Discovering Tumor Suppressor Genes Through Genome-Wide Copy Number Analysis

Classical tumor suppressor gene discovery has largely involved linkage analysis and loss-of-heterozygosity (LOH) screens, followed by detailed mapping of relatively large chromosomal regions. Subsequent efforts made use of genome-wide PCR-based methods to detect rare homozygous deletions. More recently, high-resolution genomic arrays have been applied to cancer gene discovery. However, accurate characterization of regions of genomic loss is particularly challenging due to sample heterogeneity, the small size of deleted regions and the high frequency of germline copy number polymorphisms. Here, we review the application of genome-wide copy number analysis to the specific problem of identifying tumor suppressor genes

Tributes to Professor Alan Hornstein

Tributes to Professor Alan Hornstein upon his retirement from the University of Maryland School of Law

Emerging airborne contaminants in India : Platinum Group Elements from catalytic converters in motor vehicles

© The Author(s), 2016. This is the author's version of the work and is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Applied Geochemistry 75 (2016): 100-106, doi:10.1016/j.apgeochem.2016.10.006.Platinum Group Element (PGE) pollution on the Indian subcontinent is a growing concern because vehicle sales in India have rapidly increased over the last decade, and it is well known that automobile catalytic converters are one of the major source of anthropogenic PGE in the environment. Despite the rapid growth of the Indian automobile industry, the sources and magnitude of PGE contamination in Indian airborne particles are unknown. In this study we report PGE and mercury (Hg) concentrations, as well as osmium isotope ratios (187Os/188Os) of airborne particles (PM10) collected in Kanpur, a large industrial city in India. We estimate that 61±22%, 32±24%, and 7±3% of the total Os fraction are derived from eroding upper continental crust, catalytic converters fitted in the exhaust system of motor vehicles, and fossil fuel combustion, respectively. Only one sample had a ten times higher (~76%) than average contribution from fossil fuel. Unlike Os, Pt is predominantly (84±10%) derived from anthropogenic sources. Platinum Group Element and Hg concentrations are not well correlated. However, the highest concentration of particulate Hg corresponds to the most radiogenic 187Os/188Os isotope ratios (4.6). Our results further indicated that PGE/Ir ratios could be successfully used to quantify the relative proportions of natural and anthropogenic PGE sources in aerosol samples. Since PGE and Hg data on Indian environmental samples are scarce, this study provides an interpretive framework that calls for additional assessments of PGE and Hg concentrations in environmental samples from India.I.S. acknowledges an Indian Institute of Technology Kanpur Initiation Grant that supported this research.2018-10-2

Recommendations for Medical Management of Adult Lead Exposure

Research conducted in recent years has increased public health concern about the toxicity of lead at low dose and has supported a reappraisal of the levels of lead exposure that may be safely tolerated in the workplace. In this article, which appears as part of a mini-monograph on adult lead exposure, we summarize a body of published literature that establishes the potential for hypertension, effects on renal function, cognitive dysfunction, and adverse female reproductive outcome in adults with whole-blood lead concentrations < 40 μg/dL. Based on this literature, and our collective experience in evaluating lead-exposed adults, we recommend that individuals be removed from occupational lead exposure if a single blood lead concentration exceeds 30 μg/dL or if two successive blood lead concentrations measured over a 4-week interval are ≥ 20 μg/dL. Removal of individuals from lead exposure should be considered to avoid long-term risk to health if exposure control measures over an extended period do not decrease blood lead concentrations to < 10 μg/dL or if selected medical conditions exist that would increase the risk of continued exposure. Recommended medical surveillance for all lead-exposed workers should include quarterly blood lead measurements for individuals with blood lead concentrations between 10 and 19 μg/dL, and semiannual blood lead measurements when sustained blood lead concentrations are < 10 μg/dL. It is advisable for pregnant women to avoid occupational or avocational lead exposure that would result in blood lead concentrations > 5 μg/dL. Chelation may have an adjunctive role in the medical management of highly exposed adults with symptomatic lead intoxication but is not recommended for asymptomatic individuals with low blood lead concentrations

Eosinophilic and neutrophilic leukemoid reaction in a woman with spindle cell sarcoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>We report a case of a patient with marked eosinophilia and neutrophilia as a manifestation of a spindle cell sarcoma.</p> <p>Case presentation</p> <p>A 41-year-old African American woman presented with an enlarging, painful mass in her right knee area. Four years previously, she had had a mass similar to this diagnosed as an osteosarcoma, and had undergone a radical resection and hinge-knee replacement. Before the surgery, she was treated with neoadjuvant docetaxel and gemcitabine. A biopsy was taken from the recurrent mass, and histological examination revealed high-grade soft-tissue sarcoma. The patient received no further treatment. Complete blood counts revealed a white blood cell (WBC) count of 13.6 to 17.9 × 10⁹/L, with neutrophils being 8.2 to 10.9 × 10⁹/L and eosinophils 1.8 to 1.9 × 10⁹/L. At readmission six months later, WBC was 126.7 × 10⁹/L, with neutrophils being 57.02 × 10⁹/L and eosinophils 60.82 × 10⁹/L. The eosinophils peaked at 77.79 × 10⁹/L two days later. Evaluations for allergies, infection, and autoimmune mechanisms were negative. Bone marrow revealed increased eosinophils without blasts. After resection, blood counts abruptly decreased to the normal range. Pathology confirmed high-grade spindle cell sarcoma. Approximately one year after resection, the patient was readmitted with metastatic disease to her lungs. During this presentation, her eosinophil and neutrophil count was again increased. WBC was 107.8 × 10⁹/L, with eosinophil count of 47.43 × 10⁹/L and neutrophil count of 44.10 × 10⁹/L. Interleukin-5 was normal, and granulocyte–macrophage colony-stimulating factor (GM-CSF) was elevated at 208.8 (normal < 4.8).</p> <p>Conclusion</p> <p>In our case, the patient had eosinophilia and neutrophilia associated with a spindle cell sarcoma, possibly representing a paraneoplastic syndrome secondary to GM-CSF. There were no signs of infectious, allergic, or autoimmune causes for the eosinophilia or neutrophilia. Even though the occurrence of eosinophilia and neutrophilia with malignancy is rare, patients who have either condition without an apparent cause should be checked for malignancy.</p

Irinotecan plus folinic acid/continuous 5-fluorouracil as simplified bimonthly FOLFIRI regimen for first-line therapy of metastatic colorectal cancer

BACKGROUND: Combination therapy of irinotecan, folinic acid (FA) and 5-fluorouracil (5-FU) has been proven to be highly effective for the treatment of metastatic colorectal cancer. However, in light of safety and efficacy concerns, the best combination regimen for first-line therapy still needs to be defined. The current study reports on the bimonthly FOLFIRI protocol consisting of irinotecan with continuous FA/5-FU in five German outpatient clinics, with emphasis on the safety and efficiency, quality of life, management of delayed diarrhea, and secondary resection of regressive liver metastases. METHODS: A total of 35 patients were treated for metastatic colorectal cancer. All patients received first-line treatment according to the FOLFIRI regimen, consisting of irinotecan (180 mg/m(2)), L-FA (200 mg/m(2)) and 5-FU bolus (400 mg/m(2)) on day 1, followed by a 46-h continuous infusion 5-FU (2400 mg/m(2)). One cycle contained three fortnightly administrations. Staging was performed after 2 cycles. Dosage was reduced at any time if toxicity NCI CTC grade III/IV was observed. Chemotherapy was administered only to diarrhea-free patients. RESULTS: The FOLFIRI regimen was generally well tolerated. It was postponed for one-week in 51 of 415 applications (12.3%). Dose reduction was necessary in ten patients. Grade III/IV toxicity was rare, with diarrhea (14%), nausea/vomiting (12%), leucopenia (3%), neutropenia (9%) and mucositis (3%). The overall response rate was 31% (4 CR and 7 PR), with disease control in 74%. After primary chemotherapy, resection of liver metastases was achieved in three patients. In one patient, the CR was confirmed pathologically. Median progression-free and overall survival were seven and 17 months, respectively. CONCLUSIONS: The FOLFIRI regimen proved to be safe and efficient. Outpatient treatment was well tolerated. Since downstaging was possible, combinations of irinotecan and continuous FA/5-FU should further be investigated in neoadjuvant protocols

Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment

During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch-activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus 'poising' function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b expression, these inputs act in a stage-specific manner, providing a multitiered mechanism for developmental gene regulation

The Role of Vaccine Coverage within Social Networks in Cholera Vaccine Efficacy

Traditional vaccine trial methods have an underlying assumption that the effect of a vaccine is the same throughout the trial area. There are, however, many spatial and behavioral factors that alter the rates of contact among infectious and susceptible individuals and result in different efficacies across a population. We reanalyzed data from a field trial in Bangladesh to ascertain whether there is evidence of indirect protection from cholera vaccines when vaccination rates are high in an individual's social network.We analyzed the first year of surveillance data from a placebo-controlled trial of B subunit-killed whole-cell and killed whole-cell-only oral cholera vaccines in children and adult women in Bangladesh. We calculated whether there was an inverse trend for the relation between the level of vaccine coverage in an individual's social network and the incidence of cholera in individual vaccine recipients or placebo recipients after controlling for potential confounding variables.Using bari-level social network ties, we found incidence rates of cholera among placebo recipients were inversely related to levels of vaccine coverage (5.28 cases per 1000 in the lowest quintile vs 3.27 cases per 1000 in the highest quintile; p = 0.037 for trend). Receipt of vaccine by an individual and the level of vaccine coverage of the individual's social network were independently related to a reduced risk of cholera.Findings indicate that progressively higher levels of vaccine coverage in bari-level social networks can lead to increasing levels of indirect protection of non-vaccinated individuals and could also lead to progressively higher levels of total protection of vaccine recipients

Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment

During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch-activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus 'poising' function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b expression, these inputs act in a stage-specific manner, providing a multitiered mechanism for developmental gene regulation