Targeting T cells with tetravalent bispecific antibodies for the treatment of graft-versus-host disease.

Allogeneic hematopoietic stem cell transplantation is an established treatment for hematological malignancies and some genetic diseases. Acute graft-versus-host disease (GVHD) is the most common and debilitating side effect with poor survival rates of 5% to 30% for severe cases. In this manuscript, we describe a tetravalent T-cell-engaging bispecific antibody (BsAb) based on the immunoglobulin G-[L]-single-chain variable fragment (IgG-[L]-scFv) platform, with all 4 binding domains specific for CD3.

DNA Damage, Genome Stability, and Adaptation: A Question of Chance or Necessity?

DNA damage causes the mutations that are the principal source of genetic variation. DNA damage detection and repair mechanisms therefore play a determining role in generating the genetic diversity on which natural selection acts. Speciation, it is commonly assumed, occurs at a rate set by the level of standing allelic diversity in a population.

Delayed Onset of Symptoms After a Rattlesnake Bite in a Renal Transplant Patient: A Case Report.

Introduction: The United States is home to two major families of venomous snakes, Crotalids and Elapids. The Crotalid family, also known as pit vipers, is well known for being among the most frequent causes of snakebites reported. Crotalid envenomation can present with local findings, hematologic toxicity, and systemic toxicity.

Open Questions about the Roles of DnaA, Related Proteins, and Hyperstructure Dynamics in the Cell Cycle.

The DnaA protein has long been considered to play the key role in the initiation of chromosome replication in modern bacteria. Many questions about this role, however, remain unanswered. Here, we raise these questions within a framework based on the dynamics of hyperstructures, alias large assemblies of molecules and macromolecules that perform a function.

Kimura's Theory of Non-Adaptive Radiation and Peto's Paradox: A Missing Link?

Karyotype diversity reflects genome integrity and stability. A strong correlation between karyotype diversity and species richness, meaning the number of species in a phylogenetic clade, was first reported in mammals over forty years ago: in mammalian phylogenetic clades, the standard deviation of karyotype diversity (KD) closely corresponded to species richness (SR) at the order level. These initial studies, however, did not control for phylogenetic signal, raising the possibility that the correlation was due to phylogenetic relatedness among species in a clade.

Patient-derived Siglec-6-targeting antibodies engineered for T-cell recruitment have potential therapeutic utility in chronic lymphocytic leukemia.

Background: Despite numerous therapeutic options, safe and curative therapy is unavailable for most patients with chronic lymphocytic leukemia (CLL). A drawback of current therapies such as the anti-CD20 monoclonal antibody (mAb) rituximab is the elimination of all healthy B cells, resulting in impaired humoral immunity. We previously reported the identification of a patient-derived, CLL-binding mAb, JML-1, and identified sialic acid-binding immunoglobulin-like lectin-6 (Siglec-6) as the target of JML-1.

Genome size variation and species diversity in salamanders.

Salamanders (Urodela) have among the largest vertebrate genomes, ranging in size from 10 to 120 pg. Although changes in genome size often occur randomly and in the absence of selection pressure, nonrandom patterns of genome size variation are evident among specific vertebrate lineages. Several reports suggest a relationship between species richness and genome size, but the exact nature of that relationship remains unclear both within and across different taxonomic groups.

Exclusion of Non-English Speakers in Published Emergency Medicine Research - A Comparison of 2004 and 2014.

Background: Non-English speakers (NES) as a proportion of the United States population have steadily increased in recent years. There remains substantial risk of excluding NES from research.

Objective: To assess whether the percentage of emergency medicine (EM) studies that exclude Non-English speakers from participation has changed with time.

Impact of Starting an Emergency Medicine Residency Program on Overall Mortality Rate in a Regional Trauma Center.

Background: CHRISTUS Spohn Hospital Corpus Christi - Memorial began an Emergency Medicine Residency Program in March 2007. During each of the three years of their residency, residents are required to complete a trauma surgery rotation. These emergency medicine residents are the only residents participating on this rotation as there is no surgical residency.

Genetic variation and DNA replication timing, or why is there late replicating DNA?

Mutation rates vary significantly within the genome and across species. Recent studies revealed a long suspected replication-timing effect on mutation rate, but the mechanisms that regulate the increase in mutation rate as the genome is replicated remain unclear. Evidence is emerging, however, that DNA repair systems, in general, are less efficient in late replicating heterochromatic regions compared to early replicating euchromatic regions of the genome.

Head multidetector computed tomography: emergency medicine physicians overestimate the pretest probability and legal risk of significant findings.

Objectives: This study focuses on clinically assigned prospective estimated pretest probability and pretest perception of legal risk as independent variables in the ordering of multidetector computed tomographic (MDCT) head scans. Our primary aim is to measure the association between pretest probability of a significant finding and pretest perception of legal risk. Secondarily, we measure the percentage of MDCT scans that physicians would not order if there was no legal risk.

Defects and DNA replication.

We introduce a rate-equation formalism to study DNA replication kinetics in the presence of defects resulting from DNA damage and find a crossover between two regimes: a normal regime, where the influence of defects is local, and an initiation-limited regime. In the latter, defects have a global impact on replication, whose progress is set by the rate at which origins of replication are activated, or initiated. Normal, healthy cells have defect densities in the normal regime.

DnaA-ATP acts as a molecular switch to control levels of ribonucleotide reductase expression in Escherichia coli.

Ribonucleotide reductase (RNR) is the bottleneck enzyme in the synthesis of dNTPs required for DNA replication. In order to avoid the mutagenic effects of imbalances in dNTPs the amount and activity of RNR enzyme in the cell is tightly regulated. RNR expression from the nrdAB operon is thus coupled to coincide with the initiation of DNA replication.

The dynamic replicon: adapting to a changing cellular environment.

Eukaryotic cells are often exposed to fluctuations in growth conditions as well as endogenous and exogenous stress-related agents. During development, global patterns of gene transcription change substantially, and these changes are associated with altered patterns of DNA replication and larger distances between replication origins in somatic cells compared to embryos. Conversely, when cells experience difficulties while replicating DNA, the replication program is dramatically altered and distances between replication origins decrease.

Introduction to molecular combing: genomics, DNA replication, and cancer.

The sequencing of the human genome inaugurated a new era in both fundamental and applied genetics. At the same time, the emergence of new technologies for probing the genome has transformed the field of pharmaco-genetics and made personalized genomic profiling and high-throughput screening of new therapeutic agents all but a matter of routine. One of these technologies, molecular combing, has served to bridge the technical gap between the examination of gross chromosomal abnormalities and sequence-specific alterations.

Pseudoaneurysm of the radial artery diagnosed by bedside ultrasound.

A 42-year-old male presented to the emergency department with pain and swelling of his distal right wrist. Bedside ultrasound placed over the swelling revealed a pseudoaneurysm of the radial artery. The patient received percutaneous thrombin injection of the aneurysm sac followed by direct ultrasound compression therapy of the pseudoaneurysm neck, resulting in thrombosis of the sac.

Acute ischemic stroke in a pediatric patient.

Acute ischemic stroke in a pediatric patient is a complex disease with a variety of etiologies that differ from adults. Though rare, they are a real phenomenon with potentially devastating consequences. Some treating institutions are using anti-thrombotic drug therapy with unclear benefits.

Global regulation of genome duplication in eukaryotes: an overview from the epifluorescence microscope.

In eukaryotes, DNA replication is initiated along each chromosome at multiple sites called replication origins. Locally, each replication origin is "licensed" or specified at the end of the M and the beginning of the G1 phases of the cell cycle. During the S phase when DNA synthesis takes place, origins are activated in stages corresponding to early and late-replicating domains.

Replication fork velocities at adjacent replication origins are coordinately modified during DNA replication in human cells.

The spatial organization of replicons into clusters is believed to be of critical importance for genome duplication in higher eukaryotes, but its functional organization still remains to be fully clarified. The coordinated activation of origins is insufficient on its own to account for a timely completion of genome duplication when interorigin distances vary significantly and fork velocities are constant. Mechanisms coordinating origin distribution with fork progression are still poorly elucidated, because of technical difficulties of visualizing the process.

Unscheduled DNA replication origin activation at inserted HPV 18 sequences in a HPV-18/MYC amplicon.

Oncogene amplification is a critical step leading to tumorigenesis, but the underlying mechanisms are still poorly understood. Despite data suggesting that DNA replication is a major source of genomic instability, little is known about replication origin usage and replication fork progression in rearranged regions. Using a single DNA molecule approach, we provide here the first study of replication kinetics on a previously characterized MYC/papillomavirus (HPV18) amplicon in a cervical cancer.

Ribonucleotide reductase and the regulation of DNA replication: an old story and an ancient heritage.

All organisms that synthesize their own DNA have evolved mechanisms for maintaining a constant DNA/cell mass ratio independent of growth rate. The DNA/cell mass ratio is a central parameter in the processes controlling the cell cycle. The co-ordination of DNA replication with cell growth involves multiple levels of regulation.

Genomic organization of amplified MYC genes suggests distinct mechanisms of amplification in tumorigenesis.

Integration of the human papillomavirus (HPV) genome into the host genome is associated with the disruption of the HPV E2 gene and with amplification and rearrangement of the viral and flanking cellular sequences. Molecular characterization of the genomic structures of coamplified HPV sequences and oncogenes provides essential information concerning the mechanisms of amplification and their roles in carcinogenesis. Using fluorescent hybridization on stretched DNA molecules in two cervical cancer-derived cell lines, we have elucidated the genomic structures of amplified regions containing HPV/myc genes over several hundreds of kilobases.

Persistence length of chromatin determines origin spacing in Xenopus early-embryo DNA replication: quantitative comparisons between theory and experiment.

In Xenopus early embryos, replication origins neither require specific DNA sequences nor is there an efficient S/M checkpoint, even though the whole genome (3 billion bases) is completely duplicated within 10-20 minutes. This leads to the "random-completion problem" of DNA replication in embryos, where one needs to find a mechanism that ensures complete, faithful, timely reproduction of the genome without any sequence dependence of replication origins. We analyze recent DNA replication data in Xenopus laevis egg extracts and find discrepancies with models where replication origins are distributed independently of chromatin structure.