Biomedical subjects

K M Lo

Publications and source records attributed to K M Lo.

At least 19 recordsLinked to original sources

PubMed2006

Estimation of glomerular filtration rate in patients with systemic lupus erythematosus.

The objective of this study was to compare the limit of agreement of creatinine clearance (CrCl) estimated by different equations with the CrCl measured by 24-hour urine collection in Hong Kong Chinese patients with systemic lupus erythematosus (SLE). Forty-three SLE patients with mild to moderate renal impairment (serum creatinine concentration >80 micromol/L to <300 micromol/L for females; and >106 micromol/L to <300 micromol/L for males) and not requiring renal replacement therapy were assessed. The estimated clearances were calculated by the Cockcroft-Gault (CG) equation, the Modification of Diet in Renal Disease (MDRD) study equation and the abbreviated MDRD (aMDRD) study equation. The estimated clearances were compared against the measured CrCl by 24-hour urine collection for their limit of agreement. Forty-three patients with mean (+/-SD) age of 41.6 (+/-8.4) years were assessed. As compared to the measured CrCl in patients with SLE, the clearances by CG equation, MDRD and aMDRD equations predicted a mean difference of -0.8% (95% confidence interval, -43.9-42.3%); -8.6% (95% CI, -24.3-7.2%) and -4.7% (95% CI, -21.4-12%), respectively. There is a tendency for the MDRD and aMDRD study equations to underestimate CrCl. The MDRD and aMDRD study equations have better predictive value than the CG equation.

Adult↗

PubMed2002

Fractures after stroke: frequency, types, and associations.

BACKGROUND AND PURPOSE: Stroke patients may have an increased risk of fractures because of weak bones or an increased risk of falling. Our goal was to estimate the frequency of fracture after stroke and to identify those at greatest risk. METHODS: This study incorporated 2 complementary strategies: a prospective, single-center, cohort study and an analysis of Scottish routine hospital discharge data. RESULTS: Eighty-eight fractures (30% hip) occurred in 2696 hospital-referred stroke patients. The proportions sustaining any fracture or hip fracture within 2 years were 4% and 1.1%, respectively, 1.4 (95% CI, 0.92 to 2.07) times the rate of hip fracture in the general population (ie, observed number divided by expected number or standardized morbidity ratio). Female sex, older age, low abbreviated mental test score, and prestroke dependence were associated with an increased hip fracture rate. Routine data identified 129 935 acute stroke patients admitted to Scottish hospitals. During 363 447 patient-years, 4528 patients had hip fractures, 2.0% had fractures by 1 year, and 10.6% had fractures by 10 years. This is 1.7 times the rate of hip fracture in the general population and 2.3 times that in patients with myocardial infarction. Older patients predictably had the highest rate of poststroke hip fractures but a lower standardized morbidity ratio than younger patients. CONCLUSIONS: Fractures after stroke are probably frequent and serious enough to justify the development of preventive strategies, but the modest event rate would mean that randomized, controlled trials to test these strategies specifically in stroke patients would need to enroll thousands of patients.

Age Factors↗

PubMed2001

Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer.

PURPOSE: Most breast cancer survivors experience hot flashes; many use complementary or alternative remedies for these symptoms. We undertook a randomized clinical trial of black cohosh, a widely used herbal remedy for menopausal symptoms, among breast cancer patients. PATIENTS AND METHODS: Patients diagnosed with breast cancer who had completed their primary treatment were randomly assigned to black cohosh or placebo, stratified on tamoxifen use. At enrollment, patients completed a questionnaire about demographic factors and menopausal symptoms. Before starting to take the pills and at 30 and 60 days, they completed a 4-day hot flash diary. At the final visit, they completed another menopausal symptom questionnaire. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured in a subset of patients at the first and final visits. RESULTS: Of 85 patients (59 on tamoxifen, 26 not on tamoxifen) enrolled in the study, 42 were assigned to treatment and 43 were assigned to placebo; 69 completed all three hot flash diaries. Both treatment and placebo groups reported declines in number and intensity of hot flashes; the differences between the groups were not statistically significant. Both groups also reported improvements in menopausal symptoms that were, for the most part, not significantly different. Changes in blood levels of FSH and LH also did not differ in the two groups. CONCLUSION: Black cohosh was not significantly more efficacious than placebo against most menopausal symptoms, including number and intensity of hot flashes. Our study illustrates the feasibility and value of standard clinical trial methodology in assessing the efficacy and safety of herbal agents.

Antineoplastic Agents, Hormonal↗

PubMed2001

Oligomerization-dependent regulation of motility and morphogenesis by the collagen XVIII NC1/endostatin domain.

Collagen XVIII (c18) is a triple helical endothelial/epithelial basement membrane protein whose noncollagenous (NC)1 region trimerizes a COOH-terminal endostatin (ES) domain conserved in vertebrates, Caenorhabditis elegans and Drosophila. Here, the c18 NC1 domain functioned as a motility-inducing factor regulating the extracellular matrix (ECM)-dependent morphogenesis of endothelial and other cell types. This motogenic activity required ES domain oligomerization, was dependent on rac, cdc42, and mitogen-activated protein kinase, and exhibited functional distinction from the archetypal motogenic scatter factors hepatocyte growth factor and macrophage stimulatory protein. The motility-inducing and mitogen-activated protein kinase-stimulating activities of c18 NC1 were blocked by its physiologic cleavage product ES monomer, consistent with a proteolysis-dependent negative feedback mechanism. These data indicate that the collagen XVIII NC1 region encodes a motogen strictly requiring ES domain oligomerization and suggest a previously unsuspected mechanism for ECM regulation of motility and morphogenesis.

Angiogenesis Inhibitors↗

PubMed2001

Effect of antiangiogenic therapy on slowly growing, poorly vascularized tumors in mice.

BACKGROUND: Angiogenesis is essential for tumor growth and progression. Therefore, inhibition of angiogenesis is being studied as a new anticancer therapy. Because cytotoxic chemotherapy is more effective on rapidly growing tumors than on slowly growing tumors, it has been assumed that antiangiogenic therapy will also be effective only on rapidly growing, highly vascularized tumors. We compared the effects of two angiogenesis inhibitors, TNP-470 and angiostatin, on slowly growing, poorly vascularized and rapidly growing, highly vascularized human tumors in mice. METHODS: Slowly growing (RT-4) and rapidly growing (MGH-U1) human bladder carcinoma cell lines were grown in severe combined immunodeficiency mice. Established tumors were treated with one of the two angiogenesis inhibitors. Tumor volumes, vascularity, and proliferation indices were determined. The in vitro effects of TNP-470 and of angiostatin on the proliferation of RT-4 and MGH-U1 cells were also investigated. All statistical tests were two-sided. RESULTS: RT-4 and MGH-U1 tumor growth was statistically significantly inhibited by both angiogenesis inhibitors (P<.001). Both inhibitors decreased the blood vessel density in both tumor types but did not alter the in vivo proliferation indices of the tumors. TNP-470, but not angiostatin, marginally decreased the in vitro proliferation of MGH-U1 cells. CONCLUSION: Slowly growing, poorly vascularized tumors in animal models respond as well as rapidly growing, highly vascularized tumors to therapy with the angiogenesis inhibitors TNP-470 and angiostatin.

Angiogenesis Inhibitors↗

PubMed2001

Expression of Periostin, homologous with an insect cell adhesion molecule, as a prognostic marker in non-small cell lung cancers.

We used our palindromic polymerase chain reaction (PCR)-driven cDNA differential display technique to identify and isolate a gene, designated periostin, from cancer tissues and found it to be overexpressed in several human tumors. We attempted to determine the influence of periostin expression on clinical outcome in patients with non-small cell lung cancer (NSCLC) by reverse transcriptase (RT)-PCR analysis. Periostin gene was highly expressed at the tumor periphery of lung cancer tissue but not within the tumor by in situ RNA hybridization, suggesting that expression of periostin may be involved in the process of tumor invasion. Periostin transcripts were detected in 50 (49.0%) of the tumor samples, although some paired normal lung samples showed weak expression. There was no relationship between periostin gene expression and gender, N- or T-status. The NSCLC patients with periostin expression had significantly poorer survival than the patients without periostin expression (P = 0.0338).

Adenocarcinoma↗

PubMed1999

HRad17, a human homologue of the Schizosaccharomyces pombe checkpoint gene rad17, is overexpressed in colon carcinoma.

Using the palindromic PCR-cDNA display method, we have cloned a novel gene overexpressed by human colon carcinoma relative to normal colon. Among normal tissues examined, only testis expresses it at a high level. Sequence analysis revealed its extensive homology with checkpoint genes rad17 of Schizosaccharomyces pombe and RAD24 of Saccharomyces cerevisiae. This novel gene designated as hRad17 is localized to chromosome 5q12,13.1, a region known to be deleted in a variety of human cancers. Promoter region and one pseudogene of hRad17 have been identified. Whereas the increased expression of hRad17 by human colon carcinomas may be related to the known resistance of these cells to DNA-damaging agents during therapy, the deletion of hRad17 in a variety of cancers may predispose them to increased rate of mutation and heightened sensitivity to DNA-damaging agents, including radiation and anticancer drugs.

Animals↗

PubMed1999

Improving the efficacy of antibody-interleukin 2 fusion proteins by reducing their interaction with Fc receptors.

Fusion proteins between whole antibodies (Abs) and cytokines (immunocytokines) such as interleukin 2 have shown efficacy in several mouse tumor models despite a circulating half-life that is significantly shorter than that of the original Ab. We have examined the potential mechanisms responsible for clearance and shown that an important factor is enhanced binding to Fc receptor (FcR). Improvements in the half-lives of two different immunocytokines were made by changing the isotype of the human heavy chain C region from IgG1 or IgG3 to those with reduced binding to FcR, e.g., IgG4. The same effect could also be achieved through site-directed mutagenesis of the FcR binding site in the IgG1 H chain. In vitro studies using mouse J774 FcR-expressing cells showed increased binding of interleukin 2-based immunocytokines, relative to their corresponding Abs, and that this was reversed in those fusion proteins made with IgG4 or mutated IgG1 H chains. All of the fusion proteins showing reduced FcR binding also had reduced Ab-dependent cellular cytotoxicity activity, as measured in 4-h chromium release assays. A complete loss of complement-dependent cytotoxicity activity was seen with an IgG4-based immunocytokine derived from an IgG1 Ab with potent activity. Despite these reduced effector functions, the IgG4-based immunocytokines with extended circulating half-lives showed equivalent (in the case of severe combined immunodeficiency mouse xenograft models) or better (in the case of syngeneic models) efficacy in mouse tumor models than the original IgG1-based molecules. These novel immunocytokines may show improved efficacy in therapeutic situations where T cell- rather than natural killer- or complement-mediated antitumor mechanisms are involved.

Animals↗

PubMed1999

Effects of angiogenesis inhibitors on multistage carcinogenesis in mice.

Solid tumors depend on angiogenesis for their growth. In a transgenic mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2), an angiogenic switch occurs in premalignant lesions, and angiogenesis persists during progression to expansive solid tumors and invasive carcinomas. RIP1-Tag2 mice were treated so as to compare the effects of four angiogenesis inhibitors at three distinct stages of disease progression. AGM-1470, angiostatin, BB-94, and endostatin each produced distinct efficacy profiles in trials aimed at preventing the angiogenic switch in premalignant lesions, intervening in the rapid expansion of small tumors, or inducing the regression of large end-stage cancers. Thus, anti-angiogenic drugs may prove most efficacious when they are targeted to specific stages of cancer.

Angiostatins↗

PubMed1999

Low-dose vincristine-associated bilateral vocal cord paralysis.

BACKGROUND: Vincristine-associated peripheral neuropathy is a well-described entity. We describe a case of vincristine-induced vocal cord paralysis, which is a rare complication of this drug. We report herein the second case of bilateral vocal cord paralysis in a patient receiving conventional doses of vincristine. OBJECTIVE: To present a case report of vincristine-associated vocal cord paralysis and to review the relevant English language literature on this subject. DESIGN: Report and review of the literature. SETTING: Outpatient community cancer center. PATIENT: A 58-year-old female with a diffuse large cell lymphoma stage IV receiving cyclophosphamide, doxorubicin, vincristine, and prednisone. RESULTS: Bilateral vocal cord paralysis occurred in this patient receiving vincristine as part of her chemotherapy regimen. In addition to this case there have been a total of 25 prior reports, which are reviewed in the text. CONCLUSION: The incidence of bilateral vocal cord paralysis in patients receiving vincristine on the usual low-dose schedule is low. Prompt withdrawal of the offending agent results in prompt recovery without untoward long-lasting sequela.

Antineoplastic Agents, Phytogenic↗

PubMed1998

Zinc-dependent dimers observed in crystals of human endostatin.

The crystal structure of human endostatin reveals a zinc-binding site. Atomic absorption spectroscopy indicates that zinc is a constituent of both human and murine endostatin in solution. The human endostatin zinc site is formed by three histidines at the N terminus, residues 1, 3, and, 11, and an aspartic acid at residue 76. The N-terminal loop ordered around the zinc makes a dimeric contact in human endostatin crystals. The location of the zinc site at the amino terminus, immediately adjacent to the precursor cleavage site, suggests the possibility that the zinc may be involved in activation of the antiangiogenic activity following cleavage from the inactive collagen XVIII precursor or in the cleavage process itself.

Base Sequence↗

PubMed1998

Antibody-IL-12 fusion proteins are effective in SCID mouse models of prostate and colon carcinoma metastases.

IL-12 is a complex cytokine in both its structure and its range of biologic activities. Fusions of this heterodimeric molecule with an intact antitumor Ab were made to test the feasibility and efficacy of targeting IL-12 to tumors to elicit a local immune response. Fusion proteins composed of the human p35 and p40 subunits had IL-12 bioactivities that were nearly as potent on human immune cells as the rIL-12 standard, but were inactive on mouse cells. Hybrid IL-12 fusion proteins composed of mouse p35 and human p40, fused to Ab, were capable of inducing IFN-gamma, but were much less active on mouse spleen cells than a mouse IL-12 standard. Despite this relatively low activity, the hybrid fusion protein was as effective in a SCID mouse model as a fully active Ab-IL-2 fusion protein in eliminating established pulmonary metastases of CT26 colon carcinoma. Specific targeting of a human IL-12 fusion protein to metastatic prostate carcinoma xenografts was also shown to be effective in SCID mice transplanted with human lymphocyte-activated killer cells. These results demonstrate the importance of directing this potent cytokine to the tumor microenvironment and suggest an important alternative to systemic IL-12 administration or gene therapy for increasing its therapeutic index.

Animals↗

PubMed1998

High level expression and secretion of Fc-X fusion proteins in mammalian cells.

We have developed a general expression system that enhances the production and secretion of proteins in mammalian cells. The protein of interest is expressed as a fusion to a signal peptide and the Fc fragment of immunoglobulin as the N-terminal fusion partner, which can direct the cellular processes into expressing and secreting high levels of many different types of proteins. These include secretory proteins, enzymes and soluble domains of membrane proteins, as well as nuclear and regulatory proteins. Typical expression levels of these proteins from stable cell lines ranged from several to 100 microg/ml in conditioned media. The Fc domain helps to solubilize hydrophobic proteins and provides a handle for easy detection and purification of the fusion proteins; and it can be cleaved off by treatment with protease if desired.

Animals↗

PubMed1997

Elimination of established murine colon carcinoma metastases by antibody-interleukin 2 fusion protein therapy.

A recombinant humanized antibody-interleukin 2 fusion protein (huKS1/4-IL-2) was used to direct IL-2 to the tumor microenvironment and elicit a T cell-mediated eradication of established pulmonary and hepatic CT26-KSA colon carcinoma metastases in syngeneic BALB/c mice. This antitumor effect was specific because a fusion protein, which was nonreactive with these tumor cells, failed to exert any such effect. The efficacy of the huKS1/4-IL-2 fusion protein in eliminating metastases was documented because mixtures of monoclonal antibody huKS1/4 with recombinant human IL-2 were ineffective and, at best, only partially reduced tumor load. Two lines of evidence indicated the eradication of metastases and the absence of minimal residual disease in animals treated with the fusion protein: first, the lack of detection of CT26-KSA cells by reverse transcription-PCR, which can detect one tumor cell in 10(6) liver cells; and second, the tripling of life span. The effector mechanism involved in this tumor eradication is dependent on T cells because the IL-2-directed therapy is ineffective in T cell-deficient SCID mice. The essential effector cells were further characterized as CD8+ T cells by in vivo depletion studies. Such T cells, isolated from tumor-bearing mice after fusion protein therapy, elicited MHC class I-restricted cytotoxicity in vitro against colon carcinoma target cells. Taken together, these data indicate that fusion protein-directed IL-2 therapy induces a T cell-dependent host immune response capable of eradicating established colon cancer metastases in an animal tumor model.

Animals↗

PubMed1997

FP-21399 blocks HIV envelope protein-mediated membrane fusion and concentrates in lymph nodes.

The identification of fusin and other chemokine receptors as coreceptors for HIV-1 has renewed the interest in agents that may prevent viral entry. Polyanionic compounds such as dextran sulfate, curdian sulfate, and suramin act on the V3 loop of the viral envelope and may prevent its interaction with fusin. These agents show activity against a wide range of HIV-1 strains, but have undesirable circulating half-life, bioavailability, and toxicity. We have developed a small molecule inhibitor of HIV-1 that has several advantages over these other agents. FP-21399 is a novel compound of the bis(disulfonaphthalene) dimethoxybenzene class that blocks entry of HIV into CD4+ cells and blocks fusion of infected and noninfected CD4+ cells. This compound only weakly inhibits binding of CD4 and gp120, at concentrations much greater than are required to block viral entry. Furthermore, FP-21399 can block the interaction between gp120 and antibodies directed against the V3 loop, but does not block binding of antibodies directed against the V4 loop. Animal studies demonstrate that FP-21399 is concentrated in lymph nodes, making it a promising compound for anti-HIV therapy. In SCID mice reconstituted with human immune cells, maintenance of HIV-1 infection was blocked by a 5-day treatment with low doses of FP-21399, suggesting that lymph node accumulation may contribute to antiviral activity. Finally, attempts to generate drug-resistant virus in cell culture resulted in only weakly resistant variants with IC90 values that are much lower than concentrations of FP-21399 found in lymph nodes.

Animals↗

PubMed1996

[The practicability of preceptorship in the curriculum of medical education].

Physicians who have graduated from traditional medical education curriculum focus on technological and organ system training, and are deficient in modern community health care concepts and skills. A preceptorship course integrates at various medical educational periods is one of the important goals at education reform in America. In this study, we attempt to ascertain the opinions of family physicians about the current family medicine curriculum and the practicability of preceptorship in Taiwan. The result can be a reference for future medical curriculum design. Two hundreds and thirty-five (40.8%) questionnaires were collected and analyzed. They showed most respondents were dissatisfied with the current curriculum of family medicine, and most agree that primary care physicians involvement would be helpful in producing efficient and well-qualified physicians. They suggested that preceptorship should best be first integrated in a basic knowledge course. We suggest that faculties who are responsible for curriculum design should evaluate the current curriculum and the appropriateness of preceptorship in Taiwan. Prior to the reform, faculty development and evaluation are the essential and crucial tasks.

Adult↗

PubMed1992

Infection of human natural killer (NK) cells with replication-defective human T cell leukemia virus type I provirus. Increased proliferative capacity and prolonged survival of functionally competent NK cells.

Human T-cell leukemia virus type I (HTLV-I) can infect a variety of human cell types, but only T lymphocytes are efficiently immortalized after HTLV-I infection. This study reports an attempt to infect and to immortalize NK cells with HTLV-I. Co-cultivation of freshly isolated NK cells with a HTLV-I-producing T cell line did not result in NK cell infection. However, NK cells activated with an anti-CD16 mAb and co-cultivated with a HTLV-I-producing T cell line were reproducibly infected by HTLV-I. HTLV-I infection was documented in NK cell lines and clones by the detection of defective integrated provirus by both Southern blot and polymerase chain reaction analysis. Although HTLV-I-infected NK cells produced viral proteins, they did not produce infectious viral particles. HTLV-I-infected NK cells were phenotypically indistinguishable from their uninfected counterparts (CD16+, CD2+, CD56+, CD3-). They also retained the ability to mediate both natural and antibody-dependent cell cytotoxicity. The IL-2-dependent proliferation of HTLV-I-infected NK cells was significantly greater than that of uninfected NK cells. The doubling time of this infected population was reduced from 9 days to 3 days, and the overall survival of the culture in the absence of restimulation was extended from 5 wk to 18 wk. Unlike T lymphocytes, HTLV-I-infected NK cells were not immortal, implying a fundamental difference between these two lymphocyte populations.

Base Sequence↗

PubMed1992

The use of a wild-type dihydrofolate reductase-encoding cDNA as a dominant selectable marker and induction of expression by methotrexate.

The cDNA (DHFR) encoding the wild-type (wt) dihydrofolate reductase (DHFR) was used as a dominant selectable marker in the transfection of murine hybridoma Sp2/0-Ag14 cells by protoplast fusion. The initial clones contained 100-400 copies of integrated plasmid DNA, and the high level of wt DHFR protein produced enabled the cells to survive the drug selection at 100 nM methotrexate (MTX). The expression of the gene of interest was several fold higher than when the mutant DHFR with decreased MTX binding was used as the selection marker, presumably because the clones were more sensitive to the stress induced by MTX. When the clones were propagated at higher concentrations of MTX, expression of both DHFR and the gene of interest increased. This induction is freely reversible, and we have shown that it is controlled at the transcriptional level, by nuclear run-off transcription assays.

Base Sequence↗