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Analyzing the effects of space weather on aviation is a new and developing topic. It has been commonly accepted that the flight time of the polar flights may increase during solar proton events because the flights have to change their route to avoid the high-energy particles. However, apart from such phenomenon, researches related to the flight time during space weather events is very rare. Based on the analyses of 39 representative international air routes around westerlies, it is found that 97.44% (94.87%) of the commercial airplanes on the westbound (eastbound) air routes reveal shorter (longer) flight time during solar proton events compared to those during quiet periods, and the averaged magnitude of change in flight time is ~10 min or 0.21%-4.17% of the total flight durations. Comparative investigations reassure the certainty of such phenomenon that the directional differences in flight time are still incontrovertible regardless of over-land routes (China-Europe) or over-sea routes (China-Western America). Further analyses suggest that the solar proton events associated atmospheric heating will change the flight durations by weakening certain atmospheric circulations, such as the polar jet stream. While the polar jet stream will not be obviously altered during solar flares so that the directional differences in flight time are not found. Besides the conventional space weather effects already known, this paper is the first report that indicates a distinct new scenario of how the solar proton events affect flight time. These analyses are also important for aviation since our discoveries could help the airways optimize the air routes to save passenger time costs, reduce fuel costs and even contribute to the global warming issues., submitted to Scientific Reports

To explore the efficacy and value of personalized surgical schemes in the repair of maxillary sinus perforation and maxillary sinus fistula based on the size of the maxillary sinus perforation and maxillary sinus fistula. A total of 28 patients with maxillary sinus perforation and maxillary sinus fistula who were admitted to the Department of Oral and Maxillofacial Surgery, Stomatology Hospital of Kunming Medical University from July 2017 to May 2020 were included to conduct a prospective case clinical study. After the inflammation in the maxillary sinus was controlled, a proper surgical repair method was selected according to the size of the perforation and fistula based on the double-layer closure technique. The diameter of the perforation and fistula was measured with the assistance of cone-beam CT. After that, the platelet rich fibrin (PRF) repair was performed on the perforation and fistula with 3 mm≤diameter7 mm in size in 14 patients. The PRF repair and buccal flap repair were performed on the perforation and fistula with 7 mm ≤diameter15 mm in size in 7 patients. The adjacent buccal pad repair, palatine flap repair, and buccal flap repair were performed on the perforation and fistula with 15 mm≤ diameter25 mm in size in 4 patients. The nasolabial axial flap repair and nasolabial free flap repair were performed on the perforation and fistula with a diameter ≥25 mm in size in 3 patients. The medical follow-up was conducted in all patients in the 1st, 2nd, and 4th week after surgery, with an overall success rate reaching 96.4% (27/28) after the initial intervention. The relapse of disease occurred in one patient (4.6%) with diabetes and a smoking history in the 2nd week after surgery. Identifying a proper surgical repair method according to the size of the oral and maxillary sinus perforation and maxillary sinus fistula based on the double-layer closure technique can improve the one-time cure rate in these patients under the premise that the inflammation in the maxillary sinus can be controlled.根据患者上颌窦穿孔及上颌窦瘘孔大小，选择个性化手术方案，探索在口腔上颌窦穿孔及上颌窦瘘修复中的应用疗效和意义。纳入2017年7月至2020年5月就诊于昆明医科大学附属口腔医院口腔颌面外科的口腔上颌窦穿孔及上颌窦瘘患者28例，进行前瞻性病例临床研究。在保证上颌窦内炎症得以控制的情况下，以双层封闭技术为核心，根据穿孔及瘘孔的大小选择相应的手术修复方法。通过锥形束CT测量穿孔和瘘孔直径大小，对直径≥3 mm且7 mm的14例患者，采用富血小板纤维蛋白（platelet rich fibrin，PRF）填充修复法；对直径≥7 mm且15 mm 的7例患者，采用PRF+颊侧组织瓣修复方法；对直径≥15 mm且25 mm的4例患者，采用邻位颊脂垫组织瓣+腭侧组织瓣+颊侧组织瓣重叠修复法；对直径≥25 mm的3例患者，采用鼻唇沟轴型皮瓣或鼻唇沟任意皮瓣修复法。所有患者在术后第1、2、4周随访检查，初次干预后总成功率为96.4%（27/28）；1例（4.6%）患者术后第2周复发。在保证上颌窦内炎症得以控制的情况下，以双层封闭技术为核心，根据穿孔及瘘孔的大小程度选择相应的手术修复方法，可提高口腔与上颌窦穿孔及上颌窦瘘的一次性治愈率。.

On May 13, 2022, World Health Organization(WHO) Position Paper on Influenza Vaccine (2022 edition) was published. This position paper updates information on influenza epidemiology, high risk population, the impact of immunization on disease, influenza vaccines and effectiveness and safety, and propose WHO's position and recommendation that all countries should consider implementing seasonal influenza vaccine immunization programmes to prepare for an influenza pandemic. In addition, it proposes that the influenza surveillance platform can be integrated with the surveillance of other respiratory viruses, such as SARS-CoV-2 and Respiratory Syncytial Virus. This position paper has some implications for the prevention and control of influenza and other respiratory infectious diseases in China: (1) Optimize influenza vaccine policies to facilitate the implementation of immunization services; (2) Influenza prevention and control should from the perspective of Population Medicine focus on the individual and community to integrate with "Promotion, Prevention, Diagnosis, Control, Treatment, Rehabilitation"; (3) Incorporate prevention and control of other respiratory infectious diseases such as influenza, COVID-19, respiratory syncytial virus and adenovirus, and intelligently monitor by integrating multi-channel data to achieve the goal of co-prevention and control of multiple diseases.2022年5月13日，《世界卫生组织流感疫苗立场文件（2022年版）》（以下简称立场文件）发布。本文总结了立场文件更新的主要内容，包括流感流行病学、风险人群、免疫接种对疾病的影响、流感疫苗及其效果与安全性，世界卫生组织的立场等，推荐各国均应考虑实施流感疫苗免疫规划项目以应对流感大流行。此外，还提出流感监测平台可与新型冠状病毒、呼吸道合胞病毒等其他呼吸道病毒监测整合。分析了对我国流感等呼吸道传染病防控和疫苗接种的启示：（1）优化流感疫苗政策，以促进免疫服务的实施；（2）流感防控应从群医学角度，关注个体和群体“促防诊控治康”一体化；（3）应将流感、新冠、呼吸道合胞病毒、腺病毒等呼吸道传染病联合防控，整合利用多渠道数据，建立多渠道监测和智慧化预警技术和平台，实现多病共防共控。.

A novel electromagnetic bandgap (EBG) power plane etched with multiring complementary split ring resonators (CSRRs) is proposed for effectively suppressing simultaneous switching noise. Its equivalent circuit model is derived for predicting its bandwidth numerically. The measured insertion losses, i.e., S21-parameters of the two fabricated samples agree well with the simulated ones obtained by using the commercial software HFSS, respectively. It is shown that –40 dB suppression is achieved over an ultrawideband from 600 MHz to 13.26 GHz, when the two-ring CSRRs EBG power plane is used. While for four-ring CSRRs EBG case, the suppression level can be extended to –60 dB. Comparative studies are also performed on the signal integrity of a pair of differential transmission lines over L-bridge EBG with and without CSRRs, respectively, and similar performance is achieved.

Sinus floor elevation was needed in 11 patients having 15 implant sites with the residual bone height (RBH) was less than 10 mm in the posterior maxillary region from Feb to May 2017. The RBH ranged from 3.10 to 8.34 mm [averaged (6.18±1.60) mm]. RBH6 mm was observed in 40% implant sites (6 implant sites) and RBH≥6 mm was observed in 60% implant sites (9 implant sites). The thickness of the sinus floor membrane correspond to the implant site measured by cone beam CT (CBCT) ranged from 0.50 to 4.24 mm [averaged (1.21±0.92) mm]. Sequential drills with stops were used to perforate the cortical bone of the sinus floor firstly, then the transcrestal around detached sinus floor elevation technique (TADSFET) was carried with osteotomes. Anorganic bovine bone was used as the augmentation material.Fifteen implants were placed in 15 implant sites. CBCT pictures showed that there was a smooth and continuous tent-shaped apophysis on each lifted site and no air fluid level was observed in the sinus immediately after operation. The mean elevated height of the 15 implant sites was (7.83±1.57) mm (ranged from 5.94 to 11.01 mm). The mean follow-up time was 7.91 months (7-10 months). The survival rate was 100% during the follow up period.纳入2017年2月至5月于清华大学附属垂杨柳医院口腔科就诊的11例上颌后牙缺失患者（15个种植位点），术前锥形束CT测量剩余骨高度（residual bone height，RBH）10 mm，需行上颌窦底提升术。术前RBH为（6.18±1.60）mm [（3.10~8.34）mm]，其中6个位点RBH6 mm，9个位点RBH≥6 mm。种植位点对应上颌窦底黏膜厚度（1.21±0.92）mm [（0.50~4.24）mm]。15个种植位点均应用带止动环序列钻逐级备洞磨穿上颌窦底骨皮质后用新型骨凿行穿牙槽嵴顶四周剥离上颌窦底提升术，术中植入无机牛骨基质及种植体15枚。术后即刻拍摄锥形束CT显示所有上颌窦底提升种植位点区域均形成一外形连续界限清晰的"帐篷状"隆起，上颌窦内均未见异常液平面。上颌窦底提升高度（7.83±1.57）mm [（5.94~11.01）mm]。随访7~10个月，随访期间所有种植体均存留无松动脱落。.

This paper presents a model of double-ring type grounding pole unequal depth embedding for high-voltage direct current (HVDC) transmission system; and introduces calculation formula of DC ground potential distribution when double-ring type grounding pole is unequal buried. Furthermore the ground potential distribution and stride voltage level around the grounding pole and influence of grounding depth and soil parameters on the current field are discussed in this paper. The electric field zoning model of the ring current source is established by using the power system grounding pole analysis software CDEGS to verify the feasibility of this method. As the model is able to make the grounding current overflow density and potential distribution as uniform as possible, there is no serious local current concentration.

Visceral hypersensitivity is enhanced in irritable bowel syndrome (IBS) patients. Treatment of IBS visceral pain by moxibustion methods has a long history and rich clinical experience. In the clinic, moxibustion on the Tianshu (ST25) and Shangjuxu (ST37) acupoints can effectively treat bowel disease with visceral pain and diarrhea symptoms. To investigate the regulatory function of moxibustion on the Tianshu (ST25) and Shangjuxu (ST37) acupoints on spinal cord NR1, NR2B, and PKCεprotein and mRNA expression in irritable bowel syndrome (IBS) visceral hypersensitivity rats, we did some research. In the study, we found that moxibustion effectively relieved the IBS visceral hyperalgesia status of rats. Analgesic effect of moxibustion was similar to intrathecal injection of Ro 25-6981. The expression of NR1, NR2B, and PKCεin the spinal dorsal horns of IBS visceral hyperalgesia rats increased. Moxibustion on the Tianshu and Shangjuxu acupoints might inhibit the visceral hypersensitivity, simultaneously decreasing the expression of NR1, NR2B, and PKCεin spinal cord of IBS visceral hyperalgesia rats. Based on the above experimental results, we hypothesized NR1, NR2B, and PKCεof spinal cord could play an important role in moxibustion inhibiting the process of central sensitization and visceral hyperalgesia state.

SUMMARY The aim of this study was to explore the association of C20orf54 functional single nucleotide polymorphism (SNP) with the susceptibility to esophageal squamous cell carcinoma (ESCC) in a northern China population. The C20orf54 SNP was genotyped by direct sequencing in 240 cancer patients and 198 controls in northern China. The results showed that drinking status, family history of ESCC, and body mass index have great influence on the risk of developing ESCC. The overall genotype frequencies of C20orf54 in ESCC patients have a significant difference with healthy controls (χ2 = 8.06, P = 0.018). By using C/C genotype as the reference, the C/T genotype showed a significantly decreased risk to the development of ESCC. Thus, compared with the C/C genotype, smokers, drinkers with C/T genotype significantly decreased the risk of developing ESCC. A positive family history of ESCC with C/T and T/T genotype both increased the risk of developing ESCC. Body mass index between 18.5 and 24 with C/T genotype significantly decreased the risk of developing ESCC. The present study suggests that the C20orf54 functional SNP might be associated with a risk of development in ESCC.

The information integration of geometric design, finite/boundary element analysis (FEA/BEA), and numerical control (NC) machining is an important issue in e-Manufacturing and product development in geographically distributed sites. In this paper, a unified information-integrated framework based on XML (the eXtensible Markup Language) was created to support e-Manufacturing and integrate geometric design, FEA/BEA, and NC machining via the Internet. The structures of DTDs (Document Type Definitions) and XML files of geometric design, FEA/BEA, and NC machining were developed. Key technologies of supporting the XML-based integration and information communication, such as SAX (the Simple API (Application Programming Interface) for XML), DOM (the Document Object Model), SOAP (Simple Object Access Protocol), etc., are discussed. XML-based information integration via the Internet will shorten the development cycle, save costs in product development, and, finally, improve the competitive capability of e-Manufacturing in the global competition of product development.

To evaluate the diagnostic values of using autoantibodies in sera to a panel of eight tumor-associated antigens (TAAs) of P53, Koc, P62, C-myc, IMP1, Survivn, P16 and Cyclin B1 full-length recombinant proteins for early detection of patients with gastric cardia adenocarcinoma (GCA) and high-risk subjects screening. Enzyme-linked immunosorbent assay was used to detect autoantibodies against the eight selected TAAs in 383 sera samples from four groups, including 140 subjects with normal gastric cardia epithelia (NOR), 76 patients with chronic atrophic gastritis (CAG), 79 patients with gastric cardia dysplasia (DYS) and 88 patients with GCA. In addition, the expression of the eight antigens was analyzed in gastric cardia tissues by immunohistochemical method. The individual autoantibodies to six TAAs (P53, P62, IMP1, Survivn P16 and Cyclin B1) were significantly higher in sera from patients with GCA than that in normal subjects (P0.05). When autoantibody assay successively accumulated to seven TAAs (P53, Koc, P62, C-myc, IMP1, Survivn and P16), a stepwise increased detection frequency of autoantibodies was found in the four sera groups (13% in NOR, 39% in CAG, 46% in DYS, and 64% in GCA, respectively), the risks to CAG, DYS and GCA steadily increased about 4.4-, 5.7- and 12.0-fold. The sensitivity and the specificity for autoantibodies against the seven TAAs in diagnosing GCA reached up to 64% and 87%, respectively. The area under the receiver operating characteristic curve for the seven anti-TAA autoantibodies was 0.73 (95%CI: 0.68-0.78) No more increase in sensitivity was found with the addition of new anti-TAA autoantibodies. A combination detection of autoantibodies to TAAs might be helpful to distinguish GCA patients from normal subjects and the patients with gastric cardia precancerous lesions. In addition, further studies in patients with GCA and precancerous lesions using enlarged TAA panels might improve the sensitivity and specificity of cancer detection and high-risk subjects screening.

The photodissociation of 1,2-C2H2Br2 at 248 nm has been studied by product translational spectroscopy. The results show that the molecule dissociates exclusively into the products (1) Br2+C2H2 and (2) Br (fast)+Br (slow)+C2H2 with a branching ratio ∼0.2:0.8. While the cleavages of the C–Br bonds are not symmetric, producing the Br atoms at unequal velocities, the anisotropy of the products indicates that both reactions occur in a fraction of a rotational period. Following an asynchronous concerted reaction, the triple products were simulated with the P(Et) distributions coupled by asymmetric angular distributions. A mechanism consistent with the measured results is proposed that the Br2 elimination is a result of a fast intersystem crossing from the ππ* pumped state while the triple products occur via a simultaneous asymmetric scission of the C–Br bonds along the nσ* state.

Background: Oesophageal squamous cell carcinoma (SCC) causes the highest number of cancer deaths in some regions of Northern China. Previously, we narrowed down a critical region at 9q33-34, identified to be associated with tumour-suppressive function of deleted in oesophageal cancer 1 (DEC1) in oesophageal SCC. Methods: We generated DEC1 antibody and constructed tissue microarrays (TMAs) utilising tissue specimens from Henan, a high-risk region for oesophageal SCC, to investigate the importance of DEC1 expression in this cancer. Results: Tissue microarray immunohistochemical staining reveals significant loss of DEC1 from hyperplasia, to tumour, and to lymph node metastasis. In addition, the loss of DEC1 in tumour is age-dependent. Interestingly, there is significant abrogation of DEC1 expression in patients with a family history of oesophageal SCC. Deleted in oesophageal cancer 1 localises to both the cytoplasm and nucleus. The vesicular pattern of DEC1 in the cytoplasm appears to localise at the Golgi and Golgi-endoplasmic reticulum intermediate compartment. Conclusion: This is the first TMA study to suggest a clinical association of DEC1 in lymph node metastatic oesophageal SCC, early onset oesophageal SCC and familial oesophageal SCC development. Subcellular localisation of DEC1 and its expression in oesophageal SCC tissues provide important insight for further deciphering the molecular mechanism of DEC1 in oesophageal SCC development. © 2011 Cancer Research UK All rights reserved., published_or_final_version

This study examined the involvement of glucose regulated protein 94 (GRP94) in chemotherapy-resistance in human ovarian cancer cells.Three human ovarian cancer cells were examined for basal levels of GRP94 mRNA by RT-PCR and protein by Western blotting. Sensitivities to adriamycin of these cell lines were determined by means of MTT assay. The suppression of GRP94 expression was performed using specific siRNA in HO-8910PM cells, and cell apoptosis was assessed by flow cytometry. One-way ANOVA and the Student-Newman-Keuls test were used to determine which were significantly different.HO-8910PM cells, with the highest basal levels of GRP94, exhibited the lowest sensitivity to adriamycin. In HO-8910PM cells, the sensitivity to adriamycin was increased when the GRP94 gene was disturbed by specific siRNA transfection.High GRP94 expression might be one of the molecular mechanisms causing resistance to adriamycin, and therefore GRP94 siRNA maybe useful in tumor-specific gene therapy in ovarian cancer.

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B cell development is a process tightly regulated by the orchestrated signaling of cytokine receptors, the pre-B cell receptor (BCR) and the B cell receptor (BCR). It commences with common lymphoid progenitors (CLP) up-regulating the expression of B cell-related genes and committing to the B cell lineage. Cytokine signaling (IL-7, stem cell factor, FLT3-L) is essential at this stage of development as it suppresses cell death, sustains proliferation and facilitates heavy chain rearrangements. As a result of heavy chain recombination, the pre-BCR is expressed, which then becomes the primary determiner of survival, cell cycle entry and allelic exclusion. In this review, we discuss the mechanisms of B cell lineage commitment and describe the signaling pathways that are initiated by the pre-BCR. Finally, we compare pre-BCR and pre-TCR structure, signal transduction and function, drawing parallels between early pre-B and pre-T cell development.

To investigate the antifungal effect of three natural products on the genetic substance of Saccharomyces cerevisiae GL7 and Prototheca wickerhamii.The normal and treated cells were observed by confocal laser scanning microscope (CLSM) and image analysis to quantitatively described the cell morphology, area, DNA and RNA content.The morphology, area, DNA and RNA contents were changed greatly in the treated cells.Solasodine, 4'-hydroxy-3, 5-dimethoxystilbene and dictamnine directly or indirectly interfered the synthesis and function of genetic substance in S. cerevisiae and P. wickerhamii.

Background To assess the response time and the details of the operating procedure of the Beijing 120 Emergency Medical Service (EMS). Methods Between June and December 2005, 51 918 EMS cases recorded in the Dispatch Center of the Beijing Emergency Medical Center were analysed. Results The median response time of the 51 918 cases was 16.5 min; the cumulative proportions were 2.28%, 9.64% and 18.04% for less than 5 min, 8 min and 10 min of response time respectively, whereas the proportion was 19.20% for more than 30 min of response time. Conclusions On the basis of this analysis, the response time of the Beijing 120 EMS system was found to be longer than that indicated by the national standards.

The 9p21 gene cluster, harboring growth suppressive genes p14ARF, p15INK4b, and p16INK4a, is one of the major aberration hotspots in human cancers. It was shown that p14ARF and p16INK4a play active roles in the p53 and Rb tumor suppressive pathways, respectively, and p15INK4b is a mediator of the extracellular growth inhibition signals. To elucidate specific targets and aberrations affecting this subchromosomal region, we constructed a detailed alteration map of the 9p21 gene cluster by analyzing homozygous deletion, hypermethylation, and mutation of the p14ARF, p15INK4b, and p16INK4a genes individually in 40 esophageal squamous cell carcinomas (ESCCs) and compared the genetic alterations with mRNA expression in 18 of these samples. We detected aberrant promoter methylation of the p16INK4a gene in 16 (40%), of p14ARF in 6 (15%), and of p15INK4b in 5 (12.5%) tumor samples. Most p16INK4a methylations were exclusive, whereas all but one of the p14ARF/p15INK4b methylations were accompanied by concomitant p16INK4a methylation. We detected homozygous deletion of p16INK4a in 7 (17.5%), of p14ARF-E1beta in 13 (33%), and of p15INK4b in 16 (40%) tumor samples. Most deletions occurred exclusively on the E1beta-p15INK4b loci. Two samples contained p14ARF deletion but with p16INK4a and p15INK4b intact. No mutation was detected in the p14ARF and p16INK4a genes. Comparative RT-PCR showed good concordance between suppressed mRNA expression and genetic alteration for p15INK4b and p16INK4a genes in the 18 frozen samples, whereas 5 of the 13 cases with suppressed p14ARF mRNA expression contained no detectable E1beta alteration but aberrations in the p16INK4a locus. Our results show that in human ESCCs, p14ARF is a primary target of homozygous deletion along with p15INK4b, whereas p16INK4a is the hotspot of hypermethylation of the 9p21 gene cluster. The frequent inactivation of the p14ARF and p16INK4a genes may be an important mechanism for the dysfunction of both the Rb and p53 growth regulation pathways during ESCC development.

To understand the alterations of Rb tumor suppressor gene and the relationship between defects in the Rb and p53 pathways in human esophageal carcinogenesis, we examined the loss of heterozygosity (LOH) of the Rb gene and immunohistochemical staining of pRb protein in 56 esophageal squamous cell carcinoma specimens and related the results to the p53 gene alterations. Using four introgenic polymorphic markers as probes, we observed LOH of the Rb gene in 30 of the 55 informative tumor samples. Immunohistochemical analysis revealed different patterns of pRb expression among the tumor samples. In the 56 cases, 16 displayed extensive pRb staining comparable to that of the adjacent normal epithelia, whereas 33 showed either significantly decreased or no pRb staining and 7 had a focal staining pattern reflecting heterogeneous cancer nests in the tumor with respect to Rb status. In the tumor samples containing Rb LOH, 90% showed low or no pRb expression, whereas in samples without Rb LOH, only 20% had altered pRb expression. There was a strong association between LOH of the Rb gene and alteration of pRb expression in our samples (P0.0001), suggesting LOH is a main event leading to Rb inactivation. We found that Rb LOH was more frequent in tumors with p53 mutations (P0.05), which occurred in 31 of the 49 cases analyzed. When the status of Rb and p53 alterations was evaluated by the combined results of immunohistochemical and genetic analyses, we found that alteration of Rb and p53 had an even stronger association in our esophageal squamous cell carcinoma samples (P = 0.0015). Among the 51 cases in which both the Rb and p53 status were determined, 31 contained alterations in both genes, and only 5 and 6 cases were altered in only Rb and only p53, respectively. Our results suggest that defects in the Rb and p53 pathways and their potential synergistic effect in deregulating cell cycle and apoptosis are major mechanisms for esophageal carcinogenesis.

Changes in cell proliferation and cell death might be key factors in regulating the rate of neoplasm progression and tumor growth. The extent of apoptosis and its possible relationship with cell proliferation at different stages of esophageal carcinogenesis, however, have not been characterized. In this study, 241 esophageal biopsy samples from symptom-free subjects and 38 surgically resected esophageal carcinoma tissues from a high-risk population for esophageal cancer in Henan, China, were used to analyze the changes of apoptosis and its relationship with cell proliferation as determined by proliferating cell nuclear antigen (PCNA). The apoptotic cells, identified morphologically, were located in the same proliferative compartment of hyperproliferative cell population in the esophageal epithelium. The apoptotic indices (total number of apoptotic cells and apoptotic bodies per mm2 of the tissue section) were low in the normal epithelia, and increased significantly as the lesions progressed from basal cell hyperplasia (BCH) to dysplasia (DYS) and to squamous cell carcinoma (SCC). The extent of apoptosis correlated well with the cell proliferation indices. The present findings indicate that apoptosis occurs in the early stage of esophageal carcinogenesis, and as the lesions progress, both the apoptotic index and PCNA labelled index increase, suggesting that hyperproliferative cells might be more susceptible to apoptosis.

We previously demonstrated that the histamine H2 receptor can activate both adenylate cyclase (AC) and phospholipase C (PLC) signaling pathways via separate GTP-dependent mechanisms. We examined whether H2 receptor-specific peptides corresponding to the amino (N) or carboxyl terminus (C) of the second (2i) or third (3i) intracytoplasmic loops or the carboxyl terminal tail (P4iN) could effect histamine- stimulated AC and PLC activity in cell membranes prepared from HEPA cells stably transfected to express the canine H2 histamine receptor cDNA. Tiotidine binding and basal signaling were not altered by the synthetic peptides. H2P2iN, H2P2iC, H2P3iN and H2P4iN did not effect histamine stimulated AC activity although H2P3iC (10(-4) M) significantly inhibited this parameter (65.6 +/- 7.2% of maximal stimulation) (n = 6). Combination of the five peptides (H2P2iN, H2P2iC, H2P3iN, H2P3iC and H2P4iN) abolished histamine stimulated AC activity. Although all of the peptides inhibited histamine-stimulated PLC activity to a moderate degree individually, H2P3iC (10(-4) M) had the greatest effect, decreasing PLC activation to 20.8 +/- 6.3% of maximal stimulation (IC50 = 7.5 X 10(-7) M) (n = 6). H2P3iC and the peptide combination did not alter, forskolin, GTP gamma s or epinephrine-stimulated AC activity nor GTP gamma s and vasopressin-stimulated PLC. These studies demonstrate that both the second and third intracytoplasmic loops of the histamine H2 receptor are linked to separate signaling pathways in a differential manner.

Linxian and the nearby county Huixian, in the Henan province in Northern China, have a very high incidence of esophageal squamous cell carcinoma (SCC). Previous studies from these counties have suggested that increased proliferation of esophageal epithelial cells, morphologically manifested as basal cell hyperplasia (BCH) and dysplasia (DYS), is an early indicator of abnormality in persons predisposed to SCC. A high incidence of gastric cardia adenocarcinoma (AC) was also found in these areas. To determine proliferation patterns of esophageal and gastric cardia epithelia with normal and different severities of precancerous lesions, we measured proliferating cell nuclear antigen (PCNA), Ki-67, and bromodeoxyuridine (BrdU) incorporation and compared the results. Esophageal biopsies (175) and gastric cardia biopsies (41) were collected from symptom-free subjects in Huixian. Of these, 23 esophageal biopsies were incubated with BrdU. The avidin-biotin-peroxidase complex (ABC) method was used to detect PCNA, Ki-67, and BrdU. The number of immunostain-positive cells was counted manually. Intense immunostaining for PCNA, Ki-67, and BrdU was observed in the cell nuclei of tissues with normal and different severities of precancerous lesions. With esophageal biopsies, both PCNA and Ki-67 increased significantly as the epithelia progressed from normal to BCH and to DYS. The number of PCNA- and Ki-67-positive cells was three times higher than that of BrdU incorporation in the same category of BCH. With cardia biopsies, the number of Ki-67 positive cells was lower in normal tissue and increased significantly from chronic superficial gastritis to chronic atrophic gastritis to DYS. Staining patterns for PCNA and Ki-67 were correlated with the histopathology of the esophagus. The correlation was not as clear with gastric cardia. BrdU studies appear to be more complicated. The PCNA and Ki-67 methods may be useful for screening high-risk esophageal and gastric cardia cancer subjects, and for monitoring chemoprevention effects.

Accumulation of p53 protein occurs in human oesophageal precancerous lesions and even in near-normal oesophageal epithelium. In some instances, p53 gene mutations have been detected. In many of the cases of p53 protein accumulation in early lesions, however, p53 mutations were not detected due to either the lack of mutation or the low abundance of cells with a mutation. In order to enrich p53 immunostain-positive cells for single strand conformation polymorphism (SSCP) analysis and DNA sequencing, an immunohisto-selective sequencing (IHSS) method was developed. Anti-p53 antibody-peroxidase stained oesophageal tissue sections were subjected to ultraviolet (UV) irradiation to damage the DNA in p53 immunostain-negative cells. The immunostain protected p53 immunostain-positive cells from the UV light and thus preserved the DNA in those cells for PCR amplification. Comparison of the SSCP results from sections with and without UV treatment showed that the IHSS method selectively enriched p53 immunostain-positive cells. With this method, we could analyse mutations in samples with as few as 30 p53 immunostain-positive cells per tissue section. Analysis was carried out on tissues with precancerous lesions from six surgically-resected oesophageal specimens and 13 oesophageal biopsies from symptom-free subjects. The results of mutation analysis for some of the samples were confirmed by microdissection to enrich the p53-positive cells. The mutations in tissues with precancerous lesions were compared with those in the corresponding squamous cell carcinomas. The IHSS method is shown to be a simple and effective way to analyse mutations in p53 immunostain-positive cells. IHSS may also be a general method for molecular analysis of biological specimens after immunohistochemical staining.

The objective of this study was to evaluate the reproducibility of the biopsy sampling procedure in research on esophageal lesions. Biopsies were taken from the middle and lower thirds of the esophagus, one from each site, from 25 subjects in a high-incidence area for esophageal cancer in Xinye County of Henan Province, China. The biopsy sampling procedure was repeated on the same subjects 10 days later. When the biopsies were analyzed together and those with worse pathologies were used for diagnosis, 52% of the subjects had the same grade of lesions in the second biopsy examination, 32% had lower-grade lesions, and 16% had higher-grade lesions.

Multifocal occurrence of precancerous lesions of the esophagus has been observed among individuals in a high incidence area for esophageal carcinoma in Henan Province, China. Results from recent studies suggest that p53 protein accumulation and mutation occur early in the pathogenesis of esophageal carcinoma. Discordant p53 gene mutations have been observed in invasive carcinoma and preinvasive lesions from a patient with esophageal carcinoma. The p53 alterations in the multifocal precancerous lesions from symptom-free subjects, however, have not been investigated.Two biopsy samples, one each from the middle-third and the lower-third of the esophagus, from each subject, were taken from 55 symptom-free subjects in a high incidence area for esophageal cancer in Huixian, Henan Province, China. p53 protein accumulation and p53 gene mutation were analyzed in the multifocal esophageal precancerous lesions from these subjects.Histopathologic examination showed that among the 110 biopsies, 20 had dysplasia, 72 had basal cell hyperplasia, and 18 had normal epithelia. Concurrent lesions at the middle- and lower-third biopsy occurred in 2 subjects with dysplasia (2 of 55 subjects, 4%) and 26 subjects with basal cell hyperplasia (26 of 55 subjects, 47%). Analysis by immunohistochemistry showed high concurrent rates of p53 protein accumulation (51 of 55 subjects, 93%). p53 sequence analysis of 32 samples from 16 subjects identified missense mutations in 5. In one subject, there were three different mutations in the middle-third biopsy (codon 161, GCC--GAC) and the lower-third biopsy (codon 159, GCC--CCC). A single mutation was detected in the other four subjects in either the middle- or lower-third biopsy.The present findings indicate that p53 protein accumulation and mutations occur in the early stages of human esophageal carcinogenesis. Independent somatic mutations of the p53 tumor suppressor gene and protein accumulation in different regions of the esophageal "field" might be key molecular events in multifocal esophageal carcinogenesis.

To understand whether p53 gene mutation is an early or late event in esophageal carcinogenesis, biopsy samples of esophageal epithelium from symptom-free subjects in a high incidence area, Huixian county of Henan Province, China, were analyzed. Mutations in exons 5, 6, 7, and 8 of p53 were analyzed by single-strand conformation polymorphism analysis and DNA sequencing. Among the 37 biopsy samples showing accumulation of p53 protein in immunohistochemical staining, missense mutations of p53 gene were detected in 1 of 3 samples with normal epithelia, 3 of 23 samples with basal cell hyperplasia, and 4 of 11 samples with dysplasia. All mutations occurred at exon 5 with 3 at codon 175, 2 at codon 176, and 1 each at codons 159, 135, and codon 132. Of the 8 mutations, there were 3 G to A transitions and 3 G to T transversions. To understand the mutation spectrum and possible causative factors of esophageal cancer in this area, surgically resected human primary esophageal carcinomas from Linxian county were analyzed for p53 gene mutations in exons 5, 6, 7, and 8. Mutations were detected in 16 of 29 samples (55%). Twelve samples contained different missense point mutations, with 75% transitions (7 G to A and 2 A to G) and 25% transversions (2 G to T and 1 G to C). Most of the mutations were located at either exon 5 or exon 7. A deletion and an insertion of nucleotides leading to frame-shift mutations were detected in each of two other samples. The results demonstrate that p53 protein accumulation and gene mutation may occur at very early stages of esophageal carcinogenesis. In carcinomas, there was a higher frequency of p53 gene mutations, which accounts for most of the cases with p53 protein accumulation.

The level of p53 protein was determined immunohistochemically in normal tissues and tissues with different severities of lesions (basal cell hyperplasia, dysplasia, carcinoma in situ, and carcinoma) from surgically resected human esophagi and esophageal biopsies of symptom-free subjects. The samples were from an area with high esophageal cancer incidence in northern China (Linxian and Huixian in the Henan province). Tissue sections were incubated with p53 antibodies for immunostaining. Conventional hematoxylin and eosin stain was also used. In surgically resected esophageal specimens, elevated p53 protein levels were found in the cell nuclei in tissues with precancerous and cancerous lesions. From basal cell hyperplasia to dysplasia to carcinoma in situ, the p53 immunostain-positive cells increased in number, and their distribution had roughly the same pattern as that of the proliferating cells. However, positive stain was not observed in the dividing basal cells of the normal epithelium of the surgically resected tissues. A similar pattern of immunostaining was observed in the abnormal tissues of the biopsy samples from the symptom-free subjects. An intriguing observation is that some p53 immunostain-positive cells were observed in 3 of 6 cases of histologically normal epithelia of biopsy samples. Only the papillary immunostaining pattern was observed in these three "normal" cases. Although the molecular basis for such positive stain remains to be investigated, it is possible that p53 protein accumulation occurs early in the pathogenesis of esophageal cancer and that p53 mutation is closely associated with the initiation of this cancer. The accumulation of p53 protein may be a promising early biomarker for identifying high-risk subjects for esophageal cancer.

To determine whether dietary calcium supplementation affects esophageal precancerous lesions, 200 subjects with esophageal lesions in a high-risk area for esophageal cancer in China (Huixian, Henan) were randomly divided into 2 groups (100 subjects/group). Subjects in one group received an oral supplementation of calcium carbonate tablets (1200 mg of calcium daily), and subjects in the other group received placebo pills for 11 months. At the entry and the end of the trial, esophagoscopy was performed, and 2 or 3 biopsy specimens were taken from the middle and lower thirds of the esophagus and from macroscopic lesions, if any, of each subject for histopathology and cell proliferation analysis with deoxythymidine labeling. In comparison to normal epithelium, increased proliferative compartment size was observed in epithelia with hyperplasia or dysplasia. After the intervention, the percentage of individuals with "normal epithelium," "basal cell hyperplasia," "basal cell hyperplasia II," and "basal cell hyperplasia III and dysplasia" were 44, 31, 13, and 11% in the calcium group and 35, 39, 17, and 6% in the placebo group, respectively. The labeling index was 0.046 in the calcium group and 0.044 in the placebo group. After the intervention, the labeling index in basal cell layers 1 to 5, the major zone of cell proliferation, fell 38% in the calcium group and 44% in the placebo group from before the intervention. Therefore, in this study, calcium supplementation was not shown to have beneficial effects in alleviating precancerous lesions and abnormal cell proliferation patterns.

This paper reports the prevalence of chronic esophagitis and nutritional status among 538 persons 15-26 years old in the high-risk area of esophageal cancer. 166 subjects were from households with history of esophageal cancer while 372 from households without. The frequency of chronic esophagitis among male and female adolescents in the high risk areas (37.6% and 36%) was significantly, higher than that in the low risk areas. Furthermore, the frequency of chronic esophagitis in the adolescents in households with history of esophageal cancer was also higher than that without history of this cancer. There was a positive correlation between avitaminosis C and chronic esophagitis. Suffering from avitaminosis C and B2, these people are prone to develop chronic esophagitis which, in turn, may serve as an early phase in the carcinogenesis of esophageal epithelium.

Effect of secretin on gastric motility was studied on the preparation of isolated vascular perfused rat stomach. The results showed: (1) Secretin markedly inhibited spontaneous as well as pentagastrin stimulated antral motility. (2) Antisecretin serum completely abolished the inhibitory effect of secretin on antral motility. (3) Antisomatostatin serum and indomethacin blocked the inhibitory effect on antral motility induced by secretin. The results indicated that the inhibitory effect of secretin might be produced through direct action of secretin on secretin receptors and mediated partially by the local somatostatin and prostaglandin in gastric antrum.

A randomized double blind intervention trial was carried out in Huixian County Henan Province, a high risk area for esophageal cancer, to observe the effect of oral calcium supplementation on esophageal precancerous lesions. Two hundred and fourteen cases with basal cell hyperplasia and 40 with dysplasia of the esophagus aged 25-75 randomly received daily oral supplementation of 600 mg calcium or placebo for 7 months. In the calcium supplementation group, the basal cell hyperplasia and dysplasia of the esophagus were significantly improved and the profile of esophageal epithelial proliferation cells labeled with 3H-TdR approached that of the normal subjects in low risk area for esophageal cancer. The results indicate that calcium supplementation can inhibit basal cell hyperplasia and dysplasia of the esophageal epithelium in high risk area for esophageal cancer. The mechanism of interruption of esophageal precancerous lesions by calcium is discussed.

The pattern of proliferation of epithelial cells in esophageal epithelium was studied by means of [3H]deoxythymidine labeling of esophageal epithelium in subjects from Huixian, Henan Province, China, a high-risk geographical region for esophageal cancer. Comparisons were made among patterns of cell proliferation observed in normal esophagus, in hyperplasia, in mild dysplasia, and in moderate dysplasia in a total of 118 subjects. The amount of cell proliferation observed was lowest in normal esophageal epithelium and increased progressively in subjects having hyperplasia, mild dysplasia, and moderate dysplasia. The location of proliferating cells was limited mainly to the base of the esophageal epithelium in normal esophagus, but expanded toward the surface of the esophageal lining in individuals with hyperplasia and dysplasia. The larger total numbers of proliferating cells in the esophageal epithelium and the progressive expansion of the proliferative compartment toward the epithelial surface found in hyperplasia and in dysplasia could both facilitate the screening of subjects for esophageal cancer risk and serve as intermediate biomarkers in prophylactic dietary or pharmacological intervention studies.

The photodissociation of CH2=CClF at 193 nm has been studied by product translational spectroscopy. A total of five primary dissociation channels was detected for the products of Cl (fast), HCl, HF, Cl (slow), and F in the decreasing order of relative yield. Product translational energy distributions have been measured for these reaction products. While a thermal-like distribution was detected for the slow Cl and F atoms, a nonthermal distribution was determined for the fast Cl atom and the molecular elimination of HCl and HF. Apart from the fast Cl atom with anisotropy parameter β=0.5, the remaining products recoil isotropically following photolysis with linearly polarized light. By analogy with the photodissociation of chloroethylenes, these products are found to originate from two potential energy surfaces. In addition to the primary dissociation channels, we have detected the secondary products of F+C2H2 from the internally excited α-fluorovinyl radical through a fast fragment isomerization.