Effect of BCR::ABL1 transcript type and droplet digital polymerase chain reaction on successful treatment-free remission in chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitor.

Background: Droplet digital polymerase chain reaction (ddPCR) is an exact method of measurement. Objectives: We conducted this study to identify the prognostic factors for successful treatment-free remission in patients with chronic-phase chronic myeloid leukemia who discontinued tyrosine kinase inhibitors (TKIs). We also aimed to validate ddPCR for predicting molecular relapse. Design: This is a prospective, multicenter study. Methods: We enrolled patients treated with TKIs for at least 3 years with a confirmed sustained deep molecular response (DMR) for at least 1 year. TKI was re-administered in patients who experienced the loss of major molecular response (MMR). Results: A total of 66 patients from five institutions in South Korea were enrolled. During a median follow-up period of 16.5 months, 29/66 (43.9%) patients experienced molecular relapse; the probability of molecular relapse-free survival (RFS) at 6 or 12 months after TKI discontinuation was 65.6% or 57.8%, respectively, with most molecular relapses occurring within the first 7 months. All patients who lost MMR were re-treated with TKI, and all re-achieved MMR at a median of 2.8 months. E14a2 transcript type (p = 0.005) and longer DMR duration (⩾48 months) prior to TKI discontinuation (p = 0.002) were associated with prolonged molecular RFS and with sustained DMR. Patients with both e13a2 transcript type and detectable BCR::ABL1 (⩾MR5.0) by ddPCR at the time of TKI discontinuation showed shorter duration of molecular RFS (p = 0.015). Conclusion: Our data suggest that transcript type and BCR::ABL1 transcript levels on ddPCR should be taken into consideration when deciding whether to discontinue TKI therapy.

IDH1/2 mutations in acute myeloid leukemia.

The mutational and epigenetic landscape of acute myeloid leukemia (AML) has become increasingly well understood in recent years, informing on biological targets for precision medicine. Among the most notable findings was the recognition of mutational hot-spots in the isocitrate dehydrogenase (IDH) genes. In this review, we provide an overview on the IDH1/2 mutation landscape in Korean AML patients, and compare it with available public data. We also discuss the role of IDH1/2 mutations as biomarkers and drug targets. Taken together, occurrence of IDH1/2 mutations is becoming increasingly important in AML treatment, thus requiring thorough examination and follow-up throughout the clinical course of the disease.

The association of genetic alterations with response rate in newly diagnosed chronic myeloid leukemia patients.

Genetic differences may be associated with the response to tyrosine kinase inhibitor (TKI) in patients with chronic myeloid leukemia (CML). In this study, we identified genetic alterations between rapid and slow responders (BCR/ABL1 International Scale at 6 months: ≤0.1 % vs. > 0.1 %) of TKI treatment in chronic phase CML patients. Our analyses involved single nucleotide polymorphism (SNP), a Genome Wide Association Study and a Network-wide Association Study (NetWAS). Seventy-two patients from 16 institutions were enrolled and treated with a TKI, nilotinib. Gene Set Analysis identified genetic alterations in pathways related to the differentiation, proliferation, and activity of various innate immune cells. The NetWAS analysis found that genes associated with natural killer (NK) cells (PTPRCAP, BLNK, HCK, ARHGEF11, GPR183, TRPV2, SHKBP1, CD2) showed significant differences between rapid and slow responders of nilotinib. However, we found no significantly different genetic alterations according to the response in the SNP analysis. In conclusion, we found that rapidity of response to TKI was associated with pathway-associated genetic alterations in immune cells, particularly with respect to NK cell activity. These results suggested that the innate immune system at initial diagnosis had an important role in treatment response in patients with CML.

Ultra-deep sequencing mutation analysis of the BCR/ABL1 kinase domain in newly diagnosed chronic myeloid leukemia patients.

Ultra-deep sequencing detects low-frequency genetic mutations with high sensitivity. We used this approach to prospectively examine mutations in the BCR/ABL1 tyrosine kinase from patients with newly diagnosed, chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor nilotinib. Between May 2013 and November 2014, 50 patients from 18 institutions were enrolled in the study. We screened 103 somatic mutations and found that mutations in the P-loop domain were the most frequent (173/454 mutations in the P-loop) and noted the presence of the V299 L mutation (dasatinib-resistant/nilotinib-sensitive) in 98 % of patients (49/50). No patients had Y253H, E255 V, or F359 V/C/I mutations, which would recommend dasatinib rather than nilotinib treatment. The S417Y mutation was associated with lower achievement of a major molecular response (MMR) at 6 months, and the V371A mutation was associated with reduced MMR and MR4.5 durations (MMR for 2 years: 100 % for no mutation vs. 75 % for mutation, P=0.039; MR4.5 for 15 months: 94.1 % vs. 25 %, P=0.002). Patients with known nilotinib-resistant mutations had lower rates of MR4.5 achievement. In conclusion, ultra-deep sequencing is a sensitive method for genetic-based treatment decisions. Based on the results of these mutational analyses, nilotinib treatment is a promising option for Korean patients with CML.

Smart Decentralization of Personal Health Records with Physician Apps and Helper Agents on Blockchain: Platform Design and Implementation Study.

BACKGROUND: The Health Avatar Platform provides a mobile health environment with interconnected patient Avatars, physician apps, and intelligent agents (termed IoA3) for data privacy and participatory medicine; however, its fully decentralized architecture has come at the expense of decentralized data management and data provenance. OBJECTIVE: The introduction of blockchain and smart contract technologies to the legacy Health Avatar Platform with a clinical metadata registry remarkably strengthens decentralized health data integrity and immutable transaction traceability at the corresponding data-element level in a privacy-preserving fashion. A crypto-economy ecosystem was built to facilitate secure and traceable exchanges of sensitive health data. METHODS: The Health Avatar Platform decentralizes patient data in appropriate locations (ie, on patients' smartphones and on physicians' smart devices). We implemented an Ethereum-based hash chain for all transactions and smart contract-based processes to guarantee decentralized data integrity and to generate block data containing transaction metadata on-chain. Parameters of all types of data communications were enumerated and incorporated into 3 smart contracts, in this case, a health data transaction manager, a transaction status manager, and an application programming interface transaction manager. The actual decentralized health data are managed in an off-chain manner on appropriate smart devices and authenticated by hashed metadata on-chain. RESULTS: Metadata of each data transaction are captured in a Health Avatar Platform blockchain node by the smart contracts. We provide workflow diagrams each of the 3 use cases of data push (from a physician app or an intelligent agents to a patient Avatar), data pull (request to a patient Avatar by other entities), and data backup transactions. Each transaction can be finely managed at the corresponding data-element level rather than at the resource or document levels. Hash-chained metadata support data element-level verification of data integrity in subsequent transactions. Smart contracts can incentivize transactions for data sharing and intelligent digital health care services. CONCLUSIONS: Health Avatar Platform and interconnected patient Avatars, physician apps, and intelligent agents provide a decentralized blockchain ecosystem for health data that enables trusted and finely tuned data sharing and facilitates health value-creating transactions with smart contracts.

Clinical Genome Data Model (cGDM) provides Interactive Clinical Decision Support for Precision Medicine.

In light of recent developments in genomic technology and the rapid accumulation of genomic information, a major transition toward precision medicine is anticipated. However, the clinical applications of genomic information remain limited. This lag can be attributed to several complex factors, including the knowledge gap between medical experts and bioinformaticians, the distance between bioinformatics workflows and clinical practice, and the unique characteristics of genomic data, which can make interpretation difficult. Here we present a novel genomic data model that allows for more interactive support in clinical decision-making. Informational modelling was used as a basis to design a communication scheme between sophisticated bioinformatics predictions and the representative data relevant to a clinical decision. This study was conducted by a multidisciplinary working group who carried out clinico-genomic workflow analysis and attribute extraction, through Failure Mode and Effects Analysis (FMEA). Based on those results, a clinical genome data model (cGDM) was developed with 8 entities and 46 attributes. The cGDM integrates reliability-related factors that enable clinicians to access the reliability problem of each individual genetic test result as clinical evidence. The proposed cGDM provides a data-layer infrastructure supporting the intellectual interplay between medical experts and informed decision-making.

Use of Droplet Digital Polymerase Chain Reaction for Detecting Minimal Residual Disease: A Prospective Multi-Institutional Study.

BACKGROUND/AIM: Droplet digital polymerase chain reaction (ddPCR) is an exact method of measuring nucleic acids. The aim of this prospective study was to evaluate minimal residual disease (MRD) using ddPCR in chronic myeloid leukemia (CML) patients. PATIENTS AND METHODS: Between May 2013 and November 2014, CML patients treated with nilotinib were enrolled in our study. BCR/ABL1 transcripts levels were evaluated using ddPCR at the first time of complete molecular response (CMR). We enrolled 15 patients from 7 Institutions. The treatment period and median follow-up period were 45 months and 47 months, respectively. RESULTS: Patients with a high level of BCR/ABL1 transcript had a greater tendency to lose the CMR during the follow-up period (p=0.095). In addition, patients with a low level of BCR/ABL1 transcript showed a longer duration of CMR compared to those with a high level (p=0.032). CONCLUSION: We found that ddPCR is a sensitive method for detecting MRD and that MRD could affect the duration of the treatment response.

A phase 4 study of nilotinib in Korean patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTKorea.

Although nilotinib has improved efficacy compared to imatinib, suboptimal response and intolerable adverse events (AEs) limit its effectiveness in many patients with chronic myeloid leukemia in chronic phase (CML-CP). We investigated the 2-year efficacy and safety of nilotinib and their relationships with plasma nilotinib concentrations (PNCs). In this open-label, multi-institutional phase 4 study, 110 Philadelphia chromosome-positive CML-CP patients were treated with nilotinib at a starting dose of 300 mg twice daily. Molecular responses (MRs) and AEs were monitored for up to 24 months. The 24-month cumulative MR4.5 rate was evaluated as the primary endpoint. Plasma samples were collected from 94 patients to determine PNCs, and the per-patient mean was used to categorize them into four mean PNC (MPNC) groups. Cumulative MR rates and safety were compared between groups. With a median follow-up of 22.2 months, the 24-month cumulative MR4.5 rate was 56.2% (95% confidence interval, 44.0%-8.3%), and the median time to MR4.5 was 23.3 months. There were no significant differences in the cumulative rates of major molecular response, MR4 , and MR4.5 between MPNC groups. One patient died due to acute viral hepatitis, and two developed hematological or cytogenetic relapse, while no progression to accelerated or blast phase was observed. Safety results were consistent with previous studies with no new safety signal identified. Across the MPNC groups, there was no significant linear trend in the frequency of AEs. Nilotinib is highly effective for the treatment of CML-CP with manageable AEs. The measurement of PNC has no predictive value for patient outcomes and is thus not found to be clinically useful. This study is registered with clinicaltrials.gov, Number NCT03332511.

Impact of the cation composition on the electrical performance of solution-processed zinc tin oxide thin-film transistors.

This study examined the structural, chemical, and electrical properties of solution-processed (Zn,Sn)O3 (ZTO) films with various Sn/[Zn+Sn] ratios for potential applications to large-area flat panel displays. ZTO films with a Zn-rich composition had a polycrystalline wurtzite structure. On the other hand, the Sn-rich ZTO films exhibited a rutile structure, where the Zn atom was speculated to replace the Sn site, thereby acting as an acceptor. In the intermediate composition regions (Sn/[Zn+Sn] ratio from 0.28 to 0.48), the ZTO films had an amorphous structure, even after annealing at 450 °C. The electrical transport properties and photobias stability of ZTO thin film transistors (TFTs) were also examined according to the Sn/[Zn+Sn] ratio. The optimal transport property of ZTO TFT was observed for the device with an amorphous structure at a Sn/[Zn+Sn] ratio of 0.48. The mobility, threshold voltage, subthreshold swing, and on/off current ratio were 4.3 cm(2)/(V s), 0 V, 0.4 V/decade, and 4.1 × 10(7), respectively. In contrast, the device performance for the ZTO TFTs with either a higher or lower Sn concentration suffered from low mobility and a high off-state current, respectively. The photoelectrical stress measurements showed that the photobias stability of the ZTO TFTs was improved substantially when the ZTO semiconducting films had a lower oxygen vacancy concentration and an amorphous structure. The relevant rationale is discussed based on the phototransition and subsequent migration mechanism from neutral to positively charged oxygen vacancies.

Role of induction and consolidation chemotherapy in elderly acute myeloid leukemia patients.

The present study sought to elucidate the role of induction and consolidation therapy in elderly patients. We retrospectively collected data of 477 patients who were aged over 60 years at the time of acute myeloid leukemia (AML) diagnosis. The median overall survival (OS) was 339 days in the induction group (n = 266) and 86 days in the best supportive care group (n = 211) (P < 0.001). In the induction group, the complete remission (CR) rate was 58.3 %, and treatment-related death was 15.4 %. Successful induction was related to good performance [Eastern Cooperative Oncology Group (ECOG <2)] [hazard ratio (HR) 3.215; P = 0.002]. Mortality correlated with failure to achieve CR (HR 4.059; P < 0.001) and poor performance status (ECOG >2) (HR 2.731; P = 0.035). In CR patients, poor karyotype and absence of consolidation (HR 2.313; P = 0.003) correlated with mortality. More than one cycle of consolidation was associated with better OS (P < 0.001). Lack of salvage therapy was associated with mortality in patients who did not achieve CR (HR 3.223; P = 0.005). Intensive induction in patients with good performance and >1 cycle of consolidation after CR may be the best strategy for improving OS in elderly AML patients.

Multicenter study evaluating the impact of hypomethylating agents as bridging therapy to hematopoietic stem cell transplantation in myelodysplastic syndromes.

Allogeneic hematopoietic stem cell transplantation (alloSCT) is currently the only curative treatment modality for myelodysplastic syndromes (MDS). The treatment paradigm for MDS has changed in recent years with the introduction of hypomethylating agents (HMAs). The present retrospective multicenter study was designed to assess the effects of pre-transplant HMA on transplant outcome and determine which patients would benefit most from this therapy. A total of 109 patients who received alloSCT at one of five institutions between 2007 and 2010 were enrolled in this study regardless of pre-transplant HMA therapy. 81 of the 109 patients enrolled were treated with HMA prior to alloSCT. 28 patients received alloSCT without HMA bridging. The distributions of WHO classification groups and IPSS scores were similar between the two groups (P = 0.752 and P = 0.265, respectively). Pre-transplant HMA did not affect OS (P = 0.244), and there were no differences in response to HMA therapy within the HMA-treated group. The cumulative incidence of NRM was not significantly different between the two groups (P = 0.500). However, for patients with a high blast count (>5 % of bone marrow at the time of diagnosis), pre-transplant HMA therapy had a NRM benefit (83.3 vs. 48.6 %, P = 0.014).

Analysis of cariogenic bacteria in saliva of cancer patients.

This study examined salivary flow and salivary pH and the prevalence and levels of cariogenic bacteria in the saliva of oncological patients and healthy controls. Quantitative real-time polymerase chain reaction was used to assess the levels of microbes including Streptococcus mutans, Streptococcus sobrinus, Lactobacillus salivarius, and Lactobacillus acidophilus in the saliva of 41 patients with a solid tumor (SO), 30 patients with a hematologic malignancy (HE), and 40 healthy controls. Salivary flow and pH were lower in oncological patients than in controls. The frequencies of all four cariogenic bacteria were highest in the SO group. S. mutans and L. salivarius were the most commonly detected in all three study groups. Mean numbers of S. sobrinus and L. salivarius in the SO group were significantly higher than in controls (p<0.05). There were no significant differences between patients and controls with respect to mean numbers of S. mutans and L. acidophilus in saliva. However, the proportions of S. mutans, S. sobrinus, and L. salivarius versus total bacteria in the SO group were significantly higher than in controls. Within patients, both mean numbers and the proportions of S. mutans and S. sobrinus were significantly different (p<0.05). In summary, significant differences were found in salivary pH values and the levels of S. mutans, S. sobrinus, and L. salivarius between SO patients and healthy controls.

Photobias instability of high performance solution processed amorphous zinc tin oxide transistors.

The effects of the annealing temperature on the structural and chemical properties of soluble-processed zinc-tin-oxide (ZTO) films were examined by transmission electron microscopy, atomic force microscopy, high resolution X-ray reflectivity, and X-ray photoelectron spectroscopy. The density and purity of the resulting ZTO channel layer increased with increasing annealing temperature, whereas the oxygen vacancy defect density decreased. As a result, the device performance of soluble ZTO thin film transistors (TFTs) was improved at higher annealing temperature. Although the 300 °C-annealed ZTO TFT showed a marginal field-effect mobility (µFE) and high threshold voltage (Vth) of 0.1 cm(2)/(V s) and 7.3 V, respectively, the 500 °C-annealed device exhibited a reasonably high µFE, low subthreshold gate swing (SS), Vth, and Ion/off of 6.0 cm(2)/(V s), 0.28 V/decade, 0.58 V, and 4.0 × 10(7), respectively. The effects of dark negative bias stress (NBS) and negative bias illumination stress (NBIS) on the degradation of transfer characteristics of ZTO TFTs were also investigated. The instability of Vth values of the ZTO TFTs under NBS and NBIS conditions was suppressed with increasing annealing temperature. To better understand the charge trapping mechanism, the dynamics of Vth shift with NBS and NBIS time for all ZTO TFTs was analyzed on the basis of the stretched exponential relaxation. The negative Vth shift for each transistor was accelerated under NBIS conditions compared to NBS, which resulted in a higher dispersion parameter and smaller relaxation time for NBIS degradation. The relaxation time for NBS and NBIS instability increased with increasing annealing temperature, which is discussed on the basis of the transition mechanism of oxygen vacancy defects.

SiO2 doped Ge2Sb2Te5 thin films with high thermal efficiency for applications in phase change random access memory.

This study examined the various physical, structural and electrical properties of SiO(2) doped Ge(2)Sb(2)Te(5) (SGST) films for phase change random access memory applications. Interestingly, SGST had a layered structure (LS) resulting from the inhomogeneous distribution of SiO(2) after annealing. The physical parameters able to affect the reset current of phase change memory (I(res)) were predicted from the Joule heating and heat conservation equations. When SiO(2) was doped into GST, thermal conductivity largely decreased by ∼ 55%. The influence of SiO(2)-doping on I(res) was examined using the test phase change memory cell. I(res) was reduced by ∼ 45%. An electro-thermal simulation showed that the reduced thermal conductivity contributes to the improvement of cell efficiency as well as the reduction of I(res), while the increased dynamic resistance contributes only to the latter. The formation and presence of the LS thermal conductivity in the set state test cell after repeated switching was confirmed.

Effect of catalyst layer density and growth temperature in rapid atomic layer deposition of silica using tris(tert-pentoxy)silanol.

Rapid atomic layer deposition (RALD) of SiO2 thin films was achieved using trimethyl-aluminum and tris(tert-pentoxy)silanol (TPS) as the catalyst and Si precursor, respectively. A maximum growth rate as high as ∼28 nm/cycle was obtained by optimizing the catalyst layer density, whereas the previous reports showed lower values of 12 to 17 nm/cycle [Hausmann et al. Science2002, 298, 402-406; Burton et al. Chem. Mater. 2008, 20, 7031-7043]. When the growth temperature was increased from 140 to 230 °C, the growth rate was not much reduced and the TPS pulse time showing a saturated growth rate became rather longer. Si-CH3, Si-OH, and Si-H bonds were not detected in infrared spectra from the RALD SiO2 film grown at 230 °C. The film quality could be enhanced substantially by applying a higher growth temperature and an in situ post plasma treatment process.

A novel route to the synthesis of silica nanowires without a metal catalyst at room temperature by chemical vapor deposition.

Silica nanowires were synthesized by employing inherent directionality of chemical vapor reaction between bis(ethylmethylamino)silane (H(2)Si[N(C(2)H(5))(CH(3))](2)) precursor and water without a metal catalyst at room temperature. The difference in the oxidation reactivity between Si-H and Si-N bonds with water leads to the formation of silica nanowires. The mean diameter and length of the silica nanowires grown for 10 min were 60-80 nm and 1.9 µm, respectively. Transmission electron microscopy revealed that the obtained nanowires had the concave tip, differing from other silica nanowires produced by a conventional vapor-liquid-solid method, and were amorphous. Energy dispersive X-ray spectroscopy, Fourier transform infrared, and X-ray photoelectron spectroscopy results also proved that the nanowires have a close composition to stoichiometric SiO(2). Silica nanowires were successfully synthesized on a poly(ethylene terephthalate) film. The nanowires can emit strong blue light and ultraviolet light under excitation at 266 nm.

Predictive value of pretreatment risk group and baseline LDH levels in MDS patients receiving azacitidine treatment.

This study analyzed the outcomes of myelodysplastic syndrome patients treated with azacitidine. Between August 2006 and June 2008, a total of 126 patients were treated with azacitidine at a dose of 75 mg/m(2)/day subcutaneously for 7 days, which was repeated every 28 days. The median age of the patients was 64 (range, 20-82) years. Forty-three patients (33.4%) were classified as intermediate-2 and high risk according to International Prognostic Scoring System (IPSS), while 61 patients (47.3%) were classified as high and very high risk according to WHO Prognostic Scoring System (WPSS). Sixty patients (47.6%) exhibited a response at the median of 3 (range, 1-5) cycles. A complete response was observed in 21 patients (16.7%), a partial response in six patients (4.8%), and total hematologic improvement in 61 patients (48.4%). For the IPSS risk group, the median survival for the patients with intermediate-1 was 20.0 months, for intermediate-2 was 14.9 months, and for high risk was 6.3 months (p = 0.008). For the WPSS risk group, the median survival duration was 21.3 months for the very low and low risk patients, 16.5 months for intermediate risk patients, and 14.9 months for the high and very high risk patients (p = 0.003). The patients with higher than normal lactate dehydrogenase (LDH) levels at the time of diagnosis showed a poor survival (p = 0.003). The median survival duration for the patients with high LDH levels was 13.9 months, while that for the patients with normal LDH levels was 20.6 months. The multivariate analyses revealed that high LDH levels [hazard ratio (HR) 4.384, p < 0.001] and high and very high WPSS risk group (HR 3.855, p = 0.014) were significantly associated with a worse survival, whereas a response to azacitidine was identified as a good prognostic factor for survival (HR 0.224, p = 0.019). In conclusion, while the pretreatment risk group and initial LDH levels were both confirmed as important prognostic factors to predict the outcomes for patients treated with azacitidine, more effective therapies are still needed to prevent disease progression.

Device fabrication with solid-liquid-solid grown silicon nanowires.

High quality, single-crystal silicon nanowires were successfully grown from silicon wafers with a nickel catalyst by utilizing a solid-liquid-solid (SLS) mechanism. The nanowires were composed of a crystalline silicon core with an average diameter of 10 nm and a thick outer oxide layer of between 20 and 30 nm at a growth temperature of 1000 °C. When utilizing the SLS growth mechanism, the diameter of the silicon nanowire is dependent solely upon the growth temperature, and has no relation to either the size or the shape of the catalyst. The characteristics of the silicon nanowires are highly dependent upon the properties of the silicon substrate, such as the crystal phase of silicon itself, as well as the doping type. The possibility of doping of silicon nanowires grown via the SLS mechanism without any external dopant source was demonstrated by measuring the electrical properties of a silicon nanowire field effect transistor.

Differential involvement of protein kinase C in human promyelocytic leukemia cell differentiation enhanced by artemisinin.

Artemisinin, a sesquiterpene lactone endoperoxide that exists in several medicinal plants, is a well-known anti-malarial agent. In this report, we investigated the effect of artemisinin on cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system. Artemisinin markedly increased the degree of HL-60 leukemia cell differentiation when simultaneously combined with low doses of 1 alpha,25-dihydoxyvitamin D(3) [1,25-(OH)(2)D(3)] or all-trans retinoic acid (all-trans RA). Artemisinin by itself had very weak effects on the differentiation of HL-60 cells. Cytofluorometric analysis and cell morphologic studies indicated that artemisinin potentiated 1,25-(OH)(2)D(3)-induced cell differentiation predominantly into monocytes and all-trans RA-induced cell differentiation into granulocytes, respectively. Extracellular-regulated kinase (ERK) inhibitors markedly inhibited HL-60 cell differentiation induced by artemisinin in combination with 1,25-(OH)(2)D(3) or all-trans RA, whereas phosphatidylinositol 3-kinase (PI3-K) inhibitors did not. Particularly, protein kinase C (PKC) inhibitors inhibited HL-60 cell differentiation induced by artemisinin in combination with 1,25-(OH)(2)D(3) but not with all-trans RA. Artemisinin enhanced PKC activity and protein level of PKC beta I isoform in only 1,25-(OH)(2)D(3)-treated HL-60 cells. Taken together, these results indicate that artemisinin strongly enhanced 1,25-(OH)(2)D(3)- and all-trans RA-induced cell differentiation in which PKC is differentially involved in arteminisin-mediated enhancement of leukemia cell differentiation.