PubMed Health⌕ Search

Biomedical subjects

H S Chan

Publications and source records attributed to H S Chan.

At least 19 recordsLinked to original sources
PubMed1995

Principles of protein folding--a perspective from simple exact models.

General principles of protein structure, stability, and folding kinetics have recently been explored in computer simulations of simple exact lattice models. These models represent protein chains at a rudimentary level, but they involve few parameters, approximations, or implicit biases, and they allow complete explorations of conformational and sequence spaces. Such simulations have resulted in testable predictions that are sometimes unanticipated: The folding code is mainly binary and delocalized throughout the amino acid sequence. The secondary and tertiary structures of a protein are specified mainly by the sequence of polar and nonpolar monomers. More specific interactions may refine the structure, rather than dominate the folding code. Simple exact models can account for the properties that characterize protein folding: two-state cooperativity, secondary and tertiary structures, and multistage folding kinetics--fast hydrophobic collapse followed by slower annealing. These studies suggest the possibility of creating "foldable" chain molecules other than proteins. The encoding of a unique compact chain conformation may not require amino acids; it may require only the ability to synthesize specific monomer sequences in which at least one monomer type is solvent-averse.

Amino Acid Sequence↗
PubMed1995

Primary spontaneous pneumothorax treated by video assisted thoracoscopic surgery--results of intermediate follow up.

BACKGROUND: Primary spontaneous pneumothorax (PSP) is a common clinical condition associated with high recurrence if no definitive treatment is given and could be life threatening if left untreated. The best treatment for this condition, however, remains controversial. AIMS: A prospective study of patients with PSP treated by video assisted thoracoscopic surgery (VATS) after a mean follow up of 16 months. METHODS: Between September 1992 and April 1994, 114 VATS procedures were performed on 110 patients with PSP (including four patients with bilateral presentation) by one surgical team from a single institution. Mechanical pleurodesis with Marlex mesh was performed on all patients. In addition, apical bullae were identified in 100 cases (88%) and these were resected. RESULTS: There was no mortality. The median hospital stay was three days. The procedure was well accepted by patients and this was reflected subjectively in a visual analogue scale and objectively in the requirement of postoperative analgesia. Complications included one wound infection, one bleeding, eight persistent air leaks over ten days. We had two failures with recurrence of pneumothorax occurring one week and two months postoperatively (mean follow up of 16 months). Late morbidity with intercostal neuropathy was identified in nine patients but only two of them required oral analgesics. CONCLUSION: VATS is a quick and effective treatment for PSP. We currently recommend VATS for patients with recurrent spontaneous pneumothorax, as well as first time pneumothoraces associated with tension, bilaterality, frequent travelling, unreliable follow up and persistent air leak over three days.

Adolescent↗
PubMed1995

Anaphylactoid reactions in children receiving high-dose intravenous cyclosporine for reversal of tumor resistance: the causative role of improper dissolution of Cremophor EL.

PURPOSE: An unusually high incidence of anaphylactoid reactions was observed during a phase I/II trial of high-dose intravenous cyclosporine (CsA) therapy to attenuate tumor multidrug resistance (MDR). Five of 21 children experienced severe anaphylactoid reactions shortly after initiation of the first or second CsA infusion. We hypothesized that improper dissolution of the vehicle Cremophor EL may have been a cause for these anaphylactoid reactions. METHODS: All nurses who had administered intravenous CsA were interviewed regarding their technique of preparing the infusion and the occurrence of an anaphylactoid reaction. The responses were statistically analyzed. The effect of various mixing techniques on the distribution of Cremophor EL in the infusion was experimentally evaluated. Different mixing techniques were used to assess their effect on the distribution of Cremophor EL in the solution. RESULTS: Analysis of the preparation techniques of the CsA infusion showed significant correlation between suboptimal mixing of CsA by nurses and the occurrence of anaphylactoid reactions (P = .02). Experimental simulation showed that suboptimal mixing results in an uneven distribution of Cremophor EL, which subsequently sinks to the bottom of the vial. CONCLUSION: Improper mixing of high-dose CsA infusions causes nonsolubilized Cremophor EL to sink to the outflow area of the bottle. An initial bolus infusion of highly concentrated Cremophor EL may produce an anaphylactoid-like response. This mechanism of toxicity is important to recognize, because it is easily preventable by proper preparation of the infusion, thus reducing the incidence of potentially life-threatening anaphylactoid reactions.

Adolescent↗
PubMed1995

Multidrug drug resistance in pediatric sarcomas.

PURPOSE: Although P-glycoprotein overexpression is an important cause of multidrug resistance in vitro, whether this resistance mechanism is equally applicable to the clinic has still to be fully established. This review has examined the immunohistochemical and molecular biologic tools used to evaluate soft tissue sarcomas of children and adults, in order to determine whether P-glycoprotein can limit the efficacy of chemotherapy. DESIGN: Because soft tissue sarcomas are successfully treated by cytotoxic substrates of P-glycoprotein in many, but not all children, these tumors may be useful models for determining whether this drug efflux transporter is a clinically relevant cause of chemoresistance. RESULTS: Certain studies of acute myelogenous leukemia, lymphoma, and myeloma in adults and rhabdomyosarcoma, neuroblastoma, and acute lymphoblastic leukemia in children have provided the best current evidence for a strong corelation between the expression of P-glycoprotein and outcome of chemotherapy. Based on these observations, several clinical trials have been initiated to determine whether pharmacologic chemosensitization improves chemotherapy responses and cure rates in P-glycoprotein-expressing malignancies. Thus, early identification of lower levels of P-glycoprotein in tumors that still might respond to chemosensitizer-modulated chemotherapy may be highly pertinent to conducting more informative multidrug resistance reversal trials. CONCLUSION: The question of whether the multidrug resistance P-glycoprotein is a clinically relevant cause of chemoresistance may ultimately be answered by the successful prevention of chemotherapy failure by chemosensitizers that specifically reverse this drug efflux mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Multidrug resistance in pediatric malignancies.

PURPOSE: Increased expression of P-glycoprotein is an important cause of multidrug resistance in tumor cell lines in vitro. Whether this mechanism is equally relevant as a cause of clinical chemoresistance has not been established and is currently being investigated. This review has examined the immunohistochemical and molecular biologic tools suitable for assessing P-glycoprotein expression in patient samples and methodologic issues important for evaluating the results of clinical studies. Current evidence that supports a role for P-glycoprotein in limiting the efficacy of cancer chemotherapy has been reviewed. DESIGN: Malignancies that have been successfully treated by chemotherapeutic substrates of P-glycoprotein, in which a proportion of patients still fail therapy, may be the most useful models for determining whether this drug efflux transporter is a clinically relevant cause of chemoresistance. RESULTS: Studies of acute myelogenous leukemia, lymphoma, and myeloma in adults have so far provided the best evidence for a relevant role for P-glycoprotein as a cause of clinical multidrug resistance. A similar strong association has been observed between the expression of P-glycoprotein and outcome of treatment in certain malignancies in children, such as neuroblastoma, rhabdomyosarcoma, and acute lymphoblastic leukemia. Some apparent controversies related to this issue of clinical relevance may be explained by the differences in P-glycoprotein detection techniques, methodology, and experimental designs used in different studies. Because several clinical trials have already been initiated to determine whether pharmacologic chemosensitization improves the outcome of chemotherapy in certain malignancies, the successful verification of multidrug resistance limiting the cure rates of these tumors becomes a more critical issue, and identification of those patients with lower levels of P-glycoprotein expression early in the course of their disease, when they are most likely to benefit from multidrug resistance reversal, has assumed an even greater relevance. CONCLUSION: The clinical relevance of the multidrug resistance P-glycoprotein may ultimately be confirmed by the successful prevention of chemotherapy failure by chemosensitizers that specifically reverse this drug efflux mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Recurrent acute pancreatitis induced by isoniazid.

A 31-year-old man on haemodialysis who developed recurrent attacks of acute pancreatitis during the treatment of pulmonary tuberculosis is presented. The pancreatitis rapidly subsided once isoniazid was withdrawn, but the problem recurred again upon reintroduction of the drug. There was no further recurrence during successful treatment with full doses of rifampicin and pyrazinamide for 1 year.

Acute Disease↗
PubMed1994

Circulating adhesion molecules in asthma.

There is increasing evidence that leukocyte-endothelial adhesion molecules are important in inflammatory airway disease because of their involvement in the primary steps of entrapment and migration of leukocytes to the site of inflammation. Recently, circulating forms of these adhesion molecules have been described, although their origin, fate, and function are still unknown. We have used an antigen capture ELISA to measure the concentrations of circulating intercellular adhesion molecule-1 (cICAM-1), E-selectin (cE-selectin), and vascular cell adhesion molecule-1 (cVCAM-1) in the peripheral blood of 13 atopic and 16 non-atopic normal subjects, 29 patients with stable asthma, and inpatients with acute asthma on Day 1 (n = 38), Day 3 (n = 29), and Day 28 (n = 13) of an asthmatic episode. Circulating ICAM-1 and E-selectin levels were significantly raised in acute asthma on all three study days when compared with those observed in stable asthma, atopic normal, or nonatopic normal volunteers with no significant differences among the latter three groups. Circulating VCAM-1 was not significantly increased in any of the groups studied. There were no correlations among the concentrations of these three circulating adhesion molecules. The elevated concentrations of cICAM-1 and cE-selectin in acute asthma may reflect the extensive inflammatory response occurring in the airways during acute exacerbations of the disease with airway obstruction. It is possible that the cytokine and mediator profiles in acute asthma lead to the preferential synthesis and expression of these two circulating adhesion molecules in comparison with cVCAM-1.

Acute Disease↗
PubMed1993

Cooperativity in protein-folding kinetics.

How does a protein find its native state without a globally exhaustive search? We propose the "HZ" (hydrophobic zipper) hypothesis: hydrophobic contacts act as constraints that bring other contacts into spatial proximity, which then further constrain and zip up the next contacts, etc. In contrast to helix-coil cooperativity, HZ-heteropolymer collapse cooperativity is driven by nonlocal interactions, causes sheet and irregular conformations in addition to helices, leads to secondary structures concurrently with early hydrophobic core formation, is much more sequence dependent than helix-coil processes, and involves compact intermediate states that have much secondary--but little tertiary--structure. Hydrophobic contacts in the 1992 Protein Data Bank have the type of "topological localness" predicted by the hypothesis. The HZ paths for amino acid sequences that mimic crambin and bovine pancreatic trypsin inhibitor are quickly found by computer; the best configurations thus reached have single hydrophobic cores that are within about 3 kcal/mol of the global minimum. This hypothesis shows how proteins could find globally optimal states without exhaustive search.

Amino Acid Sequence↗
PubMed1992

Modeling the effects of mutations on the denatured states of proteins.

We develop a model for the reversible denaturation of proteins and for the effects of single-site mutations on the denatured states. The model is based on short chains of sequences of H (hydrophobic) and P (other) monomers configured as self-avoiding walks on the two-dimensional square lattice. The N (native) state is defined as the unique conformation of lowest contact energy, whereas the D (denatured) state is defined as the collection of all other conformations. With this model we are able to determine the exact partition function, and thus the exact native-denatured equilibrium for various solvent conditions, using the computer to exhaustively enumerate every possible configuration. Previous studies confirm that this model shows many aspects of protein-like behavior. The present study attempts to model how the denatured state (1) depends on the amino acid sequence, and (2) is changed by single-site mutations. The model accounts for two puzzling experimental results: (1) the replacement of a polar residue by a hydrophobic amino acid on the surface of a protein can destabilize a native protein, and (2) the "denaturant slope," m = partial delta G/partial c (where c is the concentration of denaturant--urea, guanidine hydrochloride), can sometimes change by as much as 30% due to a single mutation. The principal conclusion of the present study is that, under strong folding conditions, the denatured conformations that are in equilibrium with the native state are not open random configurations. Instead, they are an ensemble of highly compact conformations with a distribution that depends on the residue sequence and that can be substantially altered by single mutations. Most importantly, we conclude that mutations can exert their dominant effects on protein stability by changing the entropy of folding.

Amino Acid Sequence↗
PubMed1992

Chemotherapy and surgical resection combined with immediate reconstruction in a 1-year-old child with rhabdomyosarcoma of the maxilla.

Parameningeal head and neck rhabdomyosarcomas of childhood are often considered unresectable and are treated with irradiation and chemotherapy. High-dose radiation therapy has a very long-term detrimental effect on the developing face and also results in many other significant long-range complications. With the availability of advanced craniofacial surgical and free-tissue-transfer techniques, one-stage resection and immediate reconstruction, along with the use of effective preoperative and postresection chemotherapy instead of local radiation, may be the logical approach to the treatment of selected patients with chemosensitive parameningeal head and neck rhabdomyosarcomas.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Teflon injection for unilateral vocal cord paralysis and its effect on lung function.

We present a prospective analysis of the lung function of 22 patients with unilateral vocal cord paralysis before and after Teflon injection. In the majority of patients the vocal cord paralysis was caused by an underlying malignant condition. Full spirometric and flow-volume loop studies demonstrated an increase in airway resistance after Teflon injection which was not clinically evident. The improvement in symptom score for aspiration was greater than that for dysphonia.

Adult↗
PubMed1992

Therapeutic problems in the management of elderly patients with tuberculosis.

Adverse reactions to antituberculous drugs are more common in the elderly. With the increasing numbers of elderly people and the higher incidence of tuberculosis in this age group, clinicians will encounter more therapeutic problems in the use of antituberculous drugs than in younger patients. Existing studies regarding pharmacological and non-pharmacological factors which may predispose to increased adverse effects in the elderly are reviewed. Reduced clearances of isoniazid and rifampicin at steady state, possible increase in free drug concentration of drugs normally bound to albumin, possible differences in disposition of toxic metabolites such as hydrazine, concomitant administration of both isoniazid and rifampicin, poor nutrition and severity of the disease in the elderly may be contributing factors. Further studies in these areas should provide clearer guidelines on whether dosages or drug combinations should be modified in elderly patients with tuberculosis.

Aged↗
PubMed1991

P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma.

BACKGROUND AND METHODS: Multidrug resistance in chemotherapy for cancer is characterized by increased genetic expression of P-glycoprotein, which acts as an ATP-dependent drug-efflux pump. To determine whether P-glycoprotein levels are of prognostic value in such cases, we measured these levels immunohistochemically in a retrospective study of sequential tumor samples from 67 children with neuroblastoma. RESULTS: P-glycoprotein was not detected in pretreatment samples from either of the 2 patients with Stage I disease, any of the 21 with Stage II disease, or any of the 8 with Stage IVS disease, but it was detected in the samples from 1 of the 17 patients with Stage III disease (6 percent) and 12 of the 19 with Stage IV disease (63 percent). Of the 44 patients with nonlocalized neuroblastoma (Stage III, IVS, or IV), 26 of the 31 who were negative for P-glycoprotein had a complete response to primary treatment, as compared with 6 of the 13 who were positive for P-glycoprotein (84 percent vs. 46 percent, P = 0.0232 by Fisher's exact test). Log-rank analysis of outcome, with simultaneous stratification according to tumor stage and age, showed that the group that was negative for P-glycoprotein had significantly longer relapse-free survival (P = 0.0011) and overall survival (P = 0.0373) than the group that was positive. CONCLUSIONS: Expression of P-glycoprotein before treatment may predict the success or failure of therapy for nonlocalized neuroblastoma. Neuroblastoma may be a promising tumor to treat with anticancer drug therapy combined with a chemosensitizing agent capable of reversing P-glycoprotein-mediated multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Neuroblastoma stage IV-S: a heterogeneous disease.

Eighteen patients were diagnosed and treated for Stage IV-S neuroblastoma at The Hospital for Sick Children, Toronto between January 1971 and December 1988. All patients were 6 months of age or younger at diagnosis. Nine patients (50%) have remained disease free with a mean follow-up of 9.3 years. Of the seven patients under 6 weeks of age at presentation, four presented in the early neonatal period and died, three due to mechanical complications related to progressive disease, and one due to late recurrence. The remaining three patients under 6 weeks of age, two of whom had skin involvement at diagnosis, are alive and disease free. Six of the 11 patients over 6 weeks of age at presentation survived, combined modality therapy (CMT) being more effective than single modality treatment. N-myc was studied from tumor tissue at diagnosis in four patients and was amplified in three (25x, 25x, 100x), all of whom had late disease progression and died. The patient with a single gene copy has no evidence of disease 24 months following diagnosis. Our study confirms the heterogeneity described in this clinically defined group of patients. Because of it, management of Stage IV-S neuroblastoma cannot be uniform and until further development of a subclassification, or a reclassification based on molecular biologic markers is developed, pediatric oncologists will regularly be confronted with a decision whether or not to treat a newly presenting patient that fits into the clinical classification IV-S.

Adrenal Gland Neoplasms↗
PubMed1991

The genetics of retinoblastoma. Relevance to the patient.

The understanding of the molecular biology of human cancer has advanced rapidly in the last decade, in part due to discoveries in the rare, pediatric ocular tumor, retinoblastoma. RB studies have led to recognition of a class of human genes, the tumor suppressor genes, that are critical in the initiation and progression of the malignant process. Mutations in the RB1 gene initiate RB and other specific tumors. They may also contribute to progressive stages of many other malignancies. The protein product of RB1 (p110RB1) is a basic regulator of the cell cycle. In the absence of normal protein, the cell proceeds to the next cell division without the potential to become quiescent. Understanding the genetics of RB has benefited the patients, as the precise identification of the RB1 mutations in families has led to accurate prediction of individuals at risk for RB tumors. It seems unlikely, in the foreseeable future, that direct genetic manipulation of mutant RB1 genes will play a role in therapy, but complete understanding of the function of p110RB1 may eventually allow exploitation of its powerful antiproliferative effect. Other molecular genetic events in addition to RB1 mutations are documented in RB tumors, and may play a critical role in the full malignant phenotype. The oncogene, N-myc, is amplified in some RB tumors and is expressed in normal fetal retina. The cytogenetic abnormality, i(6p), is almost unique to RB tumors. The molecular and tissue-specific roles of these abnormalities are not yet known. Many RB tumors also acquire excessive expression of the cell surface membrane glycoprotein, p170, linked to multidrug resistance, whether or not the RB tumor has been exposed to chemotherapy. We anticipate that ways to avoid or counteract the drug resistance of excessive p170 expression will be developed for other pediatric tumors and eventually will be applied to chemotherapy for RB patients.

Child↗
PubMed1991

Multidrug-resistant phenotype in retinoblastoma correlates with P-glycoprotein expression.

Chemotherapy plays an important role in therapy for patients with extraocular and metastatic retinoblastoma. The authors used chemotherapy for management of selected patients with uncontrolled intraocular tumors or tumors larger and more posteriorly located than those conventionally treated with local cryotherapy or photocoagulation. Rapid regrowth of some tumors after an initial excellent chemotherapy response led us to investigate the hypothesis that failure of treatment is caused by P-glycoprotein-related multidrug resistance. By using a sensitive immunoperoxidase method, increased P-glycoprotein was detected in five multidrug-resistant and two selectively plant alkaloid-resistant retinoblastoma cell lines and in the intraocular and metastatic tumors from which they were derived. In four chemotherapy-treated cases, increased P-glycoprotein in the tumor samples correlated with clinically relevant drug resistance. None of the four chemosensitive tumor cell lines had increased P-glycoprotein expression. Continuous surveillance of P-glycoprotein levels in metastatic retinoblastoma may be a useful guide to drug therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗