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We propose how to achieve chiral photon blockade by spinning a nonlinear optical resonator. We show that by driving such a device at a fixed direction, completely different quantum effects can emerge for the counter-propagating optical modes, due to the spinning-induced breaking of time-reversal symmetry, which otherwise is unattainable for the same device in the static regime. Also, we find that in comparison with the static case, robust non-classical correlations against random backscattering losses can be achieved for such a quantum chiral system. Our work, extending previous works on the spontaneous breaking of optical chiral symmetry from the classical to purely quantum regimes, can stimulate more efforts towards making and utilizing various chiral quantum effects, including applications for chiral quantum networks or noise-tolerant quantum sensors.

Objective: To investigate the relationship between IGF2BP3 gene expression and prognosis in patients with acute myeloid leukemia (AML)., Methods: High throughput transcriptome sequencing was performed on bone marrow primary leukemia cells from 27 patients with AML in our center, the relationship between IGF2BP3 expression levels and clinical characteristics were analyzed and verify the samples from patients with newly treated AML and refractory AML. The expression level of IGF2BP3 gene were analyzed in 20 healthy subjects and 26 patients with AML. The expression of IGF2BP3 in two anthracycline-resistant cell lines (HL60/ADR, K562/ADR) was detected by RT-qPCR and Western blot, and the expression difference of IGF2BP3 was compared with that in sensitive cells (HL60, K562). The relationship between the expression level of IGF2BP3 in patients with AML and prognostic were analyzed through data analysis of 746 patients with AML, and the prognostic value of IGF2BP3 in AML was analyzed by multivariate Cox regression analysis., Results: In the bone marrow primary leukemia cells of 27 AML patients in our center, the expression level of IGF2BP3 in patients with refractory AML was significantly higher than that in chemotherapy sensitive patients ( P =0.0343). The expression of IGF2BP3 in leukemia patients with extramedullary infiltration (EMI) was significantly higher than that in AML patients without extramedullary infiltration ( P =0.0049). Compared with healthy subjects ( n =20), IGF2BP3 expression in AML patients ( n =26) was higher ( P =0.0009). The expression of IGF2BP3 mRNA in the anthracycline resistant cell lines (HL60/ADR, K562/ADR) was significantly higher than that in the sensitive cell lines (K562/ADR vs K562, P =0.0430; HL60/ADR vs HL60, P =0.7369). Western blot results showed that the expression of IGF2BP3 protein in mycin resistant cells was significantly higher than that in sensitive cells ( P < 0.001). qPCR results showed that the expression level of IGF2BP3 mRNA in refractory AML patients was significantly higher than that in patients with chemotherapy sensitive ( P =0.002). High expression of IGF2BP3 was associated with poor prognosis in AML ( P < 0.05) in 3 large sample cohorts of AML patients. Univariate and multivariate prognostic analyses demonstrated that high expression of IGF2BP3 was significantly associated with shorter event-free survival (EFS, HR =1.887, P =0.024) and overall survival (OS, HR =1.619, P =0.016)., Conclusion: The high expression of IGF2BP3 gene may be an important factor in the poor prognosis of AML, suggesting that IGF2BP3 gene may be a new molecular marker for the clinical prognosis evaluation and treatment strategy of AML.

Objective: To investigate the efficacy and safety of Venetoclax combined with CACAG regimen in treatment of patients with refractory/relapse acute myeloid leukemia(R/R AML)., Methods: The study was a singlecenter prospective clinical trial. The enrolled patients met the criteria for R/R AML. Treatment included Azacidine(75 mg/m 2 ，d 1-7), Ara-C (75-100 mg/m 2 , q12h, d 1-5), Aclacinomycin(20 mg d1,d3,d5), Chidamide(30 mg d1,d4), Venetoclax(100 mg d1, 200 mg d2, 400 mg d3-d14, in combination with Triazole Drug, reduced to 100 mg/d), and granulocyte colony-stimulating factor (300 μg /d until neutrophil recovery). The primary endpoint of observation was overall response rate after 1 course of treatment., Results: A total of 19 patients were enrolled from January 2022 to April 2023. After 1 course of treatmen, the overall response rate was 81.3%(13/16), the CR rate was 68.8%(11/16), and the PR was 12.5%(2/16). Among the 11 patients who got CR/CRi, 8 cases achieved CRm (minimal residual disease negative CR) and 3 cases did not. As of March 27, 2023, the median follow-up time was 111(19-406) days. The six-month overall survival and progression-free survival rates were both 55.7%, the 1-year overall survival and progression-free survival rates were 46.4% and 47.7%, respectively. In addition, compared with the non-CRm group, CRm patients had a better PFS (377 days vs 111 days, P =0.046). Treatment-related adverse events were mainly 3-4 degrees of bone marrow suppression, complicated by various degrees of infection( n =12), hypokalemia( n =12) and hypocalcemia ( n =10) and elevated liver enzymes ( n =8), of which 3/4 degrees accounted for 47.4%(9/19)., Conclusion: The Venetoclax combined with CACAG regimen is an effective salvage therapy for patients with R/R AML, with high remission rate and safety profile.

Cavity optomechanical (COM) entanglement, playing an essential role in building quantum networks and enhancing quantum sensors, is usually weak and easily destroyed by noises. As feasible and effective ways to overcome this obstacle, optical or mechanical parametric modulations have been used to improve the quality of quantum squeezing or entanglement in various COM systems. However, the possibility of combining these powerful means to enhance COM entanglement has yet to be explored. Here, we fill this gap by studying a COM system containing an intra-cavity optical parametric amplifier (OPA), driven optically and mechanically. By tuning the relative strength and the frequency mismatch of optical and mechanical driving fields, we find that constructive interference can emerge and significantly improve the strength of COM entanglement and its robustness to thermal noises. This work sheds what we believe to be a new light on preparing and protecting quantum states with multi-field driven COM systems for diverse applications.

Emerging zoonoses of wildlife origin caused by previously unknown agents are one of the most important challenges for human health. The Qinghai-Tibet Plateau represents a unique ecological niche with diverse wildlife that harbours several human pathogens and numerous previously uncharacterized pathogens. In this study, we identified and characterized a novel arenavirus (namely, plateau pika virus, PPV) from plateau pikas ( Ochotona curzoniae ) on the Qinghai-Tibet Plateau by virome analysis. Isolated PPV strains could replicate in several mammalian cells. We further investigated PPV pathogenesis using animal models. PPV administered via an intraventricular route caused trembling and sudden death in IFNαβR -/- mice, and pathological inflammatory lesions in brain tissue were observed. According to a retrospective serological survey in the geographical region where PPV was isolated, PPV-specific IgG antibodies were detected in 8 (2.4%) of 335 outpatients with available sera. Phylogenetic analyses revealed that this virus was clearly separated from previously reported New and Old World mammarenaviruses. Under the co-speciation framework, the estimated divergence time of PPV was 77-88 million years ago (MYA), earlier than that of OW and NW mammarenaviruses (26-34 MYA).

Objectives: Our previous clinical trial showed that etomidate requirements to reach an appropriate level of anesthesia in patients with obstructive jaundice were reduced, which means that these patients are more sensitive to etomidate. However, the mechanism is still not completely clear. The present study was aimed to investigate the mechanism by which bilirubin facilitates etomidate induced sedation., Methods: A bile duct ligation (BDL) rat model was used to simulate obstructive jaundice. Anesthesia sensitivity to etomidate was determined by the time to loss of righting reflex (LORR). Intrathecal injection of bilirubin was used to test the effects of bilirubin on etomidate induced sedation. The modulating effects of bilirubin on GABA responses were studied using the whole-cell patch clamp technique., Results: The time to LORR induced by etomidate was significantly decreased in the BDL groups (p < 0.05), and unconjugated bilirubin in serum and cerebrospinal fluid (CSF) were markedly increased (p < 0.05). The time to LORR induced by etomidate was decreased after intrathecal injection of bilirubin (p < 0.05). A bilirubin concentration of 1.0 μM increased the GABA-induced currents of rat cortical pyramidal neurons (p < 0.05). Furthermore, 1.0 μM bilirubin enhanced GABA-induced currents modulated by etomidate (p < 0.05)., Conclusions: Our results demonstrated that pathologic bilirubin in CSF could enhance etomidate induced sedation. The mechanism may be that bilirubin increase the GABA-induced currents of rat pyramidal neurons., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background and Aim: With the increasing burden of colorectal cancer (CRC), the practice of colonoscopy is gaining attention worldwide. However, it exhibits distinct trends between developing and developed countries. This study aims to explore its development and identify influencing factors in China., Methods: The Chinese Digestive Endoscopy Censuses were conducted twice in mainland China under the supervision of health authorities. Information regarding the practice of colonoscopy was collected through a structured online questionnaire. The authenticity of the data was evaluated through logical tests, and a random selection of endoscopic reports underwent manual validation by Quality Control Centers. Potential factors associated with colonoscopy were analyzed using real-world information., Results: From 2012 to 2019, the number of hospitals that performed colonoscopy increased from 3,210 to 6,325 (1.97-fold), and the volume increased from 5.83 to 12.92 million (2.21-fold). The utilization rate rose from 436.0 to 914.8 per 100,000 inhabitants (2.10-fold). However, there was an exacerbation of regional inequality in the adequacy of colonoscopy. Regions with higher incidence of CRC, higher gross domestic product per capita, more average numbers of endoscopists and tertiary hospitals tended to provide more accessible colonoscopy (P<0.001). Nationwide, the cecal intubation rate improved from 83.9% to 94.4% and the unadjusted adenoma detection rate (ADR) improved from 16.3% to 18.1%. Overall, hospital grading, educational background of endoscopists, economic income, and colonoscopy volume were observed as the significantly positive factors affecting ADR (P<0.05), but not the incidence of CRC or the number of endoscopists., Conclusions: Tremendous progress in colonoscopy has been made in China, but some issues needed timely reflection. Our findings provide timely evidence for better colonoscopy strategies and measures, such as quality control and medical education of endoscopists., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jiao, Cheng, Gao, Yu, Jiang, Wang, Deng, Lin, Wang, Wang, Wan, Li, Xin and Wang.)

Background: Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy. Patient prognosis cannot be accurately assessed in National Comprehensive Cancer Network (NCCN) risk stratification subgroups based on the current criteria. This study aimed to develop a novel prognostic score model for the quantitative prediction of prognosis in AML., Results: We developed a prognostic risk scoring model of AML using differentially expressed genes to predict prognosis in patients with AML. Furthermore, we evaluated the effectiveness and clinical significance of this prognostic model in 4 AML cohorts and 905 patients with AML. A prognostic risk scoring model of AML containing eight prognosis-related genes was constructed using a multivariate Cox regression model. The model had a higher predictive value for the prognosis of AML in the training and validation sets. In addition, patients with lower scores had significantly better overall survival (OS) and even-free survival (EFS) than those with higher scores among patients with intermediate-risk AML according to the NCCN guidelines, indicating that the model could be used to further predict the prognosis of the intermediate-risk AML populations. Similarly, patients with high scores had remarkably poor OS and EFS in the normal-karyotype populations, indicating that the scoring model had an excellent predictive performance for patients with AML having normal karyotype., Conclusions: Our study provided an individualized prognostic risk score model that could predict the prognosis of patients with AML., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yu, Wang, Yang, Fang, Wen, Jiao, Qian, Le, Shan, Gao, Hua and Li.)

Aims: Chronification of postoperative pain is a common clinical phenomenon following surgical operation, and it perplexes a great number of patients. Estrogen and its membrane receptor (G protein-coupled estrogen receptor, GPER) play a crucial role in pain regulation. Here, we explored the role of GPER in the rostral ventromedial medulla (RVM) during chronic postoperative pain and search for the possible mechanism., Methods and Results: Postoperative pain was induced in mice or rats via a plantar incision surgery. Behavioral tests were conducted to detect both thermal and mechanical pain, showing a small part (16.2%) of mice developed into pain persisting state with consistent low pain threshold on 14 days after incision surgery compared with the pain recovery mice. Immunofluorescent staining assay revealed that the GPER-positive neurons in the RVM were significantly activated in pain persisting rats. In addition, RT-PCR and immunoblot analyses showed that the levels of GPER and phosphorylated μ-type opioid receptor (p-MOR) in the RVM of pain persisting mice were apparently increased on 14 days after incision surgery. Furthermore, chemogenetic activation of GPER-positive neurons in the RVM of Gper-Cre mice could reverse the pain threshold of pain recovery mice. Conversely, chemogenetic inhibition of GPER-positive neurons in the RVM could prevent mice from being in the pain persistent state., Conclusion: Our findings demonstrated that the GPER in the RVM was responsible for the chronification of postoperative pain and the downstream pathway might be involved in MOR phosphorylation., (© 2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Transient receptor potential canonical (TRPC) channels, as important membrane proteins regulating intracellular calcium (Ca 2+ i ) signaling, are involved in a variety of physiological and pathological processes. Activation and regulation of TRPC are more dependent on membrane or intracellular signals. However, how extracellular signals regulate TRPC6 function remains to be further investigated. Here, we suggest that two distinct small molecules, M085 and GSK1702934A, directly activate TRPC6, both through a mechanism of stimulation of extracellular sites formed by the pore helix (PH) and transmembrane (TM) helix S6. In silico docking scanning of TRPC6 identified three extracellular sites that can bind small molecules, of which only mutations on residues of PH and S6 helix significantly reduced the apparent affinity of M085 and GSK1702934A and attenuated the maximal response of TRPC6 to these two chemicals by altering channel gating of TRPC6. Combing metadynamics, molecular dynamics simulations, and mutagenesis, we revealed that W679, E671, E672, and K675 in the PH and N701 and Y704 in the S6 helix constitute an orthosteric site for the recognition of these two agonists. The importance of this site was further confirmed by covalent modification of amino acid residing at the interface of the PH and S6 helix. Given that three structurally distinct agonists M085, GSK1702934A, and AM-0883, act at this site, as well as the occupancy of lipid molecules at this position found in other TRP subfamilies, it is suggested that the cavity formed by the PH and S6 has an important role in the regulation of TRP channel function by extracellular signals., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Remifentanil is a potent, short-acting opioid analgesic drug that can protect tissues from ischemia and reperfusion injury though anti-inflammatory effects. However, the utility of remifentanil in liver regeneration after hepatectomy is not known. Using a 70% hepatectomy mouse model (PHx), we found that preconditioning animals with 4 μg/kg remifentanil enhanced liver regeneration through supporting hepatocyte proliferation but not through anti-inflammatory effects. These effects were also phenocopied in vitro where 40 mM remifentanil promoted the proliferation of primary mouse hepatocyte cultures. We further identified that remifentanil treatment increased the expression of β-arrestin 2 in vivo and in vitro. Demonstrating specificity, remifentanil preconditioning failed to promote liver regeneration in liver-specific β-arrestin 2 knockout (CKO) mice subjected to PHx. While remifentanil increased the expression of activated (phosphorylated)-ERK and cyclin D1 in PHx livers, their levels were not significantly changed in remifentanil-treated CKO mice nor in WT mice pretreated with the ERK inhibitor U0126. Our findings suggest that remifentanil promotes liver regeneration via upregulation of a β-arrestin 2/ERK/cyclin D1 axis, with implications for improving regeneration process after hepatectomy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Nausea and vomiting are among the most common and distressing side effects of chemotherapy. Difference in views about the effectiveness of auricular acupuncture (AA) versus electroacupuncture (EA) of chemotherapy-induced nausea and vomiting (CINV) lies at the heart of the debate. The aim of this study is to compare the antiemetic efficacy and safety of AA and EA for CINV., Methods: One hundred twenty participants, 18 to 75 years old malignant tumors will receiving chemotherapy with cisplatin, will be recruited and randomized into 3 groups equally, Group A (the AA group), Group B (the EA group), and Group C (the control group). The participants in Group A and Group B will receive AA or EA regimens, alternatively, beginning on the day before first day of chemotherapy for a third consecutive cycles. All participants will continue to receive conventional treatment. The incidence and severity of CINV will be assessed using the definition and classification of nausea and vomiting (NCI-CTC AE4.0) and the MASCC (Multinational Association for Supportive Care in Cancer) Antiemesis Tool (MAT). Secondary outcome measures include the degree of abdominal distension, the first time of flatus and defecation, and life quality. Additionally, adverse events will also be documented during the period of the treatment., Discussion: This trial may provide evidence regarding the clinical effectiveness and safety of AA versus EA for CINV following cisplatin-based regimens., Trail Registration: This study is registered with the Chinese Clinical Trial Registry: ChiCTR2000040942., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

We propose how to achieve nonreciprocal quantum entanglement of light and motion and reveal its counterintuitive robustness against random losses. We find that by splitting the counterpropagating lights of a spinning resonator via the Sagnac effect, photons and phonons can be entangled strongly in a chosen direction but fully uncorrelated in the other. This makes it possible both to realize quantum nonreciprocity even in the absence of any classical nonreciprocity and also to achieve significant entanglement revival against backscattering losses in practical devices. Our work provides a way to protect and engineer quantum resources by utilizing diverse nonreciprocal devices, for building noise-tolerant quantum processors, realizing chiral networks, and backaction-immune quantum sensors.

Endothelial progenitor cell (EPC)-induced angiogenesis activity is enhanced in hepatocellular carcinoma (HCC); however, the contributing factors remain unknown. The present study aimed to investigate the factors influencing the number of EPCs and circulating progenitor cells (CPCs), as well as the expression levels of vascular endothelial growth factor receptor 2 (VEGFR-2) and CD34, in patients with HCC. The expression levels of VEGFR-2 and CD34 were assessed in 72 HCC tumor and matched adjacent tissue microarrays by immunohistochemistry. The associations between VEGFR-2 or CD34 expression in tumors, clinicopathological characteristics and overall survival rates were analyzed. The number of EPCs and CPCs were analyzed in the peripheral blood of patients with HCC. In this study, high expression levels of VEGFR-2 and CD34 were detected in the tumor tissues of 41 (56.9%) and 44 (61.1%) patients, respectively. VEGFR-2 expression was significantly associated with tumor size (P<0.001), bile acid level (P=0.014) and α-fetoprotein level (P=0.011). However, CD34 expression was associated with tumor size (P=0.009), recrudescence (P<0.001) and bile acid (P=0.009). Next, the expression levels of VEGFR-2 and CD34 in tumor and adjacent tissues were compared according to the bile acid level. VEGFR-2 and CD34 expression levels were both higher in the high bile acid group, whereas expression levels of the markers were higher in adjacent tissues compared with tumor tissues. Kaplan-Meier curve analysis identified that patients with low CD34 expression had a longer overall survival compared with patients with high CD34 expression (P=0.029). Multivariate analysis also indicated that both VEGFR-2 (P=0.020) and CD34 (P=0.035) were independent prognostic risk factors. Moreover, flow cytometry demonstrated that the number of EPCs and CPCs was negatively related with the bile acid levels in patients with HCC. In conclusion, in patients with HCC, bile acid promotes EPC-induced angiogenesis. Furthermore, EPCs and CPCs may be activated by bile acid in tumors but are more so in adjacent tissues., (Copyright: © Chen et al.)

In both normal turnover of the hepatic tissue and acute hepatic injury, the liver predominantly activates terminally differentiated hepatocytes to proliferate and repair. However, in chronic and severe chronic injury, this capacity fails, and liver progenitor cells (LPCs) can give rise to hepatocytes to restore both hepatic architecture and liver metabolic function. Although the promotion of LPC-to-hepatocyte differentiation to acquire a considerable number of functional hepatocytes could serve as a potentially new therapeutic option for patients with end-stage liver disease, its development first requires the identification of the molecular mechanisms driving this process. Here, we found that the epithelial cell adhesion molecule (EpCAM), a progenitor cell marker, regulates the differentiation of LPCs into hepatocytes through Notch1 signaling pathway. Western blotting (WB) revealed a consistent expression pattern of EpCAM and Notch1 during LPC-to-hepatocyte differentiation in vitro. Additionally, overexpression of EpCAM blocked LPC-to-hepatocyte differentiation, which was in consistent with the repressive role of Notch signaling during hepatic differentiation. WB and immunofluorescence data also showed that the upregulation of EpCAM expression increased the generation of Notch intracellular domain (N 1 ICD), indicating the promotion of Notch1 activity. Our results established the EpCAM-Notch1 signaling axis as an inhibitory mechanism preventing LPC-to-hepatocyte differentiation in vitro., Competing Interests: Declaration of competing interest The authors declared no conflicts of interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: This study aimed to examine the performance of the four risk of malignancy index (RMI) in discriminating borderline ovarian tumors (BOTs) and benign ovarian masses in daily clinical practice., Methods: A total of 162 women with BOTs and 379 women with benign ovarian tumors diagnosed at the Second Affiliated Hospital of Harbin Medical University from January 2012 to December 2016 were enrolled in this retrospective study. Also, we classified these patients into serous borderline ovarian tumor (SBOT) and mucinous borderline ovarian tumor (MBOT) subgroup. Preoperative ultrasound findings, cancer antigen 125 (CA125) and menopausal status were reviewed. The area under the curve (AUC) of receiver operator characteristic curves (ROC) and performance indices of RMI I, RMI II, RMI III and RMI IV were calculated and compared for discrimination between benign ovarian tumors and BOTs., Results: RMI I had the highest AUC (0.825, 95% CI: 0.790-0.856) among the four RMIs in BOTs group. Similar results were found in SBOT (0.839, 95% CI: 0.804-0.871) and MBOT (0.791, 95% CI: 0.749-0.829) subgroups. RMI I had the highest specificity among the BOTs group (87.6, 95% CI: 83.9-90.7%), SBOT (87.6, 95% CI: 83.9-90.7%) and MBOT group (87.6, 95% CI: 83.9-90.7%). RMI II scored the highest overall in terms of sensitivity among the BOTs group (69.75, 95% CI: 62.1-76.7%), SBOT (74.34, 95% CI: 65.3-82.1%) and MBOT (59.18, 95% CI: 44.2-73.0%) group., Conclusion: Compared to other RMIs, RMI I was the best-performed method for differentiation of BOTs from benign ovarian tumors. At the same time, RMI I also performed best in the discrimination SBOT from benign ovarian tumors.

Aims: Demyelination, one of the major pathological changes of white matter injury, is closely related to T-cell-mediated immune responses. Thus, we investigate the role of an IL-2 monoclonal antibody (IL-2mAb, JES6-1) in combatting demyelination during the late phase of stroke., Methods: IL-2mAb or IgG isotype antibody (0.25 mg/kg) was injected intraperitoneally 2 and 48 hours after middle cerebral artery occlusion (MCAO) surgery. Infarct volume, peripheral immune cell infiltration, microglia activation, and myelin loss were measured by 2,3,5-triphenyte trazoliumchloride staining, immunofluorescence staining, flow cytometry, and Western blot. Intraperitoneal CD8 neutralizing antibody (15 mg/kg) was injected 1 day before MCAO surgery to determine the role of CD8 + T cells on demyelinating lesions., Results: IL-2mAb treatment reduced brain infarct volume, attenuated demyelination, and improved long-term sensorimotor functions up to 28 days after dMCAO. Brain infiltration of CD8 + T cells and peripheral activation of CD8 + T cells were both attenuated in IL-2 mAb-treated mice. The protection of IL-2mAb on demyelination was abolished in mice depleted of CD8 + T cell 1 week after stroke., Conclusions: IL-2mAb preserved white matter integrity and improved long-term sensorimotor functions following cerebral ischemic injury. The activation and brain infiltration of CD8 + T cells are detrimental for demyelination after stroke and may be the major target of IL-2mAb posttreatment in the protection of white matter integrity after stroke., (© 2018 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Objective: To characterize clinicopathological characteristics of the non-neoplastic colorectal polyps for accurate diagnosis. Methods: 1 190 cases were collected from the Second Affiliated Hospital of Harbin Medical University from January 2012 to December 2016 and their clinicopathological characteristics were reviewed. Results: There were 746 males and 444 females patients with male/female ratio of 1.7∶1.0. The average age was 52 and 85.4% (1 016/1 190) of cases were over 40 years old. A total of 1 289 polyps were found in the study cohort including 1 238 inflammatory polyps (96.0%), 47 harmartomatous polyps (3.7%) and 4 other types of polypoid lesions (0.3%). Among 1 249 inflammatory polyps, 1 212 were inflammatory pseudopolyps (97.9%), 15 post-inflammatory polyps (1.2%), 8 inflammatory myoglandular polyps (0.6%), and 3 prolapse-type inflammatory polyps (colitis cystica profunda). Among 47 hamartomatous polyps, there were 39 juvenile polyps (83.0%), 8 Peutz-Jegher polyps (17.0%). Four polypoid lesions of endometriosis. Among 1 289 polyps, 751 polyps were located in sigmoid and rectum (58.3%). 168 polyps were pedunculated (12.9%) and 1 132 polyps were sessile (87.1%). Conclusions: For non-neoplastic colorectal polyps, the average age of patients is 40 years. The polyps generally involve the sigmoid colon and rectum. The most common pathological type is inflammatory pseudopolyp and the most common pathological type of hamartomatous polyp is juvenile subtype.

This study aimed to investigate the anti-inflammatory effects of N -methylcytisine (NMC) in a dextran sulfate sodium (DSS)-induced colitis model and explore its possible mechanisms. Experimental colitis was induced by administering the mice with 5% DSS for 7 days. Different doses of NMC (1, 4 and 16 mg/kg) and 5-aminosalicylic acid (100 mg/kg) were given orally once every day for 7 days. The protective effect of NMC was evaluated using the disease activity index, colon length and results of histopathological examination. The possible mechanisms of NMC were explored by evaluating the expression levels of tumour necrosis factor-α, interleukin-1β and interleukin-6 (IL-6) using ELISA and analysing the protein expression levels of nuclear factor (NF)-κB p65, p-NF-κB p65, p-IκB, IκB, IκB kinase (IKK) and p-IKK using western blots. Results demonstrated that the oral administration of NMC attenuated the DSS-induced clinical symptoms and pathological damage. In addition, NMC treatment significantly reduced myeloperoxidase activity and level of pro-inflammatory cytokines. Further studies revealed that NMC blocked the activation of NF-κB by inhibiting IκB and IKK phosphorylation. These findings suggested that NMC exerts anti-inflammatory effects on DSS-induced colitis, and its mechanism may be related to the suppression of NF-κB activation. Thus, NMC may have potential therapeutic value in the treatment of colitis., Competing Interests: The authors declare that they have no conflicts of interest.

Background: Traditional serrated adenoma (TSA) features a unique serrated configuration because it involves two cell types: tall and short columnar cells. The serrated neoplasia pathway is related to the carcinogenesis of colorectal cancer. CpG island methylator phenotype-high (CIMP-high) is a unique genetic alteration in this pathway., Materials and Methods: This study investigated the prevalence and level of methylation and CIMP in 30 TSA cases. The tall and short cells in 28 TSAs were separated by microdissection. Methylation-specific PCR was performed to detect the methylation of MGMT, MLH1, P14, P16, MINT1, MINT2 and MINT31., Results: Overall, 30 cases presented CIMP-high, and the prevalence of CIMP-high was 100% (30/30) in tall cells and 93% (28/30) in short cells., Conclusions: No significant difference was found between tall and short columnar cells. The relationship between methylation and clinicopathological characters remains to be established., Competing Interests: None., (IJCEP Copyright © 2017.)

Substantial evidence has shown that obstructive jaundice can induce vascular hyporesponsiveness. The present study was designed to investigate mechanisms of MaxiK channel and K ATP underlying cholestasis-induced vascular dysfunction. The isolated thoracic aorta was used to explore norepinephrine (NE)-induced contraction. The function of MaxiK and K ATP channels were investigated using whole-cell patch clamp recording. Compared with Sham group, NE-induced vascular contraction was blunted after bile duct ligation (BDL), which could not be ameliorated significantly after endothelial denudation. Charybdotoxin and glibenclamide induced a more pronounced recovery from vascular hyporesponsiveness to NE in BDL group compared with Sham group. BDL significantly promoted the charybdotoxin sensitive MaxiK current and K ATP current in isolated aortic smooth muscle cells. In addition, the expression of auxiliary subunits (MaxiK-β1 and SUR2B) rather pore-forming subunits (MaxiK-α and Kir6.1) was significantly up-regulated after BDL. These findings suggest that MaxiK and K ATP channels play an important role in regulating vascular hyporesponsiveness in BDL rats.

This study was designed to investigate the anti-inflammatory activity of the pure compound gentiopicroside (Gent) on dextran sulfate sodium (DSS)-induced colitis in a mouse model and to explore the possible related mechanisms. Experimental colitis was induced in ICR mice by dissolving 5% DSS in their drinking water for 7days. Gent (200, 100, and 50mg/kg) and 5-aminosalicylic acid (5-ASA, 100mg/kg) were oral administrated once a day for 7days. Anti-inflammatory effects were evaluated by comparing extend of colonic mucosal injury assessed by disease activity index (DAI), colon length, histopathological examination, and biochemical test. The possible mechanisms of Gent activities were explored by evaluating expression levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6 using real-time fluorogenic PCR and expression levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) using Western blotting. The results showed that oral administration of Gent significantly attenuated DSS-induced loss of body weight, diarrhea, shortening of colon length and histological changes, associated with the decrease in the activity of myeloperoxidase (MPO) in the colon. In addition, the mRNA expression of TNF-α, IL-1β, IL-6 and the overexpression of COX-2 and iNOS proteins in the colon were down-regulated by Gent treatment. To our knowledge, this is the first study to demonstrate that Gent treatment can exert anti-inflammatory effects on experimental acute colitis through attenuating the expression levels of TNF-α, IL-1β, IL-6, iNOS and COX-2, and it may present the therapeutic potential in the treatment of colitis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Nasal polyposis demonstrates histological features of epithelial remodeling and variable inflammatory cellular infiltration. We studied a large series of Chinese nasal polyp (NP) samples to characterize these histological features and their associations with clinical characteristics., Methods: A detailed histological study of nasal polyposis was performed employing various histopathological techniques. A total of 153 intraoperative NP biopsies were analyzed histologically. Sections were examined under microscopy to determine the percentages of different types of inflammatory cells, and types of epithelial remodeling. Two systems of subtyping NPs based on inflammatory cell infiltration were assessed. These were correlated with patient characteristics., Results: Epithelial remodeling patterns include epithelial hyperplasia (87.8% of specimens), goblet cell hyperplasia (53.2%), and squamous metaplasia (44.6%). Smoking was a strong independent association of squamous metaplasia (adjusted odds ratio [OR] 9.9; 95% confidence interval [CI], 4.2 to 22.9; p < 0.01). The most common inflammatory cells were neutrophils (median of 12.8%) and CD8+ T cells (12.8%), followed by macrophages (11.0%), CD4+ T cells (9.7%), eosinophils (8.6%), and mast cells (7.6%). We defined 2 systems to classify NPs based on proportions of eosinophils and neutrophils. The majority of NP samples were neutrophilic. The first classification system has greater histological correlation. Based on the first classification, eosinophilic nasal polyposis was associated with epithelial hyperplasia (OR 3.7, p = 0.019) and goblet cell hyperplasia (OR 3.4, p < 0.001)., Conclusion: The majority of Chinese NPs are neutrophilic and epithelial hyperplasia is the most common pattern of epithelial remodeling. We show for the first time that smoking has a strong association with squamous metaplasia in nasal polyposis., (© 2015 ARS-AAOA, LLC.)

Objective: To assess the diagnostic value of the T-SPOT.TB test in cases of breast turberculosis (BTB) in China., Methods: We enrolled 13 female patients with primary BTB as the BTB test group and 10 healthy volunteers as the control group. The 2 groups underwent T-SPOT.TB tests and tuberculin skin tests (TSTs) before receiving a core-needle biopsy or excision biopsy. We then collected and analyzed T-SPOT.TB and TST data., Results: The sensitivity of the T-SPOT.TB test for detection of BTB (84.6%) was significantly greater than that of TST (53.8%) (P <.05); the specificity of each test (80.0% and 60.0%, respectively) for BTB was not significantly different (P >.05)., Conclusion: The T-SPOT.TB test could be a useful adjunct to current tests for diagnosis of BTB and could be used for early diagnosis of this condition., (Copyright© by the American Society for Clinical Pathology (ASCP).)

Background: Propofol may result in hypotension and respiratory depression, while etomidate is considered to be a safe induction agent for haemodynamically unstable patients because of its low risk of hypotension. We hypothesized that etomidate anesthesia during ERCP caused more stable haemodynamic responses compared with propofol. The primary endpoint was to compare the haemodynamic effects of etomidate vs. propofol in ERCP cases. The secondary endpoint was overall survival., Methods: A total of 80 patients undergoing ERCP were randomly assigned to an etomidate or propofol group. Patients in the etomidate group received etomidate induction and maintenance during ERCP, and patients in the propofol group received propofol induction and maintenance. Cardiovascular parameters and procedure-related time were measured and recorded during ERCP., Results: The average percent change to baseline in MBP was -8.4±7.8 and -14.4±9.4 with P = 0.002, and in HR was 1.8±16.6 and 2.4±16.3 with P = 0.874 in the etomidate group and the propofol group, respectively. MBP values in the etomidate group decreased significantly less than those in the propofol group (P<0.05). The ERCP duration and recovery time in both groups was similar. There was no significant difference in the survival rates between groups ( p = 0.942)., Conclusions: Etomidate anesthesia during ERCP caused more stable haemodynamic responses compared with propofol.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease mainly characterized by B cell hyperactivity. Glucocorticoid (GC) is widely used in SLE for its potent anti-inflammatory and immunosuppressive effects. Despite its important clinical efficacy, high-dose or long-term use of GC can cause severe side effects, such as osteoporosis, osteonecrosis, cataracts, hyperglycemia, coronary heart disease and cognitive impairment. Our early clinical studies have shown that Jieduquyuzishen prescription (JP) can effectively reduce the adverse effects and improve the curative effect of GC in the treatment of SLE. The BAFF/BAFF-R signaling pathway plays an important role in the development of SLE and has been regarded as a potential target for the therapy of SLE. In this study, we attempt to investigate the effect of JP on the BAFF/BAFF-R signaling pathway to explore the mechanism of JP in reducing the toxicity and enhancing the efficacy of GC. YAC-1 cells, isolated rat peripheral blood lymphocytes, polymorphonuclear neutrophils and spleen lymphocytes were treated with drug-containing serum. The results of RT-PCR, Western blot and dual-luciferase reporter gene assays indicate that either JP or GC can inhibit the mBAFF-induced up-regulation of BAFF, BAFF-R, Bcl-2, IL-10 and NF-κB in YAC-1 cells and WEHI-231 cells. Furthermore, MTS, flow cytometry and CFSE results reveal that the proliferation and survival of lymphocytes activated by mBAFF are suppressed by JP, GC and their combination. Contrary to GC, JP can reduce the apoptosis and raise the survival of polymorphonuclear neutrophils and can't increase the apoptosis of the peripheral blood lymphocytes and spleen lymphocytes. Therefore, it is possible that JP can down-regulate the BAFF/BAFF-R signaling pathway as effectively as GC, which may result in the dosage reduction of GC, thus decreasing the toxicity and improving the efficacy of GC-based treatment of SLE.

Ionizing radiation (IR) can generate reactive oxygen species (ROS). Excessive ROS have the potential to damage cellular macromolecules including DNA, proteins, and lipids and eventually lead to cell death. In this study, we evaluated the potential of arbutin, a drug chosen from a series of traditional herbal medicine by measuring intracellular hydroxyl radical scavenging ability in X-irradiated U937 cells. Arbutin (hydroquinone-β-D-glucopyranoside), a naturally occurring glucoside of hydroquinone, has been traditionally used to treat pigmentary disorders. However, there are no reports describing the effect of arbutin on IR-induced apoptosis. We confirmed that arbutin can protect cells from apoptosis induced by X-irradiation. The combination of arbutin and X-irradiation could reduce intracellular hydroxyl radical production and prevent mitochondrial membrane potential loss. It also could down-regulate the expression of phospho-JNK, phospho-p38 in whole cell lysate and activate Bax in mitochondria. Arbutin also inhibits cytochrome C release from mitochondria to cytosol. To verify the role of JNK in X-irradiation-induced apoptosis, the cells were pretreated with a JNK inhibitor, and found that JNK inhibitor could reduce apoptosis induced by X-irradiation. Taken together, our data indicate that arbutin plays an anti-apoptotic role via decreasing intracellular hydroxyl radical production, inhibition of Bax-mitochondria pathway and activation of the JNK/p38 MAPK pathway.

Ionizing radiation (IR) leads to oxidizing events such as excessive reactive oxygen species (ROS) in the exposed cells, resulting in further oxidative damage to lipids, proteins and DNA. To screen the potential radio-protective drug, the intracellular ROS was measured in irradiated U937 cells pretreated with 80 candidate traditional herbal medicine, respectively. Isofraxidin (IF) was one possible radio-protector in these 80 drugs. This study investigated the radio-protective role of IF, a Coumarin compound, in human leukemia cell lines, for the first time. Results indicate that IF protects against IR-induced apoptosis in U937 cells in the time- and concentration- dependent manner. IF decreases IR-induced intracellular ROS generation, especially hydroxyl radicals formation, inhibits IR-induced mitochondrial membrane potential loss and reduces IR-induced high intracellular Ca(2+) levels regardless of ER stress. IF down-regulates the expression of caspase-3, phospho-JNK, phospho-p38 and activates Bax in mitochondria. IF inhibits cytochrome c release from mitochondria to cytosol. IF also moderates IR-induced Fas externalization and caspase-8 activation. IF also exhibits significant protection against IR-induced cell death in other leukemia cell lines such as Molt-4 cells and HL60 cells regardless of p53. Taken together, the data demonstrate that IF protects leukemia cells from radiation-induced apoptosis via ROS/mitochondria pathway in a p53-independent manner.

Aims: Gastric hyperplastic polyps (GHPs) are the most common polypoid lesion of the stomach, and their malignant potential has been demonstrated. In the present study, we evaluated the mucin phenotypes of GHPs and investigated the relationships among mucin phenotypes and clinical-pathological factors, proliferative activity and p53 expression in GHPs., Methods: The CD10, MUC2, MUC5AC and MUC6 expression patterns of 238 GHPs were examined by immunohistochemical staining. The GHP mucin phenotypes were divided into 4 subtypes: the gastric mucin phenotype (G-type), the intestinal mucin phenotype (I-type), the mixed or gastrointestinal mucin phenotype (GI-type) and the unclassified mucin phenotype (U-type)., Results: The G and GI types were observed in 58% and 42% of the GHPs, respectively. However, no I or U type GHPs were found in the present study. The GI type was more common in lesions with dysplasia or carcinoma than in polyps without dysplasia or carcinoma (P<0.001). P53-positivity rate and high index of Ki-67 tumors were significantly more common in the GI-type than in the G-type polyps (P<0.001)., Conclusions: The mucin phenotype may serve as a useful marker for the malignant potential of GHPs, and GI-type GHPs should be considered to be a lesion with malignant potential.

Traditional serrated adenoma (TSA) consists of glands with tall cells and short cells. Two kinds of cells alternate to give a unique serrated configuration. The aim of this study was to identify the relationship between the alterations of both Wnt and serrated pathways and the unique morphology of TSAs. The tall and short cells in 28 TSAs were separated by microdissection. Semi-nested polymerase chain reaction was performed to detect the mutations of BRAF, β-catenin, APC, and KRAS. BRAF mutations were observed in 22 of 28 (78.6%) TSAs, and all mutations occurred at the tall cells. In conclusion, BRAF mutation is associated with the serrated morphology of TSAs. Genetic alterations in both the serrated pathway and the Wnt signaling pathway may both contribute to TSAs.

We compared the expression of chemokine receptor CCR2 protein in the dorsal root ganglia (DRG) injured by the chronic constriction injury (CCI), the spinal nerve ligation (SNL) and a chronic compression of DRG (CCD). Each of these injuries produced the same significant increase in CCR2 protein in the DRG, as assessed by Western blot analyses. Whole-cell patch-clamp recordings revealed that CCL2, a ligand for CCR2 receptor, depolarized nociceptive DRG neurons from rats of the all three models. A greater percentage of these neurons was depolarized by CCL2 after CCD than after either of the other injuries. Furthermore, CCL2 significantly lowered current threshold only in CCD neurons but not in CCI or SNL neurons. CCL2 significantly lowered the net whole-cell potassium currents in neurons after CCD but not after CCI or SNL. Thus, the injury-induced effects of CCL2 in increasing the excitability of the cell bodies of DRG neurons depend on the site of the injury--with greater effects occurring after an injury of the ganglion than after an injury of the spinal or peripheral nerve., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

The biological properties and underlying genetics of gastric cancer and gastric intestinal metaplasia evolve with neoplastic progression from the genetics of the original gland cell. PCR assay with crypt isolation was used in tumors from 20 patients to examine microsatellite alterations (allelic imbalance at 17p, 5q, 18q, 3p, 4p, and 9p, and microsatellite instability) in glands from each tumor and from intestinal metaplastic lesions. Tumor specimens were processed as either pooled-gland samples or single-gland samples. Pooled gland sample was composed of 10-20 tumor glands, intestinal metaplastic glands, or nonmetaplastic glands. Single gland sample was 10 tumor glands from tumor and single gland sample was 5 gastric intestinal metaplastic and 5 nonmetaplastic glands from its surrounding metaplastic mucosa. Multiple genetic alterations were found in individual tumor glands, with various subclonal expansions seen within the same tumor. Although microsatellite instability was found in 2 of 20 tumor single-gland samples, none was detected in metaplastic single-gland samples. Most cancers appear to have a heterogeneous composition. On the other hand, microsatellite alterations were also detected within the nonmetaplastic as well as intestinal metaplastic single-gland samples. In conclusion, the present data on tumor and corresponding intestinal metaplastic and nonmetaplastic glands suggest that genetic alterations already occur within the surrounding of the noncancerous mucosa.

Objective: To report the application of reverse second dorsal metatarsal artery island flap for From May 2005 to September 2008, 5 cases with soft tissue repairing the soft tissue defect at toes., Methods: defects at toes were treated with reverse second dorsal metatarsal artery island flaps. The flaps size ranged from 2 cm x 3 cm to 5 cm x 6 cm., Results: All the 5 flaps survived completely. The patients could walk 1-2 months after operation. The patients were followed up for 5-7 months with good appearance, texture and sensation of toes., Conclusion: The reverse second dorsal metatarsal artery island flap has a reliable blood supply and good tissue texture. It is a practical method for repairing the soft tissue defect at toes.

Objective: Serrated adenoma (SA) consists of glands both with intraluminal projection of tall columnar cells, which resemble the terminally differentiated cells in the surface epithelium, and with concave short cells, which resemble progenitor crypt cells of the colon. The aim of this study was to clarify the relationship between the serrated architecture and proliferation/differentiation process in SAs., Methods: The expressions of both terminally differentiated markers, such as p21, cytokeratin 20 and carbonic anhydrase I, and progenitor/proliferative markers, such as beta-catenin, CD44 and Ki-67, were immunohistochemically examined in 43 SAs and 20 tubular adenomas., Results: P21-positive cells were more abundant in SAs than in tubular adenomas. Cytokeratin 20 and carbonic anhydrase I expressions were confined to the tall cells, while nuclear beta-catenin and CD44 were expressed in the short cells in SAs. The Ki-67 labeling indices were significantly lower in tall cells than in short ones., Conclusions: SAs might undergo both proliferation and terminal differentiation, which is associated with unique serrated configuration., ((c) 2008 S. Karger AG, Basel.)

Although aneuploidy is commonly observed in human cancers, the molecular mechanism underlying aneuploidization remains unclear. We used multiploid cancer model that had diploid and aneuploid cancer cells within the same cancerous tissue and attempted to detect specific epigenetic alterations associated with tumor cell aneuploidy. Thirty-four multiploid colorectal cancers were subjected to crypt isolation and cell sorting, and paired diploid and aneuploid cancer cells were separated from each cancerous tissue. A methylated CpG island amplification provided a considerable number of CpG sequences that showed different methylation status between the above 2 cell populations. BLAST homology search revealed 24 different candidates (11 hypermethylated and 13 hypomethylated) from these sequences. The putative promoter sequence of the SALL4 (sal-like 4, a human homolog to Drosophila spalt) gene was particularly more frequently hypermethylated in aneuploid cells (62%) than diploid ones (35%) in the 34 multiploid cancers. Moreover, such hypermethylation occurred more often in aneuploid cancers (8 of 16, 50%) than diploid cancers (3 of 18, 17%). In combination with demethylation study on cultured cells, these results implied a possible association between epigenetic silencing of SALL4 and tumor cell aneuploidy. SALL4 may be one of important key players that act as "caretakers" for chromosomal stability. Our new approach is a powerful tool for the global identification of such key players.

To clarify distinct genetic profiles of colorectal cancers based on tumor location (left- and right-sided), we evaluated the status of loss of heterozygosity (LOH), CpG islands methylation phenotype (CIMP), microsatellite instability (MSI), and mutations of p53, Ki-ras, and APC genes in 119 colorectal cancers. Statuses of LOH (at 5q, 8p, 17p, 18q, and 22q), MSI, and CIMP (MINT1, MINT2, MINT31, MLH-1, MGMT, p14, p16, and RASSF1A) were determined using microsatellite polymerase chain reaction and methylation-specific polymerase chain reaction coupled with a crypt isolation method, respectively. In addition, mutations of p53, Ki-ras, and APC genes were also examined. LOH, MSI, and CIMP status allowed us to classify samples into two groups: low or negative and high or positive. Whereas the frequency of p53 mutations in the LOH-high status was significantly higher in left-sided cancers than in right-sided cancers, CIMP-high in the LOH-high status and MSI-positive status were more frequently found in right-sided cancers compared with left-sided cancers. Finally, location-specific methylated loci were seen in colorectal cancers: type I (dominant in right-sided cancer) and type II (common in both segments of cancer). Our data confirm that distinct molecular pathways to colorectal cancer dominate in the left and right sides of the bowel.

The clinicopathological significance of loss of heterozygosity (LOH) in gastric carcinoma remains poorly understood. We and other researchers have previously demonstrated that LOH is fairly common in intestinal- and solid-type gastric carcinomas, but rare in diffuse-type tumors. In this study, we investigated the relationship between clinicopathological variables and LOH status in intestinal- and solid-type gastric carcinomas. The crypt isolation technique was utilized to analyze LOH at 1p36, 3p14, 4p15, 5q21-22, 8p11-12, 9p21, 13q22, 17p13.1 18q21 and 22q13.31 in 113 intestinal- and solid-type gastric carcinomas using a polymerase chain reaction assay. Immunostaining with D2-40 and Elastica van Gieson staining were used to detect lymphatic invasion and vessel invasion, respectively. High LOH rates (49-71%) were observed in all chromosomal regions tested. 1p36 loss was significantly associated with advanced tumors and lymph node metastasis. 8p11-12 loss was significantly associated with lymph node metastasis, lymphatic invasion, and vessel invasion. 17p13.1 (TP53) loss was significantly associated with vessel invasion. 22q13.31 loss was significantly associated with advanced tumors, lymph node metastasis, lymphatic invasion, vessel invasion and late TNM stage. No significant associations were observed between LOH at other chromosomal regions and aggressive behaviors. In addition, significantly higher LOH rates at 1p36, 9p21, 18q21 and 22q13.31 were observed in cardiac tumors compared with noncardiac tumors. These results suggest that in intestinal- and solid-type gastric carcinomas, LOH on 3p14, 4p15, 5q21-22, 9p21, 13q22 and 18q21 is associated with carcinogenesis, while LOH on 1p36, 8p11-12, 17p31.1 and 22q13.31 is associated with tumor progression.

Background: Although recent animal studies have shown that SMAD4/DPC4 gene alterations are essential for late-stage intestinal tumorigenesis, the role of SMAD4/DPC4 gene alterations in primary human colorectal carcinomas is not fully understood. Therefore, we attempted to clarify the role of the SMAD4/DPC4 gene during tumor progression of colorectal carcinoma., Methods: Differences in allelic imbalance (AI) and mutations of the SMAD4/DPC4 gene between diploid and aneuploid populations were analyzed for 30 sporadic DNA multiploid colorectal carcinomas (used as a tumor progression model and defined as the coexistence of diploid and aneuploid cells within the same tumor). The crypt isolation technique was coupled with DNA cytometric sorting and a polymerase chain reaction assay. In addition, hypermethylation of the promoter region was examined to clarify whether inactivation of gene expression occurred., Results: Although a SMAD4/DPC4 gene AI was detected in only 5 of 27 informative diploid populations, 25 of 27 aneuploid populations had a SMAD4/DPC4 gene AI. Mutation of the SMAD4/DPC4 gene was detected in only one aneuploid population of multiploid colorectal carcinomas, but not in the corresponding diploid population. In total, 20 available multiploid carcinomas were selected for methylation analysis, and no evidence of hypermethylation of the promoter region was found., Conclusions: We suggest that, although mutation of the SMAD4/DPC4 gene and hypermethylation of the promoter region are infrequent events in colorectal tumorigenesis, AI at the SMAD4/DPC4 gene locus may play a key role in the progression of colorectal carcinomas.

Genetic changes related to colorectal carcinomas are accumulated in individual tumor glands during disease progression. Microsatellite allelic analysis of individual tumor glands from 30 colorectal carcinomas using a polymerase chain reaction (PCR) assay coupled with crypt isolation was used to detect intratumoral genetic heterogeneity, the sequence of allelic imbalances (AIs) and the microsatellite instability status of single tumor glands during neoplastic progression. In addition, the CpG islands methylated phenotype (CIMP) status was examined using a methylation-specific PCR method. The specimens were divided into 2 groups: a pooled gland sample, which was composed of more than 50 tumor glands, and a single tumor gland sample. The latter consisted of 10 single tumor glands, which were obtained from the same tumor separately. Most colorectal carcinomas (27 of 30 tumors) examined were heterogeneous for at least one genetic alteration, with from 2 to 7 genotypically different subclones detected per tumor. In 12 of the 27 heterogeneous tumors, it was possible to define the order of genetic alterations during the tumor progression. By analyzing multiple single tumor glands within the same tumor, we found that various subclonal expansions were seen within the same tumors. Finally, the AI pattern of single tumor glands was not correlated with CIMP status. Most carcinomas appeared to have a heterogeneous composition. This may have resulted from the successful progression of one clone that had different AIs in many chromosomal regions. This suggests that knowledge of the different genotypes of multiple single tumor glands may help clarify the process of tumor progression., ((c) 2004 Wiley-Liss, Inc.)

Objective: Recent studies have shown a close association between DNA ploidy status (diploidy, aneuploidy and multiploidy) identified by the crypt isolation technique and specific genetic alterations in colorectal carcinomas. However, such an association has not been elucidated for gastric tumors, even though they share common genetic features with colorectal carcinomas. In the present study, we established an association between DNA ploidy status and genetic alterations in gastric cancer., Method: The DNA ploidy status of gastric tumors was classified as diploid, aneuploid or multiploid using the crypt isolation technique, which allows isolation of pure tumor crypt from tumor tissue. Crypt isolation combined with DNA cytometric sorting, polymerase chain reaction assay using 26 microsatellite markers and direct sequencing of the p53 gene were used to detect allelic imbalances [loss of heterozygosity (LOH) or allelic loss], microsatellite imbalance (MSI) and mutation of p53 in 54 gastric cancers (13 diploid, 12 aneuploid, 29 multiploid)., Result: Diploid tumors showed few genetic alterations, including allelic imbalances and p53 mutations. In contrast, aneuploid tumors and multiploid tumors (in particular, aneuploid populations of multiploid tumors) exhibited multiple genetic alterations, including allelic imbalances and p53 mutations. In addition, the frequencies of genetic alterations observed in the corresponding diploid fractions of multiploid tumors were relatively higher than in diploid tumors. MSI was commonly observed in diploid, aneuploid and multiploid carcinomas., Conclusions: The present results indicate that in gastric carcinomas, diploid tumors are generally non-LOH and MSI, whereas aneuploid and multiploid tumors are associated with LOH and MSI, suggesting that the genetic profile of these carcinomas is dependent on the tumor's ploidy status., ((c) 2005 S. Karger AG, Basel.)

Objective: To introduce a method by reversed ulnar fasciocutaneous flap incised form the ulnar side of the fifth metacarpal area for repairing the soft tissue defect of the fifth finger., Methods: From May 2001 to September 2001, ten patients with the soft tissue defects of the thenar side, dorsal side or ulnar side of the fifth finger were treated with the reversed ulnar fasciocutaneous flap incised from the fifth metacarpal area. The axial line of the flap was the line from ulnar side of the head of the fifth metacarpal bone to the pisiform level. The revolving point of the flap pedicle was 0.5-1 cm near the proximal end of the metacarpal-phalangeal joint.The area of the flap was form 5.0 cm x 3.5 cm to 1.5 cm x 1.0 cm., Results: All flaps of the ten cases were alive. 5-7 months followed-up show that, after operation, the flap present sensation in 6-12 mm, with soft texture and good appearances., Conclusions: The advantages of this operative method were as follows: the reversed ulnar fasciocutaneous flap of the fifth metacarpal area have reliable blood supply, it was easily dissected and with good texture. So far this kind of flap is a good choice in repairing the soft tissue of the fifth finger.

The crypt isolation technique was used to analyse loss of heterozygosity (LOH) and microsatellite instability (MSI) in gastric carcinomas (36 intestinal type, 17 solid type, and 23 diffuse type) using a polymerase chain reaction assay. Increased LOH frequencies and fractional allelic losses (FAL) were observed in samples prepared using the crypt isolation technique compared with those isolated by the conventional method. A significant increase in LOH was found at several chromosomal loci, and significant differences in FAL were found in patients with intestinal- and solid-type tumours. There was no difference in the frequency of MSI using either technique. In samples prepared by the crypt isolation technique, significant allelic losses (> or =50%) were observed at most loci tested in intestinal- and solid-type tumours, but not in diffuse-type tumours. Significant losses of some of these loci are novel findings for gastric cancer. FAL values were significantly higher in intestinal- and solid-type tumours than in diffuse-type tumours. MSI-high was observed in intestinal- (17%) and solid-type (12%) tumours. The results suggest that the crypt isolation technique is useful for accurate allelic loss analysis in gastric carcinoma and that LOH and MSI are more common in intestinal- and solid-type tumours than in diffuse-type tumors.

There are differing views between Western and Japanese pathologists on the use of histological criteria to classify gastrointestinal tumors. It is therefore a priority to create a new histological classification of the stomach in order to resolve the confusion. Expression patterns were examined of mucin (MUC2, CD10, MUC5AC, pyloric gland-type mucin), p53 protein, and Ki-67 in tumor cells according to the following new classification system for differentiated-type intramucosal neoplastic lesions of the stomach, based on nuclear atypia: borderline neoplasia (adenoma (including dysplasia), indefinite tumor of adenoma or low-grade cancer, and low-grade cancer) and definite carcinoma (intermediate cancer, and high-grade cancer). The resulting grades were: adenoma, 23; indefinite tumor for adenoma or low-grade cancer, 6; low-grade cancer, 28; intermediate cancer, 48; high-grade cancer, 20. While the frequency of intestinal-type borderline neoplasias was higher than that of definite carcinomas, the mixed-type of definite carcinomas occurred with higher frequency than borderline neoplasias. The p53 protein overexpression and the Ki-67-positive rate increased with an increase in the grade assigned according to the new classification. The correlated expression levels of p53 protein, Ki-67, and various mucins, support the conclusion that this classification of intramucosal neoplastic lesions is useful for obtaining a consensus diagnosis of gastric intramucosal neoplasia between pathologists and gastrointestinal clinicians.

An inevitable limitation of conventional flow cytometric analysis of gastric cancer DNA content is that the preparations of tumor cell nuclei are contaminated with stromal cell nuclei. Using the crypt isolation technique, we separated tumor tissues from stromal tissues and analyzed the DNA content in samples of pure gastric cancer cells (64 intestinal-type and 46 diffuse-type) by flow cytometry. Morphologically, crypts from well-differentiated and moderately differentiated adenocarcinomas usually showed large tube-like or sheet structures, whereas tumor tissues isolated from poorly differentiated adenocarcinomas usually exhibited small tumor cell clumps or clusters of varying sizes. Tumor ploidy was divided into diploid, aneuploid, and multiploid subgroups. Aneuploidy and multiploidy were observed in 12% (13 of 110) and 64% (71 of 110) of gastric cancers, respectively. A high frequency of DNA aneuploidy or multiploidy was associated with intestinal-type tumors, but not with any of the other clinicopathologic variables tested. In contrast, high S-phase fraction values demonstrated a close association with tumors with abnormal ploidy, advanced stage, intestinal type, and late TNM stage. Our results suggest that S-phase fraction may be a more useful indicator of aggressive behavior in gastric cancers than DNA aneuploidy. To our knowledge, the present study is the first to report flow cytometric DNA content in a large number of gastric cancer samples obtained using the crypt isolation technique.

A unique tumor measuring 8 x 8 x 5 mm and composed of adenoma, adenocarcinoma and mixed carcinoid-adenocarcinoma arising in the ascending colon is reported. The mixed carcinoid-adenocarcinoma, in which adenocarcinomatous and carcinoid components intermingled, originated in the mucosa, penetrated the muscularis mucosa and extended into the submucosa. Immunohistochemically, carcinoid cells were positive for neuroendocrine markers and adenocarcinoma cells were intracytoplasmicly positive for carcinoembryonic antigen. Ultrastructurally, membrane-bound electron dense granules varying in shape, size and electron density were detected in the cytoplasm of carcinoid cells. No mutations of p53 and k-ras genes were detected in adenomatous, adenocarcinomatous or mixed carcinoid-adenocarcinoma components. The morphological appearances of the present case strongly suggests the histogenesis of this tumor in an adenoma-adenocarcinoma-carcinoid tumor sequence.

The evolution of DNA diploid, aneuploid and multiploid (diploid and aneuploid) states that represent DNA types that are independent of genetic alterations in colorectal tumors were examined. Changes in the DNA index (DI) accompanying tumor development from adenoma to carcinoma were assessed. In colorectal adenomas and early cancers, the DNA was diploid or multiploid. A pure aneuploid state was observed in advanced carcinomas only, whereas the aneuploid DI values of adenomas were characterized by two distinct peaks. The DI values for the carcinomas were randomly distributed. However, in advanced carcinomas, aneuploid carcinomas tended to have lower DI whereas aneuploid populations within multiploid carcinomas tended to have higher DI. Early cancers were subdivided into two groups: a cancer region associated with an adenomatous region (group A tumors) and a cancer region that exhibited an absence of or a very limited adenomatous region (group B tumors). Group A tumor DI were lower than group B. It is suggested that low DI adenomas might transform into group A tumors, which consequently progress to advanced aneuploid carcinomas. In addition, group B tumors might derive predominantly from high DI adenomas or from group A tumors by high DI evolution, and might progress into advanced multiploid carcinomas. Therefore, the evolution of the DNA index might play an important role in the development of colorectal tumors.

Although the Vienna classification has been introduced to resolve discrepancies in histological diagnoses of colorectal tumors between Western and Japanese pathologists, practical applications of this classification scheme have been problematic because invasion of the lamina propria of tumor cells is often difficult to recognize. Therefore, the following refinements of the classification criteria are needed: category 3, low-grade adenoma/dysplasia; category 4, intramucosal borderline neoplasia; 4-a, high-grade adenoma/dysplasia; 4-b, well-differentiated adenocarcinoma; category 5, definite carcinoma; 5-a, intramucosal moderately-differentiated adenocarcinoma; and 5-b, submucosal carcinoma. We attempted to test whether molecular genetic alterations are related to the modified classification scheme and whether they may help to further categorize the various intramucosal neoplasia grades of colorectal tumors. Two-hundred-thirty-two colorectal tumors were examined using flow cytometric analysis of DNA content, polymerase chain reaction microsatellite assays, and single-strand conformational polymorphism assays to detect abnormalities of DNA content, chromosomal allelic loss, and Ki-ras and p53 gene mutations. Microsatellite instability (MSI) was also examined. Frequencies of genetic alterations and DNA aneuploid states increased with an increase in the grade assigned according to the modified Vienna classification. MSI was a rare event in colorectal adenomas and their frequency of MSI did not correlate with tumor grade. The combined genetic and DNA ploidy data support the conclusion that analysis of genetic alterations and DNA aneuploid states may help in appropriate categorization of colorectal tumors according to the modified Vienna scheme. In addition, MSI-positive tumors may represent a specific subtype of colorectal adenomas.

Primary malignant fibrous histiocytoma of the gastrointestinal tract is extremely rare. To date, only 10 cases of primary malignant fibrous histiocytoma arising in the small intestine have been reported in the English literature. We describe here the genetic alterations and morphologic features of a primary malignant fibrous histiocytoma arising in the jejunum. Immunohistochemically, the tumor cells expressed vimentin, CD68 and alpha-1-antitrypsin, but were negative for other markers. Ultrastructurally, they showed features of fibroblasts and histiocytes. Immunohistochemical overexpression of p53 and MDM2 was observed. Mutation analysis of the p53 gene detected a missense mutation in codon 158 of exon 5. Our results suggest that p53 gene mutations and MDM2 overexpression may play an important role in the tumorigenesis. To our knowledge, the present report is the first genetic study of this rare lesion.