Nonsurgical treatments for prostate cancer include androgen-deprivation therapy (ADT), radiation therapy (RT), ablative therapies, chemotherapy, and newly emerging immunotherapies. These approaches ...can be used alone or in combination depending on the clinical scenario. ADT is typically reserved for high-risk locally or systemically advanced disease that is not amenable to curative surgery. Radiation therapy can be used instead of surgery as primary therapy with curative intent for low-intermediate-risk disease as well as for control of locally advanced disease not suitable for surgery. Ablative therapies can be used as primary therapy for low-intermediate-risk disease or as salvage therapy for clinically localized disease where RT has failed. Chemotherapy and immune-based therapies are currently used for androgen-independent disease, although the indications for these approaches may well change as new data from clinical trials accrue. Pathologists should be able to recognize tissue changes associated with these treatments to provide information that will optimize patient management. This is particularly true in situations where clinical history of recent or remote nonsurgical treatment is not provided with the specimen. In the absence of this information, pathologists encountering the features described herein are encouraged to review patient records or communicate directly with clinical colleagues to determine how a given patient was treated and when.
Protein structures can provide invaluable information, both for reasoning about biological processes and for enabling interventions such as structure-based drug development or targeted mutagenesis. ...After decades of effort, 17% of the total residues in human protein sequences are covered by an experimentally determined structure
. Here we markedly expand the structural coverage of the proteome by applying the state-of-the-art machine learning method, AlphaFold
, at a scale that covers almost the entire human proteome (98.5% of human proteins). The resulting dataset covers 58% of residues with a confident prediction, of which a subset (36% of all residues) have very high confidence. We introduce several metrics developed by building on the AlphaFold model and use them to interpret the dataset, identifying strong multi-domain predictions as well as regions that are likely to be disordered. Finally, we provide some case studies to illustrate how high-quality predictions could be used to generate biological hypotheses. We are making our predictions freely available to the community and anticipate that routine large-scale and high-accuracy structure prediction will become an important tool that will allow new questions to be addressed from a structural perspective.
An increasing volume of prostate biopsies and a worldwide shortage of urological pathologists puts a strain on pathology departments. Additionally, the high intra-observer and inter-observer ...variability in grading can result in overtreatment and undertreatment of prostate cancer. To alleviate these problems, we aimed to develop an artificial intelligence (AI) system with clinically acceptable accuracy for prostate cancer detection, localisation, and Gleason grading.
We digitised 6682 slides from needle core biopsies from 976 randomly selected participants aged 50–69 in the Swedish prospective and population-based STHLM3 diagnostic study done between May 28, 2012, and Dec 30, 2014 (ISRCTN84445406), and another 271 from 93 men from outside the study. The resulting images were used to train deep neural networks for assessment of prostate biopsies. The networks were evaluated by predicting the presence, extent, and Gleason grade of malignant tissue for an independent test dataset comprising 1631 biopsies from 246 men from STHLM3 and an external validation dataset of 330 biopsies from 73 men. We also evaluated grading performance on 87 biopsies individually graded by 23 experienced urological pathologists from the International Society of Urological Pathology. We assessed discriminatory performance by receiver operating characteristics and tumour extent predictions by correlating predicted cancer length against measurements by the reporting pathologist. We quantified the concordance between grades assigned by the AI system and the expert urological pathologists using Cohen's kappa.
The AI achieved an area under the receiver operating characteristics curve of 0·997 (95% CI 0·994–0·999) for distinguishing between benign (n=910) and malignant (n=721) biopsy cores on the independent test dataset and 0·986 (0·972–0·996) on the external validation dataset (benign n=108, malignant n=222). The correlation between cancer length predicted by the AI and assigned by the reporting pathologist was 0·96 (95% CI 0·95–0·97) for the independent test dataset and 0·87 (0·84–0·90) for the external validation dataset. For assigning Gleason grades, the AI achieved a mean pairwise kappa of 0·62, which was within the range of the corresponding values for the expert pathologists (0·60–0·73).
An AI system can be trained to detect and grade cancer in prostate needle biopsy samples at a ranking comparable to that of international experts in prostate pathology. Clinical application could reduce pathology workload by reducing the assessment of benign biopsies and by automating the task of measuring cancer length in positive biopsy cores. An AI system with expert-level grading performance might contribute a second opinion, aid in standardising grading, and provide pathology expertise in parts of the world where it does not exist.
Swedish Research Council, Swedish Cancer Society, Swedish eScience Research Center, EIT Health.
Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice ...require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following(1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging–targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.
Summary The number of infants infected with HIV is declining with the rise in interventions for the elimination of paediatric HIV infection, but the number of uninfected infants exposed to HIV ...through their HIV-infected mothers is increasing. Interest in the health outcomes of HIV-exposed, uninfected infants has grown in the past decade, with several studies suggesting that these infants have increased mortality rates, increased infectious morbidity, and impaired growth compared with HIV-unexposed infants. However, heterogeneous results might reflect the inherent challenges in studies of HIV-exposed, uninfected infants, which need large populations with appropriate, contemporaneous comparison groups and repeated HIV testing throughout the period of breastfeeding. We review the effects of HIV exposure on mortality, morbidity, and growth, discuss the immunological abnormalities identified so far, and provide an overview of interventions that could be effective in this susceptible population. As the number of infants infected with HIV declines, the health needs of HIV-exposed, uninfected infants should be prioritised further, to ensure that post-2015 Sustainable Development Goals are achieved.
• Leaf area (LA), mass per area (LMA), nitrogen per unit area (Narea) and the leaf-internal to ambient CO₂ ratio (χ) are fundamental traits for plant functional ecology and vegetation modelling. Here ...we aimed to assess how their variation, within and between species, tracks environmental gradients.
• Measurements were made on 705 species from 116 sites within a broad north–south transect from tropical to temperate Australia. Trait responses to environment were quantified using multiple regression; within- and between-species responses were compared using analysis of covariance and trait-gradient analysis.
• Leaf area, the leaf economics spectrum (indexed by LMA and Narea) and χ (from stable carbon isotope ratios) varied almost independently among species. Across sites, however, χ and LA increased with mean growing-season temperature (mGDD₀) and decreased with vapour pressure deficit (mVPD₀) and soil pH. LMA and Narea showed the reverse pattern. Climate responses agreed with expectations based on optimality principles. Within-species variability contributed < 10% to geographical variation in LA but > 90% for χ, with LMA and Narea intermediate.
• These findings support the hypothesis that acclimation within individuals, adaptation within species and selection among species combine to create predictable relationships between traits and environment. However, the contribution of acclimation/adaptation vs species selection differs among traits.
Immune cells are somewhat unique in that activation responses can alter quantitative phenotypes upwards of 100,000-fold. To date little is known about the metabolic adaptations necessary to mount ...such dramatic phenotypic shifts. Screening for novel regulators of macrophage activation, we found nonprotein kinases of glucose metabolism among the most enriched classes of candidate immune modulators. We find that one of these, the carbohydrate kinase-like protein CARKL, is rapidly downregulated in vitro and in vivo upon LPS stimulation in both mice and humans. Interestingly, CARKL catalyzes an orphan reaction in the pentose phosphate pathway, refocusing cellular metabolism to a high-redox state upon physiological or artificial downregulation. We find that CARKL-dependent metabolic reprogramming is required for proper M1- and M2-like macrophage polarization and uncover a rate-limiting requirement for appropriate glucose flux in macrophage polarization.
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► Screened 199 human kinases for their immunoregulatory potential ► CARKL bridges glycolysis, the pentose phosphate pathway, and immune function ► CARKL focuses cellular metabolism toward a “high-redox” state ► CARKL regulation is required for macrophage polarization
‘High functioning autism’ is a term often used for individuals with autism spectrum disorder without an intellectual disability. Over time, this term has become synonymous with expectations of ...greater functional skills and better long-term outcomes, despite contradictory clinical observations. This study investigated the relationship between adaptive behaviour, cognitive estimates (intelligence quotient) and age at diagnosis in autism spectrum disorder. Participants (n = 2225, 1–18 years of age) were notified at diagnosis to a prospective register and grouped by presence (n = 1041) or absence (n = 1184) of intellectual disability. Functional abilities were reported using the Vineland Adaptive Behaviour Scales. Regression models suggested that intelligence quotient was a weak predictor of Vineland Adaptive Behaviour Scales after controlling for sex. Whereas the intellectual disability group’s adaptive behaviour estimates were close to reported intelligence quotients, Vineland Adaptive Behaviour Scales scores fell significantly below intelligence quotients for children without intellectual disability. The gap between intelligence quotient and Vineland Adaptive Behaviour Scales scores remained large with increasing age at diagnosis for all children. These data indicate that estimates from intelligence quotient alone are an imprecise proxy for functional abilities when diagnosing autism spectrum disorder, particularly for those without intellectual disability. We argue that ‘high functioning autism’ is an inaccurate clinical descriptor when based solely on intelligence quotient demarcations and this term should be abandoned in research and clinical practice.
Selecting test populations by age and/or family history, failure to apply reference standard tests consistently, and poor conversion to definitive testing are all potential sources of bias 13. Most ...previous studies involve insurance-based healthcare systems; this is fraught with difficulty because fear of lack of reimbursement by services 17 and increased insurance premiums in individuals 18 influences testing decisions. ...the aims of this prospective study were to (1) establish the prevalence of LS and (2) evaluate the diagnostic accuracy of common LS testing strategies in an unselected EC population within a non–insurance-based healthcare system. All women gave written, informed consent to participate, providing blood-DNA, tumour, and clinical data (age, body mass index BMI, self-reported ethnicity) including detailed family histories (pedigrees). Diagnostic accuracy measures were conducted to establish the utility of clinical parameters and tumour triage strategies for risk stratifying women with EC for MMR germline sequencing, including age, family history, histological subtype, density of TILs, MMR deficiency by IHC, MSI status, and MLH1-methylation status.
We present an updated mechanism for tropospheric halogen (Cl + Br + I) chemistry in the GEOS-Chem global atmospheric chemical transport
model and apply it to investigate halogen radical cycling and ...implications for tropospheric oxidants. Improved representation of HOBr heterogeneous
chemistry and its pH dependence in our simulation leads to less efficient recycling and mobilization of bromine radicals and enables the model to
include mechanistic sea salt aerosol debromination without generating excessive BrO. The resulting global mean tropospheric BrO mixing
ratio is 0.19 ppt (parts per trillion), lower than previous versions of GEOS-Chem. Model BrO shows variable consistency and biases in comparison to
surface and aircraft observations in marine air, which are often near or below the detection limit. The model underestimates the daytime
measurements of Cl2 and BrCl from the ATom aircraft campaign over the Pacific and Atlantic, which if correct would imply a very large
missing primary source of chlorine radicals. Model IO is highest in the marine boundary layer and uniform in the free troposphere, with a global
mean tropospheric mixing ratio of 0.08 ppt, and shows consistency with surface and aircraft observations. The modeled global mean
tropospheric concentration of Cl atoms is 630 cm−3, contributing 0.8 % of the global oxidation of methane, 14 % of ethane,
8 % of propane, and 7 % of higher alkanes. Halogen chemistry decreases the global tropospheric burden of ozone by 11 %,
NOx by 6 %, and OH by 4 %. Most of the ozone decrease is driven by iodine-catalyzed loss. The resulting GEOS-Chem ozone
simulation is unbiased in the Southern Hemisphere but too low in the Northern Hemisphere.
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