The rockefeller university

Background: Despite reductions in door-to-balloon times for primary coronary intervention, mortality from ST-segment-elevation myocardial infarction has plateaued. Early pre-primary coronary intervention treatment of ST-segment-elevation myocardial infarction with glycoprotein IIb/IIIa inhibitors improves pre-primary coronary intervention coronary flow, limits infarct size, and improves survival. We report the first human use of a novel glycoprotein IIb/IIIa inhibitor designed for subcutaneous first point-of-care ST-segment-elevation myocardial infarction treatment. Methods and Results: Healthy volunteers and patients with stable coronary artery disease receiving aspirin received escalating doses of RUC-4 or placebo in a sentinel-dose, randomized, blinded fashion. Inhibition of platelet aggregation (IPA) to ADP (20 mu mol/L), RUC-4 blood levels, laboratory evaluations, and clinical assessments were made through 24 hours and at 7 days. Doses were increased until reaching the biologically effective dose (the dose producing >= 80% IPA within 15 minutes, with return toward baseline within 4 hours). In healthy volunteers, 15 minutes after subcutaneous injection, mean +/- SD IPA was 6.9%+7.1% after placebo and 71.8%+/- 15.0% at 0.05 mg/kg (n=6) and 84.7%+/- 16.7% at 0.075 mg/kg (n=6) after RUC-4. IPA diminished over 90 to 120 minutes. In patients with coronary artery disease, 15 minutes after subcutaneous injection of placebo or 0.04 mg/kg (n=2), 0.05 mg/kg (n=6), and 0.075 mg/kg (n=18) of RUC-4, IPA was 14.6%+/- 11.7%, 53.6%+/- 17.0%, 76.9%+/- 10.6%, and 88.9%+/- 12.7%, respectively. RUC-4 blood levels correlated with IPA. Aspirin did not affect IPA or RUC-4 blood levels. Platelet counts were stable and no serious adverse events, bleeding, or injection site reactions were observed. Conclusions: RUC-4 provides rapid, high-grade, limited-duration platelet inhibition following subcutaneous administration that appears to be safe and well tolerated. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NTC03844191.

A recent paper by Carter et al. identifies a novel organelle, the ribosome-associated vesicle (RAV), that might serve as a portable, local factory for producing proteins destined for the secretory pathway. The appearance of RAVs in den-drites suggests they may serve to generate membrane and secreted proteins in distal processes.

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes(1,2). The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution(1,3,4). Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such asBCL9, MCL1,ARNT(also known asHIF1B),TERTandMYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompassesBCL9, MCL1andARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassingMYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassingCCND1) in HER2(+)breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution. Chromosomal instability enables the continuous selection of somatic copy number alterations, which are established as ordered events that often occur in parallel, throughout tumour evolution and metastasis.

In humans and macaque monkeys, socially relevant face processing is accomplished via a distributed functional network that includes specialized patches in frontal cortex. It is unclear whether a similar network exists in New World primates, who diverged similar to 35 million years from Old World primates. The common marmoset is a New World primate species ideally placed to address this question given their complex social repertoire. Here, we demonstrate the existence of a putative high-level face processing network in marmosets. Like Old World primates, marmosets show differential activation in anterior cingulate and lateral prefrontal cortices while they view socially relevant videos of marmoset faces. We corroborate the locations of these frontal regions by demonstrating functional and structural connectivity between these regions and temporal lobe face patches. Given the evolutionary separation between macaques and marmosets, our results suggest this frontal network specialized for social face processing predates the separation between Platyrrhini and Catarrhini.

Interferon-stimulated gene 15 (ISG15)was the first ubiquitin-like modifier protein identified that acts by protein conjugation (ISGylation) and is thought to modulate IFN-induced inflammation. Here, we report a new patient from a non-consanguineous Argentinian family, who was followed for recurrent ulcerative skin lesions, cerebral calcifications and lung disease. Whole Exome Sequencing (WES) revealed two novel compound heterozygous variants (c.285del and c.299_312del, NM_005101.4 GRCh37(hg19), both classified as pathogenic according to ACMG criteria) in theISG15gene, resulting in a complete deficiency due to disruption of the second ubiquitin domain of the corresponding protein. The clinical phenotype of this patient is unique given the presence of recurrent pulmonary manifestations and the absence of mycobacterial infections, thus resulting in a phenotype distinct from that previously described in patients with biallelic loss-of-function (LOF)ISG15variants. This case highlights the role ofISG15as an immunomodulating factor whose LOF variants result in heterogeneous clinical presentations.

Background Preclinical testing of new locoregional therapies for pancreatic cancer has been challenging, due to the lack of a suitable large animal model. Purpose To develop and characterize a porcine model of pancreatic cancer. Unlike small animals, pigs have similar physiology, drug dosing, and immune response to humans. Locoregional therapy in pigs can be performed using the same size catheters and devices as in humans. Methods The Oncopig is a transgenic pig with Cre-inducibleTP53(R167H)andKRAS(G12D)mutations. In 12 Oncopigs, CT-guided core biopsy of the pancreas was performed. The core biopsy was incubated with an adenoviral vector carrying the Cre recombinase gene. The transformed core biopsy was injected back into the pancreas (head, tail, or both). The resulting tumors (n= 19) were characterized on multi-phase contrast-enhanced CT, and on pathology, including immunohistochemistry. Angiographic characterization of the tumors was performed in 3 pigs. Results Pancreatic tumors developed at 19 out of 22 sites (86%) that were inoculated. Average tumor size was 3.0 cm at 1 week (range: 0.5-5.1 cm). H&E and immunohistochemical stains revealed undifferentiated carcinomas, similar to those of the pancreatobiliary system in humans. Neoplastic cells were accompanied by a major inflammatory component. 1 of 12 pigs only had inflammatory nodules without evidence of neoplasia. On multiphase CT, tumors were hypovascular compared to the normal pancreas. There was no pancreatic duct dilation. In 3 pigs, angiography was performed, and in all 3 cases, the artery supplying the pancreatic tumor could be catheterized using a 2.4 F microcatheter. Selective angiography showed the pancreatic tumor, without extra-pancreatic perfusion. Conclusion Pancreatic cancer can be induced in a transgenic pig. Intra-arterial procedures using catheters designed for human interventions were technically feasible in this large animal model.

Dear Editor: Individuals with serious underlying medical conditions and those who are immunocompromised are at greatest risk for contracting coronavirus disease 2019 (COVID‐19).1 This raises concern for patients with chronic inflammatory disorders, such as hidradenitis suppurativa (HS), who may seek virtual care to reduce COVID‐19 exposure. HS is a chronic, inflammatory skin disorder with risk factors, comorbidities, and complications which, when combined, may reduce an individual's defense against infection. However, HS alone does not appear to be a specific risk factor for COVID‐19. Nevertheless, managing HS virtually poses challenges because of complex treatment regimens involving lifestyle modifications and medical and surgical therapies. Here, we explore teledermatology management strategies and treatment considerations.

Spatially localized oscillations in periodically forced systems are intriguing phenomena. They may occur in spatially homogeneous media (oscillons), but quite often emerge in heterogeneous media, such as the auditory system, where localized oscillations are believed to play an important role in frequency discrimination of incoming sound waves. In this paper, we use an amplitude-equation approach to study the spatial profile of the oscillations and the factors that affect it. More specifically, we use a variant of the forced complex Ginzburg-Landau (FCGL) equation to describe an oscillatory system below the Hopf bifurcation with space-dependent Hopf frequency, subject to both parametric and additive forcing. We show that spatial heterogeneity, combined with bistability of system states, results in spatial asymmetry of the localized oscillations. We further identify parameters that control that asymmetry, and characterize the spatial profile of the oscillations in terms of maximum amplitude, location, width and asymmetry. Our results bear qualitative similarities to empirical observation trends that have found in the auditory system. (C) 2020 Elsevier B.V. All rights reserved.

Background: Patients with rheumatoid arthritis (RA) receive transfusions more often than patients with osteoarthritis following lower extremity total joint arthroplasty (TJA), but mitigating factors are not described. Tranexamic acid (TXA) is widely used to reduce blood loss in patients undergoing TJA, but its effect on transfusion rates in patients with RA has not been studied. Methods: We retrospectively reviewed data from a prospectively collected cohort of patients with RA undergoing TJA. Disease activity measured by Clinical Disease Activity Index, patient-reported outcome measures, and serologies was obtained. Baseline characteristics were summarized and compared. Transfusion requirements and TXA usage were obtained from chart review. Logistic regression was used to determine factors associated with transfusion in RA patients undergoing TJA. Results: The cohort included 252 patients, mostly women with longstanding RA and end-stage arthritis requiring TJA. In multivariate analysis, 1 g/dL decrease in baseline hemoglobin (odds ratio [OR] = 0.394, 95% confidence interval [CI] [0.232, 0.669], P = .001), 1-minute increase in surgical duration (OR = 1.022, 95% CI [1.008,1.037], P = .003), and 1-point increase in Clinical Disease Activity Index (OR = 1.079, 95% CI [1.001, 1.162]) were associated with increased risk of transfusion. TXA use was not associated with decreased risk of postoperative transfusion. Conclusions: Preoperative health optimization should include assessment and treatment of anemia in RA patients before TJA, as preoperative hemoglobin level is the main risk factor for postoperative transfusion. Increased disease activity and increased surgical time were independent risk factors for postoperative transfusion but are less modifiable. While TXA did not decrease transfusion risk in this population, a prospective trial is needed to confirm this. (C) 2020 Elsevier Inc. All rights reserved.