Multi-organ proteomic landscape of COVID-19 autopsies.

The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report a proteomic analysis of 144 autopsy samples from seven organs in 19 COVID-19 patients. We quantified 11,394 proteins in these samples, in which 5,336 were perturbed in the COVID-19 patients compared to controls. Our data showed that cathepsin L1, rather than ACE2, was significantly upregulated in the lung from the COVID-19 patients. Systemic hyperinflammation and dysregulation of glucose and fatty acid metabolism were detected in multiple organs. We also observed dysregulation of key factors involved in hypoxia, angiogenesis, blood coagulation, and fibrosis in multiple organs from the COVID-19 patients. Evidence for testicular injuries includes reduced Leydig cells, suppressed cholesterol biosynthesis, and sperm mobility. In summary, this study depicts a multi-organ proteomic landscape of COVID-19 autopsies that furthers our understanding of the biological basis of COVID-19 pathology.

Proteomics-Derived Biomarker Panel Facilitates Distinguishing Primary Lung Adenocarcinomas With Intestinal or Mucinous Differentiation From Lung Metastatic Colorectal Cancer.

The diagnosis of primary lung adenocarcinomas with intestinal or mucinous differentiation (PAIM) remains challenging due to the overlapping histomorphological, immunohistochemical (IHC), and genetic characteristics with lung metastatic colorectal cancer (lmCRC). This study aimed to explore the protein biomarkers that could distinguish between PAIM and lmCRC. To uncover differences between the two diseases, we used tandem mass tagging-based shotgun proteomics to characterize proteomes of formalin-fixed, paraffin-embedded tumor samples of PAIM (n = 22) and lmCRC (n = 17).Then three machine learning algorithms, namely support vector machine (SVM), random forest, and the Least Absolute Shrinkage and Selection Operator, were utilized to select protein features with diagnostic significance. These candidate proteins were further validated in an independent cohort (PAIM, n = 11; lmCRC, n = 19) by IHC to confirm their diagnostic performance. In total, 105 proteins out of 7871 proteins were significantly dysregulated between PAIM and lmCRC samples and well-separated two groups by Uniform Manifold Approximation and Projection. The upregulated proteins in PAIM were involved in actin cytoskeleton organization, platelet degranulation, and regulation of leukocyte chemotaxis, while downregulated ones were involved in mitochondrial transmembrane transport, vasculature development, and stem cell proliferation. A set of ten candidate proteins (high-level expression in lmCRC: CDH17, ATP1B3, GLB1, OXNAD1, LYST, FABP1; high-level expression in PAIM: CK7 (an established marker), NARR, MLPH, S100A14) was ultimately selected to distinguish PAIM from lmCRC by machine learning algorithms. We further confirmed using IHC that the five protein biomarkers including CDH17, CK7, MLPH, FABP1 and NARR were effective biomarkers for distinguishing PAIM from lmCRC. Our study depicts PAIM-specific proteomic characteristics and demonstrates the potential utility of new protein biomarkers for the differential diagnosis of PAIM and lmCRC. These findings may contribute to improving the diagnostic accuracy and guide appropriate treatments for these patients.

Proteome Landscapes of Human Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma.

Liver cancer is among the top leading causes of cancer mortality worldwide. Particularly, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA) have been extensively investigated from the aspect of tumor biology. However, a comprehensive and systematic understanding of the molecular characteristics of HCC and CCA remains absent. Here, we characterized the proteome landscapes of HCC and CCA using the data-independent acquisition (DIA) mass spectrometry (MS) method. By comparing the quantitative proteomes of HCC and CCA, we found several differences between the two cancer types. In particular, we found an abnormal lipid metabolism in HCC and activated extracellular matrix-related pathways in CCA. We next developed a three-protein classifier to distinguish CCA from HCC, achieving an area under the curve (AUC) of 0.92, and an accuracy of 90% in an independent validation cohort of 51 patients. The distinct molecular characteristics of HCC and CCA presented in this study provide new insights into the tumor biology of these two major important primary liver cancers. Our findings may help develop more efficient diagnostic approaches and new targeted drug treatments.

Tumor-associated microbiota in colorectal cancer with vascular tumor thrombus and neural invasion and association with clinical prognosis.

Neural invasion (NI) and vascular tumor thrombus (VT) are associated with poor prognosis in patients with colorectal cancer (CRC). In this study, we apply 16S rRNA amplicon sequencing to tumor tissues and adjacent normal tissues in patients with CRC to determine the microbial differences. A discovery cohort, including 30 patients with NI, 23 with VT, and 35 with double-negative CRC tissue, is utilized. Then, we analyze the relationship between the specific bacterial taxa and indicators of different dimensions in separate cohorts. In the discovery cohort, the diversity and composition of the gut microbiome distinctly differ between the tumor and nontumor tissues in the NI and VT groups. A high abundance of Cupriavidus is found to be related to a short survival time of NI CRC, while Herbaspirillum is a potential microbial biomarker predicting the prognosis of patients with CRC with NI or VT. Moreover, the abundance of Cupriavidus or Herbaspirillum is associated with some clinical patient characteristics and prognosis, respectively. In conclusion, this study is the first to comprehensively elaborate the differences in the gut microbiota of patients with CRC with different invasion statuses and to prove the relationship between some gut microbiota and clinical patient characteristics.

Effectiveness of different intrusion modes of maxillary anterior teeth with mini-implants in clear aligner treatment: a three-dimensional finite element analysis.

BACKGROUND: The intrusion of maxillary anterior teeth is often required and there are various intrusion modes with mini-implants in clear aligner treatment. The objective of this study was to evaluate the effectiveness of maxillary anterior teeth intrusion with different intrusion modes, aiming to provide references for precise and safe intrusion movements in clinical practice. METHODS: Cone-beam computed tomography and intraoral optical scanning data of a patient were collected. Finite element models of the maxilla, maxillary dentition, periodontal ligaments (PDLs), clear aligner (CA), attachments, and mini-implants were established. Different intrusion modes of the maxillary anterior teeth were simulated by changing the mini-implant site (between central incisors, between central and lateral incisor, between lateral incisor and canine), loading site (between central incisors, on central incisor, between central and lateral incisor, between lateral incisor and canine), and loading mode (labial loading and labiolingual loading). Ten conditions were generated and intrusive forces of 100 g were applied totally. Then displacement tendency of the maxillary anterior teeth and CA, and stress of the PDLs were analyzed. RESULTS: For the central incisor under condition L14 and for the canine under conditions L11, L13, L23, and L33, the intrusion amount was negative. Under other conditions, the intrusion amount was positive. The labiolingual angulation of maxillary anterior teeth exhibited positive changes under all conditions, with greater changes under linguoincisal loading. The mesiodistal angulation of canine exhibited positive changes under labial loading, while negative changes under linguoincisal loading except for condition L14. CONCLUSIONS: The intrusion amount, labiolingual and mesiodistal angulations of the maxillary anterior teeth were affected by the mini-implant site, loading site, and loading mode. Labial and linguoincisal loading may have opposite effects on the intrusion amount of maxillary anterior teeth and the mesiodistal angulation of canine. The labiolingual angulation of the maxillary incisors would increase under all intrusion modes, with greater increases under linguoincisal loading.

Weakly Supervised Framework for Cancer Region Detection of Hepatocellular Carcinoma in Whole-Slide Pathologic Images Based on Multiscale Attention Convolutional Neural Network.

Visual inspection of hepatocellular carcinoma cancer regions by experienced pathologists in whole-slide images (WSIs) is a challenging, labor-intensive, and time-consuming task because of the large scale and high resolution of WSIs. Therefore, a weakly supervised framework based on a multiscale attention convolutional neural network (MSAN-CNN) was introduced into this process. Herein, patch-based images with image-level normal/tumor annotation (rather than images with pixel-level annotation) were fed into a classification neural network. To further improve the performances of cancer region detection, multiscale attention was introduced into the classification neural network. A total of 100 cases were obtained from The Cancer Genome Atlas and divided into 70 training and 30 testing data sets that were fed into the MSAN-CNN framework. The experimental results showed that this framework significantly outperforms the single-scale detection method according to the area under the curve and accuracy, sensitivity, and specificity metrics. When compared with the diagnoses made by three pathologists, MSAN-CNN performed better than a junior- and an intermediate-level pathologist, and slightly worse than a senior pathologist. Furthermore, MSAN-CNN provided a very fast detection time compared with the pathologists. Therefore, a weakly supervised framework based on MSAN-CNN has great potential to assist pathologists in the fast and accurate detection of cancer regions of hepatocellular carcinoma on WSIs.

Accurate interpretation of p53 immunohistochemical patterns is a surrogate biomarker for TP53 alterations in large B-cell lymphoma.

BACKGROUND: To clarify the relationship between p53 immunohistochemistry (IHC) staining and TP53 alterations (including mutations and deletions) in large B-cell lymphomas (LBCLs) and to explore the possibility of p53 IHC expression patterns as surrogate markers for TP53 alterations. METHODS: A total of 95 patients diagnosed with LBCLs were selected, and paraffin samples were taken for TP53 gene sequencing, fluorescence in situ hybridization and p53 IHC staining. The results were interpreted by experienced pathologists and molecular pathologists. RESULTS: Forty-three nonsynonymous TP53 mutations and p53 deletions were detected in 40 cases, whereas the remaining 55 cases had wild-type TP53 genes. The majority of TP53 mutations (34/43, 79.1%) occurred in exons 4-8, and R248Q was the most common mutation codon (4/43, 9.3%). The highest frequency single nucleotide variant was C > T (43.6%). p53 expression was interpreted as follows: Pattern A: p53 staining was positive in 0%-3% of tumor cells, Pattern B: p53 staining was positive in 4-65% of tumor cells, Pattern C: more than 65% of tumor cells were stained positive for p53. The p53 IHC expression patterns were associated with TP53 alterations. Gain of function variants and wild-type TP53 tended to exhibit type C and B p53 expression patterns, but loss of function variants were exclusively seen in type A cases. Additionally, interpretation of the staining by various observers produced significant reproducibility. CONCLUSIONS: The p53 IHC expression patterns can be used to predict TP53 alterations and are reliable for diverse alteration types, making them possible surrogate biomarkers for TP53 alterations in LBCLs.

Short-term effect of particulate matter on lung function and impulse oscillometry system (IOS) parameters of chronic obstructive pulmonary disease (COPD) in Beijing, China.

OBJECTIVE: This study aimed to evaluate the associations between particulate matter (PM), lung function and Impulse Oscillometry System (IOS) parameters in chronic obstructive pulmonary disease (COPD) patients and identity effects between different regions in Beijing, China. METHODS: In this retrospective study, we recruited 1348 outpatients who visited hospitals between January 2016 and December 2019. Ambient air pollutant data were obtained from the central monitoring stations nearest the participants' residential addresses. We analyzed the effect of particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) exposure on lung function and IOS parameters using a multiple linear regression model, adjusting for sex, smoking history, education level, age, body mass index (BMI), mean temperature, and relative humidity . RESULTS: The results showed a relationship between PM2.5, lung function and IOS parameters. An increase of 10 µg/m3 in PM2.5 was associated with a decline of 2.083% (95% CI: -3.047 to - 1.103) in forced expiratory volume in one second /predict (FEV1%pred), a decline of 193 ml/s (95% CI: -258 to - 43) in peak expiratory flow (PEF), a decline of 0.932% (95% CI: -1.518 to - 0.342) in maximal mid-expiratory flow (MMEF); an increase of 0.732 Hz (95% CI: 0.313 to 1.148) in resonant frequency (Fres), an increase of 36 kpa/(ml/s) (95% CI: 14 to 57) in impedance at 5 Hz (Z5) and an increase of 31 kpa/(ml/s) (95% CI: 2 to 54) in respiratory impedance at 5 Hz (R5). Compared to patients in the central district, those in the southern district had lower FEV1/FVC, FEV1%pred, PEF, FEF75%, MMEF, X5, and higher Fres, Z5 and R5 (p < 0.05). CONCLUSION: Short-term exposure to PM2.5 was associated with reductions in lung function indices and an increase in IOS results in patients with COPD. The heavier the PM2.5, the more severe of COPD.

Interaction between slow wave sleep and elevated office blood pressure in non-hypertensive obstructive sleep apnea patients: a cross-sectional study.

Purpose: Reduced slow wave sleep (SWS) has been linked to hypertension in some studies. The aim of the study is to investigate the association between SWS and office blood pressure (BP) in non-hypertensive obstructive sleep apnea (OSA).Methods: This is a retrospective study of 3350 patients who underwent polysomnography (PSG) in our hospital. Based on quartiles of percent SWS, participants were classified into four groups. BP was measured manually on the randomly chosen arm in a seated position with sphygmomanometer after PSG in the morning, and the average of the second and third measurements was used for this analysis. Elevated office BP was defined as a systolic BP≥140 mmHg or diastolic BP≥90 mmHg.Results: There were 1365 patients with OSA and 597 primary snorers included in our study. In OSA group, OSA patients with SWS <13.5% had a significant elevated risk with elevated office BP (OR,1.49[95%CI 1.05-2.10], P=0.025), compared to the highest quartile (percent SWS >39.2%). However, no significant relationship between decreased SWS and elevated office BP was found in primary snorers group.Conclusion: In non-hypertensive OSA patients, decreased SWS is associated with elevated office BP.

This is the first study to investigate the association between decreased SWS and incident elevated office BP in non-hypertensive OSA patients.Our results found that in non-hypertensive OSA patients, decreased SWS is associated with elevated office BP.The relationship between decreased SWS and elevated office BP in OSA patients was evident especially in men and in those <60 years old.

Anaplastic lymphoma kinase expression in PDGFRA-mutated gastrointestinal stromal tumors probably correlates with poor prognosis.

BACKGROUND: Anaplastic lymphoma kinase (ALK) overexpression and gene alterations have been detected in several mesenchymal tumors, with significant implications for diagnosis, therapy and prognosis. However, few studies have investigated the correlation between ALK expression status and clinicopathological characteristics in patients with gastrointestinal stromal tumors (GISTs). METHODS: A total of 506 GIST patients were enrolled. Sanger sequencing was employed to detect c-KIT and PDGFRA gene mutations. The tissue microarray (TMA) technique and immunohistochemistry were employed to identify the ALK (clone: 1A4 and D5F3) expression status in the tumor tissues. The ALK gene variants of IHC-positive cases were analyzed by fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). The clinicopathological data were analyzed using SPSS Statistics 26.0. RESULTS: Among the 506 GIST patients, the c-KIT mutation accounted for 84.2% (426/506), followed by PDGFRA mutation (10.3%, 52/506), while the wild-type accounted for the least (5.5%, 28/506). ALK-positive expression was detected in PDGFRA-mutant GISTs (7.7%, 4/52) but negative for c-KIT-mutant or wild-type GISTs by IHC. Four ALK IHC-positive patients were all male. The tumors all occurred outside the stomach. The predominant patterns of growth were epithelioid (2/4), spindle (1/4), and mixed type (1/4). They were all identified as high-risk classification according to the National Institutes of Health (NIH) classification. Aberrant ALK mutations were not identified by DNA-based NGS except in one of the 4 cases with amplification by FISH. CONCLUSION: Our study revealed 7.7% (4/52) of ALK expression in PDGFRA-mutant GISTs, indicating that molecular tests were required to rule out the possibility of PDGFRA-mutant GISTs when encountering ALK-positive mesenchymal tumors with CD117-negative or weakly positive in immunohistochemical staining.

Partial response to pralsetinib in an advanced pulmonary sarcomatoid carcinoma patient harboring a KIF5B-RET rearrangement: a case report.

BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a rare and unconventional non-small-cell lung cancer (NSCLC) that appears to be aggressive, with a poor prognosis and response to conventional treatment. Approximately 30% of PSCs have potentially targetable genomic alterations, but few studies have involved RET gene fusions, and corresponding targeted therapies are lacking. CASE PRESENTATION: In this report, we describe a patient with PSC harboring a KIF5B-RET gene fusion who was initially diagnosed with stage IVb lung cancer. Due to the poor performance status, the patient was unable to tolerate any radiotherapy or chemotherapy. Based on the next-generation sequencing (NGS) result of RET gene fusion, the patient was treated with pralsetinib. Two months after the treatment, the patient achieved a partial response. CONCLUSIONS: Our case indicates that RET is one of the main driver oncogenes of PSC and provides useful information for precise RET inhibitor administration in the future. Thus, the use of comprehensive genomic profiling may provide important treatment options for PSC.

Progression to fibrosing diffuse alveolar damage in a series of 30 minimally invasive autopsies with COVID-19 pneumonia in Wuhan, China.

AIMS: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), infection has been deemed as a global pandemic by the World Health Organisation. While diffuse alveolar damage (DAD) is recognised to be the primary manifestation of COVID-19 pneumonia, there has been little emphasis on the progression to the fibrosing phase of DAD. This topic is of great interest, due to growing concerns regarding the potential long-term complications in prolonged survivors. METHODS AND RESULTS: Here we report a detailed histopathological study of 30 autopsy cases with COVID-19 virus infection, based on minimally invasive autopsies performed between February and March, 2020. The mean age was 69 years, with 20 (67%) males and 10 (33%) females and frequent (70.0%) underlying comorbidities. The duration of illness ranged from 16 to 82 (median = 42) days. Histologically, the most common manifestation was diffuse alveolar damage (DAD) in 28 (93.3%) cases which showed predominantly acute (32%), organising (25%) and/or fibrosing (43%) patterns. Patients with fibrosing DAD were one decade younger (P = 0.034) and they had a longer duration of illness (P = 0.033), hospitalisation (P = 0.037) and mechanical ventilation (P = 0.014) compared to those with acute DAD. Patients with organising DAD had a longer duration of illness (P = 0.032) and hospitalisation (P = 0.023) compared to those with acute DAD. CONCLUSIONS: COVID-19 pneumonia patients who develop DAD can progress to the fibrosing pattern. While we observed fibrosing DAD in fatal cases, whether or not surviving patients are at risk for developing pulmonary fibrosis and the frequency of this complication will require further clinical and radiological follow-up studies.

Assessment of safety margin after microwave ablation of stage I NSCLC with three-dimensional reconstruction technique using CT imaging.

OBJECTIVE: To assess the ablative margin of microwave ablation (MWA) for stage I non-small cell lung cancer (NSCLC) using a three-dimensional (3D) reconstruction technique. MATERIALS AND METHODS: We retrospectively analyzed 36 patients with stage I NSCLC lesions undergoing MWA and analyzed the relationship between minimal ablative margin and the local tumor progression (LTP) interval, the distant metastasis interval and disease-free survival (DFS). The minimal ablative margin was measured using the fusion of 3D computed tomography reconstruction technique. RESULTS: Univariate and multivariate analyses indicated that tumor size (hazard ratio [HR] = 1.91, P < 0.01; HR = 2.41, P = 0.01) and minimal ablative margin (HR = 0.13, P < 0.01; HR = 0.11, P < 0.01) were independent prognostic factors for the LTP interval. Tumor size (HR = 1.96, P < 0.01; HR = 2.35, P < 0.01) and minimal ablative margin (HR = 0.17, P < 0.01; HR = 0.13, P < 0.01) were independent prognostic factors for DFS by univariate and multivariate analyses. In the group with a minimal ablative margin < 5 mm, the 1-year and 2-year local progression-free rates were 35.7% and 15.9%, respectively. The 1-year and 2-year distant metastasis-free rates were 75.6% and 75.6%, respectively; the 1-year and 2-year disease-free survival rates were 16.7% and 11.1%, respectively. In the group with a minimal ablative margin ≥ 5 mm, the 1-year and 2-year local progression-free rates were 88.9% and 69.4%, respectively. The 1-year and 2-year distant metastasis-free rates were 94.4% and 86.6%, respectively; the 1-year and 2-year disease-free survival rates were 88.9% and 63.7%, respectively. The feasibility of 3D quantitative analysis of the ablative margins after MWA for NSCLC has been validated. CONCLUSIONS: The minimal ablative margin is an independent factor of NSCLC relapse after MWA, and the fusion of 3D reconstruction technique can feasibly assess the minimal ablative margin.

Incremental prognostic value of biventricular longitudinal strain and high-sensitivity troponin I in COVID-19 patients.

BACKGROUND: Whether the combination of ventricular strain with high-sensitivity troponin I (hs-TNI) has an incremental prognostic value in coronavirus disease 2019 (COVID-19) patients has not been evaluated. The study aimed to evaluate the prognostic value of biventricular longitudinal strain and its combination with hs-TNI in COVID-19 patients. METHODS: A total of 160 COVID-19 patients who underwent both echocardiography and hs-TNI testing were enrolled in our study. COVID-19 patients were divided into two groups (critical and non-critical) according to severity-of-illness. The clinical characteristics, cardiac structure and function were compared between the two groups. The prognostic value of biventricular longitudinal strain and its combination with hs-TNI were evaluated by logistic regression analyses and receiver operating characteristic curves. Left ventricular longitudinal strain (LV LS) and right ventricular free wall longitudinal strain (RVFWLS) were determined by 2D speckle-tracking echocardiography. RESULTS: The LV LS and RVFWLS both were significantly lower in critical patients than non-critical patients (LV LS: -16.6±2.4 vs -17.9±3.0, P = .003; RVFWLS :-18.8±3.6 vs -23.9±4.4, P<.001). During a median follow-up of 60 days, 23 (14.4%) patients died. The multivariant analysis revealed that LV LS and RVFWLS [Odd ratio (95% confidence interval): 1.533 (1.131-2.079), P = .006; 1.267 (1.036-1.551), P = .021, respectively] were the independent predictors of higher mortality. Further, receiver-operating characteristic analysis revealed that the accuracy for predicting death was greater for the combination of hs-TNI levels with LV LS than separate LV LS (AUC: .91 vs .77, P = .001), and the combination of hs-TNI levels with RVFWLS than RVFWLS alone (AUC: .89 vs .83, P = .041). CONCLUSIONS: Our study highlights that the combination of ventricular longitudinal strain with hs-TNI can provide higher accuracy for predicting mortality in COVID-19 patients, which may enhance risk stratification in COVID-19 patients.

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.

Although the respiratory and immune systems are the major targets of Coronavirus Disease 2019 (COVID-19), acute kidney injury and proteinuria have also been observed. Currently, detailed pathologic examination of kidney damage in critically ill patients with COVID-19 has been lacking. To help define this we analyzed kidney abnormalities in 26 autopsies of patients with COVID-19 by light microscopy, ultrastructural observation and immunostaining. Patients were on average 69 years (19 male and 7 female) with respiratory failure associated with multiple organ dysfunction syndrome as the cause of death. Nine of the 26 showed clinical signs of kidney injury that included increased serum creatinine and/or new-onset proteinuria. By light microscopy, diffuse proximal tubule injury with the loss of brush border, non-isometric vacuolar degeneration, and even frank necrosis was observed. Occasional hemosiderin granules and pigmented casts were identified. There were prominent erythrocyte aggregates obstructing the lumen of capillaries without platelet or fibrinoid material. Evidence of vasculitis, interstitial inflammation or hemorrhage was absent. Electron microscopic examination showed clusters of coronavirus-like particles with distinctive spikes in the tubular epithelium and podocytes. Furthermore, the receptor of SARS-CoV-2, ACE2 was found to be upregulated in patients with COVID-19, and immunostaining with SARS-CoV nucleoprotein antibody was positive in tubules. In addition to the direct virulence of SARS-CoV-2, factors contributing to acute kidney injury included systemic hypoxia, abnormal coagulation, and possible drug or hyperventilation-relevant rhabdomyolysis. Thus, our studies provide direct evidence of the invasion of SARSCoV-2 into kidney tissue. These findings will greatly add to the current understanding of SARS-CoV-2 infection.

The clinicopathological features and prognosis of tumor MSI in East Asian colorectal cancer patients using NCI panel.

AIM: To compare test results obtained from a PCR assay for the National Cancer Institute (NCI) five loci criteria for detecting microsatellite instability (MSI) with those obtained from immunohistochemistry of mismatch repair and a five-mononucleotide site amplification system in East Asian patients with colorectal cancer. PATIENTS & METHODS:  A total of 245 East Asian patients with colorectal cancer were studied retrospectively at our institution. RESULTS: The consistency of the NCI panel PCR method compared with detection of mismatch repair protein expression by immunohistochemistry was 0.898. High level MSI (MSI-H) status was correlated with the Tumor, Node, Metastasis stage, tumor location site, metastasis, tumor grade, mucinous histological type and BRAF-type mutations. CONCLUSION: The NCI panel PCR assay has excellent sensitivity and specificity for detecting MSI in an East Asian population.

Down-regulation of KIAA1199/CEMIP by miR-216a suppresses tumor invasion and metastasis in colorectal cancer.

Colorectal cancer is one of the major causes of death from cancer. Metastasis is the leading cause of treatment failure, in which cancer stem cells and circulating tumor cells play crucial roles. Identifying the involved metastatic biomarkers and clarifying the regulation mechanisms are of great importance for targeting tumor metastasis. In the current research, we discovered that KIAA1199, a cell-migration inducing protein, showed higher expression in CD44+ cancer cells from metastatic compared with the paired primary tissues, and was upregulated in colorectal cancer and positively correlated with numbers and mesenchymal phenotype of circulating tumor cells, and predicted shorter progress-free survival. Moreover, we indicated that down-regulation of KIAA1199 suppressed migration and invasion of colorectal cancer cells in vitro, and inhibited metastasis in vivo. Furthermore, we demonstrated that KIAA1199 was one of the direct and functional targets of miR-216a, and miR-216a overexpression led to decreased migration and invasion of colorectal cancer cells in vitro, and inhibited metastasis in vivo. Collectively, KIAA1199 plays a critical role in maintaining an aggressive phenotype of tumor cells, and suppression of KIAA1199-related motilities of tumor cells contributes to reduced tumor metastasis in colorectal cancer.

Composite Serous Borderline Tumor and Adult Granulosa Cell Tumor-like Area: Is it a True Neoplastic AGCT or Tumor-like Proliferation?

We report the 402C-G FOXL2 mutation status in 1 epithelial ovarian lesion in a 38-yr-old woman showing stromal proliferations that were morphologically indistinguishable from adult granulosa cell tumor (AGCT). The lesion was a serous borderline tumor. The AGCT-like components were distributed within the septa and cyst walls. FOXL2 mutation was absent. The combination of an epithelial neoplasm and AGCT-like areas is rare but described. The AGCT-like components are likely to be tumor-like proliferations but not truly neoplastic AGCT. FOXL2 mutation testing may be useful in confirming an AGCT-like component.

Antiproliferative and Anti-inflammatory Withanolides from Physalis angulata.

Sixteen new withanolides, physangulatins A-N (1-14) and withaphysalins Y and Z (15 and 16), as well as 12 known analogues, were isolated from the stems and leaves of Physalis angulata L. Their structures were established using extensive spectroscopic data analyses. The absolute configurations of 1 and 9 were assigned via X-ray crystallography. The isolated compounds were tested for their antiproliferative effects against human prostate cancer cells (C4-2B and 22Rvl), human renal carcinoma cells (786-O, A-498, and ACHN), and human melanoma cells (A375-S2), as well as inhibitory effects on NO production induced by LPS in macrophages. Compounds 9, 17, 20, 21, 25, and 27 showed antiproliferative effects against all tested cancer cells, with IC50 values of 0.18-7.43 µM. Compounds 3-5, 9-11, 17, 20-22, 24, 25, and 27 displayed inhibitory effects against NO production, with IC50 values of 1.36-11.59 µM.

Two new lignans from the aerial part of Vitex negundo.

A new phenyldihydronaphthalene-type lignan, (3R,4S)-6-hydroxy-4-(4-hydroxy- 3-methoxyphenyl)-5,7-dimethoxy-3,4-dihydro-2-naphthaldehyde-3a-O-ß-d-glucopyranoside (1), and a new phenylnaphthalene-type lignan, 6,7,4'-trihydroxy-3'-methoxy-2,3- cycloligna-1,4-dien-2a,3a-olide (2), along with 10-known lignan derivatives (3-12) were isolated from the aerial part of Vitex negundo var. heterophylla. Their structures were established by comprehensive 1D- and 2D-NMR spectroscopic analyses.