The olfactory working memory capacity paradigm: A more sensitive and robust method of assessing cognitive function in male 5XFAD mice.

The olfactory working memory capacity (OWMC) paradigm is able to detect cognitive deficits in 5XFAD mice (an animal model of Alzheimer's disease [TG]) as early as 3 months of age, while other behavioral paradigms detect cognitive deficits only at 4-5 months of age. Therefore, we aimed to demonstrate that the OWMC paradigm is more sensitive and consistent in the early detection of declines in cognitive function than other commonly used behavioral paradigms. The prefrontal cortex (PFC), retrosplenial cortex (RSC), subiculum (SUB), and amygdala (AMY) of 5XFAD mice were harvested and subjected to immunostaining to detect the expression of ß-amyloid (Aß). Additionally, we compared the performance of 3-month-old male 5XFAD mice on common behavioral paradigms for assessing cognitive function (i.e., the open field [OF] test, novel object recognition [NOR] test, novel object location [NOL] test, Y-maze, and Morris water maze [MWM]) with that on the OWMC task. In the testing phase of the OWMC task, we varied the delay periods to evaluate the working memory capacity (WMC) of wild-type (WT) mice. Significant amyloid plaque deposition was observed in the PFC, RSC, SUB, and AMY of 3-month-old male 5XFAD mice. However, aside from the OWMC task, the other behavioral tests failed to detect cognitive deficits in 5XFAD mice. Additionally, to demonstrate the efficacy of the OWMC task in assessing WMC, we varied the retention delay periods; we found that the WMC of WT mice decreased with longer delay periods. The OWMC task is a sensitive and robust behavioral assay for detecting changes in cognitive function.

Diminished activation of excitatory neurons in the prelimbic cortex leads to impaired working memory capacity in mice.

BACKGROUND: Working memory capacity impairment is an early sign of Alzheimer's disease, but the underlying mechanisms remain unclear. Clarifying how working memory capacity is affected will help us better understand the pathological mechanism of Alzheimer's disease. We used the olfactory working memory capacity paradigm to evaluate memory capacity in 3-month-old 5XFAD (an animal model of Alzheimer's disease) mice. Immunofluorescence staining of the prefrontal cortex was performed to detect the number of FOS-positive neurons, calmodulin-dependent protein kinase II-positive neurons, and glutamate decarboxylase-positive neurons in the prelimbic cortex and infralimbic cortex. A chemogenetic method was then used to modulate the inhibition and activation of excitatory neurons in the prelimbic cortex of wild-type and 5XFAD mice and to measure the memory capacity of mice. RESULTS: Working memory capacity was significantly diminished in 5XFAD mice compared to littermate wild-type mice. Neuronal activation of the prelimbic cortex, but not the infralimbic cortex, was attenuated in 5XFAD mice performing the olfactory working memory capacity task. Subsequently, the FOS-positive neurons were co-localized with both calmodulin-dependent protein kinase II-positive neurons and glutamate decarboxylase-positive neurons. The results showed that the activation of excitatory neurons in the prelimbic cortex was correlated with working memory capacity in mice. Our results further demonstrate that the chemogenetic inhibition of prelimbic cortex excitatory neurons resulted in reduced working memory capacity in wild-type mice, while the chemogenetic activation of prelimbic cortex excitatory neurons improved the working memory capacity of 5XFAD mice. CONCLUSION: The diminished activation of prelimbic cortex excitatory neurons in 5XFAD mice during task performance is associated with reduced working memory capacity, and activation modulation of excitatory neurons by chemogenetic methods can improve memory capacity impairment in 5XFAD mice. These findings may provide a new direction for exploring Alzheimer's disease therapeutic approaches.

Regulation of Gli2 stability by deubiquitinase OTUB2.

The transcription factor Gli2 plays crucial roles in the transduction of Hedgehog (Hh) signals, yet the mechanisms that control Gli2 degradation remain unclear. Here we have identified the eubiquitinating enzyme otubain2 (OTUB2) as a regulator of Gli2 protein degradation. We found that OTUB2 was coimmunoprecipitated with Gli2. Knockdown of OTUB2 decreased Gli2 protein level while the proteasome inhibitor MG-132 treatment restored Gli2 expression. Additionally, OTUB2 overexpression stabilized Gli2 protein in U2OS cells and extended the half-life of Gli2. We also found that knockdown of OTUB2 reduced deubiquitination of Gli2 in vivo. In vitro deubiquitination assay showed that ubiquitinated Gli2 was decreased by wild-type OTUB2 but not OTUB2 mutations. We also found that OTUB2 knockdown suppressed the ALP activity and the expression of the common markers BMP2 and RUNX2 during osteogenesis of MSCs in response to Shh and Smo agonists, which indicated OTUB2 may have effect on osteogenic differentiation by regulating Hh signaling.

Fast creation and transfer of coherence in triple quantum dots by using shortcuts to adiabaticity.

Motivated by the progress on shortcuts to adiabaticity, we propose three schemes for speeding up (fractional) stimulated Raman adiabatic passage, and achieving rapid and non-adiabatic creation and transfer of maximal coherence in a triple-quantum-dot system. These different but relevant protocols, designed from counter-diabatic driving, dress-state method, and resonant technique, require their own pumping fields, applied gate voltages and varying tunneling couplings between two spatially separated dots. Such fast and reliable shortcuts not only allow for feasibly experimental realization in solid-state architectures but also may have potential applications in quantum information processing and quantum control.

USP5 promotes tumorigenesis and progression of pancreatic cancer by stabilizing FoxM1 protein.

Increased ubiquitin-specific protease 5 (USP5) has been associated with tumorigenesis of malignancy including glioblastoma, melanoma and hepatocellular carcinoma. However, the role of USP5 in tumorigenesis of pancreatic ductal adenocarcinoma (PDAC) has not been studied yet. In this study, we demonstrated that USP5 was significantly upregulated in a panel of PDAC cell lines and correlated with FoxM1 protein expression. USP5 knockdown inhibited proliferation of PANC-1 and SW1990, two PDAC cell lines. In the mouse xenografted pancreatic tumor model, suppression of USP5 significantly decreased tumor growth, correlated with down regulation of FoxM1. Additionally, we found that overexpression of USP5 stabilized the FoxM1 protein in PDAC cells. Overexpression of USP5 extended the half-life of FoxM1. Knockdown of USP5 in PANC-1 cells decreased FoxM1 protein level while the proteasome inhibitor MG-132 treatment restored FoxM1 expression. We also found that endogenous USP5 was coimmunoprecipitated with an endogenous FoxM1 from PANC-1 cells while FoxM1 was also coimmunoprecipitated with USP5. Furthermore, we also confirmed that USP5 regulated proliferation of PDAC via FoxM1 by rescuing the inhibitory effect of USP5 knockdown with ectopic expression of FoxM1 in USP5-depleted cells. Taken together, our study demonstrates that USP5 plays a critical role in tumorigenesis and progression of pancreatic cancer by stabilizing FoxM1 protein, and provides a rationale for USP5 being a potential therapeutic approach against PDAC.

Assessment of Early Clopidogrel Therapy Use among Acute Myocardial Infarction Patients in Central-rural China in 2006 and 2011.

Objective To explore the application and influencing factors of early clopidogrel use in patients with acute myocardial infarction (AMI) in the central-rural region of China in 2006 and 2011. Methods A representative sample of patients in central-rural region of China admitted to hospital for AMI was created from a two-stage random sampling. In the first phase,a simple random-sampling procedure was used to identify participating hospitals. In the second stage,we selected patients admitted to each participating hospitals for AMI with a systematic sampling approach. Then we obtained clinical information via central medical record abstraction for each patient. For analysis of early clopidogrel therapy (within 24 hours of admission) status,we used multilevel Logistical regression models with the use of generalized estimating equations. Results We identified 1464 patients eligible for early clopidogrel therapy. From 2006 to 2011,the early application rate of clopidogrel increased significantly,from 3.98% to 48.72% (P<0.0001). Logistic regression analysis showed that patients with hypertension were more likely to receive early clopidogrel(OR=1.65,95% CI=1.21-2.26,P=0.001),smokers were associated with greater likelihood to receive early clopidogrel(OR=1.87,95% CI=1.19-2.95,P=0.007),and patients with chest discomfort during hospitalization indicated association with higher likelihood of early clopidogrel use within 24 hours of admission (OR=2.17,95% CI=1.35-3.49,P=0.001). Conclusions Early clopidogrel use in AMI patients has been improved from 2006 to 2011. However,tremendous gap still exists between guidelines and clinical practice. Quality improvement initiatives are in urgent need to support further improvements in early clopidogrel use for AMI patients.

Overexpression of Long Non-Coding RNA TUG1 Promotes Colon Cancer Progression.

BACKGROUND Colon cancer is one of the most prevalent and deadly cancers worldwide. It is still necessary to further define the mechanisms and explore therapeutic targets of colon cancer. Dysregulation of long noncoding RNAs (lncRNAs) has been shown to be correlated with diverse biological processes, including tumorigenesis. This study aimed to characterize the biological mechanism of taurine-upregulated gene 1 (TUG1) in colon cancer. MATERIAL AND METHODS qRT-PCR was used to analyze the expression level of TUG1 and p63 in 75 colon cancer tissues and the matched adjacent non-tumor tissue. In vitro, cultured colon cancer cell lines HCT-116 and LoVo were used as cell models. TUG1 and p63 were silenced via transferring siRNA into HCT-116 or LoVo. The effects of TUG1 were investigated by examining cell proliferation, apoptosis, and migration. RESULTS Among the 75 colon cancer cases, the expression of TUG1 was significantly higher in colon cancer tissues compared with the matched adjacent non-tumor tissue, while p63 expression was lower in the tumor tissue. In HCT-116 and LoVo, the expression of TUG1 was significantly increased by p63 siRNA transfection. Furthermore, down-regulation of TUG1 by siRNA significantly inhibited the cell proliferation and promoted colon cancer cell apoptosis. In addition, inhibition of TUG1 expression significantly blocked the cell migration ability of colon cancer cells. CONCLUSIONS LncRNA TUG1 may serve as a potential oncogene for colon cancer. Overexpressed TUG1 may contribute to promoting cell proliferation and migration in colon cancer cells.

Significance of red cell distribution width measurement for the patients with isolated coronary artery ectasia.

BACKGROUND: Red cell distribution width (RDW) has been recognized as a novel marker for several cardiovascular diseases. The aim of this study was to evaluate the association between RDW levels and the presence of isolated coronary artery ectasia (CAE). METHODS: We studied 414 subjects including 113 patients with isolated CAE (Group A), 144 patients with coronary artery disease (CAD, group B) and 157 angiographically normal controls (group C). Baseline clinical characteristics and laboratory findings including RDW were compared among three groups. RESULTS: The levels of RDW were significantly higher in group A and B compared with that in group C (12.97 ± 1.4 and 12.88 ± 1.0 vs 12.34 ± 0.9, p = 0.020) while no difference was found between CAE and CAD (p = 0.17). Additionally, the levels of CRP were also higher in patients with CAE and CAD compared with normal controls (0.26 ± 0.14 mg/L, 0.31 ± 0.27 mg/L vs 0.20 ± 0.06 mg/L, p = 0.04). The multivariate analysis indicated that RDW and CRP were the independent variables most strongly associated with the presence of isolated CAE and CAD. There was a positive correlation between levels of RDW and CRP in patients with isolated CAE (γ=0.532, p = 0.001). CONCLUSIONS: Our data suggested that RDW may be a useful marker and independent predictor for the presence of isolated CAE.

Trends in HIV infection in the First Affiliated Hospital of Harbin, China.

BACKGROUND: Major hospitals in most Chinese cities have the capability to perform HIV testing. However, it is not a routine test for all patients and, as a result, many patients are not aware of their HIV status. To understand the rate of HIV infection and the factors associated with infection, we tested serum to determine HIV status and analyzed factors associated with HIV infection. METHODS: We collected blood samples from 348,151 patients who visited the First Affiliated Hospital of Harbin Medical University from 1 January 2007 to 31 December 2012. Serum was screened with an ELISA. If the test was positive, we conducted two additional ELISAs: a repeat with the initial kit and one with another kit. If there was a positive result with either of these two ELISA kits, western blotting was performed at Harbin Centers for Disease Control and Prevention. RESULTS: The HIV positivity rate of inpatients significantly increased during the course of this study. HIV infection in patients appeared to differ by sex, age, occupation, marital status, educational level, and route of infection. HIV was more prevalent in men than in women. More than 80% of HIV-positive patients had not received higher (>12 years) education. From 2007 to 2012, HIV-positive patients were mainly infected through sexual transmission. For sexually acquired infections, the rate of HIV infections through homosexual contact has increased rapidly in recent years, and ranged from 36.4% to 65.1%. CONCLUSIONS: The number of patients diagnosed as HIV positive has increased in recent years. Offering routine HIV testing in hospitals is feasible and can increase linkage to HIV care and treatment for many individuals.

Association of alkaline phosphatase with isolated coronary artery ectasia.

BACKGROUND: It has been shown that alkaline phosphatase (ALP) is a reliable marker for cardiovascular events and mortality. However, there is no data available regarding the association of ALP with isolated coronary artery ectasia (CAE). The aim of the present study was to assess the serum ALP activity in isolated CAE. METHODS: Seventy-nine patients with isolated CAE (59 males; mean age, 52 ± 12 years) and 88 age- and gender-matched normal subjects (73 males; mean age, 52 ± 7 years) were enrolled. Baseline characteristics were recorded in both groups and serum ALP activity were compared between the two groups. RESULTS: Patients with angiography-proved isolated CAE had significantly higher serum ALP activity compared with angiographic normal controls (72.41 ± 29.97 vs. 59.27 ± 14.46, p < 0.001). In the multivariate analysis, increased ALP (OR = 1.037, 95% CI 1.017-1.057, p < 0.001) were independent predictors for the presence of isolated CAE. A cut-off of ≥ 66.5 U/L of ALP activity measured on admission had a 60.8% sensitivity and 75.0% specificity in predicting isolated CAE by receiver operating characteristic (ROC) curve analysis. CONCLUSION: Our data firstly demonstrated that serum ALP activity, a readily available clinical laboratory value, was associated with the presence of isolated CAE.

Acute myocardial infarction in an 8-year old male child with homozygous familiar hypercholesterolemia: laboratory findings and response to lipid-lowering drugs.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, inherited metabolic disease, caused by low-density lipoprotein (LDL) receptor abnormality, consequently leading to an increase of serum levels of LDL cholesterol (LDL-C). Clinically, this disease is characterized by the deposition of LDL-C in skin, tendons, and arterial wall. Children with HoFH develop significant coronary artery disease (CAD) in the first decade of life and frequently die of myocardial infarction (MI) before 20 years of age. METHODS: An 8-year-old boy with a diagnosis of acute MI on January 15, 2012 was admitted to our hospital for further evaluation of the potential cause and treatment. He had severe hypercholesterolemia for the past several years and showed typical signs of FH. Laboratory work-up excluded secondary causes of hypercholesterolemia and a diagnosis of HoFH was made after assessing the lipid profiles of his parents and his relatives. After careful consideration, he was prescribed a combination regime of lipid-lowering therapy. The plasma pro-protein convertase subtilisin/kexin type 9 (PCSK9) levels were also evaluated for him and his family members. RESULTS: His total cholesterol (TC) was 18.96 mmol/L and both parents had hypercholesterolemia (TC of mother: 7.46 mmol/L and father: 8.74 mmol/L). The plasma level of PCSK9 of the patient was significantly higher than his parents and his uncles and this pattern was similar with the level of their lipid profile. Importantly but not surprisingly, his serum lipid profile was not significantly improved by concomitant use of rosuvastatin 10 mg and ezetimibe 10 mg daily for one month, even a double dose of rosuvastatin and ezetimibe 10 mg daily for another month. CONCLUSIONS: The present case may have an important clinical implication for future investigation regarding the relation of HoFH to statin and PCSK9.

[ACEI/ARB use among high risk patients with coronary heart disease in China: a cross-sectional study].

OBJECTIVE: This study investigated current use of ACEI/ARB among high risk patients with coronary heart disease (CHD) in China and factors affecting ACEI/ARB use in these patients. METHODS: This cross-sectional survey was performed between June to December 2007 and May to November 2009 in 51 hospitals from 14 cities. The characteristics of patients with established CHD were collected by electronic questionnaire. RESULTS: Only 45.8% high risk CHD patients were taking ACEI/ARB and the ACEI/ARB medication decreased significantly with time after initial CHD diagnosis. ACEI/ARB was taken in 46.1% CHD patients complicated with diabetes mellitus and in 56.3% CHD patients complicated with hypertension. Logistic regression analysis showed that comorbid hypertension was the strongest factor associated with ACEI/ARB use. In addition, male gender, history of myocardial infarction (MI), PCI and the time after initial CHD diagnosis were independent factors affecting the use of ACEI/ARB. Captopril was the most commonly prescribed ACEI in this cohort. CONCLUSION: ACEI/ARB is underused in secondary prevention among high risk CHD patients in China. It remains a major challenge for healthcare professionals and policy makers to make efforts on narrowing the gap between evidence and practice.

Analysis of clinicopathological features and prognostic factors of breast cancer brain metastasis.

BACKGROUND: Breast cancer (BC) has become the most common malignancy in women. The incidence and detection rates of BC brain metastasis (BCBM) have increased with the progress of imaging, multidisciplinary treatment techniques and the extension of survival time of BC patients. BM seriously affects the quality of life and sur-vival prognosis of BC patients. Therefore, clinical research on the clinicopathological features and prognostic factors of BCBM is valuable. By analyzing the clinicopathological parameters of BCBM patients, and assessing the risk factors and prognostic indicators, we can perform hierarchical diagnosis and treatment on the high-risk population of BCBM, and achieve clinical benefits of early diagnosis and treatment. AIM: To explore the clinicopathological features and prognostic factors of BCBM, and provide references for diagnosis, treatment and management of BCBM. METHODS: The clinicopathological data of 68 BCBM patients admitted to the Air Force Medical Center, Chinese People's Liberation Army (formerly Air Force General Hospital) from 2000 to 2022 were collected. Another 136 BC patients without BM were matched at a ratio of 1:2 based on the age and site of onset for retrospective analysis. Categorical data were subjected to χ2 test or Fisher's exact probability test, and the variables with P < 0.05 in the univariate Cox proportional hazards model were incorporated into the multivariate model to identify high-risk factors and independent prognostic factors of BCBM, with a hazard ratio (HR) > 1 suggesting poor prognostic factors. The survival time of patients was estimated by the Kaplan-Meier method, and overall survival was compared between groups by log-rank test. RESULTS: Multivariate Cox regression analysis showed that patients with stage III/IV tumor at initial diagnosis [HR: 5.58, 95% confidence interval (CI): 1.99-15.68], lung metastasis (HR: 24.18, 95%CI: 6.40-91.43), human epidermal growth factor receptor 2 (HER2)-overexpressing BC and triple-negative BC were more prone to BM. As can be seen from the prognostic data, 52 of the 68 BCBM patients had died by the end of follow-up, and the median time from diagnosis of BC to the occurrence of BM and from the occurrence of BM to death or last follow-up was 33.5 and 14 mo, respectively. It was confirmed by multivariate Cox regression analysis that patients with neurological symptoms (HR: 1.923, 95%CI: 1.005-3.680), with bone metastasis (HR: 2.011, 95%CI: 1.056-3.831), and BM of HER2-overexpressing and triple-negative BC had shorter survival time. CONCLUSION: HER2-overexpressing, triple-negative BC, late tumor stage and lung metastasis are risk factors of BM. The presence of neurological symptoms, bone metastasis, and molecular type are influencing prognosis factors of BCBM.

Peutz-Jeghers syndrome without STK11 mutation may correlate with less severe clinical manifestations in Chinese patients.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is an autosomal dominant genetic disease with skin mucosal pigment spots and gastrointestinal (GI) multiple hamartoma polyps as clinical characteristics. At present, it is considered that the germline mutation of STK11 gene is the genetic cause of PJS. However, not all PJS patients can be detected STK11 germline mutations. The specific clinical characteristics of these PJS patients without STK11 mutation is an interesting clinical question. Or, like wild type GI stromal tumor, whether these PJS without STK11 mutation are also called PJS is worth discussing. Therefore, we designed the study to understand the clinical characteristics of these PJS patients without STK11 mutation. AIM: To investigates whether PJS patients with known STK11 mutations have a more severe spectrum of clinical phenotypes compared to those without. METHODS: A total of 92 patients with PJS admitted to the Air Force Medical Center from 2010 to 2022 were randomly selected for study. Genomic DNA samples were extracted from peripheral blood samples, and pathogenic germline mutations of STK11 were detected by high-throughput next-generation gene sequencing. Clinical-pathologic manifestations of patients with and without STK11/LKB1 mutations were compared. RESULTS: STK11 germline mutations were observed in 73 patients with PJS. Among 19 patients with no detectable STK11 mutations, six had no pathogenic germline mutations of other genes, while 13 had other genetic mutations. Compared with PJS patients with STK11 mutations, those without tended to be older at the age of initial treatment, age of first intussusception and age of initial surgery. They also had a lower number of total hospitalizations relating to intussusception or intestinal obstruction, and a lower load of small intestine polyps. CONCLUSION: PJS patients without STK11 mutations might have less severe clinical-pathologic manifestations than those with.

Clinical features, diagnosis, and treatment of Peutz-Jeghers syndrome: Experience with 566 Chinese cases.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a clinically rare disease with pigmented spots on the lips and mucous membranes and extremities, scattered gastrointestinal polyps, and susceptibility to tumors as clinical manifestations. Effective preventive and curative methods are still lacking. Here we summarize our experience with 566 Chinese patients with PJS from a Chinese medical center with regard to the clinical features, diagnosis, and treatment. AIM: To explore the clinical features, diagnosis, and treatment of PJS in a Chinese medical center. METHODS: The diagnosis and treatment information of 566 cases of PJS admitted to the Air Force Medical Center from January 1994 to October 2022 was summarized. A clinical database was established covering age, gender, ethnicity, family history, age at first treatment, time and sequence of appearance of mucocutaneous pigmentation, polyp distribution, quantity, and diameter, frequency of hospitalization, frequency of surgical operations, etc. The clinical data was retrospectively analyzed using SPSS 26.0 software, with P < 0.05 considered statistically significant. RESULTS: Of all the patients included, 55.3% were male and 44.7% were female. Median time to the appearance of mucocutaneous pigmentation was 2 years, and median time from the appearance of mucocutaneous pigmentation to the occurrence of abdominal symptoms was 10 years. The vast majority (92.2%) of patients underwent small bowel endoscopy and treatment, with 2.3% having serious complications. There was a statistically significant difference in the number of enteroscopies between patients with and without canceration (P = 0.004, Z = -2.882); 71.2% of patients underwent surgical operation, 75.6% of patients underwent surgical operation before the age of 35 years, and there was a statistically significant difference in the frequency of surgical operations between patients with and without cancer (P = 0.000, Z = -5.127). At 40 years of age, the cumulative risk of intussusception in PJS was approximately 72.0%, and at 50 years, the cumulative risk of intussusception in PJS was approximately 89.6%. At 50 years of age, the cumulative risk of cancer in PJS was approximately 49.3%, and at 60 years of age, the cumulative risk of cancer in PJS was approximately 71.7%. CONCLUSION: The risk of intussusception and cancer of PJS polyps increases with age. PJS patients ≥ 10 years old should undergo annual enteroscopy. Endoscopic treatment has a good safety profile and can reduce the occurrence of polyps intussusception and cancer. Surgery should be conducted to protect the gastrointestinal system by removing polyps.

Optimal postoperative surveillance strategies for cancer survivors with gastric neuroendocrine carcinoma based on individual risk: a multicenter real-world cohort study.

BACKGROUND: The best follow-up strategy for cancer survivors after treatment should balance the effectiveness and cost of disease detection while detecting recurrence as early as possible. Due to the low incidence of gastric neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma [G-(MA)NEC], high-level evidence-based follow-up strategies is limited. Currently, there is a lack of consensus among clinical practice guidelines regarding the appropriate follow-up strategies for patients with resectable G-(MA)NEC. MATERIALS AND METHODS: The study included patients diagnosed with G-(MA)NEC from 21 centers in China. The random forest survival model simulated the monthly probability of recurrence to establish an optimal surveillance schedule maximizing the power of detecting recurrence at each follow-up. The power and cost-effectiveness were compared with the National Comprehensive Cancer Network, European Neuroendocrine Tumor Society, and European Society for Medical Oncology Guidelines. RESULTS: A total of 801 patients with G-(MA)NEC were included. The patients were stratified into four distinct risk groups utilizing the modified TNM staging system. The study cohort comprised 106 (13.2%), 120 (15.0%), 379 (47.3%), and 196 cases (24.5%) for modified groups IIA, IIB, IIIA, and IIIB, respectively. Based on the monthly probability of disease recurrence, the authors established four distinct follow-up strategies for each risk group. The total number of follow-ups 5 years after surgery in the four groups was 12, 12, 13, and 13 times, respectively. The risk-based follow-up strategies demonstrated improved detection efficiency compared to existing clinical guidelines. Further Markov decision-analytic models verified that the risk-based follow-up strategies were better and more cost-effective than the control strategy recommended by the guidelines. CONCLUSIONS: This study developed four different monitoring strategies based on individualized risks for patients with G-(MA)NEC, which may improve the detection power at each visit and were more economical, effective. Even though our results are limited by the biases related to the retrospective study design, we believe that, in the absence of a randomized clinical trial, our findings should be considered when recommending follow-up strategies for G-(MA)NEC.

The protocol for assessing olfactory working memory capacity in mice.

BACKGROUND: Working memory capacity (WMC) is the ability to maintain information over a few seconds. Although it has been extensively studied in healthy subjects and neuropsychiatric patients, few tasks have been developed to measure such changes in rodents. Many procedures have been used to measure WM in rodents, including the radial arm maze, the WM version of the Morris swimming task, and various delayed matching and nonmatching-to-sample tasks. It should be noted, however, that the memory components assessed in these procedures do not include memory capacity. METHODS: We developed an olfactory working memory capacity (OWMC) paradigm to assess the WMC of 3-month-old 5×FAD mice, a mouse model of Alzheimer's disease. The task is divided into five phases: context adaptation, digging training, rule learning for nonmatching to a single sample odor (NMSS), rule learning for nonmatching to multiple sample odors (NMMS), and capacity testing. RESULTS: In the NMSS rule-learning phase, there was no difference between wild-type (WT) mice and 5×FAD mice in the performance correct rate, correct option rate, and correct rejection rate. The WT mice and 5×FAD mice showed similar memory capacity in the NMMS rule-learning phase. After capacity test, we found that the WMC was significantly diminished in 5×FAD mice. As the memory load increased, 5×FAD mice also made significantly more errors than WT mice. CONCLUSION: The OWMC task, based on a nonmatch-to-sample rule, is a sensitive and robust behavioral assay that we validated as a reliable method for measuring WMC and exploring different components of memory in mice.

Two-Dimensional Shear Wave Elastography Evaluation of Post-transplantation Complications in Pediatric Receipt: A Retrospective Cohort.

Background: The 20-year survival rate in pediatric patients after liver transplantation (LT) was no more than 70%. Hepatic fibrosis is one of the principal factors affecting the long-term prognosis. Imaging evaluation was the first-line examination for pediatric liver graft assessment. However, the sensitivity and specificity were insufficient. Thus, two-dimensional shear wave elastography (2D-SWE) was performed to evaluate liver graft stiffness and complication in post-transplant pediatric receipt. Materials and Methods: In this retrospective cohort, 343 pediatric recipients who underwent liver graft biopsy in our tertiary LT center were recruited between June 2018 and December 2020. The 2D-SWE evaluation, laboratory examination, routine post-transplant biopsy, and hepatic pathological assessment were performed. Results: Ninety-eight of the 343 pediatric patients were included according to the protocol. The Liver Stiffness Measurements (LSM) value of 2D-SWE was significantly elevated in post-transplant fibrosis (p < 0.0001). The LSM value of patients with post-transplant biliary complications (p < 0.0001) and biopsy-proven rejection (BPR, p = 0.0016) also rose compared to regular recovery patients. Concerning the sensitivity and specificity of 2D-SWE in diagnosing liver graft fibrosis, the area under the ROC curve (AUC) was 88%, and the optimal cutoff value was 10.3 kPa. Conclusion: Pediatric LSM by 2D-SWE was efficient. Routine 2D-SWE evaluation could be optimal to predict significant liver graft fibrosis.

Interplay of palmitoylation and phosphorylation in the trafficking and localization of phosphodiesterase 10A: implications for the treatment of schizophrenia.

Phosphodiesterase 10A (PDE10A) is a striatum-enriched, dual-specific cyclic nucleotide phosphodiesterase that has gained considerable attention as a potential therapeutic target for psychiatric disorders such as schizophrenia. As such, a PDE10A-selective inhibitor compound, MP-10, has recently entered clinical testing. Since little is known about the cellular regulation of PDE10A, we sought to elucidate the mechanisms that govern its subcellular localization in striatal medium spiny neurons. Previous reports suggest that PDE10A is primarily membrane bound and is transported throughout medium spiny neuron axons and dendrites. Moreover, it has been shown in PC12 cells that the localization of the major splice form, PDE10A2, may be regulated by protein kinase A phosphorylation at threonine 16 (Thr-16). Using an antibody that specifically recognizes phosphorylated Thr-16 (pThr-16) of PDE10A2, we provide evidence that phosphorylation at Thr-16 is critical for the regulation of PDE10A subcellular localization in vivo. Furthermore, we demonstrate in primary mouse striatal neuron cultures that PDE10A membrane association and transport throughout dendritic processes requires palmitoylation of cysteine 11 (Cys-11) of PDE10A2, likely by the palmitoyl acyltransferases DHHC-7 and -19. Finally, we show that Thr-16 phosphorylation regulates PDE10A trafficking and localization by preventing palmitoylation of Cys-11 rather than by interfering with palmitate-lipid interactions. These data support a model whereby PDE10A trafficking and localization can be regulated in response to local fluctuations in cAMP levels. Given this, we propose that excessive striatal dopamine release, as occurs in schizophrenia, might exert differential effects on the regulation of PDE10A localization in the two striatal output pathways.

A rabbit bone tumor model for high-intensity focused ultrasound therapy.

The incidence of malignant bone tumor increases every year. Because the application of high-intensity focused ultrasound (HIFU) for the treatment of bone tumors is still at a nascent stage, it is essential to study the effectiveness of this technique in ideal animal models in order to obtain a beneficial reference for imaging studies. In this study, we established a VX2 malignant bone tumor model and evaluated this model by contrast-enhanced sonography and magnetic resonance imaging (MRI). The results show that all tumors were enhanced after injection of SonoVue. A contrast-enhanced MRI scan revealed obvious enhancement within the tumors. Histological examination revealed the presence of a large number of tumor cells. The model can serve as an ideal experimental model for the study of HIFU therapy in the treatment of malignant bone tumors and as a reference for imaging studies during follow-ups.