BackgroundHuman papillomavirus (HPV) vaccination protects against HPV, a necessary risk factor for cervical cancer. We now report results from population-based follow-up of randomised cohorts that ...vaccination provides HPV-type-specific protection against invasive cancer.MethodsIndividually and/or cluster randomised cohorts of HPV-vaccinated and non-vaccinated women were enrolled in 2002–2005. HPV vaccine cohorts comprised originally 16–17 year-old HPV 16/18-vaccinated PATRICIA (NCT00122681) and 012 trial (NCT00169494) participants (2465) and HPV6/11/16/18-vaccinated FUTURE II (NCT00092534) participants (866). Altogether, 3341 vaccines were followed by the Finnish Cancer Registry in the same way as 16 526 non-HPV-vaccinated controls. The control cohort stemmed from 15 665 originally 18–19 years-old women enrolled in 2003 (6499) or 2005 (9166) and 861 placebo recipients of the FUTURE II trial. The follow-up started 6 months after the clinical trials in 2007 and 2009 and ended in 2019. It was age aligned for the cohorts.FindingsDuring a follow-up time of up to 11 years, we identified 17 HPV-positive invasive cancer cases (14 cervical cancers, 1 vaginal cancer, 1 vulvar cancer and 1 tongue cancer) in the non-HPV-vaccinated cohorts and no cases in the HPV-vaccinated cohorts. HPV typing of diagnostic tumour blocks found HPV16 in nine cervical cancer cases, HPV18, HPV33 and HPV52 each in two cases and HPV45 in one cervical cancer case. The vaginal, vulvar and tongue cancer cases were, respectively, positive for HPV16, HPV52/66 and HPV213. Intention-to-treat vaccine efficacy against all HPV-positive cancers was 100% (95% CI 2 to 100, p<0.05).InterpretationVaccination is effective against invasive HPV-positive cancer.Trial registration numberNCT00122681, Post-results; NCT00169494, Post-results; NCT00092534, Post-results.
An opportunistic oral pathogen, Treponema denticola (Td), has been linked to orodigestive carcinogenesis, but its role in oropharyngeal squamous cell carcinoma (OPSCC) has remained open. We evaluated ...the presence of Td chymotrypsin-like protease (Td-CTLP) in a series of 201 unselected consecutive OPSCC patients, and the relation of the Td-CTLP to human papillomavirus (HPV) status, to expression of toll-like receptors (TLR) 5, 7, and 9, and to clinical parameters and patient outcome.
Clinicopathological data came from hospital registries. The expression of cell surface-bound Td-CTLP was evaluated by immunohistochemistry. Immunoexpression of TLRs 5, 7, and 9, and HPV status we studied earlier in this patient series.
We detected Td-CTLP in 81% of the OPSCC, and especially in HPV-negative tumours (48% of all OPSCCs). Among the HPV-positive tumours (52% of all OPSCCs), low Td-CTLP expression associated with low TLR 5 and high TLR 7 expression. Among those HPV-negative, higher TLR 5 and lower TLR 7 expression associated with high Td-CTLP expression. Strong Td-CTLP expression associated with poor disease-specific survival, but no similar association among HPV-positive and HPV-negative subgroups emerged.
Td-CTLP was highly expressed in OPSCC and was associated with the HPV status of tumour tissue.
•N deposition during rotation period replenished the N export by stem-only-harvest.•N deposition did not compensate the N export by whole-tree-harvest regimes.•The total biomass and N stock ranged ...178–541Mg/ha and 890–7530kg/ha, respectively.•The largest N pools were 0–40cm mineral soil profile (70%) and humus layer (16%).•The N stock in potential logging residues (stumps incl.) was 50–71% of tree N stock.
Nitrogen (N) is typically the growth-limiting factor in boreal forest ecosystems. Therefore, knowledge on forest N stocks and fluxes is crucial in order to predict and evaluate the effects of different anthropogenic factors (e.g. climate change, air pollutant deposition, forest management practices) on the condition, development and sustainability of boreal forests. In this study, we evaluated the amount and distribution of N and biomass in different compartments of forest ecosystem, including not only tree stand and soil, but also such rarely reported N stocks as litter layer, ground vegetation and fine and small roots. We also calculated the theoretical export of N in three forest harvest regimes of different intensity (stem-only harvest, whole-tree harvest, whole-tree harvest and stump uplifting) and assessed the time required for N deposition to compensate the N losses occurring in them. The study included seven Scots pine and eight Norway spruce dominated stands belonging to the UN-ECE ICP Forests Level II programme in Finland. The average effective temperature sum and stand age of the sites ranged 658–1351 d.d. and 55–200 yrs, respectively. Among the study sites, the total biomass (needles, living and dead branches, stems, bark, stumps, coarse roots, fine and small roots, understory, litter, humus and mineral soil layers) ranged from 178Mg ha−1 to 541Mg ha−1, the respective range for N stock being 1890–7530kg ha−1. The two largest pools of N in forest ecosystem were mineral soil (depth 0–40cm; mean=70%) and humus layer (mean=16%). The largest living biomass N stock was in stems in pine stands (88kg ha−1) and in needles in spruce stands (134kg ha−1). Nstored in tree biomass accounted for 7–19% of the total ecosystem N stock. The proportion of N stored in potential logging residues or biofuel (needles, living and dead branches, stumps and coarse roots) was 67±4% and 53±5% of the tree N stock in northern spruce stands and in southern pine stands, respectively. The understory vegetation N stock was the largest in northern spruce stands, and the lowest in southern spruce stands. Our results supported the hypothesis that in boreal coniferous forests, inputs of N by deposition accumulating during the following rotation period will be able to replenish the export of N caused by conventional stem-only-harvest in final cutting, but the sustainability of the site productivity will be challenged when more intense whole tree harvest regimes are practiced, especially in Norway spruce stands.
Outcomes after metastasectomy for metastatic colorectal cancer (mCRC) vary with RAS and BRAF mutational status, but their effects on resectability and conversion rates have not been extensively ...studied.
This substudy of the prospective RAXO trial included 906 patients recruited between 2011 and 2018. We evaluated repeated centralised resectability assessment, conversion/resection rates and overall survival (OS), according to RAS and BRAF status.
Patients included 289 with RAS and BRAF wild-type (RAS and BRAFwt), 529 with RAS mutated (RASmt) and 88 with BRAF mutated (BRAFmt) mCRC. Metastatic prevalence varied between the RAS and BRAFwt/RASmt/BRAFmt groups, for liver (78%/74%/61%), lung (24%/35%/28%) and peritoneal (15%/15%/32%) metastases, respectively. Upfront resectability (32%/29%/15%), conversion (16%/13%/7%) and resection/local ablative therapy (LAT) rates (45%/37%/17%) varied for RASa and BRAFwt/RASmt/BRAFmt, respectively. Median OS for patients treated with resection/LAT (n = 342) was 83/69/30 months, with 5-year OS-rates of 67%/60%/24%, while systemic therapy-only patients (n = 564) had OS of 29/21/15 months with 5-year OS-rates of 11%/6%/2% in RAS and BRAFwt/RASmt/BRAFmt, respectively. Resection/LAT was associated with improved OS in all subgroups.
There were significant differences in resectability, conversion and resection/LAT rates according to RAS and BRAF status. OS was also significantly longer for RAS and BRAFwt versus either mutant. Patients only receiving systemic therapy had poorer long-term survival, with variation according to molecular status.
NCT01531621/EudraCT2011-003158-24.
Less frequent cervical cancer screening in human papillomavirus (HPV) vaccinated birth cohorts could produce considerable savings without increasing cervical cancer incidence and loss of life‐years. ...We report here the baseline findings and interim results of safety and accuracy of infrequent screening among HPV16/18 vaccinated females. The entire 1992–1994 birth‐cohorts (30,139 females) were invited to a community‐randomized HPV16/18‐vaccination trial. A total of 9,482 female trial participants received HPV16/18‐vaccination in 2007–2009 at age of 13–15. At age 22, 4,273 (45%) of these females consented to attend a randomized trial on frequent (ages 22/25/28; Arm 1: 2,073 females) vs. infrequent screening (age 28; Arm 2: 2,200 females) in 2014–2017. Females (1,329), who had got HPV16/18 vaccination at age 18 comprised the safety Arm 3. Baseline prevalence and incidence of HPV16/18 and other high‐risk HPV types were: 0.5% (53/1,000 follow‐up years, 104) and 25% (2,530/104) in the frequently screened Arm 1; 0.2% (23/104) and 24% (2,413/104) in the infrequently screened Arm 2; and 3.1% (304/104) and 23% (2,284/104) in the safety Arm 3. Corresponding prevalence of HSIL/ASC‐H and of any abnormal cytological findings were: 0.3 and 4.2% (Arm 1), 0.4 and 5.3% (Arm 2) and 0.3 and 4.7% (Arm 3). Equally rare HSIL/CIN3 findings in the infrequently screened safety Arm A3 (0.4%) and in the frequently screened Arm 1 (0.4%) indicate no safety concerns on infrequent screening despite the up to 10 times higher HPV16/18 baseline prevalence and incidence in the former.
What's new?
As the first generation of girls vaccinated against HPV reach adulthood, it's time to re‐evaluate screening recommendations. Reducing the frequency of screenings could save money without increasing cervical cancer incidence. Here, the authors collected baseline data on the safety of less frequent cervical cancer screenings. They conducted a randomized trial of Finnish women born in 1992‐1994 and vaccinated against HPV16/18, in which participants are screened either once or three times by age 28. At baseline and the first safety interim analyses they found no difference in the incidence of HSIL/CIN3 lesions between the two groups, suggesting that infrequent screening for HPV‐vaccinated women does not compromise safety.
We investigated the stability of T2 low status, based on low levels of T2 biomarkers, and exacerbation rates in T2 low and non-T2 low asthma from clinical retrospective data of severe uncontrolled ...asthma patients. Knowledge of the T2 low biomarker profile is sparse and biomarker stability is uncharted. Secondary care patients with severe uncontrolled asthma and at least two blood eosinophil counts (BEC) and fractional exhaled nitric oxide (FeNO) measured for determination of type 2 inflammation status were evaluated from a follow-up period of 4 years. Patients were stratified into four groups: T2 low
(
= 31; BEC < 150 cells/µL and FeNO < 25 ppb), non-T2 low
(
= 138; BEC > 150 cells/µL and/or FeNO > 25 ppb), T2 low
(
= 66; BEC < 300 cells/µL and FeNO < 25 ppb), and non-T2 low
(
= 103; BEC > 300 cells/µL and/or FeNO > 25 ppb). Exacerbation rates requiring hospital care, stability of biomarker status, and cumulative OCS and ICS doses were assessed during follow-up. Among patients with severe uncontrolled asthma, 18% (
= 31) were identified as T2 low
, and 39% (
= 66) as T2 low
. In these groups, the low biomarker profile was stable in 55% (
= 11) and 72% (
= 33) of patients with follow-up measures. Exacerbation rates were different between the T2 low and non-T2 low groups: 19.7 95% CI: 4.3-45.6 in T2 low
vs. 8.4 4.7-13.0 in non-T2 low
per 100 patient-years. BEC and FeNO are useful biomarkers in identifying T2 low severe uncontrolled asthma, showing a stable follow-up biomarker profile in up to 72% of patients. Repeated monitoring of these biomarkers is essential in identifying and treating patients with T2 low asthma.
Polyploidy, or genome doubling, has occurred repeatedly through plant evolution. While polyploid plants are used extensively in agriculture and horticulture, they have so far found limited use in ...forestry. Here we review the potentials of polyploid trees under climate change, and investigate if there is support for increased use. We find that polyploid trees like other plants have consistent increases in cell sizes compared to diploids, and that leaf-area based rates of photosynthesis tend to increase with increasing levels of ploidy. While no particular trend could be discerned in terms of biomass between trees of different ploidy levels, physiology is affected by polyploidization and several studies point towards a high potential for polyploid trees to adapt to drought stress. The ploidy level of most tree species is unknown, and analysis of geographical patterns in frequencies of polyploid trees are inconclusive. Artificial polyploid trees are often created by colchicine and in a few cases these have been successfully applied in forestry, but the effects of induced polyploidization in many economically important tree species remains untested. Polyploids would also be increasingly useful in tree breeding programs, to create synthetic hybrids or sterile triploids that could control unwanted spreading of germplasm in nature. In conclusion, this review suggests that polyploid trees may be superior under climate change in some cases, but that the potential of polyploids is not yet fully known and should be evaluated on a case-to-case basis for different tree species.
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•We reviewed contemporary literature on polyploid trees.•Although polyploidy is common, the ploidy level of many tree species is unknown.•Polyploidy alters anatomy, physiology and growth of trees, making some more stress tolerant.•Increased use of polyploid trees could be advantageous under climate change conditions.•Polyploids should be further investigated for their potential to increase productivity in forestry.
The primary tumor location (PTL) is associated with the phenotype, metastatic sites, mutations, and outcomes of metastatic colorectal cancer (mCRC) patients, but this has mostly been studied ...according to sidedness (right vs. left sided). We studied right colon vs. left colon vs. rectal PTL in a real-life study population (
= 1080). Health-related quality of life (HRQoL) was assessed multi-cross-sectionally with QLQ-C30, QLQ-CR29, EQ-5D, and 15D. A chi-square, Kaplan-Meier, and Cox regression were used to compare the groups. The PTL was in the right colon in 310 patients (29%), the left colon in 396 patients (37%), and the rectum in 375 patients (35%). The PTL was associated with distinct differences in metastatic sites during the disease trajectory. The resectability, conversion, and resection rates were lowest in the right colon, followed by the rectum, and were highest in the left colon. Overall survival was shortest for right colon compared with left colon or rectal PTL (median 21 vs. 35 vs. 36 months), with the same trends after metastasectomy or systemic therapy only. PTL also remained statistically significant in a multivariable model. The distribution of symptoms varied according to PTL, especially between the right colon (with general symptoms of metastases) and rectal PTL (with sexual- and bowel-related symptoms). mCRC, according to PTL, behaves differently regarding metastatic sites, resectability of the metastases, outcomes of treatment, and HRQoL.
Plant biomass plays an increasingly important role in the circular bioeconomy, replacing non-renewable fossil resources. Genetic engineering of this lignocellulosic biomass could benefit biorefinery ...transformation chains by lowering economic and technological barriers to industrial processing. However, previous efforts have mostly targeted the major constituents of woody biomass: cellulose, hemicellulose and lignin. Here we report the engineering of wood structure through the introduction of callose, a polysaccharide novel to most secondary cell walls. Our multiscale analysis of genetically engineered poplar trees shows that callose deposition modulates cell wall porosity, water and lignin contents and increases the lignin-cellulose distance, ultimately resulting in substantially decreased biomass recalcitrance. We provide a model of the wood cell wall nano-architecture engineered to accommodate the hydrated callose inclusions. Ectopic polymer introduction into biomass manifests in new physico-chemical properties and offers new avenues when considering lignocellulose engineering.
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