Sorting Reality from What We Think We Know About Breast Cancer in Africa

Much attention has been paid to the features of breast cancer in Africa and the parallels between breast cancer in indigenous Africans and in African American women, including a shift toward earlier onset; a tendency toward poorer outcomes; and an increased likelihood for the tumors to be negative for the estrogen receptor (ER), the progesterone receptor (PR), and/or the human epidermal growth factor receptor-2 (HER2) [1,2]. One of the more aggressive forms of breast cancer is termed ‘‘triple negative,’’ i.e., ER2, PR2, HER22 [3]. Patients with triple negative breast cancer tend to be younger than patients with other forms of the disease, and at all ages, the triple negative subtype is more common in women of African descent than in the white women in the United States [4–6]

Chromosomal Localization of Nucleic Acid-Binding Proteins by Affinity Mapping: Assignment of the IRE-Binding Protein Gene to Human Chromosome 9

Three human mRNAs are regulated post-transcriptionally by iron via iron-responsive elements (IREs) contained in each mRNA. A cytoplasmic protein (IRE-BP) binds to these cis-acting elements and mediates the translational regulation of ferritin H- and L-chain mRNA and the iron-dependent stability of transferrin receptor (TfR) mRNA. We have taken advantage of the different mobilities of the human and rodent IRE/IRE-BP complexes on non-denaturing polyacrylamide gels to determine the chromosomal localization of the gene encoding the IRE-BP. Utilizing a panel of 34 different human/rodent hybrid cell lines we have assigned the IRE-BP gene to human chromosome 9. This new technique based on nucleic acid/protein interaction may allow determination of the chromosomal localization of other RNA- or DNA-binding proteins

High Proportion of Inflammatory Breast Cancer in the Population-Based Cancer Registry of Gharbiah, Egypt

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72192/1/j.1524-4741.2009.00755.x.pd

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

TP53 Gene Therapy as a Potential Treatment for Patients with COVID-19

SGT-53 is a novel investigational agent that comprises an immunoliposome carrying a plasmid vector driving expression of the human TP53 gene that encodes wild-type human p53. SGT-53 is currently in phase II human trials for advanced pancreatic cancer. Although p53 is best known as a tumor suppressor, its participation in both innate and adaptive immune responses is well documented. It is now clear that p53 is an important component of the host response to various viral infections. To facilitate their viral life cycles, viruses have developed a diverse repertoire of strategies for counteracting the antiviral activities of host immune system by manipulating p53-dependent pathways in host cells. Coronaviruses reduce endogenous p53 levels in the cells they infect by enhancing the degradation of p53 in proteasomes. Thus, interference with p53 function is an important component in viral pathogenesis. Transfection of cells by SGT-53 has been shown to transiently produce exogenous p53 that is active as a pleiotropic transcription factor. We herein summarize the rationale for repurposing SGT-53 as a therapy for infection by SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic. Because p53 regulation was found to play a crucial role in different infection stages of a wide variety of viruses, it is rational to believe that restoring p53 function based on SGT-53 treatment may lead to beneficial therapeutic outcomes for infectious disease at large including heretofore unknown viral pathogens that may emerge in the future

A Comparison of Criteria to Identify Inflammatory Breast Cancer Cases from Medical Records and the Surveillance, Epidemiology and End Results Data base, 2007–2009

Inflammatory breast cancer ( IBC ) is a relatively rare and extremely aggressive form of breast cancer that is diagnosed clinically. Standardization of clinical diagnoses is challenging, both nationally and internationally; moreover, IBC coding definitions used by registries have changed over time. This study aimed to compare diagnostic factors of IBC reported in a U.S. Surveillance, Epidemiology, and End Results ( SEER ) registry to clinical criteria found in the medical records of all invasive breast cancer cases at a single institution. We conducted a medical record review of all female invasive breast cancers ( n  = 915) seen at an NCI‐designated comprehensive cancer center in Detroit from 2007 to 2009. IBC cases were identified based on the presence of the main clinical characteristics of the disease (erythema, edema, peau d'orange). We compared the proportion of IBC out of all breast cancers, using these clinical criteria and the standard SEER IBC codes. In the reviewed cases, the clinical criteria identified significantly more IBC cases ( n  = 74, 8.1%) than the standard IBC SEER definition ( n  = 19, 2.1%; p < 0.0001). No IBC cases were identified in the cancer center records using the SEER pathologic coding, which requires the diagnosis of inflammatory carcinoma on the pathology report, a notation that is rarely made. Emphasis must be placed on the documentation of clinical and pathologic characteristics of IBC in the medical record, so that analysis of putative IBC subtypes will be possible. Our results indicate the need for a consensus on the definition of IBC to be utilized in future research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106657/1/tbj12234.pd