St Generation Research Articles

And-Gate CAR T-Cells to Improve Tumour Specificity and Targeting of Low-Expression Antigens in Multiple Myeloma

Whilst chimeric antigen receptor (CAR) T cells have shown remarkable success, further novel targets are required. However, our previous cell surface proteomics work in multiple myeloma (MM) showed that target choice is highly limited by an absence of truly tumour-specific antigens, and often very low on-tumour expression of target proteins in some primary samples. One approach to improve tumour specificity is to use combinatorial antigen recognition, or “AND-gates”, whereby a CAR T cell must recognise two different antigens for full activation and target cell elimination. It has also been reported that this approach might overcome low target expression. We therefore decided to explore the potential for AND-gate targeting in MM and identify a suitable target pairing. To determine a comprehensive list of viable AND-gate combinations for MM, we first integrated our MM proteomics data with a normal tissue proteomics dataset. From 777 extracellular proteins expressed in primary MM, we identified a total of 287,890 possible pairwise combinations. We next excluded any pairs with overlapping expression in vital, healthy tissues, reducing potential combinations to 664. Additional filtering steps to remove difficult-to-target proteins and combinations where either target was expressed on T cells - thus avoiding T cell fratricide - resulted in a final list of 92 AND-gate targets. From our prioritised candidates, we selected TNFRSF8 and TMPRSS11E as an exemplar pairing. By mass spectrometry, both TNFRSF8 and TMPRSS11E were expressed across all 8 profiled primary MM samples at comparable levels to existing CAR T cell targets, such as GPRC5D, and had no predicted overlapping expression in normal tissue. To test our AND-gate combination, we designed a ‘split-CAR’ system in which TNFRSF8 was targeted by a 1 st generation CAR with an intracellular signalling domain, but without a co-stimulatory receptor (CAR-only construct), and TMPRSS11E was targeted by a construct with a chimeric co-stimulatory receptor (CCR), but lacking an intracellular signalling domain (CCR-only construct). Constructs were initially validated in a Jurkat cell line model of T cell activation. Jurkats were transformed with CCR-only, CAR-only, or both constructs, as well as with full 2 nd generation CARs targeting TNFRSF8 or TMPRSS11E. These cells were co-cultured with the TNFRSF8+TMPRSS11E+ human MM cell line XG1 or the TNFRSF8+TMPRSS11E- erythroleukemic cell line K562. As anticipated, neither the CCR-only nor the CAR-only Jurkats were activated, with no production of IFNγ or IL2 ( Fig. 1A). Whilst Jurkats expressing the full 2 nd generation TMPRSS11E CAR were activated in co-culture with XG1, Jurkats expressing the TNFRSF8 2 nd generation CAR were not, despite expression of TNFRSF8 on XG1. Jurkats co-expressing both components of the split-CAR were markedly activated when co-cultured with TNFRSF8+TMPRSS11E+ XG1 cells (but not with TNFRSF8+TMPRSS11E- K562 cells), as demonstrated by a large increase in expression of CD69, IFNγ, and IL2 ( Fig. 1A). Thus, the split-CAR system showed a very high degree of specificity, requiring both antigens to be co-expressed on the target cell. Moreover, it was activated even when full 2 nd generation CARs against TNFRSF8 were not. Next, we sought to investigate the cytolytic activity of our split-CAR constructs in donor T cells. In a cytotoxicity assay, T cells expressing the CAR-only or CCR-only construct did not exhibit significant killing of XG1 cells ( Fig. 1B). In parallel with the Jurkat reporter assays, only 2 nd generation TMPRSS11E CAR T cells, and not 2 nd generation TNFRSF8 CAR T cells, were cytotoxic to XG1. Finally, donor T cells expressing both components of the split-CAR demonstrated potent killing of dual-positive XG1 cells ( Fig. 1B), but not single-positive K562 cells. We have thus developed an analytical pipeline for the discovery of AND-gate CAR T cell targets for MM, also applicable to other tumours. This approach led to the development of an extremely potent, but highly selective, split-CAR targeting TNFRSF8 and TMPRSS11E. Importantly, our split-CAR targeted very low levels of TNFRSF8 antigen that were insufficient to trigger activation of a 2 nd generation TNFRSF8 CAR-T. In summary, our work suggests that AND-gate targeting can increase not just specificity, but potency, even against very low expression tumour targets in MM. Link to preprint https://doi.org/10.1101/2023.04.04.535580

Debio 1562M, a Next Generation Antibody Drug Conjugate (ADC) Targeting CD37 for AML and MDS Treatment

CD37 is a trans-membrane protein specifically expressed on normal hematopoietic tissues such as B cells, neutrophils and macrophages, and has demonstrated roles in adhesion, cell migration (de Winde et al, 2018; Wee et al, 2015), survival and apoptotic signals (Lapalombella et al, 2012). Increased expression of CD37 has been observed in various hematological cancers such as lymphomas, Chronic Lymphocytic Leukemia (CLL) and Acute Myeloid Leukemia (AML) (Beckwith et al, 2014; Deckert et al, 2013; Pereira et al, 2015; Yan et al, 2021). Higher expression of CD37 was also associated with poor patient outcome in AML (Zhang et al, 2020; Larkin et al, ASH 2018). Debio 1562M is a second-generation novel ADC directed against CD37 and including Debiopharm's proprietary Multilink cleavable linker-payload technology. Multilink improves manufacturing to achieve homogenous high drug antibody ratio while retaining excellent solubility as well as favorable biologic characteristics with preserved internalization kinetics on target cells. Debio 1562M is conjugated to 8 molecules of a tubulin-binding agent and despite cleavable linker that ensure effective intracellular delivery of toxic payload, we show sustained plasma stability in vitro and in vivo with no premature extracellular release. In this work, we report Debio 1562M specificity and potent antitumor activity in multiple AML models both in vitro and in vivo. First, in our in vitro cytotoxicity assay, Debio 1562M displayed nano- to picomolar anti-proliferative activity in both AML cell lines and primary samples. Out of 30 primary samples tested, 20 were sensitive to Debio 1562M with IC50 ranging from 1 to 10nM, this regardless of their mutation status, subtype or medical history. Interestingly, we observed that AML cells have high internalization capability and therefore relatively low levels of surface CD37 is sufficient for cytotoxic activity. The specificity of Debio 1562M was demonstrated by using 3 different CD37 knock out AML cell lines which were generated by CRISPR-Cas9 technology. Parental and CD37 KO cells were treated for 72h with a dose range of Debio 1562M and viability was measured (Figure 1). While Debio 1562M has an IC50 below 1nM in all 3 parental cell lines, its activity is reduced by more than 2 log in the KO cell lines. In vivo, in 3 different AML cell line xenograft mouse models, a single injection of Debio 1562M at 5mg/kg induced complete tumor regression and all mice remained alive at study termination, more than 60 days after treatment, except one mouse in one model. In a patient derived xenograft (PDX) model, the same dose of Debio 1562M significantly reduced tumor burden in blood and bone marrow with sustained activity 42 days after treatment (37% and 98% of blasts in blood and bone marrow respectively in control animals versus 0% and 3% in treated mice, pvalue<0.001). Furthermore, we evaluated the activity of Debio 1562M over venetoclax and azacytidine combination in the MV4-11 Luciferase xenografted mouse model. NCG mice were inoculated with 1x10 7 cells in the tail vein and randomization in groups of 8 mice was performed 14 days later. Mice received either one administration of Debio 1562M at 5mg/kg or a combination of venetoclax (QDx14 100mg/kg) and azacitidine (QDx5 3,5mg/kg). Complete regression of the tumor was observed in all mice after Debio 1562M administration and all mice survived at study termination, 75 days after treatment while none survived after 56 days when treated with venetoclax and azacitidine combination (Figure 2). The toxicology profile of Debio 1562M in mice showed expected clinical signs related to the payload's off target toxicity but with a significant safety margin. Interestingly, no peripheral neuropathy symptoms were detected, as commonly observed for this class of payload. Additionally, Multilink TM-payload construct alone was not associated with any signs of toxicity. On-target toxicity profile couldn't be evaluated as Debio 1562M isn't cross reactive with mouse CD37, however 1 st generation CD37 ADC has already demonstrated safety and tolerability in Phase 1 and 2 clinical trials.Overall, our data confirm the relevance of CD37 targeting for AML treatment. The excellent antitumor activity and tolerability of Debio 1562M in several pre-clinical models now pave the way for upcoming clinical development.

Flumatinib Versus Nilotinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Introduction Tyrosine kinase inhibitors (TKIs) have considerably improved the long-term clinical outcomes in patients with chronic phase chronic myeloid leukemia (CML-CP). Most of these patients receive 1 st generation TKI imatinib as first-line therapy; however, an increasing number of patients are now receiving 2 nd generation TKIs as first-line therapy, because of the more potent BCR-ABL1 inhibition with proven efficacy in patients resistant or intolerant to imatinib. Flumatinib is a novel 2 nd generation BCR-ABL1 TKI with promising efficacy and manageable safety in newly diagnosed CML-CP. Compared to imatinib, patients treated with flumatinib have achieved significantly higher rates of 12-month major molecular response (MMR) and complete cytogenetic response were observed in patients with CML-CP and that too within a shorter time duration. Though there have been many studies comparing 2 nd generation TKIs vs imatinib in CML-CP, studies comparing clinical outcomes between different 2 nd generation TKIs are scarce. Here, we report the real-world effectiveness and safety of flumatinib and nilotinib in patients with newly diagnosed CML-CP. Methods In this study, adult patients (≥18 years old) with newly diagnosed Philadelphia chromosome-positive (Ph+) CML-CP who received either 300 mg nilotinib twice daily or 600 mg flumatinib once daily, were included, with a follow-up duration of roughly 3 years (NCT04739826). The primary endpoint was the rate of MMR at 12 months as defined by European LeukemiaNet 2020 recommendations (BCR-ABL1 transcript level ≤0.1% in peripheral blood on RT-PCR assay on International Scale [IS]).The secondary endpoints were the rate of early molecular response (EMR) at 3 months (BCR-ABL1 IS ≤10%), the rate of molecular response at 6 months (BCR-ABL1 IS ≤ 1%) and safety (adverse events [AEs] reports in accordance to Common Terminology Criteria for Adverse Events, version 4.03). Results A total of 446 patients were enrolled in the study between November 2020 and August 2022, of which 150 and 296 patients were enrolled in nilotinib and flumatinib groups, respectively. The baseline characteristics were comparable between the two groups (Table 1). No significant difference in the rate of MMR was observed at 12 months between nilotinib and flumatinib (78% vs 80%; P=0.68) . Similarly, no significant difference was observed in the rate of EMR at 3 months (85% vs 89%; P=0.26) and the rate of optimal molecular response at 6 months (93% vs 92%; P=0.70; BCR-ABL1 is ≤1%) between the two groups. The overall safety profile was similar between the two groups. However, hyperbilirubinemia (47% vs 7%), increased ALT (33% vs 12%), increased AST (24% vs 9%), rash (30% vs 18%) and anemia (19% vs 10%) were more frequent in nilotinib group than flumatinib group, whereas diarrhea was lower in nilotinib than flumatinib (2.7% vs 8.8%). The incidence rate of grade 3-4 AEs were reported to be 13% in nilotinib group and 10% in flumatinib group. The safety of flumatinib was more favorable compared to nilotinib in terms of hepatic toxicities, skin toxicities, etc. (Figure 1). Conclusion The efficacy of flumatinib is comparable to nilotinib in Chinese patients with newly diagnosed Ph+ CML-CP. The overall incidences of grade 3-4 AEs were also accessible for the two drugs, nevertheless, a few AEs inclusively hepatic toxicity, anemia and skin toxicity were remarkably lower with flumatinib intervention.

Addressing Chronic Anemia in Sickle Cell Disease: Characterizing Erythropoiesis-Stimulating Agent (ESA) Utilization and Practice Patterns Among Providers

Background: Chronic anemia exerts profound impacts on the morbidity, mortality, and quality of life in individuals with sickle cell disease (SCD), but therapeutic options are limited. Erythropoietin-stimulating agents (ESAs) are the standard of care for managing anemia in chronic kidney disease (CKD). However, their utilization in SCD remains ad hoc, with limited literature and no guidelines supporting the use of ESAs in SCD. To address this knowledge gap, we present preliminary findings from a survey designed to evaluate provider practices and identify factors influencing the use of ESAs in SCD. Methods: We conducted a cross-sectional web-based survey from March-July 2023 among providers taking care of patients with SCD in the United States (US) and internationally. Survey items were developed to assess provider demographic characteristics, practice environments, and provider practices around ESA use in SCD. The data was collected and managed using REDCap electronic data capture tools hosted at the University of Pittsburgh. Descriptive statistics were used to report the data. Results: The survey has been completed by 33 providers as of a cut date of July 23, 2023. Most providers were hematologists who practiced in an academic setting (23/33, 69.7%), with an equal gender distribution (Table 1). The number of patients with SCD seen annually varied, with 101-300 patients being the most common cohort size (13/33, 39.4%). In the 12 months prior to survey completion, 15/33 (45.5%) providers treated at least 1 patient with SCD with ESAs, usually outpatient (Table 2). Commonly reported barriers to outpatient ESA therapy included lack of insurance approval/coverage or cost concerns, lack of provider experience, and patient tolerability/adherence or inability to perform self-injections. Fewer respondents reported no barriers to prescribing ESAs in the outpatient setting, compared to in the acute/inpatient setting (18.2% vs. 48.5%). The most commonly reported indications for starting ESAs in the outpatient setting were chronic anemia from end-stage renal disease or CKD, reduction of blood transfusion requirement, and chronic anemia in patients refractory to approved therapies. Less commonly reported indications include severe or symptomatic anemia alone and chronic anemia in the setting of cardiopulmonary disease. Respondents reported several contraindications to starting ESAs, including a history of venous thromboembolism (VTE), malignancy, stroke, coronary artery disease, hypertension, and frequent vaso-occlusive crises. Respondents also expressed concerns about the cost/insurance coverage, efficacy, safety, patient burden, and appropriate dosing of ESAs in patients with SCD. Only 18/33 (54.5%) respondents reported ever treating outpatients with SCD with ESAs; nearly all of them used 1 st generation ESAs, and a majority used 2 nd generation ESAs. For 1 st generation ESAs, the most common starting dose was 3500-7000 units (U) (50-100 U/kg; 22.2%) or 7001-14000 U (101-200 U/kg; 22.2 %). Once weekly was the most common dosing interval (50%), followed by three times a week (TIW; 27.8%) and twice a week (16.7%). The maximum dose used was 56001-70000 U (801-1000 U/kg) TIW. For 2 nd generation ESAs, the most common starting dose was 141-210 mcg (2.1-3.0 mcg/kg) (22.2%), and administration often occurred once every 2 weeks (44.4%) or weekly (27.8%). The maximum dose used was 211-315 mcg (3.1-4.5 mcg/kg) weekly. Outpatient ESAs were most often initiated for hemoglobin (Hb) < 6 g/dL (8/18, 44.4%), and Hb > 9 g/dL was the most common treatment target (6/18, 33.3%). ESAs were often combined with hydroxyurea, voxelotor, and simple transfusions (Table 2). Conclusion: These preliminary survey results show considerable variability in how ESAs are currently being used in people with SCD. These variations in clinical practice highlight both significant ambiguity about what works in this setting and the need for further research into the optimal use of ESAs for the management of chronic anemia in SCD (ongoing clinical trial: ACHiEvE-SCD, NCT05451940). Future directions include evaluating differences in practice patterns among adult vs. pediatric and US-based vs. non-US-based providers.

Pre-Existing Cardiovascular Disease Increases the Risk of Cardiovascular Adverse Events during Bruton Tyrosine Kinase Inhibitor Therapy

Background Bruton tyrosine kinase inhibitors (BTKis) have revolutionized the treatment of B-cell neoplasms. BTKi treatment has been associated with a higher incidence of cardiovascular adverse events (CVAE), which contribute significantly to morbidity and mortality in this population. Ibrutinib has been more strongly associated with CVAE compared to more selective 2 nd-generation BTKis. Although predisposing factors are not clear, pre-existing cardiovascular disease (CVD) appears to increase the risk of atrial arrhythmias and mortality during BTKi treatment. Our primary objective was to evaluate and compare the rate of CVAE during BTKi therapy, in individuals with and without pre-existing CVD. In addition, we aimed to compare the outcomes of patients treated with 1 st vs. 2 nd generation BTKis and characterize management decisions. Methods A retrospective review was conducted on patients treated with BTKis for hematologic malignancies from 2013 to 2022 at Beth Israel Deaconess Medical Center. Exclusion criteria included prior treatment with anthracyclines and BTKis, prescription of BTKi therapy without administration, prior BTKi treatment for graft-vs-host disease, and loss to follow-up. CVAE were defined as new-onset or worsening atrial fibrillation (AF), new-onset or worsening hypertension (HTN), supraventricular or ventricular arrhythmias, and sudden cardiac death. Pre-existing CVD included coronary artery disease, congestive heart failure, cerebrovascular disease, and pulmonary HTN. Student's t-test and Fisher's exact test were performed to compare the differences in continuous and categorical variables between patients with and without pre-existing CVD, respectively. Logistic regression analyses were performed to evaluate the association between pre-existing CVD and CVAE. All statistics were performed using R version 4.3. Results We identified 274 patients and 180 met inclusion criteria. Primary indications were Chronic Lymphocytic Leukemia (CLL) in 106 patients (60%), Mantle Cell Lymphoma (MCL) in 31 (17.2%), Diffuse Large B-Cell Lymphoma (DLBCL) in 17 (9.4%), and Waldenström Macroglobulinemia (WM) in 16 (8.9%). In terms of BTKi selection, 141 patients (78.3%) received ibrutinib, 35 (19.4%) acalabrutinib, and 4 (2.2%) zanubrutinib. Prevalent comorbidities were HTN in 103 patients (57%), dyslipidemia in 80 (44%), and diabetes in 26 (14%). Overall, 49 patients (27.2%) had preexisting CVD, and 21 (11.6%) experienced CVAE during BTKi therapy. In our cohort, (11/49) patients with pre-existing CVD developed CVAE, compared to (10/131) patients without pre-existing CVD, (22% vs 8% respectively), OR 3.38 (95%CI = [1.3, 8.5], p-value= 0.01). The OR remained robust ranging from 3.4 to 4.1 (p < 0.05) in multiple adjusted logistic regression models, accounting for imbalances in gender, comorbidities, type of BTKi, and baseline medications. Patients with pre-existing CVD had significantly higher odds of developing new or worsening AF, (16% vs. 5% respectively), OR = 3.94, (95%CI = [1.3, 12.0], p-value= 0.02) (Table 1). In subgroup analysis, patients treated with 1 st generation BTKis had a numerically higher rate of CVAE than those treated with 2 nd generation BTKis, OR = 6.28 (95%CI = [0.8, 48.3], p-value= 0.08) (Table 2). Regarding management, BTKi treatment was discontinued in 13 patients (62%) and continued in 8 (38%). Medical interventions were required in 17 patients (80%). In contrast, the event resolved in 4 patients (19%) with only BTKi discontinuation. Following CVAE, 3 patients (14%) were transitioned to a 2 nd generation BTKi with complete resolution. Conclusions CVAE remain significant contributors to treatment discontinuation. Patients treated with 1st-generation BTKis and pre-existing CVD had significantly higher odds of developing CVAE. Our study is the first to evaluate the impact of pre-existing CVD on CVAE during treatment with 2nd-generation BTKis. Patients on Ibrutinib developed more CVAE compared to patients on 2nd-generation BTKis, though differences were not statistically significant. This study was limited due to its retrospective and single-centered nature. Results highlight the need for structured approaches to prevent and promptly detect CVAE, particularly in patients with pre-existing CVD.

Semi-automated thrombin dynamics applying the ST Genesia thrombin generation assay.

BackgroundThe haemostatic balance is an equilibrium of pro- and anticoagulant factors that work synergistically to prevent bleeding and thrombosis. As thrombin is the central enzyme in the coagulation pathway, it is desirable to measure thrombin generation (TG) in order to detect possible bleeding or thrombotic phenotypes, as well as to investigate the capacity of drugs affecting the formation of thrombin. By investigating the underlying processes of TG (i.e., prothrombin conversion and inactivation), additional information is collected about the dynamics of thrombin formation.ObjectivesTo obtain reference values for thrombin dynamics (TD) analysis in 112 healthy donors using an automated system for TG.MethodsTG was measured on the ST Genesia, fibrinogen on the Start, anti-thrombin (AT) on the STA R Max and α2Macroglobulin (α2M) with an in-house chromogenic assay.ResultsTG was measured using STG-BleedScreen, STG-ThromboScreen and STG-DrugScreen. The TG data was used as an input for TD analysis, in combination with plasma levels of AT, α2M and fibrinogen that were 113% (108–118%), 2.6 μM (2.2 μM−3.1 μM) and 2.9 g/L (2.6–3.2 g/L), respectively. The maximum rate of the prothrombinase complex (PCmax) and the total amount of prothrombin converted (PCtot) increased with increasing tissue factor (TF) concentration. PCtot increased from 902 to 988 nM, whereas PCmax increased from 172 to 508 nM/min. Thrombin (T)-AT and T-α2M complexes also increased with increasing TF concentration (i.e., from 860 to 955 nM and from 28 to 33 nm, respectively). PCtot, T-AT and T-α2M complex formation were strongly inhibited by addition of thrombomodulin (−44%, −43%, and −48%, respectively), whereas PCmax was affected less (−24%). PCtot, PCmax, T-AT, and T-α2M were higher in women using oral contraceptives (OC) compared to men/women without OC, and inhibition by thrombomodulin was also significantly less in women on OC (p < 0.05).ConclusionsTG measured on the ST Genesia can be used as an input for TD analysis. The data obtained can be used as reference values for future clinical studies as the balance between prothrombin conversion and thrombin inactivation has shown to be useful in several clinical settings.

A comprehensive study on energy meters and power tampering attempts

Electricity is the basic need of today’s scenario. In the 21 st generation, growth and development is totally dependent on electricity. Thus, measurement of consumption of electricity becomes much more important. Energy meter used to measure consumed electricity by building or electrical equipment of various end users. This paper focuses on review of energy meters and power tampering attempts. It will highlight the development of meters from electromechanical meters to smart meters. The need of an era is to develop a more reliable and intelligent smart energy meters. This paper also discussed type of power tampering efforts in energy meters for power theft. The concept of smart meters for removing the power tampering efforts is also discussed.

Strength and rupture geometry of un-irradiated C26M FeCrAl under LOCA burst testing conditions

Ferritic iron-chromium-aluminum (FeCrAl) alloys are an accident tolerant fuel candidate to replace the incumbent Zr-based claddings. Nuclear grade FeCrAl alloys are marked by superior high temperature mechanical behavior and exceptional steam oxidation resistance , both of which increase safety margins during accident scenarios. In the present study, the loss of coolant accident (LOCA) burst behaviors of three un-irradiated commercially fabricated cladding materials in a simulated LOCA environment were compared: (1) T35Y2, a 1 st generation nuclear grade FeCrAl, (2) C26M, a 2 nd generation nuclear grade FeCrAl, and (3) Zircaloy-2. Both FeCrAl alloys showed improved mechanical strength and steam oxidation resistance compared to Zircaloy-2. C26M claddings burst at significantly higher temperatures for all tested engineering hoop stresses , had limited ballooning, and demonstrated preferential fuel retention behavior in terms of burst opening area and length. High temperature tensile data for C26M is also presented. For both un-irradiated FeCrAl alloys, it was found that a distinct “threshold” burst stress signified the transition between small and large openings. Higher threshold hoop stresses were associated with higher uniaxial strength for the FeCrAl alloys, indicating that tensile data, rather than creep data, could be useful for predicting rupture size and assessing fuel dispersal concerns.

Fixed Duration Combination Therapy with Ibrutinib (ibr) and Venetoclax (ven) Leads to Deep Responses in Relapsed/Refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL): Results of a Phase 2 Study

Fixed Duration Combination Therapy with Ibrutinib (ibr) and Venetoclax (ven) Leads to Deep Responses in Relapsed/Refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL): Results of a Phase 2 Study

Targeting BCL-XL and BCL-2 By Protac 753B Effectively Eliminates AML Cells and Enhances Efficacy of Chemotherapy By Targeting Senescent Cells

Targeting BCL-XL and BCL-2 By Protac 753B Effectively Eliminates AML Cells and Enhances Efficacy of Chemotherapy By Targeting Senescent Cells

Analysis of advancement model of 1 st generation dairy smart farm based on Open API application

Analysis of advancement model of 1 st generation dairy smart farm based on Open API application

Efficacy and safety of ALK inhibitors in ALK-rearranged non-small cell lung cancer: A systematic review and meta-analysis

ObjectivesNo overall survival (OS) benefit has been reported from a mature randomized trial with the use of ALK inhibitors. We conducted a systematic review and meta-analysis to assess the efficacy of ALK inhibitors compared to chemotherapy (ALK vs. chemo) and 2nd generation ALK inhibitors compared to 1 st generation ALK inhibitors (ALK-2 G vs. ALK-1 G). MethodsThe electronic databases Medline (PubMed), EMBASE, and the Cochrane Database of Systematic Reviews were searched for relevant randomized trials. Pooled hazard ratios (HR) for OS and progression free survival (PFS), and pooled risk ratios for objective response rates (ORR) and toxicity were meta-analyzed using the generic inverse variance and the Mantel-Haenszel methods. To account for between-studies heterogeneity, random-effect models were used. Subgroup analyses compared PFS by gender, smoking status, brain metastases, race and age. ResultsSix trials were included in the analysis of ALK vs. chemo and four in the analysis of ALK-2 G vs. ALK-1 G. Treatment with ALK inhibitors improved OS compared to chemotherapy (HR: 0.84, 95 %CI 0.72−0.97) while a trend toward a better OS was seen with ALK-2 G vs. ALK-1 G (HR: 0.66, 95 %CI 0.43–1.02). PFS was improved with ALK vs. chemo and ALK-2 G vs. ALK-1 G (HR: 0.44, 95 %CI 0.35−0.54 and HR: 0.38, 95 %CI-0.29−0.51, respectively). ORR was improved with ALK vs. chemo and ALK-2 G vs. ALK-1 G. No difference in toxicity was observed. ConclusionsThis meta-analysis is the first, to our knowledge, to report an OS and PFS benefit with the use of ALK inhibitors compared to chemotherapy from randomized trial data. A trend toward a better OS was also seen with ALK-2 G vs. ALK-1 G and this is likely because of crossover effects and limited OS follow-up. Longer follow up and further research are warranted to directly compare ALK inhibitor sequences and to understand the outcomes of second generation ALK inhibitors as initial therapy.

Techno‐economic analysis of novel power generation system based on coal partial gasification technology

AbstractA novel power generation system based on coal partial gasification has been proposed of which the coal feed rate is 50kg/s. It is mainly composed of oxygen‐blown CFB gasifier, CFB char combustor, heat recovery boiler and power generation unit. Coal is partly gasified with oxygen and steam to produce syngas and the syngas is sent to GT for power generation. The residue char is combusted in char combustor for power generation. Supercritical power generation technology is adopted in ST power generation unit and the parameter of the main steam is 560°C, 22.4MPa. Techno‐economic analysis of Partial Gasification Combined Cycle (PGCC) system is conducted and compared with IGCC. Law of conservation of energy and production capacity index method are adopted for thermodynamic and economic analysis, respectively. Efficiency of power generation, internal rate of return, and payback period are obtained by detailed calculation. The simulation results show that the efficiency of power generation of APGCC and PPGCC system are 49.44% and 51.37%, respectively, which are higher than that of IGCC. The fixed capital investment of PGCC is much lower than that of IGCC. The internal rate of return and payback period of APGCC 13.38% and 7.24 years, respectively which are ~9% higher and 8 years shorter than that of IGCC, respectively. This article provides a detailed analysis of PGCC which indicates that the PGCC technology has a promising prospect.

Administrative and Social Support Services for Students with Disabilities in the Selected Higher Education Institutions of Amhara Regional State-Ethiopia

This study was conducted in universities found in Amhara regional state. There are 7 public universities in the region. One university was selected from each generation. Hence, Gondar was selected from 1 st generation, Wollo from 2 nd generation and Debre Tabor from the third generation universities. Qualitative case study design was used for this study. The participants of this study were students with disabilities, teacher, students without disabilities, special needs directorates, and library and students service coordinators. Four methods of data collection instruments were used to obtain valid and reliable information from different sources, and for the purpose of triangulation. The result showed that most students with disabilities obtained different administrative and social support services from universities. On the other hand, the findings showed that the actual support services provided for students with disabilities in the sample universities were not in line with its higher education proclamations. It is recommendation that the university should work more on the social accessibility and administrative support services given for students with disabilities. Keywords : Social and administrative assistive services, students with Disability and Higher education institution DOI : 10.7176/PPAR/9-1-03

Current and Prospects in the Use of Biomass for Energy Generation

The contribution of biomass to world’s energy production is presented as well as the current technologies in use 1 st generation for the production of ethanol and biodiesel. Second generation technologies for the production of cellulosic ethanol as well as gasification are discussed as well as the scientific and technical challenges they are facing.

BCR-ABL GENE KINASE DOMAIN MUTATION FREQUENCY IN IMATINIB RESISTANT CHRONIC MYELOID LEUKEMIA PATIENTS

Background. BCR-ABL gene mutations are the main course of tyrosine kinase 1 st generation inhibitor (TKI-1) imatinib resistance in chronic myelogenous (CML) patients. Some of them are resistant both for imatinib and TKI-2. The nilotinib and dasatinib mutation spectra are not the same. To ensure a correct choice of TKI-2 for imatinib CML resistant patient treatment it is necessary to investigate frequency of BCR-ABL gene mutations. Aim. To evaluate BCR-ABL gene mutation frequency in imatinib resistant CML patients. Materials and methods. Peripheral blood of imatinib resistant CML patients were studied by means of direct PCR product Sanger sequencing in order to reveal BCR-ABL gene mutations. Results. BCR-ABL gene mutations were found in 31 % (n=262/846) imatinib resistant patients. Proportion of resistant mutations were 40,3 % for nilotinib and 21 % for dasatinib. Conclusion. More than a halve of BCR-ABL mutations resistant for imatinib were resistant either against nilotinib or dasatinib. Consequently, prior to replace imatinib for nilotinib or dasatinib it is necessary to perform BCR-ABL mutational analysis. If to prescribe TKI-2 blindly there may be high risk that nilotinib or dasatinib would be ineffective due to improper mutation in BCR-ABL gene.

Pilot study on harmonization of cardiac troponin I immunoassays using patients and quality control plasma samples. On behalf of the Italian Section of the European Ligand Assay Society (ELAS) and of the Study Group on Cardiovascular Biomarkers of the Società Italiana di Biochimica Clinica (SIBioC)

BackgroundThe aim of this study is to evaluate whether it is possible to reduce the between-methods variability of troponin I (cTnI) immunoassays using mathematical algorithms calculated from the results of both patients' samples and quality control materials distributed in an external quality assessment (EQA) scheme. MethodsWe collected 122 heparinized plasma samples of patients admitted to the emergency department with thoracic pain or supraventricular tachyarrhythmia. Moreover, we also analyzed 20 control samples distributed in an EQA and 26 plasma pools prepared from healthy subjects and patients with myocardial infarction. We evaluated 4 different methods for cTnI assay: STAT Architect High Sensitive TnI (Abbott Diagnostics), ADVIA Centaur Troponin I Ultra (Siemens Healthcare Diagnostics), ST AIA-Pack cTnI Third Generation (Tosoh Bioscience), and Access AccuTnI+3 (Beckman Coulter Diagnostics). ResultsSystematic differences between cTnI methods were observed. However, correlation coefficients (R from 0.976 to 0.990) between the log-transformed cTnI values measured in all 168 samples were significantly better (p=0.0037) than those obtained considering only the 122 patients' samples. cTnI values measured in EQA and pool samples were included within the 95% prediction intervals of linear regressions calculated with those of patients' samples. After the recalibration of cTnI values based on the robust principal component analysis approach the between-methods variability decreased significantly (about 40% around the cut off values). ConclusionsOur pilot study suggests that EQA schemes for cTnI immunoassay methods, based on both quality control samples with tested commutability and robust statistical analyses, are able to evaluate between-methods variability as well as allow a reliable recalibration and harmonization of results.

Evaluation of analytical performance and comparison of clinical results of the new generation method AccuTnI + 3 for the measurement of cardiac troponin I using both patients and quality control plasma samples

The study aims are to evaluate the analytical performance and the clinical results of the chemiluminescent Access AccuTnI+3 immunoassay for the determination of cardiac troponin I (cTnI) with DxI 800 and Access2 platforms and to compare the clinical results obtained with this method with those of three cTnI immunoassays, recently introduced in the European market. The limits of blank (LoB), detection (LoD), and quantitation (LoQ) at 20% CV and 10% CV were 4.5ng/L and 10.9ng/L, 17.1 and 30.4ng/L, respectively. The results of STAT Architect high Sensitive TnI (Abbott Diagnostics), ADVIA Centaur Troponin I Ultra (Siemens Healthcare Diagnostics), ST AIA-Pack cTnI third generation (Tosoh Bioscience), and Access AccuTnI+3 (Beckman Coulter Diagnostics) showed very close correlations (R ranging from 0.901 to 0.994) in 122 samples of patients admitted to the emergency department. However, on average there was a difference up to 2.4-fold between the method measuring the highest (ADVIA method) and lowest cTnI values (AccuTnI+3 method). The consensus mean values between methods ranged from 6.2% to 29.6% in 18 quality control samples distributed in an external quality control study (cTnI concentrations ranging from 29.3ng/L to 1557.5ng/L). In conclusion, the results of our analytical evaluation concerning the AccuTnI+3 method, using the DxI platform, are well in agreement with those suggested by the manufacturer as well as those reported by some recent studies using the Access2 platform. Our results confirm that the AccuTnI+3 method for the Access2 and DxI 800 platforms is a clinically usable method for cTnI measurement.

Recent Development of Bioenergy and Biorefinery in China

Although energy was used throughout the history of human culture, the burst of energy production and consumption coincided with the beginnings of the Industrial Revolution. The transition from hand production methods to machines, the increasing exploration and use of fossil-derived fuels (coal, petroleum, natural gas, shale fuel) made it possible to production of energy in large quantities. The majority of global energy supply still relies on traditional fossil based energy, with abundant fossil feedstock, well-understood technologies, and significant advantages in economy and scale. However, the traditional energy industry is now being challenged by sustainability of feedstock supply and environmental pressures, especially for carbon emission issues. Reduce the use of fossil fuels and replace them by renewable energies has been widely accepted by scientists, businesses and governors. Up to date, alternative renewable energy can be industrially produced via an extensive range of processes and sources like solar, wind, hydro, nuclear and bioenergy. According to the data of World Bioenergy Association (www. worldbioenergy.org), bioenergy has now been the largest global renewable energy supply which only below the traditional fossil energy. China has abundant biomass resources to about 0.4 billion tons per year - if totally utilized the bioenergy can satisfy 10% of total energy consumption in China. However, the current utilization of bioenergy in China is of low efficiency: with immature technologies, in small production scales and hard to satisfy the market demands. For example, in global level, the final energy from biomass is bioheat, followed by transport fuels (mainly as corn/cellulose ethanol, biodiesel) and electricity. While in China, bioelectricity is the main form of bioenergy, large quantities of biomass are not efficiently utilized. Straw burning can be widely seen in agriculture area at harvesting season, which not only waste the valuable bioresources but also cause severe air pollution. Currently, national projects are prompted in research and pilot level to improve the quantity and quality of Chinese bioenergy framework. Integrated production process for both bioheat and electricity was developed in recent years which aimed to improve the conversion efficiency of bioenergy. Super biogas projects are prompted in many regions where has abundant biomass resources. Second generation bio-ethanol is in pilot scale production, which utilizes the non-food agriculture waste like the corncobs. Moreover, biorefinery and bioconversion of the biomass to value added products are in early stages of development. Exploration of advanced bio-fuels and value-added chemical building blocks using modern techniques are future trends in the business of bioenergy and biorefinery. A variety of bio-, chemo- processes may be integrated in convertion of the biomass to the complex products. For example, Sinopec, one of the Chinese leading chemical companies, has explored 1 st generation of bio-jet fuel, which is made from waste cooking oil via a variety of chemical processing techniques. Similar projects are in fast developing by industries as well as the research institutes. It is hard to answer what is the future of bioenergy and biorefinery in China. As nobody in the last century can predict the scale and the diversity of the relative business of bioenergy in nowadays. But this industry will have a promising future: a seemingly infinite and renewable bio- resources in our lands, huge members of industries, governments and research institutes are eager to contribute their endeavors in this fast developing field, and more discoveries and modern techniques will be unfolded in the near future. We will walk a long way to fill in the gap between pioneering projects and conceptions and the practical scale-up application in this field. Citation: Xian, M. (2015). Recent Development of Bioenergy and Biorefinery in China. Trends in Renewable Energy, 1(3), 129-130. DOI: 10.17737/tre.2015.1.3.0015

3차원 착빙 형상 예측을 위한 2세대 시뮬레이션 코드 개발

The 2 nd generation ice accretion analysis program has been developed and validated for various icing conditions. The essential feature of the 2 nd generation code lies in its capability of handling general 3-D geometry and improved accuracy. The entire velocity fields are obtained based on Navier-Stokes equations in order to take the massively separated flow field into account. Unlike 1 st generation code, the droplet trajectories are calculated using Eulerian approach, which is adopted to yield appropriate collection efficiency even in the shadow region. For improved thermodynamic analysis on the surfaces, water film model and modified Messinger model are newly included in the present analysis. The ice shape for a given time step is obtained by considering the exact amount of ice accreted on the surface. Each module of the icing analysis code has been seamlessly integrated on the OpenFOAM platform. The developed code was validated against available experimental data for 2D airfoils and 3D DLR-F4. Due to the lack of experimental data, the computed results of DLR-F4 were compared with those obtained from FENSAP-ICE, which is state-of-the-art 3D icing analysis code. It was clearly shown that the present code produces comparable results to those of FENSAP-ICE, in terms of prediction accuracy and the capability of handling general 3-D geometries.