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Background Multiparametric MRI has shown great promise to derive multiple quantitative imaging biomarkers for treatment response assessment. Purpose To evaluate a novel deep‐learning‐enhanced MUlti‐PArametric MR sequence (DL‐MUPA) for treatment response assessment for brain metastases patients treated with stereotactic radiosurgery (SRS) and head‐and‐neck (HN) cancer patients undergoing conventionally fractionation adaptive radiation therapy. Methods DL‐MUPA derives quantitative T1 and T2 relaxation time maps from a single 4–6‐min scan denoised via DL method using least‐squares dictionary fitting. Longitudinal phantom benchmarking was performed on a NIST‐ISMRM phantom over 1 year. In patients, longitudinal DL‐MUPA data were acquired on a 1.5T MR‐simulator, including pretreatment (PreTx) and every ∼3 months after SRS (PostTx) in brain, and PreTx, mid‐treatment and 3 months PostTx in HN. Delta analysis was performed calculating changes of mean T1 and T2 values within gross tumor volumes (GTVs), residual disease (RD, HN), parotids, and submandibular glands (HN) for treatment response assessment. Uninvolved normal tissues (normal appearing white matter in brain, masseter in HN) were evaluated for within‐subject repeatability. Results Phantom benchmarking revealed excellent inter‐session repeatability (coefficient of variation < 0.9% for T1, < 6.6% for T2), suggesting reliability for longitudinal studies with systematic bias adjustment. Uninvolved normal tissue suggested acceptable within‐subject repeatability in the brain |ΔT1mean| < 36 ms (4.9%), |ΔT2mean| < 2 ms (6.1%) and HN |ΔT1mean| < 69 ms (7.0%), |ΔT2mean| < 4 ms (17.8%) with few outliers. In brain, remarkable changes were noted in a resolved metastasis (4‐month PostTx ΔT1mean = 155 ms (13.7%)) and necrotic settings (ΔT1mean = 214‐502 ms (17.6‐39.7%), ΔT2mean = 7‐41 ms (8.7‐41.4%), 6‐month to 3‐month PostTx). In HN, two base of tongue tumors exhibited T2 enhancement (PostTx GTV ΔT2mean > 7 ms (12.8%), RD ΔT2mean > 10 ms (18.1%)). A case with nodal disease resolved PostTx (GTV ΔT1mean = ‐541 ms (‐39.5%), ΔT2mean = ‐24 ms (‐32.7%), RD ΔT1mean = ‐400 ms (‐29.2%), ΔT2mean = ‐25 ms (‐35.3%)). Parotids (PostTx ΔT1mean > 82 ms (12.4%), ΔT2mean > 6 ms (13.4%)) and submandibular glands (PostTx ΔT1mean > 135 ms (14.6%), ΔT2mean > 17 ms (34.5%)) adjacent to gross disease exhibited enhancement while distant organs remained stable. Conclusions Preliminary results suggest promise of DL‐MUPA for treatment response assessment and highlight potential endpoints for functional sparing.

Coagulation factor XII (FXII) deficiency is associated with decreased neutrophil migration, but the mechanisms remain uncharacterized. Here, we examine how FXII contributes to the inflammatory response. In 2 models of sterile inflammation, FXII-deficient mice (F12-/-) had fewer neutrophils recruited than WT mice. We discovered that neutrophils produced a pool of FXII that is functionally distinct from hepatic-derived FXII and contributes to neutrophil trafficking at sites of inflammation. FXII signals in neutrophils through urokinase plasminogen activator receptor-mediated (uPAR-mediated) Akt2 phosphorylation at S474 (pAktS474). Downstream of pAkt2S474, FXII stimulation of neutrophils upregulated surface expression of αMβ2 integrin, increased intracellular calcium, and promoted extracellular DNA release. The sum of these activities contributed to neutrophil cell adhesion, migration, and release of neutrophil extracellular traps in a process called NETosis. Decreased neutrophil signaling in F12-/- mice resulted in less inflammation and faster wound healing. Targeting hepatic F12 with siRNA did not affect neutrophil migration, whereas WT BM transplanted into F12-/- hosts was sufficient to correct the neutrophil migration defect in F12-/- mice and restore wound inflammation. Importantly, these activities were a zymogen FXII function and independent of FXIIa and contact activation, highlighting that FXII has a sophisticated role in vivo that has not been previously appreciated.

Multi-parametric MRI has shown great promise to rapidly derive multiple quantitative imaging biomarkers for treatment response assessment. To evaluate a novel Deep-Learning-enhanced MUlti-PArametric MR sequence (DL-MUPA) for treatment response assessment for brain metastases patients treated with stereotactic radiosurgery (SRS) and head-and-neck (HnN) cancer patients undergoing conventionally fractionation adaptive radiation therapy. DL-MUPA derives quantitative T1 and T2 relaxation time maps from a single 4-6-minute scan denoised via DL method using least-squares dictionary fitting. Longitudinal phantom benchmarking was performed on a NIST-ISMRM phantom over one year. In patients, longitudinal DL-MUPA data were acquired on a 1.5T MR-simulator, including pre-treatment (PreTx) and every ~3 months after SRS (PostTx) in brain, and PreTx, mid-treatment and 3 months PostTx in HnN. Delta analysis was performed calculating changes of mean T1 and T2 values within gross tumor volumes (GTVs), residual disease (RD, HnN), parotids, and submandibular glands (HnN) for treatment response assessment. Uninvolved normal tissues (normal appearing white matter in brain, masseter in HnN) were evaluated to quantify within-subject repeatability. Phantom benchmarking revealed excellent inter-session repeatability (coefficient of variance <0.9% for T1, <6.6% for T2), suggesting reliability for longitudinal studies once systematic biases are adjusted. Uninvolved normal tissue suggested acceptable within-subject repeatability (brain |ΔT1 |<36ms/5.0%, |ΔT2 |<2ms/5.0%, HnN |ΔT1 |<69ms/7.0%, |ΔT2 |<4ms/17.8% due to low T2). In brain, remarkable changes were noted in resolved metastasis (4-month PostTx ΔT1 =155ms/13.7%) and necrotic settings (ΔT1 =214-502ms/17.6-39.7%, ΔT2 =7-41ms/8.7-41.4%, 6-month to 3-month PostTx). In HnN, two base of tongue tumors exhibited T2 enhancement (PostTx GTV ΔT2 >7ms/12.8%, RD ΔT2 >10ms/18.1%). A case with nodal disease resolved PostTx (GTV ΔT1 =-541ms/-39.5%, ΔT2 =-24ms/-32.7%, RD ΔT1 =-400ms/-29.2%, ΔT2 =-25ms/-35.3%). Enhancement was found in involved parotids (PostTx ΔT1 >82ms/12.4%, ΔT2 >6ms/13.4%) and submandibular glands (PostTx ΔT1 >135ms/14.6%, ΔT2 >17ms/34.5%) while the uninvolved organs remained stable. Preliminary results suggest promise of DL-MUPA for treatment response assessment and highlight potential endpoints for functional sparing.

Increased mammographic density, caused by increased extracellular collagen matrix deposition in the breast, is associated with a 4-6 fold increased risk in the incidence of breast cancer. Interestingly, changes in the composition of the extracellular matrix can also alter various metabolic pathways in cancer cells. Here we investigate the role of collagen matrix density in regulating the metabolic pathways utilized by mammary carcinoma cells. We find changes in functional metabolism of mammary carcinoma cells in response to changes in collagen matrix density. Further, mammary carcinoma cells grown in high density collagen matrices display decreased glucose metabolism via the tricarboxylic acid (TCA) cycle compared to cells cultured in low density collagen matrices. Despite decreased glucose entry into the TCA cycle, levels of glucose uptake are not different between high and low density matrices. Interestingly, under high density conditions the contribution of glutamine as a fuel source to drive the TCA cycle is significantly enhanced. This study highlights the broad importance of the collagen microenvironment in modulating metabolic shifts of cancer cells. While changes in the composition of the tumor microenvironment can alter the metabolism of mammary carcinoma cells, the interaction between the microenvironment and tumor cells can have larger impacts on the ability of tumor cells to proliferate. While the recurrence risk in patients with definitively treated breast cancer is highest in the first five years after treatment, some patients have late recurrence of metastatic disease many years after definitive treatment. This has led to the recognition of a dormant tumor cell population that can exist in definitively treated cancer patients. Here we show that placing dormant tumor cells into an aged microenvironment is able to reactivate dormant tumor cells. Interestingly, this reactivation of dormant tumor cells is due to a combination of decreased immune surveillance in aged animals coupled with increased fibrosis at the metastatic site. In addition we identify an intracellular pathway regulated by the transcription factor Macc1 which plays a role in regulating the metastatic potential of mammary carcinoma cells. These studies provide important insight into both intra and extracellular cues responsible for metastasis and tumor dormancy.

Purpose: To evaluate a Deep-Learning-enhanced MUlti-PArametric MR sequence (DL-MUPA) for treatment response assessment for brain metastases patients undergoing stereotactic radiosurgery (SRS) and head-and-neck (HnN) cancer patients undergoing conventionally fractionation adaptive radiation therapy. Methods: DL-MUPA derives quantitative T1 and T2 maps from a single 4-6-minute scan denoised via DL method using dictionary fitting. Phantom benchmarking was performed on a NIST-ISMRM phantom. Longitudinal patient data were acquired on a 1.5T MR-simulator, including pre-treatment (PreTx) and every 3 months after SRS (PostTx) in brain, and PreTx, mid-treatment and 3 months PostTx in HnN. Changes of mean T1 and T2 values were calculated within gross tumor volumes (GTVs), residual disease (RD, HnN), parotids, and submandibular glands (HnN) for treatment response assessment. Uninvolved normal tissues (normal appearing white matter in brain, masseter in HnN) were evaluated to as control. Results: Phantom benchmarking showed excellent inter-session repeatability (coefficient of variance <1% for T1, <7% for T2). Uninvolved normal tissue suggested acceptable in-vivo repeatability (brain |\\(\\Delta\\)|<6%, HnN |\\(\\Delta\\)T1|<7%, |\\(\\Delta\\)T2|<18% (4ms)). Remarkable changes were noted in resolved brain metastasis (\\(\\Delta\\)T1=14%) and necrotic settings (\\(\\Delta\\)T1=18-40%, \\(\\Delta\\)T2=9-41%). In HnN, two primary tumors showed T2 increase (PostTx GTV \\(\\Delta\\)T2>13%, RD \\(\\Delta\\)T2>18%). A nodal disease resolved PostTx (GTV \\(\\Delta\\)T1=-40%, \\(\\Delta\\)T2=-33%, RD \\(\\Delta\\)T1=-29%, \\(\\Delta\\)T2=-35%). Enhancement was found in involved parotids (PostTx \\(\\Delta\\)T1>12%, \\(\\Delta\\)T2>13%) and submandibular glands (PostTx \\(\\Delta\\)T1>15%, \\(\\Delta\\)T2>35%) while the uninvolved organs remained stable. Conclusions: DL-MUPA shows promise for treatment response assessment and identifying potential endpoints for functional sparing.

GRIPP2 (short form and long form) is the first international guidance for reporting of patient and public involvement in health and social care research. This paper describes the development of the GRIPP2 reporting checklists, which aim to improve the quality, transparency, and consistency of the international patient and public involvement (PPI) evidence base, to ensure that PPI practice is based on the best evidence

Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex that orchestrates cargo retrieval and recycling and, importantly, is biochemically and functionally distinct from the established retromer pathway. We have called this complex ‘retriever’; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of α 5 β 1 integrin. Through quantitative proteomic analysis, we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, that require SNX17–retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway. McNally et al.  identify the retriever complex as required for endosomal cargo recycling. Retriever binds SNX17, the CCC and WASH complexes to govern cell surface expression of integrins, receptors and transporters.

Studying the albedos of the planets and moons of the Solar System dates back at least a century 1 – 4 . Of particular interest is the relationship between the albedo measured at superior conjunction, known as the ‘geometric albedo’, and the albedo considered over all orbital phase angles, known as the ‘spherical albedo’ 2 , 5 , 6 . Determining the relationship between the geometric and spherical albedos usually involves complex numerical calculations 7 – 11 , and closed-form solutions are restricted to simple reflection laws 12 , 13 . Here we report the discovery of closed-form solutions for the geometric albedo and integral phase function, which apply to any law of reflection that only depends on the scattering angle. The shape of a reflected light phase curve, quantified by the integral phase function, and the secondary eclipse depth, quantified by the geometric albedo, may now be self-consistently inverted to retrieve globally averaged physical parameters. Fully Bayesian phase-curve inversions for reflectance maps and simultaneous light-curve detrending may now be performed due to the efficiency of computation. Demonstrating these innovations for the hot Jupiter Kepler-7b, we infer a geometric albedo of 0.2 5 − 0.02 + 0.01 , a phase integral of 1.77 ± 0.07, a spherical albedo of 0.4 4 − 0.03 + 0.02 and a scattering asymmetry factor of 0.0 7 − 0.11 + 0.12 . An ab initio closed-form analytical solution for the geometric albedo and the integral phase function, which is valid for any law of reflection provided that it depends only on the scattering angle, is proposed. Such solutions can be applied to determine the scattering properties of planetary atmospheres or surfaces.

Clear cell renal cell carcinoma (ccRCC) is histologically defined by its lipid and glycogen-rich cytoplasmic deposits. Alterations in the VHL tumor suppressor stabilizing the hypoxia-inducible factors (HIFs) are the most prevalent molecular features of clear cell tumors. The significance of lipid deposition remains undefined. We describe the mechanism of lipid deposition in ccRCC by identifying the rate-limiting component of mitochondrial fatty acid transport, carnitine palmitoyltransferase 1A ( CPT1A ), as a direct HIF target gene. CPT1A is repressed by HIF1 and HIF2, reducing fatty acid transport into the mitochondria, and forcing fatty acids to lipid droplets for storage. Droplet formation occurs independent of lipid source, but only when CPT1A is repressed. Functionally, repression of CPT1A is critical for tumor formation, as elevated CPT1A expression limits tumor growth. In human tumors, CPT1A expression and activity are decreased versus normal kidney; and poor patient outcome associates with lower expression of CPT1A in tumors in TCGA. Together, our studies identify HIF control of fatty acid metabolism as essential for ccRCC tumorigenesis. Clear cell renal cancers (ccRCC) display elevated intracellular lipid storage. Here the authors show that such lipid accumulation is due to the repression of carnitine palmitoyltransferase 1A (CPT1A) enzyme that impairs fatty acid (FA) transport into the mitochondrion resulting in reduced FA beta oxidation.

Understanding the tissue-specific genetic controls of protein levels is essential to uncover mechanisms of post-transcriptional gene regulation. In this study, we generated a genomic atlas of protein levels in three tissues relevant to neurological disorders (brain, cerebrospinal fluid and plasma) by profiling thousands of proteins from participants with and without Alzheimer’s disease. We identified 274, 127 and 32 protein quantitative trait loci (pQTLs) for cerebrospinal fluid, plasma and brain, respectively. cis-pQTLs were more likely to be tissue shared, but trans-pQTLs tended to be tissue specific. Between 48.0% and 76.6% of pQTLs did not co-localize with expression, splicing, DNA methylation or histone acetylation QTLs. Using Mendelian randomization, we nominated proteins implicated in neurological diseases, including Alzheimer’s disease, Parkinson’s disease and stroke. This first multi-tissue study will be instrumental to map signals from genome-wide association studies onto functional genes, to discover pathways and to identify drug targets for neurological diseases. Yang et al. generated a genomic atlas of protein levels in brain, cerebrospinal fluid and plasma and used human genetics approaches to identify proteins implicated in neurological diseases as well as druggable targets.