Diagnostic value of circular free DNA for colorectal cancer detection

BACKGROUND Minimally invasive or noninvasive,sensitive and accurate detection of colorectal cancer(CRC)is urgently needed in clinical practice.AIM To identify a noninvasive,sensitive and accurate circular free DNA marker detected by digital polymerase chain reaction(dPCR)for the early diagnosis of clinical CRC.METHODS A total of 195 healthy control(HC)individuals and 101 CRC patients(38 in the early CRC group and 63 in the advanced CRC group)were enrolled to establish the diagnostic model.In addition,100 HC individuals and 62 patients with CRC(30 early CRC and 32 advanced CRC groups)were included separately to validate the model.CAMK1D was dPCR.Binary logistic regression analysis was used to establish a diagnostic model including CAMK1D and CEA.RESULTS To differentiate between the 195 HCs and 101 CRC patients(38 early CRC and 63 advanced CRC patients),the common biomarkers CEA and CAMK1D were used alone or in combination to evaluate their diagnostic value.The area under the curves(AUCs)of CEA and CAMK1D were 0.773(0.711,0.834)and 0.935(0.907,0.964),respectively.When CEA and CAMK1D were analyzed together,the AUC was 0.964(0.945,0.982).In differentiating between the HC and early CRC groups,the AUC was 0.978(0.960,0.995),and the sensitivity and specificity were 88.90%and 90.80%,respectively.In differentiating between the HC and advanced CRC groups,the AUC was 0.956(0.930,0.981),and the sensitivity and specificity were 81.30%and 95.90%,respectively.After building the diagnostic model containing CEA and CAMK1D,the AUC of the CEA and CAMK1D joint model was 0.906(0.858,0.954)for the validation group.In differentiating between the HC and early CRC groups,the AUC was 0.909(0.844,0.973),and the sensitivity and specificity were 93.00%and 83.30%,respectively.In differentiating between the HC and advanced CRC groups,the AUC was 0.904(0.849,0.959),and the sensitivity and specificity were 93.00%and 75.00%,respectively.CONCLUSION We built a diagnostic model including CEA and CAMK1D for differentiating between HC individuals and CRC patients.Compared with the common biomarker CEA alone,the diagnostic model exhibited significant improvement.

Mechanism of exosomal microRNA-224 in development of hepatocellular carcinoma and its diagnostic and prognostic value

BACKGROUND Exosomes contain proteins, lipids, and biological molecules such as DNA and RNA. Nucleic acids in exosomes are a group of molecules that can act as biomarkers. Currently, there are many reports on exosomal microRNAs, which are ideal biomarkers for the early diagnosis of cancer. However, there are few reports on the role of exosomal microRNAs in the diagnosis and prognosis of hepatocellular carcinoma(HCC).AIM To understand the mechanism of exosomal microRNA-224(miR-224) in the development of HCC and evaluate its diagnostic and prognostic value.METHODS Cell culture and transfection of exosomal miRNA-224, real-time quantitative PCR, luciferase reporter assay, and other methods were used to find new biomarkers related to the development of HCC that can be used to diagnose HCC and predict HCC prognosis.RESULTSBy targeting glycine N-methyltransferase, incubating exosomes with miR-224 mimic resulted in a significant increase in cell proliferation compared to that of the control group, while incubation with the miR-224 inhibitor significantly reduced cell proliferation. The same results were obtained for the cell invasion assay. Serum exosomal miR-224 did have some ability to differentiate patients with HCC from healthy controls, with an area under the curve of 0.910, and HCC patients with higher serum exosomal miR-224 expression had lower overall survival.CONCLUSION Exosomal miR-224 is a tumor promotor and can be a marker of diagnosis and prognosis of HCC patients, however, its ability to distinguish liver diseases needs further verification.

Transplantation of bone marrow-derived endothelial progenitor cells and hepatocyte stem cells from liver fibrosis rats ameliorates liver fibrosis

AIM To explore the effectiveness for treating liver fibrosisby combined transplantation of bone marrow-derived endothelial progenitor cells(BM-EPCs) and bone marrow-derived hepatocyte stem cells(BDHSCs) from the liver fibrosis environment.METHODS The liver fibrosis rat models were induced with carbon tetrachloride injections for 6 wk. BM-EPCs from rats with liver fibrosis were obtained by different rates of adherence and culture induction. BDHSCs from rats with liver fibrosis were isolated by magnetic bead cell sorting. Tracing analysis was conducted by labeling EPCs with PKH26 in vitro to show EPC location in the liver. Finally, BM-EPCs and/or BDHSCs transplantation into rats with liver fibrosis were performed to evaluate the effectiveness of BM-EPCs and/or BDHSCs on liver fibrosis.RESULTS Normal functional BM-EPCs from liver fibrosis rats were successfully obtained. The co-expression level of CD133 and VEGFR2 was 63.9% ± 2.15%. Transplanted BM-EPCs were located primarily in/near hepatic sinusoids. The combined transplantation of BM-EPCs and BDHSCs promoted hepatic neovascularization, liver regeneration and liver function, and decreased collagen formation and liver fibrosis degree. The VEGF levels were increased in the BM-EPCs(707.10 ± 54.32) and BM-EPCs/BDHSCs group(615.42 ± 42.96), compared with those in the model group and BDHSCs group(P < 0.05). Combination of BM-EPCs/BDHSCs transplantation induced maximal up-regulation of PCNA protein and HGF m RNA levels. The levels of alanine aminotransferase(AST), aspartate aminotransferase, total bilirubin(TBIL), prothrombin time(PT) and activated partial thromboplastin time in the BMEPCs/BDHSCs group were significantly improved, to be equivalent to normal levels(P > 0.05) compared with those in the BDHSC(AST, TBIL and PT, P < 0.05) and BM-EPCs(TBIL and PT, P < 0.05) groups. Transplantation of BM-EPCs/BDHSCs combination significantly reduced the degree of liver fibrosis(staging score of 1.75 ± 0.25 vs BDHSCs 2.88 ± 0.23 or BMEPCs 2.75 ± 0.16, P < 0.05).CONCLUSION The combined transplantation exhibited maximal therapeutic effect compared to that of transplantation of BM-EPCs or BDHSCs alone. Combined transplantation of autogenous BM-EPCs and BDHSCs may represent a promising strategy for the treatment of liver fibrosis, which would eventually prevent cirrhosis and liver cancer.

The effect of nursing intervention based on Autar scale results to reduce deep venous thrombosis incidence in orthopaedic surgery patients

Purpose:To reduce the incidence of deep venous thrombosis(DVT)with nursing intervention based on the Autar DVT risk assessment scale among orthopaedic surgery patients.Methods:We recruited 216 orthopaedic surgery patients at our hospital between September 2013 and March 2014.The patients were assigned to intervention and historical control groups based on the time of admission.Using the Autar DVT risk assessment scale,we assessed the DVT risk levels in both groups;the intervention group received the corresponding prophylactic measures while the control group received routine nursing.Results:The DVT incidence rate and the D-dimer level on postoperative day 3 in the intervention group were lower(1.82%;623±225 mg/L,respectively)than that of the control group(9.43%;825±201 mg/L,respectively);both differences were statistically significant(p<0.05).Conclusions:The Autar scale is beneficial when used in orthopaedic surgery patients;corresponding nursing intervention based on Autar scale assessment can prevent DVT effectively.

Expression Profile of Altered Long Non-coding RNAs in Patients with HBV-associated Hepatocellular Carcinoma

In China, hepatitis B virus （HBV） infection is the major cause of hepatocellular carcinoma （HCC）, which is called HBV-related HCC （HBV-HCC）, but the pathogenesis has not been clearly elu- cidated. Long non-coding RNAs （lncRNAs） have been paid increasing attention to, as an important regulatory molecule involved in many biological processes, as well as a variety of diseases. This study examined lncRNA that might play an important role in HBV-HCC pathogenesis by conducting lncRNA and mRNA profile comparison between HBV-HCC and normal liver tissues. The differentially ex- pressed lncRNA and mRNA profiles between HBV-HCC and normal liver tissues were analyzed by mi- croarrays. The potential protein-encoding gene regulated by lncRNA, and the biological function （gene ontology, pathway analysis） of the target gene were investigated. The results showed that the expression levels of lncRNA and mRNA in HBV-HCC tissues were different from those in normal liver tissues. As compared with normal liver tissue, 837 （4.30%） lncRNAs exhibited more than two-fold change （P〈0.05）; 325 were up-regulated, and 512 were down-regulated; 991 （5.70%） mRNAs exhibited more than 2-fold change （P〈0.05）; 733 were up-regulated and 258 were down-regulated in HBV-HCC tissue. Besides, there were 7 lncRNAs with above 10-fold elevation, 6 lncRNAs with above 10-fold decrease, 18 mRNAs with above 10-fold elevation and 11 mRNAs with above 10-fold decrease. 444 （53.05%） lncRNAs had their corresponding mRNAs, some of which were adjacent to lncRNAs. The biological analysis showed that the target gene of differentially expressed lncRNAs took part in the important bio- logical regulatory function. Target gene-related pathway analysis revealed the pathways in carcinoma and mitogen-activated protein kinase （MAPK） signaling pathways significantly changed in the HBV-HCC tissues as compared with normal liver tissues （P〈0.05）. It was suggested that as compared with normal liver tissues, the expression of lncRNAs in HBV-HCC tissues changed significantly, and lncRNAs played a key role in the pathogenesis of HBV-HCC probably by mainly regulating the carci- noma-related signaling pathway and MAPK signaling pathways.

Inhibitory Effects of Mild Hyperthermia plus Docetaxel Therapy on ER(+/–) Breast Cancer Cells and Action Mechanisms

Summary： The purpose of this study was to verify that a combination of mild hyperthermia and do- cetaxel chemotherapy produces synergistic antitumor effects and to explore the action mechanisms of this treatment approach. The effects of docetaxel on the proliferation of cells from the estrogen receptor （ER）-positive human breast cancer cell line MCF-7 and the ER-negative human breast cancer cell line MDA-MB-453 were examined by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide （MTT） assay, and effective experimental concentrations of docetaxel were determined. The effects of mild hy- perthermia plus docetaxel therapy on apoptosis rate in the MCF-7 and MDA-MB-453 human breast cancer cell lines were analyzed by using flow cytometry with Annexin-V fluorescein isothiocyanate （FITC）/propidium iodide （PI） staining. The effects of these combined treatments on cell cycle progres- sion in the MCF-7 and MDA-MB-453 human breast cancer cell lines were examined by using flow cy- tometry. The effects of these combined treatments on the expression of apoptosis-related proteins and proteins in the mitogen-activated protein kinase （MAPK） pathways were analyzed by using Western blotting. The effects of these combined treatments on the expression of the heat shock protein 70 （HSP70） and the multi-drug resistance （MDR） gene product P-glycoprotein （Pgp） were examined by using Western blotting. The results showed that the half-maximal inhibitory concentration （IC50） of do- cetaxel for MCF-7 and MDA-MB-453 cells was 19.57±1.12 and 21.64±2.31 gmol/L respectively. Mild hyperthermia with docetaxel therapy could increase apoptosis rate in the MCF-7 and MDA-MB-453 cells. Apoptosis rate in MCF-7 and MDA-MB-453 cells was increased from （23.66±3.59）% and （18.51±3.17）% in docetaxel treatment group to （47.12±6.73）% and （55.16±7.42）% in mild hyperthermia plus docetaxel group, indicating that the mild hyperthermia and docetaxel therapeutic approaches exhib- ited significant synergistic antitumor effects. Treatments of mild hyperthermia plus docetaxel induced G2/M cell cycle arrest in the MCF-7 and MDA-MB-453 cells. Western blotting demonstrated that pro- teins in the MAPK pathway were expressed at higher levels in docetaxel-treated cells following mild hypothermia than those in cells treated with docetaxel alone. As compared with blank control group, cells from the mild hyperthermia plus docetaxel group exhibited significantly decreased B-cell lym- phoma 2 （Bcl-2） protein expression but slightly increased Bcl-2-associated X protein （Bax） expression. Western blotting results revealed that HSP70 and Pgp expression levels were significantly increased following mild hypothermia. It was concluded that treatments of mild hyperthermia plus docetaxel in- hibited the proliferation of human breast cancer cells, promoted apoptosis of breast cancer cells, and produced synergistic antitumor effects.

Functional Role of Micro RNA-19b in Acinar Cell Necrosis in Acute Necrotizing Pancreatitis

The expression of micro RNA-19b（mi R-19b） in acute necrotizing pancreatitis（ANP） and its functional role in acinar cell necrosis of SD rats were investigated. Twelve SD rats were divided into two groups randomly, including control group and ANP group. The rat ANP models were established by intraperitoneal injection of L-arginine（2400 mg/kg body weight）, and equal volume of 0.9% Na Cl was injected in the control group. Mi RNA chip assay was performed to examine the expression of mi RNAs in the pancreas in two different groups. Besides, to further explore the role of mi R-19 b in ANP in vitro, taurolithocholic acid 3-sulfate disodium salt（TLC-S）（200 μmol/L） was administrated to treat the rat pancreatic acinar cell line, AR42 J, for establishing the ANP cells model. The quantitative real-time PCR（q RT-PCR） was adopted to measure the mi R-19 b expression. Moreover, the mimic mi RNA, mi RNA antisense oligonucleotide（AMO） and control vector were used to transfect AR42 J cells, the expression of mi R-19 b was confirmed by q RT-PCR and the necrotizing rate of AR42 J cells was detected with AO/EB method. The expression of mi R-19 b was significantly higher in ANP group than in control group as displayed by the mi RNA chip assay. Furthermore, after inducing necrosis of AR42 J cells in vitro, the expression of mi R-19 b was significantly increased by 2.51±0.14 times in comparison with the control group. As revealed by q RT-PCR assay, the expression of mi R-19 b was 5.94±0.95 times higher in the mimic mi RNA group than in the control vector group, companied with an obviously increased acinar cell necrotizing rate（50.3%±1.5% vs. 39.6%±2.3%, P〈0.05）. Moreover, the expression of mi R-19 b in the mi RNA AMO group was 0.38±0.15 times lower than in the control vector group, and the cell necrosis rate was much lower accordingly（23.1%±3.3% vs. 39.6%±2.3%, P〈0.05）. Besides, there was no significant difference between the control vector cells and the cells without treatment（P〈0.05）. The expression of mi R-19 b was significantly induced in ANP. In addition, up-regulation of mi R-19 b could promote the necrosis of pancreatic acinar cells and mi R-19 b deficiency could decrease the rate of pancreatic acinar cell necrosis.

Neuroendocrine,epigenetic,and intergenerational effects of general anesthetics

The progress of modern medicine would be impossible without the use of general anesthetics(GAs).Despite advancements in refining anesthesia approaches,the effects of GAs are not fully reversible upon GA withdrawal.Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly.Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research,but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects.The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents,which are far more extensively studied than any other species.Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated.Specifically,we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities(somatic effects),but also epigenetic reprogramming of germ cells(germ cell effects).The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring,who may be affected even at levels of anesthesia that are not harmful to the exposed parents.The large number of patients who require general anesthesia,the even larger number of their future unexposed offspring whose health may be affected,and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs.In this mini review,we discuss emerging experimental findings on neuroendocrine,epigenetic,and intergenerational effects of GAs.

Effects of the 24 N-terminal Amino Acids of p55PIK on Endotoxinstimulated Release of Inflammatory Cytokines by HaCaT Cells

Summary： This study aimed to examine the effect of the 24 N-terminal amino acids （N24） ofp55PIK, a regulatory subunit of phosphatidylinositol 3-kinase （PI3K）, on the endotoxin lipopolysaccharide （LPS）-stimulated release of the cytokines （CKs） by HaCaT cells. The fusion protein, trans-acting activator of transcription （TAT）-N24 （an experimental peptide, EP） containing the N24 of PI3K-p55PIK, was constructed, and TAT-N24 fusion peptide was expressed and identified in BL21 E.coli. HaCaT cells （a human keratinocyte cell line） was cultured and stimulated by LPS at 100 ng/mL for 1, 2, 4, 8, 16 or 24 h, or by LPS at 10, 100 ng/mL, 1, 10 or 100 μg/mL of for 4 h. Changes in the protein and mRNA levels of tumor necrosis factor-alpha （TNF-ct）, interleukin-6 （IL-6） and interleukin-8 （IL-8） released by HaCaT cells following EP intervention were determined by enzyme-linked immunosorbent assay （ELISA） and real-time polymerase chain reaction （PCR）. Immunofluorescence confocal laser scanning microscopy was utilized to detect the protein expression and translocation of the p65 subunit of nuclear factor kappa-light-chain-enhancer of activated B cells （NF-r,B p65） in HaCaT cells. The expression of the NF-kB inhibitor alpha （Iv, B-a） protein in LPS-stimulated HaCaT cells after the EP intervention was measured by Western blotting. The resillts showed that EP treatment increased TNF-a secretion from HaCaT cells. EP at certain concentrations could effectively inhibit the LPS-stimulated release of TNF-a, IL-6 and IL-8 from HaCaT cells. The ELISA assay demonstrated that the concentrations of TNF-a, IL-6 and IL-8 in the supernatants of LPS-stimulated cells were reduced from 208.06±30.18, 86.4±9.78 and 260.59±54.05 pg/mL to 121.78±22.26, 53.18±7.36 and 125.08±35.17 pg/mL, respectively, in the supernatants of cells treated by LPS and EP combined. Real-time PCR also revealed that the expression of the three pro-inflammatory CKs was significantly decreased after EP intervention. Immunofluorescence confocal laser scanning microscopy showed that NF-kB p65 protein was primarily expressed in the cytoplasm of non-stimulated HaCaT cells. After LPS stimulation, NF-kB p65 was translocated into the nucleus, and the nuclear expression of this protein increased. The nuclear NF-kB p65 protein expression was inhibited after the addition of EP. Western blotting showed that Ir, B-a expression began to decrease 30 min after LPS stimulation and declined to a trough 4 h later. Ir, B-a expression began to gradually recover 16 h after LPS stimulation but remained at a lower-than-normal level at 24 h. Greater Ir, B-a expression was found in cells treated with LPS and EP combined than those treated with LPS alone. It was concluded that EP can effectively inhibit the LPS-stimulated expression of TNF-a, IL-6, and IL-8, which involves the inhibition of the hydrolysis of Ir, B-a and thereby blockage of the nuclear transloca- tion of NF-kB p65.

Endoscopic ultrasonography diagnosis of gastric glomus tumors

BACKGROUND A gastric glomus tumor is relatively rare,and there is little knowledge on its endoscopic ultrasound findings.AIM To assess the accuracy of endoscopic ultrasonography(EUS)in the diagnosis of gastric glomus tumor and to discuss its value by reviewing the literature.METHODS A retrospective analysis of the EUS characteristics of gastric glomus tumor(such as tumor location,shape,size,echogenicity,homogeneity,margins,layer of origin,and so on)was performed.The study included 12 cases of gastric glomus tumor confirmed by surgery and pathology(7 females and 5 males,age range 36-74 years,average age was 58.2 years).RESULTS All the lesions were located in the gastric antrum(12 cases),protruding into the cavity,with a diameter between 1 and 3.5 cm.Glomus tumor of the stomach manifested as a circumscribed and slightly hypoechoic mass in the fourth layer,with an internal heterogeneous echo mixed with hyperechogenic spots and a marginal more hypoechoic halo.Smooth muscle actin,h-caldesmon and vimentin were shown to be positive by immunohistochemistry.CONCLUSION Although glomus tumor of the stomach is relatively rare,a typical glomus tumor of the stomach has characteristic changes under EUS.

The involvement of proline-rich protein Mus musculus predicted gene 4736 in ocular surface functions

AIM: To research the two homologous predicted proline -rich protein genes, Mus musculus predicted gene 4736 (MP4) and proline-rich protein BstNI subfamily 1 (Prb1) which were significantly upregulated in cultured corneal organs when encountering fungal pathogen preparations. This study was to confirm the expression and potential functions of these two genes in ocular surface. METHODS: A Pseudomonas aeruginosa keratitis model was established in Balb/c mice. One day post infection, mRNA level of MP4 was measured using real-time polymerase chain reaction (PCR), and MP4 protein detected by immunohistochemistry (IHC) or Western blot using a customized polyclonal anti -MP4 antibody preparation. Lacrimal glands from normal mice were also subjected to IHC staining for MP4. An online bioinformatics program, BioGPS, was utilized to screen public data to determine other potential locations of MP4. RESULTS: One day after keratitis induction, MP4 was upregulated in the corneas at both mRNA level as measured using real -time PCR and protein levels as measured using Western blot and IHC. BioGPS analysis of public data suggested that the MP4 gene was most abundantly expressed in the lacrimal glands, and IHC revealed that normal murine lacrimal glands were positive for MP4 staining. CONCLUSION: MP4 and Prb1 are closely related with the physiology and pathological processes of the ocular surface. Considering the significance of ocular surface abnormalities like dry eye, we propose that MP4 and Prb1 contribute to homeostasis of ocular surface, and deserve more extensive functional and disease correlation studies.

Recent Researches in Repair of Unilateral Cleft Lip Nasal Deformity

The cleft lip nasal deformity accounts for 84% of nasal deformities, which is one of the most common diseases in plastic surgery. The Unilateral cleft lip nasal deformity ,which has a high incidence,had many treatments but not very effective.In this article, we will focus on the repair of unilateral cleft lip nasal deformity, embryology and etiology, anatomy and pathology, classification, preoperative evaluation and repair timing strategies, surgical goals and surgical techniques, postoperative care and effect evaluation . I hope to bring some useful information for clinicians to further guide clinical work.

Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis

HMGA2,a pivotal transcription factor,functions as a versatile regulator implicated in the progression of diverse aggressive malignancies.In this study,mass spectrometry was employed to identify ubiquitin-specific proteases that potentially interact with HMGA2,and USP48 was identified as a deubiquitinating enzyme of HMGA2.The enforced expression of USP48 significantly increased HMGA2 protein levels by inhibiting its degradation,while the deprivation of USP48 promoted HMGA2 degradation,thereby suppressing tumor invasion and metastasis.We discovered that USP48 undergoes SUMOylation at lysine 258,which enhances its binding affinity to HMGA2.Through subsequent phenotypic screening of small molecules,we identified DUB-IN-2 as a remarkably potent pharmacological inhibitor of USP48.Interestingly,the small-molecule inhibitor targeting USP48 induces destabilization of HMGA2.Clinically,upregulation of USP48 or HMGA2 in cancerous tissues is indicative of poor prognosis for patients with colorectal cancer(CRC).Collectively,our study not only elucidates the regulatory mechanism of DUBs involved in HMGA2 stability and validates USP48 as a potential therapeutic target for CRC,but also identifies DUB-IN-2 as a potent inhibitor of USP48 and a promising candidate for CRC treatment.

The m^(6)A reader YTHDC2 maintains visual function and retinal photoreceptor survival through modulating translation of PPEF2 and PDE6B

Inherited retinal dystrophies (IRDs) are major causes of visual impairment and irreversible blindness worldwide, while the precise molecular and genetic mechanisms are still elusive. N6-methyladenosine (m^(6)A) modification is the most prevalent internal modification in eukaryotic mRNA. YTH domain containing 2 (YTHDC2), an m^(6)A reader protein, has recently been identified as a key player in germline development and human cancer. However, its contribution to retinal function remains unknown. Here, we explore the role of YTHDC2 in the visual function of retinal rod photoreceptors by generating rod-specific Ythdc2 knockout mice. Results show that Ythdc2 deficiency in rods causes diminished scotopic ERG responses and progressive retinal degeneration. Multi-omics analysis further identifies Ppef2 and Pde6b as the potential targets of YTHDC2 in the retina. Specifically, via its YTH domain, YTHDC2 recognizes and binds m^(6)A-modified Ppef2 mRNA at the coding sequence and Pde6b mRNA at the 5′-UTR, resulting in enhanced translation efficiency without affecting mRNA levels. Compromised translation efficiency of Ppef2 and Pde6b after YTHDC2 depletion ultimately leads to decreased protein levels in the retina, impaired retinal function, and progressive rod death. Collectively, our finding highlights the importance of YTHDC2 in visual function and photoreceptor survival, which provides an unreported elucidation of IRD pathogenesis via epitranscriptomics.

Epinephrine promotes tumor progression and M2 polarization of tumor-associated macrophages by regulating the TRIM2-NF-kB pathway in colorectal cancer cells

Tumor-associated inflammation is an important component of the tumor microenvironment,and an important factor affecting tumor progression.In the tumor microenvironment,tumor-associated macrophages(TAMs)receive different stimuli and can be polarized into classically activated M1 macrophages and alternatively activated M2 macrophages.Many studies have indicated that the polarization of TAMs is closely related to tumor progression.

Type Ⅰ and type Ⅱ Helicobacter pylori infection status and their impact on gastrin and pepsinogen level in a gastric cancer prevalent area

BACKGROUND Type I Helicobacter pylori(H.pylori)infection causes severe gastric inflammation and is a predisposing factor for gastric carcinogenesis.However,its infection status in stepwise gastric disease progression in this gastric cancer prevalent area has not been evaluated;it is also not known its impact on commonly used epidemiological gastric cancer risk markers such as gastrin-17(G-17)and pepsinogens(PGs)during clinical practice.AIM To explore the prevalence of type I and type II H.pylori infection status and their impact on G-17 and PG levels in clinical practice.METHODS Thirty-five hundred and seventy-two hospital admitted patients with upper gastrointestinal symptoms were examined,and 523 patients were enrolled in this study.H.pylori infection was confirmed by both 13C-urea breath test and serological assay.Patients were divided into non-atrophic gastritis(NAG),nonatrophic gastritis with erosion(NAGE),chronic atrophic gastritis(CAG),peptic ulcers(PU)and gastric cancer(GC)groups.Their serological G-17,PG I and PG II values and PG I/PG II ratio were also measured.RESULTS A total H.pylori infection rate of 3572 examined patients was 75.9%,the infection rate of 523 enrolled patients was 76.9%,among which type I H.pylori infection accounted for 72.4%(291/402)and type II was 27.6%;88.4%of GC patients were H.pylori positive,and 84.2%of them were type I infection,only 11.6%of GC patients were H.pylori negative.Infection rates of type I H.pylori in NAG,NAGE,CAG,PU and GC groups were 67.9%,62.7%,79.7%,77.6%and 84.2%,respectively.H.pylori infection resulted in significantly higher G-17 and PG II values and decreased PG I/PG II ratio.Both types of H.pylori induced higher G-17 level,but type I strain infection resulted in an increased PG II level and decreased PG I/PG II ratio in NAG,NAGE and CAG groups over uninfected controls.Overall PG I levels showed no difference among all disease groups and in the presence or absence of H.pylori;in stratified analysis,its level was increased in GC and PU patients in H.pylori and type I H.pylori-positive groups.CONCLUSION Type I H.pylori infection is the major form of infection in this geographic region,and a very low percentage(11.6%)of GC patients are not infected by H.pylori.Both types of H.pylori induce an increase in G-17 level,while type I H.pylori is the major strain that affects PG I and PG IIs level and PG I/PG II ratio in stepwise chronic gastric disease.The data provide insights into H.pylori infection status and indicate the necessity and urgency for bacteria eradication and disease prevention in clinical practice.

S14G-humanin restored cellular homeostasis disturbed by amyloid-beta protein

Humanin is a potential therapeutic agent for Alzheimer’s disease, and its derivative, S14G-humanin, is 1 000-fold stronger in its neuroprotective effect against Alzheimer’s disease-relevant insults. Alt-hough effective, the detailed molecular mechanism through which S14G-humanin exerts its effects remains unclear. Data from this study showed that fibril ar amyloid-beta 40 disturbed cel ular ho-meostasis through the cel membrane, increasing intracel ular calcium, generating reactive oxygen species, and decreasing the mitochondrial membrane potential. S14G-humanin restored these re-sponses. The results suggested that S14G-humanin blocked the effects of amyloid-beta 40 on the neuronal cel membrane, and restored the disturbed cel ular homeostasis, thereby exerting a neuroprotective effect on hippocampal neurons.

Regorafenib combined with programmed cell death-1 inhibitor against refractory colorectal cancer and the platelet-to-lymphocyte ratio’s prediction on effectiveness

BACKGROUND The effectiveness of regorafenib plus programmed cell death-1(PD-1)inhibitor in treating microsatellite stable(MSS)metastatic colorectal cancer(mCRC)remains controversial.AIM To investigate the benefits of regorafenib combined with PD-1 inhibitor in treating MSS mCRC and explore indicators predicting response.METHODS This retrospective study included a total of 30 patients with microsatellite stable metastatic colorectal cancer treated with regorafenib combined with programmed cell death-1 inhibitor at Henan Provincial People’s Hospital between December 2018 and December 2020.During a 4-wk treatment cycle,regorafenib was performed for 3 continuous weeks.PD-1 inhibitor was intravenously injected starting on the first day of the oral intake of regorafenib.We reviewed tumor response,progression-free survival(PFS),overall survival,and treatment-related adverse events(TRAEs)and evaluated association between platelet-tolymphocyte ratio(PLR)and outcomes in this retrospective study.RESULTS Stable disease and progressive disease were found in 18(60.0%)and 12(40.0%)patients,respectively.The disease control rate was 60.0%.The median follow-up time was 12.0 mo,and median PFS was 3.4 mo[95%confidence interval(CI):2.2-4.6 mo].Of the 12 patients with progressive disease,10(83.3%)had liver metastasis before starting the combined treatment.Among the 18 patients with SD,10(55.6%)did not have liver metastases.One patient without liver metastases at baseline was found with a substantially prolonged PFS of 11.2 mo.The liver metastasis,the choice of programmed cell death-1 inhibitor other than nivolumab or pembrolizumab and previous exposure to regorafenib was’t associated with treatment outcome.The median PFS in the low-PLR group was 4.2 mo(95%CI:3.5-4.9 mo),compared with 2.8 mo(95%CI:1.4-4.2 mo)in the high-PLR group(P=0.005).The major TRAEs included hand-foot syndrome(33.3%),hypertension(23.3%),malaise(20.0%),and gastrointestinal reaction(16.7%).The incidence of grade 3 TRAEs was 13.3%(4/30),which comprised abnormal capillary proliferation(n=1),transaminase elevation(n=1),and hand-foot syndrome(n=2).No grade 4 or higher toxicity was observed.CONCLUSION Regorafenib combined with PD-1 inhibitor could lead to a longer PFS in some patients with MSS mCRC.The PLR might be a prediction of the patient response to this therapy.

Initial study of biexponential model of intravoxel incoherent motion magnetic resonance imaging in evaluation of the liver fibrosis

Background The diagnosis of liver fibrosis is a difficult task at any time using conventional clinical imaging.Intravoxel incoherent motion （IVIM） can be used to investigate both diffusion and perfusion changes in tissues.This study was designed to determine the value of IVIM in the diagnosis and staging of liver fibrosis.Methods IVIM examinations were performed on a GE 3.0T MR scanner in 25 patients with liver fibrosis and 25 healthy volunteers as the control group.Patients with liver fibrosis diagnosis were confirmed by pathology and staged on a scale of F0-4.The standard ADC values and the values of a biexponential model （slow ADC （Dslow）,fast ADC （Dfast） and fraction of fast ADC （FF）） were measured in three liver regions per person.The mean standard ADC values,Dslow values,Dfast values and FF values from the study group were compared among the right posterior hepatic lobe,right anterior hepatic lobe and medial segment of the left lobe.Receiver Operating Characteristic （ROC） curves and independent-samples t-tests were used to calculate the mean standard ADC values,Dslow values,Dfast values and FF values from the study group and the control group.Spearman rho correlation analysis was used for the stage of liver fibrosis.The liver fibrosis stages between the groups F0-1 and F2-4,the groups F0-2 and F3-4 were compared.Results Among the liver fibrosis,there was no significant difference in the mean standard ADC values,Dslow values,Dfast values,and FF values obtained from the right posterior hepatic lobe,right anterior hepatic lobe and medial segment of the left lobe.Using ROC analysis,the Area Under the Curve （AUC） values of standard ADC,Dslow,Dfast,FF were all between 0.7 to 0.9.The mean standard ADC values,Dslow values,Dfast values and FF values of the liver in the study group were significantly lower than the values in the control group （P ＜0.05）.As the stage of the fibrosis increased,the values decreased by Spearman rho correlation analysis.The mean values （standard ADC,Dslow,Dfast,and FF） of liver fibrosis stages between the groups F0-1 and F2-4,the groups F0-2 and F3-4 showed significant differences （P＜0.05）.Conclusions IVIM can reflect the conditions of perfusion and diffusion in liver fibrosis and thus distinguish between normal liver and liver fibrosis.The IVIM technique may serve as a valuable tool for detecting and characterizing liver fibrosis,and monitoring its progression in a noninvasive manner.

Preliminary Study of Brain Glucose Metabolism Changes in Patients with Lung Cancer of Different Histological Types

Background： Cerebral glucose metabolism changes are always observed in patients suffering from malignant tumors. This preliminary study aimed to investigate the brain glucose metabolism changes in patients with lung cancer of different histological types. Methods： One hundred and twenty patients with primary untreated lung cancer, who visited People＇s Hospital of Zhengzhou University from February 2012 to July 2013, were divided into three groups based on histological types confirmed by biopsy or surgical pathology, which included adenocarcinoma （52 cases）, squamous cell carcinoma （43 cases）, and small-cell carcinoma （25 cases）. The whole body ^18F-fiuorodeoxyglucose （^18F-FDG） positron emission tomography （PET）/computed tomography （CT） of these cases was retrospectively studied. The brain PET data of three groups were analyzed individually using statistical parametric maps （SPM） software, with 50 age-matched and gender-matched healthy controls for comparison. Results： The brain resting glucose metabolism in all three lung cancer groups showed regional cerebral metabolic reduction. The hypo-metabolic cerebral regions were mainly distributed at the left superior and middle frontal, bilateral superior and middle temporal and inferior and middle temporal gyrus. Besides, the hypo-metabolic regions were also found in the right inferior parietal lobule and hippocampus in the small-cell carcinoma group. The area of the total hypo-metabolic cerebral regions in the small-cell carcinoma group （total voxel value 3255） was larger than those in the adenocarcinoma group （total voxel value 1217） and squamous cell carcinoma group （total voxel value 1292）. Conclusions： The brain resting glucose metabolism in patients with lung cancer shows regional cerebral metabolic reduction and the brain hypo-metabolic changes are related to the histological types of lung cancer.