The practical utility of AI-assisted molecular profiling in the diagnosis and management of cancer of unknown primary: an updated review.

Cancer of unknown primary (CUP) presents a complex diagnostic challenge, characterized by metastatic tumors of unknown tissue origin and a dismal prognosis. This review delves into the emerging significance of artificial intelligence (AI) and machine learning (ML) in transforming the landscape of CUP diagnosis, classification, and treatment. ML approaches, trained on extensive molecular profiling data, have shown promise in accurately predicting tissue of origin. Genomic profiling, encompassing driver mutations and copy number variations, plays a pivotal role in CUP diagnosis by providing insights into tumor type-specific oncogenic alterations. Mutational signatures (MS), reflecting somatic mutation patterns, offer further insights into CUP diagnosis. Known MS with established etiology, such as ultraviolet (UV) light-induced DNA damage and tobacco exposure, have been identified in cases of dedifferentiated/transdifferentiated melanoma and carcinoma. Deep learning models that integrate gene expression data and DNA methylation patterns offer insights into tissue lineage and tumor classification. In digital pathology, machine learning algorithms analyze whole-slide images to aid in CUP classification. Finally, precision oncology, guided by molecular profiling, offers targeted therapies independent of primary tissue identification. Clinical trials assigning CUP patients to molecularly guided therapies, including targetable alterations and tumor mutation burden as an immunotherapy biomarker, have resulted in improved overall survival in a subset of patients. In conclusion, AI- and ML-driven approaches are revolutionizing CUP management by enhancing diagnostic accuracy. Precision oncology utilizing enhanced molecular profiling facilitates the identification of targeted therapies that transcend the need to identify the tissue of origin, ultimately improving patient outcomes.

Dysregulated cellular redox status during hyperammonemia causes mitochondrial dysfunction and senescence by inhibiting sirtuin-mediated deacetylation.

Perturbed metabolism of ammonia, an endogenous cytotoxin, causes mitochondrial dysfunction, reduced NAD+ /NADH (redox) ratio, and postmitotic senescence. Sirtuins are NAD+ -dependent deacetylases that delay senescence. In multiomics analyses, NAD metabolism and sirtuin pathways are enriched during hyperammonemia. Consistently, NAD+ -dependent Sirtuin3 (Sirt3) expression and deacetylase activity were decreased, and protein acetylation was increased in human and murine skeletal muscle/myotubes. Global acetylomics and subcellular fractions from myotubes showed hyperammonemia-induced hyperacetylation of cellular signaling and mitochondrial proteins. We dissected the mechanisms and consequences of hyperammonemia-induced NAD metabolism by complementary genetic and chemical approaches. Hyperammonemia inhibited electron transport chain components, specifically complex I that oxidizes NADH to NAD+ , that resulted in lower redox ratio. Ammonia also caused mitochondrial oxidative dysfunction, lower mitochondrial NAD+ -sensor Sirt3, protein hyperacetylation, and postmitotic senescence. Mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX), but not NAD+ precursor nicotinamide riboside, reversed ammonia-induced oxidative dysfunction, electron transport chain supercomplex disassembly, lower ATP and NAD+ content, protein hyperacetylation, Sirt3 dysfunction and postmitotic senescence in myotubes. Even though Sirt3 overexpression reversed ammonia-induced hyperacetylation, lower redox status or mitochondrial oxidative dysfunction were not reversed. These data show that acetylation is a consequence of, but is not the mechanism of, lower redox status or oxidative dysfunction during hyperammonemia. Targeting NADH oxidation is a potential approach to reverse and potentially prevent ammonia-induced postmitotic senescence in skeletal muscle. Since dysregulated ammonia metabolism occurs with aging, and NAD+ biosynthesis is reduced in sarcopenia, our studies provide a biochemical basis for cellular senescence and have relevance in multiple tissues.

CSL112 Infusion Rapidly Increases APOA1 Exchange Rate via Specific Serum Amyloid-Poor HDL Subpopulations When Administered to Patients Post-Myocardial Infarction.

BACKGROUND: To characterize the effects of CSL112 (human APOA1 [apolipoprotein A1]) on the APOA1 exchange rate (AER) and the relationships with specific HDL (high-density lipoprotein) subpopulations when administered in the 90-day high-risk period post-acute myocardial infarction. METHODS: A subset of patients (n=50) from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) study received either placebo or CSL112 post-acute myocardial infarction. AER was measured in AEGIS-I plasma samples incubated with lipid-sensitive fluorescent APOA1 reporter. HDL particle size distribution was assessed by native gel electrophoresis followed by fluorescent imaging and detection of APOA1 and SAA (serum amyloid A) by immunoblotting. RESULTS: CSL112 infusion increased AER peaking at 2 hours and returning to baseline 24 hours post-infusion. AER correlated with cholesterol efflux capacity (r=0.49), HDL-cholesterol (r=0.30), APOA1 (r=0.48), and phospholipids (r=0.48; all P<0.001) over all time points. Mechanistically, changes in cholesterol efflux capacity and AER induced by CSL112 reflected HDL particle remodeling resulting in increased small HDL species that are highly active in mediating ABCA1 (ATP-binding cassette transporter 1)-dependent efflux, and large HDL species with high capacity for APOA1 exchange. The lipid-sensitive APOA1 reporter predominantly exchanged into SAA-poor HDL particles and weakly incorporated into SAA-enriched HDL species. CONCLUSIONS: Infusion of CSL112 enhances metrics of HDL functionality in patients with acute myocardial infarction. This study demonstrates that in post-acute myocardial infarction patients, HDL-APOA1 exchange involves specific SAA-poor HDL populations. Our data suggest that progressive enrichment of HDL with SAA may generate dysfunctional particles with impaired HDL-APOA1 exchange capacity, and that infusion of CSL112 improves the functional status of HDL with respect to HDL-APOA1 exchange. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02108262.

Efficacy of Zhibitai capsules combined with low-dose atorvastatin in the treatment of cervical arteriosclerosis and its effects on high-sensitivity C-reactive protein and regulatory T cells in the peripheral blood / 中国基层医药

Objective:To investigate the efficacy of Zhibitai capsules combined with low-dose atorvastatin in the treatment of cervical arteriosclerosis and its effects on high-sensitivity C-reactive protein and regulatory T cells in the peripheral blood. Methods:A total of 104 patients with carotid arteriosclerosis admitted to Fenyang Hospital from January 2021 to April 2022 were retrospectively included in this study. They were divided into a control group ( n = 52) and an observation group ( n = 52) according to different treatment methods. The control group was orally given atorvastatin calcium tablets 20 mg once a day. The observation group was orally given atorvastatin calcium tablets 10 mg once a day, and Zhibitai capsules 0.24 g, one capsule in the morning and one capsule in the evening. After 8 weeks of treatment, changes in total cholesterol, triacylglycerol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and regulatory T cell proportion in the peripheral blood were evaluated. Results:After treatment, high-density lipoprotein cholesterol level and regulatory T cell proportion in the observation group were (1.53 ± 0.29) mmol/L and (5.52 ± 1.38)%, respectively, which were significantly higher than (1.19 ± 0.21) mmol/L and (4.48 ± 0.86)% respectively in the control group ( t = 6.84, 4.61, both P < 0.05). Total cholesterol, triacylglycerol, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein levels in the observation group were (2.88 ± 0.27) mmol/L, (1.21 ± 0.15) mmol/L, (2.01 ± 0.19) mmol/L, (2.58 ± 0.43) mg/L, respectively, which were significantly lower than (3.68 ± 0.41) mmol/L, (1.33 ± 0.19) mmol/L, (2.69 ± 0.31) mmol/L, (3.70 ± 0.25) mg/L, respectively in the control group ( t = 11.75, 3.57, 12.31, 17.23, all P < 0.05). There was no significant difference in carotid plaque size pre-treatment between the two groups, but the plaque size decreased after treatment compared with before treatment. The efficacy of Zhibitai capsules combined with low-dose atorvastatin in the treatment of cervical arteriosclerosis in the observation group was superior to that in the control group ( P < 0.05). Conclusion:Oral administration of Zhibitai capsules combined with low-dose atorvastatin for the treatment of cervical arteriosclerosis is safe and has few adverse reactions. The combined therapy can decrease serum high-sensitivity C-reactive protein levels, increase the proportion of regulatory T cells in the peripheral blood, help stabilize plaques, and reduce plaque size.

Current status changing trend and influencing factors of pancreatic cancer disease burden in Chengde of Hebei Province in 2010 - 2020 / 公共卫生与预防医学

Objective To analyze the disease burden status, trends and possible influencing factors of pancreatic cancer in Chengde of Hebei from 2010 to 2020, in order to provide theoretical basis for the preventionof pancreatic cancer. Methods Using the global burden of disease open database, the incidence rate, mortality, years of life lost (YLL), years of life lost with disability (YLD) and disability adjusted life year (DALY) of pancreatic cancer in the region are obtained,average annual percent change (AAPC) was calculated using joinpoint model to test the trend of disease burden change of pancreatic cancer patients from 2010 to 2020. At the same time, the patient characteristics such as hypertension, diabetes and other categorical variables were set as dummy variables, and the risk factors affecting the mortality of patients with pancreatic cancer were analyzed by linear regression. Results In 2010, there were 15 new cases of pancreatic cancer and 13 deaths in Chengde District , Hebei Province. The YLLs caused by pancreatic cancer accounted for 70.67% of DALY. In 2020, there were 160 new cases of pancreatic cancer and 147 deaths in Chengde, Hebei Province. The YLLs caused by pancreatic cancer accounted for 96.02% of DALY. From 2010 to 2020, the incidence of pancreatic cancer increased by 9.79%, and the incidence rate increased by 7.81%, showing an obvious upward trend (APCC =2.20%, P 28.0 and pancreatitis (OR=1.574 , 95% CI: 1.328-3.045) were all risk factors for death of patients with pancreatic cancer (OR>1) . Conclusion From 2010 to 2020, the incidence and mortality of pancreatic cancer among local residents in Chengde of Hebei showed an upward trend, and the disease burden was also increasing year by year. The basic diseases of diabetes and chronic pancreatitis increase the death risk and should be protected.

Immunophenotype and function of peripheral blood lymphocyte subsets in Chinese rhesus macaques / 中华微生物学和免疫学杂志

Objective:To provide data reference for using Chinese rhesus macaques as research model by studying the immunophenotype and function of peripheral blood lymphocytes in Chinese rhesus macaques.Methods:By optimizing antibody clones and fluorescent colors, the lymphocyte subset assay and T cell function assay panels were determined. Then the panels were used to analyze the proportion of T, B, NK and other cell subsets in peripheral blood mononuclear cells (PBMCs) in 15 healthy Chinese rhesus monkeys, and the ability of T cells to secrete cytokines after non-specific stimulation.Results:Two multi-color flow cytometry analytic panels were established. Panel 1 could simultaneously detect a variety of lymphocyte subsets, including cytotoxic T lymphocytes, follicular helper T cells, regulatory T cells, B cells and NK cells. Panel 2 could detect the functions of multiple T cell subsets and the expression of immune checkpoint moleculars. The mean percentages of T, B, NK, Tfh, Treg, CD16 + NK and CD56 + NK cells in PBMCs of the Chinese rhesus macaques were (75.32±7.73)%, (13.22±7.50)%, (0.88±0.48)%, (0.73±0.27)%, (0.75±0.43)%, (47.87±22.35)% and (10.69±12.41)%. After non-specific stimulation, the proportion of CD4 + T cells secreting IL-2 and TNF-α was higher than that of CD8 + T cells, and the proportion of CD8 + T cells secreting CD107a and IFN-γ was higher than that of CD4 + T cells, while the proportion of CD4 + and CD8 + T cells secreting IL-17A was low. Conclusions:This study established a multi-color flow detection scheme that could simultaneously detect multiple cellular surface molecules and cytokines at the single cell level and could accurately and comprehensively analyze the immune cell subsets, functions and the immune checkpoint molecules in peripheral blood of Chinese rhesus macaques, providing a new experimental method and basic data for the development of vaccines and drugs against infectious diseases.

Jinyinqingre Oral Liquid alleviates LPS-induced acute lung injury by inhibiting the NF-κB/NLRP3/GSDMD pathway / 中国天然药物

Acute lung injury (ALI) is a prevalent and severe clinical condition characterized by inflammatory damage to the lung endothelial and epithelial barriers, resulting in high incidence and mortality rates. Currently, there is a lack of safe and effective drugs for the treatment of ALI. In a previous clinical study, we observed that Jinyinqingre oral liquid (JYQR), a Traditional Chinese Medicine formulation prepared by the Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, exhibited notable efficacy in treating inflammation-related hepatitis and cholecystitis in clinical settings. However, the potential role of JYQR in ALI/acute respiratory distress syndrome (ARDS) and its anti-inflammatory mechanism remains unexplored. Thus, the present study aimed to investigate the therapeutic effects and underlying molecular mechanisms of JYQR in ALI using a mouse model of lipopolysaccharide (LPS)-induced ALI and an in vitro RAW264.7 cell model. JYQR yielded substantial improvements in LPS-induced histological alterations in lung tissues. Additionally, JYQR administration led to a noteworthy reduction in total protein levels within the BALF, a decrease in MPAP, and attenuation of pleural thickness. These findings collectively highlight the remarkable efficacy of JYQR in mitigating the deleterious effects of LPS-induced ALI. Mechanistic investigations revealed that JYQR pretreatment significantly inhibited NF-κB activation and downregulated the expressions of the downstream proteins, namely NLRP3 and GSDMD, as well as proinflammatory cytokine levels in mice and RAW2647 cells. Consequently, JYQR alleviated LPS-induced ALI by inhibiting the NF-κB/NLRP3/GSDMD pathway. JYQR exerts a protective effect against LPS-induced ALI in mice, and its mechanism of action involves the downregulation of the NF-κB/NLRP3/GSDMD inflammatory pathway.

Effectiveness validation of a novel comprehensive classification for intertrochanteric fractures / 中国修复重建外科杂志

OBJECTIVE@#To validate the effectiveness of a novel comprehensive classification for intertrochanteric fracture (ITF).@*METHODS@#The study included 616 patients with ITF, including 279 males (45.29%) and 337 females (54.71%); the age ranged from 23 to 100 years, with an average of 72.5 years. Two orthopaedic residents (observers Ⅰ and Ⅱ) and two senior orthopaedic surgeons (observers Ⅲ and Ⅳ) were selected to classify the CT imaging data of 616 patients in a random order by using the AO/Orthopaedic Trauma Association (AO/OTA) classification of 1996/2007 edition, the AO/OTA classification of 2018 edition, and the novel comprehensive classification method at an interval of 1 month. Kappa consistency test was used to evaluate the intra-observer and inter-observer consistency of the three ITF classification systems.@*RESULTS@#The inter-observer consistency of the three classification systems evaluated by 4 observers twice showed that the 3 classification systems had strong inter-observer consistency. Among them, the κ value of the novel comprehensive classification was higher than that of the AO/OTA classification of 1996/2007 edition and 2018 edition, and the experience of observers had a certain impact on the classification results, and the inter-observer consistency of orthopaedic residents was slightly better than that of senior orthopaedic surgeons. The intra-observer consistency of two evaluations of three classification systems by 4 observers showed that the consistency of the novel comprehensive classification was better for the other 3 observers, except that the consistency of observer Ⅳ in the AO/OTA classification of 2018 version was slightly higher than that of the novel comprehensive classification. The results showed that the novel comprehensive classification has higher repeatability, and the intra-observer consistency of senior orthopaedic surgeons was better than that of orthopaedic residents.@*CONCLUSION@#The novel comprehensive classification system has good intra- and inter-observer consistency, and has high validity in the classification of CT images of ITF patients; the experience of observers has a certain impact on the results of the three classification systems, and those with more experiences have higher intra-observer consistency.

Dual-Proxy Modeling for Masked Face Recognition.

With the recent worldwide COVID-19 pandemic, almost everyone wears a mask daily, leading to severe degradation in the accuracy of conventional face recognition systems. Several works improve the performance of masked faces by adopting synthetic masked face images for training. However, such methods often cause performance degradation on unmasked faces, raising the contradiction between the face recognition system's accuracy on unmasked and masked faces. In this paper, we propose a dual-proxy face recognition training method to improve masked faces' performance while maintaining unmasked faces' performance. Specifically, we design two fully-connected layers as the unmasked and masked feature space proxies to alleviate the significant difference between the two data distributions. The cross-space constraints are adopted to ensure the intra-class compactness and inter-class discrepancy. Extensive experiments on popular unmasked face benchmarks and masked face benchmarks, including real-world mask faces and the generated mask faces, demonstrate our method's superiority over the state-of-the-art methods on masked faces without incurring a notable accuracy degradation on unmasked faces.

HDL Is Not Dead Yet.

High-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with coronary heart disease (CHD) in multiple epidemiological studies, but whether HDL is causal or merely associated with CHD is unclear. Recent trials for HDL-raising drugs were either not effective in reducing CHD events or, if beneficial in reducing CHD events, were not conclusive as the findings could be attributed to the drugs' LDL-reducing activity. Furthermore, the first large Mendelian randomization study did not causally relate HDL-C levels to decreased CHD. Thus, the hypothesis that HDL is protective against CHD has been rightfully challenged. However, subsequent Mendelian randomization studies found HDL characteristics that are causally related to decreased CHD. Many aspects of HDL structure and function, especially in reverse cholesterol transport, may be better indicators of HDL's protective activity than simply measuring HDL-C. Cholesterol efflux capacity is associated with lower levels of prevalent and incident CHD, even after adjustment for HDL-C and apolipoprotein A-1 levels. Also, subjects with very high levels of HDL-C, including those with rare mutations that disrupt hepatic HDL uptake and reverse cholesterol transport, may be at higher risk for CHD than those with moderate levels. We describe here several cell-based and cell-free in vitro assays of HDL structure and function that may be used in clinical studies to determine which of HDL's functions are best associated with protection against CHD. We conclude that the HDL hypothesis may need revision based on studies of HDL structure and function, but that the HDL hypothesis is not dead yet.

Production of carboxylic acids by metabolically engineered Yarrowia lipolytica: a review / 生物工程学报

Yarrowia lipolytica is a non-conventional yeast with unique physiological and metabolic characteristics. It is suitable for production of various products due to its natural ability to utilize a variety of inexpensive carbon sources, excellent tolerance to low pH, and strong ability to secrete metabolites. Currently, Y. lipolytica has been demonstrated to produce a wide range of carboxylic acids with high efficiency. This article summarized the progress in engineering Y. lipolytica to produce various carboxylic acids by using metabolic engineering and synthetic biology approaches. The current bottlenecks and solutions for high-level production of carboxylic acids by engineered Y. lipolytica were also discussed, with the aim to provide useful information for relevant studies in this field.

Quantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function.

We have previously shown that the DBA/2J versus AKR/J mouse strain is associated with decreased autophagy-mediated lysosomal hydrolysis of cholesterol esters. Our objective was to determine differences in lysosome function in AKR/J and DBA/2J macrophages, and identify the responsible genes. Using a novel dual-labeled indicator of lysosome function, DBA/2J versus AKR/J bone marrow derived macrophages had significantly decreased lysosome function. We performed quantitative trait loci mapping of lysosome function in bone marrow macrophages from an AKR/J × DBA/2J strain intercross. Four distinct lysosome function loci were identified, which we named macrophage lysosome function modifier (Mlfm) Mlfm1 through Mlfm4. The strongest locus Mlfm1 harbors the Gpnmb gene, which has been shown to recruit autophagy protein light chain 3 to autophagosomes for lysosome fusion. The parental DBA/2J strain has a nonsense variant in Gpnmb. siRNA knockdown of Gpnmb in AKR/J macrophages decreased lysosome function, and Gpnmb deletion through CRISP/Cas9 editing in RAW 264.7 mouse macrophages also demonstrated a similar result. Furthermore, a DBA/2 substrain, called DBA/2J-Gpnmb+/SjJ, contains the wildtype Gpnmb gene, and macrophages from this Gpnmb-preserved DBA/2 substrain exhibited recovered lysosome function. In conclusion, we identified Gpnmb as a causal modifier gene of lysosome function in this strain pair.

A Novel Cell-Free Fluorescent Assay for HDL Function: Low Apolipoprotein A1 Exchange Rate Associated with Increased Incident Cardiovascular Events.

BACKGROUND: Cholesterol efflux capacity is a tissue culture assay for HDL function that is not amenable for high-throughput monitoring of risk assessment. METHODS: We devised a cell-free HDL function assay to measure the exchange rate of exogenous apoA1 into serum HDL using NBD/Alexa647 double-labeled apoA1, whose NBD/Alexa647 emission ratio increased upon exchange into HDL. ApoA1 exchange rate (AER) was assayed by incubating labeled apoA1 with human serum, and the rate of the increase of the NBD/Alexa647 ratio over time was calculated as AER. RESULTS: Fast protein liquid chromatography analysis of serum confirmed that the labeled apoA1 selectively exchanged into the HDL lipoprotein fraction. Characterization studies demonstrated that the AER assay had excellent intra- and inter-day reproducibility, was stable over 3 freeze-thaw cycles, and yielded similar results with serum or plasma. We quantified AER in serum from randomly selected stable subjects undergoing elective diagnostic coronary angiography (n = 997). AER was correlated with HDL-cholesterol (r = 0.58, P < 0.0001) and apoA1 levels (r = 0.56, P < 0.0001). Kaplan-Meier survival plot showed subjects in the lowest quartile of AER experienced a significantly higher rate of incident major adverse cardiovascular events (MACE = myocardial infarction, stroke, or death) (P < 0.0069 log rank). Moreover, compared to subjects in the lowest AER quartile, the remaining subjects showed significantly lower incident (3 year) risk for MACE, even after adjustment for traditional risk factors and apoA1 (HR 0.58; 95% CI 0.40-0.85; P = 0.005). CONCLUSIONS: In a prospective cohort of stable subjects undergoing elective diagnostic cardiac evaluations, low AER was associated with increased incident risk of MACE.

Uptake of high-density lipoprotein by scavenger receptor class B type 1 is associated with prostate cancer proliferation and tumor progression in mice.

High-density lipoprotein (HDL) metabolism is facilitated in part by scavenger receptor class B, type 1 (SR-B1) that mediates HDL uptake into cells. Higher levels of HDL have been associated with protection in other diseases, however, its role in prostate cancer is not definitive. SR-B1 is up-regulated in prostate cancer tissue, suggesting a possible role of this receptor in tumor progression. Here, we report that knockout (KO) of SR-B1 in both human and mouse prostate cancer cell lines through CRISPR/Cas9-mediated genome editing reduces HDL uptake into the prostate cancer cells and reduces their proliferation in response to HDL. In vivo studies using syngeneic SR-B1 WT (SR-B1+/+) and SR-B1 KO (SR-B1-/-) prostate cancer cells in WT and apolipoprotein-AI KO (apoA1-KO) C57BL/6J mice revealed that WT hosts, containing higher levels of total and HDL-cholesterol, grew larger tumors than apoA1-KO hosts with lower levels of total and HDL-cholesterol. Furthermore, SR-B1-/- prostate cancer cells formed smaller tumors in WT hosts than SR-B1+/+ cells in the same host model. Increased tumor volume was overall associated with reduced survival. We conclude that knocking out SR-B1 in prostate cancer tumors reduces HDL-associated increases in prostate cancer cell proliferation and disease progression.

Bariatric Surgery Improves HDL Function Examined by ApoA1 Exchange Rate and Cholesterol Efflux Capacity in Patients with Obesity and Type 2 Diabetes.

Bariatric surgery improves glycemic control better than medical therapy; however, the effect of bariatric surgery on HDL function is not well characterized. Serum samples were available at baseline, 1-, and 5-years post procedures, for 90 patients with obesity and type 2 diabetes who were randomized to intensive medical therapy (n = 20), Roux-en-Y gastric bypass (RYGB, n = 37), or sleeve gastrectomy (SG, n = 33) as part of the STAMPEDE clinical trial. We examined serum HDL function by two independent assays, apolipoprotein A-1 exchange rate (AER) and cholesterol efflux capacity (CEC). Compared with baseline, AER was significantly higher at 5 years for participants in all treatment groups, but only increased significantly at 1 year in the RYGB and SG groups. CEC was divided into ABCA1-dependent and independent fractions, and the later was correlated with AER. ABCA1-independent CEC increased significantly only at 5 years in both surgical groups, but did not significantly change in the medical therapy group. There was no significant change in ABCA1-dependent CEC in any group. The increase in AER, but not ABCA1-independent CEC, was correlated with the reduction in body mass index and glycated hemoglobin levels among all subjects at 5 years, indicating that AER as a measure of HDL function would be a better reflection of therapy versus CEC.

Manifestations of liver injury in 333 hospitalized patients with coronavirus disease 2019 / 中华消化杂志

Objective:To investigate the manifestations of liver injury in hospitalized patients with coronavirus disease 2019 (COVID-19), to investigate the prognosis indicators of the disease, and to provide the reference for clinical diagnosis and treatment.Methods:From January 10 to February 14, 2020, at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, the data of 333 hospitalized patients with COVID-19 were collected. The changes of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), direct bilirubin (DBil), indirect bilirubin (IBil) and albumin of the first liver function test after admission and the reexaminations of liver function test during hospitalization period in patients with liver injury were retrospectively analyzed. Student t test and Chi-square test were used for statistical analysis. Results:Liver injury occurred in 39.6% (132/333) of COVID-19 patients. There was no statistically significant difference in the rate of liver injury between patients in intensive care unit (ICU) and in general ward (45.6%, 26/57 vs. 38.4%, 106/276; χ2=1.026, P>0.05). 67.4% (89/132) of COVID-19 patients with liver injury presented with increased ALT or AST level on admission. During hospitalization, the level of ALT was higher than that of the first examination after admission ((60.28±50.44) U/L vs. (42.25±32.21) U/L), and the difference was statistically significant ( t=-3.230, P<0.05). The levels of ALT and AST of 71.2% (94/132) patients were both <80 U/L, which indicated that most of the patients showed mild liver injury. The patients with elevated level of TBil, DBil and IBil accounted for 3.9% (13/333), 5.4% (18/333) and 2.4% (8/333) of the COVID-19 patients, respectively. The albumin level of COVID-19 patients with liver injury during hospitalization was lower than that of the first examination after admission ((31.8±5.1) g/L vs. (33.7±5.4) g/L), and the difference was statistically significant ( t=2.712, P<0.05). The albumin levels at first examination on admission and reexamination during hospitalization of patients in ICU were both significantly lower than those of patients in general ward ((29.3±3.7) g/L vs. (34.8±5.1) g/L and (27.6±2.8) g/L vs. (32.9±5.1) g/L), and the differences were statistically significant ( t=4.928 and 4.783, both P<0.05). Conclusions:The incidence of liver injury in COVID-19 patients is high. A slight increase in aminotransferase levels is particularly common. Bilirubin abnormality is relatively rare and mild. The level of albumin may be one of the indicators for the severity and prognosis of COVID-19.

Comparison of the costs of different clinical treatment plans for children with acute promyelocytic leukemia / 白血病·淋巴瘤

Objective@#To explore the costs and other information of two different treatment plans for pediatric acute promyelocytic leukemia (APL): one is the traditional intravenous drip arsenic (arsenic trioxide) combined with chemotherapy treatment, and the other is a medication family treatment program based on oral arsenic (Realgar-Indigo naturalis formula), in order to provide a reference for the promotion of pediatric APL family treatment mode and the formulation of medical insurance policies.@*Methods@#The medical record homepage data and drug using of pediatric APL from 2010 to 2018 in Institute of Hematology & Blood Diseases Hospital of Chinese Academy of Medical Sciences & Peking Union Medical College were retrospectively analyzed, and the newly diagnosed pediatric patients (≤14 years old) with APL were included. The hospitalization expenses and hospitalization time of two treatment options were compared. One treatment option was Chinese children APL treatment plan 2010 (CCAPL 2010), which was based on intravenous drip arsenic trioxide. The other was Chinese Children Cancer Group APL treatment plan 2017 (CCCG-APL 2017), which was based on oral Realgar-Indigo naturalis formula.@*Results@#A total of 79 pediatric APL patients were included and grouped according to the treatment plans, 56 patients were treated with CCAPL 2010 plan, and 23 patients were treated with CCCG-APL 2017 plan. The median costs of one single pediatric APL patient in CCAPL 2010 plan was 167 700 yuan (95 800-386 600 yuan), and the median hospital stay time of one single pediatric APL patient was 102 days (14-157 days). The median costs of one single pediatric APL patient in CCCG-APL 2017 plan group was 118 700 yuan(50 800-270 600 yuan), and the median hospital stay time of one single pediatric APL patient was 37 days(5-96 days). The costs and hospital stay time of one single pediatric APL patient with CCCG-APL 2017 plan were remarkably less than those of one single pediatric APL patient with CCAPL 2010 plan (U = 178, P < 0.01; U = 66, P < 0.01).@*Conclusions@#The CCCG-APL 2017 plan simplifies the treatment plan compared with the CCAPL 2010 plan and significantly reduces the patient's medical expenses and shortens the hospitalization days. The CCCG-APL 2017 plan is suitable for family therapy and has good social and economic benefits, which is worthy of clinical promotion.

Comparison of the costs of different clinical treatment plans for children with acute promyelocytic leukemia / 白血病·淋巴瘤

Objective To explore the costs and other information of two different treatment plans for pediatric acute promyelocytic leukemia (APL): one is the traditional intravenous drip arsenic (arsenic trioxide) combined with chemotherapy treatment, and the other is a medication family treatment program based on oral arsenic (Realgar-Indigo naturalis formula), in order to provide a reference for the promotion of pediatric APL family treatment mode and the formulation of medical insurance policies. Methods The medical record homepage data and drug using of pediatric APL from 2010 to 2018 in Institute of Hematology & Blood Diseases Hospital of Chinese Academy of Medical Sciences & Peking Union Medical College were retrospectively analyzed, and the newly diagnosed pediatric patients (≤14 years old) with APL were included. The hospitalization expenses and hospitalization time of two treatment options were compared. One treatment option was Chinese children APL treatment plan 2010 (CCAPL 2010), which was based on intravenous drip arsenic trioxide. The other was Chinese Children Cancer Group APL treatment plan 2017 (CCCG-APL 2017), which was based on oral Realgar-Indigo naturalis formula. Results A total of 79 pediatric APL patients were included and grouped according to the treatment plans, 56 patients were treated with CCAPL 2010 plan, and 23 patients were treated with CCCG-APL 2017 plan. The median costs of one single pediatric APL patient in CCAPL 2010 plan was 167 700 yuan (95 800-386 600 yuan), and the median hospital stay time of one single pediatric APL patient was 102 days (14-157 days). The median costs of one single pediatric APL patient in CCCG-APL 2017 plan group was 118 700 yuan(50 800-270 600 yuan), and the median hospital stay time of one single pediatric APL patient was 37 days (5-96 days). The costs and hospital stay time of one single pediatric APL patient with CCCG-APL 2017 plan were remarkably less than those of one single pediatric APL patient with CCAPL 2010 plan (U ＝ 178, P < 0.01; U ＝ 66, P< 0.01). Conclusions The CCCG-APL 2017 plan simplifies the treatment plan compared with the CCAPL 2010 plan and significantly reduces the patient's medical expenses and shortens the hospitalization days. The CCCG-APL 2017 plan is suitable for family therapy and has good social and economic benefits, which is worthy of clinical promotion.

V-ATPase (Vacuolar ATPase) Activity Required for ABCA1 (ATP-Binding Cassette Protein A1)-Mediated Cholesterol Efflux.

Objective- We have shown that ABCA1 (ATP-binding cassette protein A1) mediates unfolding of the apoA1 (apolipoprotein A1) N-terminal helical hairpin during apoA1 lipidation. Others have shown that an acidic pH exposes the hydrophobic surface of apoA1. We postulated that the V-ATPase (vacuolar ATPase) proton pump facilitates apoA1 unfolding and promotes ABCA1-mediated cholesterol efflux. Approach and Results- We found that V-ATPase inhibitors dose-dependently decreased ABCA1-mediated cholesterol efflux to apoA1 in baby hamster kidney cells and RAW264.7 cells; and similarly, siRNA knockdown of ATP6V0C inhibited ABCA1-mediated cholesterol efflux to apoA1 in RAW264.7 cells. Although ABCA1 expression did not alter total cellular levels of V-ATPase, ABCA1 increased the cell surface levels of the V0A1 and V1E1 subunits of V-ATPase. We generated a fluorescein isothiocyanate/Alexa647 double-labeled fluorescent ratiometric apoA1 pH indicator whose fluorescein isothiocyanate/Alexa647 emission ratio decreased as the pH drops. We found that ABCA1 induction in baby hamster kidney cells led to acidification of the cell-associated apoA1 pH indicator, compared with control cells without ABCA1 expression. The V-ATPase inhibitor bafilomycin A1 dose-dependently inhibited the apoA1 pH shift in ABCA1-expressing cells, without affecting the levels of cell-associated apoA1. However, we were not able to detect ABCA1-mediated extracellular proton release. We showed that acidic pH facilitated apoA1 unfolding, apoA1 solubilization of phosphatidycholine:phosphatidyserine liposomes, and increased lipid fluidity of these liposomes. Conclusions- Our results support a model that ABCA1 recruits V-ATPase to the plasma membrane where V-ATPase mediates apoA1 acidification and membrane remodeling that promote apoA1 unfolding and ABCA1-mediated HDL (high-density lipoprotein) biogenesis and lipid efflux.