Preclinical Analysis of JAA-F11, a Specific Anti-Thomsen-Friedenreich Antibody via Immunohistochemistry and In Vivo Imaging.

The tumor specificity of JAA-F11, a novel monoclonal antibody specific for the Thomsen-Friedenreich cancer antigen (TF-Ag-alpha linked), has been comprehensively studied by in vitro immunohistochemical (IHC) staining of human tumor and normal tissue microarrays and in vivo biodistribution and imaging by micro-positron emission tomography imaging in breast and lung tumor models in mice. The IHC analysis detailed herein is the comprehensive biological analysis of the tumor specificity of JAA-F11 antibody performed as JAA-F11 is progressing towards preclinical safety testing and clinical trials. Wide tumor reactivity of JAA-F11, relative to the matched mouse IgG3 (control), was observed in 85% of 1269 cases of breast, lung, prostate, colon, bladder, and ovarian cancer. Staining on tissues from breast cancer cases was similar regardless of hormonal or Her2 status, and this is particularly important in finding a target on the currently untargetable triple-negative breast cancer subtype. Humanization of JAA-F11 was recently carried out as explained in a companion paper "Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis" (Neoplasia 19: 716-733, 2017), and it was confirmed that humanization did not affect chemical specificity. IHC studies with humanized JAA-F11 showed similar binding to human breast tumor tissues. In vivo imaging and biodistribution studies in a mouse syngeneic breast cancer model and in a mouse-human xenograft lung cancer model with humanized 124I- JAA-F11 construct confirmed in vitro tumor reactivity and specificity. In conclusion, the tumor reactivity of JAA-F11 supports the continued development of JAA-F11 as a targeted cancer therapeutic for multiple cancers, including those with unmet need

Learning Progression of Students’ Reasoning about Life Cycles

This study explored elementary students’ reasoning about the life cycles of various organisms, including insects and amphibians. The study took place in a private school in Lebanon with 24 fifth-grade students. Students participated in a life cycle unit with pre and post-written assessments about what they learned and interviews to help determine their reasoning about life cycles. Using our findings, we suggest a learning progression (LP) approach to guide students over time in their learning about life cycles and their importance for species persistence within an ecosystem. Two LPs were developed from this study: Reasoning about the cyclic nature of life and comparison of life cycle stages. Overall, students improved their understanding of the cyclical nature of life, but comparing organisms’ structures, stages, and life cycles proved to be more challenging. These LPs have direct implications for elementary instruction about life cycles, organisms, and species

Scalable and cost-effective NGS genotyping in the cloud

Background: While next-generation sequencing (NGS) costs have plummeted in recent years, cost and complexity of computation remain substantial barriers to the use of NGS in routine clinical care. The clinical potential of NGS will not be realized until robust and routine whole genome sequencing data can be accurately rendered to medically actionable reports within a time window of hours and at scales of economy in the 10’s of dollars. Results: We take a step towards addressing this challenge, by using COSMOS, a cloud-enabled workflow management system, to develop GenomeKey, an NGS whole genome analysis workflow. COSMOS implements complex workflows making optimal use of high-performance compute clusters. Here we show that the Amazon Web Service (AWS) implementation of GenomeKey via COSMOS provides a fast, scalable, and cost-effective analysis of both public benchmarking and large-scale heterogeneous clinical NGS datasets. Conclusions: Our systematic benchmarking reveals important new insights and considerations to produce clinical turn-around of whole genome analysis optimization and workflow management including strategic batching of individual genomes and efficient cluster resource configuration.Yassine Souilmi, Alex K. Lancaster, Jae-Yoon Jung, Ettore Rizzo, Jared B. Hawkins, Ryan Powles, Saaïd Amzazi, Hassan Ghazal, Peter J. Tonellato and Dennis P. Wal

Human cytomegalovirus IE86 protein interacts with promoter-bound TATA-binding protein via a specific region distinct from the autorepression domain

The major immediate-early gene of human cytomegalovirus encodes several isoforms of an immediate-early protein which has distinct transcriptional regulatory properties. The IE86 isoform autorepresses the major immediate-early promoter by directly binding the cis repression signal element located between the TATA box and the mRNA cap site. In addition to this activity, IE86 stimulates other viral and cellular promoters. One mechanism by which eukaryotic regulatory proteins are thought to stimulate transcription is by contacting one or more general transcription factors. We show that the IE86 protein physically interacts with the DNA-binding subunit (TATA-binding protein) human transcription factor IID via the TATA-binding protein-contacting domain in the N terminus of IE86. In a mobility shift assay, IE86 was also observed to stabilize the binding of TATA-binding protein to promoter DNA. The domains within IE86 responsible for mediating transactivation and repression functioned independently. These experiments thus demonstrate the elegant ability of human cytomegalovirus to join different protein domains to produce distinct multifunctional proteins

The effect of extra dimensions on gravity wave bursts from cosmic string cusps

We explore the kinematical effect of having extra dimensions on the gravity wave emission from cosmic strings. Additional dimensions both round off cusps, and reduce the probability of their formation. We recompute the gravity wave burst, taking into account these two factors, and find a potentially significant damping on the gravity waves of the strings.Comment: 33 pages, 8 figures, published versio

Collagen Type XIX Regulates Cardiac Extracellular Matrix Structure and Ventricular Function

The cardiac extracellular matrix plays essential roles in homeostasis and injury responses. Although the role of fibrillar collagens have been thoroughly documented, the functions of non-fibrillar collagen members remain underexplored. These include a distinct group of non-fibrillar collagens, termed, fibril-associated collagens with interrupted triple helices (FACITs). Recent reports of collagen type XIX (encoded by Col19a1) expression in adult heart and evidence of its enhanced expression in cardiac ischemia suggest important functions for this FACIT in cardiac ECM structure and function. Here, we examined the cellular source of collagen XIX in the adult murine heart and evaluated its involvement in ECM structure and ventricular function. Immunodetection of collagen XIX in fractionated cardiovascular cell lineages revealed fibroblasts and smooth muscle cells as the primary sources of collagen XIX in the heart. Based on echocardiographic and histologic analyses, Col19a1 null (Col19a1(N/N)) mice exhibited reduced systolic function, thinning of left ventricular walls, and increased cardiomyocyte cross-sectional areas—without gross changes in myocardial collagen content or basement membrane morphology. Col19a1(N/N) cardiac fibroblasts had augmented expression of several enzymes involved in the synthesis and stability of fibrillar collagens, including PLOD1 and LOX. Furthermore, second harmonic generation-imaged ECM derived from Col19a1(N/N) cardiac fibroblasts, and transmission electron micrographs of decellularized hearts from Col19a1(N/N) null animals, showed marked reductions in fibrillar collagen structural organization. Col19a1(N/N) mice also displayed enhanced phosphorylation of focal adhesion kinase (FAK), signifying de-repression of the FAK pathway—a critical mediator of cardiomyocyte hypertrophy. Collectively, we show that collagen XIX, which had a heretofore unknown role in the mammalian heart, participates in the regulation of cardiac structure and function—potentially through modulation of ECM fibrillar collagen structural organization. Further, these data suggest that this FACIT may modify ECM superstructure via acting at the level of the fibroblast to regulate their expression of collagen synthetic and stabilization enzymes

The Evolving Role of Cryosurgery in Breast Cancer Management: A Comprehensive Review

Copyright © 2023 by the authors. Breast cancer is the most commonly diagnosed type of cancer, accounting for approximately one in eight cancer diagnoses worldwide. In 2020, there were approximately 2.3 million new cases of breast cancer globally, resulting in around 685,000 deaths. Consequently, there is an ongoing need to develop innovative therapeutic approaches that can improve both clinical outcomes and patient quality of life. The use of ultra-low cryogenic temperatures, facilitated by cryogenic media such as liquid nitrogen, has revolutionized the biomedical field and opened up new possibilities for advanced clinical treatments, including cryosurgery. Cryosurgery has demonstrated its feasibility as a minimally invasive technique for destroying breast tumors and eliciting a significant antitumor immune response in the host. This feature sets cryosurgery apart from other ablative techniques. It has been shown to be well tolerated and effective, offering several advantages such as simplicity, the avoidance of general anesthesia, minimal pain, low morbidity, short recovery time, cost-effectiveness, and notably, improved aesthetic outcomes. The reviewed studies indicate that cryosurgery holds promise in the management of early-stage breast cancer and metastatic disease, especially in triple-negative and Her2-positive molecular subtypes in conjunction with checkpoint inhibitors and anti-Her2 antibodies, respectively. Furthermore, the effectiveness of cryosurgery in the management of ductal carcinoma in situ should be investigated as an alternative modality to surgery or surveillance. The minimally invasive nature of cryosurgery has the potential to significantly enhance the quality of life for patients.Air Products PLC under grant agreement: 216-206-P-F

Back Reaction And Local Cosmological Expansion Rate

We calculate the back reaction of cosmological perturbations on a general relativistic variable which measures the local expansion rate of the Universe. Specifically, we consider a cosmological model in which matter is described by a single field. We analyze back reaction both in a matter dominated Universe and in a phase of scalar field-driven chaotic inflation. In both cases, we find that the leading infrared terms contributing to the back reaction vanish when the local expansion rate is measured at a fixed value of the matter field which is used as a clock, whereas they do not appear to vanish if the expansion rate is evaluated at a fixed value of the background time. We discuss possible implications for more realistic models with a more complicated matter sector.Comment: 7 pages, No figure