Configuration-dependent heat capacity of pairwise hydrophobic interactions.
Explore the source record for details and available documents.
Letter↗
Biomedical subjects
H S Chan
Publications and source records attributed to H S Chan.
Eccrine porocarcinoma in a child that evolved rapidly from an eccrine poroma.
Explore the source record for details and available documents.
Acrospiroma↗
Prevalence of Helicobacter pylori in gastric cancer in a South-East Asian population by 14C-urea breath test.
BACKGROUND: Helicobacter pylori is believed to play an important role in the aetiology of gastric cancer. There is a great variability in seropositivity and histological frequency of H. pylori in gastric cancer. The present prospective study investigates the prevalence of H. pylori infection in gastric cancer patients using 14C-urea breath testing. METHODS: Patients with endoscopic biopsy-proven gastric cancer were fasted for 6 h prior to ingesting 18.5 x 104 Bq of 14C-urea cocktail orally. Breath samples were collected after 20 min by asking them to blow into a hyamine solution and measurements were read in a scintillation counter. RESULTS: Fifty out of 51 patients (98%) with gastric cancer were positive on the 14C-urea breath test compared to 29 patients (61%) who were positive on histology. There was no association between sex, age or tumour site, stage, differentiation, Lauren type and H. pylori status. The test was negative in one patient with cardial tumour in which histology of the resected specimen was also negative for the bacteria. CONCLUSIONS: Active H. pylori infection is highly prevalent in gastric cancer in a South-East Asian population. The 14C-urea breath test is a highly sensitive method for detecting the presence of H. pylori even in gastric adenocarcinoma irrespective of the stage.
Adenocarcinoma↗
Conformational propagation with prion-like characteristics in a simple model of protein folding.
Protein refolding/misfolding to an alternative form plays an aetiologic role in many diseases in humans, including Alzheimer's disease, the systemic amyloidoses, and the prion diseases. Here we have discovered that such refolding can occur readily for a simple lattice model of proteins in a propagatable manner without designing for any particular alternative native state. The model uses a simple contact energy function for interactions between residues and does not consider the peculiarities of polypeptide geometry. In this model, under conditions where the normal (N) native state is marginally stable or unstable, two chains refold from the N native state to an alternative multimeric energetic minimum comprising a single refolded conformation that can then propagate itself to other protein chains. The only requirement for efficient propagation is that a two-faced mode of packing must be in the ground state as a dimer (a higher-energy state for this packing leads to less efficient propagation). For random sequences, these ground-state dimeric configurations tend to have more beta-sheet-like extended structure than almost any other sort of dimeric ground-state assembly. This implies that propagating states (such as for prions) are beta-sheet rich because the only likely propagating forms are beta-sheet rich. We examine the details of our simulations to see to what extent the observed properties of prion propagation can be predicted by a simple protein folding model. The formation of the alternative state in the present model shows several distinct features of amyloidogenesis and of prion propagation. For example, an analog of the phenomenon of conformationally distinct strains in prions is observed. We find a parallel between 'glassy' behavior in liquids and the formation of a propagatable state in proteins. This is the first report of simulation of conformational propagation using any heteropolymer model. The results imply that some (but not most) small protein sequences must maintain a sequence signal that resists refolding to propagatable alternative native states and that the ability to form such states is not limited to polypeptides (or reliant on regular hydrogen bonding per se) but can occur for other protein-like heteropolymers.
Amino Acid Sequence↗
Energetic components of cooperative protein folding.
A new lattice protein model with a four-helix bundle ground state is analyzed by a parameter-space Monte Carlo histogram technique to evaluate the effects of an extensive variety of model potentials on folding thermodynamics. Cooperative helical formation and contact energies based on a 5-letter alphabet are found to be insufficient to satisfy calorimetric and other experimental criteria for two-state folding. Such proteinlike behaviors are predicted, however, by models with polypeptidelike local conformational restrictions and environment-dependent hydrogen-bondinglike interactions.
Calorimetry↗
Modeling protein density of states: additive hydrophobic effects are insufficient for calorimetric two-state cooperativity.
A well-established experimental criterion for two-state thermodynamic cooperativity in protein folding is that the van't Hoff enthalpy DeltaH(vH) around the transition midpoint is equal, or very nearly so, to the calorimetric enthalpy DeltaH(cal) of the entire transition. This condition is satisfied by many small proteins. We use simple lattice models to provide a statistical mechanical framework to elucidate how this calorimetric two-state picture may be reconciled with the hierarchical multistate scenario emerging from recent hydrogen exchange experiments. We investigate the feasibility of using inverse Laplace transforms to recover the underlying density of states (i.e., enthalpy distribution) from calorimetric data. We find that the constraint imposed by DeltaH(vH)/DeltaH(cal) approximately 1 on densities of states of proteins is often more stringent than other "two-state" criteria proposed in recent theoretical studies. In conjunction with reasonable assumptions, the calorimetric two-state condition implies a narrow distribution of denatured-state enthalpies relative to the overall enthalpy difference between the native and the denatured conformations. This requirement does not always correlate with simple definitions of "sharpness" of a transition and has important ramifications for theoretical modeling. We find that protein models that assume capillarity cooperativity can exhibit overall calorimetric two-state-like behaviors. However, common heteropolymer models based on additive hydrophobic-like interactions, including highly specific two-dimensional Gō models, fail to produce proteinlike DeltaH(vH)/DeltaH(cal) approximately 1. A simple model is constructed to illustrate a proposed scenario in which physically plausible local and nonlocal cooperative terms, which mimic helical cooperativity and environment-dependent hydrogen bonding strength, can lead to thermodynamic behaviors closer to experiment. Our results suggest that proteinlike thermodynamic cooperativity may require a cooperative interplay between local and nonlocal interactions. The prospect of using calorimetric data to constrain Z-scores of knowledge-based potentials is discussed.
Calorimetry↗
Polymer principles of protein calorimetric two-state cooperativity.
The experimental calorimetric two-state criterion requires the van't Hoff enthalpy DeltaH(vH) around the folding/unfolding transition midpoint to be equal or very close to the calorimetric enthalpy DeltaH(cal) of the entire transition. We use an analytical model with experimental parameters from chymotrypsin inhibitor 2 to elucidate the relationship among several different van't Hoff enthalpies used in calorimetric analyses. Under reasonable assumptions, the implications of these DeltaH(vH)'s being approximately equal to DeltaH(cal) are equivalent: Enthalpic variations among denatured conformations in real proteins are much narrower than some previous lattice-model estimates, suggesting that the energy landscape theory "folding to glass transition temperature ratio" T(f) /T(g) may exceed 6.0 for real calorimetrically two-state proteins. Several popular three-dimensional lattice protein models, with different numbers of residue types in their alphabets, are found to fall short of the high experimental standard for being calorimetrically two-state. Some models postulate a multiple-conformation native state with substantial pre-denaturational energetic fluctuations well below the unfolding transition temperature, or predict a significant post-denaturational continuous conformational expansion of the denatured ensemble at temperatures well above the transition point, or both. These scenarios either disagree with experiments on protein size and dynamics, or are inconsistent with conventional interpretation of calorimetric data. However, when empirical linear baseline subtractions are employed, the resulting DeltaH(vH)/DeltaH(cal)'s for some models can be increased to values closer to unity, and baseline subtractions are found to correspond roughly to an operational definition of native-state conformational diversity. These results necessitate a re-assessment of theoretical models and experimental interpretations.
Calorimetry↗
Pediatric rhabdomyosarcoma of the head and neck: is there a place for surgical management?
OBJECTIVE: To review and evaluate the place of surgical treatment in the management of rhabdomyosarcoma of the head and neck in children. DESIGN: Retrospective analysis of patient charts from January 1, 1972, to December 31, 1998. SETTING: Tertiary pediatric referral center. PATIENTS: Twenty-nine consecutive children with nonorbital head and neck rhabdomyosarcoma. INTERVENTIONS: Surgery, chemotherapy, and radiotherapy. MAIN OUTCOME MEASURES: Disease-free survival and long-term morbidity from treatment. RESULTS: Twenty patients had parameningeal and 9 had nonparameningeal head and neck tumors. All were treated with chemotherapy. For 18 patients, diagnostic biopsies were performed and they received radiotherapy. Eleven patients underwent surgery as definitive therapy. Using the Intergroup Rhabdomyosarcoma Study (IRS) staging system, 5 of these 11 patients had complete resection of tumor (IRS group I) and avoided radiotherapy. The other 6 patients required radiation because of compromised, regional, or incomplete resection of tumor. One had undergone regional resection with nodal involvement, and 2 had compromised resections with microscopic residual disease (IRS group II). Three had incomplete resections with gross residual tumor (IRS group III). Only 1 patient who underwent surgery ultimately died from recurrence at 2.7 years after an incomplete resection. The other 10 patients were relapse free at a median follow-up of 3.7 years (range 0.8-21.0 years). Long-term surgical morbidity was seen in 36% (4/11) of the patients and included facial nerve paralysis, trismus, and cosmetic deformity. CONCLUSIONS: Children with localized disease of the head and neck are able to undergo complete surgical resection, with low long-term surgical morbidity. By undergoing complete surgical resection, these children are able to avoid radiotherapy and its long-term complications, with no compromise in survival.
Child, Preschool↗
Assessment of systemic toxicity in children receiving chemotherapy with cyclosporine for sarcoma.
BACKGROUND: Overexpression of P-glycoprotein in malignant tumors has been associated with poor responses to chemotherapy. It appears biologically plausible that addition of the P-glycoprotein inhibitor cyclosporine (CsA) to standard chemotherapy may improve the outcome. The protective functions of P-glycoprotein in healthy tissues, however, have not been fully elucidated. Addition of CsA may lead to increased systemic chemotherapy toxicity, so we compared the rate and severity of chemotherapy-associated systemic toxicity in the presence and absence of CsA. PROCEDURE: Standard chemotherapy consisted of etoposide/ifosfamide (VP16/IFOS) cycles, alternating with vincristine/dactinomycin/cyclophosphamide (VAC) cycles. CsA was given at a median dose of 20 mg/kg with unaltered doses of the antineoplastic drugs. The analysis of toxicity was performed by comparing clinically significant toxicity events recorded during and after chemotherapy cycles with and without CsA. RESULTS: Toxicity-related hospital admissions occurred after 93% of VAC cycles with CsA compared to 40% of the cycles without CsA (P < 0. 0001); 29% of VP16/IFOS cycles with CsA led to admissions vs. 12% with non-CsA cycles (P = 0.04). Infections or fever and neutropenia were the main reasons for these admissions. Thirty-seven percent of the VAC cycles with CsA were complicated by culture-proved sepsis, which did not occur in cycles without CsA (P < 0.0001). Requirements for blood and platelet transfusions were greatly increased after VAC cycles with CsA compared to VAC cycles without CsA. CONCLUSIONS: The chemosensitizer CsA increases the systemic toxicity of VAC chemotherapy in patients with sarcomas. Future trials of chemotherapy with chemosensitizers will have to take into account a potential increase in systemic toxicity. Careful monitoring of chemotherapy-related toxicity becomes mandatory in such studies.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Significance of a positive oesophageal margin in stomach cancer.
BACKGROUND: A positive oesophageal margin is frequently encountered in total and proximal gastrectomies. It is controversial as to whether a positive oesophageal margin in gastrectomy predisposes to anastomotic dehiscence and loco-regional recurrence. Its independent impact on survival has not been fully addressed. METHODS: A retrospective review of 137 total and proximal gastrectomies for adenocarcinoma was undertaken. Independent prognostic factors were identified in a bivariate and Cox proportional hazards regression model. RESULTS: The prevalence of positive oesophageal margin was 18.2%. A positive oesophageal margin was not associated with increased anastomotic leak (8.0 vs 10.7%; P = 0.51), operative morbidity (32.0 vs 27.7%; P = 0.85) or 30-day mortality (8.0 vs 5.4%; P = 0.48) rates when compared with a negative margin. In addition, it did not predispose to anastomotic (13.0 vs 10.4%; P = 0.47) or regional (22.7 vs 24.5%; P = 0.51) recurrences. In the multivariate analysis the TNM stage and status of the oesophageal margin were the only independent prognostic factors for survival. CONCLUSIONS: A positive oesophageal margin is an independent poor prognostic factor for long-term survival in stomach cancer. All efforts should therefore be made to clear the oesophageal margin in total and proximal gastrectomies.
Adenocarcinoma↗
Results of surgical resection of oesophageal carcinoma in Singapore.
INTRODUCTION: The 5-year survival rate after resection of oesophageal cancer is still poor, reported to be between 5% to 34% in the literatures. We conducted this retrospective study to determine the prognostic factors and long-term survival rate for surgical resection of oesophageal carcinoma in Singapore. MATERIALS AND METHODS: Sixty-seven consecutive patients who underwent surgical resection of oesophageal carcinoma from January 1989 to December 1996 were reviewed. RESULTS: Majority of the patients were Chinese (94%), males (81%) with a history of dysphagia (96%), cigarette smoking (84%) and alcohol ingestion (58%). The median age at surgery was 63.6 (range 29 to 81) years. Sixty-four patients had squamous cell carcinoma of the oesophagus and 3 patients had adenocarcinoma. The lower one-third of the oesophagus was the most common site (48.6%) followed by the middle third (46%). Postoperative complications included pneumonia (43.3%), vocal cord paralysis/paresis (19.4%) and anastomotic leakage (17.9%). Thirty-day postoperative mortality was 7.5%. There was an almost equal number of patients undergoing transhiatal (34 patients) and transthoracic approach (33 patients). There was no significant difference in postoperative complications and survival outcome for both approaches. The median survival was 15.3 months after surgery. Tumour features such as depth of involvement and TNM stage were useful in predicting survival (P < 0.05, log-rank test). CONCLUSIONS: We conclude that the poor outcome of surgical resection (5-year survival rate was 18% by Kaplan-Meier survival plots) was mainly attributed to late presentation (80% patients had T3 or T4 tumour).
Adenocarcinoma↗
Extended resection of locally advanced (T4) stomach cancer.
INTRODUCTION: The surgical management of locally advanced (T4) stomach cancer remains controversial and many still question the benefits of an extended resection. The aims of this study were to examine the morbidity and mortality associated with extended resection and also to determine the survival benefit. MATERIALS AND METHODS: A retrospective review of all stomach cancer operations performed from 1989 to 1998 was carried out and the relevant case histories retrieved and analysed. RESULTS: Out of the 980 stomach cancer operations performed, 784 (80%) had tumour resection and 20 (2.5%) also had extended resection of adjacent involved organs. These 20 patients had a 10% postoperative morbidity and the operative mortality was 15%. The survival ranged from 2 to 35 months (median 17 months). CONCLUSIONS: Extended resection of T4 stomach cancer is feasible and carries an acceptable operative morbidity and mortality. However, there is poor survival benefit and it should only be performed in a selected group of patients.
Adult↗
Modeling evolutionary landscapes: mutational stability, topology, and superfunnels in sequence space.
Random mutations under neutral or near-neutral conditions are studied by considering plausible evolutionary trajectories on "neutral nets"-i.e., collections of sequences (genotypes) interconnected via single-point mutations encoding for the same ground-state structure (phenotype). We use simple exact lattice models for the mapping between sequence and conformational spaces. Densities of states based on model intrachain interactions are determined by exhaustive conformational enumeration. We compare results from two very different interaction schemes to ascertain robustness of the conclusions. In both models, sequences in a majority of neutral nets center around a single "prototype sequence" of maximum mutational stability, tolerating the largest number of neutral mutations. General analytical considerations show that these topologies by themselves lead to higher steady-state evolutionary populations at prototype sequences. On average, native thermodynamic stability increases toward a maximum at the prototype sequence, resulting in funnel-like arrangements of native stabilities in sequence space. These observations offer a unified perspective on sequence design, native stability, and mutational stability of proteins. These principles are generalizable from native stability to any measure of fitness provided that its variation with respect to mutations is essentially smooth.
Algorithms↗
Thermodynamics of model prions and its implications for the problem of prion protein folding.
Prion disease is caused by the propagation of a particle containing PrPSc, a misfolded form of the normal cellular prion protein (PrPC). PrPC can re-fold to form PrPSc with loss of alpha-helical structure and formation of extensive beta-sheet structure. Here, we model this prion folding problem with a simple, low-resolution lattice model of protein folding. If model proteins are allowed to re-fold upon dimerization, a minor proportion of them (up to approximately 17%) encrypts an alternative native state as a homodimer. The structures in this homodimeric native state re-arrange so that they are very different in conformation from the monomeric native state. We find that model proteins that are relatively less stable as monomers are more susceptible to the formation of alternative native states as homodimers. These results suggest that less-stable proteins have a greater need for a well-designed energy landscape for protein folding to overcome an increased chance of encrypting substantially different native conformations stabilized by multimeric interactions. This conceptual framework for aberrant folding should be relevant in Alzheimer's disease and other disorders associated with protein aggregation.
Amino Acid Substitution↗
Folding alphabets.
A new computational approach optimizes searches for reduced protein folding alphabets that use fewer than 20 types of amino acids. The predicted optimal five-letter alphabet happens to be in agreement with the suggestive results of a recent experiment, but whether highly reduced alphabets are sufficient for truly protein-like properties remains an open experimental question.
Algorithms↗
Grandparents in the United States and the Republic of China: a comparison of generations and cultures.
Grandparent behaviors in the United States and the Republic of China are examined to identify curriculum themes for helping them adjust to their changing role. The 3,286 non-consanguineous subjects included Chinese (n = 751), African Americans (n = 777), Caucasian Americans (n = 1,086), and Mexican Americans (n = 672). Analyses were performed using 1) Generation with three levels (grandparent, parent, and grandchild) and 2) Culture with four levels (Chinese, African American, Caucasian American, and Mexican American). The results revealed significant differences in perceptions about grandparents across cultures as well as between generations within cultures. All three generations reported grandparent strengths and needs. Specific guidelines and curriculum topics are recommended for education to support grandparent development.
Aged↗
Protein stability in the amorphous carbohydrate matrix: relevance to anhydrobiosis.
The formation of intracellular glass is proposed to be relevant to protein stabilization and survival of anhydrobiotic organisms in the dry state. The stability of proteins in the amorphous carbohydrate matrix and its relevance to seed survival have been investigated in the present study. Glucose-6-phosphate dehydrogenase (G6PDH) was preserved in the amorphous glucose/sucrose (1:10, w/w) matrix by freeze-drying. The stability of freeze-dried G6PDH was examined at temperatures above and below the glass transition temperature (Tg). The rate of G6PDH inactivation in the amorphous carbohydrate matrix deviated significantly from the Arrhenius kinetics, and conformed to the Williams-Landel-Ferry (WLF) relationship. The temperature dependence of G6PDH inactivation in two sets of samples with different Tg values was compared. Identical temperature dependence of G6PDH inactivation was observed after temperature normalization by (T-Tg). Seed survival of Vigna radiata Wilczek (mung bean) showed a similar WLF kinetics at storage temperatures T > or = Tg. In situ protein stability in mung bean embryonic axes was studied using differential scanning calorimetry (DSC). Thermal stability of seed proteins exhibited a strong dependence on the Tg of intracellular glass. These results indicate an important role of the glassy state in protein stabilization. Our data suggest an association between protein stability in intracellular glass and seed survival during storage.
Calorimetry, Differential Scanning↗
Protein folding. Matching speed and locality.
Explore the source record for details and available documents.
Acid Anhydride Hydrolases↗