Outcomes of Breast Cancer Patients Treated with Chemotherapy, Biologic Therapy, Endocrine Therapy, or Active Surveillance During the COVID-19 Pandemic.

Purpose: Provide real-world data regarding the risk for SARS-CoV-2 infection and mortality in breast cancer (BC) patients on active cancer treatment.

Methods: Clinical data were abstracted from the 3778 BC patients seen at a multisite cancer center in New York between February 1, 2020 and May 1, 2020, including patient demographics, tumor histology, cancer treatment, and SARS-CoV-2 testing results. Incidence of SARS-CoV-2 infection by treatment type (chemotherapy [CT] vs endocrine and/or HER2 directed therapy [E/H]) was compared by Inverse Probability of Treatment Weighting.

Features of triple-negative breast cancer: Analysis of 38,813 cases from the national cancer database.

The aim of this study was to determine the features of triple-negative breast cancer (TNBC) using a large national database. TNBC is known to be an aggressive subtype, but national epidemiologic data are sparse. All patients with invasive breast cancer and known molecular subtype diagnosed in 2010 to 2011 were identified from the National Cancer Data Base (NCDB).

Somatic alterations in juvenile polyps from BMPR1A and SMAD4 mutation carriers.

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder predisposing to gastrointestinal hamartomatous polyps and cancer with a pathogenic SMAD4 or BMPR1A germline mutation (1st-hit) being identified in about 40-50% of patients. Little is known, however, about the occurrence and nature of somatic alterations (2nd-hit) in SMAD4-/BMPR1A-related juvenile polyps. In this study, we screened 25 polyps from three patients carrying either a pathogenic SMAD4 (c.

Discordant gene expression signatures and related phenotypic differences in lamin A- and A/C-related Hutchinson-Gilford progeria syndrome (HGPS).

Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N), we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C. Here, we aimed to elucidate the molecular mechanisms underlying the pathogenesis in both, lamin A- (sporadic) and lamin A and C-related (hereditary) HGPS.

Accelerating stem cell proliferation by down-regulation of cell cycle regulator p21.

Background: Tissue engineering is often limited by the time required for culture expansion of cells necessary for scaffold seeding. Cell cycle regulators control entry and exit into the cell cycle and as such regulate cellular proliferation rates. The authors hypothesized that transient alteration in cell cycle regulators can be utilized as a means to accelerate stem cell proliferation.

Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion.

Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.

Mutation analysis of the Cx26, Cx30, and Cx31 genes in autosomal recessive nonsyndromic hearing impairment.

Conclusion: Biallelic Cx26 mutations are the most common cause of autosomal recessive nonsyndromic hearing impairment (ARNHI) in Switzerland. Mutations in Cx30 and 31, digenic mutations as well as large deletions/duplications, are unlikely to be a major cause of hearing loss in Swiss patients with ARNHI. Multiplex ligation-dependent probe amplification (MLPA) is a highly accurate screening method for detection of c.

NUP98 dysregulation in myeloid leukemogenesis.

Nucleoporin 98 (NUP98) is a component of the nuclear pore complex that facilitates mRNA export from the nucleus. It is mapped to 11p15.5 and is fused to a number of distinct partners, including nine members of the homeobox family as a consequence of leukemia-associated chromosomal translocations.

Enforced expression of NUP98-HOXA9 in human CD34(+) cells enhances stem cell proliferation.

The t(7;11)(p15;p15) translocation, observed in acute myelogenous leukemia and myelodysplastic syndrome, generates a chimeric gene where the 5' portion of the sequence encoding the human nucleoporin NUP98 protein is fused to the 3' region of HOXA9. Here, we show that retroviral-mediated enforced expression of the NUP98-HOXA9 fusion protein in cord blood-derived CD34(+) cells confers a proliferative advantage in both cytokine-stimulated suspension cultures and stromal coculture. This advantage is reflected in the selective expansion of hematopoietic stem cells as measured in vitro by cobblestone area-forming cell assays and in vivo by competitive repopulation of nonobese diabetic/severe combined immunodeficient mice.

A de novo MLH1 germ line mutation in a 31-year-old colorectal cancer patient.

Hereditary nonpolyposis colorectal cancer is an autosomal dominant cancer predisposition syndrome caused by inherited germ line mutations in DNA mismatch repair genes, predominantly MSH2 and MLH1. Here we report the first proven de novo germ line mutation in MLH1 (c.666dupA) identified in a 31-year-old colorectal cancer patient with the alteration being present in a heterozygous state in all three germ layers and homozygously in his colon cancer.

Molecular strategies for detection and quantitation of clonal cytotoxic T-cell responses in aplastic anemia and myelodysplastic syndrome.

Immune mechanisms are involved in the pathophysiology of aplastic anemia (AA) and myelodysplastic syndrome (MDS). Immune inhibition can result from cytotoxic T cell (CTL) attack against normal hematopoiesis or reflect immune surveillance. We used clonally unique T-cell receptor (TCR) variable beta-chain (VB) CDR3 regions as markers of pathogenic CTL responses and show that while marrow failure syndromes are characterized by polyclonal expansions, overexpanded clones exist in these diseases and can serve as investigative tools.

A de novo PABPN1 germline mutation in a patient with oculopharyngeal muscular dystrophy.

Background: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominantly inherited disorder characterized by dysphagia, ptosis, and proximal limb weakness and is caused by germline mutations (triplet repeat expansions) in the polyadenylate binding protein nuclear 1 (PABPN1) gene.

Objective: To describe a 70-year-old female patient with OPMD on the clinical and molecular genetic level and to develop a rapid and efficient molecular genetic screening method to study large patient groups.

Methods: Detailed family history and clinical assessment of the OPMD patient were followed by mutation analysis of the PABPN1 gene by direct DNA sequencing and by our newly developed method, fluorescent PABPN1 polymerase chain reaction (PCR) product (flPPP) method.

Gene conversion is a frequent mechanism of inactivation of the wild-type allele in cancers from MLH1/MSH2 deletion carriers.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer predisposition syndrome caused by germ line mutations in DNA mismatch repair genes, predominantly MLH1 and MSH2, with large genomic rearrangements accounting for 5% to 20% of all mutations. Although crucial to the understanding of cancer initiation, little is known about the second, somatic hit in HNPCC tumorigenesis, commonly referred to as loss of heterozygosity. Here, we applied a recently developed method, multiplex ligation-dependent probe amplification, to study MLH1/MSH2 copy number changes in 16 unrelated Swiss HNPCC patients, whose cancers displayed microsatellite instability and loss of MLH1 or MSH2 expression, but in whom no germ line mutation could be detected by conventional screening.

Evidence for genetic anticipation in hereditary non-polyposis colorectal cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal, dominantly inherited, colorectal cancer (CRC) predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1 and MSH2. Thus far, only limited data exist on the occurrence of genetic anticipation in HNPCC, i.e.

In-vivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing.

Background: Aplastic anaemia is a bone-marrow-failure syndrome characterised by low blood-cell counts and fatty bone marrow. In most cases, no obvious aetiological factor can be identified. However, clinical responses to immunosuppression strongly suggest an immune pathophysiology.

Shared and individual specificities of immunodominant cytotoxic T-cell clones in paroxysmal nocturnal hemoglobinuria as determined by molecular analysis.

Objective: Similar immune mechanisms have been suggested to operate in aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH), and the presence of PNH clones in AA may indicate that an immune reaction directed against hematopoietic stem cells may be responsible for the immune selection pressure leading to PNH evolution. We previously described expansions of selective cytotoxic T-lymphocyte (CTL) clones in AA patients.

Materials And Methods: We applied a molecular analysis of the T-cell receptor repertoire to study the characteristics of CTL response in patients with various forms of PNH.

Exclusion of an extracolonic disease modifier locus on chromosome 1p33-36 in a large Swiss familial adenomatous polyposis kindred.

Familial adenomatous polyposis (FAP), an autosomal dominantly inherited colorectal cancer predisposition syndrome, displays considerable inter- and intrafamilial phenotypic heterogeneity, which represents a major problem in genetic counselling of APC mutation carriers. The Min mouse model indicated a putative disease modifier locus on chromosome 4, which is syntenic to human chromosome 1p35-36. This finding was subsequently supported by parametric and nonparametric linkage analyses in FAP families, however, without identifying functional variants in candidate genes.

Molecular analysis of TCR clonotypes in LGL: a clonal model for polyclonal responses.

Large granular lymphocytic (LGL) leukemia is a clonal lymphoproliferative disorder of CTL associated with cytopenias resulting from an immune and cytokine attack on hemopoietic progenitor cells. Extreme clonality of CTL expansions seen in LGL leukemia makes it an ideal model to study the role of the T cell repertoire in other less-polarized immune-mediated disorders. Complementarity-determining region 3 (CDR3) of the TCR is a unique Ag-specific region that can serve as a molecular marker, or clonotype, of the disease-specific T cells.

Genetic predisposition as a basis for chemoprevention, surgical and other interventions in colorectal cancer.

Strategies of cancer prevention are generally developed with the population at large in mind. However, special attention is warranted for those persons with rare genetic traits associated with a greatly elevated risk of developing colorectal cancer (CRC) and some other malignancies: Orphan diseases demand Orphan preventive measures! Recent advances in modern genetics have enhanced our understanding of several genes and the specific germ-line mutations responsible for colorectal carcinogenesis. A number of features provide evidence for a genetic predisposition to CRC.

Diamond blackfan anemia stem cells fail to repopulate erythropoiesis in NOD/SCID mice.

Diamond Blackfan Anemia (DBA) is a congenital disorder characterized by decreased red blood cell production and developmental abnormalities. We herein show that DBA progenitors produced lower numbers of phenotypically normal erythroid colonies in vitro, whereas nonerythroid colonies were normally abundant and developed. To determine whether DBA stem cells are capable of producing early erythroid, monocyto-granulocytic, and lymphoid progenitors in vivo we used a mouse xenotransplantation model.

Application of the molecular analysis of the T-cell receptor repertoire in the study of immune-mediated hematologic diseases.

The basis for the vast recognition spectrum of the T-cell receptor (TCR) can be determined by the rearrangement and recombination of the variable, diversity and joining regions of the variable portions of beta (B) and alpha (A) chains as well as their recombination and modification. Analysis of the TCR rearrangement has been routinely used to detect clonality for the diagnosis of lymphoid malignancies. However, molecular analysis of the TCR repertoire can be a powerful tool in the study of T-cell responses to pathogens and in autoimmune diseases.

Mitochondria play a central role in apoptosis induced by alpha-tocopheryl succinate, an agent with antineoplastic activity: comparison with receptor-mediated pro-apoptotic signaling.

alpha-Tocopheryl succinate (alpha-TOS) is a semisynthetic vitamin E analogue with high pro-apoptotic and anti-neoplastic activity [Weber, T et al. (2002) Clin. Cancer Res.

Expression of genes regulating angiogenesis in human circulating hematopoietic cord blood CD34+/CD133+ cells.

Objectives: Human CD34+ cells represent a heterogeneous population of immature cells which may differentiate to various cell types. The aim of the study was to determine angiogenesis regulating genes expression in CD34+ cells, their subpopulations, and during their differentiation induced by hematopoietic growth factors.

Material And Methods: We have measured the expression of angiogenesis regulating genes angiopoietin-1 (Ang-1), angiopoietin-1 (Ang-2) and their receptor Tie-2, vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2 in sorted population of CD34+ and CD34+/CD133+ cells from human cord blood and bone marrow, and in their differentiating progeny, using real time reverse transcriptase polymerase chain reaction.

TRAIL (Apo2L) suppresses growth of primary human leukemia and myelodysplasia progenitors.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, APO2L) has been shown to induce apoptosis in a number of tumor cell lines as well as in some primary tumors whereas cells from most normal tissues are highly resistant to TRAIL-induced apoptosis. We have studied the susceptibility of primary malignant and normal bone marrow hematopoietic progenitors to TRAIL-induced apoptosis. Extracellular domain of human TRAIL with N-terminal His(6) tag (His-TRAIL, amino acids 95-281) was produced in E.