Convergently evolved placental villi show multiscale structural adaptations to differential placental invasiveness.

Despite having a single evolutionary origin and conserved function, the mammalian placenta exhibits radical structural diversity. The evolutionary drivers and functional consequences of placental structural diversity are poorly understood. Humans and equids both display treelike placental villi, however these villi evolved independently and exhibit starkly different levels of invasiveness into maternal tissue (i.e. the number of maternal tissue layers between placental tissue and maternal blood). The villi in these species therefore serve as a compelling evolutionary case study to explore whether placentas have developed structural adaptations to respond to the challenge of reduced nutrient availability in less invasive placentas. Here, we use three-dimensional X-ray microfocus computed tomography and electron microscopy to quantitatively evaluate key structures involved in exchange in human and equid placental villi. We find that equid villi have a higher surface area to volume ratio and deeper trophoblastic vessel indentation than human villi. Using illustrative computational models, we propose that these structural adaptations have evolved in equids to boost nutrient transfer to compensate for reduced invasiveness into maternal tissue. We discuss these findings in relation to the 'maternal-fetal conflict hypothesis' of placental evolution.

Early life exposure to phthalates and the development of childhood asthma among Canadian children.

BACKGROUND: Studies have demonstrated an association between phthalate exposure and childhood asthma, although results have been inconsistent. No epidemiological studies have examined exposure during the first year of life. OBJECTIVE: To investigate the association between phthalate exposures in the home environment during the first year of life, and subsequent development of childhood asthma and related symptoms. METHODS: This study used a case-cohort design including 436 randomly selected children and all additional cases of asthma at 5 years (ntotal = 129) and recurrent wheeze between 2 and 5 years (ntotal = 332) within the CHILD Cohort Study, a general population Canadian birth cohort of 3455 children. Phthalate exposure was assessed using house dust samples collected during a standardized home visit when children were 3-4 months of age. All children were assessed by specialist clinicians for asthma and allergy at 1, 3 and 5 years. Logistic regression was used to assess the association between exposure to five phthalates and asthma diagnosis at 5 years, and recurrent wheeze between 2 and 5 years, with further stratification by wheeze subtypes (late onset, persistent, transient) based on the timing of onset and persistence of wheeze symptoms. RESULTS: Di(2-ethylhexyl) phthalate (DEHP) had the highest concentration in dust (mediansubcohort = 217 µg/g), followed by benzyl butyl phthalate (BzBP) (20 µg/g). A nearly four-fold increase in risk of developing asthma was associated with the highest concentration quartile of DEHP (OR = 3.92, 95% CI: 1.87-8.24) including a positive dose-response relationship. A two-fold increase in risk of recurrent wheeze was observed across all quartiles compared to the lowest quartile of DEHP concentrations. Compared to other wheeze subtypes, stronger associations for DEHP were observed with the late onset wheezing subtype, while stronger associations for di-iso-butyl phthalate (DiBP) and BzBP were observed with the transient subtype. DISCUSSION: DEHP exposure at 3-4 months, at concentrations lower than other studies that reported an association, were associated with increased risks of asthma and recurrent wheeze among children at 5 years. These findings suggest the need to assess whether more stringent regulations are required to protect children's health, which can be informed by future work exploring the main sources of DEHP exposure.

Insecticide use and risk of non-Hodgkin lymphoma subtypes: A subset meta-analysis of the North American Pooled Project.

Insecticide use has been linked to increased risk of non-Hodgkin lymphoma (NHL), however, findings of epidemiologic studies have been inconsistent, particularly for NHL subtypes. We analyzed 1690 NHL cases and 5131 controls in the North American Pooled Project (NAPP) to investigate self-reported insecticide use and risk of NHL overall and by subtypes: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and small lymphocytic lymphoma (SLL). Odds ratios (OR) and 95% confidence intervals for each insecticide were estimated using logistic regression. Subtype-specific associations were evaluated using ASSET (Association analysis for SubSETs). Increased risks of multiple NHL subtypes were observed for lindane (OR = 1.60, 1.20-2.10: FL, DLCBL, SLL), chlordane (OR = 1.59, 1.17-2.16: FL, SLL) and DDT (OR = 1.36, 1.06-1.73: DLBCL, SLL). Positive trends were observed, within the subsets with identified associations, for increasing categories of exposure duration for lindane (Ptrend = 1.7 × 10-4 ), chlordane (Ptrend = 1.0 × 10-3 ) and DDT (Ptrend = 4.2 × 10-3 ), however, the exposure-response relationship was nonlinear. Ever use of pyrethrum was associated with an increased risk of FL (OR = 3.65, 1.45-9.15), and the relationship with duration of use appeared monotonic (OR for >10 years: OR = 5.38, 1.75-16.53; Ptrend = 3.6 × 10-3 ). Our analysis identified several novel associations between insecticide use and specific NHL subtypes, suggesting possible etiologic heterogeneity in the context of pesticide exposure.

The American lifestyle-induced obesity syndrome diet in male and female rodents recapitulates the clinical and transcriptomic features of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the progression to nonalcoholic steatohepatitis (NASH) and increased risk of hepatocellular carcinoma remain poorly understood. Additionally, there is increasing recognition of the extrahepatic manifestations associated with NAFLD and NASH. We demonstrate that intervention with the American lifestyle-induced obesity syndrome (ALIOS) diet in male and female mice recapitulates many of the clinical and transcriptomic features of human NAFLD and NASH. Male and female C57BL/6N mice were fed either normal chow (NC) or ALIOS from 11 to 52 wk and underwent comprehensive metabolic analysis throughout the duration of the study. From 26 wk, ALIOS-fed mice developed features of hepatic steatosis, inflammation, and fibrosis. ALIOS-fed mice also had an increased incidence of hepatic tumors at 52 wk compared with those fed NC. Hepatic transcriptomic analysis revealed alterations in multiple genes associated with inflammation and tissue repair in ALIOS-fed mice. Ingenuity Pathway Analysis confirmed dysregulation of metabolic pathways as well as those associated with liver disease and cancer. In parallel the development of a robust hepatic phenotype, ALIOS-fed mice displayed many of the extrahepatic manifestations of NAFLD, including hyperlipidemia, increased fat mass, sarcopenia, and insulin resistance. The ALIOS diet in mice recapitulates many of the clinical features of NAFLD and, therefore, represents a robust and reproducible model for investigating the pathogenesis of NAFLD and its progression.NEW & NOTEWORTHY Nonalcoholic fatty liver disease (NAFLD) affects 30% of the general population and can progress to nonalcoholic steatohepatitis (NASH) and potentially hepatocellular carcinoma. Preclinical models rely on mouse models that often display hepatic characteristics of NAFLD but rarely progress to NASH and seldom depict the multisystem effects of the disease. We have conducted comprehensive metabolic analysis of both male and female mice consuming a Western diet of trans fats and sugar, focusing on both their hepatic phenotype and extrahepatic manifestations.

Pesticide use and risk of Hodgkin lymphoma: results from the North American Pooled Project (NAPP).

PURPOSE: The purpose of this study was to investigate associations between pesticide exposures and risk of Hodgkin lymphoma (HL) using data from the North American Pooled Project (NAPP). METHODS: Three population-based studies conducted in Kansas, Nebraska, and six Canadian provinces (HL = 507, Controls = 3886) were pooled to estimate odds ratios and 95% confidence intervals for single (never/ever) and multiple (0, 1, 2-4, ≥ 5) pesticides used, duration (years) and, for select pesticides, frequency (days/year) using adjusted logistic regression models. An age-stratified analysis (≤ 40/ > 40 years) was conducted when numbers were sufficient. RESULTS: In an analysis of 26 individual pesticides, ever use of terbufos was significantly associated with HL (OR: 2.53, 95% CI 1.04-6.17). In age-stratified analyses, associations were stronger among those ≤ 40 years of age. No significant associations were noted among those > 40 years old; however, HL cases ≤ 40 were three times more likely to report ever using dimethoate (OR: 3.76 95% CI 1.02-33.84) and almost twice as likely to have ever used malathion (OR: 1.86 95% CI 1.00-3.47). Those ≤ 40 years of age reporting use of 5 + organophosphate insecticides had triple the odds of HL (OR: 3.00 95% CI 1.28-7.03). Longer duration of use of 2,4-D, ≥ 6 vs. 0 years, was associated with elevated odds of HL (OR: 2.59 95% CI 1.34-4.97). CONCLUSION: In the NAPP, insecticide use may increase the risk of HL, but results are based on small numbers.

Silica and asbestos exposure at work and the risk of bladder cancer in Canadian men: a population-based case-control study.

BACKGROUND: Silica and asbestos are recognized lung carcinogens. However, their role in carcinogenesis at other organs is less clear. Clearance of inhaled silica particles and asbestos fibers from the lungs may lead to translocation to sites such as the bladder where they may initiate carcinogenesis. We used data from a Canadian population-based case-control study to evaluate the associations between these workplace exposures and bladder cancer. METHODS: Data from a population-based case-control study were used to characterize associations between workplace exposure to silica and asbestos and bladder cancer among men. Bladder cancer cases (N = 658) and age-frequency matched controls (N = 1360) were recruited within the National Enhanced Cancer Surveillance System from eight Canadian provinces (1994-97). Exposure concentration, frequency and reliability for silica and asbestos were assigned to each job, based on lifetime occupational histories, using a combination of job-exposure profiles and expert review. Exposure was modeled as ever/never, highest attained concentration, duration (years), highest attained frequency (% worktime) and cumulative exposure. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated using adjusted logistic regression. RESULTS: A modest (approximately 20%) increase in bladder cancer risk was found for ever having been exposed to silica, highest attained concentration and frequency of exposure but this increase was not statistically significant. Relative to unexposed, the odds of bladder cancer were 1.41 (95%CI: 1.01-1.98) times higher among men exposed to silica at work for ≥27 years. For asbestos, relative to unexposed, an increased risk of bladder cancer was observed for those first exposed ≥20 years ago (OR:2.04, 95%CI:1.25-3.34), those with a frequency of exposure of 5-30% of worktime (OR:1.45, 95%CI:1.06-1.98), and for those with < 10 years of exposure at low concentrations (OR:1.75, 95%CI:1.10-2.77) and the lower tertile of cumulative exposure (OR:1.69, 95%CI:1.07-2.65). However, no clear exposure-response relationships emerged. CONCLUSIONS: Our results indicate a slight increase in risk of bladder cancer with exposure to silica and asbestos, suggesting that the effects of these agents are broader than currently recognized. The findings from this study inform evidence-based action to enhance cancer prevention efforts, particularly for workers in industries with regular exposure.

Phthalates: Relationships between Air, Dust, Electronic Devices, and Hands with Implications for Exposure.

Exposure to phthalates is pervasive and is of concern due to associations with adverse health effects. Exposures and exposure pathways of six phthalates were investigated for 51 women aged 18-44 years in Ontario, Canada, based on measured phthalate concentrations in hand wipes and indoor media in their residences. All six phthalates had detection frequencies of 100% in air (∑6670 ng m-3 geomean) and floor dust (∑6630 µg g-1), nearly 100% detection frequencies for hand palms and backs that were significantly correlated and concentrations were repeatable over a 3 week interval. Phthalates on hands were significantly correlated with levels in air and dust, as expected according to partitioning theory. Total exposure was estimated as 4860 ng kg bw-1 day-1 (5th and 95th percentiles 1980-16 950 ng kg bw-1 day-1), with dust ingestion, followed by hand-to-mouth transfer, as the dominant pathways. With the exception of diethyl phthalate (DEP), phthalates had over 50% detection frequencies in surface wipes of most electronic devices sampled, including devices in which the use of phthalates was not expected. Phthalate concentrations on surfaces of hand-held devices were ∼10 times higher than on non-hand-held devices and were correlated with levels on hands. The data are consistent with phthalate emissions from sources such as laminate flooring and personal care products (e.g., scented candles), followed by partitioning among air, dust, and surface films that accumulate on electronic devices and skin, including hands. We hypothesize that hands transfer phthalates from emission sources and dust to hand-held electronic devices, which accumulate phthalates due to infrequent washing and which act as a sink and then a secondary source of exposure. The findings support those of others that exposure can be mitigated by increasing ventilation, damp cloth cleaning, and minimizing the use of phthalate-containing products and materials.

Exposure to crystalline silica in Canadian workplaces and the risk of kidney cancer.

OBJECTIVES: The causes of kidney cancer are not well understood though occupational exposures are thought to play a role. Crystalline silica is a known human carcinogen, and despite previous links with kidney disease, there have been few studies investigating its association with kidney cancer. We addressed this research gap using a population-based case-control study of Canadian men. METHODS: Questionnaire data were obtained from individuals with histologically confirmed kidney cancer, and population-based controls recruited from eight Canadian provinces (1994-1997). An industrial hygienist characterised participants' lifetime occupational exposure, and their confidence in the assessment (possibly, probably or definitely exposed) to silica on three dimensions (intensity, frequency and duration), and cumulative exposure was estimated. Logistic regression was used to estimate ORs and 95% CIs, adjusting for potential confounders. RESULTS: Nearly half of the 689 kidney cancer cases (49%) and 2369 controls (44%) had ever been occupationally exposed to crystalline silica. In a fully adjusted model, workers ever-exposed to silica had a slightly increased risk of kidney cancer relative to those who were unexposed (OR 1.10, 95% CI 0.92 to 1.32). Odds were modestly (and generally not statistically significantly) increased for models with duration of exposure and cumulative exposure, though exposure-response relationships were not evident. CONCLUSIONS: Our findings do not provide evidence that occupational exposure to crystalline silica increases risk of kidney cancer in men.

Hypothyroidism in utero stimulates pancreatic beta cell proliferation and hyperinsulinaemia in the ovine fetus during late gestation.

KEY POINTS: Thyroid hormones are important regulators of growth and maturation before birth, although the extent to which their actions are mediated by insulin and the development of pancreatic beta cell mass is unknown. Hypothyroidism in fetal sheep induced by removal of the thyroid gland caused asymmetric organ growth, increased pancreatic beta cell mass and proliferation, and was associated with increased circulating concentrations of insulin and leptin. In isolated fetal sheep islets studied in vitro, thyroid hormones inhibited beta cell proliferation in a dose-dependent manner, while high concentrations of insulin and leptin stimulated proliferation. The developing pancreatic beta cell is therefore sensitive to thyroid hormone, insulin and leptin before birth, with possible consequences for pancreatic function in fetal and later life. The findings of this study highlight the importance of thyroid hormones during pregnancy for normal development of the fetal pancreas. ABSTRACT: Development of pancreatic beta cell mass before birth is essential for normal growth of the fetus and for long-term control of carbohydrate metabolism in postnatal life. Thyroid hormones are also important regulators of fetal growth, and the present study tested the hypotheses that thyroid hormones promote beta cell proliferation in the fetal ovine pancreatic islets, and that growth retardation in hypothyroid fetal sheep is associated with reductions in pancreatic beta cell mass and circulating insulin concentration in utero. Organ growth and pancreatic islet cell proliferation and mass were examined in sheep fetuses following removal of the thyroid gland in utero. The effects of triiodothyronine (T3 ), insulin and leptin on beta cell proliferation rates were determined in isolated fetal ovine pancreatic islets in vitro. Hypothyroidism in the sheep fetus resulted in an asymmetric pattern of organ growth, pancreatic beta cell hyperplasia, and elevated plasma insulin and leptin concentrations. In pancreatic islets isolated from intact fetal sheep, beta cell proliferation in vitro was reduced by T3 in a dose-dependent manner and increased by insulin at high concentrations only. Leptin induced a bimodal response whereby beta cell proliferation was suppressed at the lowest, and increased at the highest, concentrations. Therefore, proliferation of beta cells isolated from the ovine fetal pancreas is sensitive to physiological concentrations of T3 , insulin and leptin. Alterations in these hormones may be responsible for the increased beta cell proliferation and mass observed in the hypothyroid sheep fetus and may have consequences for pancreatic function in later life.

Prostate cancer in firefighting and police work: a systematic review and meta-analysis of epidemiologic studies.

OBJECTIVES: We conducted a systematic review and meta-analysis to evaluate potential associations between firefighting and police occupations, and prostate cancer incidence and mortality. METHODS: Original epidemiological studies published from 1980 to 2017 were identified through PubMed and Web of Science. Studies were included if they contained specific job titles for ever/never firefighting and police work and associated prostate cancer risk estimates with 95% confidence intervals (CI). Study quality was assessed using a 20-point checklist. Prostate cancer meta-risk estimates (mRE) and corresponding 95% CIs were calculated for firefighting and police work separately and by various study characteristics using random effects models. Between-study heterogeneity was evaluated using the I2 score. Publication bias was assessed using Begg's and Egger's tests. RESULTS: A total of 26 firefighter and 12 police studies were included in the meta-analysis, with quality assessment scores ranging from 7 to 19 points. For firefighter studies, the prostate cancer incidence mRE was 1.17 (95% CI = 1.08-1.28, I2 = 72%) and the mortality mRE was 1.12 (95% CI = 0.92-1.36, I2 = 50%). The mRE for police incidence studies was 1.14 (95% CI = 1.02-1.28; I2 = 33%); for mortality studies, the mRE was 1.08 (95% CI = 0.80-1.45; I2 = 0%). By study design, mREs for both firefighter and police studies were similar to estimates of incidence and mortality. CONCLUSION: Small excess risks of prostate cancer were observed from firefighter studies with moderate to substantial heterogeneity and a relatively small number of police studies, respectively. There is a need for further studies to examine police occupations and to assess unique and shared exposures in firefighting and police work.

Pesticide exposures and the risk of multiple myeloma in men: An analysis of the North American Pooled Project.

Multiple myeloma (MM) has been consistently linked with agricultural activities, including farming and pesticide exposures. Three case-control studies in the United States and Canada were pooled to create the North American Pooled Project (NAPP) to investigate associations between pesticide use and haematological cancer risk. This analysis used data from 547 MM cases and 2700 controls. Pesticide use was evaluated as follows: ever/never use; duration of use (years); and cumulative lifetime-days (LD) (days/year handled × years of use). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression adjusted for age, province/state of residence, use of proxy respondents and selected medical conditions. Increased MM risk was observed for ever use of carbaryl (OR = 2.02, 95% CI = 1.28-3.21), captan (OR = 1.98, 95% CI = 1.04-3.77) and DDT (OR = 1.44, 95% CI = 1.05-1.97). Using the Canadian subset of NAPP data, we observed a more than threefold increase in MM risk (OR = 3.18, 95% CI = 1.40-7.23) for ≤10 cumulative LD of carbaryl use. The association was attenuated but remained significant for >10 LD of carbaryl use (OR = 2.44; 95% CI = 1.05-5.64; ptrend = 0.01). For captan, ≤17.5 LD of exposure was also associated with a more than threefold increase in risk (OR = 3.52, 95% CI = 1.32-9.34), but this association was attenuated in the highest exposure category of >17.5 LD (OR = 2.29, 95% CI = 0.81-6.43; ptrend = 0.01). An increasing trend (ptrend = 0.04) was observed for LD of DDT use (LD > 22; OR = 1.92, 95% CI = 0.95-3.88). In this large North American study of MM and pesticide use, we observed significant increases in MM risk for use of carbaryl, captan and DDT.

Long-term outcomes of persistent disease and relapse in primary membranous nephropathy.

BACKGROUND: Primary membranous nephropathy is associated with variable clinical course ranging from spontaneous remission to slow progression to end stage renal failure. Achieving remission confers better renal survival in primary membranous nephropathy (PMN). Longer term outcomes such as patient survival and relapse of active disease remain poorly understood. METHODS: We performed a retrospective study of 128 consecutive adult patients diagnosed with biopsy proven PMN at a single UK centre between 1980 and 2010. These patients were followed prospectively over a median of 128 months. We assessed impact of persistent disease and relapse on Stage 5 chronic kidney disease (CKD-5) and patient survival and present longer term cumulative incidences of different end points. RESULTS: One hundred patients achieved partial remission (PartRem) and 28 patients did not achieve remission (NoRem). Nine per cent of patients achieving first remission developed CKD-5 and 75% of those with NoRem developed CKD-5 [hazard ratio (HR) 0.07, 95% confidence interval 0.03-0.19). Relapse following PartRem occurred in 31 patients (31%) during follow-up and was significantly associated with progression to CKD-5. Progression to CKD-5 was strongly associated with death (47 versus 6%, HR 23.4; P < 0.01). Cumulative incidence at 15 years following first presentation included: death, 14%; CKD-5, 28%; and relapse 40% (in patients who achieved first remission). CONCLUSIONS: Our data strongly suggest that mortality in PMN is seen in patients with disease progression to CKD-5. Achieving remission is strongly associated with improved renal survival after first presentation and following relapse. We suggest that patients who achieve remission should be followed up in longer term, and better strategies to help improve outcomes are needed in clinical practice.

Natural resource-based industries and prostate cancer risk in Northeastern Ontario: a case-control study.

OBJECTIVE: Prostate cancer continues to be the most commonly diagnosed cancer in men, and there is limited knowledge on its preventable risk factors. A number of occupational exposures in natural resource-based industries are suspected to be related to prostate cancer risk. This study investigates associations between employment in these industries and prostate cancer. METHODS: Data were from a population-based, case-control study previously conducted in Northeastern Ontario. Incident cases (N=760) aged 45-85 years and diagnosed with prostate cancer between 1995 and 1998 were identified from the Ontario Cancer Registry. Controls (N=1632) were recruited using telephone listings, and were frequency matched to cases by age. Lifetime occupational history was collected for all participants. Logistic regression was used to estimate ORs and their associated 95% CIs. RESULTS: Elevated risks were observed for employment in forestry and logging industries (OR=1.87, 95% CI 1.32 to 2.73) and occupations (OR=1.71, 95% CI 1.24 to 2.35), and these risks increased with duration of employment for ≥10 years. Elevated risks were also found for employment in wood products industries (OR=1.45, 95% CI 1.07 to 1.97), and paper and allied products industries (OR=1.43, 95% CI 1.03 to 2.00), and when duration of employment was ≥10 years. There were also elevated risks in agriculture and mining-related work; however, these findings were not consistent across industry and occupation categories. CONCLUSIONS: Prostate cancer risk may be associated with work in several natural resource industries, primarily in the forest industries. To further evaluate observed associations, studies should focus on natural resource-based exposures in larger populations with improved exposure assessment.

Workplace exposure to diesel and gasoline engine exhausts and the risk of colorectal cancer in Canadian men.

BACKGROUND: The International Agency for Research on Cancer (IARC) classified diesel exhaust as carcinogenic to humans (Group 1) and gasoline exhaust as a possible carcinogen (Group 2B) based studies of lung cancer, however the evidence for other sites is limited. We addressed this question by investigating exposure to diesel and gasoline emissions with respect to risk of colorectal cancer in men. METHODS: We used data from a population-based case-control study with incident cases of colon (n = 931) and rectal (n = 840) cancer and 1360 controls from 7 Canadian provinces conducted in 1994-1997. Lifetime occupational history and information on other risk factors was collected. Occupational hygienists, blinded to case-control status, assigned exposures to each job for 3 dimensions: concentration, frequency, and reliability. Logistic regression was used to estimate odds ratios (OR) and their 95 % confidence intervals (CI), adjusted for age, province, use of proxy respondents, smoking, body-mass index, physical activity, intake of alcohol, processed meats, and occupational exposure to asbestos and aromatic amines. RESULTS: Among CRC cases, 638 (36 %) were exposed to diesel and 814 (46 %) were exposed to gasoline emissions. Relative to the unexposed, elevated risks were observed among subjects ever exposed to high concentration levels of diesel emissions for colorectal cancer (OR = 1.65, 95 % CI = 0.98-2.80) and rectal cancer (OR = 1.98, 95 % CI = 1.09-3.60), but not colon cancer. Prolonged (>10 years) exposure at high concentrations was also associated with high risks of rectal cancer (OR = 2.33 95 % CI = 0.94-5.78; p-trend = 0.02). No statistically significant associations were observed for gasoline emissions. CONCLUSIONS: Our findings suggest that sustained high-level exposure diesel emissions may increase the risk of rectal cancer.

Environmental immune disruptors, inflammation and cancer risk.

An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.

Glomerular cell cross-talk influences composition and assembly of extracellular matrix.

The glomerular basement membrane (GBM) is a specialized extracellular matrix (ECM) compartment within the glomerulus that contains tissue-restricted isoforms of collagen IV and laminin. It is integral to the capillary wall and therefore, functionally linked to glomerular filtration. Although the composition of the GBM has been investigated with global and candidate-based approaches, the relative contributions of glomerular cell types to the production of ECM are not well understood. To characterize specific cellular contributions to the GBM, we used mass spectrometry-based proteomics to analyze ECM isolated from podocytes and glomerular endothelial cells in vitro. These analyses identified cell type-specific differences in ECM composition, indicating distinct contributions to glomerular ECM assembly. Coculture of podocytes and endothelial cells resulted in an altered composition and organization of ECM compared with monoculture ECMs, and electron microscopy revealed basement membrane-like ECM deposition between cocultured cells, suggesting the involvement of cell-cell cross-talk in the production of glomerular ECM. Notably, compared with monoculture ECM proteomes, the coculture ECM proteome better resembled a tissue-derived glomerular ECM dataset, indicating its relevance to GBM in vivo. Protein network analyses revealed a common core of 35 highly connected structural ECM proteins that may be important for glomerular ECM assembly. Overall, these findings show the complexity of the glomerular ECM and suggest that both ECM composition and organization are context-dependent.

Occupational exposure to crystalline silica and the risk of lung cancer in Canadian men.

Crystalline silica is a recognized carcinogen, but the association with lung cancer at lower levels of exposure has not been well characterized. This study investigated the relationship between occupational silica exposure and lung cancer and the combined effects of cigarette smoking and silica exposure on lung cancer risk. A population-based case-control study was conducted in eight Canadian provinces between 1994 and 1997. Self-reported questionnaires were used to obtain a lifetime occupational history and information on other risk factors. Occupational hygienists assigned silica exposures to each job based on concentration, frequency and reliability. Data from 1681 incident lung cancer cases and 2053 controls were analyzed using logistic regression to estimate odds ratios (OR) and their 95% confidence intervals (CI). Models included adjustments for cigarette smoking, lifetime residential second-hand smoke and occupational exposure to diesel and gasoline engine emissions. Relative to the unexposed, increasing duration of silica exposure at any concentration was associated with a significant trend in lung cancer risk (OR ≥ 30 years: 1.67, 1.21-2.24; ptrend = 0.002). The highest tertile of cumulative silica exposure was associated with lung cancer (OR = 1.81, 1.34-2.42; ptrend = 0.004) relative to the lowest. Men exposed to silica for ≥30 years with ≥40 cigarette pack-years had the highest risk relative to those unexposed with <10 pack-years (OR = 42.53, 23.54-76.83). The joint relationship with smoking was consistent with a multiplicative model. Our findings suggest that occupational exposure to silica is a risk factor for lung cancer, independently from active and passive smoking, as well as from exposure to other lung carcinogens.

Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia.

We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10(-16)). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development.

Evaluating the Clinical Relevance of Antibodies against Non-Human Leukocyte Antigen in Kidney Transplantation.

Introduction: Kidney transplantation is the preferred modality of kidney replacement therapy for eligible patients with end-stage kidney disease (ESKD), given that it has been found to reduce mortality rates, improve quality of life, and is cost-effective compared to dialysis. Recent advancements in human leukocyte antigen (HLA) typing and donor-specific antibody (DSA) detection have helped to reduce the risk of rejection, but antibody-mediated rejection (AMR) can still occur without DSA. Previous studies suggest that rejection can be attributed to antibodies against Non-Human Leucocyte Antigens (non-HLAs). We aimed to acquire further understanding of the prevalence and distribution of non-HLA antibodies in our local population and attempt to correlate these findings with graft outcomes, as well as assess whether non-HLA antibodies can be utilized to determine graft impairment and dysfunction. Methods: We conducted a retrospective study involving kidney transplant recipients between January 2010 and December 2020. All included individuals were aged over 18 and underwent kidney-alone transplants; were ABO- and HLA-compatible; and were matched at A, B, and DR loci (mismatch 0:0:0). HLA testing was negative at the time of transplantation. The samples from both cases of early graft rejection and the control group were tested for non-HLA antibodies using One Lambda LABScreenTM, Autoantibody kit groups 1, 2, and 3, as well as the Immucor LIFECODES non-HLA autoantibody assay. Results: A total of 850 kidney transplant recipients were included, in which 12 patients experienced early graft rejection within the first month post transplant and 18 patients who did not experience graft rejection were selected as study controls. Our study reported no correlation between the total burden of non-HLA antibodies and early rejection, most likely as the result of a small sample size. Nevertheless, a sub-analysis revealed that specific high-frequency pre-transplant non-HLA antibodies such as GSTT, CXCL11, CXCL10, and HNR, detected by LIFECODES, were associated with rejection (Fisher's exact test with Bonferroni correction, p < 0.001). Most pre-transplant non-HLA antibody levels were reduced after transplantation, which was attributed to immunosuppression. Conclusion: The 'high frequency' non-HLA antibodies displayed an association with graft rejection, though the overall associations between the burden of non-HLA antibodies and rejection episodes remain inconclusive. Further work is needed to establish the rebound phenomenon of non-HLA antibodies, the development of de novo non-HLA antibodies in the long run, and their implications on graft survival.

Multiple pesticide exposures and the risk of multiple myeloma in Canadian men.

Multiple myeloma (MM) has been linked to certain agricultural exposures, including pesticides. This analysis aimed to investigate the association between lifetime use of multiple pesticides and MM risk using two exposure metrics: number of pesticides used and days per year of pesticide use. A frequency-matched, population-based case-control study was conducted among men in six Canadian provinces between 1991 and 1994. Data from 342 MM cases and 1,357 controls were analyzed using logistic regression to calculate odds ratios (OR) and 95% confidence intervals. Pesticides were grouped by type, chemical class and carcinogenic potential, using a composite carcinogenic probability score. Selected individual pesticides were also examined. Regression models were adjusted for age, province of residence, use of proxy respondents, smoking and selected medical history variables. The overall pattern of results was complex. Positive trends in risk were observed for fungicides (ptrend=0.04) and pesticides classified as probably carcinogenic or higher (ptrend=0.03). Excess risks of MM were observed among men who reported using at least one carbamate pesticide (OR=1.94, 1.16-3.25), one phenoxy herbicide (OR=1.56, 1.09-2.25) and ≥3 organochlorines (OR=2.21, 1.05-4.66). Significantly higher odds of MM were seen for exposure to carbaryl (OR=2.71, 1.47-5.00) and captan (OR=2.96, 1.40-6.24). Use of mecoprop for >2 days per year was also significantly associated with MM (OR=2.15, 1.03-4.48). Focusing on multiple pesticide exposures is important because this more accurately reflects how exposures occur in occupational settings. Significant associations observed for certain chemical classes and individual pesticides suggest that these may be MM risk factors.