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Papers by Victor Ling

Molecular and Cellular Biology, May 1, 1986

Multidrug-resistant cells are cross-resistant to a wide range of unrelated drugs, many of which a... more Multidrug-resistant cells are cross-resistant to a wide range of unrelated drugs, many of which are used in cancer chemotherapy. We constructed a cDNA library from RNA of the multidrug-resistant Chinese hamster ovary cell line CHRC5. By differential screening we isolated cDNAs derived from mRNAs that are overexpressed in this cell line. The cDNAs could be grouped in five dasses on the basis of transcript lengths detected in RNA blots. We infer that each dass codes for a separate protein. The corresponding genes are amplified 10 or 30 times in CHRCS DNA, providing an explanation for the constitutive overexpression found in this cell line. Despite differential amplification, the genes may be linked in one large amplicon as indicated by the hybridization analysis of large fragments of CHRC5 DNA separated by pulsed field gradient gel electrophoresis. Therefore, some of these genes might be fortuitously coamplified and not contribute functionally to the resistant phenotype. It is also possible, however, that genes involved in drug resistance are clustered. One of our clones cross-hybridized with the recently described cDNA pCHP1 (J.

Journal of Clinical and Translational Hepatology

Background and Aims: We asked if comprehensive bile acid profiling could provide insights into th... more Background and Aims: We asked if comprehensive bile acid profiling could provide insights into the physiopathology of ABCB4-mutated patients and evaluated the prognostic value of taurine-conjugated tetrahydroxylated bile acid (tauro-THBA) in cholestasis. Methods: Serum bile acid profiles were evaluated in 13 ABCB4-mutated patients with 65 healthy controls by ultra-high-performance liquid chromatography/multiple-reaction monitoring-mass spectrometry (UPLC/MRM-MS). The concentration of tauro-THBA was compared between ABCB4-mutated patients with different prognoses. The areas under the curve (AUCs) of tauro-THBA were compared between ABCB11-mutated patients with native liver survival and those who died or underwent liver transplantation before 3 years of age by receiver operating characteristic curve (ROC), with another patient cohort for further verification. Results: The overall hydrophobicity indices of bile acids in ABCB4-mutated patients (12.99±3.25 m) were significantly lower than those of healthy controls (14.02±1.74 m, p<0.000). That was due to markedly increased bile acid modifications including conjugation, sulfation, and ketonization. Differences in the tauro-THBA concentration in ABCB4-mutated patients with different prognoses

The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting i... more The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting its prognosis are poorly understood. We asked whether or not the composition of bile acids in ALGS patients with good clinical outcomes differs from those with poor outcomes, and whether bile acids could be used as prognostic biomarkers. Blood for bile acid profiling were collected from genetically confirmed JAG1-associated ALGS patients before one year of age. Good prognosis was defined as survival with native liver and total bilirubin (TB) < 85.5 µmol/L, while poor prognosis as either liver transplanted, died of liver failure, or TB ≥ 85.5 µmol/L at last follow-up. We found that the concentrations of two poly-hydroxylated bile acids, tauro-2β,3α,7α,12α-tetrahydroxylated bile acid (THBA), and glyco-hyocholic acid (GHCA), were significantly increased in patients with good prognosis compared to those with poor prognosis (AUC = 0.836 and 0.782, respectively) in the discovery cohort. The ...

Journal of Biological Chemistry, 1990

Journal of Lipid Research, 2018

nutrients, and as signaling molecules to maintain lipid homeostasis (1, 2). Bile acids, especiall... more nutrients, and as signaling molecules to maintain lipid homeostasis (1, 2). Bile acids, especially the more hydrophobic ones, are lipolytic and are cytotoxic when in high concentrations. Thus, bile acids constitute a constant potential source of inflammatory stress in the liver, particularly in cholestatic conditions (1, 3, 4). Progressive familial intrahepatic cholestasis (PFIC) is a group of heterogeneous genetic defects leading to imbalances in bile formation (5, 6). Three types of PFIC have been described: PFIC1, caused by mutations in the ATP8B1 gene; PFIC2, caused by mutations in the ABCB11 [bile salt export pump (BSEP)] gene; and PFIC3, caused by mutations in the ABCB4 [multidrug resistance protein 3 (MDR3)] gene. Animal models, in which orthologs of these genes have been inactivated, have been generated. In the current study, we focus on the mouse models for PFIC2 and PFIC3. The ABCB11 gene, associated with PFIC2, encodes the major energy-dependent BSEP translocating bile salts across the canalicular membranes in the liver (7-9). This is the rate-limiting step in the enterohepatic circulation of bile salts and a major driving force for bile flow. Severe BSEP deficiency in humans causes a fatal childhood disease, PFIC2, with low or normal serum -glutamyl transferase (-GT), secretion of bile salts into the bile reduced to less than 1% of normal (10), hepatic inflammation, dilated canalicular lumens lacking microvilli (6, 11), and an increased propensity for developing hepatocellular carcinoma (HCC) (12) and cholangiocarcinoma (13). Unlike Abstract Bile acid imbalance causes progressive familial intrahepatic cholestasis type 2 (PFIC2) or type 3 (PFIC3), severe liver diseases associated with genetic defects in the biliary bile acid transporter bile salt export pump (BSEP; ABCB11) or phosphatidylcholine transporter multidrug resistance protein 3 (MDR3; ABCB4), respectively. Mdr2 / mice (a PFIC3 model) develop progressive cholangitis, ductular proliferation, periportal fibrosis, and hepatocellular carcinoma (HCC) because the nonmicelle-bound bile acids in the bile of these mice are toxic. We asked whether the highly hydrophilic bile acids generated by Bsep / mice could protect Mdr2 / mice from progressive liver damage. We generated double-KO (DKO: Bsep / and Mdr2 /) mice. Their bile acid composition resembles that of Bsep / mice, with increased hydrophilic muricholic acids, tetrahydroxylated bile acids (THBAs), and reduced hydrophobic cholic acid. These mice lack the liver pathology of their Mdr2 / littermates. The livers of DKO mice have gene expression profiles very similar to Bsep / mice, with 4,410 of 6,134 gene expression changes associated with the Mdr2 / mutation being suppressed. Feeding with THBAs partially alleviates liver damage in the Mdr2 / mice. Hydrophilic changes to biliary bile acid composition, including introduction of THBA, can prevent the progressive liver pathology associated with the Mdr2 / (PFIC3) mutation.

Molecular and Cellular Biology, 1982

Colchicine-resistant Chinese hamster ovary (CHO) cell mutants whose resistance results from reduc... more Colchicine-resistant Chinese hamster ovary (CHO) cell mutants whose resistance results from reduced drug permeability have been isolated previously in our laboratories. This reduced permeability affects a wide range of unrelated drugs, resulting in the mutants displaying a multiple drug resistance phenotype. A 170,000-dalton cell surface glycoprotein (P-glycoprotein) was identified, and its expression appears to correlate with the degree of resistance. In this study we were able to confer the multiple drug resistance phenotype on sensitive mouse L cells by DNA-mediated gene transfer of DNA obtained from the colchicine-resistant mutants. P-glycoprotein was detected in plasma membranes of these DNA transformants by staining with an antiserum raised against membranes of mutant CHO cells. These results are consistent with a causal relationship between P-glycoprotein expression and the multiple drug resistance phenotype.

Current Oncology, 2010

Pancreatic cancer is an aggressive, drug-resistant disease; its first-line chemotherapeutic, gemc... more Pancreatic cancer is an aggressive, drug-resistant disease; its first-line chemotherapeutic, gemcitabine, is only marginally effective. Intracellular depletion of glutathione, a major free-radical scavenger, has been associated with growth arrest and reduced drug resistance (chemosensitization) of cancer cells. In search of a new therapeutic approach for pancreatic cancer, we sought to determine whether specific inhibition of the plasma membrane xc− cystine transporter could lead to reduced uptake of cysteine, a key precursor of glutathione, and subsequent glutathione depletion. Sulfasalazine (approximately 0.2 mmol/L), an anti-inflammatory drug with potent xc−-inhibitory properties, markedly reduced L-[14C]-cystine uptake, glutathione levels, and growth and viability of human MIA PaCa-2 and PANC-1 pancreatic cancer cells in vitro. These effects were shown to result primarily from inhibition of cystine uptake mediated by the xc− cystine transporter and not from inhibition of nuclear...

Clinical cancer research : an official journal of the American Association for Cancer Research, 1997

About half of nonlocalized neuroblastomas have MYCN gene amplification and usually progress rapid... more About half of nonlocalized neuroblastomas have MYCN gene amplification and usually progress rapidly, but the half without such amplification also do poorly, albeit progressing more slowly. We hypothesize that overexpression of MYCN protein can occur without gene amplification and that this expression reliably predicts the prognosis of neuroblastoma. To determine whether MYCN expression correlated with outcome, we assayed MYCN protein immunohistochemically in 180 archival pretreatment and posttreatment samples and stratified the 57 conventionally treated stage IVS, III, and IV patients by these conventional prognostic factors: stage, age, serum ferritin, Shimada histology, urinary catecholamine ratio, and MYCN gene status. At a median follow-up of >/=6.8 years, we found in patients with known MYCN gene status that the 23 of 37 without gene amplification fared no better than the 14 of 37 with gene amplification (P = 0.35 and 0.21, comparing relapse-free and survival rates). Convers...

Cancer research, 1981

Heterogeneity in metastatic ability has been demonstrated in model systems for in vitro-cloned ce... more Heterogeneity in metastatic ability has been demonstrated in model systems for in vitro-cloned cell lines for a number of different tumors. We have examined the clonal diversity of mouse KHT sarcoma cells cloned either in vitro or in vivo by determining their ability to form lung colonies following i.v. injection into syngeneic mice. A wide range of metastatic ability was found in both the in vitro- and in vivo-isolated clones, suggesting that the diversity observed is not due to any selection occurring during in vitro growth. The stability of four in vitro-isolated clones, two of high metastatic and two of low metastatic ability, was then studied over a period of 3 to 4 months of growth in vitro. The phenotype of the highly metastatic cells remained relatively stable, declining only slightly over time. The clones with low metastatic ability, however, demonstrated a significant increase in ability to form lung colonies over the first 30 days in culture before becoming stable at leve...

Nature Genetics, 2004

We constructed a tiling resolution array consisting of 32,433 overlapping BAC clones covering the... more We constructed a tiling resolution array consisting of 32,433 overlapping BAC clones covering the entire human genome. This increases our ability to identify genetic alterations and their boundaries throughout the genome in a single comparative genomic hybridization (CGH) experiment. At this tiling resolution, we identified minute DNA alterations not previously reported. These alterations include microamplifications and deletions containing oncogenes, tumor-suppressor genes and new genes that may be associated with multiple tumor types. Our findings show the need to move beyond conventional marker-based genome comparison approaches, that rely on inference of continuity between interval markers. Our submegabase resolution tiling set for array CGH (SMRT array) allows comprehensive assessment of genomic integrity and thereby the identification of new genes associated with disease.

JNCI Journal of the National Cancer Institute, 1994

FEBS Letters, 1995

NMR spectroscopy was used to study the structure of the C‐terminal signal sequences of the bacter... more NMR spectroscopy was used to study the structure of the C‐terminal signal sequences of the bacterial toxins, hemolysin A(HlyA) and leukotoxin A (LktA). The two signals share little sequence homology; however, both can direct toxin transport with equal efficiency. We report here that in a membrane mimetic environment both peptides form two short non‐interacting α‐helices separated by a short loop. This higher order structure may be a common feature of C‐terminal signals and may be required for interaction with the membrane associated transporter complex.

Advances in Pharmacology, 1990

Note: This is a one-page preview only. You will need to have a browser plugin installed capable o... more Note: This is a one-page preview only. You will need to have a browser plugin installed capable of showing PDF content in the order to view the PDF excerpt online. Click here to download excerpt. ... Enable JavaScript for PDF Excerpt to view it inline.

Molecular and Cellular Biology, 1987

The overexpression of a plasma membrane glycoprotein, P-glycoprotein, is strongly correlated with... more The overexpression of a plasma membrane glycoprotein, P-glycoprotein, is strongly correlated with the expression of multidrug resistance. This phenotype (frequently observed in cell lines selected for resistance to a single drug) is characterized by cross resistance to many drugs, some of which are used in cancer chemotherapy. In the present study we showed that DNA-mediated transformants of mouse LTA cells with DNA from multidrug-resistant hamster cells acquired the multidrug resistance phenotype, that the transformants contained hamster P-glycoprotein DNA sequences, that these sequences were amplified whereas the recipient mouse P-glycoprotein sequences remained at wild-type levels, and that the overexpressed P-glycoprotein in these cells was of hamster origin. Furthermore, we showed that the hamster P-glycoprotein sequences were transfected independently of a group of genes that were originally coamplified and linked within a 1-megabase-pair region in the donor hamster genome. Th...

Anticancer research

Drug resistance eventually limits the effectiveness of antiestrogens in breast cancer treatment. ... more Drug resistance eventually limits the effectiveness of antiestrogens in breast cancer treatment. Pharmacological reversal of this refractoriness has been attempted with R-Verapamil, a well tolerated calcium channel blocker. This drug significantly decreased the incidence of lung foci after intravenous seeding of the R3230AC rat adenocarcinoma; this effect was correlated with reduction in the expression of P-glycoprotein. The simultaneous administration of antiestrogens with a non-toxic enantiomer of Verapamil was beneficial in the tumour model investigated.

Journal of Biological Chemistry, 1992

Drug Metabolism and Pharmacokinetics, 2000

Journal of Biological Chemistry, 1969

Journal of Biological Chemistry, 1972

... 1). Falvey and Staehelin (15) described a similar procedure for the translation of poly(U) in... more ... 1). Falvey and Staehelin (15) described a similar procedure for the translation of poly(U) in mouse and rat liver cell-free systems. Preliminary incubation does not markedly affect the synt'hetic capacity of the system provided energy regeneration is maintained. ...

Annals of Translational Medicine, 2020

Background: We ask if plasma bile acid profiles can be used to monitor the effectiveness of parti... more Background: We ask if plasma bile acid profiles can be used to monitor the effectiveness of partial internal biliary diversion (PIBD) for treating uncontrolled cholestasis in progressive familial intrahepatic cholestasis type 2 (PFIC2) patients. Methods: Plasma bile acids were profiled in 3 cases of ATP-binding cassette, sub-family B member 11 (ABCB11)-mutated PFIC2 children before and after PIBD compared to healthy controls and 8 PFIC2 patients. The quantitation of bile acids was performed by reversed-phase ultrahigh-performance liquid chromatography/multiple-reaction monitoring-mass spectrometry (UPLC/MRM-MS) with negative ion detection. Results: Before PIBD, all three patients presented with >50-fold higher levels of total plasma bile acids, 2-7 folds higher ratios of taurine: glycine conjugated primary bile acids, and unchanged secondary bile acids levels compared to healthy controls. After PIBD, only one of the three patients (P3) showed relief of cholestasis. The bile acid profiles of the two nonresponding patients showed little change while that of the responding patient showed a 5-fold reduction in total plasma primary bile acids, a reduced taurine: glycine conjugate ratio, and an unexpected 26-and 12-fold increase in secondary bile acids DCA and LCA respectively. One year later, the responder suffered a recurrence of cholestasis, and the bile acid profile shifted back to a more pre-PIBD-like profile. Conclusions: Plasma bile acid profiles may potentially be useful as sensitive biomarkers for monitoring the clinical course of PIBD patients. Relief of cholestasis after PIBD appears to be associated with significantly increased circulating toxic secondary bile acids and this may limit the utility of PIBD in PFIC2 patients in the long run.