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Biomedical subjects

K Tan

Publications and source records attributed to K Tan.

At least 37 records · Page 2Linked to original sources
PubMed1999

Novel super-high affinity sheep monoclonal antibodies against CEA bind colon and lung adenocarcinoma.

We have developed technology to create monoclonal antibodies (MAbs) using lymphocytes from immunized sheep. The affinities of these sheep monoclonal antibodies (SMA) can be several orders of magnitude higher than mouse MAbs. This paper reports the development and validation of a modified enzyme-linked immunoadsorbent assay (ELISA) method to select high-affinity antibodies of the desired specificity at the first screen. Using this method, we have isolated high affinity SMA to carcinoembryonic antigen (CEA), a marker of colon cancer. Comparisons of our novel SMA with mouse MAbs using the new ELISA and BIAcore technology (BIAcore AB, Stevenage, Herts, UK) have confirmed that we have made super-high affinity antibodies to CEA. One of these has a t(1/2) for dissociation of 8 days, which could provide a longer therapeutic window than is available with murine monoclonals currently being used in the clinic. This antibody has a specific tissue staining profile; it thus appears to be an excellent candidate for use in the clinic.

Adenocarcinoma↗
PubMed1999

Mutational analysis of MAdCAM-1/alpha4beta7 interactions reveals significant binding determinants in both the first and second immunuglobulin domains.

The selective emigration of blood born leukocytes into tissues is mediated, in part by interactions of Ig-like cell adhesion molecules (IgCAMs) expressed on vascular endothelium and their cognate ligands, the leukocyte integrins. Within mucosal lymphoid tissues and gastrointestinal sites the mucosal vascular addressin. MAdCAM-1 is the predominant IgCAM, mediating specific lymphocyte homing via interactions with its ligand on lymphocytes, the integrin alpha4beta7. Previous studies have shown that an essential binding motif resides in the first Ig domain of all IgCAMs, containing an acidic residue (D or E) preceded by an aliphatic residue (L or I) that resides in strand C or the CD loop. However, domain swap experiments with MAdCAM-1 and VCAM-1 have shown a requirement for both Ig domains 1 and 2 for efficient integrin binding. We describe the use of chimeric MAdCAM-1/VCAM-1 receptors and point mutations in MAdCAM-1 to define other sites that are required for binding to the integrin alpha4beta7. We find that, in addition to critical CD loop residues, other regions in both domain one and two contribute to MAdCAM-1/alpha4beta7 interactions, including a buried arginine residue in the F strand of domain one and several acidic residues in a highly extended DE ribbon in domain 2. These mutations, when placed in the recently solved crystal structure of human MAdCAM-1 give insight into the integrin binding preference of this unique receptor.

Amino Acid Sequence↗
PubMed1998

DNA-Directed alkylating agents. 7. Synthesis, DNA interaction, and antitumor activity of bis(hydroxymethyl)- and bis(carbamate)-substituted pyrrolizines and imidazoles.

A series of bis(hydroxymethyl)-substituted imidazoles, thioimidazoles, and pyrrolizines and related bis(carbamates), linked to either 9-anilinoacridine (intercalating) or 4-(4-quinolinylamino)benzamide (minor groove binding) carriers, were synthesized and evaluated for sequence-specific DNA alkylation and cytotoxicity. The imidazole and thioimidazole analogues were prepared by initial synthesis of [(4-aminophenyl)alkyl]imidazole-, thioimidazole-, or pyrrolizine dicarboxylates, coupling of these with the desired carrier, and reduction to give the required bis(hydroxymethyl) alkylating moiety. The pyrrolizines were the most reactive alkylators, followed by the thioimidazoles, while the imidazoles were unreactive. The pyrrolizines and some of the thioimidazoles cross-linked DNA, as measured by agarose gel electrophoresis. Strand cleavage assays showed that none of the compounds reacted at purine N7 or N3 sites in the gpt region of the plasmid gpt2Eco, but the polymerase stop assay showed patterns of G-alkylation in C-rich regions. The corresponding thioimidazole bis(carbamates) were more selective than the bis(hydroxymethyl) pyrrolizines, with high-intensity bands at 5'-NCCN, 5'-NGCN and 5'-NCGN sequences in the PCR stopping assay ( indicates block sites). The data suggest that these targeted compounds, like the known thioimidazole bis(carbamate) carmethizole, alkylate exclusively at guanine residues via the 2-amino group, with little or no alkylation at N3 and N7 guanine or adenine sites. The cytotoxicities of the compounds correlated broadly with their reactivities, with the bis(hydroxymethyl)imidazoles being the least cytotoxic (IC50s >1 microM; P388 leukemia) and with the intercalator-linked analogues being more cytotoxic than the corresponding minor-groove-targeted ones. This was true also for the more reactive thioimidazole bis(carbamates) (IC50s 0.8 and 11 microM, respectively), but both were more active than the analogous "untargeted" carmethizole (IC50 20 microM). The bis(hydroxymethyl)pyrrolizine analogues were the most cytotoxic, with IC50s as low as 0.03 microM.

Alkylation↗
PubMed1998

The structure of immunoglobulin superfamily domains 1 and 2 of MAdCAM-1 reveals novel features important for integrin recognition.

BACKGROUND: Mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is a cell adhesion molecule that is expressed on the endothelium in mucosa, and guides the specific homing of lymphocytes into mucosal tissues. MAdCAM-1 belongs to a subclass of the immunoglobulin superfamily (IgSF), the members of which are ligands for integrins. Human MAdCAM-1 has a unique dual function compared to other members in the same subclass in that it binds both the integrin alpha4beta7, through its two IgSF domains, and a selectin expressed on leukocytes, via carbohydrate sidechains. The structure determination of the two IgSF domains and comparison to the N-terminal two-domain structures of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecules (ICAM-1 and ICAM-2) allow us to assess the molecular basis of the interactions between integrins and their preferred ligands. RESULTS: The crystal structure of a fragment containing the two IgSF domains of human MAdCAM-1 has been determined to 2.2 A resolution. The structure of MAdCAM-1 reveals two separate integrin-recognition motifs. The key integrin-binding residue, Asp42, resides in the CD loop of domain 1; a buried arginine residue (Arg70) plays a critical role in maintaining the conformation of this loop. The second binding site is associated with an unusual long D strand in domain 2. The D and E strands extend beyond the main body of the domain, forming a negatively charged beta ribbon unique to MAdCAM-1. This ribbon is located on the same face as the key aspartate residue in domain 1, consistent with evidence that it is involved in integrin binding. CONCLUSIONS: The structural comparison of MAdCAM-1 to other members of the same IgSF subclass reveals some interesting features. Firstly, MAdCAM-1, like VCAM-1, has the key integrin-binding residue located on the protruding CD loop of domain 1 and binds to an integrin that lacks an I domain. This is in contrast to ICAM-1 and ICAM-2 where the key residue is located at the end of the C strand on a flat surface and which bind to integrins that contain I domains. Secondly, architectural differences in the CD loops of MAdCAM-1 and VCAM-1 cause an 8 A shift in position of the critical aspartate residue, and may partly determine their binding preference for different integrins. Finally, the unusual charge distribution of the two-domain fragment of MAdCAM-1 is predicted to orient the molecule optimally for integrin binding on the top of its long mucin-like stalk.

Amino Acid Sequence↗
PubMed1998

Prediction of maintenance of sinus rhythm after cardioversion of atrial fibrillation by analysis of serial signal-averaged P waves.

After cardioversion from atrial fibrillation (AF) many patients develop early recurrence of the arrhythmia. While these patients may be appropriate for immediate prophylaxis against AF recurrence their identification at the time of cardioversion is not possible. Since the signal-averaged P wave (SAPW) is abnormal in individuals with atrial arrhythmia, we assessed its utility for predicting early AF recurrence after cardioversion. Seventy-five cardioversions in 31 patients were evaluated. The mean age was 59 (range 28-79) years; 26 were male. Fifty-eight cardioversions were internal using low energy biphasic DC shocks delivered via electrodes placed in the right atrial appendage and coronary sinus. P wave specific signal averaging was performed at 3 and 24 hours after each cardioversion to estimate filtered P wave duration and energy from 20, 40, and 60 to 150 Hz. Follow-up was by regular clinic visits and transtelephonic ECG monitoring. Early recurrence of AF (prospectively defined as sinus rhythm duration < 1 week) occurred after 30 cardioversions. No differences were found in any P wave variable measured at 3 hours between these cardioversions and those that resulted in a longer duration of sinus rhythm. Paired 3- and 24-hour signal-averaged data were available in 47 cardioversions. There were significant falls in P wave energy from 3 to 24 hours after 31 cardioversions that resulted in sinus rhythm for > 1 week, (P40: 3 hours 11.2 [+/- 1.5] micro V2.s, 24 hours 8.6 [+/- 1.2] micro V2.s, P < 0.001), but not following the 16 after which AF returned within 1 week (P40: 3 hours 9.0 [+/- 1.2] micro V2.s, 24 hours 8.5 [+/- 1.2 micro V2.s, P = NS). A fall in P40 of > 25% had a positive predictive accuracy for maintenance of sinus rhythm of 87%; negative predictive accuracy was only 37%. Similar falls in P wave energy occurred after cardioversions that resulted in longer term (> 4 weeks) sinus rhythm, but not in those that did not. However, the predictive accuracy of a fall in P40 was less (positive predictive accuracy 38%, negative predictive accuracy 62%). Patients with relapsing permanent AF who remain in sinus rhythm for at least 1 week after cardioversion show a fall in P wave energy within the first 24 hours. However, in these patients the technique does not predict recurrent AF within 1 week nor sinus rhythm > 4 weeks. These observations suggest persistent disordered atrial activation as a mechanism for early recurrence of AF after cardioversion.

Adult↗
PubMed1998

[Current status of cancer pain control in home hospice care--assessment by family members].

To improve the quality of life of terminally ill cancer patients, we care for them in the home whenever possible, making use of home parenteral nutrition (HPN) and continuous intravenous infusion of morphine. The purpose of this study was to assess the current status of and problems associated with our home hospice care program, with emphasis placed on the effectiveness of cancer pain control as viewed by the family of the patient. A questionnaire was sent to six families of patients who died at home. The members of each family were divided into two groups (spouse group or non-spouse group) and evaluated for their reaction to the patient's suffering. It was found that the two groups displayed a different reaction to the patient's suffering. The difference may have derived from the different mixture of objectivity and affection in each group. Therefore, we believe it is necessary to provide emotional support to each group based on this point of view. All respondents expressed a desire to receive home hospice care if they themselves were afflicted with end-stage cancer. This result showed that overall our home hospice care was successful. We intend to proceed with our program to provide patients and their families with more comfortable care, paying due regard to the difference in the reaction of family members to the patient's suffering depending on their relation to patient.

Aged↗
PubMed1997

Atomic structure of a thermostable subdomain of HIV-1 gp41.

Infection by HIV-1 involves the fusion of viral and cellular membranes with subsequent transfer of viral genetic material into the cell. The HIV-1 envelope glycoprotein that mediates fusion consists of the surface subunit gp120 and the transmembrane subunit gp41. gp120 directs virion attachment to the cell-surface receptors, and gp41 then promotes viral-cell membrane fusion. A soluble, alpha-helical, trimeric complex within gp41 composed of N-terminal and C-terminal extraviral segments has been proposed to represent the core of the fusion-active conformation of the HIV-1 envelope. A thermostable subdomain denoted N34(L6)C28 can be formed by the N-34 and C-28 peptides connected by a flexible linker in place of the disulfide-bonded loop region. Three-dimensional structure of N34(L6)C28 reveals that three molecules fold into a six-stranded helical bundle. Three N-terminal helices within the bundle form a central, parallel, trimeric coiled coil, whereas three C-terminal helices pack in the reverse direction into three hydrophobic grooves on the surface of the N-terminal trimer. This thermostable subdomain displays the salient features of the core structure of the isolated gp41 subunit and thus provides a possible target for therapeutics designed selectively to block HIV-1 entry.

Amino Acid Sequence↗
PubMed1997

Ambulatory patient-activated arrhythmia monitoring: comparison of a new wrist-applied monitor with a conventional precordial device.

A wrist-applied transtelephonic device (WrTTD) and a precordial (PrTTD) patient-activated transtelephonic electrocardiographic (ECG) recorder were compared objectively (quality of ECG traces) and subjectively (device preference) in a prospective randomized crossover study of 24 patients. All underwent cardioversion for chronic atrial fibrillation and were then randomized to each device for 1 month. The ECG traces were sent weekly with additional traces if symptomatic. Self-administered questionnaires were completed after 1 month with each device, and the first five telemetered ECG traces for each patient were blindly assessed by two experienced cardiologists. Although the QRS complexes were smaller with the WrTTD (P < .001), the quality of the traces was similar. In particular, there was no significant difference in number of nondiagnostic traces, ability to detect atrial activity, degree of baseline fluctuation, or amount of artifact. Overall, patients preferred the PrTTD (P = .02). Patients found the PrTTD easier to use (P = .007) and were able to apply it more rapidly (P = .02). The quality of ECG traces obtained from the upper limbs by using a wrist-applied transtelephonic device was concluded to be comparable with those obtained by direct precordial application. In order to increase patient acceptability of the former, further improvements to simplify its operation are necessary.

Adolescent↗
PubMed1997

Is mode switching beneficial? A randomized study in patients with paroxysmal atrial tachyarrhythmias.

OBJECTIVES: We sought 1) to compare three pacing modalities-DDDR with mode switching (DM), DDDR with conventional upper rate behavior (DR) and VVIR (VR)-in patients with a history of atrial tachyarrhythmias, and 2) to assess the efficacy of six mode-switching algorithms. BACKGROUND: A history of atrial tachyarrhythmias has been a relative contraindication to dual-chamber pacing. Several mode-switching algorithms have recently been developed to prevent rapid tracking of atrial tachyarrhythmias. METHODS: Forty-eight patients (mean age 64 years, 58% male) with a history of atrial tachyarrhythmias and heart block had a DM pacemaker implanted. Pacemakers were programmed to DM, DR and VR modes for 4 weeks each in a randomized crossover design. All subjects used a patient-activated electrocardiographic (ECG) recorder throughout the study and additionally underwent ambulatory ECG monitoring and a treadmill exercise test in each mode. They completed three symptom questionnaires at the end of each pacing period. At the end of the study, patients chose their preferred pacing period. RESULTS: DM was significantly better than VR mode objectively (exercise time DM 8.1 min, VR 7.0 min, p < 0.01) and subjectively (perceived well-being DM 69, VR 51, p < 0.001; functional class DM 2.2, VR 2.5, p < 0.05; subjective symptom score DM 21.2, VR 26.8, p = 0.01). Patient-perceived well-being was significantly better with DM than with DR mode (DM 69, DR 60, p = 0.02). DM mode was the preferred pacing period (DM 51%, DR 14%, VR 14%). Early termination of pacing because of adverse symptoms was requested by 33% of patients during VR, 19% during DR but only 3% during DM mode. A higher proportion of patients with a fast mode-switching device preferred DM mode (fast 55%, slow 49%), whereas no patients with a fast mode-switching device chose VR as the preferred mode (fast 0%, slow 19%). In the subgroup of patients who had had atrioventricular node ablation, DM was also preferred to VR mode (DM 53%, VR 27%). Overall, there were only two cases of inappropriate mode switching and one case of inappropriate tracking of an atrial tachyarrhythmia. CONCLUSIONS: DM is the pacing mode of choice of patients with paroxysmal atrial tachyarrhythmias. With optimal programming, inappropriate mode switching and tracking of atrial tachyarrhythmias was very uncommon.

Algorithms↗
PubMed1997

The Colorectal Cancer Recurrence Support (CARES) System.

Colorectal cancer has risen in incidence to become the second commonest form of cancer in Singapore. The primary treatment is surgery but up to 50% of patients still suffer from recurrence of the cancer after surgery. Early identification of recurrence will increase the effectiveness of therapy and the survival of patients. This paper describes the CARES (Cancer Recurrence Support) System, whose objective is to predict the recurrence of colorectal cancer, using Case-based Reasoning (CBR), and supported by other techniques such as data mining and natural language processing. The CARES System employs CBR to compare and contrast between the new and past colorectal cancer patient cases, and makes inferences based on those comparisons to determine the high risk patient groups. The features and functionality of the system are described.

Artificial Intelligence↗
PubMed1996

Dual sensor VVIR mode pacing: is it worth it?

Dual sensor ventricular demand rate responsive (VVIR mode) pacing was compared with single sensor rate responsive pacing to assess whether this new development should be more widely incorporated in modern pacemaker devices. A within patient randomized, double-blind crossover study involving ten patients, mean age 67.4 years (70% male), had Medtronic Legend Plus dual sensor VVIR pacemakers implanted for high grade AV block and chronic or persistent paroxysmal atrial fibrillation. Performance values were compared to 20 healthy control subjects of a similar age and gender. Patients were both subjectively and objectively assessed after 2 weeks of out-of-hospital activity in VVIR mode (minute ventilation sensing), VVIR mode (activity sensing), VVIR mode (dual sensor), and VVI mode (no rate response). All patients were assessed for subjective preference for, and objective improvement in, any pacing modality as assessed by standardized daily activity protocols and graded exercise treadmill testing. Subjective perception of exercise capacity and functional status was significantly lower in VVI mode (P < 0.05) compared to any of the VVIR modes, which did not differ. After completion of the study 70% of patients chose VVIR as their preferred mode, with 30% expressing no preference. Forty percent preferred activity sensor VVIR mode pacing, 30% preferred dual sensor VVIR mode pacing, and 70% found either dual sensor VVIR mode, minute ventilation sensor VVIR mode, or both modalities least acceptable. No patient found activity sensing VVIR mode least acceptable. Graded treadmill testing revealed significantly lower exercise tolerance during VVI mode pacing (P < 0.01) compared to the VVIR modalities, which did not differ. Overall, chronotropic response was best with dual sensor pacing during standardized daily activity protocols and during the standard car journey. The data from this study suggest that there is no marked clinical advantage obtained from the use of dual sensor devices over current activity sensing ventricular demand rate responsive pacemakers, but with the probable added disadvantages of increased size, complexity, cost, and decreased longevity.

Activities of Daily Living↗
PubMed1996

Evaluation of a new pacing algorithm to prevent rapid tracking of atrial tachyarrhythmias.

The new SMARTracking (SMT) algorithm was evaluated in seven patients with the Intermedics Relay DDDR pacemakers and a history of atrial tachyarrhythmias. The SMT algorithm uses the sensor calculated rate to define a physiological band whose upper limit is defined by the SMT rate. Pacemakers were programmed to DDDR with SMT (DDDRSM), DDDR with Conditional Ventricular Tracking Limit (DDDRC), DDDR with standard upper rate behavior, and VVIR, for a period of one month each. Patients underwent a CAEP exercise test and 24-hour ECG Holter monitoring in each mode. They also had ambulatory ECG monitoring during daily activities including rest, slow and fast walk, stairs ascent and descent. Three patients were in atrial fibrillation during the daily activities protocol. Their ventricular rates were paced and highly irregular, in both DDDRSM and DDDRC modes. The heart rate was lower in DDDRSM than DDDRC at rest and low levels of exercise but not during more strenuous activity. Two patients in DDDRSM and 3 in DDDRC requested early change of their mode due to unacceptable symptoms. Two patients exhibited Wenckebach behavior at atrial rates below the upper rate limit in both DDDRSM and DDDRC modes. In conclusion, CVTL or SMARTracking are not adequate protection against atrial tachyarrythmias in patients with DDDR pacemakers.

Activities of Daily Living↗
PubMed1996

Pacemaker upgrade for recurrent pacemaker syndrome using a redundant contralateral electrode in a patient with bilateral venous stenoses.

Following His-bundle ablation and VVIR pacemaker implantation, severe pacemaker syndrome developed and was treated with DDDR pacing, in a 70-year-old woman. Due to bilateral subclavian vein stenoses, DDDR pacing could not be maintained and an unusual method of restoring atrioventricular synchrony is described using the contralateral redundant atrial electrode connected to the ipsilateral dual chamber pacemaker and ventricular electrode.

Aged↗
PubMed1996

Pacemaker upgrade for recurrent pacemaker syndrome using a redundant contralateral electrode in a patient with bilateral venous stenoses.

Following His-bundle ablation and VVIR pacemaker implantation, severe Pacemaker syndrome developed and was treated with DDDR pacing in a 70-year-old woman. Due to bilateral subclavian vein stenosis, DDDR pacing could not be maintained and an unusual method of restoring atrioventricular synchrony is described using the contralateral redundant atrial electrode connected to the ipsilateral dual chamber pacemaker and ventricular electrode.

Aged↗