Biomedical subjects

S J Lee

Publications and source records attributed to S J Lee.

At least 19 recordsLinked to original sources

PubMed1998

Calmodulin-dependent regulation of inducible and neuronal nitric-oxide synthase.

Neuronal and endothelial nitric-oxide synthases depend upon Ca2+/calmodulin for activation, whereas the activity of the inducible nitric-oxide synthase is Ca2+-independent, presumably due to tightly bound calmodulin. To study these different mechanisms, a series of chimeras derived from neuronal and inducible nitric- oxide synthases were analyzed. Chimeras containing only the oxygenase domain, calmodulin-binding region, or reductase domain of inducible nitric-oxide synthase did not confer significant Ca2+-independent activity. However, each chimera was more sensitive to Ca2+ than the neuronal isoform. The calmodulin-binding region of inducible nitric-oxide synthase with either its oxygenase or reductase domains resulted in significant, but not total, Ca2+-independent activity. Co-immunoprecipitation experiments showed no calmodulin associated with the former chimera in the absence of Ca2+. Trifluoperazine also inhibited this chimera in the absence of Ca2+. The combined interactions of calmodulin bound to inducible nitric-oxide synthase calmodulin-binding region with the oxygenase domain may be weaker than with the reductase domain. Thus, Ca2+-independent activity of inducible nitric-oxide synthase appears to result from the concerted interactions of calmodulin with both the oxygenase and reductase domains in addition to the canonical calmodulin-binding region. The neuronal isoform is not regulated by a unique autoinhibitory element in its reductase domain.

Binding Sites↗

PubMed1998

Efficacy and costs of granulocyte colony-stimulating factor in allogeneic T-cell depleted bone marrow transplantation.

Hematopoietic growth factors have shown clinical benefits in patients undergoing chemotherapy and stem cell transplantation, but few studies have been performed to assess whether the benefits are worth the costs. We reviewed 196 patients undergoing T-cell depleted related donor bone marrow transplantation (BMT) between 1990 and 1996 to assess the effect of growth factor use on time to engraftment and costs of hospitalization. Beginning in 1994, based on encouraging results in autologous transplantation, patients (n = 81) were treated with granulocyte colony-stimulating factor (G-CSF) starting at day +1 after marrow infusion until engraftment. Between January 1, 1990 and January 1, 1994, patients (n = 115) did not receive growth factor. CD6 depletion of donor marrow was the only form of prophylaxis against graft-versus-host disease (GVHD). Despite receiving a lower stem cell dose (P = .004), the group receiving G-CSF had a decreased time to engraftment (20 days v 12 days, P < .0001) and time from marrow infusion to discharge (23 days v 17 days, P < .0001). In multivariate modeling, the use of G-CSF was the most significant factor predicting time to engraftment and discharge. Incidence of grades II-IV GVHD, early mortality, percentage of patients who engrafted, and relapse rates did not differ between the groups. Inpatient charges during the first 50 days after marrow infusion (including readmissions) were available on 110 patients and were converted to costs using departmental ratios of costs of charges. Median costs were significantly lower in the group receiving G-CSF ($80,600 v $84,000, P = .0373). Thus, use of G-CSF in this setting allows earlier hospital discharge with lower costs.

Adolescent↗

PubMed1998

A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-kappaB.

The signaling pathway through which ionizing radiation induces NF-kappaB activation is not fully understood. IkappaB-alpha, an inhibitory protein of NF-kappaB mediates the activation of NF-kappaB in response to various stimuli, including cytokines, mitogens, oxidants and other stresses. We have now identified an ionizing radiation-induced signaling pathway that is independent of TNF-alpha. IkappaB-alpha degradation is rapid in response to TNF-alpha induction, but it is absent in response to ionizing radiation exposure in cells from individuals with ataxia-telangiectasia (AT). Overexpression of wild-type ATM, the product of the gene defective in AT patients, restores radiation-induced degradation of IkappaB-alpha. Furthermore, phosphorylation of IkappaB-alpha by immunoprecipitated ATM kinase is increased in control fibroblasts and transfected AT cells following ionizing radiation exposure. These data provide support for a novel ionizing radiation-induced signaling pathway for activation of NF-kappaB and a molecular basis for the sensitivity of AT patients to oxidative stresses.

Acetylcysteine↗

PubMed1998

Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors.

A novel family of cofactors that differentially interact with homeoproteins have been identified via a yeast two-hybrid screen. The proteins contain a conserved protein kinase domain that is separated from a domain that interacts with homeoproteins and hence are termed homeodomain-interacting protein kinases (HIPKs): HIPK1, HIPK2, and HIPK3. We show that HIPKs are nuclear kinases using GFP-HIPK fusion constructs. The DNA binding activity of the NK-3 homeoprotein is greatly enhanced by HIPK2, but this effect is independent of its phosphorylation by HIPK2. In cultured cells, HIPKs localize to nuclear speckles and potentiate the repressor activities of NK homeoproteins. The co-repressor activity of HIPKs depends on both its homeodomain interaction domain and a co-repressor domain that maps to the N terminus. Thus, HIPKs represent a heretofore undescribed family of co-repressors for homeodomain transcription factors.

Amino Acid Sequence↗

PubMed1998

Purification and molecular cloning of a platelet aggregation inhibitor from the snake (Agkistrodon halys brevicaudus) venom.

A platelet glycoprotein IIb-IIIa (GP IIb-IIIa) antagonist, salmosin, was purified to homogeneity from Korean snake (Agkistrodon halys brevicaudus) venom by means of chromatographic fractionations. We have isolated the cDNA encoding salmosin by using the cDNA library of the snake venom gland and analyzed its complete nucleotide sequence. The molecular identity was confirmed by comparison of the deduced amino acid sequence with the directly determined primary structure of salmosin. This protein is a single-chain polypeptide composed of 73 amino acids including 12 cysteines as well as the sequence Arg-Gly-Asp, a proposed recognition site of adhesive proteins. The primary sequence of salmosin shows considerable homology to previously described proteins of snake venom GP IIb-IIIa antagonist family. A molecular mass of 7474 for the protein was determined by matrix-assisted laser desorption ionization mass spectrometry. Salmosin inhibits GP IIb-IIIa binding to immobilized fibrinogen with an IC50 of 2.2 nM and ADP-induced platelet aggregation with an IC50 of 131 nM, respectively. This work demonstrates the purification, characterization, and cDNA cloning of salmosin, a platelet aggregation inhibitor that may have therapeutic potential as an antithrombotic agent.

Agkistrodon↗

PubMed1998

U73122 blocked the cGMP-induced calcium release in sea urchin eggs.

U73122, a phospholipase C inhibitor, dose dependently blocks the cGMP-induced Ca2+ release in sea urchin eggs and homogenates. U73122 inhibition was prevented by cotreatment with dithiothreitol (DTT), but DTT is ineffective when eggs or homogenates were pretreated with U73122. U73122 action is different from the other sulfhydryl reagents, thimerosal and N-ethylmaleimide, which cause Ca2+ release in egg homogenates at high concentration, but at lower concentration have no significant effect on cGMP-induced Ca2+ release. Histone, a reported NAD glycohydrolase (NADase) activator, was found to induce Ca2+ release in egg homogenates via the same pathway as the cGMP response, since histone-induced Ca2+ release is blocked by Rp-8-pCPT-cGMPS, a cGMP-dependent protein kinase (PKG) inhibitor, and nicotinamide, a NADase inhibitor. Histone-induced Ca2+ release is similarly blocked by U73122. The aminosteroid U73122 does not inhibit cADPR-induced Ca2+ release, which is significantly reduced by PKG inhibitors. Furthermore, U73122 has no significant effect on phorbol 12-myristate 13-acetate induced-cytoplasmic alkalinization in intact eggs, which depends on protein kinase C activity. These results suggest that U73122 does not act as a general serine-threonine protein kinase inhibitor, and the aminosteroid inhibition of the cGMP-induced Ca2+ release may interfere with ADP ribosyl cyclase activity.

Adenosine Diphosphate Ribose↗

PubMed1998

Temporal variation in hepatotoxicity and metabolism of acetaminophen in mice.

Temporal variation in metabolism and hepatotoxicity of acetaminophen (APAP) was examined using male ICR mice. Animals were injected with a single dose of APAP (400 mg/kg, i.p.) at 08:00, 14:00 or 20:00 h. APAP at this dose was markedly hepatotoxic to mice when administered at 20:00 h as determined by increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and by decreases in hepatic glucose-6-phosphatase (G-6-Pase) activity. However, mice appeared to be entirely insensitive to an identical dose of APAP given either at 08:00 or 14:00 h. Hepatic glutathione (GSH) level was significantly higher at 08:00, but no difference in GSH levels between 14:00 and 20:00 h was observed in normal mice. APAP and its metabolites in blood were monitored using HPLC for 3 h following the treatment. There were no significant differences in the plasma concentrations of APAP, APAP-glucuronide, APAP-sulfate, or APAP-mercapturate among the mice treated with this drug at 08:00, 14:00 or 20:00 h. However, the APAP-cysteine and APAP-GSH levels measured at 1 h following the APAP treatment were significantly lower in mice treated with this analgesic either at 14:00 or 20:00 h. In vitro hepatic microsomal p-nitrophenol hydroxylase activities were not different between 08:00, 14:00 and 20:00 h. But ethoxyresorufin O-deethylase and aminopyrine N-demethylase activities measured at 14:00 h were significantly lower than those of 08:00 or 20:00 h. Thus, the greater hepatotoxicity of APAP administered at 20:00 h appears to be related to the marked decrease in hepatic GSH at this time period, whereas the simultaneous reduction in APAP activation may be responsible for the lack of hepatotoxicity in mice treated with this analgesic at 14:00 h. These results suggest that the temporal variation in hepatotoxicity and metabolism of APAP is determined by interactions of multiple factors including the hepatic GSH level and drug metabolizing activities.

Acetaminophen↗

PubMed1998

Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway induces p53-independent transcriptional regulation of p21(WAF1/CIP1) in human prostate carcinoma cells.

Progression through the cell cycle is controlled by the induction of cyclins and the activation of cognate cyclin-dependent kinases. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin induces growth arrest and cell death in certain cancer cell types. We have pursued the mechanism of growth arrest in PC-3-M cells, a p53-null human prostate carcinoma cell line. Lovastatin treatment increased protein and mRNA levels of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1), increased binding of p21 with Cdk2, markedly inhibited cyclin E- and Cdk2-associated phosphorylation of histone H1 or GST-retinoblastoma protein, enhanced binding of the retinoblastoma protein to the transcription factor E2F-1 in vivo, and induced the activation of a p21 promoter reporter construct. By using p21 promoter deletion constructs, the lovastatin-responsive element was mapped to a region between -93 and -64 relative to the transcription start site. Promoter mutation analysis indicated that the lovastatin-responsive site coincided with the previously identified transforming growth factor-beta-responsive element. These data indicate that in human prostate carcinoma cells an inhibitor of the HMG-CoA reductase pathway can circumvent the loss of wild-type p53 function and induce critical downstream regulatory events leading to transcriptional activation of p21.

Apoptosis↗

PubMed1998

Controlled release of platelet-derived growth factor from porous poly(L-lactide) membranes for guided tissue regeneration.

Platelet-derived growth factor-BB (PDGF-BB) was incorporated into porous poly (L-lactide) (PLLA) membranes with an aim of improving early bone healing in guided tissue regeneration (GTR) therapy. Porous PDGF-BB loaded membranes were fabricated by coating PDGF-BB-dissolved PLLA methylene chloride-ethyl acetate solutions on polyglycolic acid (PGA) meshes. Release kinetics of PDGF-BB, biologic activity, degradability and guided tissue regenerative potentials of the membranes were investigated. Release of PDGF-BB could be controlled by adding bovine serum albumin that may provide porous diffusion channels for PDGF-BB release and by varying initial loading content of PDGF-BB. Biologic activity of PDGF-BB in the membranes was ascertained by fibroblast chemotaxis. PDGF-BB loaded membranes maintained proper degradation property for periodontal application. PDGF-BB loaded membrane markedly increased new bone formation in rat calvarial defects, and completed bony reunion after 2 weeks of implantation period. These results suggested that PDGF-BB loaded PLLA membrane might potentially enhance guided tissue regenerative efficacy.

Acetates↗

PubMed1998

The calcium transient in sea urchin eggs during fertilization requires the production of inositol 1,4,5-trisphosphate.

The production of inositol 1,4,5-trisphosphate (InsP3) has been reported to mediate the transient rise in intracellular Ca2+ activity ([Ca2+]i) in sea urchin eggs during fertilization. However, direct evidence of an absolute requirement for generation of InsP3 during fertilization is still lacking. We investigated this question by blocking the InsP3 synthesizing enzyme phospholipase C (PLC) during fertilization with U73122, an aminosteroid. U73122 inhibited the sperm-induced Ca2+ release in a dose-dependent manner, although above 15 microM U73122 eggs showed an elevated resting [Ca2+]i and a lower fertilization rate. The inhibition of Ca2+ transient by U73122 was not due to a failure of fertilization, since incorporated sperm nuclei were evident in eggs used to measure the Ca2+ response. U73122 also prevented the accompanying rise in intracellular pH (pHi), which is mediated by the activation of the Na+-H+ antiporter. The antiporter is regulated through activation of protein kinase C by 1,2-diacylglycerol, which is the other hydrolytic product of phosphatidylinositol 4,5-bisphosphate by PLC. Further evidence of the specificity of U73122 action was inhibition of the increase in InsP3 mass during the first 2 min of fertilization. In addition, U73122 inhibited the GTPgammaS-induced Ca2+ release and pHi rise in unfertilized eggs. These results suggested that the transient rise in Ca2+ in sea urchin during fertilization requires the production of InsP3.

Animals↗

PubMed1998

Metabolism and distribution of [2,3-14C]acrolein in Sprague-Dawley rats. II. Identification of urinary and fecal metabolites.

The metabolites of [2,3-14C]acrolein in the urine and feces of Sprague-Dawley rats were identified after either intravenous administration in saline at 2.5 mg/kg or oral administration by gavage as an aqueous solution as either single or multiple doses at 2.5 mg/kg or as a single dose of 15 mg/kg. Selected urine and feces samples were pooled by sex and collection interval and profiled by combinations of reverse-phase, anion-exchange, cation-exchange, and ion-exclusion high-performance liquid chromatography (HPLC). Feces were also profiled by size-exclusion chromatography. Metabolites were identified by comparison with well-characterized standards by HPLC and by mass spectrometry. The urinary metabolites were identified as oxalic acid, malonic acid, N-acetyl-S-2-carboxy-2-hydroxyethylcysteine, N-acetyl-S-3-hydroxypropylcysteine, N-acetyl-S-2-carboxyethylcysteine, and 3-hydroxypropionic acid. The fecal radioactivity from the oral dose groups was partitioned into methanol-soluble, water-soluble, and insoluble radioactivity, some of which could be liberated by dilute acid hydrolysis. HPLC analysis of these extracts revealed no discrete metabolites. Size-exclusion chromatography indicated a molecular weight range of 2,000 to 20,000 Da for the radioactivity, which was unaffected by hydrolysis at reflux with 6 M acid or base. This radio-activity was thought to be a homopolymer of acrolein, which was apparently formed in the gastrointestinal tract. The pathways of acrolein metabolism were epoxidation followed by conjugation with glutathione, Michael addition of water followed by oxidative degradation, and glutathione addition to the double bond either following or preceding oxidation or reduction of the aldehyde. The glutathione adducts were further metabolized to the mercapturic acids.

Acrolein↗

PubMed1998

Clinical courses of pure sleep epilepsies.

This study aims to understand seizure control outcomes and the risk of developing new wake seizures (WS) related to the different types of pure sleep epilepsies (SE), which is important in making rational management plans. A retrospective review of the Yonsei Epilepsy Clinic Registry identified 63 patients with pure SE not belonging to any specific epileptic syndromes. They were divided into the group of generalized tonic-clonic seizures during sleep (S-GTCS : n = 21) and the group of partial epilepsies during sleep (S-PE: n = 42) on the basis of seizure phenomenology, EEG, and neuroimaging data. These patients were followed for 2 years and their clinical variables were analysed for seizure control outcomes and development of new WS. Of 21 patients with S-GTCS, 17 achieved a seizure-free outcome and only one patient developed a new WS, which was consistent with a partial-onset secondary GTCS in phenomenology. Of 42 patients with S-PE only 15 patients achieved a seizure-free outcome and 11 patients developed WS during the 2-year follow-up period. Higher baseline seizure frequency and longer duration of epilepsy were associated with a higher incidence of new WS. The results suggest that the patients with S-GTCS carry a favorable clinical course, thus driving privileges or freedom of daily activities can be conferred without delay once their seizures are well controlled. However, the seizure control outcome was poor and the development of WS was frequent in patients with recurrent S-PE.

Adolescent↗

PubMed1998

A detergent-insoluble membrane compartment contains A beta in vivo.

Ordered assembly of the amyloid-beta protein (A beta) into amyloid fibrils is a critical step in Alzheimer's disease (AD). To release the amyloidogenic peptide A beta from the Alzheimer amyloid precursor protein (APP), two secretases act sequentially: first, beta-secretase cleaves close to the membrane within the ectodomain and then gamma-secretase cuts within the transmembrane domain. The sites of gamma-secretase cleavage are after residues 40 or 42 of A beta. Except in those rare cases of AD caused by a mutation, levels of secreted A beta are not elevated; thus, the secretory pathway may be unaffected, and factors other than the extracellular concentration of A beta may contribute to the aggregation properties of the peptide. A beta is also present in intracellular compartments. The two gamma-secretase cleavage products, A beta42 and A beta40, were found in different compartments: A beta42 in the endoplasmic reticulum (ER)/intermediate compartment, and A beta40 in the trans-Golgi network (TGN). The cellular compartments that harbor A beta are target sites for therapeutic intervention. Here we report that in the brain, the principal compartment in which A beta resides is a detergent-insoluble glycolipid-enriched membrane domain (DIG). Also present in the DIG fractions are the endoproteolytic fragments of presenilin-1 (PS1) and APP. The presence of these proteins, which all contribute to the generation of A beta, indicates that the DIG fraction is probably where the intramembranous cleavage of APP occurs.

Alzheimer Disease↗

PubMed1998

Perceptions and preferences of autologous blood donors.

BACKGROUND: The public's perception of autologous blood donation and transfusion as a worthwhile alternative to allogeneic blood transfusion increased dramatically with discovery of the human immunodeficiency virus. However, new concerns are being raised about the health outcomes and cost-effectiveness of the procedure. As more restrictive guidelines for autologous blood donation evolve, opposition from patients concerned about exposure to allogeneic blood may arise. Physicians' ability to reassure patients and garner their support for more restrictive policies requires an understanding of patients' concerns. The motivations, perceptions, and preferences of patients currently participating in autologous blood donation programs were investigated in this study. STUDY DESIGN AND METHODS: Results from two questionnaire studies of 647 autologous blood donors are presented. The questionnaires assessed demographics, risk perceptions, preferences, willingness to pay, and reactions to different interventions designed to decrease patient preference for autologous blood donation. RESULTS: Patients expressed a strong preference for the availability of autologous blood and indicated that they would be willing to pay substantial amounts of money even if the procedure were not covered by insurance. Despite education about the low risks of complications from allogeneic transfusions, an aversion to allogeneic transfusion and a willingness to pay for autologous blood donation persisted. Patients were not reassured by information on better infectious disease testing or physician recommendation against autologous blood donation. CONCLUSION: Patients currently participating in autologous blood donor programs strongly prefer continued access to this procedure, primarily because they remain concerned about the complications of allogeneic transfusions. They may not be significantly reassured despite increasingly rigorous and costly improvements in donor and component screening.

Attitude↗

PubMed1998

In vitro antigenotoxic activity of novel ginseng saponin metabolites formed by intestinal bacteria.

Ginseng saponin metabolites produced by human intestinal bacteria were evaluated for antigenotoxic properties by testing their effects on benzo[a]pyrene (B[a]P)-induced mutagenicity and clastogenicity. They include 20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol (IH-901), 20-O-(alpha-D-arabinopyranosyl(1-->6)-beta-D-glucopyranosyl]- 20(S)-protopanaxadiol (IH-902) and 20-O-[alpha-D-arabinofuranosyl(1-->6)-beta-D-glucopyranosyl]-20(S)- protopanaxadiol (IH-903). IH-901, IH-902 and IH-903 inhibited the mutagenicity of B[a]P in a dose-dependent manner. In the chromosome aberration assay, IH-901 and IH-903 reduced the frequency of chromosome aberration induced by B[a]P. These results suggest that the ginseng saponin metabolites tested in the present study have potential as chemopreventive agents.

Animals↗

PubMed1998

The impact of risk information on patients' willingness to pay for autologous blood donation.

OBJECTIVES: For contingent valuation to provide valid values for policy making, it is important that respondents be well informed about the goods they are asked to value. Few studies, however, have tested the impact of providing this information This study assessed the impact of risk information on patients' willingness to pay for autologous blood donation and derived the willingness to pay in a sample of informed patients. METHODS: Patients were randomized either to receive information about the risks of complications from allogeneic (volunteer) blood transfusions or to base their willingness to pay responses on their own prior knowledge. Four hundred twelve autologous blood donors were recruited from three study sites. Self-administered questionnaires collected information on willingness to pay, risk perceptions, and socioeconomic information. RESULTS: As predicted by our theoretical model, providing risk information reduced the variance in the willingness to pay for autologous blood donation. A tendency for information to reduce the willingness to pay was also found, suggesting that uninformed patients, on average, overestimate the risks of allogeneic blood transfusions. The median willingness to pay in the informed sample was approximately $750 to $1,100, depending on the estimation method, compared with $800 to $1,900 in the uninformed group. Willingness to pay was significantly related to perceived transfusion risk, personal income, and dread of transfusions. CONCLUSIONS: Our results are consistent with an economic model where individuals update their prior risk perceptions with new information. The willingness to pay in the informed sample was far higher than the costs of autologous blood donation, suggesting that total benefits outweigh the costs of the procedure.

Adult↗

PubMed1998

Screening for diabetic retinopathy using a non-mydriatic retinal camera in rural Victoria.

PURPOSE: To develop a screening programme for the early detection of diabetic retinopathy using non-mydriatic retinal photography. METHODS: A community based screening service was offered to all people with known diabetes mellitus in selected townships in the LaTrobe and Goulburn Valleys in Victoria. At the local examination centre, basic sociodemographic information was collected as well as details of previous use of eye care services for the early detection of diabetic retinopathy. The examination included visual acuity (VA), glycosylated haemoglobin level and Polaroid photographs of each fundus using a Canon CR5-45NM non-mydriatic retinal camera (Canon, Tochigiken, Japan). Dilating drops were not used. Photographs were subsequently reviewed and letters were sent to all participants (with copies to their general practitioners) with recommendations for appropriate follow up. RESULTS: A total of 1177 people with diabetes attended the screening service, which is estimated to be 40% of the total population with known diabetes in the study area. The mean age was 65 years (range 20-94 years); 559 (48%) people reported not having a dilated fundus examination within the past 2 years; 345 (29%) people had never had a dilated fundus examination. Of the 2354 eyes, 2126 (90%) of the photographs were gradable. A total of 704 people (60%) had normal VA and no evidence of diabetic retinopathy, 209 people (18%) had diabetic retinopathy, 101 people (9%) had evidence of other fundus pathology, 42 people (3%) had reduced acuity (< 6/18) in one or both eyes (with no fundus pathology evident) and 121 people (10%) had ungradable photographs in one or both eyes. CONCLUSIONS: The present study demonstrates the usefulness of a screening programme with non-mydriatic retinal photography as an adjunct to current eye care services for the early detection of diabetic retinopathy.

Adult↗

PubMed1998

Initial therapy for chronic myelogenous leukemia: playing the odds.

For patients with newly diagnosed CML, the life expectancy is much better than it was 5 years ago. However, with improvements in both transplant and nontransplant therapy comes controversy over optimal first-line therapy. We argue that an evidence-based analysis that weighs the likelihoods of surviving transplantation and responding to interferon should help guide selection of initial therapy. Such a strategy would aggressively triage appropriate patients to curative therapy while advising those who are unlikely to do well with transplantation to elect less toxic therapy, which still confers a survival benefit. We realize that many other factors beside the ones mentioned here affect a clinician's recommendation for initial therapy and a patient's ultimate choice. Many extenuating circumstances, coexisting medical conditions, and personal values need to be a part of the ultimate decision. However, we hope that this guideline summarizes the current evidence and offers a rational approach to help guide newly diagnosed patients.

Adult↗