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Models that recapitulate the complexity of human tumors are urgently needed to develop more effective cancer therapies. We report a bank of human patient-derived xenografts (PDXs) and matched organoid cultures from tumors that represent the greatest unmet need: endocrine-resistant, treatment-refractory and metastatic breast cancers. We leverage matched PDXs and PDX-derived organoids (PDxO) for drug screening that is feasible and cost-effective with in vivo validation. Moreover, we demonstrate the feasibility of using these models for precision oncology in real time with clinical care in a case of triple-negative breast cancer (TNBC) with early metastatic recurrence. Our results uncovered a Food and Drug Administration (FDA)-approved drug with high efficacy against the models. Treatment with this therapy resulted in a complete response for the individual and a progression-free survival (PFS) period more than three times longer than their previous therapies. This work provides valuable methods and resources for functional precision medicine and drug development for human breast cancer.

Abstract Model systems that recapitulate the complexity of human tumors and the reality of variable treatment responses are urgently needed to better understand cancer biology and to develop more effective cancer therapies. Here we report development and characterization of a large bank of patient-derived xenografts (PDX) and matched organoid cultures from tumors that represent some of the greatest unmet needs in breast cancer research and treatment. These include endocrine-resistant, treatment-refractory, and metastatic breast cancers and, in some cases, multiple tumor collections from the same patients. The models can be grown long-term with high fidelity to the original tumors. We show that development of matched PDX and PDX-derived organoid (PDxO) models facilitates high-throughput drug screening that is feasible and cost-effective, while also allowing in vivo validation of results. Our data reveal consistency between drug screening results in organoids and drug responses in breast cancer PDX. Moreover, we demonstrate the feasibility of using these patient-derived models for precision oncology in real time with patient care, using a case of a triple negative breast cancer with early metastatic recurrence as an example. Our results uncovered an FDA-approved drug with high efficacy against the models. Treatment with the PDxO-directed therapy resulted in a complete response for the patient and a progression-free survival period more than three times longer than her previous therapies. This work provides valuable new methods and resources for functional precision medicine and drug development for human breast cancer. Figure1 Figure1 * Download figure * Open in new tab Competing Interest Statement University of Utah may license the models described herein to for-profit companies, which may result in tangible property royalties to members of the Welm labs who developed the models (K.P.G., M.F., A.J.B., S.D.S., Z.C., Y.S.D., L.Z., E.C-S., C-H.Y., J.T., G.W., A.L.W., B.E.W.) M.T.L. is a Manager in StemMed Holdings L.L.C., a limited partner in StemMed Ltd., and holds an equity stake in Tvardi Therapeutics. L.E.D. is a compensated employee of StemMed, Ltd. S.O. has received research support/reagents from AstraZeneca, Illumina, H3 Biomedicine and Blueprint Medicine. The other authors declare no conflicts. Footnotes * Figure 4a is updated with new data.

• Leaf shape, a spectacularly diverse plant trait, varies across taxonomic levels, geography and in response to environmental differences. However, comprehensive intraspecific analyses of leaf shape variation across variable environments is surprisingly absent. Here, we performed a multilevel analysis of leaf shape using diverse accessions of sweet potato (Ipomoea batatas), and uncovered the role of genetics, environment, and G × E on this important trait. • We examined leaf shape using a variety of morphometric analyses, and complement this with a transcriptomic survey to identify gene expression changes associated with shape variation. Additionally, we examined the role of genetics and environment on leaf shape by performing field studies in two geographically separate common gardens. • We showed that extensive leaf shape variation exists within I. batatas, and identified promising candidate genes associated with this variation. Interestingly, when considering traditional measures, we found that genetic factors are largely responsible for most of leaf shape variation, but that the environment is highly influential when using more quantitative measures via leaf outlines. • This extensive and multilevel examination of leaf shape shows an important role of genetics underlying a potentially important agronomic trait, and highlights that the environment can be a strong influence when using more quantitative measures of leaf shape.

The genetic basis of variation in the progression of primary tauopathies has not been determined. We aimed to identify genetic determinants of survival in progressive supranuclear palsy (PSP). In stage one of this two stage genome-wide association study (GWAS), we included individuals with PSP, diagnosed according to pathological and clinical criteria, from two separate cohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic (Jacksonville, FL, USA) and in Munich (Germany), and the University College London PSP cohort, from brain banks and the PROSPECT study, a UK-wide longitudinal study of patients with atypical parkinsonian syndromes. Individuals were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death or to the date of censoring, Dec 1, 2019, if individuals were alive), and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data were used to do a survival GWAS using a Cox proportional hazards model. In stage two, data from additional individuals from the Mayo Clinic brain bank, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the expression quantitative trait loci (eQTL) profile of variants that passed genome-wide significance in our GWAS using the Functional Mapping and Annotation of GWAS platform, and did colocalisation analyses using the eQTLGen and PsychENCODE datasets. Data were collected and analysed between Aug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of white European ancestry with PSP in stage one. We found a genome-wide significant association with survival at chromosome 12 (lead single nucleotide polymorphism rs2242367, p=7·5 × 10−10, hazard ratio 1·42 [95% CI 1·22–1·67]). rs2242367 was associated with survival in the individuals added in stage two (n=238; p=0·049, 1·22 [1·00–1·48]) and in the pooled analysis of both stages (n=1239; p=1·3 × 10−10, 1·37 [1·25–1·51]). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and two long intergenic non-coding RNAs (lncRNAs), LINC02555 and AC079630.4, in whole blood. Although we did not detect a colocalisation signal for LRRK2, analysis of the PSP survival signal and eQTLs for LINC02555 in the eQTLGen blood dataset revealed a posterior probability of hypothesis 4 of 0·77, suggesting colocalisation due to a single shared causal variant. Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association might be through a lncRNA-regulated effect on LRRK2 expression because LINC02555 has previously been shown to regulate LRRK2 expression. LRRK2 has been associated with sporadic and familial forms of Parkinson's disease, and our finding suggests a genetic overlap with PSP. Further functional studies will be important to assess the potential of LRRK2 modulation as a disease-modifying therapy for PSP and related tauopathies. PSP Association, CBD Solutions, Medical Research Council (UK).

Osmoporation is an innovative method that can be used with food-grade yeast cells of Saccharomyces cerevisiae as natural encapsulating matrices. This technique overcomes barriers that difficult encapsulation and enables the internalization of fragile bioactive molecules such as fisetin into yeasts. In the present study, we assessed the effects of concentration, osmotic pressure, and temperature on the encapsulation efficiency (EE) and internalized fisetin content (IF). Two different quantification strategies were investigated: direct extraction (DE) without cell washing or freeze-drying steps and indirect extraction (IE) performed after washings with ethanol and freeze-drying. Our results showed that osmoporation improved EE (33 %) and IF (1.199 mg). The best experimental conditions were found by using DE. High-resolution images showed that the yeast cell envelope was preserved during osmoporation at 30 MPa and 84 % of yeast cells remained viable after treatment. Washing cells with organic solvent led to decreased EE (0.65 %) and IF (0.023 mg). This was probably due to either damages caused to yeast cell envelope or fisetin dragged out of cell. Overall, the results demonstrated the adequacy and relevant biotechnological potential of yeasts as encapsulating matrices for hydrophobic compounds. This fresh biotechnological approach has proven to be a promising tool for the production of bioactive-rich food products.

Platelet count, international normalized ratio, chemistry, and abdominal ultrasound with doppler were normal. Identification in this case may have been limited on standard evaluation due to bowel preparation quality and lack of active bleeding. Benign vascular tumors are reported primarily in adults with few reported cases of gastrointestinal vascular tumors in pediatric literature, most of which are extraintestinal.2–6 VCE and DBE, as well as immunostains for genetic and oncologic causes aid significantly in the diagnosis.7 Management involves resection, with endoscopic resection preferred for small lesions and surgical resection preferred for larger lesions and those at risk for malignancy progression such as leiomyosarcoma.8 Risk of recurrence is low in cases with clear surgical margins.2 CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest.

Cardiac function requires appropriate proteins in each chamber. Atria requires slow myosin to act as reservoirs, while ventricles demand fast myosin for swift pumping. Myosins are thus under chamber-biased cis -regulation, with myosin gene expression imbalances leading to congenital heart dysfunction. To identify regulatory inputs leading to cardiac chamber-biased expression, we computationally and molecularly dissected the quail Slow Myosin Heavy Chain III ( SMyHC III ) promoter that drives preferential expression to the atria. We show that SMyHC III gene states are orchestrated by a complex Nuclear Receptor Element (cNRE) of 32 base pairs. Using transgenesis in zebrafish and mice, we demonstrate that preferential atrial expression is achieved by a combinatorial regulatory input composed of atrial activation motifs and ventricular repression motifs. Using comparative genomics, we show that the cNRE might have emerged from an endogenous viral element through infection of an ancestral host germline, revealing an evolutionary pathway to cardiac chamber-specific expression. A complex Nuclear Receptor Element (cNRE) of 32 base pairs that emerged from a viral infection drives the quail Slow Myosin Heavy Chain III (SMyHC III) promoter preferential expression to the atria.

Background EM Talk is a communication skills training program designed to improve emergency providers’ serious illness conversational skills. Using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework, this study aims to assess the reach of EM Talk and its effectiveness. Methods EM Talk consisted of one 4-h training session during which professional actors used role-plays and active learning to train providers to deliver serious/bad news, express empathy, explore patients’ goals, and formulate care plans. After the training, emergency providers filled out an optional post-intervention survey, which included course reflections. Using a multi-method analytical approach, we analyzed the reach of the intervention quantitatively and the effectiveness of the intervention qualitatively using conceptual content analysis of open-ended responses. Results A total of 879 out of 1,029 (85%) EM providers across 33 emergency departments completed the EM Talk training, with the training rate ranging from 63 to 100%. From the 326 reflections, we identified meaning units across the thematic domains of improved knowledge, attitude, and practice. The main subthemes across the three domains were the acquisition of Serious Illness (SI) communication skills, improved attitude toward engaging qualifying patients in SI conversations, and commitment to using these learned skills in clinical practice. Conclusion Our study showed the extensive reach and the effectiveness of the EM Talk training in improving SI conversation. EM Talk, therefore, can potentially improve emergency providers’ knowledge, attitude, and practice of SI communication skills. Trial registration Clinicaltrials.gov: NCT03424109; Registered on January 30, 2018.

Cystatin C, an endogenous low-molecular-weight marker of glomerular filtration rate, has recently been shown to be associated with future cardiovascular disease in healthy elderly populations and patients with documented atherosclerosis in a dose-dependent manner that possibly reflects a very early stage of chronic renal dysfunction. At the same time, local cystatin C deficiency has been demonstrated in atherosclerotic and aneurismal lesions, suggesting a protective role of cystatin C in the vessel wall, possibly in concert with TGF-beta1. Although cystatin C is not an acute phase reactant, large epidemiological studies have documented a highly significant association between serum cystatin C and mildly increased C-reactive protein (CRP) levels, the hallmark of the chronic inflammatory state associated with atherosclerosis and chronic renal failure. Since cystatin C is produced by all nucleated cells, it is unlikely that local variations in cystatin C synthesis in diseased arteries--rather than global cystatin C production and renal elimination--should determine its serum concentration. Consequently, the present review proposes microinflammation as the unifying concept for both lines of evidence.