Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix.

Metastasis requires tumor cells to navigate through a stiff stroma and squeeze through confined microenvironments. Whether tumors exploit unique biophysical properties to metastasize remains unclear. Data show that invading mammary tumor cells, when cultured in a stiffened three-dimensional extracellular matrix that recapitulates the primary tumor stroma, adopt a basal-like phenotype. Metastatic tumor cells and basal-like tumor cells exert higher integrin-mediated traction forces at the bulk and molecular levels, consistent with a motor-clutch model in which motors and clutches are both increased. Basal-like nonmalignant mammary epithelial cells also display an altered integrin adhesion molecular organization at the nanoscale and recruit a suite of paxillin-associated proteins implicated in invasion and metastasis. Phosphorylation of paxillin by Src family kinases, which regulates adhesion turnover, is similarly enhanced in the metastatic and basal-like tumor cells, fostered by a stiff matrix, and critical for tumor cell invasion in our assays. Bioinformatics reveals an unappreciated relationship between Src kinases, paxillin, and survival of breast cancer patients. Thus adoption of the basal-like adhesion phenotype may favor the recruitment of molecules that facilitate tumor metastasis to integrin-based adhesions. Analysis of the physical properties of tumor cells and integrin adhesion composition in biopsies may be predictive of patient outcome

Formal Analysis of Quantum Systems using Process Calculus

Quantum communication and cryptographic protocols are well on the way to becoming an important practical technology. Although a large amount of successful research has been done on proving their correctness, most of this work does not make use of familiar techniques from formal methods, such as formal logics for specification, formal modelling languages, separation of levels of abstraction, and compositional analysis. We argue that these techniques will be necessary for the analysis of large-scale systems that combine quantum and classical components, and summarize the results of initial investigation using behavioural equivalence in process calculus. This paper is a summary of Simon Gay's invited talk at ICE'11.Comment: In Proceedings ICE 2011, arXiv:1108.014

A necroptosis-independent function of RIPK3 promotes immune dysfunction and prevents control of chronic LCMV infection

Necroptosis is a lytic and inflammatory form of cell death that is highly constrained to mitigate detrimental collateral tissue damageand impaired immunity. These constraints make it difficult to define the relevance of necroptosis in diseases such as chronic andpersistent viral infections and within individual organ systems. The role of necroptotic signalling is further complicated becauseproteins essential to this pathway, such as receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like(MLKL), have been implicated in roles outside of necroptotic signalling. We sought to address this issue by individually defining therole of RIPK3 and MLKL in chronic lymphocytic choriomeningitis virus (LCMV) infection. We investigated if necroptosis contributesto the death of LCMV-specific CD8+ T cells or virally infected target cells during infection. We provide evidence showing thatnecroptosis was redundant in the pathogenesis of acute forms of LCMV (Armstrong strain) and the early stages of chronic (Docilestrain) LCMV infection in vivo. The number of immune cells, their specificity and reactivity towards viral antigens and viral loads arenot altered in the absence of either MLKL or RIPK3 during acute and during the early stages of chronic LCMV infection. However, weidentified that RIPK3 promotes immune dysfunction and prevents control of infection at later stages of chronic LCMV disease. Thiswas not phenocopied by the loss of MLKL indicating that the phenotype was driven by a necroptosis-independent function ofRIPK3. We provide evidence that RIPK3 signaling evoked a dysregulated type 1 interferone response which we linked to animpaired antiviral immune response and abrogated clearance of chronic LCMV infectio

Protocol for randomized personalized trial for stress management compared to standard of care

Stress is a significant public health burden in the United States, with most Americans reporting unhealthy levels of stress. Stress management techniques include various evidence-based treatments shown to be effective but with heterogeneous treatment responses, indicating a lack of uniform benefits for all individuals. Designed to assess a participant’s response to a specific intervention, personalized (N-of-1) trials provide guidance for which treatment (s) work (s) best for the individual. Prior studies examining the effects of mindfulness meditation, yoga, and walking for stress reduction found all three interventions to be associated with significant reductions in self-reported measures of stress. Delivering these treatments using a personalized trial approach has the potential to assist clinicians in identifying the best stress management techniques for individuals with persistently high stress while fostering treatment decisions that consider their personal condition/barriers. This trial will evaluate a personalized approach compared to standard of care for three interventions (guided mindfulness meditation; guided yoga; and guided brisk walking) to manage perceived stress. Participants will respond to daily surveys and wear a Fitbit device for 18 weeks. After a 2-week baseline period, participants in the personalized trial groups will receive 12 weeks of interventions in randomized order, while participants in the standard-of-care group will have access to all interventions for self-directed stress management. After intervention, all participants will undergo 2 weeks of observation, followed by two additional weeks of the stress management intervention of their choosing while continuing outcome measurement. At study completion, all participants will be sent a satisfaction survey. The primary analysis will compare perceived stress levels between the personalized and standard of care arms. The results of this trial will provide further support for the use of personalized designs for managing stress.Clinical Trial Registration: clinicaltrials.gov, NCT05408832.Protocol version: 9/14/2022, 21-0968-MRB

Spectrum of Infection and Risk Factors for Human Monkeypox, United States, 2003

Infection is associated with proximity to virus-infected animals and their excretions and secretions

In Vitro Neutralisation of Rotavirus Infection by Two Broadly Specific Recombinant Monovalent Llama-Derived Antibody Fragments

Rotavirus is the main cause of viral gastroenteritis in young children. Therefore, the development of inexpensive antiviral products for the prevention and/or treatment of rotavirus disease remains a priority. Previously we have shown that a recombinant monovalent antibody fragment (referred to as Anti-Rotavirus Proteins or ARP1) derived from a heavy chain antibody of a llama immunised with rotavirus was able to neutralise rotavirus infection in a mouse model system. In the present work we investigated the specificity and neutralising activity of two llama antibody fragments, ARP1 and ARP3, against 13 cell culture adapted rotavirus strains of diverse genotypes. In addition, immunocapture electron microscopy (IEM) was performed to determine binding of ARP1 to clinical isolates and cell culture adapted strains. ARP1 and ARP3 were able to neutralise a broad variety of rotavirus serotypes/genotypes in vitro, and in addition, IEM showed specific binding to a variety of cell adapted strains as well as strains from clinical specimens. These results indicated that these molecules could potentially be used as immunoprophylactic and/or immunotherapeutic products for the prevention and/or treatment of infection of a broad range of clinically relevant rotavirus strains

Investigation of rheumatoid arthritis susceptibility loci in juvenile idiopathic arthritis confirms high degree of overlap

<p>Objectives: Rheumatoid arthritis (RA) shares some similar clinical and pathological features with juvenile idiopathic arthritis (JIA); indeed, the strategy of investigating whether RA susceptibility loci also confer susceptibility to JIA has already proved highly successful in identifying novel JIA loci. A plethora of newly validated RA loci has been reported in the past year. Therefore, the aim of this study was to investigate these single nucleotide polymorphisms (SNP) to determine if they were also associated with JIA.</p> <p>Methods: Thirty-four SNP that showed validated association with RA and had not been investigated previously in the UK JIA cohort were genotyped in JIA cases (n=1242), healthy controls (n=4281), and data were extracted for approximately 5380 UK Caucasian controls from the Wellcome Trust Case–Control Consortium 2. Genotype and allele frequencies were compared between cases with JIA and controls using PLINK. A replication cohort of 813 JIA cases and 3058 controls from the USA was available for validation of any significant findings.</p> <p>Results: Thirteen SNP showed significant association (p<0.05) with JIA and for all but one the direction of association was the same as in RA. Of the eight loci that were tested, three showed significant association in the US cohort.</p> <p>Conclusions: A novel JIA susceptibility locus was identified, CD247, which represents another JIA susceptibility gene whose protein product is important in T-cell activation and signalling. The authors have also confirmed association of the PTPN2 and IL2RA genes with JIA, both reaching genome-wide significance in the combined analysis.</p&gt

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat