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Papers by Bruce Ng

Journal of Applied Physiology, Apr 1, 1994

Endotracheal intubation in small laboratory animals is often necessary for survival experiments. ... more Endotracheal intubation in small laboratory animals is often necessary for survival experiments. Methods of airway control have included tracheostomy, blind intubation, and intubation under direct vision. Most of these methods are unsatisfactory and associated with high failure and complication rate. We developed an easy method of endotracheal intubation in the rat that requires simple material that is easily available to any research facility. The animals were anesthetized with pentobarbital sodium, the tongue was pulled out, and an otoscope was introduced into the oropharynx. By direct vision, a guide wire was inserted into the trachea and a 16-gauge intravenous catheter was glided over the wire. The first group of 70 rats underwent left thoracotomy with endotracheal intubation and mechanical ventilation at our laboratory as part of a study on isolated lung perfusion. The second group of five rats was anesthetized with pentobarbital, and a left carotid catheter and an endotracheal tube were inserted. Animals were ventilated with 100% O2. Arterial blood gases were sampled before intubation, 30 min after ventilation, and 60 min after extubation. In the first group, 94.3% (66 of 70) of the animals survived surgery and mortality was not directly related to the intubation and/or ventilation. All five animals of the second group survived the procedure to be extubated. Arterial PO2 before intubation, 30 min after intubation and ventilation, and 60 min after extubation was 77.1 +/- 8.5, 465.0 +/- 55.6, and 98.9 +/- 12.8 Torr, respectively. PCO2 at the same time points was 42.5 +/- 10.1, 35.1 +/- 6.3, and 32.7 +/- 6.5 Torr, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The Annals of Thoracic Surgery, Aug 1, 1993

Journal of Surgical Oncology, Nov 1, 1994

Tumors depend on their blood supply for growth. The blood supply to metastatic neoplasia of lung ... more Tumors depend on their blood supply for growth. The blood supply to metastatic neoplasia of lung is usually from the pulmonary circulation or both the pulmonary and systemic circulation. The antineoplastic effect of pulmonary artery occlusion was investigated in a rat model of methylcholanthrene‐induced metastatic pulmonary sarcoma. Left pulmonary artery ligation was performed on day 7 after tumor inoculation, and animals were sacrificed on day 14. The tumor burden of the left lung decreased 44% when compared with the control group. The survival of non‐tumor‐bearing rats undergoing left pulmonary artery ligation for 24 hours followed by right pneumonectomy after 2 weeks was also studied. No significant lung damage after a period of left pulmonary artery ligation was seen, as evidenced by both survival after contralateral right pneumonectomy and histology. Balloon occlusion of pulmonary artery, together with regional chemotherapy for patients with lung metastases, may warrant investigation. © 1994 Wiley‐Liss, Inc.

The Annals of Thoracic Surgery, Jul 1, 1997

A pulmonary tumor model is necessary to study the biology and therapy of lung cancer. Methods to ... more A pulmonary tumor model is necessary to study the biology and therapy of lung cancer. Methods to establish a solitary intrapulmonary nodule are not well defined. Two methods for solitary intrapulmonary tumor nodule development in the Fischer rat are described. Methylcholanthrene-induced sarcoma cell suspensions were introduced into lung parenchyma of Fischer rats via limited thoracotomy and lung puncture, or instilled into a distal airway after tracheal puncture and catheterization. Intrapulmonary tumor location, implantation mortality, procedure length, and animal survival were recorded. Single pulmonary nodules developed at the implanted position in 100% (n = 320) and 95% (62/65) of animals after direct injection into the pulmonary parenchyma or via tracheal puncture and instillation. Operative mortality was 2% and 5% via lung or tracheal implantation, respectively. Less than 5 minutes was required for each implantation. Mean survival time was 24 +/- 2 and 26 +/- 6 days after lung or tracheal implantation in animals allowed to survive until tumor-induced death. These easily performed, reproducible methods of establishing solitary intrapulmonary tumors are useful tools for lung cancer research.

Surgery, Mar 1, 2001

Many gene therapy strategies would benefit from efficient, regional organ delivery of therapeutic... more Many gene therapy strategies would benefit from efficient, regional organ delivery of therapeutic genes. Regional perfusions of lung, liver, or bladder were performed to determine if rapid and efficient gene transfer can be accomplished in vivo, and to determine if in vivo gene transfer can be limited to the organ of interest. In addition, herpes simplex virus tumor necrosis factor (HSVtnf), carrying the human tumor necrosis factoralpha gene was used as a treatment for methylcholanthrene sarcoma in a syngeneic lung metastases model in Fisher rats. A 20-minute perfusion using HSV carrying beta-galactosidase (HSVlac) produced significant expression of this marker gene isolated to the target organs, without organ-specific tissue injury or inflammation. Regional perfusion of organs with HSV carrying the cytokine gene tumor necrosis factor alpha also resulted in high-level local organ production of this cytokine (2851 +/- 53 pg/g tissue in perfused lung versus 0 for the contralateral lung). For the current vector construct, expression of the gene of interest peaked between 2 and 4 days and was undetectable by 2 weeks after perfusion. In animals undergoing perfusion as treatment for pulmonary sarcoma, there was no difference between tumor counts in lungs perfused with HSVlac (17 +/- 6) or HSVtnf (22 +/- 8), but either treatment resulted in lower tumor counts than controls (111 +/- 24 nodules per lung, P <.02). Regional organ perfusion using herpes viral vectors is an effective and well-tolerated in vivo method of transiently delivering potentially toxic gene products to target organs in directing gene therapy. Regional lung perfusion with HSV amplicons reduces tumor burden in a rat model of pulmonary metastases, though HSVtnf cannot be demonstrated to augment the cytopathic effect of the HSV amplicon alone in the current model.

Annals of Surgical Oncology, Jul 1, 1994

Background: The relative effects of growth hormone on tumor versus host growth and protein metabo... more Background: The relative effects of growth hormone on tumor versus host growth and protein metabolism are not known. This study examines the influence of recombinant rat growth hormone (r-rGH) on host and tumor growth, host body composition, and protein synthesis of tumor and host in tumorbearing rats. Methods: After left flank implantation of methylcholanthrene-induced sarcoma, 28 Fischer rats with palpable tumor were treated with s.c. saline or 1 mg/kg/day r-rGH for 11 days. At death, fractional protein synthetic rates (FSRs) of tumor, liver, and gastrocnemius muscle were determined. In a separate experiment, 27 tumor-bearing rats received saline or 1 mg/kg/day r-rGH for 2 weeks. Tumor and host growth and host body composition were analyzed. Results: Animals treated with r-rGH had significantly higher liver FSR than did controls (233-+ 27%/day vs. 110-+ 4%/day, respectively). No significant differences were associated with growth hormone administration with respect to tumor growth, host composition, or FSR of tumor or muscle. Conclusions: Growth hormone stimulates liver protein synthesis, without changing tumor growth, protein synthesis, or host composition in this rat sarcoma model. Further investigation of growth hormone as an anticachectic agent is warranted.

Journal of Clinical Oncology, Jun 20, 2007

8550 Background: Our preclinical data suggest that a newly identified cryptic epitope HU177 withi... more 8550 Background: Our preclinical data suggest that a newly identified cryptic epitope HU177 within collagen regulates endothelial and tumor cell adhesion in-vitro and angiogenesis and tumor growth in-vivo. We investigated whether 1) HU177 shedding can be measured in melanoma patients’ sera, and 2) if HU177 concentration correlates with clinicopathological features, recurrence and survival. Methods: Sera from 291 melanoma patients (primary Stage I, n=140; II n=41; III n=29; recurrent/metastatic n=81) and 30 normal volunteers prospectively enrolled at the NYU School of Medicine were analyzed for HU177 epitope concentration (ng/ml) by ELISA. Microtiter plates were incubated overnight with monoclonal antibody (anti-HU177 epitope). Patients’ sera and standards (denatured type-IV collagen) were added in duplicate followed by dilutions of biotinylated anti-collagen type IV polyclonal and HRP-labeled anti-biotin antibodies with multiple washes after each incubation. Absorbance was monitored at 400 nm. Results: The mean concentration of anti-HU177 epitope was 5.8 ng/ml (range 0.1 to 139.8). Normal volunteers were 1.6±0.3 (mean ± SEM). A significant correlation was observed between HU177 concentration and tumor thickness in patients who presented with primary melanoma (=1.00 mm, n=113, 3.8±0.4; 1.01–3.99 mm, n=72, 8.9 ±2.1; =4.00 mm, n=22, 10.3±2.2; P=0.003 by ANOVA test) and nodular melanoma histological subtype (nodular, n=47, 10.5±3.1; superficial spreading, n=95, 4.4±0.5; others, n=68, 6.0±2.1; P=0.02, ANOVA). Multivariate analysis confirmed the independent correlation between higher HU177 concentration and nodular subtype after controlling for tumor thickness (P=0.04). Primary patients with ulcerated melanomas and those who developed recurrences both showed higher HU177 epitope levels, however, the difference was not significant (P&amp;amp;amp;gt;0.05). Conclusions: This is the first study on HU177 epitope shedding in melanoma patients. Data demonstrate the clinical feasibility of HU177 testing in melanoma patients’ sera and suggest that HU177 epitope shedding correlates with thicker primary melanomas. Longer follow-up is required to better define the prognostic value of HU177 epitope shedding in melanoma patients. [Table: see text]

The Annals of Thoracic Surgery, Aug 1, 1996

Journal of Surgical Research, Mar 1, 1996

The role of human growth hormone (hGH) as a nutritional adjunct for cancer patients is controvers... more The role of human growth hormone (hGH) as a nutritional adjunct for cancer patients is controversial because of its potential mitogenic effects on tumor growth. No studies to date have examined the effect of hGH on human tumor response in vivo. In Vitro: Athymic mice were injected (s.c.) daily with hGH (GH, n=14) or saline (CTL, n=14). On Day 10, serum was collected and added to human pancreatic carcinoma cells in culture. In Vivo: Athymic mice were inoculated (s.c.) with human pancreatic carcinoma cells. On Day 14, mice were randomized to receive daily either hGH (GH, n=14) or saline (CTL, n=12). On Day 29, animals received [3H]phenylalanine for tissue protein fractional synthetic rate (FSR) measurement. Tumors were excised and cell cycle kinetics analyzed. Data are expressed as mean +/- SEM. Statistical analysis was performed by unpaired t test and/or ANOVA where appropriate. In Vitro: Serum from GH-treated animals had elevated IGF-1 levels (287 +/- 34 ng/ml vs 157 +/- 53 ng/ml, P<0.001) and significantly stimulated cell growth (No. cells x 10(3)/well) compared with CTL serum (925 +/- 31 vs 747 +/- 38, P<0.001). In Vivo: Serum for GH-treated animals had elevated IGF-1 levels (287 +/- 34 ng/ml vs 157 +/- 53 ng/ml, P<0.001) and significantly stimulated cell growth (No. cells x 10(3)/well) compared with CTL serum (925 +/- 31 vs 747 +/- 38, P<0.001). In Vivo: Growth hormone had no significant effect on tumor growth rate (mm3/day) (1.45 +/- 0.47 CTL vs 1.57 +/- 0.66 GH), final tumor weight (mg) (0.19 +/- 0.15 CTL vs 0.17+/- 0.06 GH), DNA Index (1.5 +/- 0.1 CTL vs 1.5 +/- 0.1 GH), percent S phase (20.3 +/- 3.3 CTL vs 22.1 +/- 3.0 GH), or tumor FSR (%/day) (51.1 +/- 17.8 CTL vs 70.2 +/- 61.1 GH). Growth hormone significantly elevated serum IGF-1 levels (ng/ml) (176 +/- 48 CTL vs 222 +/- 53 GH, P<0.005) and liver FSR (%/day) (62.8 +/- 17.8 CTL vs 79.7 +/- 12.7 GH, P<0.005). Serum of GH-treated mice increased human pancreatic cell growth in vitro. In vivo, GH administration raised serum IGF-1 levels and increased liver protein FSR, without tumor growth, cell cycle kinetics, or protein FSR.

The Journal of Thoracic and Cardiovascular Surgery, 1994

Journal of Applied Physiology, Jun 1, 1993

To evaluate isolated single lung perfusion with chemotherapy in a rat lung metastasis model, we d... more To evaluate isolated single lung perfusion with chemotherapy in a rat lung metastasis model, we developed a model of in vivo isolated single lung perfusion. Twenty male rats were anesthetized with pentobarbital sodium (50 mg/kg) and intubated endotracheally. A left thoracotomy was performed with an operating microscope (x16 magnification), the left pulmonary artery was cannulated, and a left pulmonary venotomy was performed. Isolated left lung perfusion was performed for 10 min at 0.5 ml/min with heparinized whole blood (n = 10) or 0.9% normal saline (n = 10). Pulmonary vein effluent was collected by suction. Nineteen of the 20 (95%) animals survived isolated left single lung perfusion. Twenty-one days after isolated left lung perfusion right pneumonectomy was performed. Fifteen of the 19 animals (78%) survived right pneumonectomy. Postoperatively, animals that survived surgery recovered preoperative body weight. In vivo isolated single lung perfusion in rats is feasible with low mortality and morbidity and may be useful in the study of isolated perfusion with chemotherapy and in diverse physiological and pharmacological experiments.

The Annals of Thoracic Surgery, Nov 1, 1995

Background. We compared pharmacokinetics, toxicity, and treatment efficacy of pulmonary artery pe... more Background. We compared pharmacokinetics, toxicity, and treatment efficacy of pulmonary artery perfusion of low-dose doxorubicin with blood flow occlusion to intravenous doxorubicin injection in a metastatic sarcoma model in the rat. Methods. Animals received left pulmonary artery perfusion with 0.1, 0.2, or 0.5 mg/kg doxorubicin at a rate of 0.1 mL/min for 1 minute with 20 minutes of blood flow occlusion. Doxorubicin levels of the lung, heart, and serum were assayed. Body weights after treatment were recorded and right pneumonectomy was performed. The results were compared with those in rats that received 5 mg/kg doxorubicin by intravenous injection or the saline group. Pulmonary sarcoma metastases were treated with 0.5 mg/kg doxorubicin through lung perfusion or intravenously, or with saline solution. Results. Doxorubicin levels in the lung, heart, and M anagement of pulmonary metastases remains a major clinical problem. Surgical resection has demonstrated benefit, yet 5-year survival after surgery alone ranges from 15% to 25% [1, 2]. To date, systemic chemotherapy for metastatic pulmonary sarcoma holds little promise for long-term survival. Doxorubicin is the most effective single agent in the treatment of soft-tissue sarcoma; however, its toxicity, especially cardiotoxicity, precludes effective therapy [3]. To investigate less invasive modalities for the treatment of pulmonary metastases, we developed a regional chemotherapeutic model of pulmonary artery perfusion with blood flow occlusion in the rat. The objectives of this study were as follows: (1) to measure lung, heart, and plasma concentrations of doxorubicin after doxorubicin pulmonary artery perfusion with blood flow occlusion as compared with systemic administration of doxorubicin, (2) to evaluate local lung and systemic toxicity, and (3) to evaluate the efficacy of pulmonary artery perfusion with doxorubicin for pulmonary metastatic sarcoma. Material and Methods Animal Care Experiments were carried out on Fischer 344 male rats weighing 200 to 250 g (Charles River, Kingston, NY).

Hepatology, 1996

has been shown to modulate the growth of An increasing number of hepatic resections are being exp... more has been shown to modulate the growth of An increasing number of hepatic resections are being experimental liver metastases. 7-8 performed as potentially curative surgery for malignant Interferon gamma (IFN-g) is a glycoprotein produced by T liver neoplasms. Hepatectomy and subsequent liver relymphocytes and natural killer cells, whose functions include generation produce a local environment that enhances inhibition of viral replication and upregulation of class I and growth of microscopic residual tumor. To determine if II major histocompatibility complex antigens. 9 This cytokine pretreatment with murine interferon gamma (IFN-g) also enhances the efficiency of macrophage-mediated killing can protect against such enhanced tumor growth, Bufand lymphocyte activity in vitro. IFN-g has a low toxicity falo rats were randomized to receive a 3-day treatment profile and already has been used in clinical studies. 10-15 The of IFN-g (50,000 U/qD intraperitoneally) or saline. current experiments were performed to determine if IFN-g Groups then underwent intrasplenic injection of 10 6 may be useful in preventing hepatectomy-enhanced tumor Morris hepatoma cells, followed 1 hour later by sham growth and to decipher the potential mechanisms involved. (control) or partial hepatectomy (PH) of 70%. PH significantly enhanced tumor growth within the liver (control, MATERIALS AND METHODS 8 { 3 nodules per liver; PH, 73 { 12 nodules per liver; P õ .001). This enhancement was attenuated by prior Animals. Specific pathogen-free male Buffalo rats (Harlan administration of IFN-g IFN-g/PH, 16 { 3; P õ .001 vs. Sprague Dawley, Indianapolis, IN, or the National Cancer Institute) PH). Growth factor release and liver regeneration were were housed in individual cages in a temperature-(22ЊC) and humidity-controlled room with an automatic day/night cycle of 12 hours not affected significantly by pretreatment with IFN-g. each. Animals were provided rodent chow (P.M.I. Mills, St. Louis, The effect of IFN-g on tumor growth is associated with MO) and water ad libitum. Food consumption and body weight were a significant enhancement of Kupffer cell (KC)-mediated measured daily. All animals received care in compliance with Memotumoricidal activity (percentage of specific lysis, 55 { rial Sloan-Kettering Cancer Center's Institutional Animal Care and 10% control, 78 { 11% IFN-g; P õ .01) but not lymphocyte-Use Committee guidelines. mediated tumoricidal activity. Because microscopic re-Tumors. A syngeneic tumor, Morris hepatoma McA-RH7777 sidual disease may be present after hepatectomies for (ATCC no. CRL 1601), was sequentially passaged subcutaneously cancer, IFN-g may be a useful agent in retarding growth in Buffalo rats. For splenic injections, tumor cell suspensions were of residual tumors. (HEPATOLOGY 1996;24:374-379.) prepared by excising tumor from the previous host, cutting it into 2-5 mm pieces, and incubating it in 5 to 10 mL of trypsin (0.125% trypsin/0.125% ethylenediaminetetraacetic acid in phosphate-buf-Liver tumors, both metastatic and primary, are a signififered saline without Ca / Mg) for 5 minutes at 37ЊC, 5% CO 2. Trypsin cant health problem. For the approximately 1,250,000 annual digestion was stopped with 40 mL of RPMI 1640, NEAA, 5% fetal calf cases of hepatocellular carcinoma worldwide or the 60,000 serum (media 1). Tissue was gently homogenized and the resulting suspension filtered through 50-mm nylon mesh, spun (900g, 5 min-cases of metastatic colorectal cancer in the United States, utes), and resuspended in media 1. Cells were diluted and counted, surgical excision represents effective therapy and the only and assessed for viability by Trypan blue exclusion. Media was added potential cure. 1 Surgical resection of hepatic tumors is possito bring the cells to the appropriate concentration. For tumoricidal ble because of the remarkable ability of the liver to regenerassays, hepatoma cells were also kept in culture and periodically ate, such that within days after extensive resection of up to implanted in flanks to ensure tumor-producing capacity. 80% of the liver, the organ has grown to approximately the K562. K562 is a natural killer-sensitive Ph/ erythroblastic cell same size as the original. This regeneration process is govline kept in culture in RPMI / 10% fetal calf serum / 50 mg/mL erned by a myriad of growth factors secreted by the remaining gentamicin (media 2). 16 liver after hepatectomy. Recovery after partial hepatectomy Recombinant Murine IFN-g. Recombinant murine IFN-g was supplied through the courtesy of Genentech (San Francisco, CA). The (PH) is also characterized by general and local immunosupagent was diluted with sterile water prior to injection. Animals were pression. Both of these phenomena have been suspected to injected intraperitoneally with 5 1 10 4 U/100 mL/d of IFN-g for 3 contribute to growth of residual micrometastases after hepadays prior to or after surgery. This dosage has previously been shown tectomy. It is a clinical impression supported by experimental to produce significant biological responses, including enhanced exdata that PH also enhances local tumor growth. 2-5 The same pression of tumor necrosis factor a receptors. 17 growth factors that cause liver regeneration may also en-Surgical Procedures. Splenectomy and PH of 70% were performed hance tumor growth 6 ; alternatively, inhibition of Kupffer cell under pentobarbital anesthesia (25 mg/kg of body weight intraperitoneally) via midline abdominal incision. For PH, left and median lobes of the liver were excised according to the methods of Higgins and Anderson. 18 Animals received 3 mL of normal saline (NS) intraperito-Abbreviations: PH, partial hepatectomy; KC, Kupffer cell; IFN-g, interferon gamma; neally prior to skin closure with wound clips. NS, normal saline; bFGF, basic fibroblast growth factor; TGF-b, transforming growth factor Splenocyte Isolation. Groups (n Å 8 per group) were injected intrab.

Journal of Clinical Oncology, 2007

Journal of Applied Physiology, 1993

The Annals of Thoracic Surgery, 1993

European Journal of Cancer Supplements, 2004

Journal of Applied Physiology, 1994

Molecular Therapy - Nucleic Acids

Molecular Cancer Therapeutics, Aug 1, 2002

Treatment with the proteasome inhibitor, PS-341 resulted in concentration-and time-dependent effe... more Treatment with the proteasome inhibitor, PS-341 resulted in concentration-and time-dependent effects on Bcl-2 phosphorylation and cleavage in H460 cells that coincided with the PS-341-induced G 2-M phase arrest. The observed Bcl-2 cleavage paralleled the degree of PS-341-induced apoptosis but was detected to a similar extent with comparable concentrations of two other proteasome inhibitors (MG-132 and PSI). Calpain inhibitors, ALLM and ALLN, and the caspase inhibitors, Z-VAD and AC-YVAD did not induce Bcl-2 phosphorylation and cleavage. Exposure to PS-341 resulted in an additional M r 25,000 cleavage fragment of Bcl-2, whereas only a M r 23,000 fragment was observed with other anticancer agents. The formation of the M r 25,000 fragment was not prevented by caspase inhibitors unlike the M r 23,000 fragment, which suggests mediation by a caspase-independent pathway. Cell fractionation studies revealed that the Bcl-2 cleaved fragments localize within membrane structures and was an early event (at ϳ12 h, posttreatment), and before the observed cleavage of poly(ADP-ribose) polymerase (PARP), ␤-catenin, and DNA fragmentation (at ϳ36 h posttreatment). The M r 23,000 Bcl-2 cleavage product was inhibited by the pan-caspase inhibitor and the inhibitors of capase-3,-8,-9; but the PARP cleavage was prevented only by the pan-caspase and caspase-3 inhibitors, which suggests that the M r 23,000 Bcl-2 cleavage occurred at both the initiation and execution stages of apoptosis. The inhibition of the ubiquitin/proteasome pathway by PS-341 leads, at an early stage of apoptosis, to Bcl-2 phosphorylation and a unique proteolytic cleavage product, which are associated with G 2-M phase arrest and the induction of apoptosis.