Environmental carcinogens in the city air and lung cancer incidence

Summary Possible contribution of polycyclic hydrocarbons, trace metals, and gaseous pollutants to the incidence of lung cancer in the urban populations has been considered, including the role of carcinogens in the cigarette smoke. A long-term plan has been proposed for the epidemiological studies and control of urban lung cancer incidence. A comparative assessment of lung cancer mortality rate for occupational, urban, and rural exposure to levels of benzo(a)-pyrene typical of these environments is presented.     

Environmental Exposures and Hepatocellular Carcinoma

Infection with hepatitis B and/or hepatitis C virus is a well-established risk factor for the development of hepatocellular carcinoma (HCC). However, it is now clear that certain occupational, environmental, and lifestyle factors also play a role in cancer development. Among these factors are smoking, alcohol consumption, workplace exposure to vinyl chloride, and exposure to polycylic aromatic hydrocarbons and aflatoxins. There is also evidence that several other chemical and infectious agents have a role in inducing HCC in humans. Epidemiologic studies and the use of biomarkers have provided essential data to demonstrate the importance of some of these factors in human risk, while animal studies have suggested that other chemicals may also play a role. Although immunization against hepatitis B virus infection remains the primary method of preventing HCC in regions of the world where this virus is a primary etiologic agent, there is currently no vaccine for hepatitis C virus. Thus, limiting exposure to other known risk factors remains an important mechanism in preventing HCC.     

Weight loss is not associated with hyperleptinemia in humans with pancreatic cancer

Pathological weight loss is a feature of many diseases and contributes to mortality and morbidity. Although cytokines have been implicated in some models of pathological weight loss, little is known about cellular mechanisms responsible for cachexia in patients with cancer. Leptin is a fat cell product that acts centrally to reduce appetite and decrease metabolism. Leptin synthesis is stimulated by cytokines, and circulating levels of cytokines are elevated in some cancer patients. We hypothesized that cytokine-induced hyperleptinemia contributes to pathological weight loss in patients with pancreatic cancer. To evaluate this hypothesis, fasting serum leptin concentrations were measured in 64 patients undergoing surgery for pancreatic cancer. Preoperative interviews were used to assess body weight and appetite history. Thirty of 64 pancreatic cancer patients had cachexia (weight loss of >10% over the 6 months before surgery). Self-reported loss of appetite was associated with the presence of cachexia. Leptin concentrations, when corrected for body mass index, were lower than levels reported in healthy humans. Six patients had leptin levels more than 2 times those predicted by body mass index. There was no association between patients with increased leptin concentration and weight loss or anorexia. We conclude that a reduced appetite contributes to weight loss in patients with pancreatic cancer. High plasma leptin levels, however, do not appear to contribute to cachexia in these patients.     

Lack of acute effect of amylin (islet associated polypeptide) on insulin sensitivity during hyperinsulinaemic euglycaemic clamp in humans

Summary It is suggested that amylin (islet associated polypeptide), co-secreted with insulin from the pancreatic beta cells acts as a circulating hormone which opposes the action of insulin on muscle and increases hepatic glucose production. We have tested the effect of amylin in human subjects on postabsorptive glucose homeostasis and on insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. The amylin used opposed insulin-mediated glucose disposal in rat soleus muscle at concentrations of 10 nmol/l. Seven subjects were studied on two occasions and infused with either amylin or placebo for 6 h, initially when postabsorptive and then during a euglycaemic hyperinsulinaemic clamp. Mean plasma amylin concentrations during the first 3 h were 2006±327 pmol/l during amylin infusion and 20±9 pmol/l during the control infusion. Amylin infusion had no effect on postabsorptive plasma concentrations of insulin (control: 32±16 vs amylin: 25±8 pmol/l) or glucose (5.1±0.1 vs 5.3±0.1 mmol/l). During the clamp, amylin concentrations were 1636 ±422 pmol/l when it was infused and 24±6 during control infusions. Plasma glucose and insulin concentrations were well matched during the control and amylin infusions (glucose: 4.7±0.1 vs 4.8±0.1 mmol/l; insulin: 198±37 vs 195±22 pmol/l). Exogenous glucose infusion rates were a mean of 13 % lower than control values during the amylin infusion but were not statistically different (p =0.17). Therefore, an approximately 100-fold elevation of plasma amylin concentration failed to consistently alter glucose metabolism. Our data suggest that amylin does not act as a circulating hormone to influence glucose metabolism in humans. [Diabetologia (1994) 37: 166–169] Received: 1 June 1993 and in revised form: 16 August 1993     

Notch pathway activation is associated with pancreatic cancer treatment failure

BackgroundPancreatic cancer is resistant to conventional treatment. The aim of the study was to confirm the hypothesis that changes in cancer stem cells (CSCs) and developmental pathway after treatment was responsible for treatment failure in pancreatic cancer.MethodsAfter recovery from a gemcitabine treatment, the percentage of pancreatic cancer CSCs and Notch pathway in BxPC3 and HPAC pancreatic cancer cell lines were analyzed by FACS (CD24 and CD44) and western blot (Notch1, Hes1, β-catenin, and pAKT). The effect of DAPT, a gamma-secretase inhibitor, was similarly investigated. The association between immunohistochemical expression of Hes1 and survival was analyzed.ResultsThe percentage of CD24⁺CD44⁺ cells was higher in gemcitabine-treated BxPC3 and HPAC cells than at pre-treatment. CD24⁺CD44⁺ cells sorted from the gemcitabine-treated cell lines showed higher migration and invasion ability than CD24⁻CD44⁻ or CD24⁻CD44⁺ cells from the same cell lines. Western blot analysis showed an increased expression of Notch1 and Hes1 in gemcitabine-treated cell lines. The overall survival of pancreatic cancer patients with strong expression of Hes1 was shorter than that in patients with no or weak expression (11.1 vs. 21.6 months, P = 0.036). Treatment with DAPT reversed the increase in Hes1, β-catenin, and pAKT expression and the proportion of CD24⁺CD44⁺ cells in gemcitabine-treated cell lines. The treatment also decreased migration and invasion ability.ConclusionOur data suggested that an increase in CSCs and activation of the Notch pathway might contribute to the failure of treatment in pancreatic cancer. Notch pathway can be a potential target to overcome treatment failure.     

The gene associated with trichorhinophalangeal syndrome in humans is overexpressed in breast cancer

A comprehensive differential gene expression screen on a panel of 54 breast tumors and >200 normal tissue samples using DNA microarrays revealed 15 genes specifically overexpressed in breast cancer. One of the most prevalent genes found was trichorhinophalangeal syndrome type 1 (TRPS-1), a gene previously shown to be associated with three rare autosomal dominant genetic disorders known as the trichorhinophalangeal syndromes. A number of corroborating methodologies, including in situ hybridization, e-Northern analysis using ORF EST (ORESTES) and Unigene EST abundance analysis, immunoblot and immunofluorescence analysis of breast tumor cell lines, and immunohistochemistry, confirmed the microarray findings. Immunohistochemistry analysis found TRPS-1 protein expressed in >90% of early- and late-stage breast cancer, including ductal carcinoma in situ and invasive ductal, lobular, and papillary carcinomas. The TRPS-1 gene is also immunogenic with processed and presented peptides activating T cells found after vaccination of HLA-A2.1 transgenic mouse. Human T cell lines from HLA-A*0201+ female donors exhibiting TRPS-1-specific cytotoxic T lymphocyte activity could also be generated.     

Passage of salivary amylase through the stomach in humans

With an inhibitor assay technique rates of passage of salivary and pancreatic isoamylase through the jejunum were measured in six healthy volunteers after different liquid, intragastric meals. In all subjects and in 13/17 experiments, more than 2500 units of salivary amylase were passed over 200 postcibal minutes. Salivary amylase comprised 13.8±3.9% (X ±SEM) of the total amylase and appeared predominantly as single, distinct peak. The inhibitor method was validated by isoelectric focusing (r=0.988;P<0.001;N=7). The frequency of detection of salivary amylase in gastric or jejunal samples fell as gastric pH fell below 3.0.In vitro, amylase was inactivated in gastric juice as pH fell between 3.8 and 3.3. Salivary amylase accounted for 11% of total amylase output in a normal and 27% in an achlorhydric subject after a hamburger meal. We conclude that amylase should not be measured in postprandial studies of pancreatic secretion in humans without correction for salivary amylase.Dr. Michael Fried is supported by the Swiss National Science Foundation. Partial support was provided by the Swiss Foundation for the Support of Nutritional Research.     

双吻合器低位前切除治疗低位直肠癌207例报告

采用双吻合关闭器低位前切除术治疗低位直肠癌 (癌肿下缘距肛缘 4～ 7cm)患者 2 0 7例。均无手术死亡 ;发生吻合口漏 10例 ,吻合口狭窄 19例。术后 2～ 4周肛门排便功能优良 ,排便次数控制在 2～ 4次 / d。术后平均随访 37(8～ 72 )个月 ,局部复发 13例 ;3年和 5年生存率平均为 89.2 %和 6 96 1%。认为只要合理选择手术适应症 ,双吻合器低位直肠癌前切除是一种安全、有效的术式     

Mucosa-associated microbiota dysbiosis in colitis associated cancer

Gut microbiota dysbiosis has been associated with inflammatory bowel diseases (IBD). In colorectal cancer, the gut microbiota has also been recognized as potentially involved in aggravating or favoring the tumor development. However, very little is known on the structure and role of the microbiota in colitis associated cancer (CAC), an important complication of IBD in human. Here we analyzed the bacterial and fungal composition of the mucosa associated microbiota of patients suffering CAC, sporadic cancer (SC) and of healthy subjects (HS) by barcode sequences analysis on the following cohort: 7 CAC patients, 10 SC patients and 10 HS using 16S (MiSeq) and ITS2 (pyrosequencing) sequencing, for bacteria and fungi respectively. Mucosa-associated bacterial microbiota in CAC was significantly different from the ones in SC or in HS, while the fungal showed no differences. Comparison between mucosa-associated microbiota on the tumor site or in normal mucosa near the tumor showed very similar patterns. The global mucosa-associated bacterial microbiota in cancer patients was characterized by a restriction in biodiversity but no change for the fungal community. Compared to SC, CAC was characterized by an increase of Enterobacteriacae family and Sphingomonas genus and a decrease of Fusobacterium and Ruminococcus genus. Our study confirms the alteration of the mucosa-associated bacterial microbiota in IBD and SC. Although the cohort is limited in number, this is the first evidence of the existence of an altered bacterial microbiota in CAC clearly different from the one in SC patients.     

Effects of dietary intake and genetic factors on hypermethyiation of the hMLH1 gene promoter in gastric cancer

AIM: Hypermethylation of the promoter of the hMLH1 gene, which plays an important role in mismatch repair during DNA replication, occurs in more than 30% of human gastric cancer tissues. The purpose of this study was to investigate the effects of environmental factors, genetic polymorphisms of major metabolic enzymes, and microsatellite instability on hypermethylation of the promoter of the hMLH1 gene in gastric cancer. METHODS: Data were obtained from a hospital-based, case-control study of gastric cancer. One hundred and ten gastric cancer patients and 220 age- and sex-matched control patients completed a structured questionnaire regarding their exposure to environmental risk factors. Hypermethylation of the hMLH1 gene promoter, polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2 and L-myc genes, microsatellite instability and mutations of p53 and Ki-ras genes were investigated. RESULTS: Both smoking and alcohol consumption were associated with a higher risk of gastric cancer with hypermethylation of the hMLH1 gene promoter. High intake of vegetables and low intake of potato were associated with increased likelihood of gastric cancer with hypermethylation of the hMLH1 gene promoter. Genetic polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2, and L-myc genes were not significantly associated with the risk of gastric cancer either with or without hypermethylation in the promoter of the hMLH1 gene. Hypermethylation of the hMLH1 promoter was significantly associated with microsatellite instability (MSI): 10 of the 14 (71.4%) MSI-positive tumors showed hypermethylation, whereas 28 of 94 (29.8%) the MSI-negative tumors were hypermethylated at the hMLH1 promoter region, Hypermethylation of the hMLH1 gene promoter was significantly inversely correlated with mutation of the p53 gene. CONCLUSION: These results suggest that cigarette smoking and alcohol consumption may influence the development of hMLH1-positive gastric cancer. Most dietary factors and polymorphisms of GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2, and L-myc genes are not independent risk factors for gastric cancer with hypermethylation of the hMLH1 promoter. These data also suggest that there could be two or more different molecular pathways in the development of gastric cancer, perhaps involving tumor suppression mechanisms or DNA mismatch repair.     

Effects of dietary intake and genetic factors on hypermethylation of the hMLH1 gene promoter in gastric cancer

AIM: Hypermethylation of the promoter of the hMLH1 gene, which plays an important role in mismatch repair during DNA replication, occurs in more than 30% of human gastric cancer tissues. The purpose of this study was to investigate the effects of environmental factors, genetic polymorphisms of major metabolic enzymes, and microsatellite instability on hypermethylation of the promoter of the hMLH1 gene in gastric cancer. METHODS: Data were obtained from a hospital-based, case-control study of gastric cancer. One hundred and ten gastric cancer patients and 220 age- and sex-matched control patients completed a structured questionnaire regarding their exposure to environmental risk factors. Hypermethylation of the hMLH1 gene promoter, polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2 and L-myc genes, microsatellite instability and mutations of p53 and Ki-ras genes were investigated. RESULTS: Both smoking and alcohol consumption were associated with a higher risk of gastric cancer with hypermethylation of the hMLH1 gene promoter. High intake of vegetables and low intake of potato were associated with increased likelihood of gastric cancer with hypermethylation of the hMLH1 gene promoter. Genetic polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2, and L-myc genes were not significantly associated with the risk of gastric cancer either with or without hypermethylation in the promoter of the hMLH1 gene. Hypermethylation of the hMLH1 promoter was significantly associated with microsatellite instability (MSI): 10 of the 14 (71.4%) MSI-positive tumors showed hypermethylation, whereas 28 of 94 (29.8%) the MSI-negative tumors were hypermethylated at the hMLH1 promoter region. Hypermethylation of the hMLH1 gene promoter was significantly inversely correlated with mutation of the p53 gene. CONCLUSION: These results suggest that cigarette smoking and alcohol consumption may influence the development of hMLH1-positive gastric cancer. Most dietary factors and polymorphisms of GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2, and L-myc genes are not independent risk factors for gastric cancer with hypermethylation of the hMLH1 promoter. These data also suggest that there could be two or more different molecular pathways in the development of gastric cancer, perhaps involving tumor suppression mechanisms or DNA mismatch repair.     

几种新现人体隐孢子虫种和基因型流行现状

隐孢子虫是一种寄生于宿主胃肠道上皮细胞内的原虫。人感染后,免疫功能正常者,常引起自限性腹泻;但在高危人群(如儿童、老人和免疫缺陷者等)中可发生严重腹泻和肠外感染,尤其是艾滋病患者。目前,隐孢子虫的分子流行病学研究已鉴定了30个有效种和40多种基因型,其中21个隐孢子虫种和基因型在人体发现。人体隐孢子虫病多数由人隐孢子虫(C.hominis)和微小隐孢子虫(C.parvum)引起。火鸡隐孢子虫(C.meleagridis)、泛在隐孢子虫(C.ubiquitum)、猫隐孢子虫(C.felis)和犬隐孢子虫(C.canis)引起的隐孢子虫病例也逐渐增多。除此之外,随着人体隐孢子虫病分子流行病学数据的增加,在人体内鉴定到一些新的隐孢子虫和基因型。特对上述新现的人体隐孢子虫种和基因型的流行现状进行综述。     

Role of endogenous endothelin-1 in ethanol-induced gastric mucosal damage in humans

Gastric microcirculatory disturbances are involved in the ethanol-induced gastric mucosal damage. In this study in humans we evaluated the time course of plasma and gastric mucosal endothelin-1 (ET-1) concentrations after intragastric ethanol administration; furthermore we determined the correlation among changes in gastric tissue endothelin-1 and microscopic and gross gastric hemorrhagic damage. ET-1 concentrations in plasma and gastric mucosa were measured by radioimmunoassay. The endoscopic appearance of the gastric mucosa was evaluated and scored on a scale of 0–5, and gastric biopsies for histological evaluation were obtained from the antral and the corpus mucosa just before and 30 min after 40% ethanol administration in seven healthy volunteers. Plasma ET-1 concentration increased as soon as 20 min after ethanol administration, reached a significant peak at 30 min (P < 0.01), and returned to near basal level within 120 min. Gastric mucosal ET-1 concentration significantly increased 30 min after ethanol administration in both the body (P < 0.05) and the antrum (P < 0.05) of the stomach; however the ET-1 increase was significantly higher in the body. Moreover, data obtained 30 min after ethanol administration showed a significant correlation between gastric mucosal ET-1 levels and gross hemorrhagic damage (r = 0.84). A significant correlation was also observed between antral gastric mucosal ET-1 and microscopic lesions (r = 0.70). We conclude that 40% ethanol, given orally, stimulates the release of gastric mucosalendothelin-1 and causes a rapid and time-dependent increase of ET-1 plasma level in humans. The increased plasma and gastric tissue endothelin-1 concentration may play a role in ethanol-induced gastric hemorrhagic injury in humans.     

Melatonin in relation to physiology in adult humans

Abstract: The role exerted by melatonin in human physiology has not been completely ascertained. Melatonin levels have been measured in different physiopathological conditions, but the effects induced by melatonin administration or withdrawal have been tested only recently. Some effects have been clearly documented. Melatonin has hypothermic properties, and its nocturnal secretion generates about 40% of the amplitude of the circadian body temperature rhythm. Melatonin has sleep inducing properties, and exerts important activities in the regulation of circadian rhythms. Melatonin is capable of phase shifting human circadian rhythms, of entraining free-running circadian rhythms, and of antagonizing phase shifts induced by nighttime exposure to light. Its effect on human reproduction is not completely clear, but stimulatory effects on gonadotropin secretion have been reported in the follicular phase of the menstrual cycle. Direct actions on ovarian cells and spermatozoa have been also documented. Beside these, new important actions for melatonin may be proved. Melatonin may exert protective effects on the cardiovascular system, by reducing the risk of atherosclerosis and hypertension, and may influence immune responses. Finally, by acting as an antioxidant, melatonin could be important in slowing the processes of ageing.     

Comparative cancer risk associated with methotrexate,other non-biologic and biologic disease-modifying anti-rheumatic drugs

Objective

There is little information comparing the potential risk of cancer across conventional and biologic disease-modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). Methotrexate has not been the focus of most contemporary pharmacoepidemiologic studies of cancer.

Methods

We conducted a comparative effectiveness study with cancer as the outcome. A large observational cohort of RA was followed up from 2001 to 2010. Reports of any cancer prompted a confirmation process that included adjudication of the primary cancer records. We used a propensity score (PS) with relevant covariates and cohort trimming to improve the balance between DMARD cohorts. Cox proportional hazard regression models were constructed to estimate the risk of cancer with various DMARDs, all compared with methotrexate.

Results

We identified 6806 DMARD courses for analysis (1566 methotrexate; 904 nbDMARDs; 3761 TNF antagonists; 408 abatacept; and 167 rituximab). Non-biologic DMARDs (HR 0.17, 95% CI 0.05–0.65) and TNF antagonists (HR 0.29, 95% CI 0.05–0.65) were associated with a reduced adjusted risk of cancer compared with methotrexate. Abatacept (HR 1.55, 95% CI 0.40–5.97) and rituximab (HR 0.42, 95% CI 0.07–2.60) were similar in risk of cancer with methotrexate. These results were robust to sensitivity analyses. After controlling for DMARD exposures, risk factors for cancer included male gender, age, and alcohol consumption.

Conclusions

Cancer risk was elevated for methotrexate users compared with nbDMARDs and TNF antagonists.     

Hepatic injury associated with paraquat toxicity in humans

ABSTRACT— Thirteen patients are reported who developed evidence of hepatic damage after exposure to paraquat and subsequently died. At autopsy, the main changes involved the bile excretory pathways. Ten of the thirteen cases had cholestasis, usually localized to the centrilobular zone. There was cholangiocellular injury involving the small and medium-sized bile ducts in portal areas. It consisted of shrinkage of cells, poor definition of outline, separation from the basement membrane, desquamation of cells into the lumen, infiltration of the wall by neutrophils and possible loss of integrity of the basement membrane. These bile duct lesions have not been previously described in association with paraquat toxicity. On the basis of the overall histologic findings in this study and extrapolation from experimental studies, it is hypothesized that paraquat injury to the liver is biphasic; it is initially hepatocellular but becomes cholangiocellular after the first 2 days.     

Arterial hypertension is associated with hypalgesia in humans

An association between increased blood pressure and hypalgesia has been reported in several studies in animals and in a few reports in humans. We investigated the relationship between hypertension and pain perception by comparing the response to graded electrical stimulation of the tooth pulp, which is thought to represent an exclusively nociceptive system. The test was performed with a commercial tooth pulp tester in a large series of subjects with borderline or established hypertension and in three groups of normotensive controls: volunteers, nonhypertensive patients, and medical students with a well-established or no family history of hypertension. Subjects had to report when they started to feel pulp stimulation (sensory threshold) and when this became painful (pain threshold). Sensory and pain thresholds were obtained as means of the measurements on four healthy, unfilled teeth. Sensory thresholds were significantly higher in subjects with borderline or established hypertension than in two of the three normotensive groups (volunteers and normotensive patients), whereas no significant difference was observed between the two hypertensive groups. The results for the pain threshold were qualitatively similar but less clear and less amenable to statistical analysis because this parameter could not be determined with accuracy in a number of subjects in whom the subjective pain threshold was above the upper range of stimulation of the instrument. The association between blood pressure levels and pain perception was further confirmed by the highly significant correlation found for the overall data between mean arterial blood pressure and both thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)     

中国胃癌的分布与第三系地层出露的关系

目的验证第三系地质因素是胃癌高发的因素。方法把胃癌死亡率分布图与地质图进行对照，计算各省第三系地层出露区占其总面积的百分比及冲积平原土壤中第三系地层物质的百分比，再与胃癌死亡率进行相关分析。结果可见胃癌高死亡率的地区分布在大面积出露的第三系地质区，少数分布在第三系地层冲积平原区。各省第三系地层出露面积的百分比与胃癌死亡率呈正相关（ｔ＝０４５６５，Ｐ＜００１）。此外，冲积平原土壤中第三系地层物质的含量与男性胃癌死亡率有显著相关（ｒ＝０９８７７，Ｐ＜００５）。结论与胃癌高发相关的致癌物存在于出露的第三系地层或来源于这一地区的沉积物之中