a sequencing library for next generation sequencing (NGS). Changes of larger than 5Mb CNV in this study were analyzed and scored. The nuclear grading and score of tumor cells in the surgery and pleural effusion cytology of lung adenocarcinoma specimens were evaluated separately. For each case, we evaluated (1) nuclear size, (2) mitotic counts, (3) nuclear atypia, (4) atypical mitoses. The data of disease-free survive (DFS) and overall survive (OS) were collected for assessing the prognostic value of WGCNV score. Meanwhile, receiver operating characteristic (ROC) and area under curve (AUC) were used to define a cut-off value and evaluate the diagnostic significance in lung adenocarcinoma.Results:The WGCNV scores of twenty adjacent non-tumor lung tissue samples were treated as normal control and all of WGCNV scores of tumor samples range from 0 to 9.95, the median score was 2.7. The WGCNV scores were divided into three groups: low score group <1.74, medium score grade 1.74~4.23, high score grade >4.23. The WGCNV score was positively associated with the nuclear grade scoring ( r=0.780 90, P<0.001). The result for evaluation of prognostic value of the WGCNV scores showed that comparing with low WGCNV score group, Hazard Ratio (HR) of medium score group was 4.11 (95% CI=0.72~23.57) and high score group was 2.07 (95% CI=0.30~14.12). These results suggested that the risks of the medium and high WGCNV score group elevated. According to the analysis results of ROC curve, when the cut off value was 0.01, the sensitivity and specificity for lung adenocarcinoma diagnosis were 97.8% and 95.0% respectively, the positive predictive value (PPV) and negative predictive value (NPV) were 99.0% and 90.1%, respectively, the AUC was 0.981. In the differentiation of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) group and invasive adenocarcinoma group, when the cut off value was 1.8, the sensitivity and specificity between the two groups were 78.1% and 94.4%, and the PPV and NPV were 98.0% and 52.0%, respectively, the AUC was 0.896. Conclusion:This study verifies that WGCNV scoring system has a potential diagnostic and prognostic value in lung adenocarcinoma.

Objective To grasp the current situation of drinking water-borne endemic fluorosis in Shandong Province,and provide a scientific basis for formulating preventive strategies.Methods In 2016,according to the "National Surveillance Scheme of Drinking Water-Borne Endemic Fluorosis" and "Shandong Provincial Surveillance Scheme of Drinking Water-Borne Endemic Fluorosis",10 counties (cities,districts) were selected in Shandong Province,3-5 villages were selected in each county (city,district),to investigate the operation of water improvement and fluorine reduction project and the water fluorine,and 1 tap water sample in each village was collected to detect water fluorine.At the same time,dental fluorosis examination was performed on all children aged 8-12 years old and fluorosis X-ray examination was performed on adults aged ≥25 years old.Water fluorine was detected by ion selective electrode method;the water fluorine was determined according to "Standards for Drinking Water Quality" (GB 5749-2006);criteria for diagnosis,grading and epidemic intensity of dental fluorosis were based on "Diagnosis of Dental Fluorosis" (WS/T 208-2011);the diagnostic and grading criteria for skeletal fluorosis were based on the "Diagnostic Criteria for Endemic Skeletal Fluorosis" (WS 192-2008).Results All the 32 villages in 10 counties (cities,districts) changed water,water improvement and fluorine reduction project ran normally,24 villages had qualified water fluorine (≤ 1.20 mg/L),and 8 villages had water fluorine exceeding the standard.The detection rate of dental fluorosis in children was 25.75％ (419/1 627),and the difference between 10 counties (cities,districts) was statistically significant (x2 =288.55,P ＜ 0.01);the dental fluorosis index was 0.48,and the defect rate was 2.77％ (45/1 627).The detection rate of skeletal fluorosis in adults was 4.72％ (72/1 525),and the difference between 10 counties (cities,districts) was statistically significant (x2 =18.83,P ＜ 0.01).Conclusions The problem of water fluorine exceeding the standard in water improvement and fluorine reduction project in Shandong Province is still serious.The condition of fluorosis has not been fully controlled,and the prevention and treatment measures need to be further strengthened.

Objective To explore the CT and MRI imaging and clinicopathological features of extranodal NK/T cell lymphoma (NK/TCL). Methods Sixty-six patients with NK/TCL diagnosed from 2002 June to 2016 April in Beijing Tongren Hospital with intact CT and/or MRI imaging results were enrolled in this study. All the patients had tailed clinical information and follow-up. The imaging and clinicopathological features were analyzed retrospectively and their prognostic value on overall survival was analyzed. Results There were 49 males and 17 females with median age of 42 years. The median follow-up time was 18 months. The cases showed surrounding invasions including 10 cases (15.2 %) in soft palate, 5 cases (7.6 %) in hard palate, 2 cases(3.0 %) in tonsil, 8 cases(12.1 %) in upper lip, 13 cases(19.7 %) in maxillofacial soft tissue, 9 cases (13.6 %) in eyelid, 10 cases (15.2 %) in orbital, 3 cases (4.5 %) in maxilla, 6 cases (9.1 %) in pterygopalatine fossa,6 cases(9.1 %)in infratemporal fossa,3 cases(4.5 %)in skull base, 3 cases(4.5 %) in eyeball and 2 cases (3.0 %) in brain tissue. Kaplan-Meier survival analysis found that the 2-year overall survival rates of the patients with the involvement of hard palate, upper lip, maxillofacial soft tissue, eyelid, orbital, maxillary, eyeball and brain organizer were lower than those of the patients without the involvement of these sites(χ2values were 4.470,4.041,4.456,13.933,8.986,4.000,44.121,6.527,16.822,respectively, all P< 0.05). Further multivariate Cox regression analysis showed that maxilla and brain involvement were independent adverse factors (RR=34.717, 95 % CI 3.404-354.035, P=0.003; RR=37.545, 95 % CI 3.188-442.187, P= 0.004). Conclusions MRI and CT examinations are of great value in diagnosis and prognostic assessment of NK/TCL. Clinicians can make correct and timely diagnosis by comprehensive clinical, radiological and pathological features and can make a detailed clinical assessment to give patients appropriate treatment,thus improving the outcome of the NK/TCL patients.

Objective To understand the implementation effects of control measures and the dynamic prevalence of drinking water-borne endemic fluorosis in Shandong Province.Methods From 2013 to 2017 in Shandong Province drinking water-borne endemic fluorosis areas,in accordance with the method of simple random sampling,10 monitored counties were selected,10 water fluorine decreasing projects were investigated of its running effect,and water fluoride was detected.In each monitored county,3 villages in the diseased areas were selected as fixed monitored villages.If the monitored village had changed its water,the operation of the project would be investigated.If the monitored village had not changed the water,one water sample would be collected according to 5 directions of east,west,south,north and middle to determine the water fluorine.All children aged from 8 to 12 in the village were also examined for dental fluorosis.X-ray fluorosis and urinary fluorosis in adults aged over 25 were detected in 2013 and 2017.Results From 2013 to 2017,in monitored counties,the normal operation rate of improved-water defluoridation projects was 99.19％ (368/371),the qualified rate of water fluoride content was 66.85％ (248/371).In 128 improved water projects,the normal operation rate was 100.00％ (128/128),the qualified rate of water fluoride content was 67.19％ (86/128).The average detection rate of dental fluorosis and community fluorosis index (CFI) in children aged 8-12 were 33.92％ (2 608/7 689) and 0.68 in all monitored counties from 2013 to 2017.The detection rate presented a declining trend year by year (x2 =152.47 P ＜ 0.01).The average detection rate and CFI in the villages with normal operation projects and qualified fluoride content were 26.10％ (1 311/5 023) and 0.47.The detection rate presented a declining trend year by year (x2 =207.67 P ＜ 0.01).The detection rate and CFI in the villages with water improvement projects under abnormal operation or excessive fluoride were 48.65％ (1 297/2 666) and 0.90.The detection rate of dental fluorosis in the villages with normal operation projects and qualified fluoride content was lower than the rate of the villages with water improvement projects under abnormal operation or excessive fluoride (x2 =193.98,P ＜ 0.01).In 2013 and 2017,X-ray detection rates of skeletal fluorosis in adults aged over 25 were 8.04％ (119/1 481) and 6.04％ (81/1 342),respectively.The adult urinary fluoride geometric mean values (1.24,1.49 mg/L) were lower than the normal limit of 1.6 mg/L both in qualified villages of water ffuoride content and exceeding-standard villages in 2017.Conclusions In Shandong Province,the effective water improvement has acquired some effects in control of drinking water-borne endemic fluorosis.But the water fluoride content of improved water defluoridation projects exceeds the national standard seriously and fluorosis has not been effectively controlled.