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Introduction: Platelet transfusion is a standard treatment to prevent bleeding in patients with hematological malignancies. Although transfusions can improve platelet count, their impact on platelet function remains controversial., Methods: We conducted flow cytometry to assess platelet function before and after transfusion and performed subgroup analyses to examine differences based on blood type, corrected count increment (CCI), and platelet microparticles., Results: Overall, 50 patients who received prophylactic platelet transfusion were enrolled. CD42b expression increased, whereas CD41 expression decreased after transfusion. Apheresis platelets exhibited the lowest expression of PAC-1 and P-selectin when exposed to agonist stimulations. PAC-1 expression increased under high adenosine diphosphate (ADP) stimulation, while P-selectin expression increased under both high ADP and thrombin receptor-activating peptide stimulation. In the subgroup analysis, patients with a CCI >4500 and those with the same blood types exhibited a more significant increase in PAC-1 and P-selectin expression under agonist stimulation. When comparing apheresis platelets collected on different days, only the percentage of platelet-derived microparticles showed a significant increase., Conclusion: Prophylactic transfusion improved platelet function. Platelet function significantly improved in patients with a CCI >4500, those with the same blood types as that of apheresis platelets, or those with platelet-derived microparticle levels <4.7%. No significant improvement in platelet function was noted after the transfusion of different blood types with acceptable compatibility or the transfusion of incompatible blood types. Our results suggest that transfusing platelets with the same blood type remains the optimal choice., (© 2024 John Wiley & Sons Ltd.)

Hematopoietic stem cell transplantation (HSCT) can cure malignant and nonmalignant hematological disorders. From 1983 to 2022, Taiwan performed more than 10,000 HSCT transplants. The Taiwan Blood and Marrow Transplantation Registry collects clinical information to gather everyone's experience and promote the advances of HSCT in Taiwan to gather everyone's experience and promote advances of HSCT in Taiwan. Compared with matched sibling donors, transplants from matched unrelated donors exhibited a trend of superior survival. In Taiwan, transplant donors showed remarkable growth from unrelated (24.8%) and haploidentical (10.5%) donors. The number of older patients (17.4%; aged ≥61 years) who underwent transplantation has increased markedly. This review summarizes several significant developments in HSCT treatment in Taiwan. First, the use of Anti-thymocyte globulin (ATG) and intravenous busulfan regimens were important risk factors for predicting hepatic sinusoidal obstruction syndrome. Second, a new, machine learning-based risk prediction scoring system for posttransplantation lymphoproliferative disorder has identified five risk factors: aplastic anemia, partially mismatched related donors, fludarabine use, ATG use, and acute skin graft-versus-host disease. Third, although the incidence of idiopathic pneumonia syndrome was low (1.1%), its mortality rate was high (58.1%). Fourth, difficult-to-treat mantle cell and T-cell lymphomas treated with autologous HSCT during earlier remission had higher survival rates. Fifth, treatment of incurable multiple myeloma with autologous HSCT showed a median progression-free survival and overall survival of 46.5 and 70.4 months, respectively. Sixth, different haploidentical transplantation strategies were compared. Seventh, caution should be taken in administering allogeneic HSCT treatment in older patients with myeloid leukemia with a Charlson Comorbidity Index ≥3 because of a higher risk of nonrelapse mortality., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Tzu Chi Medical Journal.)

Background: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients., Methods: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion., Results: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan., Conclusions: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: In recent years, advancements in cancer treatment have enabled cancer cell inhibition, leading to improved patient outcomes. However, the side effects of chemotherapy, especially leukopenia, impact patients' ability to tolerate their treatments and affect their quality of life. Traditional Chinese medicine is thought to provide complementary cancer treatment to improve the quality of life and prolong survival time among patients with cancer., Objective: This study aims to evaluate the effectiveness of Chinese herbal medicine (CHM) as a complementary treatment for neutropenia prevention and immunity modulation during chemotherapy in patients with breast cancer., Methods: We will conduct a real-world pragmatic clinical trial to evaluate the effectiveness of CHM as a supplementary therapy to prevent neutropenia in patients with breast cancer undergoing chemotherapy. Patients will be classified into CHM or non-CHM groups based on whether they received CHM during chemotherapy. Using generalized estimating equations or repeated measures ANOVA, we will assess differences in white blood cell counts, absolute neutrophil counts, immune cells, and programmed cell death protein 1 (PD-1) expression levels between the 2 groups., Results: This study was approved by the research ethics committee of Hualien Tzu Chi Hospital (IRB 110-168-A). The enrollment process began in September 2021 and will stop in December 2024. A total of 140 patients will be recruited. Data cleaning and analysis are expected to finish in the middle of 2025., Conclusions: Traditional Chinese medicine is the most commonly used complementary medicine, and it has been reported to significantly alleviate chemotherapy-related side effects. This study's findings may contribute to developing effective interventions targeting chemotherapy-related neutropenia among patients with breast cancer in clinical practice., Trial Registration: International Traditional Medicine Clinical Trial Registry ITMCTR2023000054; https://tinyurl.com/yc353hes., International Registered Report Identifier (irrid): DERR1-10.2196/55662., (©Kai-Hung Wang, Hsuan-Shu Shen, Sung-Chao Chu, Tso-Fu Wang, Ching-Wei Lin, Wei-Han Huang, Yi-Feng Wu, Ching-Chun Ho, Cheng-Yoong Pang, Chi-Cheng Li. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.03.2024.)

After Epstein-Barr virus (EBV) genome replication and encapsidation in the nucleus, nucleocapsids are translocated into the cytoplasm for subsequent tegumentation and maturation. The EBV BGLF4 kinase, which induces partial disassembly of the nuclear lamina, and the nuclear egress complex BFRF1/BFLF2 coordinately facilitate the nuclear egress of nucleocapsids. Here, we demonstrate that within EBV reactivated epithelial cells, viral capsids, tegument proteins, and glycoproteins are clustered in the juxtanuclear concave region, accompanied by redistributed cytoplasmic organelles and the cytoskeleton regulator IQ-domain GTPase-activation protein 1 (IQGAP1), close to the microtubule-organizing center (MTOC). The assembly compartment (AC) structure was diminished in BGLF4-knockdown TW01-EBV cells and BGLF4-knockout bacmid-carrying TW01 cells, suggesting that the formation of AC structure is BGLF4-dependent. Notably, glycoprotein gp350/220 was observed by confocal imaging to be distributed in the perinuclear concave region and surrounded by the endoplasmic reticulum (ER) membrane marker calnexin, indicating that the AC may be located within a globular structure derived from ER membranes, adjacent to the outer nuclear membrane. Moreover, the viral capsid protein BcLF1 and tegument protein BBLF1 were co-localized with IQGAP1 near the cytoplasmic membrane in the late stage of replication. Knockdown of IQGAP1 did not affect the AC formation but decreased virion release from both TW01-EBV and Akata + cells, suggesting IQGAP1-mediated trafficking regulates EBV virion release. The data presented here show that BGLF4 is required for cytoskeletal rearrangement, coordination with the redistribution of cytoplasmic organelles and IQGAP1 for virus maturation, and subsequent IQGAP1-dependent virion release.IMPORTANCEEBV genome is replicated and encapsidated in the nucleus, and the resultant nucleocapsids are translocated to the cytoplasm for subsequent virion maturation. We show that a cytoplasmic AC, containing viral proteins, markers of the endoplasmic reticulum, Golgi, and endosomes, is formed in the juxtanuclear region of epithelial and B cells during EBV reactivation. The viral BGLF4 kinase contributes to the formation of the AC. The cellular protein IQGAP1 is also recruited to the AC and partially co-localizes with the virus capsid protein BcLF1 and tegument protein BBLF1 in EBV-reactivated cells, dependent on the BGLF4-induced cytoskeletal rearrangement. In addition, virion release was attenuated in IQGAP1-knockdown epithelial and B cells after reactivation, suggesting that IQGAP1-mediated trafficking may regulate the efficiency of virus maturation and release., Competing Interests: The authors declare no conflict of interest.

Targeted therapy with Bruton tyrosine kinase (BTK) inhibitors have revolutionized the treatment of patients with various B-cell malignancies. BTK inhibitors such as ibrutinib, zanubrutinib, orelabrutinib, and acalabrutinib have shown good clinical efficacy and better safety profiles than those of traditional chemotherapy and chemoimmunotherapy regimens. Multiple studies on new BTK inhibitors are ongoing, which may provide more therapeutic options for the treatment of B-cell malignancies. Considering the unmet need of evidence on BTK inhibitors in all clinical settings and to standardize the use of BTK inhibitors available in mainland China, Taiwan, Hong Kong, and Macau regions, this consensus has been formulated for the treatment of various B-cell malignancies based on the clinical practice and available evidences on the use of BTK inhibitors. The recommendations of this consensus will provide guidance to physicians and clinical researchers on the effective treatment of B-cell malignancies with BTK inhibitors., (© 2023. YUMED Inc. and BioMed Central Ltd.)

We report the mixotrophic growth of Escherichia coli based on recombinant 2-oxoglutarate:ferredoxin oxidoreductase (OGOR) to assimilate CO 2 using malate as an auxiliary carbon source and hydrogen as an energy source. We employ a long-term (~184 days) two-stage adaptive evolution to convert heterotrophic E. coli into mixotrophic E. coli . In the first stage of evolution with serine, diauxic growth emerges as a prominent feature. At the end of the second stage of evolution with malate, the strain exhibits mixotrophy with CO 2 as an essential substrate for growth. We expect this work will open new possibilities in the utilization of OGOR for microbial CO 2 assimilation and future hydrogen-based electro-microbial conversion.

Objectives: Myelodysplastic syndrome (MDS) is a heterogeneous hematopoietic stem cell disorder with thrombocytopenia. Flow cytometric immunophenotyping of blood cells has been instrumental in diagnosis as co-criteria, but the data regarding platelets remains lacking. This study aims to determine if there is a difference in surface antigen levels on platelets by comparing surface antigen levels in MDS patients and healthy control subjects. Concurrently, as flow cytometric gating can reveal the diameter of cells, this study will investigate differences in giant platelet percentage by comparing these percentages in high- and low-risk MDS patients., Study Design: Twenty newly diagnosed MDS patients were enrolled in this study. Platelet surface antigen levels were determined by measuring the binding capacity of antibodies with flow cytometry., Results: Platelets of MDS patients were shown to have a lower level of CD61 and higher levels of CD31 and CD36 than healthy controls. Judged by forward scatter (FSC), MDS patients' platelets appeared to be larger than those of healthy control subjects, whereas the MFI adjusted by diameter (MFI/FSC ratio) of CD31, CD41a, CD42a, CD42b and CD61 on platelets were lower in MDS patients than in healthy control subjects. There was a significant quantity of giant platelets found in MDS patients, and the high-risk MDS patients tended to have a higher percentage of giant platelets than low-risk patients. Conclusions: All the results indicate that MDS patients exhibit a lower antigen presentation (MFI) adjusted by diameter on platelets than healthy controls and the giant platelets detected by flow cytometry might correlate with the condition of MDS., Competing Interests: NO - The authors have declared that no competing interests exist., (Copyright: © 2022 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Immune thrombocytopenia (ITP) is a condition that is distinct from thrombosis with thrombocytopenia syndrome (TTS) that may also occur after coronavirus disease 2019 (COVID-19) vaccinations. Previous reports revealed an increased ITP incidence after ChAdOx1, a vaccine for COVID-19. Our study aimed to highlight the key features of ITP after COVID-19 vaccination. From April to October 2021, we collected data on 23 patients, including nine men and 14 women, with ITP from five hospitals across Taiwan who received either the ChAdOx1 or mRNA-1273 vaccine before development or exacerbation of ITP. Our findings revealed that both ChAdOx1 and mRNA-1273 vaccines were associated with ITP. Many patients responded well to steroids and immune suppressants, which may also suggest that the nature of thrombocytopenia is more like ITP rather than TTS. Lack of thrombosis, low D-dimer level, and negative anti-PF4 result could help to exclude TTS, which is also a rare but a far more lethal condition.

Background: Thrombocytosis is a common finding in hospitalized patients and is of two main types, essential thrombocytosis (ET) and reactive thrombocytosis (RT). It is important to distinguish the two due to increased risk of developing marrow fibrosis, acute leukemia, and thrombosis in the former. Molecular studies are the main tools to differentiate the two but are not available in all hospitals. We aimed to design a highly sensitive scoring system using routine lab data to classify thrombocytosis as essential or reactive. Methods: A total of 145 patients were enrolled in this study. Potential predictors included patient demographics and clinical laboratory parameters. Receiver operating characteristic curve analysis was used to decide the optimal cutoff level. Multivariate logistic regression with forward model selection method was performed to decide the predictors. Results: The risk scores by multivariate analysis were as follows: 1 point for WBC > 13,500/μL; 2.5 points for Hb > 10.9 g/dL; 3 points for platelet count > 659,000/μL; and 2 points for MPV > 9.3 fL. The cut off value was set as 4.5 points, and sensitivity of 91.1% and specificity of 75.8% were noted. Conclusion: In this study, we investigated lab data and developed a high-sensitivity convenient-to-use scoring system to differentiate ET from RT. The scoring system was assigned to the resulting model to make it more economical, simple, and convenient for clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shen, Hsieh, Wang, Huang, Chu and Wu.)

During the development of a multicellular organism, the specification of different cell lineages originates in a small group of pluripotent cells, the epiblasts, formed in the preimplantation embryo. The pluripotent epiblast is protected from premature differentiation until exposure to inductive cues in strictly controlled spatially and temporally organized patterns guiding fetus formation. Epiblasts cultured in vitro are embryonic stem cells (ESCs), which recapitulate the self-renewal and lineage specification properties of their endogenous counterparts. The characteristics of totipotency, although less understood than pluripotency, are becoming clearer. Recent studies have shown that a minor ESC subpopulation exhibits expanded developmental potential beyond pluripotency, displaying a characteristic reminiscent of two-cell embryo blastomeres (2CLCs). In addition, reprogramming both mouse and human ESCs in defined media can produce expanded/extended pluripotent stem cells (EPSCs) similar to but different from 2CLCs. Further, the molecular roadmaps driving the transition of various potency states have been clarified. These recent key findings will allow us to understand eutherian mammalian development by comparing the underlying differences between potency network components during development. Using the mouse as a paradigm and recent progress in human PSCs, we review the epiblast's identity acquisition during embryogenesis and their ESC counterparts regarding their pluripotent fates and beyond.

Background: Systemic sclerosis (SSc), characterized by fibrosis of the skin and other organs, is a devastating systemic autoimmune disease. Lung involvement is frequent in SSc and contributes to the high rate of mortality., Objective: To describe the first case report of SSc and interstitial lung disease (ILD) receiving autologous hematopoietic stem cell transplantation (ASCT) in Taiwan., Methods: Case report., Results: A 51-year-old man presented with rapid skin thickening and shortness of breath. Early progressive SSc-associated ILD was diagnosed. Because his lung function rapidly declined and his skin disease progressed, he received ASCT with satisfactory treatment responses in both skin thickness and lung function. In addition, lung imaging analysis showed remarkable improvements in ILD after treatment., Conclusions: We suggest that ASCT can be considered in selected patients with early, rapidly progressive SSc associated with ILD.

Multiple myeloma (MM) is typically featured by the increased levels of inflammatory cytokines in the neoplastic plasma cells (PCs) producing monoclonal immunoglobulin. PCs proliferate in the bone marrow, which will lead to extensive skeletal destruction with osteolytic lesions, osteopenia, or pathologic fractures. The diagnostic biology of MM has progressed from morphology and low-sensitivity protein analysis into multiomics-based high-throughput readout, whereas therapeutics has evolved from single active agent to potential active drug combinations underlying precision medicine. Many studies have focused on the cytokine networks that control growth, progression, and dissemination of the disease. The complexity of cytokines in MM development remains to be elucidated comprehensively. Apart from knowing that interleukin (IL)-6 is important in the pathogenesis of MM, it has been shown that IL-6 is a paracrine factor supplied by the microenvironment comprising of those cells from the myeloid compartment. Due to IL-10 was considered an immunosuppressive cytokine to promote cancer escape from immune surveillance, the role of IL-10 in this regard has been underestimated although recent advances have reported that IL-10 induces both PC proliferation and angiogenesis in MM. In addition, cumulative studies have suggested that IL-10 plays an important role in the induction of chemoresistance in many cancers; a virtual requirement of autocrine IL-10 for MM cells to escape from an IL-6-dependent proliferation loop was implicated. In this review, we summarize the available information to elucidate a new understanding of the molecular and functional roles of IL-10 in MM., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Tzu Chi Medical Journal.)

This observational study evaluated the treatment outcomes of clinical factors on the patients with lung adenocarcinoma with epidermal growth factor receptor mutations who received tyrosine kinase inhibitors as first-line treatment.Patients with stage IIIb or IV lung adenocarcinoma with mutated epidermal growth factor receptor were enrolled retrospectively between March 2010 and December 2017. The hematologic markers on progression-free survival (PFS) and overall survival (OS) were analyzed.Totally 190 patients were enrolled. In univariate analysis by hematologic markers, lower lymphocyte percentage and higher platelet count were associated with significantly poor PFS and OS. Multivariate analysis showed lower lymphocyte percentage was independent poor prognostic factors for PFS and OS. Higher platelet count was an independent poor prognostic factor for OS only.Patients with lung adenocarcinoma receiving tyrosine kinase inhibitors with lower lymphocyte percentage and higher platelet count had poorer prognoses compared with other patients.

Objective: Human interleukin-10 (IL-10) is a dimeric and pleiotropic cytokine that plays a crucial role in cellular immunoregulatory responses. As IL-10 binds to its receptors, IL-10Ra and IL-10Rb, it will suppress or induce the downstream cellular immune responses to protect from diseases., Materials and Methods: In this study, a potential peptide derived from IL-10 based on molecular docking and structural analysis was designed and validated by a series of cell assays to block IL-10 binding to receptor IL-10Ra for the inhibition of cell growth., Results: The simulation results indicate that the designed peptide IL10NM25 bound to receptor IL-10Ra is dominated by electrostatic interactions, whereas van der Waals (VDW) and hydrophobic interactions are minor. The cell experiments showed that IL10NM25 specifically binds to receptor IL-10Ra on the cell surface of two B-lineage cell lines, B lymphoma derived (BJAB), and lymphoblastoid cell line, whereas the mutant and scramble peptides are not able to suppress the binding of IL-10 to receptor IL-10Ra, consistent with the molecular simulation predictions., Conclusion: This study demonstrates that structure-based peptide design can be effective in the development of peptide drug discovery., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Tzu Chi Medical Journal.)

Introduction: Immune thrombocytopenia (ITP) is known as an immune-mediated disease and often evolves to chronic type in adult. Corticosteroids only work in around 60% of patients. This study evaluated the roles of subgroup lymphocytes from peripheral blood in ITP adults with different treatment response., Methods: Between October 2009 and March 2017, 37 adults were newly diagnosed as ITP requiring treatment. The patients were separated into two groups: 23 patients with platelet count <50,000/μL with corticosteroid dependence or second-line treatment (Poor-responder Group), and 14 patients with platelet counts <50,000/μL with standard steroid treatment, which stopped within three months (Good-responder Group). Subgroup lymphocyte percentages of peripheral blood were determined through flow cytometry before treatment. Data analysis with Mann-Whitney test and receiver operating characteristic curves were performed using GraphPad Prism (Version 7). A p-value of <0.05 was considered significant., Results: Lymphocyte percentage was significantly lower in Poor-responder Group than in Good-responder Group (p = 0.008). In subgroup lymphocytes, higher percentages of CD19+ B lymphocytes were found in Good-responder Group (p = 0.03). In Poor-responder Group, a higher CD2+ and CD56+ lymphocytes were observed (p = 0.02 and 0.03). By the cut-off value of percentage of CD56+ lymphocytes with 24.5% or CD2+ lymphocytes with 85.7%, the specificity showed 92.86%., Conclusions: This study found that newly diagnosed ITP patients with increased percentages of CD56+ or CD2+ lymphocytes in peripheral blood associated with a poorer response to steroid treatment., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Diabetic nephropathy is the most common cause of end-stage renal disease. Traditional therapy for diabetic nephropathy has focused on supportive treatment, and there is no significant effective therapy. We investigated the effect of low-energy extracorporeal shock wave therapy on a diabetic nephropathy rat model., Methods: Streptozotocin-induced diabetic nephropathy rats were treated with six sessions of low-energy extracorporeal shock wave therapy (weekly for six consecutive weeks) or left untreated. We assessed urinary creatinine and albumin, glomerular volume, renal fibrosis, podocyte number, renal inflammation, oxidative stress, and tissue repair markers (SDF-1 and VEGF) six weeks after the completion of treatment., Results: The six-week low-energy extracorporeal shock wave therapy regimen decreased urinary albumin excretion as well as reduced glomerular hypertrophy and renal fibrosis in the rat model of diabetic nephropathy. Moreover, low-energy extracorporeal shock wave therapy increased podocyte number in diabetic nephropathy rats. This was likely primarily attributed to the fact that low-energy extracorporeal shock wave therapy reduced renal inflammation and oxidative stress as well as increased tissue repair potency and cell proliferation., Conclusions: Low-energy extracorporeal shock wave therapy preserved kidney function in diabetic nephropathy. Low-energy extracorporeal shock wave therapy may serve as a novel noninvasive and effective treatment of diabetic nephropathy.

Since it was discovered as the first human tumor virus in 1964, Epstein-Barr Virus (EBV) is now implicated in several types of malignancies. Accordingly, certain aspects of EBV pathobiology have shown promise in anti-cancer research in developing virus-targeting methods for EBV-associated cancers. The unique role of EBV nuclear antigen 1 (EBNA1) in triggering episome-dependent functions has made it as the only latent gene to be expressed in most EBV+ neoplasms. Dimeric EBNA1 binds to the replication origin (oriP) to display its biological impact on EBV-driven cell transformation and maintenance. Hence, EBNA1/oriP has been made an ideal drug target site for anti-EBV protocol development. GAP31 protein was originally isolated from the seeds of an ancient medicinal plant Gelonium multiflorum. Although GAP31 has been shown to exhibit both anti-viral and anti-tumor activity, current understanding of the mechanistic picture underlying GAP31 functioning is not clear. Herein, we identify the EBNA1 DNA-binding domain as a core for GAP31 binding by performing affinity pulldown assays. Recombinant GAP31 (rGAP31) was shown to impair EBNA1-induced dimerization; consequently, it abrogated both EBNA1/oriP-mediated binding and transcription. Importantly, the therapeutic effects of GAP31 showed its capability to abrogate EBV-driven cell transformation and proliferation, and EBV-dependent tumorigenesis in xenograft animal models. Notably, the EBNA1 binding-mutant rGAP31 R166A/R169A simply exhibits defective phenotypes in the above-mentioned studies. Our data suggest rGAP31 is a potential anti-viral drug which can be applied to the development of therapeutic strategies against EBV-related malignancies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: This study was conducted to evaluate the effect of clinical factors on the treatment outcomes of lung cancer patients with active epidermal growth factor receptor (EGFR) mutations treated by first-line tyrosine kinase inhibitors (TKIs)., Methods: Patients of stage IIIb or IV lung adenocarcinoma harboring mutated EGFR were enrolled between March 2010 and June 2014 and followed up until December 2015. The effects of various clinical features, such as age, sex, smoking history, EGFR mutation types, TKIs used, presence of pleural effusion, metastatic sites on progression-free survival (PFS) and overall survival (OS), were analyzed retrospectively., Results: A total of 104 patients were included in this study. Patients with pleural effusion at initial diagnosis had significantly shorter PFS and OS than those without pleural effusion (median PFS: 8.2 months vs 15.3 months, P = 0.0004; median OS: 16.3 months vs 28.2 months, P = 0.0003). Univariate analysis revealed that being male or a smoker was associated with short PFS, whereas smoking history, bony metastasis and malignant pleural effusion were associated with poor OS. Stepwise multivariate Cox regression analysis showed that the presence of pleural effusion and different TKI use were independent prognostic factors for PFS [hazard ratio [HR] = 2.50 (95% confidence interval [CI], 1.53-4.10), P = 0.0003 and HR = 0.55 (95% CI, 0.31-0.97), P = 0.0396, respectively], whereas the presence of pleural effusion and liver metastasis were associated with poor OS [HR = 2.79 (95% CI: 1.46-5.30), P = 0.0018 and HR = 2.12 (95% CI, 1.02-4.40), P = 0.0440, respectively]., Conclusion: The presence of pleural effusion predicts poor PFS and OS in lung adenocarcinoma patients receiving TKIs as the first-line treatment. Additional studies are warranted to elucidate the underlying mechanisms and determine novel strategies for improving the outcome of these patients., (© 2017 John Wiley & Sons Australia, Ltd.)

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and acquired hematopoietic stem cell disease, with florid clinical presentations. Although this disease has been characterized in the western countries, its clinical and laboratory features in Taiwan have not yet been reported., Results: As a part of an international prospective, non-interventional, observational registration trial of PNH, we have analyzed 63 patients recruited between 2009 and 2015 in Taiwan, with comparison to the 3857 patients in the rest of the world (ROW). The median age of diagnosis of our patients is 46 (range 9-84), without sex preponderance. While most of the clinical and laboratory presentations of our patients are similar to the ROW, ours have higher lactate dehydrogenase levels, lower hemoglobin, and higher frequencies of symptoms including shortness of breath and erectile dysfunction at the time of diagnosis. The incidence of thromboembolism was not statistically different between ours and the ROW (6.7 % vs 13.5 %, P = 0.178). The patients in Taiwan were treated more frequently with corticosteroid (53.2 % vs 32 %, P < 0.001), but less frequently with cyclosporine/anti-thymocyte globulin and heparin/warfarin, both P < 0.001)., Conclusions: This is the first systematic review on the Taiwanese PNH patients. Our analysis would provide key information about our PNH patients and would help understanding the basic characteristics of this rare disease in Taiwan., Trial Registration: This trial has been registered to ClinicalTrails.gov NCT01374360.

Primary myelofibrosis is a clonal disease of chronic myeloproliferative neoplasm, and is a progressive clinical course with short median survival of less than 5 years after diagnosis. Leukemic transformation occurs in 8-23 % of myelofibrosis patients, and survival is about 3 months after transformation to leukemia. Thalidomide, an oral immunomodulatory drug, has been used effectively in the treatment of primary myelofibrosis, in which some patients could become transfusion independent, and showed improvement in thrombocytopenia and reduction in spleen size. Here, we report a patient with primary myelofibrosis with leukemic transformation who survived for more than 6 years with thalidomide monotherapy. Thalidomide may be beneficial for some myelofibrosis patients with leukemic transformation for whom intensive chemotherapy is not indicated.

Background: Extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae isolates are important clinical pathogens. In addition, the efficacy of cefepime for such infections is controversial., Methods: We performed a retrospective study of monomicrobial bacteremia caused by ESBL producers at 2 medical centers between May 2002 and August 2007. The patients definitively treated with in vitro active cefepime (cases) were compared with those treated with a carbapenem (controls) in a propensity score-matched analysis to assess therapeutic effectiveness. The 30-day crude mortality is the primary endpoint., Results: A total of 178 patients were eligible for the study. Patients who received cefepime (n = 17) as definitive therapy were more likely to have a clinical failure (odds ratio [OR] 6.2; 95% confidence interval [CI], 1.7-22.5; P = .002), microbiological failure (OR 5.5; 95% CI, 1.3-25.6; P = .04), and 30-day mortality (OR 7.1; 95% CI, 2.5-20.3; P < .001) than those who received carbapenem therapy (n = 161). Multivariate regression revealed that a critical illness with a Pitt bacteremia score ≥ 4 points (OR 5.4; 95% CI, 1.4-20.9; P = .016), a rapidly fatal underlying disease (OR 4.4; 95% CI, 1.5-12.6; P = .006), and definitive cefepime therapy (OR 9.9; 95% CI, 2.8-31.9; P < .001) were independently associated with 30-day crude mortality. There were 17 case-control pairs in the propensity scores matched analysis. The survival analysis consistently found that individuals who received cefepime therapy had a lower survival rate (log-rank test, P = .016)., Conclusions: Based on the current Clinical and Laboratory Standards Institute susceptible breakpoint of cefepime (minimum inhibitory concentration ≤ 8 μg/mL), cefepime definitive therapy is inferior to carbapenem therapy in treating patients with so-called cefepime-susceptible ESBL-producer bacteremia.

A retrospective study was conducted at two medical centers in Taiwan to evaluate the clinical characteristics, outcomes, and risk factors for mortality among patients treated with a carbapenem for bacteremia caused by extended-spectrum-beta-lactamase (ESBL)-producing organisms. A total of 251 patients with bacteremia caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates treated by a carbapenem were identified. Among these ESBL-producing isolates, rates of susceptibility to ertapenem (MICs ≤ 0.25 μg/ml) were 83.8% and 76.4%, respectively; those to meropenem were 100% and 99.3%, respectively; and those to imipenem were 100% and 97.9%, respectively. There were no significant differences in the critical illness rate (P = 0.1) or sepsis-related mortality rate (P = 0.2) for patients with bacteremia caused by ESBL-producing K. pneumoniae (140 isolates, 55.8%) and E. coli (111 isolates, 44.2%). Multivariate analysis of variables related to sepsis-related mortality revealed that the presence of severe sepsis (odds ratio [OR], 15.9; 95% confidence interval [CI], 5.84 to 43.34; P < 0.001), hospital-onset bacteremia (OR, 4.65; 95% CI, 1.42 to 15.24; P = 0.01), and ertapenem-nonsusceptible isolates (OR, 5.12; 95% CI, 2.04 to 12.88; P = 0.001) were independent risk factors. The patients receiving inappropriate therapy had a higher sepsis-related mortality than those with appropriate therapy (P = 0.002), irrespective of ertapenem, imipenem, or meropenem therapy. Infections due to the ertapenem-susceptible isolates (MICs ≤ 0.25 μg/ml) were associated with a more favorable outcome than those due to ertapenem-nonsusceptible isolates (MICs > 0.25 μg/ml), if treated by a carbapenem. However, the mortality for patients with bacteremic episodes due to isolates with MICs of ≤ 0.5 μg/ml was similar to the mortality for those whose isolates had MICs of >0.5 μg/ml (P = 0.8). Such a finding supports the rationale of the current CLSI 2011 criteria for carbapenems for Enterobacteriaceae.

Background: The purpose of this study is to delineate clinical characteristics of urosepsis caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae (ESBL-EK) in different clinical settings, with an emphasis on community-acquired infections., Methods: A retrospective study was conducted at two medical centers in Taiwan. From May 2002 to August 2007, clinical data of adults with urosepsis caused by ESBL-EK were collected. Patients were categorized into three groups according to the place of acquisition. Baseline characteristics, microbiological data and clinical outcomes were compared., Results: Ninety-three cases of ESBL-EK urosepsis were included. Their mean age was 69.4 years, and 48.4% were men. Eleven (11.8%), 41 (44.1%), and 41 (44.1%) patients were categorized as having community-acquired, healthcare-associated, and hospital-acquired infections, respectively. Cases of ESBL-EK urosepsis from different settings shared similar characteristics in terms of age, gender, comorbidity and resistance profiles of bacterial strains. Of the bacterial isolates, 75% and 38.7% were resistant to fluoroquinolones and aminoglycosides, respectively. Cases of community-acquired urosepsis had a lower disease severity than those acquired in healthcare facilities or hospitals. Of note, there was no case fatality in 11 cases of community-acquired urosepsis and, in contrast, a crude mortality rate of 41.5% was found among adults with hospital-acquired urosepsis (p < 0.001)., Conclusion: A limited number of adults with community-acquired urosepsis caused by ESBL-EK in the present study had a favorable outcome. Nonetheless, clinicians should be cautious of the emergence of urinary tract infections caused by ESBL-producers in the community setting., (Copyright © 2011. Published by Elsevier B.V.)

Background: Clinical information about bacteremia due to extended-spectrum β-lactamase (ESBL)-producing pathogens in cancer patients was limited. The study was aimed to identify the clinical manifestations and risk factors for mortality in ESBL-producer bacteremia in cancer patients., Methods: A retrospective study of bacteremia caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae in adults with cancer in National Cheng Kung University Hospital and National Taiwan University Hospital from July 2002 to August 2007 was conducted. Clinical characteristics, initial manifestations, and antimicrobial therapy were analyzed for their association with crude mortality at 14 days after bacteremia onset., Results: A total 113 episodes of bacteremia caused by E coli (59.3%), K pneumoniae (39.8%) or both (0.9%) were included. Patients with hematological malignancy were younger (55 ± 22 vs. 69 ± 14 years, p < 0.003) and had less co-morbidity, but were more likely to have neutropenia (73.1% vs. 4.6%, p < 0.001) than those with solid tumor. By the univariate analysis in 113 episodes of ESBL-producer bacteremia, several risk factors, including pneumonia or soft-tissue infection as the bacteremia source, initial manifestations with high Pitt bacteremia scores, shock, respiratory failure or severe sepsis, and inappropriate definitive therapy were associated with 14-day crude mortality. By multivariate analysis, only pneumonia [adjusted odds ratio (AOR), 5.2; 95% confident interval (CI), 1.3-21.0; p = 0.021], severe sepsis (AOR, 24.3; 95% CI, 5.6-105.0; p < 0.001), and inappropriate definitive therapy (AOR, 11.3; 95% CI, 1.7-72.8; p = 0.011) were independently associated with a fatal outcome., Conclusion: The presence of neutropenia or underlying hematological malignancy in cancer patients with ESBL-producer bacteremia was not associated with an increase in the mortality rate. Appropriate definitive antimicrobial therapy will be beneficial in improving clinical outcome., (Copyright © 2011. Published by Elsevier B.V.)

For 244 patients with bacteremia due to extended-spectrum β-lactamase (ESBL)-producing Escherichia coli or Klebsiella pneumoniae treated by ertapenem (73, 29.9%) or either imipenem or meropenem (171, 70.1%), the therapeutic efficacy was evaluated. Ertapenem therapy was effective for patients with ESBL-producing E. coli or K. pneumoniae bacteremia in terms of mortality and microbiological responses, as compared with imipenem or meropenem., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Here we report a novel electrophoretic deposition technology for assembling surface-roughened inorganic nanoplatelets into ordered multilayers that mimic the brick-and-mortar nanostructure found in the nacreous layer of mollusk shells. A thin layer of sol-gel silica is coated on smooth gibbsite nanoplatelets in order to increase the surface roughness to mimic the asperity of aragonite platelets found in nacres. To avoid the severe cracking caused by the shrinkage of sol-gel silica during drying, polyelectrolyte polyethyleneimine is used to reverse the surface charge of silica-coated-gibbsite nanoplatelets and increase the adherence and strength of the electrodeposited films. Polymer nanocomposites can then be made by infiltrating the interstitials of the aligned nanoplatelet multilayers with photocurable monomer followed by photopolymerization. The resulting self-standing films are highly transparent and exhibit nearly three times higher tensile strength and one-order-of-magnitude higher toughness than those of pure polymer. The measured tensile strength agrees with that predicted by a simple shear lag model., (Published by Elsevier Inc.)