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Biomedical subjects

T Rich

Publications and source records attributed to T Rich.

At least 19 recordsLinked to original sources
PubMed2007

Evidence for the receipt of DNA damage stimuli by PML nuclear domains.

Promyelocytic leukaemia nuclear domains (PML-NDs) comprise a shell of PML protein and many labile cargo proteins. The nature of their cargo, their juxtaposition to foci of damaged DNA following ionizing radiation (IR), and the altered DNA damage responses in PML null cells all implicate PML-NDs in the DNA damage response. In this work, the propensity of PML-NDs to increase in number and decrease in size following IR has been studied. Serial quantitative studies of endogenous PML-NDs prove that the PML-ND response to IR is not the result of the asymmetry in cell cycle distribution that can follow IR, but reflects more directly the process of DNA damage. The response is swift, sensitive (evident after 1 Gy), and potentially reversible in untransformed fibroblasts. In these cells and in HCT116 colon cancer cells, failure to restore PML-ND number within 24 h correlates with later loss of growth potential--in fibroblasts, through prolonged cell cycle arrest and in HCT116 cells, through apoptosis. Failure to express an intact ATM/CHK2 DNA damage signalling pathway in either cell type leads to a delay in the PML-ND response to IR. Conversely, cell cycle progression following IR in cells that detect damaged DNA accelerates PML-ND reorganization. Collectively, these data show that the increase in PML-ND number seen after irradiation is, in part, triggered by the receipt of the DNA damage stimulus. The senescent cell state is also associated with chronic DNA damage and Hayflick-limited fibroblasts were found to express nuclei with elevated numbers of PML-NDs before IR that remained unresponsive to IR. Though the underlying reasons for damage-induced PML alteration remain obscure, it is noteworthy that significant numbers of PML-NDs juxtapose with ionizing radiation-induced foci after IR. The co-regulation of these structures may necessitate the stereotyped increases in PML-ND number following damage.

Apoptosis↗
PubMed2001

Chemoradiation in conservation therapy for esophageal cancer.

Irradiation alone can be highly beneficial for patients with advanced or metastatic esophageal cancer, but external beam irradiation alone is now usually reserved for patients only requiring palliation. Higher cure rates are achieved with irradiation delivered with radiosensitizing chemotherapy based on clinical trials performed over the last decade. Chemoradiation programs based on the modest success with infusional 5-FU, cisplatin, and 50 Gy are justified for either palliative or curative treatment as long as the toxicity is acceptable. One challenge is to increase the incidence of pathologic complete response rates without incurring unacceptable acute toxicity, which is the major dose-limiting factor in current trials. Newer methods that may ameliorate acute injury are different dose schedules for chemoradiation and different methods of dose delivery. Infusional administration of chemotherapy and new dose planning and delivery systems for irradiation (conformal irradiation) are currently under study. Organ preservation for larger numbers of patients may be possible if any of these methods hold up to the early indications of success.

Combined Modality Therapy↗
PubMed2001

University of Rochester laboratory inspection checklist.

In early 1999, the University of Rochester significantly revised our laboratory inspection program. As part of this revision, we developed a new checklist to be used during laboratory inspections to help promote consistency between inspections and between inspectors.

Forms and Records Control↗
PubMed2000

Defying death after DNA damage.

DNA damage frequently triggers death by apoptosis. The irreversible decision to die can be facilitated or forestalled through integration of a wide variety of stimuli from within and around the cell. Here we address some fundamental questions that arise from this model. Why should DNA damage initiate apoptosis in the first place? In damaged cells, what are the alternatives to death and why should they be selected in some circumstances but not others? What signals register DNA damage and how do they impinge on the effector pathways of apoptosis? Is there a suborganellar apoptosome complex effecting the integration of death signals within the nucleus, just as there is in the cytoplasm? And what are the consequences of failure to initiate apoptosis in response to DNA damage?

Animals↗
PubMed2000

Common toxicity criteria: version 2.0. an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy.

In 1997, the National Cancer Institute (NCI) led an effort to revise and expand the Common Toxicity Criteria (CTC) with the goal of integrating systemic agent, radiation, and surgical criteria into a comprehensive and standardized system. Representatives from the Radiation Therapy Oncology Group (RTOG) participated in this process in an effort to improve acute radiation related criteria and to achieve better clarity and consistency among modalities. CTC v. 2.0 replaces the previous NCI CTC and the RTOG Acute Radiation Morbidity Scoring Criteria and includes more than 260 individual adverse events with more than 100 of these applicable to acute radiation effects. One of the advantages of the revised criteria for radiation oncology is the opportunity to grade acute radiation effects not adequately captured under the previous RTOG system. A pilot study conducted by the RTOG indicated the new criteria are indeed more comprehensive and were preferred by research associates. CTC v. 2.0 represents an improvement in the evaluation and grading of acute toxicity for all modalities.

Antineoplastic Agents↗
PubMed1999

Isolation, sequencing and expression of RED, a novel human gene encoding an acidic-basic dipeptide repeat.

A novel human gene RED, and the murine homologue, MuRED, were cloned. These genes were named after the extensive stretch of alternating arginine (R) and glutamic acid (E) or aspartic acid (D) residues that they contain. We term this the 'RED' repeat. The genes of both species were expressed in a wide range of tissues and we have mapped the human gene to chromosome 5q22-24. MuRED and RED shared 98% sequence identity at the amino acid level. The open reading frame of both genes encodes a 557 amino acid protein. RED fused to a fluorescent tag was expressed in nuclei of transfected cells and localised to nuclear dots. Co-localisation studies showed that these nuclear dots did not contain either PML or Coilin, which are commonly found in the POD or coiled body nuclear compartments. Deletion of the amino terminal 265 amino acids resulted in a failure to sort efficiently to the nucleus, though nuclear dots were formed. Deletion of a further 50 amino acids from the amino terminus generates a protein that can sort to the nucleus but is unable to generate nuclear dots. Neither construct localised to the nucleolus. The characteristics of RED and its nuclear localisation implicate it as a regulatory protein, possibly involved in transcription.

Animals↗
PubMed1999

Apoptosis: the germs of death.

From the initial recognition that programmed cell suicide existed, to the elucidation of the underlying death and survival pathways at the molecular level, the story of apoptosis has unfolded rapidly. But much still remains to be discovered.

Animals↗
PubMed1999

Disassembly of nuclear inclusions in the dividing cell--a novel insight into neurodegeneration.

Spinocerebellar ataxias and Huntington's disease are examples of neurodegenerative diseases caused by a trinucleotide repeat expansion. One hallmark of such diseases is the formation of inclusion bodies (IBs) within neuronal tissue. Although these inclusions may play a pivotal role in the disease process, the reasons underlying their specific accumulation remain obscure. By studying intranuclear IBs in dividing cells we demonstrate for the first time that inclusions such as those of ataxin-1 disperse during mitosis, thus reducing the nuclear aggregate burden. IBs reform in the interphase nucleus. By high-resolution confocal microscopy we also show that inclusions comprise ordered structures capable of homotypic interactions. Unlike those of a non-pathologic protein, ataxin-1 inclusions were shown to be capable of non-specific protein sequestration. Our studies indicate that the specific accumulation of inclusions in terminally differentiated cells such as neurons is a direct consequence of their inability to divide and therefore provides a key to explaining their persistence in neurodegenerative disease.

Amino Acid Sequence↗
PubMed1999

Changing role of radiotherapy in the management of cancer of the esophagus.

BACKGROUND: Cancer of the esophagus remains a highly lethal disease, but new treatment approaches that build onto traditional surgical and radiotherapeutic methods are making an impact on organ preservation while offering hope for improved survival. METHODS: Reviewed here are recent data from trials on the use of new radiotherapeutic approaches. RESULTS: There is clinical trial evidence for improved treatment results with radiotherapy and concurrent systemic chemotherapy. For some patients with responsive cancers, the use of chemoradiation results in about 25% being cured-a marked departure from the results of treatment with radiotherapy alone in the preceding decades. This idea is being explored further with new trials using advanced radiotherapy treatment planning systems called "conformal therapy," in which the high irradiation dose envelope is designed to fit tightly around the cancer. CONCLUSIONS: Cancer of the esophagus can now be treated aggressively with chemoradiation to offer a choice for local symptom control, organ preservation, and cure.

Endoscopy↗
PubMed1998

cDNA cloning, tissue distribution and chromosomal localization of the human ID4 gene.

A cDNA e encoding the human Id4 protein has been isolated from an astrocytoma library. The predicted protein product shares 98% identity with the mouse Id4 protein and is markedly different from that already reported. By FISH analysis, the human ID4 gene was more precisely mapped to chromosome 6p22.3-p23. Northern blot analysis showed that ID4 is mainly expressed in thyroid, brain and fetal tissue and in some nervous system tumor cell lines.

Amino Acid Sequence↗
PubMed1998

Stathmin overexpression in 293 cells affects signal transduction and cell growth.

Stathmin is a ubiquitous cytoplasmic protein whose phosphorylation state changes markedly in response to extracellular signals, and during the cell cycle. To clarify the function of stathmin, its four phosphorylation sites were mutated to either alanines (4A-stathmin) or glutamates (4E-stathmin). In transfected cells, 4A-stathmin caused a strong G2/M block and also inhibited the responsiveness of a co-transfected fos promoter/ luciferase reporter plasmid to serum stimulation, whereas wild type and 4E-stathmin had relatively minor effects. These results support the idea that stathmin plays a role in multiple cellular processes and indicate that the regulation of the phosphorylation state of stathmin is likely to determine its action.

Alanine↗
PubMed1998

Performance of six cell lines in the suspension-infection test used for the detection of herpes simplex virus.

Six cell lines were assessed in the suspension-infection (SI) test for suitability for the rapid culture of herpes simplex virus (HSV). For the SI test, the specimen was combined in growth medium with trypsinized, suspended culture cells before allowing the cells to settle into a monolayer growth pattern. The cells tested in the SI assay were MV1-Lu, vero C1008, BSC-1, RD, and MRC-9 cells. Fifty clinical specimens composed of 7 HSV-1-positive samples, 9 HSV-2-positive samples, 12 positive for HSV (not typed), and 22 HSV-negative samples were tested. For the detection of HSV in clinical specimens, MV1Lu cells were most sensitive and demonstrated large, darkly stained foci of virus infection.

Animals↗