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Abstract No consensus strategies exist for prognosticating metastatic castration-resistant prostate cancer (mCRPC). Circulating tumor DNA fraction (ctDNA%) is increasingly reported by commercial and laboratory tests but its utility for risk stratification is unclear. Here, we intersect ctDNA%, treatment outcomes, and clinical characteristics across 738 plasma samples from 491 male mCRPC patients from two randomized multicentre phase II trials and a prospective province-wide blood biobanking program. ctDNA% correlates with serum and radiographic metrics of disease burden and is highest in patients with liver metastases. ctDNA% strongly predicts overall survival, progression-free survival, and treatment response independent of therapeutic context and outperformed established prognostic clinical factors. Recognizing that ctDNA-based biomarker genotyping is limited by low ctDNA% in some patients, we leverage the relationship between clinical prognostic factors and ctDNA% to develop a clinically-interpretable machine-learning tool that predicts whether a patient has sufficient ctDNA% for informative ctDNA genotyping (available online: https://www.ctDNA.org ). Our results affirm ctDNA% as an actionable tool for patient risk stratification and provide a practical framework for optimized biomarker testing.

Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene alteration and intra-tumor genetic heterogeneity as well as by pan-cancer trends in metabolic dysregulation. Taken together, our results indicate that measuring cell-type-specific total mRNA expression in tumor cells predicts tumor phenotypes and clinical outcomes.

Abstract Background Prostate cancer (PrCa) genomic heterogeneity causes resistance to therapies such as androgen deprivation. Such heterogeneity can be deciphered in the context of evolutionary principles, but current clinical trials do not include evolution as an essential feature. Whether or not analysis of genomic data in an evolutionary context in primary prostate cancer can provide unique added value in the research and clinical domains remains an open question. Methods We used novel processing techniques to obtain whole genome data together with 3D anatomic and histomorphologic analysis in two men (GP5 and GP12) with high-risk PrCa undergoing radical prostatectomy. A total of 22 whole genome-sequenced sites (16 primary cancer foci and 6 lymph node metastatic) were analyzed using evolutionary reconstruction tools and spatio-evolutionary models. Probability models were used to trace spatial and chronological origins of the primary tumor and metastases, chart their genetic drivers, and distinguish metastatic and non-metastatic subclones. Results In patient GP5, CDK12 inactivation was among the first mutations, leading to a PrCa tandem duplicator phenotype and initiating the cancer around age 50, followed by rapid cancer evolution after age 57, and metastasis around age 59, 5 years prior to prostatectomy. In patient GP12, accelerated cancer progression was detected after age 54, and metastasis occurred around age 56, 3 years prior to prostatectomy. Multiple metastasis-originating events were identified in each patient and tracked anatomically. Metastasis from prostate to lymph nodes occurred strictly ipsilaterally in all 12 detected events. In this pilot, metastatic subclone content analysis appears to substantially enhance the identification of key drivers. Evolutionary analysis’ potential impact on therapy selection appears positive in these pilot cases. Conclusions PrCa evolutionary analysis allows tracking of anatomic site of origin, timing of cancer origin and spread, and distinction of metastatic-capable from non-metastatic subclones. This enables better identification of actionable targets for therapy. If extended to larger cohorts, it appears likely that similar analyses could add substantial biological insight and clinically relevant value.

Amoxicillin is recommended as primary treatment for community-acquired bacterial pneumonia (CABP). 5–10% of CABP cases are caused by Chlamydia pneumoniae, an obligate intracellular bacterium which responds to beta-lactam antibiotics by converting to a persistent phenotype. To support rational pharmacotherapy of C. pneumoniae infections, we investigated how clinically relevant concentrations of azithromycin and doxycycline affect amoxicillin induced C. pneumoniae persistence. Given the known role of redox state alterations in the action of bactericidal antibiotics and widespread use of redox-active dietary supplements when experiencing respiratory symptoms, we also studied how redox active compounds affect the studied antibiotic treatments. Our data demonstrate that clinically applied amoxicillin concentrations (10 and 25 mg/l) fail to eradicate C. pneumoniae infection in respiratory epithelial cells. Transmission electron microscopy (TEM) of amoxicillin-treated C. pneumoniae infected cells reveal aberrant bacterial morphology characteristic of chlamydial stress response. Amoxicillin was also found to significantly limit the antichlamydial effect of azithromycin or doxycycline. However, based on quantitative culture and quantitative PCR data, azithromycin was superior to doxycycline in C. pneumoniae eradication either as monotherapy or in combination with amoxicillin. Amoxicillin was also found to decrease respiratory epithelial cell glutathione (GSH) levels, whereas redox-active dibenzocyclooctadiene lignans increased C. pneumoniae load in amoxicillin-treated cultures up to two-fold. These data highlight the impact of relative administration time on the efficacy of antichlamydial antibiotics and indicate unfavorable interactions between amoxicillin and redox-active small molecules.

Prostate cancer is one of the leading causes of death among men worldwide, and thus, research on the genetic factors enabling the formation of treatment-resistant cancer cells is crucial for improving patient outcomes. Here, we report a cell line-specific dependence on FANCI and related signaling pathways to counteract the effects of DNA-damaging chemotherapy in prostate cancer. Our results reveal that FANCI depletion results in significant downregulation of Fanconi anemia (FA) pathway members in prostate cancer cells, indicating that FANCI is an important regulator of the FA pathway. Furthermore, we found that FANCI silencing reduces proliferation in p53-expressing prostate cancer cells. This extends the evidence that inactivation of FANCI may convert cancer cells from a resistant state to an eradicable state under the stress of DNA-damaging chemotherapy. Our results also indicate that high expression of FA pathway genes correlates with poorer survival in prostate cancer patients. Moreover, genomic alterations of FA pathway members are prevalent in prostate adenocarcinoma patients; mutation and copy number information for the FA pathway genes in seven patient cohorts (N = 1,732 total tumor samples) reveals that 1,025 (59.2%) tumor samples have an alteration in at least one of the FA pathway genes, suggesting that genomic alteration of the pathway is a prominent feature in patients with the disease.

Identifying the molecular mechanisms of response to systemic therapy in prostate cancer remains crucial. Here, the authors apply single cell-ATAC and RNAseq to models of early treatment response and resistance to enzalutamide and identify chromatin and gene expression patterns that can predict treatment response.

Background: Systematic identification of data essential for outcome prediction in metastatic prostate cancer (mPC) would accelerate development of precision oncology. Objective: To identify novel phenotypes and features associated with mPC outcome, and to identify biomarker and data requirements to be tested in future precision oncology trials. Design, setting, and participants: We analyzed deep longitudinal clinical, neuroendocrine expression, and autopsy data of 33 men who died from mPC between 1995 and 2004 (PELICAN33), and related findings to mPC biomarkers reported in the literature. Intervention: Thirty-three men prospectively consented to participate in an integrated clinical-molecular rapid autopsy study of mPC. Outcome measurements and statistical analysis: Data exploration with correction for multiple testing and survival analysis from the time of diagnosis to time to death and time to first occurrence of severe pain as outcomes were carried out. The effect of seven complications on the modeled probability of dying within 2 yr after presenting with the complication was evaluated using logistic regression. Results and limitations: Feature exploration revealed novel phenotypes related to mPC outcome. Four complications (pleural effusion, severe anemia, severe or controlled pain, and bone fracture) predict the likelihood of death within 2 yr. Men with Gleason grade group 5 cancers developed severe pain sooner than those with lower-grade tumors. Surprisingly, neuroendocrine (NE) differentiation was frequently observed in the setting of high serum prostate-specific antigen (PSA) levels (≥30 ng/ml). In 4/33 patients, no controlled (requiring analgesics) or severe pain was detected, and strikingly, 14/15 metastatic sites studied in these men did not express NE markers, suggesting an inverse relationship between NE differentiation and pain in mPC. Intracranial subdural metastasis is common (36%) and is usually clinically undetected. Categorization of “skeletal-related events” complications used in recent studies likely obscures the understanding of spinal cord compression and fracture. Early death from prostate cancer was identified in a subgroup of men with a low longitudinal PSA bandwidth. Cachexia is common (body mass index

In metastatic urothelial carcinoma, it has not been established whether circulating tumor DNA (ctDNA) can replace archival primary tissue to assess mutations and biomarkers. Here, the authors show high mutation concordance between ctDNA and tumour tissue, with high consistency in serial samples.

The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. Here, the authors use deep genomic sequencing and histopathological information to trace tumor evolution both within the prostate and during metastasis in ten men.

Triggered by changes in macrophage redox status and lipid metabolism, foam cells represent a hallmark of atherosclerosis. Induction of macrophage foam cell formation by Chlamydia pneumoniae, a gram-negative human pathogen, has been established in various earlier studies in vitro and in vivo. Oxidation of low-density lipoprotein (LDL) by C. pneumoniae and alterations in macrophage lipid metabolism do not require chlamydial replication, making conventional antibiotics useless in the intervention of the process. In this work, we report on the ability of schisandrin B and schisandrin C, two dibenzocyclooctadiene lignans, to suppress the C. pneumoniae -induced foam cell formation in RAW264.7 macrophages. This effect was accompanied with the upregulation of PPARγ, a nuclear receptor acting as a major transcriptional regulator of lipid metabolism and inflammatory responses. Schisandrin B and schisandrin C also increased the total intracellular glutathione content of the macrophages. In the case of schisandrin B, this was accompanied with the upregulation of GSH biosynthetic genes glutamate cysteine ligase (both the catalytic and the modifier subunits GCLc and GCLm) as well as gamma-glutamyl transpeptidase GGT1. In addition, schisandrin B and schisandrin C upregulated the expression of a lipid transport protein ABCA1 gene mediating cholesterol efflux from macrophages translating into a reduction in total cholesterol concentration in the schisandrin B -treated cells. Collectively, these data indicate that both schisandrin B and schisandrin C are able to alleviate the pathogenic consequences of C. pneumoniae infection in macrophages by altering the cellular redox balance and lipid trafficking.

Background: Prosthetic vascular grafts in humans characteristically lack confluent endothelialization regardless of the duration of implantation. Use of high-porosity grafts has been proposed as a way to induce endothelialization through transgraft capillarization, although early experiments failed to show increased healing in man. Objectives: We hypothesized that transduction of tissues around the prosthetic conduit with vectors encoding VEGF receptor-2 (VEGFR2) ligands would augment transinterstitial capillarization and induce luminal endothelialization of high-porosity ePTFE grafts. Methods: Fifty-two NZW rabbits received 87 ePTFE uni- or bilateral end-to-end interposition grafts in carotid arteries. Rabbits were randomized to local therapy with adenoviruses encoding AdVEGF-A165, AdVEGF-A109 or control AdLacZ and analyzed at 6 and 28 days after surgery by contrast-enhanced ultrasound and histology. Results: AdVEGF-A165 and AdVEGF-A109 dramatically increased perfusion in perigraft tissues at 6 days (14.2 ± 3.6 or 16.7 ± 2.6-fold increases, P < 0.05 and P < 0.01). At 28 days, the effect was no longer significantly higher than baseline. At 6 days, no luminal endothelialization was observed in any of the groups. At 28 days, AdVEGF-A109- and AdVEGF-A165-treated animals showed enhanced ingrowth of transinterstitial capillaries (66.0 ± 13.7% and 77.4 ± 15.7% of graft thickness vs 44.7 ± 24.4% in controls, P < 0.05) and improved luminal endothelialization (11.2 ± 26.3% and 11.4 ± 22.2%, AdVEGF-A109 and AdVEGF-A165 vs 0% in controls, P < 0.05). No increased stenosis was observed in the treatment groups as compared to LacZ controls. Conclusions: This study suggests that transient local overexpression of VEGFR2 ligands in the peri-implant tissues at the time of graft implantation is a novel strategy to increase endothelialization of high-porosity ePTFE vascular grafts and improve the patency of small-diameter vascular prostheses.

Abstract Tuberculosis ranks as one of the world’s deadliest infectious diseases causing more than a million casualties annually. IL10 inhibits the function of Th1 type cells, and IL10 deficiency has been associated with an improved resistance against Mycobacterium tuberculosis infection in a mouse model. Here, we utilized M. marinum infection in the zebrafish (Danio rerio) as a model for studying Il10 in the host response against mycobacteria. Unchallenged, nonsense il10 e46/e46 mutant zebrafish were fertile and phenotypically normal. Following a chronic mycobacterial infection, il10 e46/e46 mutants showed enhanced survival compared to the controls. This was associated with an increased expression of the Th cell marker cd4-1 and a shift towards a Th1 type immune response, which was demonstrated by the upregulated expression of tbx21 and ifng1, as well as the down-regulation of gata3. In addition, at 8 weeks post infection il10 e46/e46 mutant zebrafish had reduced expression levels of proinflammatory cytokines tnfb and il1b, presumably indicating slower progress of the infection. Altogether, our data show that Il10 can weaken the immune defense against M. marinum infection in zebrafish by restricting ifng1 response. Importantly, our findings support the relevance of M. marinum infection in zebrafish as a model for tuberculosis.

Abstract The large volcanic eruptions of AD 536 and 540 led to climate cooling and contributed to hardships of Late Antiquity societies throughout Eurasia, and triggered a major environmental event in the historical Roman Empire. Our set of stable carbon isotope records from subfossil tree rings demonstrates a strong negative excursion in AD 536 and 541–544. Modern data from these sites show that carbon isotope variations are driven by solar radiation. A model based on sixth century isotopes reconstruct an irradiance anomaly for AD 536 and 541–544 of nearly three standard deviations below the mean value based on modern data. This anomaly can be explained by a volcanic dust veil reducing solar radiation and thus primary production threatening food security over a multitude of years. We offer a hypothesis that persistently low irradiance contributed to remarkably simultaneous outbreaks of famine and Justinianic plague in the eastern Roman Empire with adverse effects on crop production and photosynthesis of the vitamin D in human skin and thus, collectively, human health. Our results provide a hitherto unstudied proxy for exploring the mechanisms of ‘volcanic summers’ to demonstrate the post-eruption deficiencies in sunlight and to explain the human consequences during such calamity years.

The dysregulation of chromatin and epigenetics has been defined as the overarching cancer hallmark. By disrupting transcriptional regulation in normal cells and mediating tumor progression by promoting cancer cell plasticity, this process has the ability to mediate all defined hallmarks of cancer. In this review, we collect and assess evidence on the contribution of chromatin and epigenetic dysregulation in prostate cancer. We highlight important mechanisms leading to prostate carcinogenesis, the emergence of castration-resistance upon treatment with androgen deprivation therapy, and resistance to antiandrogens. We examine in particular the contribution of chromatin structure and epigenetics to cell lineage commitment, which is dysregulated during tumorigenesis, and cell plasticity, which is altered during tumor progression.

Antibiotic-tolerant persister bacteria involve frequent treatment failures, relapsing infections and the need for extended antibiotic treatment. The virulence of an intracellular human pathogen C. pneumoniae is tightly linked to its propensity for persistence and means for its chemosensitization are urgently needed. In the current work, persistence of C. pneumoniae clinical isolate CV6 was studied in THP-1 macrophages using quantitative PCR and quantitative culture. A dibenzocyclooctadiene lignan schisandrin reverted C. pneumoniae persistence and promoted productive infection. The concomitant administration of schisandrin and azithromycin resulted in significantly improved bacterial eradication compared to sole azithromycin treatment. In addition, the closely related lignan schisandrin C was superior to azithromycin in eradicating the C. pneumoniae infection from the macrophages. The observed chemosensitization of C. pneumoniae was associated with the suppression of cellular glutathione pools by the lignans, implying to a previously unknown aspect of chlamydia−host interactions. These data indicate that schisandrin lignans induce a phenotypic switch in C. pneumoniae, promoting the productive and antibiotic-susceptible phenotype instead of persistence. By this means, these medicinal plant -derived compounds show potential as adjuvant therapies for intracellular bacteria resuscitation.

Abstract Angiogenic growth factors have recently been linked to tissue metabolism. We have used genetic gain‐ and loss‐of function models to elucidate the effects and mechanisms of action of vascular endothelial growth factor‐B (VEGF‐B) in the heart. A cardiomyocyte‐specific VEGF‐B transgene induced an expanded coronary arterial tree and reprogramming of cardiomyocyte metabolism. This was associated with protection against myocardial infarction and preservation of mitochondrial complex I function upon ischemia‐reperfusion. VEGF‐B increased VEGF signals via VEGF receptor‐2 to activate Erk1/2, which resulted in vascular growth. Akt and mTORC1 pathways were upregulated and AMPK downregulated, readjusting cardiomyocyte metabolic pathways to favor glucose oxidation and macromolecular biosynthesis. However, contrasting with a previous theory, there was no difference in fatty acid uptake by the heart between the VEGF‐B transgenic, gene‐targeted or wildtype rats. Importantly, we also show that VEGF‐B expression is reduced in human heart disease. Our data indicate that VEGF‐B could be used to increase the coronary vasculature and to reprogram myocardial metabolism to improve cardiac function in ischemic heart disease.

This article continues a series of studies connected with the Scientific Thought-styles project (1995-), and discusses the formation of genre conventions of vernacular medical case reports in a long diachronic perspective. The theoretical background is explained first, with accompanying material from medical history and the philosophy of science. The epistemological status of the genre is on the practical side: besides theories, experience is valued, and relating what happened in a typical case of illness is the core function of the genre. In addition, the function of enhancing the efficacy of the cure grows prominent in some texts. Case studies are narratives of illness and endangered human life, and the model of natural narratives (Labov & Waletzky, 1967) can be identified in these stories. The method of analysis is qualitative and relies on illuminative examples from two electronic corpora Middle English Medical Texts (2005) and Early Modern Medical Texts (2010). The article finishes with a modern example that shows a shift to non-human technical facts.

Ancient DNA analysis offers a way to detect changes in populations over time. To date, most studies of ancient cattle have focused on their domestication in prehistory, while only a limited number of studies have analysed later periods. Conversely, the genetic structure of modern cattle populations is well known given the undertaking of several molecular and population genetic studies.Bones and teeth from ancient cattle populations from the North-East Baltic Sea region dated to the Prehistoric (Late Bronze and Iron Age, 5 samples), Medieval (14), and Post-Medieval (26) periods were investigated by sequencing 667 base pairs (bp) from the mitochondrial DNA (mtDNA) and 155 bp of intron 19 in the Y-chromosomal UTY gene. Comparison of maternal (mtDNA haplotypes) genetic diversity in ancient cattle (45 samples) with modern cattle populations in Europe and Asia (2094 samples) revealed 30 ancient mtDNA haplotypes, 24 of which were shared with modern breeds, while 6 were unique to the ancient samples. Of seven Y-chromosomal sequences determined from ancient samples, six were Y2 and one Y1 haplotype. Combined data including Swedish samples from the same periods (64 samples) was compared with the occurrence of Y-chromosomal haplotypes in modern cattle (1614 samples).The diversity of haplogroups was highest in the Prehistoric samples, where many haplotypes were unique. The Medieval and Post-Medieval samples also show a high diversity with new haplotypes. Some of these haplotypes have become frequent in modern breeds in the Nordic Countries and North-Western Russia while other haplotypes have remained in only a few local breeds or seem to have been lost. A temporal shift in Y-chromosomal haplotypes from Y2 to Y1 was detected that corresponds with the appearance of new mtDNA haplotypes in the Medieval and Post-Medieval period. This suggests a replacement of the Prehistoric mtDNA and Y chromosomal haplotypes by new types of cattle.

The relics of Turku Cathedral are remains belonging to the bodies of holy persons, different from ours, even today, although the cathedral is the see for the archbishop of the Evangelical Lutheran Church of Finland, and relics are not on public display. Among the relics of the cathedral, there is a fragment of a radius, which according to its authentica, belongs to St Henry. Relics and reliquaries were in the core of medieval piety, and the cult of saints had infused throughout the society. Due to their central position in culture, relics offer glimpses at a range of material, social and cultural phenomena related to medieval embodiment.The Department of Archaeology at the University of Turku began to study the finger relic of St Eric and other items in the assemblage of Turku Cathedral in 2007. Relics and reliquaries are being opened and documented and organic as well as inorganic samples are being taken for a range of scientific analyses. So far the project has concentrated on building a chronological chart of individual artefacts. The majority of the relics date to the fourteenth century, although much more recent datings have also been obtained. The challenge of the project is not to stop when a better understanding of materials, their origins and age has been accomplished, but to use the results as a steppingstone into a study of the practices of medieval relic veneration. Medieval bodies and those material processes which authenticate relics, or distinguish saints’ bodies from other human remains, are thus at the heart of this article discussing embodiment.

Accession to the European Union caused a drop of nearly 60 per cent from 1994 to 1995 in prices of wheat, barley and oats in Finland. The economic use of fertilizer therefore decreased accordingly. To calculate the effect of the price changes on the economic optima, the physical production function must be known. Three physical production functions, the quadratic, the linear response and plateau (LRP) and the exponential function were estimated for this purpose. The models differed little in respect of the R 2 adj value (0.82-0.90) but the calculated optimum varied, depending on the production function. Data on a long-term field trial (21 years) were analysed. The field trial was established in 1973 to demonstrate the effect of mineral fertilizer in crop production. The crops grown in the trial were barley, wheat and oats. Different varieties were included in the models.

The aim of this paper is to outline a history of useful entertainment through genres of secular instruction. My focus is on Late Medieval and Early Modern texts, but I shall touch upon a longer diachrony as well. I shall first go through the title word by word, to explain my method of analysis and approach, and show how useful entertainment and instruction are linked in the history of English. In the empirical part of my paper I shall focus first on discourse forms and then on the linguistic features of some typical texts.

Accession to the European Union caused a drop of nearly 60 per cent from 1994 to 1995 in prices of wheat, barley and oats in Finland. The economic use of fertilizer therefore decreased accordingly. To calculate the effect of the price changes on the economic optima, the physical production function must be known. Three physical production functions, the quadratic, the linear response and plateau (LRP) and the exponential function were estimated for this purpose. The models differed little in respect of the R2adj value (0.82-0.90) but the calculated optimum varied, depending on the production function. Data on a long-term field trial (21 years) were analysed. The field trial was established in 1973 to demonstrate the effect of mineral fertilizer in crop production. The crops grown in the trial were barley, wheat and oats. Different varieties were included in the models.

Abstract Background Several molecular and population genetic studies have focused on the native sheep breeds of Finland. In this work, we investigated their ancestral sheep populations from Iron Age, Medieval and Post-Medieval periods by sequencing a partial mitochondrial DNA D-loop and the 5’-promoter region of the SRY gene. We compared the maternal (mitochondrial DNA haplotypes) and paternal (SNP oY1) genetic diversity of ancient sheep in Finland with modern domestic sheep populations in Europe and Asia to study temporal changes in genetic variation and affinities between ancient and modern populations. Results A 523-bp mitochondrial DNA sequence was successfully amplified for 26 of 36 sheep ancient samples i.e. five, seven and 14 samples representative of Iron Age, Medieval and Post-Medieval sheep, respectively. Genetic diversity was analyzed within the cohorts. This ancient dataset was compared with present-day data consisting of 94 animals from 10 contemporary European breeds and with GenBank DNA sequence data to carry out a haplotype sharing analysis. Among the 18 ancient mitochondrial DNA haplotypes identified, 14 were present in the modern breeds. Ancient haplotypes were assigned to the highly divergent ovine haplogroups A and B, haplogroup B being the major lineage within the cohorts. Only two haplotypes were detected in the Iron Age samples, while the genetic diversity of the Medieval and Post-Medieval cohorts was higher. For three of the ancient DNA samples, Y-chromosome SRY gene sequences were amplified indicating that they originated from rams. The SRY gene of these three ancient ram samples contained SNP G-oY1, which is frequent in modern north-European sheep breeds. Conclusions Our study did not reveal any sign of major population replacement of native sheep in Finland since the Iron Age. Variations in the availability of archaeological remains may explain differences in genetic diversity estimates and patterns within the cohorts rather than demographic events that occurred in the past. Our ancient DNA results fit well with the genetic context of domestic sheep as determined by analyses of modern north-European sheep breeds.