Fluctuation of BCR-ABL1 qPCRIS level beyond 0.1%IS after stopping tyrosine kinase inhibitor in chronic myeloid leukaemia patients with deep molecular response for at least two years

Fluctuation of BCR-ABL1 real-time quantitative polymerase chain reaction in International Scale (qPCRIS ) level below major molecular response (MMR) (0.1%IS ) is a known phenomenon after stopping tyrosine kinase inhibitor (TKI) in chronic myeloid leukaemia (CML) patients who are attempting treatment free remission (TFR). We report here four cases of fluctuation beyond MMR during conduct of a Malaysia Stop TKI Trial (MSIT) to examine the validity of the commonly used relapse criterion – loss of MMR for one reading – aiming to provide evidence in setting relapse criteria for future CML patients who want to attempt TFR

A randomized control trial comparing peginterferon-α-2a versus observation after stopping tyrosine kinase inhibitor in chronic myeloid leukemia with deep molecular response for at least two years

Background: There is much advancement in treatment of chronic myeloid leukemia (CML) since the approval of first tyrosine kinase inhibitor (TKI), imatinib, by US FDA in 2001. One of them is definitely the concept of stopping TKI, starting at the CML patients who have achieved deep molecular response (MR) of MR4.5 for a reasonable long period of at least two years, pioneered by the researchers from French and Australia. Meanwhile, interferon, the standard treatment of CML before the era of TKI, showed that interferon-responded patients may indeed retain the response once interferon was withdrawn via interferon-induced immunity towards the leukemic clone. This is further supported by stop trial in Japan, in which after stopping TKI, interferon was given for 2 years and it showed a higher drug-free rate compared to stop trial from French and Australia. Hence, it is logical to postulate the use of interferon after TKI was stopped when patients have attained deep MR for more than two years will increase the percentage of patients remain TKI-free on follow-up. Materials and Methods: This is a multi-center randomized controlled trial. Adult CML patients, diagnosed in chronic phase, treated with ongoing TKI for at least 3 years without previous history of TKI failure and have achieved stable deep MR on International Scale for ≥2 years with at least 2 readings of MR4.5 (including the latest before study entry), were randomized into 2 arms: (1) peginterferon-α-2a, subcutaneous weekly, starting at 180 mcg, or (2) observation. Disease is monitored by PCR (centralized in Ampang Hospital) at monthly for the first year, 2 monthly for the second year and 3 monthly for the third year. Relapse is defined as either (i) one reading of loss of major MR, i.e. reading of >0.1% IS and confirmed by second analysis taken 1 month later if the first analysis point reading is ≤1% IS, or (ii) positivity of BCR-ABL1 transcripts, as confirmed by a second analysis point, indicating the increase (at least 1 log) in relation to the first analysis point at two successive assessments. Quality of Life is assessed using EORTC QLO-C30. Results: At the time of writing, total of 8 patients were randomized, 5 into peginterferon arm, 3 into observation arm, all were on imatinib, M:F = 4:4, Malay: Chinese:Indian = 3:4:1, median age 49.5 (range 25-58), median follow-up 4 months (range 1-6) and none of them relapse. Two patients developed imatinib withdrawal syndrome, both female on observation arm, one was mild and resolved after 2 months but one was severe and needed termination after 2 months and restarted on imatinib. Two patients in peginterferon arm developed mild hepatitis with liver enzymes <2x of ULN. Four patients were able to tolerate peginterferon-α-2a at the dose of 180 mcg weekly, while one patient needed dose reduction to 90 mcg weekly. Quality of life score comparing two months after stopping TKI and baseline will be presented in the conference later. Conclusion: No conclusive date can be drawn so far because sample size is small and follow-up is short. Nonetheless, this trial provides Malaysian CML a platform to stop TKI safely

DNA metabarcoding unravels unknown diversity and distribution patterns of tropical freshwater invertebrates

Tropical freshwater invertebrate species are becoming extinct without being described, and effective conservation is hampered by a lack of taxonomic and distribution data. DNA metabarcoding is a promising tool for rapid biodiversity assessments that has never been applied to tropical freshwater invertebrates across large spatial and taxonomic scales. Here we use DNA metabarcoding to comprehensively assess the benthic freshwater invertebrate fauna of the Perak River basin, Malaysia. Specific objectives were to: (1) assess performance of two DNA metabarcoding protocols; (2) identify gaps in reference databases; (3) generate new data on species diversity and distribution; and (4) draw conclusions regarding the potential value of DNA metabarcoding in tropical freshwater conservation. Organisms were collected by hand and net at 34 sites and divided into small (retained in 0.5-mm but passing through 1-mm mesh) and large (retained in 1-mm mesh) fractions, and a 313-bp cytochrome c oxidase subunit I fragment amplified and sequenced using general Metazoa primers. Bioinformatic analysis resulted in 468 operational taxonomic units (~species) from 12 phyla. Only 29% of species could be assigned binominal names through matches to public sequence libraries, indicating varying levels of library completeness across Orders. Extraction of small-fraction DNA with a soil kit resulted in a significantly higher species count than with a general kit, but this was not even across taxa. Metabarcoding (amplification) success rate, estimated via comparison to morphological identifications of the large-fraction specimens, was high in most taxa analysed but low, for example, in ampullariid and viviparid gastropods. Conversely, a large proportion of species-site records for Decapoda and Bivalvia came from metabarcoding only. Species richness averaged 29 ± 16 species per site, dominated by Diptera, Annelida, and Odonata, and was particularly high in tributaries of the mountainous Titiwangsa Range. At least eight species are new records for Malaysia, including the non-natives Ferrissia fragilis (Gastropoda) and Dugesia notogaea (Platyhelminthes). Our study showed that DNA metabarcoding is generally more effective in detecting tropical freshwater invertebrate species than traditional morphological approaches, and can efficiently improve knowledge of distribution patterns and ranges of native and non-native species. However, current gaps in reference databases, particularly for bioindicator taxa, such as the Plecoptera, Ephemeroptera, and Coleoptera, need to be addressed urgently

Role of ARABIDOPSIS A-FIFTEEN in regulating leaf senescence involves response to reactive oxygen species and is dependent on ETHYLENE INSENSITIVE2

Leaf senescence is a highly regulated developmental process that is coordinated by several factors. Many senescence-associated genes (SAGs) have been identified, but their roles during senescence remain unclear. A sweet potato (Ipomoea batatas) SAG, named SPA15, whose function was unknown, was identified previously. To understand the role of SPA15 in leaf senescence further, the orthologue of SPA15 in Arabidopsis thaliana was identified and characterized, and it was named ARABIDOPSIS A-FIFTEEN (AAF). AAF was expressed in early senescent leaves and in tissues with highly proliferative activities. AAF was localized to the chloroplasts by transient expression in Arabidopsis mesophyll protoplasts. Overexpression of AAF (AAF-OX) in Arabidopsis promoted, but the T-DNA insertion mutant (aaf-KO), delayed age-dependent leaf senescence. Furthermore, stress-induced leaf senescence caused by continuous darkness was enhanced in AAF-OX but suppressed in aaf-KO. Transcriptome analysis of expression profiles revealed up-regulated genes related to pathogen defence, senescence, and oxidative stress in 3-week-old AAF-OX plants. Indeed, elevated levels of reactive oxygen species (ROS) and enhanced sensitivity to oxidative and dark stress were apparent in AAF-OX but reduced in aaf-KO. ETHYLENE INSENSITIVE2 (EIN2) was required for the dark- and ROS-induced senescence phenotypes in AAF-OX and the induction of AAF expression by treatment with the immediate precursor of ethylene, 1-aminocyclopropane-1-carboxylic acid. The results indicate the functional role of AAF is an involvement in redox homeostasis to regulate leaf senescence mediated by age and stress factors during Arabidopsis development

DNA metabarcoding unravels unknown diversity and distribution patterns of tropical freshwater invertebrates

Tropical freshwater invertebrate species are becoming extinct without being described, and effective conservation is hampered by a lack of taxonomic and distribution data. DNA metabarcoding is a promising tool for rapid biodiversity assessments that has never been applied to tropical freshwater invertebrates across large spatial and taxonomic scales. Here we use DNA metabarcoding to comprehensively assess the benthic freshwater invertebrate fauna of the Perak River basin, Malaysia. Specific objectives were to: (1) assess performance of two DNA metabarcoding protocols; (2) identify gaps in reference databases; (3) generate new data on species diversity and distribution; and (4) draw conclusions regarding the potential value of DNA metabarcoding in tropical freshwater conservation. Organisms were collected by hand and net at 34 sites and divided into small (retained in 0.5-mm but passing through 1-mm mesh) and large (retained in 1-mm mesh) fractions, and a 313-bp cytochrome c oxidase subunit I fragment amplified and sequenced using general Metazoa primers. Bioinformatic analysis resulted in 468 operational taxonomic units (~species) from 12 phyla. Only 29% of species could be assigned binominal names through matches to public sequence libraries, indicating varying levels of library completeness across Orders. Extraction of small-fraction DNA with a soil kit resulted in a significantly higher species count than with a general kit, but this was not even across taxa. Metabarcoding (amplification) success rate, estimated via comparison to morphological identifications of the large-fraction specimens, was high in most taxa analysed but low, for example, in ampullariid and viviparid gastropods. Conversely, a large proportion of species-site records for Decapoda and Bivalvia came from metabarcoding only. Species richness averaged 29 ± 16 species per site, dominated by Diptera, Annelida, and Odonata, and was particularly high in tributaries of the mountainous Titiwangsa Range. At least eight species are new records for Malaysia, including the non-natives Ferrissia fragilis (Gastropoda) and Dugesia notogaea (Platyhelminthes). Our study showed that DNA metabarcoding is generally more effective in detecting tropical freshwater invertebrate species than traditional morphological approaches, and can efficiently improve knowledge of distribution patterns and ranges of native and non-native species. However, current gaps in reference databases, particularly for bioindicator taxa, such as the Plecoptera, Ephemeroptera, and Coleoptera, need to be addressed urgently

Вихретоковый анизотропный термоэлектрический первичный преобразователь лучистого потока

Представлена оригинальная конструкция первичного преобразователя лучистого потока, который может служить основой для создания приемника неселективного излучения с повышенной чувствительностью

Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis