Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression

Cancers may escape elimination by the host immune system by rewiring the tumour microenvironment towards an immune suppressive state. Transforming growth factor-β (TGF-β) is a secreted multifunctional cytokine that strongly regulates the activity of immune cells while, in parallel, can promote malignant features such as cancer cell invasion and migration, angiogenesis, and the emergence of cancer-associated fibroblasts. TGF-β is abundantly expressed in cancers and, most often, its abundance associated with poor clinical outcomes. Immunotherapeutic strategies, particularly T cell checkpoint blockade therapies, so far, only produce clinical benefit in a minority of cancer patients. The inhibition of TGF-β activity is a promising approach to increase the efficacy of T cell checkpoint blockade therapies. In this review, we briefly outline the immunoregulatory functions of TGF-β in physiological and malignant contexts. We then deliberate on how the therapeutic targeting of TGF-β may lead to a broadened applicability and success of state-of-the-art immunotherapies.Cancer Signaling networks and Molecular Therapeutic

Greenhouse gas observations from Cabauw Tall Tower (1992–2010)

Since 1992 semi-continuous in-situ observations of greenhouse gas concentrations have been performed at the tall tower of Cabauw (4.927° E, 51.971° N, −0.7 m a.s.l.). Through 1992 up to now, the measurement system has been gradually extended and improved in precision, starting with CO<sub>2</sub> and CH<sub>4</sub> concentrations from 200 m a.g.l. in 1992 to vertical gradients at 4 levels of the gases CO<sub>2</sub>, CH<sub>4</sub>, SF<sub>6</sub>, N<sub>2</sub>O, H<sub>2</sub>, CO and gradients at 2 levels for <sup>222</sup>Rn. In this paper the measurement systems and measurement results are described for the main greenhouse gases and CO, for the whole period. The automatic measurement system now provides half-hourly concentration gradients with a precision better than or close to the WMO recommendations. <br><br> The observations at Cabauw show a complex pattern caused by the influence of sources and sinks from a large area around the tower with significant contributions of sources and sinks at distances up to 500–700 km. The concentration footprint area of Cabauw is one the most intensive and complex source areas of greenhouse gases in the world. Despite this, annual mean trends for the most important greenhouse gases, compatible with the values derived using the global network, can be reproduced from the measured concentrations at Cabauw over the entire measurement period, with a measured increase in the period 2000–2009 for CO<sub>2</sub> of 1.90 ± 0.1 ppm yr<sup>−1</sup>, for CH<sub>4</sub> of 4.4 ± 0.6 ppb yr<sup>−1</sup>, for N<sub>2</sub>O of 0.86 ± 0.04 ppb yr<sup>−1</sup>, and for SF<sub>6</sub> of 0.27 ± 0.01 ppt yr<sup>−1</sup>; for CO no significant trend could be detected. <br><br> The influences of strong local sources and sinks are reflected in the amplitude of the mean seasonal cycles observed at Cabauw, that are larger than the mean Northern Hemisphere average; Cabauw mean seasonal amplitude for CO<sub>2</sub> is 25–30 ppm (higher value for lower sampling levels). The observed CH<sub>4</sub> seasonal amplitude is 50–110 ppb. All gases except N<sub>2</sub>O show highest concentrations in winter and lower concentrations in summer, N<sub>2</sub>O observations show two additional concentration maxima in early summer and in autumn. <br><br> Seasonal cycles of the day-time mean concentrations show that surface concentrations or high elevation concentrations alone do not give a representative value for the boundary layer concentrations, especially in winter time, but that the vertical profile data along the mast can be used to construct a useful boundary layer mean value. The variability at Cabauw in the atmospheric concentrations of CO<sub>2</sub> on time scales of minutes to hours is several ppm and is much larger than the precision of the measurements (0.1 ppm). The diurnal and synoptical variability of the concentrations at Cabauw carry information on the sources and sinks in the footprint area of the mast, that will be useful in combination with inverse atmospheric transport model to verify emission estimates and improve ecosystem models. For this purpose a network of tall tower stations like Cabauw forms a very useful addition to the existing global observing network for greenhouse gases

The contribution of HPV18 to cervical cancer is underestimated using high-grade CIN as a measure of screening efficiency

In one geographical area, 14 high-risk human papillomavirus types in cervical intraepithelial neoplasia (CIN2/3; n=139) and cervical squamous cell carcinoma (SCC; n=84) were analysed. HPV18 was more prevalent in SCC than CIN2/3 (OR 9.8; 95% confidence interval: 2.5–39). Other high-risk types prevalences corresponded in CIN2/3 and SCC. Evaluations using CIN2/3 as a measure of efficiency underestimate the contribution of HPV18 to SCC

Field comparison of two novel open-path instruments that measure dry deposition and emission of ammonia using flux-gradient and eddy covariance methods

Dry deposition of ammonia (NH3) is the largest contributor to the nitrogen deposition from the atmosphere to soil and vegetation in the Netherlands, causing eutrophication and loss of biodiversity; however, data sets of NH3 fluxes are sparse and in general have monthly resolution at best. An important reason for this is that measurement of the NH3 flux under dry conditions is notoriously difficult. There is no technique that can be considered as the gold standard for these measurements, which complicates the testing of new techniques. Here, we present the results of an intercomparison of two novel measurement set-ups aimed at measuring dry deposition of NH3 at half hourly resolution. Over a 5-week period, we operated two novel optical open-path techniques side by side at the Ruisdael station in Cabauw, the Netherlands: the RIVM-miniDOAS 2.2D using the aerodynamic gradient technique, and the commercial Healthy Photon HT8700E using the eddy covariance technique. These instruments are widely different in their measurement principle and approach to derive deposition values from measured concentrations; however, both techniques showed very similar results (r=0.87) and small differences in cumulative fluxes (∼ 10 %) as long as the upwind terrain was homogeneous and free of nearby obstacles. The observed fluxes varied from ∼ −80 to ∼ +140 ng NH3 m−2 s−1. Both the absolute flux values and the temporal patterns were highly similar, which substantiates that both instruments were able to measure NH3 fluxes at high temporal resolution. However, for wind directions with obstacles nearby, the correlations between the two techniques were weaker. The uptime of the miniDOAS system reached 100 % once operational, but regular intercalibration of the system was applied in this campaign (35 % of the 7-week uptime). Conversely, the HT8700E did not measure during and shortly after rain, and the coating of its mirrors tended to degrade (21 % data loss during the 5-week uptime). In addition, the NH3 concentrations measured by the HT8700E proved sensitive to air temperature, causing substantial differences (range: −15 to +6 µg m−3) between the two systems. To conclude, the miniDOAS system appears ready for long-term hands-off monitoring. The current HT8700E system, on the other hand, had a limited stand-alone operational time under the prevailing weather conditions. However, under relatively dry and low-dust conditions, the system can provide sound results, opening good prospects for future versions, also for monitoring applications. The new high temporal resolution data from these instruments can facilitate the study of processes behind NH3 dry deposition, allowing an improved understanding of these processes and better parameterisation in chemical transport models.</p

Forest tree growth is linked to mycorrhizal fungal composition and function across Europe

Most trees form symbioses with ectomycorrhizal fungi (EMF) which influence access to growth-limiting soil resources. Mesocosm experiments repeatedly show that EMF species differentially affect plant development, yet whether these effects ripple up to influence the growth of entire forests remains unknown. Here we tested the effects of EMF composition and functional genes relative to variation in well-known drivers of tree growth by combining paired molecular EMF surveys with high-resolution forest inventory data across 15 European countries. We show that EMF composition was linked to a three-fold difference in tree growth rate even when controlling for the primary abiotic drivers of tree growth. Fast tree growth was associated with EMF communities harboring high inorganic but low organic nitrogen acquisition gene proportions and EMF which form contact versus medium-distance fringe exploration types. These findings suggest that EMF composition is a strong bio-indicator of underlying drivers of tree growth and/or that variation of forest EMF communities causes differences in tree growth. While it may be too early to assign causality or directionality, our study is one of the first to link fine-scale variation within a key component of the forest microbiome to ecosystem functioning at a continental scale

Preferential risk of HPV16 for squamous cell carcinoma and of HPV18 for adenocarcinoma of the cervix compared to women with normal cytology in The Netherlands

We present the type-distribution of high-risk human papillomavirus (HPV) types in women with normal cytology (n=1467), adenocarcinoma in situ (ACIS) (n=61), adenocarcinoma (n=70), and squamous cell carcinoma (SCC) (n=83). Cervical adenocarcinoma and ACIS were significantly more frequently associated with HPV18 (ORMH 15.0; 95% CI 8.6–26.1 and 21.8; 95% CI 11.9–39.8, respectively) than normal cytology. Human papillomavirus16 was only associated with adenocarcinoma and ACIS after exclusion of HPV18-positive cases (ORMH 6.6; 95% CI 2.8–16.0 and 9.4; 95% CI 2.8–31.2, respectively). For SCC, HPV16 prevalence was elevated (ORMH 7.0; 95% CI 3.9–12.4) compared to cases with normal cytology, and HPV18 prevalence was only increased after exclusion of HPV16-positive cases (ORMH 4.3; 95% CI 1.6–11.6). These results suggest that HPV18 is mainly a risk factor for the development of adenocarcinoma whereas HPV16 is associated with both SCC and adenocarcinoma

High-risk HPV type-specific clearance rates in cervical screening

We assessed clearance rates of 14 high-risk human papillomavirus (hrHPV) types in hrHPV-positive women with normal cytology and borderline/mild dyskaryosis (BMD) in a population-based cervical screening cohort of 44 102 women. The 6-month hrHPV type-specific clearance rates, that is, clearance of the same type as detected at baseline, in women with normal and BMD smears were 43% (95% confidence interval (CI) 39–47) and 29% (95% CI 24–34), respectively. Corresponding 18-month clearance rates were markedly higher, namely 65% (95% CI 60–69) and 41% (95% CI 36–47), respectively. The lowest clearance rates in women with normal cytology were observed for HPV16, HPV18, HPV31, and HPV33. Significantly reduced 18-month clearance rates at a significance level of 1% were observed for HPV16 (49%, 95% CI 41–59) and HPV31 (50%, 95% CI 39–63) in women with normal cytology, and for HPV16 (19%, 95% CI 12–29) in women with BMD. Among women who did not clear hrHPV, women with HPV16 persistence displayed an increased detection rate of ⩾CIN3 (normal P<0.0001; BMD, P=0.005). The type-specific differences in clearance rates indicate the potential value of hrHPV genotyping in screening programs. Our data support close surveillance (i.e. referral directly, or within 6 months) of women with HPV16 and are inconclusive for surveillance of women with HPV18, HPV31, and HPV33. For the other hrHPV-positive women, it seems advisable to adopt a conservative management with a long waiting period, as hrHPV clearance is markedly higher after 18 months than after 6 months and the risk for ⩾CIN3 is low

Papillomavirus infection in rural women in southern India

To investigate the prevalence of, and the risk factors for, cervical infection with 44 types of human papillomavirus (HPV) in a rural area in the Dindigul District, Tamil Nadu, India, we interviewed and obtained cervical cell samples from 1891 married women aged 16–59 years. HPV prevalence was 16.9% overall and 14.0% among women without cervical abnormalities, or 17.7 and 15.2%, respectively, age-standardised to the world standard population. In all, 21.9% of infections involved more than one HPV type. High-risk HPV types predominated, particularly HPV 16 (22.5% of women infected), followed by HPV 56, HPV 31, HPV 33 and HPV 18. Unlike most populations studied in developed countries, HPV prevalence was constant across the age groups. HPV positivity was inversely associated with education level (odds ratio (OR) among women with high school vs no education=0.6) and positively associated with widowhood and divorce (OR=1.7), nulligravidity (OR=2.3), and condom use (OR=2.6). It is unclear how much low clearance of, or frequent reinfection with HPV accounted for the study prevalence of infection in different age groups