Preoperative CA19-9 and GGT ratio as a prognostic indicator in ampullary carcinoma.

BACKGROUND AND AIMS: In recent years, more and more inflammatory indicators have been studied to predict the long-term survival of patients with ampullary carcinoma (AC) after radical resection, but these prognostic indicators are still controversial. Therefore, based on previous inflammation scores, this study established a novel, easily accessible, more feasible and more predictive prognostic marker [Carbohydrate antigen199 to gamma-glutamyltransferase ratio (CA19-9/GGT)] to better assess the prognostic significance in AC patients undergoing radical resection. METHODS: Overall survival (OS) and recurrence-free survival (RFS) were analyzed by Cox regression model. Correlation between CA19-9/GGT and clinicopathological variables were analyzed by Chi-squared test, Fisher ' s exact test, independent sample t test and Mann-Whitney U test. The performance of prognostic indexes is compared by the consistency index (C-index). The prediction accuracy of nomogram is further confirmed by calibration curve and decision curve analysis (DCA). RESULTS: CA19-9/GGT was an independent risk factor affecting OS [P = 0.001, hazard ratio (HR) 2.459, 95% confidence intervals (CI) 1.450-4.167] and RFS (P = 0.002, HR 2.333, 95% CI 1.371-3.971) in multivariate analysis. The optimal cut-off value of CA19-9/GGT was 0.14. In CA19-9/GGT correlation analysis, high risk group (> 0.14) was significantly associated with poor prognosis. The predictive performance of CA19-9/GGT (OS: C-index = 0.753, RFS: C-index = 0.745) was confirmed to be superior to other prognostic indicators according to the C-index. Compared with the simple AJCC staging system, the Nomogram prediction model (OS: C-index = 0.787, RFS: C-index = 0.795) established by the combination of CA19-9/GGT and AJCC 8th TNM staging system has higher prediction accuracy. CONCLUSIONS: CA19-9/GGT was an independent prognostic indicator after radical resection of AC. Incorporating CA19-9/GGT into the AJCC TNM staging system optimized the prediction accuracy of the TNM staging system, and further verified the predictive value of CA19-9/GGT.

The Importance of Tumor Necrosis Factor-α-Induced Protein-8 Like-2 in the Pathogenesis of Cervical Cancer and Preeclampsia via Regulation of Cell Invasion.

Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) as a novel negative immune regulator plays an important role in several human diseases. However, its influences in cervical cancer and preeclampsia (PE) remain unclear. This study aims to explore the important role of TIPE2 in cervical cancer and PE via regulating cell invasion. TIPE2 expression in the cervical cancer tissues or the placenta of PE patients was detected. Human cervical cancer cell lines and trophoblasts were transfected with adenovirus expressing human TIPE2 and green fluorescent protein (GFP) (Ad-TIPE2), or the control adenovirus expressing GFP (Ad-GFP). Xenograft models were also constructed on nude mice, aiming to clarify how TIPE2 affects in vivo growth of cervical cancer cells. TIPE2 was down-regulated in the tumor tissues or placenta of patients with cervical cancer or PE. As a result, CaSKi and Hela cells in the Ad-TIPE2 group had decreased migration and invasion, with significant up-regulations of TIPE2 and E-cadherin, but down-regulations of ß-catenin and N-cadherin. Ad-TIPE2 decreased the volume and weight of xenograft tumors in the nude mice, with the down-regulation of Ki67. The quantity of cells (HTR8/SVneo and JEG3 cells) transfected with Ad-TIPE2 had increased, with up-regulations of TIPE2, matrix metalloproteinase (MMP)-2 and MMP-9. TIPE2 overexpression could reduce the invasion and migration of cervical cancer cells via inhibiting the epithelial-mesenchymal transition (EMT) process, and promote trophocyte invasion via upregulating the expression of MMPs, and it may be used as a potential therapeutic target for cervical cancer and PE.

Tunable acoustic metasurface based on tunable piezoelectric composite structure.

Due to the potential engineering needs, the passive tunable metasurfaces with a high performance equivalent to the active phased array is worthy of research. Here, a passive ultrathin metasurface unit composed of a piezoelectric composite structure (PCS) connected to an external capacitor, which can modulate the phase of the transmitted acoustic waves at a deep subwavelength scale only by controlling the external capacitor but without changing the structure, is proposed. Then, a tunable acoustic metasurface composed of 20 identical PCSs is introduced to realize three acoustic functions, beam steering, beam focusing, and tweezer-like beam generating, just by changing the external capacitors. The phase-control abilities of the PCS unit and three functions of the designed metasurface are proved both numerically and experimentally. This study provides the possibility to design ultrathin tunable acoustic metasurfaces with the ability of precise control and passive materials.

Effect of PAK1 gene silencing on proliferation and apoptosis in hepatocellular carcinoma cell lines MHCC97-H and HepG2 and cells in xenograft tumor.

This study intends to explore the effect of the PAK1 gene silencing on apoptosis and proliferation of hepatocellular carcinoma (HCC) MHCC97-H and HepG2 cells and cells in xenograft tumor. MHCC97-H and HepG2 cells and mice with xenograft tumor in vivo were randomly divided into control, empty vector and PAK1 shRNA groups. Morphology and the expression of green fluorescent protein of MHCC97-H and HepG2 cells and cells in xenograft tumor were observed. MTT assay and flow cytometry were used to detect proliferation, cell cycle and apoptosis of MHCC97-H and HepG2 cells and cells in xenograft tumor. The expressions of PAK1, PCNA, Ki67, Cyclin E, CDK2, p21, p53, Bax and Bcl-2 were measured using the quantitative reverse transcription polymerase chain reaction and western blotting. Compared with the control and empty vector groups, number of adherent cells of MHCC97-H and HepG2 cells and cells in xenograft tumor was reduced, and green fluorescent cells became round and reduced in the PAK1 shRNA group. Cell proliferation, the cells at S phase, the mRNA and protein expressions of PAK1, PCNA, Ki67, Cyclin E, CDK2 and Bcl-2 of MHCC97-H and HepG2 cells and cells in xenograft tumor were decreased, while the cells at G1 phase, apoptosis rate, the mRNA and protein expressions of p21, p53 and Bax of MHCC97-H and HepG2 cells and cells in xenograft tumor were increased in the PAK1 shRNA group. PAK1 gene silencing decreases proliferation of MHCC97-H cells, HepG2 cells and cells in xenograft tumor through the p53/p21 pathway.

Development and validation of a machine learning-based early prediction model for massive intraoperative bleeding in patients with primary hepatic malignancies.

BACKGROUND: Surgical resection remains the primary treatment for hepatic malignancies, and intraoperative bleeding is associated with a significantly increased risk of death. Therefore, accurate prediction of intraoperative bleeding risk in patients with hepatic malignancies is essential to preventing bleeding in advance and providing safer and more effective treatment. AIM: To develop a predictive model for intraoperative bleeding in primary hepatic malignancy patients for improving surgical planning and outcomes. METHODS: The retrospective analysis enrolled patients diagnosed with primary hepatic malignancies who underwent surgery at the Hepatobiliary Surgery Department of the Fourth Hospital of Hebei Medical University between 2010 and 2020. Logistic regression analysis was performed to identify potential risk factors for intraoperative bleeding. A prediction model was developed using Python programming language, and its accuracy was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Among 406 primary liver cancer patients, 16.0% (65/406) suffered massive intraoperative bleeding. Logistic regression analysis identified four variables as associated with intraoperative bleeding in these patients: ascites [odds ratio (OR): 22.839; P < 0.05], history of alcohol consumption (OR: 2.950; P < 0.015), TNM staging (OR: 2.441; P < 0.001), and albumin-bilirubin score (OR: 2.361; P < 0.001). These variables were used to construct the prediction model. The 406 patients were randomly assigned to a training set (70%) and a prediction set (30%). The area under the ROC curve values for the model's ability to predict intraoperative bleeding were 0.844 in the training set and 0.80 in the prediction set. CONCLUSION: The developed and validated model predicts significant intraoperative blood loss in primary hepatic malignancies using four preoperative clinical factors by considering four preoperative clinical factors: ascites, history of alcohol consumption, TNM staging, and albumin-bilirubin score. Consequently, this model holds promise for enhancing individualised surgical planning.

Utility, benefits, and risks of newborn genetic screening carrier reports for families.

Background: Newborn genetic screening (NBGS) based on next-generation sequencing offers enhanced disease detection and better detection rates than traditional newborn screening. However, challenges remain, especially around reporting the NBGS carrier results. Therefore, we aimed to investigate the NBGS carrier parents' views on NBGS and NBGS reports in China. Methods: We distributed a survey querying demographic information, knowledge and perceptions of NBGS, the impact of NBGS on a total of 2930 parents, and their decision-making to parents of newborns reported as carriers in NBGS in Nanjing, China in 2022. Results: The average age of the survey respondents was 30.7 years (standard deviation = 3.6). Most (68.38%) felt informed about NBGS, especially women, the highly educated, and high earners. Nearly all (98.74%) saw NBGS as crucial for early disease detection, with 73.18% believing it positively impacts their future. However, 19.16% felt it might cause anxiety, especially among the less educated. Concerns included potential discrimination due to exposed genetic data and strained family ties. Many suggested NBGS coverage by medical insurance to ease financial burdens. Conclusions: Through our study, we gained insights into parents' perspectives and concerns regarding the NBGS carrier result reporting, thus providing relevant information for further refinement and clinical promotion of the NBGS project.

Newborn genetic screening for Fabry disease: Insights from a retrospective analysis in Nanjing, China.

Fabry disease (FD), an X-linked disorder resulting from dysfunction of α-galactosidase A, can result in significant complications. Early intervention yields better outcomes, but misdiagnosis or delayed diagnosis is common, impacting prognosis. Thus, early detection is crucial in the clinical diagnosis and treatment of FD. While newborn screening for FD has been implemented in certain regions, challenges persist in enzyme activity detection techniques, particularly for female and late-onset patients. Further exploration of improved screening strategies is warranted. This study retrospectively analyzed genetic screening results for pathogenic GLA variants in 17,171 newborns. The results indicated an estimated incidence of FD in the Nanjing region of China of approximately 1 in 1321. The most prevalent pathogenic variant among potential FD patients was c.640-801G > A (46.15 %). Furthermore, the residual enzyme activity of the pathogenic variant c.911G > C was marginally higher than that of other variants, and suggesting that genetic screening may be more effective in identifying potential female and late-onset patients compared to enzyme activity testing. This research offers initial insights into the effectiveness of GLA genetic screening and serves as a reference for early diagnosis, treatment, and genetic counseling in FD.

Low expression of SEMA4D as a potential predictive molecular marker of poor survival in patients with melanoma combined with liver cancer.

This study explored the correlation between semaphorin 4D (SEMA4D) and the prognosis and survival time of patients with melanoma combined with liver cancer. A total of 272 patients were recruited, and clinical and follow-up data were recorded. The expression levels of SEMA4D and SEMA3B were determined. Pearson's χ2 test and Spearman's rank correlation coefficient were used to analyze the relationship between prognosis and the assessed parameters of melanoma patients. Univariate and multivariate Logistic regression and Cox proportional risk regression analyses were used for further analysis. Additionally, receiver operating characteristic curve and survival curves of subjects were plotted. The Pearson's χ2 test showed that the prognosis of melanoma patients was significantly correlated with age, tumor grade, and decreased SEMA4D expression. Additionally, Spearman's correlation coefficient analysis showed that age, tumor grade, and SEMA4D expression were significantly correlated with prognosis. Univariate logistic regression analysis showed that age and tumor grade, and SEMA4D expression, were significantly correlated with prognosis. Older patients, a higher tumor grade, and lower SEMA4D expression were associated with a poorer prognosis. Multivariate logistic regression analysis showed that older patients had a poorer prognosis, and patients with lower SEMA4D expression levels had a significantly worse prognosis than patients with higher SEMA4D expression levels. Kaplan-Meier analysis showed that the survival time of older patients was lower than that of the younger patients. The survival times of patients with lower SEMA4D expression levels were significantly lower than that of patients with higher SEMA4D expression levels. Multivariate Cox regression analysis showed that the survival time of older patients was lower than that of younger patients. The survival time of melanoma patients with low SEMA4D expression was significantly lower than that of patients with higher SEMA4D expression. SEMA4D was significantly associated with melanoma, and lower SEMA4D expression was associated with a poorer survival prognosis in melanoma patients.

Newborn genetic screening is highly effective for high-risk infants: A single-centre study in China.

Background: Newborn genetic screening (NBGS) is promising for early detection of genetic diseases in newborns. However, little is known about its clinical effectiveness in special groups like high-risk infants. To address this gap, we aimed to investigate the impact of NBGS on high-risk infants. Methods: We screened 10 334 healthy newborns from the general maternity unit and 886 high-risk infants from the neonatal ward using both traditional newborn screening (tNBS) and NBGS, and collected clinical data from electronic medical records. Results: We found that high-risk infants had a higher proportion of eutocia (P < 0.01) and prematurity (P < 0.01). For high-risk infants vs healthy newborns screened by tNBS, the primary screening positive rate was 3.84% vs 1.31%, the false positive rate (FPR) was 3.62% vs 1.18% (P < 0.001), and the positive predictive value (PPV) was 5.88% vs 8.27%. For NBGS vs tNBS in high-risk infants, the primary screening positive rate was 0.54% vs 3.68%, the FPR was 0.22% vs 3.47%, and the PPV was 60.00% vs 5.88%. Conclusions: We found that combined newborn screening can effectively reduce the FPR caused by the high-risk symptoms and improve the PPV in high-risk infants, sufficient for more accurately showing the true status of the disease.

The effect of perceptual grouping on perisaccadic spatial distortions.

Perisaccadic spatial distortion (PSD) occurs when a target is flashed immediately before the onset of a saccade and it appears displaced in the direction of the saccade. In previous studies, the magnitude of PSD of a single target was affected by multiple experimental parameters, such as the target's luminance and its position relative to the central fixation target. Here we describe a contextual effect in which the magnitude of the PSD for a target was influenced by the synchronous presentation of another target: PSD for simultaneously presented targets was more uniform than when each was presented individually. Perisaccadic compression was ruled out as a causal factor, and the results suggest that both low- and high-level perceptual grouping mechanisms may account for the change in PSD magnitude. We speculate that perceptual grouping could play a key role in preserving shape constancy during saccadic eye movements.

Current attitudes and preconceptions on newborn genetic screening in the Chinese reproductive-aged population.

PURPOSE: Newborn screening (NBS) applications are limited as they can only cover a few genetic diseases and may have false positive or false negative rates. A new detection program called newborn genetic screening (NBGS) has been designed to address the potential defects of NBS. This study aimed to investigate the perceptions, acceptance, and expectations of childbearing people related to NBGS to provide the basis for the targeted improvement in the NBGS program carried out in Hospitals. METHODS: A questionnaire with 20 items was designed on www.wjx.cn . Individuals who came to the Nanjing maternity and child health care Hospital for consultation from June 2021 to August 2021 participated in the survey. The data of the study was arranged properly and analyzed after the investigation. RESULTS: A total of 1141 valid questionnaires were collected in the survey, in which the average age of the participants was 31 (± 4) years, and a 1:4 ratio of males to females. Additionally, 65.12% of the participants possessed a bachelor's degree or above qualification. Overall, 50.57% of participants had an annual household income of 100,000-250,000 RMB, while about 86.68% of the participants supported the development of NBGS. The participation cost to pay for NBGS depended on the family incomes; about 59.42% of them were willing to pay a participation fee of 1000-2000 RMB. CONCLUSION: Our research provisionally demonstrated that the residents generally supported the use of NBGS, especially those with higher educational degrees, but the understanding of the genetic diseases and NBGS among the low-educated population still needs to be strengthened.

Application of a novel computer-assisted surgery system in percutaneous nephrolithotomy: A controlled study.

BACKGROUND: Most complex renal stones are managed primarily with percutaneous nephrolithotomy (PCNL). However, PCNL is still a great challenge for surgeons because of poor comprehension on complex adjacent structures. Novel techniques are required to assist in planning and navigation. AIM: To apply and evaluate the Hisense computer-assisted surgery (CAS) system in PCNL. METHODS: A total of 60 patients with complex renal stones were included. Thirty patients in the CAS group had three-dimensional (3D) virtual models constructed with the CAS system. The model assisted in planning and navigating in the CAS system. Thirty patients in the control group planned and navigated as standard PCNL, without the application of the CAS system. Success rate of one attempt, operation time, initial stone-free rate, decrease in hemoglobin, and complications were collected and analyzed. RESULTS: There were no statistically significant differences in the baseline characteristics or planning characteristics. The success rate of one puncturing attempt (90% vs 67%, P = 0.028) and the initial stone-free rate (87% vs 63%, P = 0.037) were significantly higher in the CAS group. However, there were no statistically significant differences in the operation time (89.20 ± 29.60 min vs 92.33 ± 33.08 min, P = 0.859) or in the decrease in hemoglobin (11.07 ± 8.32 g/L vs 9.03 ± 11.72 g/L, P = 0.300) between the CAS group and the control group. No statistically significant differences in the incidence of complications (Clavien-Dindo grade ≥ 2) were found. CONCLUSION: Compared with standard PCNL, CAS-assisted PCNL had advantages in terms of the puncturing success rate and stone-free rate. The Hisense CAS System was recommended to assist in preoperative planning and intraoperative navigation for an intuitive, precise and convenient PCNL.

Combined genetic screening and traditional biochemical screening to optimize newborn screening systems.

Newborn screening can detect around 40 different diseases based on biochemical indicators and has resulted in the improved quality of life for children suffering from genetic diseases. However, NBS is limited as it does not cover all genetic diseases in newborns and has high rates of false positives and negatives. Genetic screening can be used to address the shortcomings of traditional biochemical screening, however, the comprehensive clinical value of genetic screening is yet to be systematically studied. In this study, we used two different genetic screening methods to examine 200 cases of NBS. We found that genetic screening can be used to identify a broader spectrum of diseases and is not limited to traditional biochemical screening diseases; it can identify positive cases of disease and can eliminate false positives caused by multiple factors such as pathogenic variants carrier or the mode of childbirth. Genetic screening has shortened the time to diagnosis and reduced the costs of testing. Furthermore, we found that the biochemical detection results were limited when patients simultaneously carried multiple pathogenic mutations. Our research provisionally demonstrates the necessity, feasibility and significance of clinical genetic screening in newborns and provides a solid basis for future clinical developments.

Special type of distal junctional failure exhibits pelvic incidence changes: sacroiliac joint-related pain following lumbar spine surgery.

Background: Currently, change in pelvic incidence (PI) in patients after spinal surgery have not been associated with clear clinical symptoms. This study sought to compare changes in the sagittal parameters of different patients before and after thoracolumbar spine surgery, the relationship between PI change and sacroiliac joint pain (SIJP) after surgery was clarified, and the correlation between PI change and sacroiliac joint (SIJ) activity was verified. Methods: This study retrospectively analyzed the data of patients who underwent thoracolumbar fusion at Sun Yat-sen Memorial Hospital from January 2019 to June 2021. The spinal and pelvic parameters [including pelvic tilt (PT), sacral slope (SS), PI, lumbar lordosis (LL) angle, etc.] of 409 patients with standard standing lateral radiographs before and after surgery were compared and analyzed. Postoperative follow-up of all patients with standardized SIJP assessment. The incidence of postoperative SIJP, and its correlation with sagittal parameters of the spine and pelvis, surgical methods, and the basic characteristics of patients were analyzed. The Chi-square test was used for categorical variables, the independent-sample t-test was used for generally conformed normally distributed continuous variables. Risk factors associated with the development of SIJP were analyzed using logistics regression. Correlations among SS, PI, and the 4 other sagittal parameters were analyzed using the Pearson correlation coefficient (r). Results: Postoperative PI changes tended to be larger in the lowest instrumented vertebra (LIV) (L4 and above: 1.63°; L5: 2.43°; S1: 3.83°; P<0.05) and longer fixed segment. The risk factors for SIJP included a PI >4° [odds ratio (OR) =13.051; P<0.001], LIV S1 (OR =3.378; P=0.023), and fixed total segment ≥3 (OR =2.632; P=0.038). ∆PI was significantly correlated with ∆SS in patients with non-S1 distal fixation vertebrae (R2=0.388; P<0.01), but no such correlation was found in patients with S1 distal fixation vertebrate. Conclusions: Changes in PI values after thoracolumbar spine surgery can correctly reflect the motion state of the SIJ. Excessive changes in PI (>4°) are similar to the mechanism of distal junctional kyphosis (DJK), while such changes make patients prone to SIJP following lumbar spine surgery.

Saikosaponin A improved depression-like behavior and inhibited hippocampal neuronal apoptosis after cerebral ischemia through p-CREB/BDNF pathway.

Post-stroke depression(PSD) is a common complication and associates with poor physical recovery, low quality of life and high mortality after cerebral infarction. However, the pathogenesis of PSD have not been elucidated thoroughly now, and there is a lack of effective therapy in clinic. It reported that Saikosaponin A, one of the main constituents from Chinese herb Bupleurum chinense, has pharmacological activity in anti-depression. Thus, this study aimed to elucidate the potential effects and mechanisms of Saikosaponin A on the depression-like behavior after cerebral ischemic injury in rats. The rat model of PSD was induced by middle cerebral artery occlusion(MCAO) combined with chronic unpredictable mild stress(CUMS) and isolation. Behavior tests including open field test, beam-walking test, sucrose preference and forced swimming tests were performed. Western blot and immunohistochemistry were adopted to evaluate expression of phosphorylated cAMP response element binding protein(p-CREB), brain derived neurotrophic factor(BDNF) and apoptosis-related molecules in the dentate gyrus region of rat hippocampus. The TUNEL assay was used to determine neuronal apoptosis. We found that the rats subjected to MCAO combined with CUMS and isolation experienced significant depressive-like behavior. Administration of Saikosaponin A significantly ameliorated depressive-like behavior, and inhibited neuronal apoptosis, enhanced the level of p-CREB, BDNF and Bcl-2, reduced the level of Bax, Caspase-3 in the hippocampus of PSD rats. These results revealed that Saikosaponin A improved depression-like behavior and inhibited hippocampal neuronal apoptosis after cerebral ischemia, presumably through increasing the expression of BDNF, p-CREB and Bcl-2, as well as decreasing the level of Bax, Caspase-3.

A newly improved POSSUM scoring system for prediction of morbidity in patients with pancreaticoduodenectomy.

BACKGROUND: Postoperative morbidity of pancreaticoduodenectomy (PD) is still prevalent in hospitals around the world all over the world. Chirurgia B and Chen Yingtai et al. compared the existing POSSUM and p-POSSUM scoring system in pancreatoduodenectomy. However, in this retrospective cohort study our aim was to investigate the risk factors associated with post-PD complications, and develop a POSSUM scoring system more specific to PD, which we define as PD-POSSUM. METHODS: Data was gathered from 201 patients who underwent PD procedure at No.4 Hospital of Hebei Medical University between January 2016 and December 2018. All 201 patients were included in the modeling group. The morbidity and associated risk factors were collected and analyzed. The risk factors of complication were investigated by the Pearson χ2 test, Spearman rho test, multivariable linear regression, univariate/multivariate logistic regression. In addition, the discriminating ability of the PD-POSSUM system to predict morbidity is estimated by the area under the receiver operating characteristic curve (ROC-AUC). RESULTS: Morbidity was 45.5% for the 201 patients. Multivariate logistic regression analysis demonstrated a significant connection between postoperative complications and body mass index (BMI) [odd ratio (OR): 3.700; 95% confidence interval (95% CI): 1.594-4.572], pre-existing respiratory diseases (OR: 3.000; 95% CI: 1.542-5.837), international normalized ratio of prothrombin time (OR: 0.321; 95% CI: 0.099-1.038), alanine aminotransferase (OR: 0.573; 95% CI: 0.375-0.874); total bilirubin level (OR: 1.477; 95% CI: 1.068-2.043); diameter of pancreatic duct (OR: 1.837; 95% CI: 1.221-2.763) and diameter of tumor diameter (OR: 1.837; 95% CI: 1.221-2.763). CONCLUSIONS: Ln R/(1 - R) = Score PD - POSSUM  = 0 .140*Score PS - 0 .053*Score OS - 5 .850 . This risk assessment formula can help estimate and predict postoperative morbidity rate after PD.

Somatic Mutation Profiling of Intrahepatic Cholangiocarcinoma: Comparison between Primary and Metastasis Tumor Tissues.

INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) exhibited increasing incidence and mortality around the world, with a 35% five-year survival rate. In this study, the genetic alteration of primary ICC and metastasis ICC was exhibited to discover novel personalized treatment strategies to improve the clinical prognosis. METHODS: Based on 153 primary and 49 metastasis formalin-fixed paraffin-embedded ICC samples, comprehensive genomic profiling was carried out. RESULTS: In primary tumor samples (PSs) and metastasis tumor samples (MSs), the top alteration genes were TP53 (41.8% vs 36.7%), KRAS (30.7% vs 36.7%), and ARID1A (22.2% vs 14.2%). In the top 20 most frequent alteration genes, BRAF showed lower mutation frequency in MSs as compared to PSs (0 vs 11.1%, P=0.015), while LRP1B exhibited opposed trend (22.4% vs 10.4%, P=0.032). In PSs, patients with MSI-H showed all PDL1 negative, and patients with PDL1 positive exhibited MSS both in PSs and MSs. It was found that the Notch pathway had more alteration genes in MSI-H patients (P=0.027). Furthermore, the patients with mutated immune genes in PSs were more than that in MSs (28.8% vs 8.2%, P=0.003, odd ratio = 0.2). Interestingly, the platinum drug resistance pathway was only enriched by mutated genes of MSs. CONCLUSIONS: In this study, the identification of two meaningful mutated genes, BRAF and LRP1B, highly mutated immune gene harbored by primary ICC patients. Both in PSs and MSs, no patients with MSI-H showed PDL1 positive. The Notch pathway had more alteration genes in patients with MSI-H. And the enrichment of the platinum drug resistance pathway in MSs might offer reference for the novel therapeutic strategy of ICC.

Fastigial nucleus electrostimulation promotes axonal regeneration after experimental stroke via cAMP/PKA pathway.

Axon regeneration after cerebral ischemia in mammals is inadequate to restore function, illustrating the need to design better strategies for improving outcomes. Improvement of axon regeneration has been achieved through fastigial nucleus electrostimulation (FNS) in animal researches. However, the mechanisms underlying this neuroprotection remain poorly understood. Increasing the levels of the second messenger cyclic AMP (cAMP) enhances axon regeneration, making it an excellent candidate molecule that has therapeutic potential. In the present study, we examined the expression of cAMP signaling in ischemic brain tissues following focal cerebral ischemia. Adult rats were subjected to ischemia induced by middle cerebral artery occlusion (MCAO). A dipolar electrode was placed into the cerebellum to stimulate the cerebellar fastigial nucleus for 1 h after ischemia. Neurological deficits and the expressions of cAMP, PKA (protein kinase A) and ROCK (Rho-kinase) were determined. Axonal regeneration was measured by upregulation of growth-associated protein 43 (GAP43). The data indicated that FNS significantly enhanced axonal regeneration and motor function recovery after cerebral ischemia. FNS also significantly increased cAMP and PKA levels after ischemic brain injury. All the beneficial effects of FNS were blocked by Rp-cAMP, an antagonist of PKA. Our research suggested that the axonal regeneration conferred by FNS was likely achieved via the regulation of cAMP/PKA pathway.

Effects of luminance and saccadic suppression on perisaccadic spatial distortions.

Visual directions of foveal targets flashed just prior to the onset of a saccade are misperceived as shifted in the direction of the eye movement. We examined the effects of luminance level and temporal interactions on the amplitude of these perisaccadic spatial distortions (PSDs). PSDs were larger for both single and sequentially double-flashed stimuli with low than high luminance levels, and there was a reduction of PSDs for low luminance targets flashed immediately before the saccade. Significant temporal interactions were suggested by PSDs for a pair of sequentially presented flashes (ISI = 50 ms) that could not be predicted from the single-flash distortions: PSD increased for the first flash and decreased for the second compared to the single-flash distortions. We also found that when the flash pair was presented near saccade onset, the perceived distortion of the earlier flash overtook that of the later flash, even though the late flash occurred closer in time to the saccade. To explain these effects, we propose that stimulus-dependent nonlinearities (contrast gain control and saccadic suppression) influence the duration of the temporal impulse response of both single- and double-flashed stimuli.