LINK-A: unveiling its functional role and clinical significance in human tumors.

LINK-A, also recognized as LINC01139, has emerged as a key oncological lncRNA in cancer. LINK-A is upregulated in solid and liquid tumor samples, including breast cancer, ovarian cancer, glioma, non-small-cell lung cancer, and mantle cell lymphoma. Notably, LINK-A is involved in regulating critical cancer-related pathways, such as AKT and HIF1α signaling, and is implicated in a range of oncogenic activities, including cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), cell invasion and migration, and glycolysis reprogramming. LINK-A's differential expression and its correlation with clinical features enable it to be a promising biomarker for cancer diagnosis, prognosis, and the stratification of tumor progression. Additionally, LINK-A's contribution to the development of resistance to cancer therapies, including AKT inhibitors and immunotherapy, underscores its potential as a therapeutic target. This review provides a comprehensive overview of the available data on LINK-A, focusing on its molecular regulatory pathways and clinical significance. By exploring the multifaceted nature of LINK-A in cancer, the review aims to offer a valuable resource for future research directions, potentially guiding the development of novel therapeutic strategies targeting this lncRNA in cancer treatment.

US-based Sequential Algorithm Integrating an AI Model for Advanced Liver Fibrosis Screening.

Background Noninvasive tests can be used to screen patients with chronic liver disease for advanced liver fibrosis; however, the use of single tests may not be adequate. Purpose To construct sequential clinical algorithms that include a US deep learning (DL) model and compare their ability to predict advanced liver fibrosis with that of other noninvasive tests. Materials and Methods This retrospective study included adult patients with a history of chronic liver disease or unexplained abnormal liver function test results who underwent B-mode US of the liver between January 2014 and September 2022 at three health care facilities. A US-based DL network (FIB-Net) was trained on US images to predict whether the shear-wave elastography (SWE) value was 8.7 kPa or higher, indicative of advanced fibrosis. In the internal and external test sets, a two-step algorithm (Two-step#1) using the Fibrosis-4 Index (FIB-4) followed by FIB-Net and a three-step algorithm (Three-step#1) using FIB-4 followed by FIB-Net and SWE were used to simulate screening scenarios where liver stiffness measurements were not or were available, respectively. Measures of diagnostic accuracy were calculated using liver biopsy as the reference standard and compared between FIB-4, SWE, FIB-Net, and European Association for the Study of the Liver guidelines (ie, FIB-4 followed by SWE), along with sequential algorithms. Results The training, validation, and test data sets included 3067 (median age, 42 years [IQR, 33-53 years]; 2083 male), 1599 (median age, 41 years [IQR, 33-51 years]; 1124 male), and 1228 (median age, 44 years [IQR, 33-55 years]; 741 male) patients, respectively. FIB-Net obtained a noninferior specificity with a margin of 5% (P < .001) compared with SWE (80% vs 82%). The Two-step#1 algorithm showed higher specificity and positive predictive value (PPV) than FIB-4 (specificity, 79% vs 57%; PPV, 44% vs 32%) while reducing unnecessary referrals by 42%. The Three-step#1 algorithm had higher specificity and PPV compared with European Association for the Study of the Liver guidelines (specificity, 94% vs 88%; PPV, 73% vs 64%) while reducing unnecessary referrals by 35%. Conclusion A sequential algorithm combining FIB-4 and a US DL model showed higher diagnostic accuracy and improved referral management for all-cause advanced liver fibrosis compared with FIB-4 or the DL model alone. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Ghosh in this issue.

Biological roles of SLC16A1-AS1 lncRNA and its clinical impacts in tumors.

Recent studies have increasingly highlighted the aberrant expression of SLC16A1-AS1 in a variety of tumor types, where it functions as either an oncogene or a tumor suppressor in the pathogenesis of different cancers. The expression levels of SLC16A1-AS1 have been found to significantly correlate with clinical features and the prognosis of cancer patients. Furthermore, SLC16A1-AS1 modulates a range of cellular functions, including proliferation, migration, and invasion, through its interactions with diverse molecules and signaling pathways. This review examines the latest evidence regarding the role of SLC16A1-AS1 in the progression of various tumors and explores its potential clinical applications as a novel prognostic and diagnostic biomarker. Our comprehensive review aims to deepen the understanding of SLC16A1-AS1's multifaceted role in oncology, underscoring its potential as a significant biomarker and therapeutic target.

A nomogram based on TFE3 IHC results and clinical factors as a preliminary screening scheme for TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3 immunohistochemistry (TFE3-IHC) is controversial in the diagnosis of TFE3-rearranged renal cell carcinoma (TFE3-rearranged RCC). This study is to investigate the accuracy and sensitivity of IHC and establish a predictive model to diagnose TFE3-rearranged RCC. METHODS: Retrospective analysis was performed by collecting IHC and fluorescence in situ hybridization (FISH) results from 228 patients. IHC results were evaluated using three scoring systems. Scoring system 1 is graded based on nuclear staining intensity, scoring system 2 is graded based on the percentage of stained tumor cell nuclei, and scoring system 3 is graded based on both the nuclear staining intensity and the percentage. We collected patients' IHC results and clinical information. Important variables were screened based on univariate logistic regression analysis. Then, independent risk factors were established through multivariate logistic regression, and a nomogram model was constructed. The model was validated in internal test set and external validation set. The receiver operating characteristic curve (ROC curve), calibration curve, and decision curve analysis (DCA) were generated to assess discriminative ability of the model. RESULTS: The accuracy of IHC based on three scoring systems were 0.829, 0.772, and 0.807, respectively. The model included four factors including age, gender, lymph node metastasis and IHC results. Area under the curve (AUC) values were 0.935 for the training set, 0.934 for the internal test set, 0.933 for all 228 patients, and 0.916 for the external validation set. CONCLUSIONS: TFE3 IHC has high accuracy in the diagnosis of TFE3-rearranged RCC. Clinical information such as age and lymph node metastasis are independent risk factors, which can be used as a supplement to the results of TFE3 IHC. This study confirms the value of IHC in the diagnosis of TFE3-rearranged RCC. The accuracy of the diagnosis can be improved by incorporating IHC with other clinical risk factors.

Quantitative assessment of inflammation and evaluation of spatial heterogeneity for non-alcoholic fatty liver disease in mice based on iron-adjustive T1.

Background: A sensitive and non-invasive method is necessary to diagnose non-alcoholic fatty liver disease (NAFLD). We explored the iron-adjustive T1 (aT1) ability to quantify the degree of liver inflammation and evaluate the spatial heterogeneity. Methods: Male C57BL/6J mice were randomly categorized as the NAFLD model (n=40), NAFLD-related liver cirrhosis model (n=20), and normal mice (n=10). T1 and T2* maps were acquired using a 3.0T scanner of magnetic resonance imaging (MRI) and aT1 maps through post-processing corrected iron's effect on T1 using T2*. Pathological changes in the left and right liver lobes were assessed using the Non-alcoholic Steatohepatitis-Clinical Research Network scoring system, though hepatic ballooning lesion were rare in models. Spearman's and partial correlation analyses were used to evaluate correlations, and the receiver operating characteristic curve was used to analyze the diagnostic performance. Results: aT1 was highly correlated with NAFLD activity score (NAS) (r=0.747, P<0.001) but not with the fibrosis stage when adjusted by NAS (r=-0.135, P=0.147). The area under the curve (AUC) of the aT1 value distinguishing groups with 0< NAS <4 and NAS ≥4 was 0.802. On analyzing the histogram features of aT1, the entropy, interquartile range, range, and variance were significantly different between the groups with 0< NAS <4 and NAS ≥4 (P<0.05). The entropy was the risk factor of NAS ≥4. Conclusions: aT1 could help evaluate the inflammatory activity in NAFLD mice unaffected by mild fibrosis, and the higher the degree of inflammation, the higher the heterogeneity of the aT1 map.

Multimodal recurrence scoring system for prediction of clear cell renal cell carcinoma outcome: a discovery and validation study.

BACKGROUND: Improved markers for predicting recurrence are needed to stratify patients with localised (stage I-III) renal cell carcinoma after surgery for selection of adjuvant therapy. We developed a novel assay integrating three modalities-clinical, genomic, and histopathological-to improve the predictive accuracy for localised renal cell carcinoma recurrence. METHODS: In this retrospective analysis and validation study, we developed a histopathological whole-slide image (WSI)-based score using deep learning allied to digital scanning of conventional haematoxylin and eosin-stained tumour tissue sections, to predict tumour recurrence in a development dataset of 651 patients with distinctly good or poor disease outcome. The six single nucleotide polymorphism-based score, which was detected in paraffin-embedded tumour tissue samples, and the Leibovich score, which was established using clinicopathological risk factors, were combined with the WSI-based score to construct a multimodal recurrence score in the training dataset of 1125 patients. The multimodal recurrence score was validated in 1625 patients from the independent validation dataset and 418 patients from The Cancer Genome Atlas set. The primary outcome measured was the recurrence-free interval (RFI). FINDINGS: The multimodal recurrence score had significantly higher predictive accuracy than the three single-modal scores and clinicopathological risk factors, and it precisely predicted the RFI of patients in the training and two validation datasets (areas under the curve at 5 years: 0·825-0·876 vs 0·608-0·793; p<0·05). The RFI of patients with low stage or grade is usually better than that of patients with high stage or grade; however, the RFI in the multimodal recurrence score-defined high-risk stage I and II group was shorter than in the low-risk stage III group (hazard ratio [HR] 4·57, 95% CI 2·49-8·40; p<0·0001), and the RFI of the high-risk grade 1 and 2 group was shorter than in the low-risk grade 3 and 4 group (HR 4·58, 3·19-6·59; p<0·0001). INTERPRETATION: Our multimodal recurrence score is a practical and reliable predictor that can add value to the current staging system for predicting localised renal cell carcinoma recurrence after surgery, and this combined approach more precisely informs treatment decisions about adjuvant therapy. FUNDING: National Natural Science Foundation of China, and National Key Research and Development Program of China.

PRPF8 controls alternative splicing of PIRH2 to modulate the p53 pathway and survival of human ESCs.

Human embryonic stem cells (hESCs) have great potential for developmental biology and regenerative medicine. However, extensive apoptosis often occurs when hESCs respond to various stresses or injuries. Understanding the molecular control and identifying new factors associated with hESC survival are fundamental to ensure the high quality of hESCs. In this study, we report that PRPF8, an RNA spliceosome component, is essential for hESC survival. PRPF8 knockdown (KD) induces p53 protein accumulation and activates the p53 pathway, leading to apoptosis in hESCs. Strikingly, silencing of p53 rescues PRPF8 KD-induced apoptosis, indicating that PRPF8 KD triggers hESC apoptosis through activating the p53 pathway. In search for the mechanism by which p53 pathway is activated by PRPF8 KD, we find that PRPF8 KD alters alternative splicing of many genes, including PIRH2 which encodes an E3 ubiquitin ligase of p53. PIRH2 has several isoforms such as PIRH2A, PIRH2B, and PIRH2C. Intriguingly, PRPF8 KD specifically increases the transcript level of the PIRH2B isoform, which lacks a RING domain and E3 ligase activity. Functionally, PIRH2B KD partially rescues the reduction in cell numbers and upregulation of P21 caused by PRPF8 KD in hESCs. The finding suggests that PRPF8 controls alternative splicing of PIRH2 to maintain the balance of p53 pathway activity and survival of hESCs. The PRPF8/PIRH2/p53 axis identified here provides new insights into how p53 pathway and hESC survival are precisely regulated at multiple layers, highlighting an important role of posttranscriptional machinery in supporting hESC survival.

Effectiveness of Peer Support on Quality of Life and Anxiety in Breast Cancer Patients: A Systematic Review and Meta-Analysis.

Background: Breast cancer patients report high levels of psychosocial maladjustment after hospital discharge. Peer support may play an important role in improving anxiety and quality of life in breast cancer patients. This study aimed to assess the effect of peer support on quality of life and anxiety in breast cancer patients. Method: A systematic review and meta-analysis of randomized controlled studies were conducted, using data sourced from PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, SinoMed, China Science and Technology Periodical Database, China National Knowledge Infrastructure, and Wanfang Data for randomized controlled trials (RCTs) from inception to October 15, 2021. The RCTs reporting the effect of peer support intervention on quality of life and anxiety in breast cancer patients were included. The quality of evidence was assessed using the Cochrane risk of bias tool, that is, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated for the pooled effect size. Results: A total of 14 studies were included in the systematic review and 11 in the meta-analysis. The pooled results revealed that peer support significantly improved quality of life (SMD = 0.69, 95% CI = 0.28-1.11) and anxiety (SMD = -0.45, 95% CI = -0.88 to -0.02) in breast cancer patients. The quality of evidence was low as all studies showed the risk of bias and inconsistency. Conclusion: Peer support intervention has the potential to effectively improve psychosocial adaptations in breast cancer patients. Future studies with a robust design and larger sample size are needed to investigate the potential factors associated with the beneficial effects of peer support.

Lignin-derived polyphenols with enhanced antioxidant activities by chemical demethylation and their structure-activity relationship.

Lignin valorization to biobased polyphenols antioxidants is increasingly attractive in the modern industry due to their inherent phenolic structures. Herein, lignin-derived polyphenols with enhanced antioxidant activities were prepared from the most available technical lignin including organosolv lignin (OL), alkali lignin (AL), and enzyme lignin (EL) by iodocyclohexane (ICH) chemical demethylation. The structural evolution of lignin indicated that the CAr-OCH3 group and the CAr-O-Calkyl side-chain could be effectively transformed into the CAr-OH group, resulting in a significant increase of the phenolic-OH content and a slight decrease of the molecular weight. The 1,1-diphenyl-2-picrylhydrazyl radical (DPPH·) scavenging activity was in the order of ICHOL-24 > ICHAL-24 > ICHEL-24 ≈ FA > BHT, and the IC50 value of ICHOL-24 was 0.56 times lower than that of BHT. The structure-activity relationship demonstrated the activities were quasi-linearly related to phenolic-OH contents and could be affected by molecular weights. The H/G/S proportions of lignin could be an indicator for accurate screening of efficient lignin-derived polyphenols antioxidants (LPA). It was preliminarily estimated to have economic feasibility for producing LPA from technical lignin by demethylation compared with synthetic or natural antioxidants. This work will help to develop efficient biobased antioxidants for lignin valorization.

Endovascular Treatment of Ruptured or Symptomatic Thoracoabdominal and Pararenal Aortic Aneurysms Using Octopus Endograft Technique: Mid-Term Clinical Outcomes.

OBJECTIVE: To evaluate the effectiveness and safety of using off-the-shelf "Octopus" technique to treat ruptured or symptomatic thoracoabdominal aortic aneurysm (TAAA) and pararenal abdominal aortic aneurysm (PRAAA). METHODS AND RESULTS: All cases who underwent "Octopus" technique from May 2016 to May 2019 at our center were retrospectively analyzed. A total of 10 cases (8 males) were included. The mean age was 54.5±14.2 years (range: 31-80 years). Eight cases presented as aneurysm rupture or impending rupture accepted emergency repair. Technical success, defined by placement of all endografts as planned, was achieved in all cases. A total of 30 target visceral branches were successfully cannulated, 9 celiac arteries were covered intentionally. Intraoperative endoleak was observed in 6 patients, all of them were gutter leak. During hospital stay, there was no death, no side branch occlusion or spinal cord ischemia. Median follow-up was 30 months (range: 12-50 months). One patient died of lung cancer at 14-month follow-up. There was no secondary endoleak. The primary endoleak were found spontaneously resolved in 3 cases at 7 days, 3-month, and 1-year imaging. One persistent endoleak totally resolved after sealing of gutter spaces at 4-month follow-up. The other 2 persistent endoleak decreased during follow-up, which are still under observation. The branch patency rate was 90.3% (28/31). All the 3 occluded branches were renal arteries. Branch occlusion occurred in 2 cases at 1-month follow-up and 1 case at 2-year follow-up, but renal insufficiency was not observed in these cases. Obvious aneurysm sac shrinkage (≥5 mm) was observed in all cases. The aneurysm size shrunk from 7.6±1.9 to 5.5±1.4 cm. No spinal cord ischemia occurred during follow-up. CONCLUSION: Treatment of ruptured TAAA and PRAAA with "Octopus" technique is feasible and safe for high surgical risk patients in the absence of fenestrated and branched devices. The long-term clinical outcomes needed to be investigated.

CCDC86 promotes the aggressive behavior of nasopharyngeal carcinoma by positively regulating EGFR and activating the PI3K/Akt signaling.

Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck. A number of studies have confirmed that coiled-coil domain-containing protein 86 (CCDC86) plays an important role in the pathogenesis of lymphoma but the role of CCDC86 in NPC has not yet been reported. Here, in vivo and in vitro experiments were conducted to explore whether CCDC86 plays a role in the pathogenesis of NPC and to identify the specific mechanism. We found that CCDC86 was highly expressed in NPC tissues and cells, and the expression level of CCDC86 was correlated with the prognosis of patients with advanced NPC. CCDC86 promoted the proliferation, invasion, and migration of NPC cells in vivo and in vitro by promoting the EMT process and upregulating the expression of MMPs. Then, we confirmed that EGFR is a downstream target gene of CCDC86 and that CCDC86 can promote the proliferation, invasion, and migration of NPC cells by upregulating the expression of EGFR and activating downstream PI3K/Akt. Furthermore, we confirmed that CCDC86 did not directly bind to EGFR but positively regulated EGFR by binding to NPM1. CCDC86 is expected to be used as a novel biomarker and therapeutic target for predicting the prognosis of NPC.

Discrepancies between Nonalcoholic and Metabolic-associated Fatty Liver Disease by Multiple Steatosis Assessment.

Background and Aims: The redefinition of metabolic-associated fatty liver disease (MAFLD) from nonalcoholic fatty liver disease (NAFLD) has caused a revolution in clinical practice, and the characteristics of patients with steatosis but not MAFLD remain unclear. The aims were to compare the diagnosis rate of MAFLD in NAFLD using different steatosis methods and explore the features of non-MAFLD-NAFLD and MAFLD-non-NAFLD. Methods: A cross-sectional study enrolling consecutive individuals was conducted at three medical centers in southern China from January 2015 to September 2020. Steatosis was evaluated by liver biopsy or magnetic resonance imaging-based proton density fat fraction (MRI-PDFF), ultrasound, controlled attenuation parameter (CAP), and fatty liver index (FLI). Fibrosis was assessed by the NAFLD fibrosis score, transient elastography, or shear wave elastography. Results: The study enrolled 14,985 Chinese adults. The agreement of MAFLD and NAFLD diagnoses were 83% for FLI, 95% for ultrasound, 94% for both CAP and MRI-PDFF, and 95% for liver biopsy. The body mass index, blood pressure and lipid levels among non-MAFLD-NAFLD patients were similar metabolic parameters (p>0.05 for all), but not the alanine aminotransferase and the proportion of patients with insulin resistance, which were significantly higher in non-MAFLD-NAFLD with significant fibrosis. Conclusions: The new MAFLD definition ruled out 5-17% of NAFLD cases. NAFLD and MAFLD-NAFLD involved more severe metabolic abnormalities than MAFLD and MAFLD-non-NAFLD. Non-MAFLD-NAFLD patients with significant fibrosis had more severe liver injury and increased glycemic dysregulation within the normal range. Attention should be paid to its progression.

Association of mental distress with chronic diseases in 1.9 million individuals: A population-based cross-sectional study.

OBJECTIVE: Mental distress has a high global prevalence and is associated with poor health outcomes. This study aimed to estimate the relationship between mental distress and the risk of 10 chronic diseases using data from the Behavioral Risk Factor Surveillance System (BRFSS). METHODS: Cross-sectional data from the 2013, 2014, 2015, 2016 and 2017 BRFSS were analyzed. The association between mental distress based on the number of days of poor mental health and the risk of 10 chronic diseases, namely obesity, diabetes, asthma, chronic obstructive pulmonary disease (COPD), arthritis, kidney disease, coronary heart disease (CHD), stroke, skin cancer, and other cancers, were assessed by logistic regression models to calculate odds ratios and 95% confidence intervals. Subgroup analyses stratified by age and sex were also conducted. RESULTS: Positive associations between mental distress and chronic diseases were observed. We also found a dose-response gradient between mental distress levels and the risk of all chronic diseases except skin cancer. In respondents aged 18-44 years reporting ≥23 days/month of mental distress, there has the largest odds ratio between mental distress levels and each chronic disease. Moreover, mental distress was associated with higher risks of obesity and arthritis in women relative to men. CONCLUSIONS: Mental distress was positively associated with chronic diseases. Age and sex are crucial in this relationship. Further studies with longitudinal data are needed to clarify the direction of this association.

Predictive Role of NEK6 in Prognosis and Immune Infiltration in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC), as one of the common malignant tumors, seriously threatens human health. NEK6 (Never in Mitosis A (NIMA) related kinases 6), as a cyclin, promotes cancer cell proliferation and cancer progression. However, the prognostic value of NEK6 and its correlation with immune cell infiltration in HNSCC remain unclear. In this study, we comprehensively elucidated the prognostic role and potential function of NEK6 expression in HNSCC. The expression of NEK6 was significantly up-regulated by immunohistochemistry in HNSCC. Upregulation of NEK6 expression in gene expression studies predicts poor prognosis in HNSCC patients. The results of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set variation analysis indicated that NEK6 is mainly involved in extracellular matrix metabolism and EMT processes. The expression of NEK6 increased with the level of immune cell infiltration and the expression of various immune checkpoints. In conclusion, NEK6 may serve as a candidate prognostic predictor and may predict the response of HNSCC patients to immunotherapy.

Association of the "Weekend Warrior" and Other Leisure-time Physical Activity Patterns With All-Cause and Cause-Specific Mortality: A Nationwide Cohort Study.

Importance: It is unclear whether the weekly recommended amount of moderate to vigorous physical activity (MVPA) has the same benefits for mortality risk when activity sessions are spread throughout the week vs concentrated in fewer days. Objective: To examine the association of weekend warrior and other patterns of leisure-time physical activity with all-cause and cause-specific mortality. Design, Setting, and Participants: This large nationwide prospective cohort study included 350 978 adults who self-reported physical activity to the US National Health Interview Survey from 1997 to 2013. Participant data were linked to the National Death Index through December 31, 2015. Exposures: Participants were grouped by self-reported activity level: physically inactive (<150 minutes per week [min/wk] of MVPA) or physically active (≥150 min/wk of moderate or ≥75 min/wk of vigorous activity). The active group was further classified by pattern: weekend warrior (1-2 sessions/wk) or regularly active (≥3 session/wk); and then, by frequency, duration/session, and intensity of activity. Main Outcomes and Measures: All-cause, cardiovascular disease (CVD), and cancer mortality. Statistical analyses were performed in April 2022. Results: A total of 350 978 participants (mean [SD] age, 41.4 [15.2] years; 192 432 [50.8%] women; 209 432 [67.8%] Non-Hispanic White) were followed during a median of 10.4 years (3.6 million person-years). There were 21 898 deaths documented, including 4130 from CVD and 6034 from cancer. Compared with physically inactive participants, hazard ratios (HR) for all-cause mortality were 0.92 (95% CI, 0.83-1.02) for weekend warrior and 0.85 (95% CI, 0.83-0.88) for regularly active participants; findings for cause-specific mortality were similar. Given the same amount of total MVPA, weekend warrior participants had similar all-cause and cause-specific mortality rates as regularly active participants. The HRs for weekend warrior vs regularly active participants were 1.08 (95% CI, 0.97-1.20) for all-cause mortality; 1.14 (95% CI, 0.85-1.53) for CVD mortality; and 1.07 (95% CI, 0.87-1.31) for cancer mortality. Conclusions and Relevance: The findings of this large prospective cohort study suggest that individuals who engage in active patterns of physical activity, whether weekend warrior or regularly active, experience lower all-cause and cause-specific mortality rates than inactive individuals. Significant differences were not observed for all-cause or cause-specific mortality between weekend warriors and regularly active participants after accounting for total amount of MVPA; therefore, individuals who engage in the recommended levels of physical activity may experience the same benefit whether the sessions are performed throughout the week or concentrated into fewer days.

The functional role of OGDH for maintaining mitochondrial respiration and identity of primed human embryonic stem cells.

Human embryonic stem cells (hESCs) can self-renew infinitely and differentiate into the cell types of all lineages of our body, holding great promise for investigating early human embryo development and providing functional cells for disease treatment. For the full application of hESCs, it is necessary to elucidate how hESCs maintain their identity. Recent studies have shown that glycolysis and mitochondrial respiration are linked to pluripotency states. However, the function of mitochondrial respiration in hESCs has not been fully understood. Herein, we report that the adenosine triphosphate (ATP) production rate is comparable between mitochondrial respiration and glycolysis, suggesting an important contribution of mitochondrial respiration to ATP production in conventionally cultured hESCs. To investigate the function of mitochondrial respiration, we silence OGDH expression in hESCs by the inducible CRISPRi method, and find that OGDH knockdown (KD) results in disrupted TCA (tricarboxylic acid) cycle, and diminished mitochondrial respiration activity and total ATP level. Moreover, OGDH KD leads to hESC death and aberrant transcriptional program. Interestingly, blockage of the electron transport chain (ETC) by small molecule inhibitors gives rise to the phenotype similar to that observed in OGDH deficient hESCs. Therefore, genetic and pharmacological perturbations of the mitochondrial respiration impair identity of hESCs. Collectively, our study highlights the pivotal role of the mitochondrial respiration activity for the stemness maintenance of primed hESCs, and unveils OGDH as a key regulator for the proper production of ATP and TCA cycle metabolites in primed hESCs.

Self-reported chronic kidney disease and the risk of all-cause and cause-specific mortality: outcome-wide association study of 54 causes of death in the National Health Interview Survey.

BACKGROUND: A diagnosis of chronic kidney disease has been strongly associated with cardiovascular disease and mortality in a number of studies, but the association with specific causes of death has not been assessed in detail. We analysed the association between chronic kidney disease and all-cause mortality and 54 causes of death in the National Health Interview Survey, a prospective study of 210,748 US adults. METHODS: We used multivariable Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality associated with self-reported chronic kidney disease. Men and women aged 18-84 years were recruited between 1997 and 2004 and followed up for mortality through December 31, 2006. RESULTS: During an average of 6 years follow-up, 9564 deaths occurred. A history of chronic kidney disease vs. no chronic kidney disease was associated with increased risk of all-cause mortality (HR = 2.69, 95% CI: 2.38-3.04), and mortality from septicemia (5.65, 2.84-11.25), viral hepatitis (10.67, 2.43-46.95), other infectious parasitic diseases (10.58, 3.59-31.21), total cancer (1.48, 1.05-2.09), lung cancer (1.94, 1.10-3.44), kidney cancer (4.74, 1.81-12.41), diabetes mellitus (8.57, 5.60-13.11), circulatory disease overall (3.36, 2.70-4.18) and 11 specific circulatory diseases with the strongest associations observed for primary hypertension/renal disease (13.60, 6.42-28.84), hypertensive heart/renal disease (10.72, 2.47-46.49), and other diseases of circulatory system (7.36, 3.22-16.81). Elevated risk was also observed for alcoholic liver disease (5.63, 1.90-16.66), other chronic liver disease (4.41, 1.74-11.17), kidney failure (13.07, 8.23-20.77), and five other causes of death. CONCLUSIONS: A history of chronic kidney disease was associated with increased risk of all-cause mortality and 27 out of 54 causes of death. Further studies are needed to clarify associations with less common causes of death.

[Ectopic thyroid carcinoma in front of hyoid bone misdiagnosed as thyroglossal cyst：a case report].

A clinical case of ectopic thyroid carcinoma in front of hyoid bone was reported in this paper. The patient, a 17-year-old female, presented with an enlarging neck mass of 1-week history. Physical examination revealed a 3 cm×2 cm neck mass in front of the hyoid bone. Ultrasonographic depicted as a cystic solid mixed echogenic mass with punctate strong echogenicity. CT scan showed a cystic-solid mass in front of the hyoid bone with punctate calcifications. The patient was misdiagnosed as a thyroglossal duct cyst and underwent surgery. The final pathological diagnosis was papillary thyroid carcinoma with cyst formation.

Deep learning for evaluation of microvascular invasion in hepatocellular carcinoma from tumor areas of histology images.

BACKGROUND: Microvascular invasion (MVI) is essential for the management of hepatocellular carcinoma (HCC). However, MVI is hard to evaluate in patients without sufficient peri-tumoral tissue samples, which account for over a half of HCC patients. METHODS: We established an MVI deep-learning (MVI-DL) model with a weakly supervised multiple-instance learning framework, to evaluate MVI status using only tumor tissues from the histological whole slide images (WSIs). A total of 350 HCC patients (2917 WSIs) from the First Affiliated Hospital of Sun Yat-sen University (FAHSYSU cohort) were divided into a training and test set. One hundred and twenty patients (504 WSIs) from Dongguan People's Hospital and Shunde Hospital of Southern Medical University (DG-SD cohort) formed an external test set. Unsupervised clustering and class activation mapping were applied to visualize the key histological features. RESULTS: In the FAHSYSU and DG-SD test set, the MVI-DL model achieved an AUC of 0.904 (95% CI 0.888-0.920) and 0.871 (95% CI 0.837-0.905), respectively. Visualization results showed that macrotrabecular architecture with rich blood sinus, rich tumor stroma and high intratumor heterogeneity were identified as the key features associated with MVI ( +), whereas severe immune infiltration and highly differentiated tumor cells were associated with MVI (-). In the simulation of patients with only one WSI or biopsies only, the AUC of the MVI-DL model reached 0.875 (95% CI 0.855-0.895) and 0.879 (95% CI 0.853-0.906), respectively. CONCLUSION: The effective, interpretable MVI-DL model has potential as an important tool with practical clinical applicability in evaluating MVI status from the tumor areas on the histological slides.

Langerhans cell histiocytosis developing acute lymphoblastic leukemia.

The sequential occurrence of Langerhans cell histiocytosis and acute leukemia in only one individual has been reported previously; however, it is rarely observed that Langerhans cell histiocytosis can transform into acute lymphoblastic leukemia, and the underlying mechanisms remain unclear. In this report, we have analyzed a case of acute lymphoblastic leukemia converted from Langerhans cell histiocytosis using high-throughput sequencing method, and found that mitogen-activated protein kinase gene mutation, which can act as a marker for poor prognosis, might be involved in disease transformation. This is the first description about acute lymphoblastic leukemia B-cell type after Langerhans cell histiocytosis diagnosis and therapy in China.