Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair

OBJECTIVE: Esophageal adenocarcinoma (EAC) continues to be a disease associated with high mortality. Among the factors leading to poor outcomes are innate resistance to currently available therapies, advanced stage at diagnosis, and complex biology. Platinum and ionizing radiation form the backbone of treatment for the majority of patients with EAC. Of the multiple processes involved in response to platinum chemotherapy or ionizing radiation, deoxyribonucleic acid (DNA) repair has been a major player in cancer sensitivity to these agents. DNA repair defects have been described in various malignancies. The purpose of this study was to determine whether alterations in DNA repair are present in EAC compared with normal gastroesophageal tissues. METHODS: We analyzed the expression of genes involved in homologous recombination (HR), nonhomologous end-joining, and nucleotide excision repair (NER) pathways in 12 EAC tumor samples with their matched normal counterparts. These pathways were chosen because they are the main pathways involved in the repair of platinum- or ionizing-radiation-induced damage. In addition, abnormalities in these pathways have not been well characterized in EAC. RESULTS: We identified increased expression of at least one HR gene in eight of the EAC tumor samples. Alterations in the expression of EME1, a structure-specific endonuclease involved in HR, were the most prevalent, with messenger (m)RNA overexpression in six of the EAC samples. In addition, all EAC samples revealed decreased expression of at least one of numerous NER genes including XPC, XPA, DDB2, XPF, and XPG. CONCLUSION: Our study identified DNA repair dysregulation in EAC involving two critical pathways, HR and NER, and is the first demonstration of EME1 upregulation in any cancer. These DNA repair abnormalities have the potential to affect a number of processes such as genomic instability and therapy response, and the consequences of these defects deserve further study in EAC

Host cell invasion by Staphylococcus aureus stimulates the shedding of microvesicles

During severe sepsis, microvesicles that are positive for tissue factor (TF) are at increased levels within blood and in pulmonary lavage. These microvesicles potentially disperse TF, the major initiator of the coagulation cascade, throughout multiple organ systems, initiating fibrin deposition and resultant ischemia. The source of these microvesicles has remained incompletely defined. Although TF+ microvesicles are shed from cells that express nascent TF transcript in response to injury, recent findings revealed that circulating, full-length TF protein is detectable prior to these nascent transcripts. This finding suggested that the protein is released from constitutive sources as an acute response. We examined whether Staphylococcus aureus, the Gram-positive bacteria that is emerging as one of the most common etiologic agents in sepsis, is capable of stimulating the release of TF+ microvesicles from a pulmonary cell line that constitutively expresses TF protein. We found that host cell invasion stimulated an acute release of TF+ microvesicles and that these microvesicles mediated the transfer of the protein to TF-negative endothelial cells. We also found that transfer was inhibited by cholesterol-lowering simvastatin. Taken together, our findings reveal that S. aureus pathogenesis extends to the acute release of TF+ microvesicles and that inhibiting dispersal by this mechanism may provide a therapeutic target

A phylogenetic classification of the world’s tropical forests

Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition and dynamics. Such understanding will enable anticipation of region specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present the first classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (1) Indo-Pacific, (2) Subtropical, (3) African, (4) American, and (5) Dry forests. Our results do not support the traditional Neo- versus Palaeo-tropical forest division, but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar and India. Additionally, a northern hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern hemisphere forests

An estimate of the number of tropical tree species

The high species richness of tropical forests has long been recognized, yet there remains substantial uncertainty regarding the actual number of tropical tree species. Using a pantropical tree inventory database from closed canopy forests, consisting of 657,630 trees belonging to 11,371 species, we use a fitted value of Fisher’s alpha and an approximate pantropical stem total to estimate the minimum number of tropical forest tree species to fall between ∼40,000 and ∼53,000, i.e. at the high end of previous estimates. Contrary to common assumption, the Indo-Pacific region was found to be as species-rich as the Neotropics, with both regions having a minimum of ∼19,000–25,000 tree species. Continental Africa is relatively depauperate with a minimum of ∼4,500–6,000 tree species. Very few species are shared among the African, American, and the Indo-Pacific regions. We provide a methodological framework for estimating species richness in trees that may help refine species richness estimates of tree-dependent taxa

Phylogenetic classification of the world's tropical forests

Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region-specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern-hemisphere forests.</p

Staphylococcus aureus stimulates the release of constitutive tissue factor in lung epithelial cells

Sepsis is a life threatening condition caused by infectious agents, including the Gram-positive bacterium Staphylococcus aureus. Symptoms of sepsis often include intravascular coagulation and organ failure. Tissue factor (TF), the initiator of coagulation, may contribute to fibrin deposition in the lungs of patients with sepsis. We have found that lung epithelial cells constitutively express TF on the cell surface and in intracellular pools. Levels of TF diminished in response to S. aureus invasion possibly indicating a release in the form of shedding vesicles. TF levels diminish in response to viable bacteria, but not in response to heat killed (HK) bacteria. Our studies indicate that bacterial attachment at the host cell surface is insufficient to diminish levels of constitutive TF. Finally, we established that levels of constitutive intracellular TF diminish in response to the bacterial toxin, α-hemolysin, alone. This approach may provide a basis for understanding the role of TF in coagulation seen in sepsis.Thesis (M.S.)Department of Biolog

Staphylococcus aureus stimulates the release of constitutive tissue factor in lung epithelial cells

Sepsis is a life threatening condition caused by infectious agents, including the Gram-positive bacterium Staphylococcus aureus. Symptoms of sepsis often include intravascular coagulation and organ failure. Tissue factor (TF), the initiator of coagulation, may contribute to fibrin deposition in the lungs of patients with sepsis. We have found that lung epithelial cells constitutively express TF on the cell surface and in intracellular pools. Levels of TF diminished in response to S. aureus invasion possibly indicating a release in the form of shedding vesicles. TF levels diminish in response to viable bacteria, but not in response to heat killed (HK) bacteria. Our studies indicate that bacterial attachment at the host cell surface is insufficient to diminish levels of constitutive TF. Finally, we established that levels of constitutive intracellular TF diminish in response to the bacterial toxin, α-hemolysin, alone. This approach may provide a basis for understanding the role of TF in coagulation seen in sepsis.Thesis (M.S.)Department of Biolog

Determining a transitional scoring link between PROMIS® pediatric and adult physical health measures

Purpose Having independent versions of the PROMIS® scales (for Pediatric and Adults) is problematic as scores cannot be evaluated longitudinally as individuals move from childhood into adulthood. The primary aim of this research project is to use item response theory (IRT) to develop a transitional scoring link (or “crosswalk”) between the PROMIS adult and pediatric physical health measures. Setting Sample 1 was collected at 6 rehabilitation hospitals in the U.S., and participants in Sample 2 were recruited from public health insurance programs and an online research panel. Methods PROMIS pediatric and adult physical function, mobility, upper extremity, fatigue, and pain measures were administered to a sample of 874 individuals aged 14–20 years old with special health needs and a sample of 641 individuals aged 14–25 years with a disability. IRT-based scores were linked using a linear approximation to calibrated projection. Results Estimated latent variable correlations ranged between 0.84 and 0.95 for the PROMIS pediatric and adult scores. Root Expected Mean Square Difference values were below the 0.08 threshold in all cases except when comparing genders on the Mobility (0.097) and Pain (0.10) scales in the special health care needs sample. Sum score conversion tables for the pediatric and adult PROMIS measures are presented. Conclusions The linking coefficients can be used to calculate scale scores on PROMIS adult measures from pediatric measure scores and vice versa. This may lead to more accurate measurement in cross-sectional studies spanning multiple age groups or longitudinal studies that require comparable measurement across distinct developmental stages

In This World but Not of It: Midwives, Amish, and the Politics of Power

In this paper, I investigate the role of the non-Amish midwife in Amish society. Conventional research on the Amish has overlooked the role the midwife plays in the structure of the Amish community, given that midwives who serve the Amish are not members of the community they serve and are not themselves Amish. Despite their status as outsiders to Amish society, I draw on ethnographic data collected during a two-year study with a non-Amish midwife to argue that the non-Amish midwife provides Amish women and men access to knowledge about sex and sexuality, provides them resources such as books and condoms, and shapes the structure of Amish society through these channels. Her power is clearly demonstrated in her ability to broker access between the Amish and non-Amish worlds, and her fingerprints on the community she serves exist long after she has caught a baby. So while the non-Amish midwife has largely remained invisible when viewed from conventional analyses of Amish society, I suggest that her position on the margin between Amish and non-Amish society is worth considering. As an analytic category, this position \u27neither fully part of Amish society nor fully extricated from it\u27 has something to offer studies of community power within the field of Sociology and augment future studies of Amish society