Immune DNA signature of T-cell infiltration in breast tumor exomes.

Tumor infiltrating lymphocytes (TILs) have been associated with favorable prognosis in multiple tumor types. The Cancer Genome Atlas (TCGA) represents the largest collection of cancer molecular data, but lacks detailed information about the immune environment. Here, we show that exome reads mapping to the complementarity-determining-region 3 (CDR3) of mature T-cell receptor beta (TCRB) can be used as an immune DNA (iDNA) signature. Specifically, we propose a method to identify CDR3 reads in a breast tumor exome and validate it using deep TCRB sequencing. In 1,078 TCGA breast cancer exomes, the fraction of CDR3 reads was associated with TILs fraction, tumor purity, adaptive immunity gene expression signatures and improved survival in Her2+ patients. Only 2/839 TCRB clonotypes were shared between patients and none associated with a specific HLA allele or somatic driver mutations. The iDNA biomarker enriches the comprehensive dataset collected through TCGA, revealing associations with other molecular features and clinical outcomes

A mechanistic model linking insect (Hydropsychidae) silk nets to incipient sediment motion in gravel‐bedded streams

Plants and animals affect stream morphodynamics across a range of scales, yet including biological traits of organisms in geomorphic process models remains a fundamental challenge. For example, laboratory experiments have shown that silk nets built by caddisfly larvae (Trichoptera: Hydropsychidae) can increase the shear stress required to initiate bed motion by more than a factor of 2. The contributions of specific biological traits are not well understood, however. Here we develop a theoretical model for the effects of insect nets on the threshold of sediment motion, τ * crit , that accounts for the mechanical properties, geometry, and vertical distribution of insect silk, as well as interactions between insect species. To parameterize the model, we measure the tensile strength, diameter, and number of silk threads in nets built by two common species of caddisfly, Arctopsyche californica and Ceratopsyche oslari . We compare model predictions with new measurements of τ * crit in experiments where we varied grain size and caddisfly species composition. The model is consistent with experimental results for single species, which show that the increase in τ * crit above the abiotic control peaks at 40–70% for 10–22 mm sediments and declines with increasing grain size. For the polyculture experiments, however, the model underpredicts the measured increase in τ * crit when two caddisfly species are present in sediments of larger grain sizes. Overall, the model helps explain why the presence of caddisfly silk can substantially increase the forces needed to initiate sediment motion in gravel‐bedded streams and also illustrates the challenge of parameterizing the behavior of multiple interacting species in a physical model. Key Points Caddisfly silk nets are incorporated into a model of incipient sediment motion Silk nets increase critical shear stress in gravel‐bedded streams Species‐specific silk and behaviors control the range of grain sizes affectedPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109329/1/jgrf20303.pd

Personalising laboratory medicine in the ‘real world’:assessing clinical utility, by clinical indication, of serum total B12 and Active-B12® (holotranscobalamin) in the diagnosis of vitamin B12 deficiency

BACKGROUND: Assessing the pre- and post-test probability of disease in the context of routine health care is challenging. We wished to study how test performance parameters relating to clinical utility vary by clinical indication in a ‘real-world’ setting. METHODS: The diagnostic accuracy of serum total B(12) and Active-B(12)® (holotranscobalamin) was evaluated in a primary care population, using serum methylmalonic acid as the reference standard. We used electronic requesting to establish the clinical indication for each request. Routine requests from primary care for serum total B(12) were included if creatinine was also measured and estimated glomerular filtration rate was at least 60 mL/min/1.73 m(2). RESULTS: Clinical indications included peripheral neuropathy (n = 168), anaemia (n = 168), cognitive decline (n = 125), suspected dietary deficiency (n = 76), other (n = 362). For peripheral neuropathy, the area under the receiver operator curve ± 95% confidence interval (AUC ± CI) was 0.63 (0.54–0.71) (P = 0.002) for total B(12) and 0.68 (0.60–0.77) (P < 0.0001) for Active-B(12)®. For anaemia, AUC ± CI was 0.56 (0.47–0.66) (P = 0.10) for total B(12) and 0.69 (0.59–0.78) (P < 0.0001) for Active-B(12)®. For cognitive decline, AUC ± CI was 0.54 (0.43–0.65) (P = 0.26) for total B(12) and 0.69 (0.58–0.80) (P = 0.0002) for Active-B(12)®. The pre–post-test change in probability of disease varied by clinical indication. CONCLUSION: Combining diagnostic accuracy studies and electronic testing in a ‘real-world’ setting allows clinical utility to be assessed by clinical indication. Wider application of this would permit more personalised laboratory medicine. In this study, diagnostic performance of total B(12) and Active-B(12)® varied across all indications. Active-B(12)® provided better discrimination, but this may have reflected the cut-offs used

A Comparison of Delivery Methods of Cognitive-Behavioral Therapy for Panic Disorder: An International Multicenter Trial

Cognitive-behavioral therapy (CBT) is the psychological treatment of choice for panic disorder (PD). However, given limited access to CBT, it must be delivered with maximal cost-effectiveness. Previous researchers have found that a brief computer-augmented CBT was as effective as extended therapist-delivered CBT. To test this finding, this study randomly allocated 186 patients with PD across 2 sites in Scotland and Australia to 12 sessions of therapist-delivered CBT (CBT12), 6 sessions of therapist-delivered (CBT6) or computer-augmented CBT (CBT6-CA), or a waitlist control. On a composite measure, at post-treatment, the outcome for CBT12 was statistically better than the outcome for CBT6. The outcome for CBT6-CA fell between CBT12 and CBT6, but could not be statistically distinguished from either treatment. The active treatments did not differ statistically at 6-month follow-up. The study provided some support for the use of computers as an innovative adjunctive-therapy tool and merits further investigation

START-online: acceptability and feasibility of an online intervention for carers of people living with dementia

BACKGROUND: With increasing numbers of people living with dementia relying on family to care for them at home, there is an urgent need for practical and evidence-based programs to support carers in maintaining their mental health and well-being. The objective of this study was to evaluate the acceptability and feasibility of a modified STrAtegies for RelaTives (START) program delivered online (START-online). METHOD: A mixed-methods non-blinded evaluation of START-online (using Zoom as videoconferencing platform) for acceptability and feasibility (completion rates and qualitative feedback through surveys and focus groups) and quantitative evaluation. This occurred at the National Ageing Research Institute, in metropolitan Victoria, Australia. RESULTS: Twenty-nine eligible carers were referred, 20 (70%) consented to the study. Of these, 16 (80%) completed all 8 sessions, 2 completed only 3 sessions, and 2 withdrew. Carers' qualitative feedback indicated that the therapist interaction was valued, content and online delivery of the program was acceptable. Feedback was mixed on the appropriate stage of caring. CONCLUSION: START-online was feasible and acceptable for carers, including those living outside of metropolitan areas who might otherwise be unable to access face-to-face programs. With the recent COVID-19 pandemic necessitating social distancing to avoid infection, interventions such as this one have increasing relevance in the provision of flexible services

Flood vulnerability assessment : City of Beaufort, SC

Beaufort is at risk to tidal flooding, storm surge, and high intensity rain events. In order to understand how vulnerable City assets are to tidal and precipitation-based flooding, the City engaged a collaborative team of investigators to conduct a study. This report summarizes the methods utilized by the research team to produce flood layers and analyze the vulnerabilities they conferred, the results of the vulnerability assessment, and a discussion of the implications of those results

Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation

Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy