Ningbo No. 2 Hospital

Background: Increasing evidence supported the possible neuro-invasion potential of SARS-CoV-2. However, no studies were conducted to explore the existence of the micro-structural changes in the central nervous system after infection. We aimed to identify the existence of potential brain micro-structural changes related to SARS-CoV-2. Methods: In this prospective study, diffusion tensor imaging (DTI) and 3D high-resolution T1WI sequences were acquired in 60 recovered COVID-19 patients (56.67% male; age: 44.10 16.00) and 39 ageand sex-matched non-COVID-19 controls (56.41% male; age: 45.88 13.90). Registered fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were quantified for DTI, and an index score system was introduced. Regional volumes derived from Voxel-based Morphometry (VBM) and DTI metrics were compared using analysis of covariance (ANCOVA). Two sample t-test and Spearman correlation were conducted to assess the relationships among imaging indices, index scores and clinical information. Findings: In this follow-up stage, neurological symptoms were presented in 55% COVID-19 patients. COVID-19 patients had statistically significantly higher bilateral gray matter volumes (GMV) in olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl's gyrus and right cingulate gyrus and a general decline of MD, AD, RD accompanied with an increase of FA in white matter, especially AD in the right CR, EC and SFF, and MD in SFF compared with non-COVID-19 volunteers (corrected p value <0.05). Global GMV, GMVs in left Rolandic operculum, right cingulate, bilateral hippocampi, left Heschl's gyrus, and Global MD of WM were found to correlate with memory loss (p value <0.05). GMVs in the right cingulate gyrus and left hippocampus were related to smell loss (p value <0.05). MD-GM score, global GMV, and GMV in right cingulate gyrus were correlated with LDH level (p value <0.05). Interpretation: Study findings revealed possible disruption to micro-structural and functional brain integrity in the recovery stages of COVID-19, suggesting the long-term consequences of SARS-CoV-2.

Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the "hot" (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct "cold" (immune-desert) phenotype, differing from the features of "hot" tumors. Additionally, there is a more nuanced "excluded" immune phenotype, positioned between the "cold" and "hot" categories, known as the immune "excluded" type. Effective differentiation between "cold" and "hot" tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on "hot" tumors, with limited efficacy against "cold" or "altered" tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert "cold" or "altered" tumors into "hot" ones. Therefore, aligning with the traits of "cold" and "hot" tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on "cold" and "hot" tumors to assess clinical efficacy.

Computed tomography scans were taken of 21 middle-aged men (M age 46.3 years) and 20 older men (M age 69.4 years) to measure differences in body composition with age. Overall, the older men weighed 8.2 kg less than the middle-aged men, and this difference was primarily the result of their having less lean tissue. Although fat mass was only slightly less in older men, there were clear distributional differences in fat between the age groups. Total abdomen fat area was similar in both groups, although the subcutaneous portion of the abdomen fat was less in the older men, and they had correspondingly greater intra-abdominal fat. Muscle areas of the leg and arm were significantly less in the older men, as were all lean tissues of the abdomen and chest. Analysis of fat accumulation between muscles of the abdomen and leg indicated fat infiltration into lean tissue in the older men. Causes of this apparent fat redistribution and lean body mass decline with age are presently unknown.

BACKGROUND: We projected global trends in ischemic stroke from 2020 to 2030 according to age, sex, and socio-demographic index (SDI) quintile. METHODS: Estimated annual percentage changes (EAPCs) were used to project trends in the incidence of deaths from and disability-adjusted life years (DALYs) due to ischemic stroke between 2020 and 2030. EAPCs were computed using generalized additive models and data from the Global Burden of Disease study during the 1990 to 2019 period. RESULTS: The global age-standardized incidence rate of ischemic stroke was projected to increase to 89.32 per 100 000 population in 2030 (EAPC=0.89), whereas the associated global age-standardized death and DALY rates were projected to decrease to 18.28 (EAPC, -3.58) and 500.37 per 100 000 (EAPC=-1.75), respectively, in 2030. The projections indicated a higher age-standardized incidence rate of ischemic stroke among women than among men in 2030 (90.70 versus 87.64 per 100 000). The incidence rate of ischemic stroke was projected to increase across all age groups and SDI quintiles between 2020 and 2030. At the national level, the greatest increase in the age-standardized incidence rate of ischemic stroke between 2020 and 2030 was projected to occur in Cyprus (EAPC=4.16), followed by Palestine (EAPC=3.50) and South Africa (EAPC=2.64). Additionally, the projections suggested increases in the age-standardized death and DALY rates due to ischemic stroke for countries in low-SDI quintiles (EAPC=3.68 and EAPC=5.30, respectively). CONCLUSIONS: The projections indicated that the incidence rate of ischemic stroke will increase both sexes, all age groups, and all SDI quintiles and in some countries between 2020 and 2030. Furthermore, countries with a low SDI should be aware of potential increases in the age-standardized death and DALY due to ischemic stroke.

BACKGROUND AND AIM: MicroRNAs (miRNAs) play important roles in carcinogenesis. The global miRNA expression profile of gastric cancer has not been reported. The purpose of the present study was to determine the miRNA expression profile of gastric cancer. METHODS: Total RNA were first extracted from primary gastric cancer tissues and adjacent non-tumorous tissues and then small isolated RNAs (< 300 nt) were 3'-extended with a poly(A) tail. Hybridization was carried out on a microParaflo microfluidic chip (LC Sciences, Houston, TX, USA). After hybridization detection by fluorescence labeling using tag-specific Cy3 and Cy5 dyes, hybridization images were collected using a laser scanner and digitized using Array-Pro image analysis software (Media Cybernetics, Silver Spring, MD, USA). To validate the results and investigate the biological meaning of differential expressed miRNAs, immunohistochemistry was used to detect the differential expression of target genes. RESULTS: The most highly expressed miRNAs in non-tumorous tissues were miR-768-3p, miR-139-5p, miR-378, miR-31, miR-195, miR-497 and miR-133b. Three of them, miR-139-5p, miR-497 and miR-768-3p, were first found in non-tumorous tissues. The most highly expressed miRNAs in gastric cancer tissues were miR-20b, miR-20a, miR-17, miR-106a, miR-18a, miR-21, miR-106b, miR-18b, miR-421, miR-340*, miR-19a and miR-658. Among them, miR-340*, miR-421 and miR-658 were first found highly expressed in cancer cells. The expression of some target genes (such as Rb and PTEN) in cancer tissues was found to be decreased. CONCLUSION: To our knowledge, this is the first report about these miRNAs associated with gastric cancer. This new information may suggest the potential roles of these miRNAs in the diagnosis of gastric cancer.

Importance: In adults undergoing hip fracture surgery, regional anesthesia may reduce postoperative delirium, but there is uncertainty about its effectiveness. Objective: To investigate, in older adults undergoing surgical repair for hip fracture, the effects of regional anesthesia on the incidence of postoperative delirium compared with general anesthesia. Design, Setting, and Participants: A randomized, allocation-concealed, open-label, multicenter clinical trial of 950 patients, aged 65 years and older, with or without preexisting dementia, and a fragility hip fracture requiring surgical repair from 9 university teaching hospitals in Southeastern China. Participants were enrolled between October 2014 and September 2018; 30-day follow-up ended November 2018. Interventions: Patients were randomized to receive either regional anesthesia (spinal, epidural, or both techniques combined with no sedation; n = 476) or general anesthesia (intravenous, inhalational, or combined anesthetic agents; n = 474). Main Outcomes and Measures: Primary outcome was incidence of delirium during the first 7 postoperative days. Secondary outcomes analyzed in this article include delirium severity, duration, and subtype; postoperative pain score; length of hospitalization; 30-day all-cause mortality; and complications. Results: Among 950 randomized patients (mean age, 76.5 years; 247 [26.8%] male), 941 were evaluable for the primary outcome (6 canceled surgery and 3 withdrew consent). Postoperative delirium occurred in 29 (6.2%) in the regional anesthesia group vs 24 (5.1%) in the general anesthesia group (unadjusted risk difference [RD], 1.1%; 95% CI, -1.7% to 3.8%; P = .48; unadjusted relative risk [RR], 1.2 [95% CI, 0.7 to 2.0]; P = .57]). Mean severity score of delirium was 23.0 vs 24.1, respectively (unadjusted difference, -1.1; 95% CI, -4.6 to 3.1). A single delirium episode occurred in 16 (3.4%) vs 10 (2.1%) (unadjusted RD, 1.1%; 95% CI, -1.7% to 3.9%; RR, 1.6 [95% CI, 0.7 to 3.5]). Hypoactive subtype in 11 (37.9%) vs 5 (20.8%) (RD, 11.5; 95% CI, -11.0% to 35.7%; RR, 2.2 [95% CI, 0.8 to 6.3]). Median worst pain score was 0 (IQR, 0 to 20) vs 0 (IQR, 0 to 10) (difference 0; 95% CI, 0 to 0). Median length of hospitalization was 7 days (IQR, 5 to 10) vs 7 days (IQR, 6 to 10) (difference 0; 95% CI, 0 to 0). Death occurred in 8 (1.7%) vs 4 (0.9%) (unadjusted RD, -0.8%; 95% CI, -2.2% to 0.7%; RR, 2.0 [95% CI, 0.6 to 6.5]). Adverse events were reported in 106 episodes in the regional anesthesia group and 102 in the general anesthesia group; the most frequently reported adverse events were nausea and vomiting (47 [44.3%] vs 34 [33.3%]) and postoperative hypotension (13 [12.3%] vs 10 [9.8%]). Conclusions and Relevance: In patients aged 65 years and older undergoing hip fracture surgery, regional anesthesia without sedation did not significantly reduce the incidence of postoperative delirium compared with general anesthesia. Trial Registration: ClinicalTrials.gov Identifier: NCT02213380.

UNLABELLED: Patients with acute-on-chronic liver failure (ACLF) represent a heterogeneous population. The aim of the study is to identify distinct groups according to the etiologies of precipitating events. A total of 405 ACLF patients were identified from 1,361 patients with cirrhosis with acute decompensation and categorized according to the types of acute insults. Clinical characteristics and prognosis between the hepatic group and extrahepatic group were compared, and the performance of prognostic models was tested in different groups. Two distinct groups (hepatic-ACLF and extrahepatic-ACLF) were identified among the ACLF population. Hepatic-ACLF was precipitated by hepatic insults and had relatively well-compensated cirrhosis with frequent liver and coagulation failure. In contrast, extrahepatic-ACLF was exclusively precipitated by extrahepatic insults, characterized by more severe underlying cirrhosis and high occurrence of extrahepatic organ failures (kidney, cerebral, circulation, and respiratory systems). Both groups had comparably high short-term mortality (28-day transplant-free mortality: 48.3% vs. 50.7%; P = 0.22); however, the extra-hepatic-ACLF group had significantly higher 90-day and 1-year mortality (90-day: 58.9% vs. 68.3%, P = 0.035; 1-year: 63.9% vs. 74.6%, P = 0.019). In hepatic-ACLF group, the integrated Model for End-Stage Liver Disease (iMELD) score had the highest area under the receiver operating characteristic curve (auROC = 0.787) among various prognostic models in predicting 28-day mortality, whereas CLIF-Consortium scores for ACLF patients (CLIF-C-ACLF) had the highest predictive value in the other group (auROC = 0.779). CONCLUSIONS: ACLF precipitated by hepatic insults is distinct from ACLF precipitated by extrahepatic insults in clinical presentation and prognosis. The iMELD score may be a better predictor for hepatic-ACLF short-term prognosis, whereas CLIF-C-ACLF may be better for extrahepatic-ACLF patients.

// Tianwen Li 1 , Xiaoyan Mo 1 , Liyun Fu 1,2 , Bingxiu Xiao 1 and Junming Guo 1 1 Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, China 2 Department of Hepatology, Ningbo No.2 Hospital, Ningbo, China Correspondence to: Junming Guo, email: // Keywords : lncRNA, gastric cancer, miRNA, ceRNA, gene expression Received : October 18, 2015 Accepted : January 13, 2016 Published : January 17, 2016 Abstract Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. Aberrant expression of lncRNAs has been found associated with gastric cancer, one of the most malignant tumors. By complementary base pairing with mRNAs or forming complexes with RNA binding proteins (RBPs), some lncRNAs including GHET1, MALAT1, and TINCR may mediate mRNA stability and splicing. Other lncRNAs, such as BC032469, GAPLINC, and HOTAIR, participate in the competing endogenous RNA (ceRNA) network. Under certain circumstances, ANRIL, GACAT3, H19, MEG3, and TUSC7 exhibit their biological roles by associating with microRNAs (miRNAs). By recruiting histone-modifying complexes, ANRIL, FENDRR, H19, HOTAIR, MALAT1, and PVT1 may inhibit the transcription of target genes in cis or trans . Through these mechanisms, lncRNAs form RNA-dsDNA triplex. CCAT1, GAPLINC, GAS5, H19, MEG3, and TUSC7 play oncogenic or tumor suppressor roles by correlated with tumor suppressor P53 or onco-protein c-Myc, respectively. In conclusion, interaction with DNA, RNA and proteins is involved in lncRNAs&rsquo; participation in gastric tumorigenesis and development.

INTRODUCTION: Studies have demonstrated that mesenchymal stromal cells (MSCs) could reverse acute and chronic kidney injury by a paracrine or endocrine mechanism, and microvesicles (MVs) have been regarded as a crucial means of intercellular communication. In the current study, we focused on the therapeutic effects of human Wharton-Jelly MSCs derived microvesicles (hWJMSC-MVs) in renal ischemia/reperfusion injury and its potential mechanisms. METHODS: MVs isolated from conditioned medium were injected intravenously in rats immediately after ischemia of the left kidney for 60 minutes. The animals were sacrificed at 24 hours, 48 hours and 2 weeks after reperfusion. The infiltration of inflammatory cells was identified by the immunostaining of CD68+ cells. ELISA was employed to determine the inflammatory factors in the kidney and serum von Willebrand Factor (VWF). Tubular cell proliferation and apoptosis were identified by immunostaining. Renal fibrosis was assessed by Masson's tri-chrome straining and alpha-smooth muscle actin (α-SMA) staining. The CX3CL1 expression in the kidney was measured by immunostaining and Western blot, respectively. In vitro, human umbilical vein endothelial cells were treated with or without MVs for 24 or 48 hours under hypoxia injury to test the CX3CL1 by immunostaining and Western blot. RESULTS: After administration of hWJMSC-MVs in acute kidney injury (AKI) rats, renal cell apoptosis was mitigated and proliferation was enhanced, inflammation was also alleviated in the first 48 hours. MVs also could suppress the expression of CX3CL1 and decrease the number of CD68+ macrophages in the kidney. In the late period, improvement of renal function and abrogation of renal fibrosis were observed. In vitro, MVs could down-regulate the expression of CX3CL1 in human umbilical vein endothelial cells under hypoxia injury at 24 or 48 hours. CONCLUSIONS: A single administration of MVs immediately after ischemic AKI could ameliorate renal injury in both the acute and chronic stage, and the anti-inflammatory property of MVs through suppression of CX3CL1 may be a potential mechanism. This establishes a substantial foundation for future research and treatment.

To observe the diagnostic values of circular RNAs (circRNAs), their expression profiles between gastric cancer patients' plasma and healthy controls were first assessed by circRNA microarray. Then, circRNA levels were measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and RT-droplet digital PCR (RT-ddPCR), respectively. A total of 343 differentially expressed circRNAs were found. The top 10 elevated circRNAs in patients were hsa_circ_0088300, hsa_circ_0075825, hsa_circ_0019172, hsa_circ_0000220, hsa_circ_0035277, hsa_circ_0000301, hsa_circ_0000189, hsa_circ_0090080, hsa_circ_0001888, and hsa_circ_0001874. The top 10 reduced circRNAs were hsa_circ_0004771, hsa_circ_0001190, hsa_circ_0061276, hsa_circ_0092337, hsa_circ_0058495, hsa_circ_0061274, hsa_circ_0075829, hsa_circ_0080845, hsa_circ_0001006, and hsa_circ_0003764. In cancer and dysplasia tissues, hsa_circ_0001017 and hsa_circ_0061276 were downregulated. Their levels were significantly associated with distal metastasis. The area under receiver operating characteristic curve in combinative use was 0.966 with 95.5% sensitivity and 95.7% specificity. Patients with low plasma hsa_circ_0001017 or hsa_circ_0061276 had a much shorter overall survival than those with high levels. Patients whose plasma hsa_circ_0001017 or hsa_circ_0061276 levels recovered to normal after operation had a longer disease-free survival. Finally, the in vitro model indicated gastric cancer cells secreting circRNAs into plasma. In conclusion, RT-ddPCR is a potent non-invasive and absolute quantification method for simultaneous detection of multiple circRNAs. Hsa_circ_0001017 and hsa_circ_0061276 are new potential biomarkers for gastric cancer. KEY MESSAGE: A total of 343 circRNAs are differentially expressed between gastric cancer patients' plasma and healthy controls. Hsa_circ_0001017 and hsa_circ_0061276 are downregulated in gastric cancer tissues. The RT-ddPCR is a potent method for simultaneous detection of multiple circRNAs in plasma. Hsa_circ_0001017 and hsa_circ_0061276 are potential biomarkers for gastric cancer.

Abstract Fe‐based Fenton agents can generate highly reactive and toxic hydroxyl radicals (·OH) in the tumor microenvironment (TME) for chemodynamic therapy (CDT) with high specificity. However, the strict condition (lower pH environment: 3–4) of the highly efficient Fenton reaction limits its practical application in the clinic. Development of new CDT agents more suitable for TME is significant and challenging. A highly efficient Cu(I)‐based CDT agent, copper(I) phosphide nanocrystals (CP NCs), which is more adaptable to the pH value of TME than Fe‐based agents, thereby producing more ·OH to trigger the apoptosis of cancer cells, is prepared. Moreover, the excess glutathione (GSH) in TME can reduce the Cu(II) produced by a Fenton‐like reaction to Cu(I), further increasing the generation rate of ·OH and relieving tumor antioxidant ability. Furthermore, owing to their strong absorption in the NIR II region, CP NCs exhibit an excellent photothermal conversion effect, which can further improve the Fenton reaction. What is more, CP NCs can act as in situ self‐generation magnetic resonance imaging (MRI) agents owing to the generation of paramagnetic Cu(II) in response to excess H 2 O 2 in the TME. These properties may open up the exploration of copper‐based materials in clinical application of self‐generation imaging‐guided synergetic treatment.

Cancer metastasis is a serious concern and a major reason for treatment failure. Herein, we have reported the development of an effective and safe nanotherapeutic strategy that can eradicate primary tumors, inhibit metastasizing to lung, and control the metastasis and growth of distant tumors. Briefly, ferrimagnetic vortex-domain iron oxide nanoring (FVIO)-mediated mild magnetic hyperthermia caused calreticulin (CRT) expression on the 4T1 breast cancer cells. The CRT expression transmitted an “eat-me” signal and promoted phagocytic uptake of cancer cells by the immune system to induce an efficient immunogenic cell death, further leading to the macrophage polarization. This mild thermotherapy promoted 88% increase of CD8+ cytotoxic T lymphocyte infiltration in distant tumors and triggered immunotherapy by effectively sensitizing tumors to the PD-L1 checkpoint blockade. The percentage of CD8+ cytotoxic T lymphocytes can be further increased from 55.4% to 64.5% after combining with PD-L1 blockade. Moreover, the combination treatment also inhibited the immunosuppressive response of the tumor, evidenced by significant down-regulation of myeloid-derived suppressor cells (MDSCs). Our results revealed that the FVIO-mediated mild magnetic hyperthermia can activate the host immune systems and efficiently cooperate with PD-L1 blockade to inhibit the potential metastatic spreading as well as the growth of distant tumors.

Objective To develop a gastric cancer (GC) risk prediction rule as an initial prescreening tool to identify individuals with a high risk prior to gastroscopy. Design This was a nationwide multicentre cross-sectional study. Individuals aged 40–80 years who went to hospitals for a GC screening gastroscopy were recruited. Serum pepsinogen (PG) I, PG II, gastrin-17 (G-17) and anti- Helicobacter pylori IgG antibody concentrations were tested prior to endoscopy. Eligible participants (n=14 929) were randomly assigned into the derivation and validation cohorts, with a ratio of 2:1. Risk factors for GC were identified by univariate and multivariate analyses and an optimal prediction rule was then settled. Results The novel GC risk prediction rule comprised seven variables (age, sex, PG I/II ratio, G-17 level, H. pylori infection, pickled food and fried food), with scores ranging from 0 to 25. The observed prevalence rates of GC in the derivation cohort at low-risk (≤11), medium-risk (12–16) or high-risk (17–25) group were 1.2%, 4.4% and 12.3%, respectively (p&lt;0.001).When gastroscopy was used for individuals with medium risk and high risk, 70.8% of total GC cases and 70.3% of early GC cases were detected. While endoscopy requirements could be reduced by 66.7% according to the low-risk proportion. The prediction rule owns a good discrimination, with an area under curve of 0.76, or calibration (p&lt;0.001). Conclusions The developed and validated prediction rule showed good performance on identifying individuals at a higher risk in a Chinese high-risk population. Future studies are needed to validate its efficacy in a larger population.

BACKGROUND: Long non-coding RNAs (lncRNAs) are prevalently transcribed in the genome yet their potential roles in human cancers are not well understood. The aim of the present study was to determine the lncRNA expression profile in gastric cancer and its potential clinical value. METHODS: The global lncRNA expression profile in gastric cancer was measured by lncRNA microarray. Levels of two representative lncRNAs, H19 and uc001lsz, were confirmed by real-time reverse transcriptase-polymerase chain reaction. The relationship between their levels and clinicopathological factors of patients with gastric cancer was explored. A receiver operating characteristic (ROC) curve was constructed for differentiating gastric cancer from benign gastric diseases. RESULTS: Total of 135 lncRNAs, which differential expression levels between tumor and non-tumorous tissues were more than twofold, were found (GEO No. GSE47850). The most down-regulated lncRNAs in gastric cancer tissues were FER1L4, uc001lsz, BG491697, AF131784, uc009ycs, BG981369, AF147447, HMlincRNA1600, and AK054588; while the most up-regulated ones were H19, HMlincRNA717, BM709340, BQ213083, AK054978, and DB077273. H19 was found highly expressed in stomach and liver cancer cell lines, while lowly expressed in lung cancer and prostate cancer cell lines. Uc001lsz was lowly expressed in gastric, lung and liver cancer cell lines, while highly expressed in prostate cancer. The areas under ROC curves were up to 0.613, 0.751, and 0.761 for H19, uc001lsz, and the combination, respectively. CONCLUSIONS: The lncRNA expression profile in gastric cancer suggests the potential roles of lncRNAs in gastric cancer occurrence and development. The overexpression of H19 in gastric cancer suggests that H19 may be participated in gastric cancer. The reduced expression of uc001lsz in gastric cancer cell lines and tissues, its associations with TNM stage, and its dysregulation in early cancer and precancerous lesions suggest that uc001lsz may be a potential marker for the diagnosis of early gastric cancer.

The "hotness" or "coldness" of the tumors are determined by the information of the cancer cells themselves, tumor immune characteristics, tumor microenvironment, and signaling mechanisms, which are key factors affecting cancer patients' clinical efficacy. The switch mechanism of "hotness" and "coldness" and its corresponding pathological characteristics and treatment strategies are the frontier and hot spot of tumor treatment. How to distinguish the "hotness" or "coldness" effectively and clarify the causes, microenvironment state, and characteristics are very important for the tumor response and efficacy treatments. Starting from the concept of hot and cold tumor, this review systematically summarized the molecular characteristics, influencing factors, and therapeutic strategies of "hot and cold tumors," and analyzed the immunophenotypes, the tumor microenvironment, the signaling pathways, and the molecular markers that contribute to "hot and cold tumors" in details. Different therapeutic strategies for "cold and hot tumors" based on clinical efficacy were analyzed with drug targets and proteins for "cold and hot tumors." Furthermore, this review combines the therapeutic strategies of different "hot and cold tumors" with traditional medicine and modern medicine, to provide a basis and guidance for clinical decision-making of cancer treatment.

Although immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with many advanced malignancies, only 15–60% of patients respond, leaving a broad swath of patients who do not derive benefit. Identifying biomarkers to optimally identify patients who will benefit from ICIs is a major research focus for the oncology community. Thus far, predictive biomarker research has focused on tumor signatures such as microsatellite instability, programmed death-ligand 1 (PD-L1) expression and tumor mutational burden; clinical biomarkers have been far less studied. One potential clinical biomarker for ICI response in patients is immune-related adverse event (IRAE) onset. IRAEs are thought to represent bystander effects from activated T-cells and it is plausible that patients responding to ICIs would have greater likelihood of autoimmune toxicities (e.g. due to a more competent/treatment-responsive immune system, or cross-reactivity between tumor and host tissue). Earlier studies in melanoma patients however, suggested no association between IRAE onset and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody efficacy. In contrast, a growing body of literature suggests IRAE onset is predictive of anti-programmed cell death protein 1 (PD-1) and anti-PD-L1 antibody response across a variety of solid tumors. Most of these studies report that patients who experienced IRAEs demonstrate marked improvements in progression-free survival, overall survival and overall response rate compared to those lacking toxicity. Key questions regarding the association between IRAE onset and ICI efficacy remain. The most pertinent of these involve whether the association is only relevant for patients treated with anti-PD-1 and anti-PD-L1 antibodies and whether IRAE site, severity, timing of onset and management influence ICI efficacy. Herein, we discuss the seminal studies which have begun to address these questions and have shaped the narrative about the predictive value of IRAE onset for patients on ICIs, in this review.

// Liyun Fu 1 , Ting Yao 2 , Qingqing Chen 2 , Xiaoyan Mo 2 , Yaoren Hu 1 and Junming Guo 2 1 Department of Hepatology, Ningbo No. 2 Hospital and The Affiliated Hospital, Medical School of Ningbo University, Ningbo 315010, China 2 Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China Correspondence to: Junming Guo, email: guojunming@nbu.edu.cn Yaoren Hu, email: hu510@126.com Keywords: hsa_circ_0004018, circular RNA, hepatocellular carcinom, microRNA, biomarker Received: February 08, 2017&emsp;&emsp;&emsp;&emsp; Accepted: March 14, 2017&emsp;&emsp;&emsp;&emsp; Published: April 06, 2017 ABSTRACT Circular RNAs (circRNAs) have been emerged as an indispensable part of endogenous RNA network. However, the expression significance of circRNAs in hepatocellular carcinoma (HCC) is rarely revealed. The aim of this study was to determine the circRNA expression profile in HCC, and to investigate their clinical significances and relevant mechanisms for cancer progression. The global circRNA expression profile in HCC was measured by circRNA microarray. Levels of one representative circRNAs, hsa_circ_0004018, were confirmed by real-time reverse transcription-polymerase chain reaction. The expression levels of hsa_circ_0004018 in HCC were significantly lower compared with para-tumorous tissue ( P &lt;0.001). Our data further showed that lower expression of hsa_circ_0004018 was correlated with serum alpha-fetoprotein (AFP) level, tumor diameters, differentiation, Barcelona Clinic Liver Cancer stage and Tumor-node-metastasis stage. More importantly, we detected liver tissues from chronic hepatitis, cirrhosis and HCC patients; and found that hsa_circ_0004018 harbored HCC-stage-specific expression features in diverse chronic liver diseases ( P &lt;0.001). The area under receiver operating characteristic curve was up to 0.848 (95% CI=0.803&ndash;0.894, P &lt;0.001). The sensitivity and specificity were 0.716 and 0.815, respectively. Finally, hsa_circ_0004018 might be involved in cancer-related pathways via interactions with miRNAs.

// Yongfu Shao 1, 4 , Meng Ye 2 , Qier Li 2 , Weiliang Sun 3 , Guoliang Ye 2 , Xinjun Zhang 2 , Yunben Yang 1 , Bingxiu Xiao 1 , Junming Guo 1 1 Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211, China 2 Department of Gastroenterology, The Affiliated Hospital of Ningbo University School of Medicine, Ningbo, 315020, China 3 Ningbo Yinzhou People&rsquo;s Hospital and The Affiliated Hospital, Ningbo University School of Medicine, Ningbo, 315040, China 4 Current address: Department of Gastroenterology, The Affiliated Hospital of Ningbo University School of Medicine, Ningbo, 315020, China Correspondence to: Junming Guo, email: guojunming@nbu.edu.cn Meng Ye, email: yemeng@nbu.edu.cn Keywords: gene expression, miRNA sponge, cell cycle, biomarker, gastric cancer Received: March 19, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: April 27, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: May 12, 2016 ABSTRACT Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis. However, the mechanisms of most lncRNAs in cancers are largely unknown. Because the RNA component of mitochondrial RNA processing endoribonuclease (RMRP) is one of the dysregulated lncRNAs in gastric cancer, this study explored its molecular mechanisms in carcinogenesis. RMRP levels in 792 tissues, plasma and gastric juices from patients with various stages of gastric tumorigenesis were analyzed by quantitative reverse transcription-polymerase chain reaction. Overexpression and RNA interference were used to manipulate RMRP expression by RMRP expression vector and small interfering RNAs, respectively. Its mechanisms were evaluated by flow cytometry, real-time cell analysis, plate colony formation assays, and xenograft models. RMRP levels in tissue, plasma and gastric juices from patients with gastric cancer were significantly different from those from controls. Its levels were significantly associated with Borrmann type and metastasis. Plasma and gastric juice RMRP had higher sensitivity and specificity than commonly used markers (such as carcinoembryonic antigen and carbohydrate antigen 19&ndash;9). Knockdown of RMRP significantly inhibited cell proliferation in vitro and in vivo , whereas overexpression of RMRP promoted cell growth. Acting as a miR-206 sponge, RMRP modulated cell cycle by regulating Cyclin D2 expression. RMRP plays a crucial role in gastric cancer occurrence and can be used as a novel biomarker for gastric cancer.

BACKGROUND/OBJECTIVE: Inadvertent intraoperative hypothermia (core temperature <36°C) is a frequently preventable complication with several adverse consequences. Our study aimed to determine the overall incidence of inadvertent intraoperative hypothermia and its risk factors associated with clinical outcomes in this national survey in China. METHODS: We conducted a national cross-sectional study with 30 days postoperative follow-up from November 2014 through August 2015. A total of 3132 eligible patients underwent general anesthesia were randomly selected from 28 hospitals in the nationwide of China. RESULTS: The overall incidence of intraoperative hypothermia was as high as 44.3%, in which cumulative incidence rates of hypothermia being 17.8%, 36.2%, 42.5% and 44.1% within 1 h, 2 h, 3 h and 4 h respectively following induction of anesthesia. All patients were warmed passively by covering of surgical draping, sheets or cotton blankets, whereas only 14.2% of patients received active warming with space heaters or electric heater or electronic blankets. Compared to normothermic patients, patients with hypothermia is associated with more postoperative ICU admit, longer PACU and more postoperative hospital days, but no difference in surgical site infection (SSI) rates or 30-day mortality. Several factors were shown to be associated with decreased risk of hypothermia. They are active warming (OR = 0.46, 95% CI 0.26-0.81), BMI ≥ 25 (OR = 0.54, 95% CI 0.45-0.65), higher baseline core temperature (OR = 0.04, 95% CI 0.03-0.06), and higher ambient temperature (OR = 0.83, 95% CI 0.78-0.88). Risk factors associated with an increased risk of hypothermia included major-plus surgery (OR = 1.49, 95% CI 1.23-1.79), and long anesthesia (>2 h) (OR = 2.60, 95% CI 2.09-3.24). CONCLUSIONS: The incidence of intraoperative hypothermia in China is high, and the rate of active warming of patients during operation is low. Hypothermia is associated with more postoperative shivering, increased ICU admissions, and longer postoperative hospital days.

BACKGROUND: Mesenchymal stromal cells (MSCs) derived extracellular vesicles (EVs) were regarded as a potent medium for kidney injury repair and angiogenesis were regarded as an important step in tissue regeneration. However, the pro-angiogenesis effect of MSC-EVs in ischemia-reperfusion induced kidney injury and its potential mechanisms have yet to be determined. METHODS: EVs were isolated from the medium of human umbilical cord-derived MSCs (huMSCs) were injected in rats intravenously after unilateral kidney ischemia. Animals were sacrificed at 24 h and 2 weeks after injury. The renal functions and histology staining were examined to assess the therapeutic effect of the EVs. Moreover, we investigated the pro-angiogenesis effects of EVs in injured kidneys and tested the angiogenesis-related factors to further illuminate the probable mechanisms. RESULTS: , EVs could deliver human VEGF directly to renal tubular epithelial cells (TECs) and increase VEGF levels. Most important, all the beneficial effects of EVs were abrogated by RNase treated except for the delivery of human VEGF. CONCLUSIONS: Human MSC-EVs could protect against ischemic/reperfusion injury induced kidney injury through pro-angiogenesis effects in HIF-1α independent manner, and both the delivery of pro-angiogenesis related VEGF and RNAs were involved in this process.