Is adaptive therapy natural?

Research suggests that progression-free survival can be prolonged by integrating evolutionary principles into clinical cancer treatment protocols. The goal is to prevent or slow the proliferation of resistant malignant cell populations. The logic behind this therapy relies on ecological and evolutionary processes. These same processes would be available to natural selection in decreasing the probability of an organism\u27s death due to cancer. We propose that organisms\u27 anticancer adaptions include not only ones for preventing cancer but also ones for directing and retarding the evolution of life-threatening cancer cells. We term this last strategy natural adaptive therapy (NAT). The body\u27s NAT might include a lower than otherwise possible immune response. A restrained immune response might forego maximum short-term kill rates. Restraint would forestall immune-resistant cancer cells and produce long-term durable control of the cancer population. Here, we define, develop, and explore the possibility of NAT. The discovery of NAT mechanisms could identify new strategies in tumor prevention and treatments. Furthermore, we discuss the potential risks of immunotherapies that force the immune system to ramp up the short-term kill rates of malignant cancer cells in a manner that undermines the body\u27s NAT and accelerates the evolution of immune resistance

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

Atypical pathogens in hospitalized patients with community-acquired pneumonia: A worldwide perspective

Background: Empirical antibiotic coverage for atypical pathogens in community-acquired pneumonia (CAP) has long been debated, mainly because of a lack of epidemiological data. We aimed to assess both testing for atypical pathogens and their prevalence in hospitalized patients with CAP worldwide, especially in relation with disease severity. Methods: A secondary analysis of the GLIMP database, an international, multicentre, point-prevalence study of adult patients admitted for CAP in 222 hospitals across 6 continents in 2015, was performed. The study evaluated frequency of testing for atypical pathogens, including L. pneumophila, M. pneumoniae, C. pneumoniae, and their prevalence. Risk factors for testing and prevalence for atypical pathogens were assessed through univariate analysis. Results: Among 3702 CAP patients 1250 (33.8%) underwent at least one test for atypical pathogens. Testing varies greatly among countries and its frequency was higher in Europe than elsewhere (46.0% vs. 12.7%, respectively, p &lt; 0.0001). Detection of L. pneumophila urinary antigen was the most common test performed worldwide (32.0%). Patients with severe CAP were less likely to be tested for both atypical pathogens considered together (30.5% vs. 35.0%, p = 0.009) and specifically for legionellosis (28.3% vs. 33.5%, p = 0.003) than the rest of the population. Similarly, L. pneumophila testing was lower in ICU patients. At least one atypical pathogen was isolated in 62 patients (4.7%), including M. pneumoniae (26/251 patients, 10.3%), L. pneumophila (30/1186 patients, 2.5%), and C. pneumoniae (8/228 patients, 3.5%). Patients with CAP due to atypical pathogens were significantly younger, showed less cardiovascular, renal, and metabolic comorbidities in comparison to adult patients hospitalized due to non-atypical pathogen CAP. Conclusions: Testing for atypical pathogens in patients admitted for CAP in poorly standardized in real life and does not mirror atypical prevalence in different settings. Further evidence on the impact of atypical pathogens, expecially in the low-income countries, is needed to guidelines implementation

Microbiological testing of adults hospitalised with community-acquired pneumonia: An international study

This study aimed to describe real-life microbiological testing of adults hospitalised with community-acquired pneumonia (CAP) and to assess concordance with the 2007 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) and 2011 European Respiratory Society (ERS) CAP guidelines. This was a cohort study based on the Global Initiative for Methicillin-resistant Staphylococcus aureus Pneumonia (GLIMP) database, which contains point-prevalence data on adults hospitalised with CAP across 54 countries during 2015. In total, 3702 patients were included. Testing was performed in 3217 patients, and included blood culture (71.1%), sputum culture (61.8%), Legionella urinary antigen test (30.1%), pneumococcal urinary antigen test (30.0%), viral testing (14.9%), acute-phase serology (8.8%), bronchoalveolar lavage culture (8.4%) and pleural fluid culture (3.2%). A pathogen was detected in 1173 (36.5%) patients. Testing attitudes varied significantly according to geography and disease severity. Testing was concordant with IDSA/ATS and ERS guidelines in 16.7% and 23.9% of patients, respectively. IDSA/ATS concordance was higher in Europe than in North America (21.5% versus 9.8%; p&lt;0.01), while ERS concordance was higher in North America than in Europe (33.5% versus 19.5%; p&lt;0.01). Testing practices of adults hospitalised with CAP varied significantly by geography and disease severity. There was a wide discordance between real-life testing practices and IDSA/ATS/ERS guideline recommendations

Prevalence and etiology of community-acquired pneumonia in immunocompromised patients

Background. The correct management of immunocompromised patients with pneumonia is debated. We evaluated the prevalence, risk factors, and characteristics of immunocompromised patients coming from the community with pneumonia. Methods. We conducted a secondary analysis of an international, multicenter study enrolling adult patients coming from the community with pneumonia and hospitalized in 222 hospitals in 54 countries worldwide. Risk factors for immunocompromise included AIDS, aplastic anemia, asplenia, hematological cancer, chemotherapy, neutropenia, biological drug use, lung transplantation, chronic steroid use, and solid tumor. Results. At least 1 risk factor for immunocompromise was recorded in 18% of the 3702 patients enrolled. The prevalences of risk factors significantly differed across continents and countries, with chronic steroid use (45%), hematological cancer (25%), and chemotherapy (22%) the most common. Among immunocompromised patients, community-acquired pneumonia (CAP) pathogens were the most frequently identified, and prevalences did not differ from those in immunocompetent patients. Risk factors for immunocompromise were independently associated with neither Pseudomonas aeruginosa nor non\u2013community-acquired bacteria. Specific risk factors were independently associated with fungal infections (odds ratio for AIDS and hematological cancer, 15.10 and 4.65, respectively; both P = .001), mycobacterial infections (AIDS; P = .006), and viral infections other than influenza (hematological cancer, 5.49; P < .001). Conclusions. Our findings could be considered by clinicians in prescribing empiric antibiotic therapy for CAP in immunocompromised patients. Patients with AIDS and hematological cancer admitted with CAP may have higher prevalences of fungi, mycobacteria, and noninfluenza viruses

Burden and risk factors for Pseudomonas aeruginosa community-acquired pneumonia:a Multinational Point Prevalence Study of Hospitalised Patients

Pseudornonas aeruginosa is a challenging bacterium to treat due to its intrinsic resistance to the antibiotics used most frequently in patients with community-acquired pneumonia (CAP). Data about the global burden and risk factors associated with P. aeruginosa-CAP are limited. We assessed the multinational burden and specific risk factors associated with P. aeruginosa-CAP. We enrolled 3193 patients in 54 countries with confirmed diagnosis of CAP who underwent microbiological testing at admission. Prevalence was calculated according to the identification of P. aeruginosa. Logistic regression analysis was used to identify risk factors for antibiotic-susceptible and antibiotic-resistant P. aeruginosa-CAP. The prevalence of P. aeruginosa and antibiotic-resistant P. aeruginosa-CAP was 4.2% and 2.0%, respectively. The rate of P. aeruginosa CAP in patients with prior infection/colonisation due to P. aeruginosa and at least one of the three independently associated chronic lung diseases (i.e. tracheostomy, bronchiectasis and/or very severe chronic obstructive pulmonary disease) was 67%. In contrast, the rate of P. aeruginosa-CAP was 2% in patients without prior P. aeruginosa infection/colonisation and none of the selected chronic lung diseases. The multinational prevalence of P. aeruginosa-CAP is low. The risk factors identified in this study may guide healthcare professionals in deciding empirical antibiotic coverage for CAP patients

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60&nbsp;years old

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer