The human health effects of unconventional oil and gas development (UOGD): A scoping review of epidemiologic studies.

OBJECTIVE: Unconventional oil and gas development (UOGD, sometimes termed "fracking" or "hydraulic fracturing") is an industrial process to extract methane gas and/or oil deposits. Many chemicals used in UOGD have known adverse human health effects. Canada is a major producer of UOGD-derived gas with wells frequently located in and around rural and Indigenous communities. Our objective was to conduct a scoping review to identify the extent of research evidence assessing UOGD exposure-related health impacts, with an additional focus on Canadian studies. METHODS: We included English- or French-language peer-reviewed epidemiologic studies (January 2000-December 2022) which measured exposure to UOGD chemicals directly or by proxy, and where health outcomes were plausibly caused by UOGD-related chemical exposure. Results synthesis was descriptive with results ordered by outcome and hierarchy of methodological approach. SYNTHESIS: We identified 52 studies from nine jurisdictions. Only two were set in Canada. A majority (n = 27) used retrospective cohort and case-control designs. Almost half (n = 24) focused on birth outcomes, with a majority (n = 22) reporting one or more significant adverse associations of UOGD exposure with: low birthweight; small for gestational age; preterm birth; and one or more birth defects. Other studies identified adverse impacts including asthma (n = 7), respiratory (n = 13), cardiovascular (n = 6), childhood acute lymphocytic leukemia (n = 2), and all-cause mortality (n = 4). CONCLUSION: There is a growing body of research, across different jurisdictions, reporting associations of UOGD with adverse health outcomes. Despite the rapid growth of UOGD, which is often located in remote, rural, and Indigenous communities, Canadian research on its effects on human health is remarkably sparse. There is a pressing need for additional evidence.

RéSUMé: OBJECTIF: L'exploitation pétrolière et gazière non conventionnelle (EPGNC, parfois appelée « fracturation ¼ ou « fracturation hydraulique ¼) est un processus industriel d'extraction du méthane et/ou de gisements de pétrole. De nombreux produits chimiques utilisés dans l'EPGNC ont des effets indésirables connus sur la santé humaine. Le Canada est un grand producteur de gaz dérivé de l'EPGNC, dont les puits sont souvent situés à l'intérieur et autour de communautés rurales et autochtones. Nous avons mené une étude de champ pour déterminer l'étendue des données de recherche évaluant les effets sur la santé de l'exposition à l'EPGNC, en nous concentrant plus particulièrement sur les études canadiennes. MéTHODE: Nous avons inclus des études épidémiologiques en anglais ou en français évaluées par les pairs (janvier 2000 à décembre 2022) qui mesuraient l'exposition directe ou indirecte aux produits chimiques de l'EPGNC et dans lesquelles les résultats cliniques étaient plausiblement causés par l'exposition aux produits chimiques liés à l'EPGNC. La synthèse des résultats est descriptive, et les résultats sont ordonnés selon les résultats cliniques et l'approche méthodologique. SYNTHèSE: Nous avons identifié 52 études menées dans neuf juridictions. Deux seulement étaient canadiennes. La majorité (n = 27) faisaient appel à des cohortes rétrospectives ou étaient des études cas-témoins. Près de la moitié (n = 24) portaient sur les issues de la grossesse, et la majorité (n = 22) déclaraient une ou plusieurs associations indésirables significatives entre l'exposition à l'EPGNC et : l'insuffisance de poids à la naissance; la petite taille du bébé pour son âge gestationnel; la naissance avant terme; et une ou plusieurs anomalies congénitales. D'autres études faisaient état d'effets indésirables, dont l'asthme (n = 7), les troubles respiratoires (n = 13), les troubles cardiovasculaires (n = 6), la leucémie aiguë lymphoblastique infantile (n = 2) et la mortalité toutes causes confondues (n = 4). CONCLUSION: Il existe dans différents pays un corpus croissant d'études qui font état d'associations entre l'EPGNC et des résultats sanitaires indésirables. Malgré la croissance rapide de l'EPGNC, souvent présente dans des communautés éloignées, rurales et autochtones, la recherche canadienne sur ses effets sur la santé humaine est remarquablement clairsemée. Il y a un besoin urgent de recueillir d'autres données probantes à ce sujet.

The Putative S1PR1 Modulator ACT-209905 Impairs Growth and Migration of Glioblastoma Cells In Vitro.

Glioblastoma (GBM) is still a deadly tumor due to its highly infiltrative growth behavior and its resistance to therapy. Evidence is accumulating that sphingosine-1-phosphate (S1P) acts as an important tumor-promoting molecule that is involved in the activation of the S1P receptor subtype 1 (S1PR1). Therefore, we investigated the effect of ACT-209905 (a putative S1PR1 modulator) on the growth of human (primary cells, LN-18) and murine (GL261) GBM cells. The viability and migration of GBM cells were both reduced by ACT-209905. Furthermore, co-culture with monocytic THP-1 cells or conditioned medium enhanced the viability and migration of GBM cells, suggesting that THP-1 cells secrete factors which stimulate GBM cell growth. ACT-209905 inhibited the THP-1-induced enhancement of GBM cell growth and migration. Immunoblot analyses showed that ACT-209905 reduced the activation of growth-promoting kinases (p38, AKT1 and ERK1/2), whereas THP-1 cells and conditioned medium caused an activation of these kinases. In addition, ACT-209905 diminished the surface expression of pro-migratory molecules and reduced CD62P-positive GBM cells. In contrast, THP-1 cells increased the ICAM-1 and P-Selectin content of GBM cells which was reversed by ACT-209905. In conclusion, our study suggests the role of S1PR1 signaling in the growth of GBM cells and gives a partial explanation for the pro-tumorigenic effects that macrophages might have on GBM cells.

Platelet-Derived S1P and Its Relevance for the Communication with Immune Cells in Multiple Human Diseases.

Sphingosine-1-phosphate (S1P) is a versatile signaling lipid involved in the regulation of numerous cellular processes. S1P regulates cellular proliferation, migration, and apoptosis as well as the function of immune cells. S1P is generated from sphingosine (Sph), which derives from the ceramide metabolism. In particular, high concentrations of S1P are present in the blood. This originates mainly from erythrocytes, endothelial cells (ECs), and platelets. While erythrocytes function as a storage pool for circulating S1P, platelets can rapidly generate S1P de novo, store it in large quantities, and release it when the platelet is activated. Platelets can thus provide S1P in a short time when needed or in the case of an injury with subsequent platelet activation and thereby regulate local cellular responses. In addition, platelet-dependently generated and released S1P may also influence long-term immune cell functions in various disease processes, such as inflammation-driven vascular diseases. In this review, the metabolism and release of platelet S1P are presented, and the autocrine versus paracrine functions of platelet-derived S1P and its relevance in various disease processes are discussed. New pharmacological approaches that target the auto- or paracrine effects of S1P may be therapeutically helpful in the future for pathological processes involving S1P.

Second malignancies after treatment of childhood non-Hodgkin lymphoma: a report of the Berlin-Frankfurt-Muenster study group.

Second malignant neoplasms pose a concern for survivors of childhood cancer. We evaluated incidence, type and risk factors for second malignant neoplasms in patients included in Berlin-Frankfurt-Muenster protocols for childhood non-Hodgkin lymphoma. 3590 patients <15 years of age at diagnosis registered between 01/1981 and 06/2010 were analyzed. Second malignant neoplasms were reported by the treating institutions and the German Childhood Cancer Registry. After median follow-up of 9.4 years (Quartile, Q1 6.7 and Q3 12.1) 95 second malignant neoplasms were registered (26 carcinomas including 9 basal cell carcinomas, 21 acute myeloid leukemias/myelodysplastic syndromes, 20 lymphoid malignancies, 12 CNS-tumors, and 16 other). Cumulative incidence at 20 years was 5.7±0.7%, standard incidence ratio excluding basal cell carcinomas was 19.8 (95% CI 14.5-26.5). Median time from initial diagnosis to second malignancy was 8.7 years (range: 0.2-30.3). Acute-lymphoblastic-leukemia-type therapy, cumulative anthracycline dose, and cranial radiotherapy for brain tumor-development were significant risk factors in univariate analysis only. In multivariate analysis including risk factors significant in univariate analysis, female sex (HR 1.87, 95% CI 1.23-2.86, p=0.004), CNS-involvement (HR 2.24, 95% CI 1.03-4.88, p=0.042), lymphoblastic lymphoma (HR 2.60, 95% CI 1.69-3.97, p<0.001), and cancer-predisposing condition (HR 11.2, 95% CI 5.52-22.75, p<0.001) retained an independent risk. Carcinomas were the most frequent second malignant neoplasms after non-Hodgkin lymphoma in childhood followed by acute myeloid leukemia and lymphoid malignancies. Female sex, lymphoblastic lymphoma, CNS-involvement, or/and known cancer-predisposing condition were risk factors for second malignant neoplasm-development. Our findings set the basis for individualized long-term follow-up and risk assessment of new therapies.

Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma.

In the European Intergroup EURO-LB02 trial, children and adolescents with lymphoblastic lymphoma underwent the non-Hodgkin lymphoma Berlin-Frankfurt-Münster protocol without prophylactic cranial radiotherapy. The primary aims of this trial were to test whether replacing prednisone with dexamethasone during induction increases event-free survival in the subgroups with T-cell lymphoblastic lymphoma and whether therapy duration could be reduced from 24 to 18 months (factorial design, randomizations). These questions could not be answered due to premature closure of the trial. Here we report on the secondary aims of the trial: whether the results of the NHL-BFM90 study could be reproduced and evaluation of disease features and prognostic factors. Three hundred and nineteen patients (66 with precursor B-cell lymphoblastic lymphoma, 233 with T-cell lymphoblastic lymphoma, 12 with mixed phenotype, 8 not classifiable) were enrolled. In induction, 215 patients received prednisone and 104 patients received dexamethasone. The median follow-up was 6.8 years (range, 3.0-10.3). The 5-year event-free survival was 82±2% [12 toxic deaths, 5 secondary malignancies, 43 non-response/relapse (central nervous system n=9; all received prednisone during induction)]. The event-free survival rate was 80±5% for patients with precursor B-cell lymphoblastic lymphoma, 82±3% for those with T-cell lymphoblastic lymphoma, and 100% for patients with a mixed phenotype. During induction, significantly more grade III/IV toxicities were observed in patients receiving dexamethasone, resulting in significant treatment delays. The number of toxic deaths did not differ significantly. The only variable associated with outcome was performance status at diagnosis. The 90% event-free survival rate for patients with T-cell lymphoblastic lymphoma shown in study NHL-BFM90 was not replicated, mainly due to more toxic deaths and central nervous system relapses. Dexamethasone in induction may prevent central nervous system relapse more effectively than prednisone but produces a higher burden of toxicity. (#NCT00275106).

Sustained Off-Treatment Response After Discontinuation of Long-Term Nucleos(t)ide Analogue Treatment in HBeAg-Seronegative Hepatitis B: A Case Series.

International guidelines recommend lifelong nucleos(t)ide analogue (NA) treatment in individuals with chronic hepatitis B (CHB) infection who are hepatitis B e antigen (HBeAg) seronegative, because hepatitis B surface antigen (HBsAg) seroconversion is rarely achieved. However, after terminating therapy, sustained responses and HBsAg loss have been observed. Clinical characteristics identifying persons with favorable outcomes after discontinuing NA therapy have not yet been defined. This case series describes outcomes of 6 individuals with HBeAg-seronegative CHB infection without cirrhosis and low plasma levels of HBsAg who discontinued long-term NA treatment. All individuals had a virologic relapse and 4 of 6 had a biochemical relapse; but 5 of 6 later developed a sustained virologic and biochemical response and a marked reduction of quantitative HBsAg (qHBsAg). Two of the 6 individuals experienced HBsAg loss. Only 1 patient was retreated, and none showed signs of hepatic decompensation. NA treatment can be safely stopped in selected HBeAg-seronegative patients. Sustained offtreatment responses seem to be frequently preceded by a virologic and biochemical flare. Loss of HBsAg possibly reflects restoration of antiviral immunity during prolonged NA treatment. Predictive factors, such as qHBsAg, may be valuable in selecting patients who could benefit from NA discontinuation.

Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen-breakage syndrome): a retrospective survey.

Children with chromosomal instability syndromes have an increased risk of developing lymphoma and leukaemia. The treatment of these malignancies is hampered by therapy-associated toxicity and infectious complications. This retrospective analysis evaluated the therapy outcome of 38 children with Ataxia teleangiectasia or Nijmegen-breakage syndrome with acute lymphoblastic leukaemia (ALL, n = 9), Non-Hodgkin lymphoma (NHL, n = 28) and Hodgkin lymphoma (HL, n = 1). All patients with NHL or ALL were treated in accordance to Berlin-Frankfurt-Münster (BFM)- or Co-operative study group for childhood ALL (CoALL)-oriented chemotherapy schedules. 22 patients received significantly reduced-intensity chemotherapy. After a median follow-up of 3·7 years the 10-year overall survival was 58%. Dosage-reduction of chemotherapeutic drugs seemed to have no disadvantages and reduced toxic side effects. On the other hand, reduced-intensity chemotherapy did not prevent second malignancies, which occurred in ten patients with a 10-year incidence of 25%. After individual treatment approaches three of these patients with second malignancies were in complete clinical remission for more than 5 years. We conclude that BFM- or CoALL-oriented chemotherapy is effective and can be administered in children with AT or NBS. Moreover, we show that even second lymphoid malignancies can successfully be treated in these patients.

Generating oscillatory bursts from a network of regular spiking neurons without inhibition.

Avian nucleus isthmi pars parvocellularis (Ipc) neurons are reciprocally connected with the layer 10 (L10) neurons in the optic tectum and respond with oscillatory bursts to visual stimulation. Our in vitro experiments show that both neuron types respond with regular spiking to somatic current injection and that the feedforward and feedback synaptic connections are excitatory, but of different strength and time course. To elucidate mechanisms of oscillatory bursting in this network of regularly spiking neurons, we investigated an experimentally constrained model of coupled leaky integrate-and-fire neurons with spike-rate adaptation. The model reproduces the observed Ipc oscillatory bursting in response to simulated visual stimulation. A scan through the model parameter volume reveals that Ipc oscillatory burst generation can be caused by strong and brief feedforward synaptic conductance changes. The mechanism is sensitive to the parameter values of spike-rate adaptation. In conclusion, we show that a network of regular-spiking neurons with feedforward excitation and spike-rate adaptation can generate oscillatory bursting in response to a constant input.

Distributed delays stabilize neural feedback systems.

We consider the effect of distributed delays in neural feedback systems. The avian optic tectum is reciprocally connected with the isthmic nuclei. Extracellular stimulation combined with intracellular recordings reveal a range of signal delays from 3 to 9 ms between isthmotectal elements. This observation together with prior mathematical analysis concerning the influence of a delay distribution on system dynamics raises the question whether a broad delay distribution can impact the dynamics of neural feedback loops. For a system of reciprocally connected model neurons, we found that distributed delays enhance system stability in the following sense. With increased distribution of delays, the system converges faster to a fixed point and converges slower toward a limit cycle. Further, the introduction of distributed delays leads to an increased range of the average delay value for which the system's equilibrium point is stable. The system dynamics are determined almost exclusively by the mean and the variance of the delay distribution and show only little dependence on the particular shape of the distribution.

MTHFR 677 (C-->T) polymorphism is not relevant for prognosis or therapy-associated toxicity in pediatric NHL: results from 484 patients of multicenter trial NHL-BFM 95.

We analyzed the relationship of genetic variation within the methylenetetrahydrofolate reductase gene (MTHFR 677 C-->T) with clinical characteristics, outcome, and therapy-related toxicity in pediatric non-Hodgkin's lymphoma (NHL) in our multicenter trial NHL-BFM 95. In this trial, high-dose methotrexate (MTX) infusion regimens were randomized (4- vs 24-h infusion) in patients with B-cell lymphoma; MTX was applied as 24-h infusion in all patients with lymphoblastic lymphoma and anaplastic large cell lymphoma. Toxicity data were collected per patient and therapy course according to National Cancer Institute Common Toxicity Criteria (NCI-CTC). The genotypes in 484 pediatric patients were distributed as follows: MTHFR 677 CC, 206 patients (42.6%); MTHFR 677 CT, 214 patients (44.2%); and MTHFR 677 TT, 64 patients (13.2%). Lymphoblastic lymphoma was significantly associated with homozygosity for the MTHFR 677 T allele. No association of MTHFR 677 genotype with clinical characteristics (sex, age, and tumor stage), outcome, or therapy-related toxicity could be detected. Therefore, we conclude that the MTHFR 677 C-->T polymorphism does not appear to influence outcome or therapy-associated toxicity in pediatric patients with NHL treated on BFM protocols.

MALT lymphoma in children: a report from the NHL-BFM Study Group.

Marginal zone lymphomas of MALT type comprise a considerable group of indolent B-cell non-Hodgkin lymphoma (NHL) in adult patients. In childhood, however, these tumors are extremely rare, as nearly all pediatric patients have aggressive NHL. Among 2,703 children and adolescents registered into the prospective multicenter NHL-BFM treatment studies since 1986, only 4 patients (0.1%) displayed features of MALT lymphoma. These tumors were localized in the stomach, breast, lower lid, and conjunctiva, respectively and they were associated with H. pylori infection in two patients. All children are alive but long-term follow-up will be mandatory to assess the behavior of MALT lymphoma in this age group.

Tumor necrosis factor and lymphotoxin alfa genetic polymorphisms and outcome in pediatric patients with non-Hodgkin's lymphoma: results from Berlin-Frankfurt-Münster Trial NHL-BFM 95.

PURPOSE: To analyze the association of genetic variation within the tumor necrosis factor (TNF -308 [G-->A]) and lymphotoxin alfa (LT-a +252 [A-->G]) genes with outcome in non-Hodgkin's lymphoma of childhood and adolescence. PATIENTS AND METHODS: Genotyping of the TNF -308 (G-->A) and LT-a +252 (A-->G) polymorphisms in patients (n = 488) enrolled onto the German-Austrian-Swiss multicenter trial NHL-BFM 95 from April 1996 to January 2000 was performed by polymerase chain reaction with subsequent restriction fragment length polymorphism analysis on DNA from tumor-free specimen. RESULTS: In patients with Burkitt's lymphoma (BL) and B-cell acute lymphoblastic leukemia (B-ALL; n = 219, 211 eligible patients), patients carrying at least two variant alleles (high-producer haplotypes) had an increased risk of events: probability of event-free survival (pEFS) at 3 years was 81% (SE = 5%), compared with 91% (SE = 2%) in low-producer haplotypes (P = .018). In BL/B-ALL with high tumor load (lactate dehydrogenase [LDH] > or = 500 U/L; n = 104), pEFS was 69% (SE = 8%) in high-producer versus 85% (SE = 4%) in low-producer haplotypes (P = .05). In multivariate analysis including risk factors for events (LDH > or = 500 U/L, CNS involvement, methotrexate infusion regimen), TNF -308/LT-alpha +252 haplotype kept prognostic relevance: patients with high-producer haplotypes had a 2.34-fold increase in risk of events (P = .048). The TNF -308 (G-->A) and LT-alpha +252 (A-->G) polymorphisms were not associated with pEFS in lymphoblastic lymphoma (n = 101), anaplastic large-cell lymphoma (n = 67), or diffuse large B-cell lymphoma (n = 65), nor with therapy-related toxicity. CONCLUSION: The TNF -308 (G-->A) and LT-a +252 (A-->G) polymorphisms were negative prognostic factors in pediatric BL/B-ALL. Among patients with serum LDH > or = 500 U/L, haplotype analysis further determined patients at risk for events.

Proliferation rate and outcome in children with T-cell rich B-cell lymphoma: a clinicopathologic study from the NHL-BFM-study group.

T-cell rich B-cell lymphoma (TCRBCL) is considered a rare variant of aggressive B-cell lymphoma characterized by few neoplastic cells and a large reactive infiltrate with striking similarities to nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL). In childhood, these tumors occur even less frequently. Biopsy specimens at diagnosis from 16 children (13 boys) with a median age of 12 years (range, 7 to 18) were immunophenotyped. The proliferation rate was assessed with monoclonal antibodies against Ki-67 and repp86 antigens and additional clonality analyses were performed. Ten patients had localized disease and only two had B symptoms. All patients showed high Ki-67 expression (median: 80%, range 40% to 90%), but low repp86 expression (median: 25%, range 10% to 50%). PCR-based clonality studies of the hypervariable CDR III region of the immunoglobuline heavy chain and the T-cell receptor gamma-chain genes demonstrated predominant clones in nine and five patients, respectively. Three patients had previous or concomitant NLPHL and two of them received initial treatment for Hodgkin's disease. All patients achieved remission after a brief polychemotherapy regimen. Two patients subsequently relapsed and one was rescued by salvage therapy including autologous stem cell transplantation. At a median follow-up of 23 months, 15 patients (94%) are alive. The striking contrast between the proliferation rates determined by Ki-67 and repp86 expression points to a possible arrest in the G1 cell cycle phase because repp86 expression is restricted to the S, G2 and M cell cycle phases. This G1 arrest may explain the paradoxon of high Ki-67 expression in a paucicellular lymphoma with a favorable prognosis in young patients.

K(IR)6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K(+) channels.

E23K, a common single nucleotide polymorphism in K(IR)6.2, the pore-forming subunit of pancreatic beta-cell ATP-sensitive K(+) channels, significantly enhanced open probability of these channels, thus reducing their sensitivity toward inhibitory ATP(4-) and increasing the threshold concentration for insulin release. Previous association studies and high allelic frequency suggest this effect to critically inhibit secretion and play a major role in pathogenesis of common type 2 diabetes. Based on evidence for functional relevance of E23K in both the heterozygous (E/K; with E in position 23 of K(IR)6.2 in one allele and K in the other) and homozygous (K/K; with K in position 23 of K(IR)6.2 in both alleles) genotype, we propose a model in which enhanced susceptibility to type 2 diabetes is associated with evolutionary advantage of the E/K state.

Spore adhesion of entomopathogenic fungi to larvae of Frankliniella occidentalis (Pergande, 1895)-(Thysanoptera: Thripidae).

The entomopathogenic fungus Verticillium lecanii proves to be very promising in controlling the population of Western Flower Thrips. Special investigations have been carried out to clear up the mechanisms of spore-adhesion at the insects with fluorescence-microscopy. After direct soil applications we have found a lot of spores/larva while applying low spore-concentrations. The loading with spores after indirect applications was very high as well. The addition of oils to the suspension enhanced the number of spores/insect and reduced the proportion of insects without spores.