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1
Monje, Michelle, Tabitha Cooney, John Glod, Jie Huang, Patricia Baxter, Anna Vinitsky, Lindsay Kilburn, et al. "DIPG-10. A Phase I trial of panobinostat following radiation therapy in children with diffuse intrinsic pontine glioma (DIPG) or H3K27M-mutated thalamic diffuse midline glioma (DMG): Report from the Pediatric Brain Tumor Consortium (PBTC-047)." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i19—i20. http://dx.doi.org/10.1093/neuonc/noac079.067.
Анотація:
Abstract INTRODUCTION: Panobinostat is an oral HDAC inhibitor with pre-clinical activity against DIPG. The phase I study in children with progressive DIPG (stratum 1) defined the maximum-tolerated dose (MTD) as 10 mg/m2 administered 3x/week, 3 weeks on/1 week off. Herein, we report results of stratum 2, involving children with non-progressive DIPG/DMG using an alternative schedule. Primary objectives were to describe the toxicity profile and define the MTD; secondary objectives were to describe progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Patients with non-progressive DIPG or H3K27M-mutated thalamic DMG were eligible >14 days following standard radiation therapy only. Panobinostat was given every other day, 3x/week, on alternate weeks. Patients who received at least one dose of panobinostat were evaluable for toxicity. Four dose levels (DL) were evaluated: DL1 (16mg/m2/dose), DL2 (22 mg/m2/dose), DL3 (28 mg/m2/dose) and DL4 (36 mg/m2/dose). Dose escalation was determined by a continuous reassessment method. Correlative studies included pharmacokinetics obtained on course 1, day 1, and day 3 prior to subsequent dosing. RESULTS: Thirty-four eligible patients (median age, 7.6 [3-16] years) were enrolled with 29 evaluable for dose finding; DL1, n=3; DL2, n=10; DL3, n=11; DL4, n=5. The primary toxicities were myelosuppression and gastrointestinal. Eight DLTs occurred: DL2, Grade 3 thrombocytopenia (n=1); DL3, Grade 4 neutropenia (n=3), Grade 4 neutropenia and Grade 4 thrombocytopenia, (n=1); DL4, Grade 2 nausea (n=1), Grade 3 increased ALT (n=1), Grade 4 thrombocytopenia (n=1). Median PFS from drug initiation was 4.4 (1-11.2) months; median OS from diagnosis was 11.7 (4.5-25) months. These did not significantly differ from the PBTC historical cohort (PFS, p-value 0.4967; OS, p-value 0.6457). CONCLUSION: The MTD of panobinostat administered on this schedule to children with non-progressive DIPG/DMG is 22 mg/m2/dose. The primary DLT was myelosuppression. There was no significant improvement in PFS or OS in this cohort.
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Shah, Nirali N., Sarah K. Tasian, M. Eric Kohler, Emily M. Hsieh, Susanne H. C. Baumeister, Corinne Summers, Haneen Shalabi, et al. "CD33 CAR T-Cells (CD33CART) for Children and Young Adults with Relapsed/Refractory AML: Dose-Escalation Results from a Phase I/II Multicenter Trial." Blood 142, Supplement 1 (November 28, 2023): 771. http://dx.doi.org/10.1182/blood-2023-179667.
Анотація:
Introduction: Current therapies for patients with acute myeloid leukemia (AML) push the limits of chemotherapy intensity but cure only 30% of adults and 70% of children. Recently developed antibody-based therapies and molecularly-targeted agents only modestly improve outcomes for select patient subsets. Thus, new approaches are needed. Given the success of chimeric antigen receptor (CAR) T-cell therapies for acute lymphoblastic leukemia (ALL), we developed and optimized a novel CD33 CAR T-cell (CD33CART) construct for clinical testing in a multicenter Phase I/II clinical trial in children, adolescents, and young adults (AYA) with relapsed/refractory (r/r) AML. ( Qin H, et al. JITC 2021) We report interim results following completion of the dose-escalation phase. Methods: This multicenter phase I/II clinical trial (NCT03971799) was conducted as a 3+3 dose escalation study through the Pediatric Transplantation and Cell Therapy Consortium with National Marrow Donor Program sponsorship and managed by CIBMTR CRO. Autologous CD33CART product were centrally manufactured on a ClinicMACS Prodigy® by the Biopharmaceutical Development Program at the Frederick National Laboratory for Cancer Research (NCI). Eligibility criteria were r/r AML in subjects < 35 years old with adequate organ/performance status and an identified allogeneic stem cell transplant (SCT) donor. Bone marrow assessment was used for standard morphologic evaluation and central flow cytometric minimal residual disease (MRD) quantification. All subjects received pre-CD33CART lymphodepleting chemotherapy (LD) with fludarabine (75-120 mg/m 2) and cyclophosphamide (900-1000 mg/m 2). CD33CART doses levels (DLs) were: DL1: 3 x 10 5 CD33 CAR+ T-cells/kg; DL2: 1 x 10 6/kg; DL3: 3 x 10 6/kg and DL4: 1 x 10 7/kg. Adverse event grading used CTCAE v5 with incorporation of ASTCT consensus definitions for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). Dose-limiting toxicities (DLTs) included > grade 3 CRS, > grade 3 ICANS, and persistent > grade 3 non-hematologic toxicity that did not resolve < grade 2 in 72 hours. CD33CART persistence was assessed via flow cytometric evaluation of the blood and bone marrow. Data cut-off was June 1, 2023. Results: A total of 24 subjects (median age of 16 years, range 1-34 years), were enrolled, 12 (50%) of whom underwent a prior SCT. CD33CART products were successfully manufactured for 23 subjects and infused into 19. In 4 non-infused subjects with manufactured products, 1 died from progressive disease (PD) prior to LD, 2 transitioned to palliative care and 1 withdrew consent to seek alternative therapy. Manufacturing was not performed in one subject due to death from PD after enrollment. One morbidly obese subject (BMI=49.3) enrolled at DL4 but received treatment at DL3 due to weight-based manufacturing limitations. The median time from enrollment to infusion was 47 days (range, 24-242). (Table) Three subjects each were infused at DL1 and DL2 without DLTs. At DL3, 1 subject experienced DLT (grade 4 CRS) prompting expansion at this dose level, and no subsequent DLTs were observed. At DL4, 1 subject experienced a prolonged grade 3 CRS (> 72 hours) and grade 3 ICANS, both constituting DLT and necessitating expansion of the cohort without additional DLTs seen. Across all dose-levels, CRS was seen in 13 (68%) patients and was > grade 3 in 4 (21%) with onset typically within the first 24 hours post-infusion. Complete remission (CR) was only seen at DL4 and achieved in 2 subjects, both achieving an MRD negative CR alongside myeloid aplasia. One SCT naïve subject developed candidemia during aplasia but was able to proceed to an allogenic SCT, achieved engraftment, and was in remission at Day +100 post SCT. The second patient (post-two prior SCTs) declined third SCT, had spontaneous count recovery and remained in remission until day +119 (MRD+ relapse). Transient CD33CART expansion was detected in 9 (47.4%) subjects overall and in all 6 (100%) subjects at DL4. Conclusions: CD33CART manufacturing is feasible in children and AYAs with r/r AML with acceptable toxicity experienced in treated subjects. CD33CART expansion was best in subjects treated at DL4 (1 x 10 7/kg) with MRD negative CRs and transient myeloid aplasia occurring in 2 of 5 (40%) subjects evaluable for response (Table). Based on early clinical efficacy at DL4, enrollment continues in the phase 2 portion.
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Ebben, John, Jens C. Eickhoff, Dustin A. Deming, Howard S. Hochster, Anita Ahmed Turk, Vaibhav Sahai, and Nataliya Volodymyrivna Uboha. "QUIC: Phase 2 study of gemcitabine, cisplatin, quemliclustat (AB680), and zimberelimab (AB122) during first-line treatment of advanced biliary tract cancers (BTC)—Big Ten Cancer Research Consortium study BTCRC-GI22-564." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): TPS4195. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.tps4195.
Анотація:
TPS4195 Background: Despite recent approvals of immune checkpoint inhibitors with chemotherapy in the first-line setting, the median overall survival (mOS) for patients with advanced biliary tract cancer (BTC) remains less than 15 months. CD73 is a key enzyme responsible for the conversion of extracellular adenosine 5’-monophosphate into adenosine and may play an important role in creating an immunosuppressed tumor microenvironment. High expression of CD73 in BTC is associated with decreased OS. Quemliclustat (Q) is a potent, selective, reversible inhibitor of CD73. Q in combination with chemotherapy has demonstrated promising activity in patients with advanced pancreatic cancer without significant increase in adverse events. The BTCRC-GI22-564 study evaluates safety and preliminary efficacy of Q in combination with zimberelimab (Z), a monoclonal antibody targeting human PD-1, with gemcitabine and cisplatin (GC) as first-line therapy for patients with advanced BTC, QUIC (Q and Immunotherapy in Cholangiocarcinoma). Methods: This is an open label, single arm, phase II multi-site trial, evaluating Q and Z in combination with GC in patients with advanced BTC who have not received systemic treatment for advanced disease or who completed adjuvant therapy > 6 months prior to development of recurrent disease. Chemotherapy is given on days 1, 8, 22 and 29 of each 42-day cycle as per local standards. Z is administered at a fixed dose of 360 mg via IV infusion every 3 weeks. Q is administered via IV infusion on days 1, 15, and 29. A safety run-in portion built into the study is planned to enroll 6 subjects to ensure there are no dose limiting toxicities (DLT). If a study defined DLT is observed, Q, gemcitabine and cisplatin will be reduced by 1 dose level, and an additional 6 subjects will be enrolled in the safety run-in portion. The primary efficacy endpoint is median progression free survival (mPFS) with null and alternative survival of 6.0 and 10.0 months, respectively. Based on an accrual rate of 3 patients per month, we expect to accrue 33-39 patients which will provide at least 83% power with a one-sided alpha of 0.1. Secondary endpoints include mOS, disease control rate, overall response rate, and duration of response. Correlative endpoints will assess clinical outcomes with immune infiltration within tumor microenvironment, CD73 and PD-L1 expression. The QUIC study is currently open to enrollment through BTCRC. Clinical trial information: NCT06048133 .
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Islam, Md Rafiqul, Muhammad Mahbubur Rahman, Mohammed Ataur Rahman, Muslin Har Sani Mohamad, and Abd Halim Embang. "A Review on Blockchain Technology for Distribution of Energy." International Journal of Engineering Materials and Manufacture 7, no. 2 (April 22, 2022): 61–70. http://dx.doi.org/10.26776/ijemm.07.02.2022.03.
Анотація:
The alternative energy generation sources have increased drastically from centralized systems to distributed systems which increases the stability of energy distribution management systems and reduces the distribution cost as well. On the other hand, it reduces the probability of major area electricity blackout chances and decreases the energy distribution loss. For proper distribution and management of energy, there are different types of advanced technologies like artificial intelligence, and the Internet of Things (IoT) available, but a blockchain automated system is one of the best choices and is highly recommended. Various aspects of blockchain technology and energy management system have been discussed in this review paper where a total number of 423 journal papers, articles, and online information sources have been reviewed in the initial stage, and finally, 63 published research articles have been selected for review. There are several topics, including technology overview in energy management systems, blockchain application of energy trading, blockchain technology implementation challenges, distributed energy management system with Ethereum, and a conclusion with some recommendations have been discussed. Blockchain and Distributed Ledger Technology (DLT) are highly transparent, authenticate, and secure systems that can be used for distributing the energy between distributor and consumer without an intermediator which increases the overall efficiency of the system. This paper aims to highlight the blockchain and distributed ledger technology and how it works as well as optimize the transaction processing cost among the participants of the consortium network. This paper will make a significant contribution to the new research work and in the field of energy management systems.
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Poh, Christina, Paul Frankel, Christopher Ruel, Mehrdad Abedi, Emily Schwab, Caitlin L. Costello, Jasmine Zain, et al. "Blinatumomab/Lenalidomide in Relapsed/Refractory Non-Hodgkin's Lymphoma: A Phase I California Cancer Consortium Study of Safety, Efficacy and Immune Correlative Analysis." Blood 134, Supplement_1 (November 13, 2019): 760. http://dx.doi.org/10.1182/blood-2019-124254.
Анотація:
Introduction Both blinatumomab and lenalidomide have proven, but limited, efficacy in relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). Failure of blinatumomab to mediate durable responses is due to its inability to recruit competent cytotoxic T cells which leads to eventual T cell exhaustion. Lenalidomide has been shown to improve efficacy of rituximab through T and NK cell activation even in patients who have previously failed rituximab containing regimens. Based on this, we hypothesized that lenalidomide, when combined with blinatumomab, will enhance its efficacy. We report safety, efficacy and correlative analysis of blinatumomab and lenalidomide in R/R NHL. Methods We conducted a phase I, open-label trial involving patients 18 years and older with R/R CD19+ NHL who have received at least two prior chemotherapeutic or biologic regimens and were not eligible for standard curative options at time of enrollment. Previous CD19-targeted therapy was allowed. Study consisted of a dose escalation followed by a dose expansion phase once the maximum tolerated dose (MTD)/ recommended phase II dose (RP2D) was established using a Phase I Queue modified 3+3 design. The escalation phase has been completed and consisted of blinatumomab continuous infusion (level 1 and 2: 9 mcg/day to 112 mcg/day) from days 1-56 and lenalidomide (level 1: 10 mg and level 2: 20 mg daily) days 29-49 of a 56-day induction cycle. Patients who responded underwent consolidation with blinatumomab continuous infusion days 1-7 and lenalidomide days 1-21 of a 28-day cycle for a maximum of 6 cycles followed by lenalidomide maintenance for 2 years or until unacceptable toxicity or disease progression. Dose limiting toxicities (DLT) included any grade 3/4 drug related adverse events (AE) observed during and up to 7 days after blinatumomab/lenalidomide simultaneous administration. Additional patients were accrued to replace patients who had grade 3/4 AE or progressed before receiving lenalidomide for dose-finding purposes. Primary endpoints included toxicity and determination of the MTD/RP2D during the first 8 weeks of blinatumomab/ lenalidomide induction. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, progression free survival (PFS) which was censored at time of transplant and immune response biomarkers. Results As of July 17, 2019, 18 patients initiated therapy; 7 with diffuse large B cell lymphoma, 3 with mantle cell lymphoma, 3 with follicular lymphoma, 2 with nonspecified B cell lymphoma and 1 each with marginal zone lymphoma, Burkitt's lymphoma and small lymphocytic lymphoma. Median age was 58 (range 30-84) years and the median number of prior regimens was 2.5 (range 2-5); 5 patients had previous stem cell transplant (SCT). 6 patients had disease progression prior to starting lenalidomide. 3 patients received blinatumomab/lenalidomide at dose level 1 with no DLT noted. 9 patients received blinatumomab/lenalidomide at dose level 2 with 4 requiring blinatumomab dose reduction prior to starting lenalidomide. Due to favorable safety profiles with the combination using the MTD/RP2D of lenalidomide 20 daily, upfront doublet therapy was initiated as part of the planned expansion phase. Most common grade 3/4 adverse events were lymphopenia (39%), hypophosphatemia (22%) and hyponatremia (11%). 1 patient (5.5%) experienced grade 3 neurotoxicity. No grade 3/4 cytokine release syndrome or treatment related deaths were seen. At time of data cutoff, three patients remain on active treatment. At a median follow-up time of 14.3 months, ORR was 56% for all patients and 83% (50% CR) for those who received blinatumomab/lenalidomide combination therapy. Median PFS was 3.8 months (95% CI, 1.1 to NR) for all patients and 8.3 months (95% CI, 2.2 to NR) for those who received blinatumomab/lenalidomide combination therapy. 3 patients who achieved response underwent allogeneic SCT and remained in remission for 14.2 to 22.3 months thereafter. Correlative studies are pending and will be reported at time of presentation. Conclusions The combination of blinatumomab and lenalidomide, given at the RP2D dose of 20 mg daily, is safe and well tolerated. This regimen demonstrates encouraging efficacy in this heavily pretreated patient population and is a promising alternative treatment option for R/R NHL patients who are not candidates for aggressive cytotoxic chemotherapy or as a bridge to allogeneic SCT. Disclosures Abedi: Abbie: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Gilead: Speakers Bureau. Costello:Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Zain:Seattle Genetics: Consultancy; Spectrum: Consultancy. Budde:F. Hoffmann-La Roche Ltd: Consultancy. William:Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Guidepoint Global: Consultancy. Foss:Spectrum: Other: fees for non-CME/CE services ; Acrotech: Consultancy; miRagen: Consultancy; Eisai: Consultancy; Mallinckrodt: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services . Jonas:AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. Rosenberg:Amgen: Consultancy, Research Funding. Tuscano:Seattle Genetics: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Spectrum: Research Funding; Takada: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. OffLabel Disclosure: The use of blinatumomab and lenalidomide in patients with aggressive lymphoma
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Phadke, Sneha, Kari Wisinski, Oana Danciu, Ami Shah, Menggang Yu, Yi Chen, Kathy Miller, and Mark Burkard. "Abstract PO1-06-09: Phase 2 Trial with Safety Run-In of Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast CancersBig Ten Cancer Research Consortium BTCRC-BRE18-337." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO1–06–09—PO1–06–09. http://dx.doi.org/10.1158/1538-7445.sabcs23-po1-06-09.
Анотація:
Abstract Up to 2/3 of triple negative breast cancers (TNBC) have acquired defects in homologous recombination (HR) DNA repair, yet poly (ADP-ribose) polymerase inhibitor (PARPi) monotherapy has been largely ineffective in the absence of a germline BRCA 1/2 mutation (gBRCA1/2). Phosphoinositide-3-kinase (PI3K)/mTOR pathway alterations are also common in breast cancers. Preclinical data suggest that PI3K/mTOR inhibition may disrupt normal function of the HR complex and increase dependency on PARP enzymes for HR DNA repair. Thus, combining a PI3K/mTOR inhibitor with a PARPi may result in a synergistic anti-neoplastic effect. The run-in portion of this study evaluated the safety of weekly IV gedatolisib (PI3K/mTORi) and continuous daily talazoparib to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). A 3+3 design for dose escalation explored two dose levels. The phase II study began once the MTD and R2PD were confirmed. Eligibility required age ≥ 18, 1-2 prior lines of therapy (protocol later amended to allow up to 3 lines), and advanced TNBC or advanced HER2-negative BC with gBRCA1/2 mutation. The sample size for the phase II study was determined based on a 1-sided binomial test under the null and alternative ORR of 5% vs 20% with a type I error rate of 0.1 and power level of 80%. The primary endpoint was overall response rate (ORR) in TNBC without known gBRCA1/2 with secondary endpoints of progression-free survival (PFS) and overall survival (OS). Patients with a gBRCA1/2 mutation were not included in the primary endpoint analysis. Correlative studies are planned to evaluate HR deficiency mutations, PIK3CA mutations, and other exploratory genomics. A total of 33 patients were enrolled: 14 in the safety run-in phase of the trial and 19 in the phase II study (17 TNBC, 2 with gBRCA2 mutation). In the safety run-in, 6 patients were enrolled at dose level 1 (0.75 mg talazoparib po daily and 180 mg gedatolisib IV weekly) and 8 at dose level 2 (1 mg talazoparib po daily and 180 mg gedatolisib IV weekly). 42% of the cohort developed hyperglycemia, which was mostly grade 1. There was 1 DLT of grade 3 neutropenia at dose level 1. There were 3 patients who experienced grade 4 AEs, thrombocytopenia (2) and lymphopenia (1) which were outside of the DLT window. The MTD was 1 mg of talazoparib daily and 180 mg of gedatolisib weekly, and this was selected as the RP2D. A protocol amendment was made during the phase II portion to allow for a 3 week on/1 week off schedule for gedatolisib due to emerging data showing a more favorable safety profile and enhanced antitumor activity with this dosing schedule. In the 17 patients with TNBC and no gBRCA mutation in the phase II cohort, the ORR was 12%. Best response was partial response (PR) in 2 patients (12%), stable disease (SD) in 7 patients (41%), and progressive disease (PD) in 8 patients (47%). The clinical benefit rate (ORR+SD) at 16 weeks was 23.5%. The most common adverse events (AEs) in all 33 patients were anemia (70%), fatigue (67%), oral mucositis (64%), nausea (60%), neutropenia (45%) and anorexia (45%). Of these, most were grade 1-2 other than anemia (35% grade 3), neutropenia (20% grade 3), fatigue (18% grade 3), and oral mucositis (10% grade 3). There were no grade 4 AEs in the phase II study. Median PFS was approximately 3 months and median OS was approximately 6.4 months. Although this study did not meet its primary endpoint, there were 2 TNBC patients without a gBRCA1/2 mutation who achieved a partial response to this non-chemotherapy regimen. Future biomarker testing may help elucidate these findings and possible predictors of response. Citation Format: Sneha Phadke, Kari Wisinski, Oana Danciu, Ami Shah, Menggang Yu, Yi Chen, Kathy Miller, Mark Burkard. Phase 2 Trial with Safety Run-In of Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast CancersBig Ten Cancer Research Consortium BTCRC-BRE18-337 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-09.
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Wen, P. Y., T. Cloughesy, J. Kuhn, K. Lamborn, L. E. Abrey, F. Lieberman, H. I. Robins, J. Wright, M. D. Prados, and M. Gilbert. "Phase I/II study of sorafenib and temsirolimus for patients with recurrent glioblastoma (GBM) (NABTC 05–02)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 2006. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2006.
Анотація:
2006 Background: The activity of targeted molecular therapy with single agents has been disappointing in GBM. Combination therapy simultaneously targeting both the PI3k/Akt/mTOR and the MAP kinase pathway may be more effective. Methods: The North American Brain Tumor Consortium conducted a phase I/II study of sorafenib (VEGFR/PDGFR/Raf inhibitor) in combination with temsirolimus (mTOR inhibitor) in recurrent GBM. Eligibility criteria included histologically proven GBM, radiologic progression, > 18 years old, KPS > 60, adequate bone marrow reserve, and organ function. There was no limit on the number of prior relapses for phase I and no more than two prior relapses for phase II. No enzyme-inducing antiepileptic drugs were allowed. Dose-finding used a standard 3 + 3 design with the MTD defined as the dose with DLTs in 1/6 or fewer patients. The primary endpoint for the phase II component was PFS6 (p0 = 15%; p1 = 35%). A 2-stage design was used. If > 4 of the initial 19 patients achieved PFS6, an additional 14 patients would be accrued for a total of 33 patients. Results: In phase I, 13 patients were enrolled. Median age was 50 years (32–59); median prior chemotherapy 1 (1–3). The initial doses were sorafenib 200 mg bid and temsirolimus 25 mg intravenously once weekly. The MTD was 400 mg bid of sorafenib daily combined with 25 mg of temsirolimus weekly. At this dose 1/6 patients had a DLT (grade 3 thrombocytopenia). Other grade 3 or 4 toxicities included transaminitis, hypophosphatemia, fatigue, diarrhea, and hyperlipidemia. Pharmacokinetic data were similar to that for single agent sorafenib and temsirolimus suggesting that there were no significant interaction between the two drugs. In phase II, 19 patients were accrued to stage I. Median age 50 years (24–64); median prior relapses 1 (range 1–2). One patient was found not to have GBM on central review. No patient remained progression free at 6 months, although two patients stopped treatment prior to 26 weeks for other than progression (alternative therapy, cerebral ischemia). As result, the study was terminated and did not proceed to the second stage. Conclusions: The combination of sorafenib and temsirolimus was moderately well-tolerated but did not demonstrate sufficient efficacy in recurrent GBM to warrant further investigation. No significant financial relationships to disclose.
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Minard, Charles Gene, Rachel Rau, Susan Hilsenbeck, Brenda J. Weigel, Elizabeth Fox, Peter Adamson, and Susan Blaney. "3488 A comparison between the Rolling 6 and 3+3 dose escalation study designs for phase 1 clinical trials." Journal of Clinical and Translational Science 3, s1 (March 2019): 30–31. http://dx.doi.org/10.1017/cts.2019.73.
Анотація:
OBJECTIVES/SPECIFIC AIMS: The development of new anti-cancer agents for children requires an inherently longer timeline than in adults. The 3+3 study design for Phase 1 dose escalation trials is commonly used to estimate the maximum tolerated dose and assess safety. The Rolling 6 study design was developed to shorten the study conduct timeline. METHODS/STUDY POPULATION: This study compares twenty Phase 1 COG Pilot and Phase 1 Consortium trials that employed the Rolling 6 design with hypothetical results under the assumption that a 3+3 design had been executed. The number of evaluable patients required to complete the study, number of DLTs, number of inevaluable patients, overall study duration, time suspended to enrollment (i.e., waiting for DLT evaluation), and DLT risk are compared between study designs using Wilcoxon’s signed rank test. RESULTS/ANTICIPATED RESULTS: The Rolling 6 study design required less time to complete the studies compared with 3+3 design (median 273 vs. 297 days, P = 0.01). In general, the Rolling 6 study design required more patients, had more inevaluable patients, and there were more dose limiting toxicity (DLT) events. However, there was no significant difference in DLT risk (median 0.15 vs. 0.17, P = 0.72). DISCUSSION/SIGNIFICANCE OF IMPACT: The Rolling 6 study design effectively shortens the study conduct timeline compared with the traditional 3+3 design for Phase 1 COG Pilot and Phase 1 Consortium trials without increasing the risk of toxicity.
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Guo, Dong, and Peng Zhou. "The Evolution of Financial Market Infrastructure: From Digitalization to Tokenization." International Journal of Innovation and Entrepreneurship 2, no. 1 (March 8, 2023): 1. http://dx.doi.org/10.56502/ijie2010002.
Анотація:
This paper examines the historical development and cross-sectional heterogeneities of Financial Market Infrastructure (FMI). From an evolutionary perspective, we review and compare FMIs in the US, Europe, and China. We identify an emerging trend in which the development of FMI is transitioning from digitalization to tokenization with the rise of Distributed Ledger Technology (DLT). Digitalization reinforces centralization, while tokenization promotes decentralization, posing complex challenges to regulatory framework which is also part of FMI. We then specifically analyze DLT-based FMI in the bond market, evaluate different models of tokenization, and propose a heterogeneous consortium blockchain solution.
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Mthethwa, Sthembile, and Morne Pretorius. "Academic and Skills Credentialing Using Distributed Ledger Technology (DLT) and W3C Standards: Technology Assessment." International Conference on Intelligent and Innovative Computing Applications 2022 (December 31, 2022): 170–82. http://dx.doi.org/10.59200/iconic.2022.019.
Анотація:
The ongoing push for the 4th industrial revolution is setting the stage to digitise, persist and verify identity along with credentials. Academic and skills credentials are currently verified manually and have much scope for automation using cryptographic techniques but requires standardisation to facilitate future systems interoperability. The Distributed Ledger Technology (DLT) and World Wide Web Consortium (W3C) Verifiable Credentials (VC) standards presents the possibility to achieve this credential verification automation. To accomplish this, an understanding of various DLTs and requirements for a viable skills tracking system is important. Therefore, this research aims to access the selected DLTs against the assessment criterion presented and an analysis has been completed to determine which DLT is suitable for the proposed system. The DLTs are assessed in terms of their ability to support the rapid prototyping of such a system and provide recommendations to guide a future development path from the perspective of standards compliance. We conclude that few DLTs possess the maturity to provide proper requirements coverage due to the emergent nature of the DLT space. Additionally, this paper presents the high-level requirements to achieve a minimally viable solution that can demonstrate such digital credential verification in the academic and skills tracking context.
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Gerring, John, and Daniel Pemstein. "Proposal: A Political Science Peer Review and Publication Consortium." PS: Political Science & Politics 54, no. 1 (October 28, 2020): 126–30. http://dx.doi.org/10.1017/s104909652000102x.
Анотація:
ABSTRACTThe traditional process of peer review and publication has come under intense scrutiny in recent years. The time seems propitious for a consideration of alternatives in political science. To that end, we propose a Peer Review and Publication Consortium. The Consortium retains the virtues of the traditional peer-review process (governed by academic journals) while also mitigating some of its vices.
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Antal, Claudia, Tudor Cioara, Ionut Anghel, Marcel Antal, and Ioan Salomie. "Distributed Ledger Technology Review and Decentralized Applications Development Guidelines." Future Internet 13, no. 3 (February 27, 2021): 62. http://dx.doi.org/10.3390/fi13030062.
Анотація:
The Distributed Ledger Technology (DLT) provides an infrastructure for developing decentralized applications with no central authority for registering, sharing, and synchronizing transactions on digital assets. In the last years, it has drawn high interest from the academic community, technology developers, and startups mostly by the advent of its most popular type, blockchain technology. In this paper, we provide a comprehensive overview of DLT analyzing the challenges, provided solutions or alternatives, and their usage for developing decentralized applications. We define a three-tier based architecture for DLT applications to systematically classify the technology solutions described in over 100 papers and startup initiatives. Protocol and Network Tier contains solutions for digital assets registration, transactions, data structure, and privacy and business rules implementation and the creation of peer-to-peer networks, ledger replication, and consensus-based state validation. Scalability and Interoperability Tier solutions address the scalability and interoperability issues with a focus on blockchain technology, where they manifest most often, slowing down its large-scale adoption. The paper closes with a discussion on challenges and opportunities for developing decentralized applications by providing a multi-step guideline for decentralizing the design and implementation of traditional systems.
13
Mohrbacher, Ann, Min H. Kang, Allen S. Yang, Susan G. Groshen, Lori Vergara, Martin Gutierrez, Anthony J. Murgo, et al. "Phase I trial of fenretinide (4-HPR) intravenous emulsion in hematologic malignancies: A California Cancer Consortium study (PhI-42)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8073. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8073.
Анотація:
8073 Background: Fenretinide (4-HPR) is a cytotoxic retinoid with broad anticancer activity in preclinical studies. Due to limited bioavailability of a capsule formulation an intravenous intralipid-like emulsion formulation (4-HPR ILE) was developed to increase systemic exposures. Methods: 4-HPR was administered as a continuous intravenous infusion for 120 hrs every 21 days. Systemic toxicities, responses, and pharmacokinetics were assessed. Accelerated Simon design proceeded until moderate or dose-limiting toxicities (DLT) were scored on Course 1. Doses were 80 mg/m2/day to 1810 mg/m2/day. Patients with asymptomatic hypertriglyceridemia were scored separately. All patients were heavily pretreated. Results: Toxicity-evaluable patients = 25. At 1810 mg/m2/day, two patients experienced DLT hypertriglyceridemia, one with transient Grade 2 pancreatitis; at 1280 mg/m2/day (8 pts), two had asymptomatic Grade 4 hypertriglyceridemia, one experienced DLT pleural effusions; at 905 mg/m2/day (6 pts) 2 experienced asymptomatic Grade 4 hypertriglyceridemia; All 5 pts at 640 mg/m2/day tolerated treatment. Pharmacokinetics showed a dose-to-plasma level relationship with mean steady-state 4-HPR levels of ~mid-20’s μM (640 mg/m2); ~mid-30’s μM (905 mg/m2/day); and ~mid-50’s μM (1280 mg/m2). Responses to date include a 64% CR+PR+SD response rate (36% CR+PR response rate) in 11 relapsed T-cell lymphomas which included histone deacetylase inhibitor-refractory patients, and a PRu response in a NHL B-cell lymphoma. Reversible hypertriglyceridemia related to the intralipid vehicle accounted for 6/7 DLTs. Conclusions: MTD = 1280 mg/m2/day x 5 days, every three weeks. 4-HPR ILE was safely administered and obtained 4-HPR plasma levels 6 -7 times higher than previously obtained using oral capsules. Durable complete responses were observed in T-cell lymphomas from 905 – 1810 mg/m2/day. An expanded cohort is accruing to a dosing schedule modified to decrease asymptomatic hypertriglyceridemia of 600 mg/m2 on Day 1 (to allow for induction of serum lipases) followed by 1200 mg/m2 Days 2-5. Supported by NCI U01 CA062505 and CPRIT RP10072.
14
Berg, S. L., H. Russell, M. Cairo, A. M. Ingle, P. C. Adamson, and S. M. Blaney. "Phase I and pharmacokinetic (PK) study of lenalidomide (LEN) in pediatric patients with relapsed/refractory solid tumors or myelodysplastic syndrome (MDS): A Children's Oncology Group Phase I Consortium study." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 10023. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.10023.
Анотація:
10023 Background: LEN, which has immunomodulatory, antiangiogenic, and antiproliferative effects, is indicated for the treatment of adults with MDS and multiple myeloma. We report the final results of a phase 1 and PK study of LEN in children with recurrent or refractory solid tumors (ST) or MDS. Methods: LEN was administered by mouth once daily for 21 of 28 days. Cohorts of 3 to 12 children with ST were enrolled at 15, 25, 40, 55 and 70 mg/m2/d dose levels. Children with MDS received a fixed dose of 5 mg/m2/d. PK and correlative biology studies were performed in cycle 1. Results: 49 patients (23 female), median age 16 years (range, 1–21) were enrolled and received a median of 1 cycle (range 1–11). 39/46 ST patients and 3/3 MDS patients were fully evaluable for toxicity. 0/3 patients with MDS had DLT. At 15 mg/m2/d, 1/6 ST patients developed DLT (Gr 3 hypercalcemia). At 25 mg/m2/d 1 patient had a cerebrovascular ischemic event of uncertain relationship to LEN; future subjects were screened for thromboembolic risk factors prior to enrollment. At 40 mg/m2/d 3/12 patients developed DLTs (Gr 3 hypophosphatemia/hypokalemia; Gr 4 neutropenia delaying the start of the next cycle for > 7 days; Gr 3 somnolence); at 55 mg/m2/d 1/6 patients developed DLT (Gr 3 urticaria). At 70 mg/m2/d 0/6 patients had DLT. No further dose escalation was attempted. No objective responses were observed. LEN enhanced IL-2 and IL-15 concentrations; NK expansion and activation; and NK and LAK cytotoxicity (Ayello, ASH, 2008). The median apparent LEN clearance and half-life were 135 ± 45 ml/min/m2 and 2.3 ± 1.1 hr. Conclusions: LEN is well tolerated at doses up to 70 mg/m2/d x 21d of 28 days in children with recurrent or refractory ST. Enhancement of immune function is significant. PK parameters in children are similar to those in adults. No significant financial relationships to disclose.
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Burke, Michael J., Patrick Brown, Richard Sposto, Lia Gore, and Alan S. Wayne. "Pilot Study of Decitabine and Vorinostat with Chemotherapy for Relapsed ALL: A Report from the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Consortium." Blood 128, no. 22 (December 2, 2016): 2781. http://dx.doi.org/10.1182/blood.v128.22.2781.2781.
Анотація:
Abstract Acquired drug resistance is a major reason for relapse and death in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of acquired drug resistance is a potential solution. DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) have been shown to reverse drug resistance gene signatures and restore chemosensitivity in relapsed ALL. We report results investigating decitabine (DNMTi) (10-15 mg/m2/dose) and vorinostat (HDACi) (180 mg/m2/dose) with vincristine, dexamethasone, mitoxantrone and PEG-asparaginase (UKALL R3 backbone) for relapsed/refractory ALL. Twenty-three patients with refractory or ≥2nd relapse B-ALL were enrolled (Table 1). Median age was 12 (range, 1-21) years. Toxicity was graded according to CTCAE v4.0. The most common grade (Gr) 3-4 toxicities included hypokalemia (65%), anemia (61%), febrile neutropenia (57%), hypophosphatemia (43%), hyperbilirubinemia (39%), thrombocytopenia (39%), neutropenia (35%), sepsis (30%), lung infection (30%) and infection/infestations-other (30%). Non-hematologic dose limiting toxicity (DLT) was defined as any Gr 3 or 4 adverse event that was at least possibly attributed to decitabine and/or vorinostat with the exception of nausea (Gr 3), vomiting (Gr 3), transaminase elevation that returned to Gr ≤1 or baseline prior to the end of the course, fatigue, fever/infection, electrolyte abnormalities that were transient and not associated with clinical sequelae, albumin, alkaline phosphatase, GGT and anorexia. Hematologic DLT was defined as an absence of peripheral blood count recovery within 6 weeks of starting chemotherapy. Any patient who experienced a DLT after receiving at least 1 dose of decitabine or vorinostat was evaluable for DLT. Patients who did not experience a DLT had to receive a pre-determined amount of protocol therapy as outlined in the study to be evaluable for DLT. Seventeen of 23 patients were evaluable for DLT. Three patients experienced DLTs as follows: Gr 3 cholestasis, Gr 3 steatosis, Gr 4 hyperbilirubinemia (n=1); Gr 4 seizure, Gr 4 somnolence, Gr 3 delirium (n=1); and Gr 3 pneumonitis, Gr 3 hypoxia, Gr 3 hyperbilirubinemia (n=1). The study was suspended and amended after the first 5 patients enrolled (decitabine, 15mg/m2), due to significant infectious toxicities [4 of 5 patients reporting invasive fungal infections: C. kruseii (n=2), C. lusitaniae (n=1), and C. guillermondii (n=1)] and two DLTs (reported above). The treatment schema was modified to lower the dose of decitabine (10mg/m2/dose) and to reduce the duration from days 1-7/15-21 to 1-5/15-19. The duration of vorinostat was also reduced from days 3-10/17-24 to 2-7/16-21 (Figure 1). In addition, anti-fungal prophylaxis with either an echinocandin or amphotericin agent was required. Despite these dose modifications, infectious complications remained common with 17/23 (74%) patients reporting Gr ≥3 infections including invasive fungal disease in 35% (8/23). In analyzing all 23 patients, the complete response rate (CR + CR with incomplete blood count recovery) was 39% (9/23). Fourteen patients (61%) were able to complete full protocol therapy and evaluable for response. The remaining 9 patients did not complete therapy, primarily due to treatment-related toxicities, and were not evaluable. Nine of the 14 patients (64%) achieved a complete response with the remaining 5 reporting stable disease (36%). Minimal residual disease (MRD) testing via flow cytometry was performed on 7 of 9 patients who achieved a CR with a median level of 0.087% MRD (range, 0.00% to 1.6%) detected. Overall survival at 6 months was 35.1% (95% CI, 16.0 - 54.9) and 23.4% (95% CI, 7.8 - 43.6) at 1-year. Death was reported in 18/23 (78%) patients at a median of 10 weeks from study start (range, 3-138). Cause of death was attributed to refractory leukemia (n=8), treatment related toxicity (n=5), infection (n=3) and transplant-related toxicity (n=2). Despite encouraging response rates including low MRD, the combination of decitabine and vorinostat with intensive chemotherapy in this patient population was determined not to be feasible. A future follow-up study with a less intensive chemotherapy backbone is needed to determine if these two promising epigenetic agents can be successfully incorporated into the treatment of pediatric ALL. This study is registered at http://www.clinicaltrials.gov as NCT01483690. Disclosures Wayne: Kite Pharma: Honoraria, Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel Support; Medimmune: Honoraria, Other: Travel Support, Research Funding; NIH: Patents & Royalties.
16
Kleinberg, Lawrence, Jeffrey G. Supko, Tom Mikkelsen, Jaishri O'Neill Blakeley, Glen Stevens, Xiaobu Ye, Serena Desideri, et al. "Phase I adult brain tumor consortium (ABTC) trial of ABT-888 (veliparib), temozolomide (TMZ), and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM) including pharmacokinetic (PK) data." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2065. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2065.
Анотація:
2065 Background: ABTC conducted a dose finding trial of ABT-888, an orally administered Poly(ADP-ribose) polymerase [PARP] inhibitor, during daily TMZ with post-operative RT for GBM. PARP is important in repair pathways for RT induced DNA injury and TMZ induced alkylation at N7-methylguanine and N3-methyldenine. Methods: An initial safety group (no concurrent RT), received ABT-888 10 mg BID po during 42 days of daily TMZ 75 mg/m2. After this, the planned dosing steps included ABT-888 BID concurrent with standard RT and TMZ, with planned ABT-888 dose escalation or de-escalation based on observed toxicity. Dose limiting toxicity (DLT) is ≥ grade 3 non-hematologic or neurologic not responding to steroids, and hematologic ANC<500/mm3 and platelets (PLT) < 25K/mm3. The pharmacokinetics (PK) of ABT-888 were characterized for dose 1 and at steady-state. Results: Without concurrent RT, DLT (thrombocytopenia) occurred in 1/6 patients. With concurrent RT/TMZ and ABT-888 10 mg BID, 4/12 patients had DLT (thrombocytopenia). As per the planned dose de-escalation, ABT-888 10 mg BID was then given every other week during TMZ/RT. This resulted in 3/6 patients with DLT (2 thrombocytopenia, 1 neutropenia). The hematologic toxicity with this regimen was judged high enough that accrual was discontinued. In the setting of continuous dosing for 6 weeks, the total body clearance of ABT-888 for the first dose (27.5±9.5 L/h, n = 15) and at steady-state after BID dosing (23.5±10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56±33%. Steady-state peak and trough concentrations of the drug in plasma were 66±29 ng/mL and 18±10 ng/mL, respectively. Additional PK data will be presented. Conclusions: Administering ABT-888 BID po in combination with standard RT/TMZ was not tolerable in GBM patients as a result of hematologic toxicity. ABT-888 PK in GBM patients were very similar to findings reported for solid tumor patients. There is strong scientific rationale for continued development of an appropriate dosing regimen for this agent in the initial therapy of GBM. Clinical trial information: NCT00770471.
17
Combi, Romina, Maria Salsone, Chiara Villa, and Luigi Ferini-Strambi. "Genetic Architecture and Molecular, Imaging and Prodromic Markers in Dementia with Lewy Bodies: State of the Art, Opportunities and Challenges." International Journal of Molecular Sciences 22, no. 8 (April 12, 2021): 3960. http://dx.doi.org/10.3390/ijms22083960.
Анотація:
Dementia with Lewy bodies (DLB) is one of the most common causes of dementia and belongs to the group of α-synucleinopathies. Due to its clinical overlap with other neurodegenerative disorders and its high clinical heterogeneity, the clinical differential diagnosis of DLB from other similar disorders is often difficult and it is frequently underdiagnosed. Moreover, its genetic etiology has been studied only recently due to the unavailability of large cohorts with a certain diagnosis and shows genetic heterogeneity with a rare contribution of pathogenic mutations and relatively common risk factors. The rapid increase in the reported cases of DLB highlights the need for an easy, efficient and accurate diagnosis of the disease in its initial stages in order to halt or delay the progression. The currently used diagnostic methods proposed by the International DLB consortium rely on a list of criteria that comprises both clinical observations and the use of biomarkers. Herein, we summarize the up-to-now reported knowledge on the genetic architecture of DLB and discuss the use of prodromal biomarkers as well as recent promising candidates from alternative body fluids and new imaging techniques.
18
Aplenc, Richard, Susan M. Blaney, Lewis C. Strauss, Frank M. Balis, Suzanne Shusterman, Ashish Mark Ingle, Shruti Agrawal, Junfeng Sun, John J. Wright, and Peter C. Adamson. "Pediatric Phase I Trial and Pharmacokinetic Study of Dasatinib: A Report From the Children's Oncology Group Phase I Consortium." Journal of Clinical Oncology 29, no. 7 (March 1, 2011): 839–44. http://dx.doi.org/10.1200/jco.2010.30.7231.
Анотація:
Purpose Dasatinib is an orally available tyrosine kinase inhibitor with low nanomolar activity against SRC family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGF-β receptor. Dasatinib was found to have selective activity in several tumor models in the Pediatric Preclinical Testing Program. Patients and Methods A phase I study of dasatinib in pediatric patients with refractory solid tumors or imatinib-refractory, Philadelphia chromosome–positive leukemia was performed. Dose levels of 50, 65, 85, and 110 mg/m2/dose, administered orally twice daily for 28 days, with courses repeated without interruption, were studied. Pharmacokinetic studies were performed with the initial dose. Results A total of 39 patients (solid tumors, n = 28; chronic myeloid leukemia [CML], n = 9; acute lymphoblastic leukemia, n = 2) were enrolled. No dose-limiting toxicities (DLTs) were observed at the 50, 65, and 85 mg/m2 dose levels. At 110 mg/m2, two of six patients experienced DLT including grade 2 diarrhea and headache. In children with leukemia, grade 4 hypokalemia (50 mg/m2), grade 3 diarrhea (85 mg/m2), and grade 2 creatinine elevation (50 mg/m2) were observed. DLT in later courses included pleural effusions, hemangiomatosis, and GI hemorrhage. There were three complete cytogenetic responses, three partial cytogenetic responses, and two partial/minimal cytogenetic responses observed in evaluable patients with CML. Conclusion Overall, drug disposition and tolerability of dasatinib were similar to those observed in adult patients.
19
Olanrewaju, Oluwaseyi Samuel, and Olubukola Oluranti Babalola. "Bacterial Consortium for Improved Maize (Zea mays L.) Production." Microorganisms 7, no. 11 (November 1, 2019): 519. http://dx.doi.org/10.3390/microorganisms7110519.
Анотація:
The ever-increasing human population is a major concern for food security. Maize is the third largest most important food crop. The major problems of cultivation arise from urbanization and land pollution. This reduces the amount of land available for agriculture. The use of chemicals in agriculture is not environmentally friendly. Thus, plant growth-promoting bacteria (PGPB) have been proposed as alternatives. This study aims to test the growth-promoting effect of maize inoculated with six indigenous PGPB isolates. These isolates were assayed for various biochemical and plant growth-promoting activities. They were also assayed for biocontrol activities. Based on the results, six isolates viz A1, A18, A29, NWU4, NWU14, and NWU198 were used to inoculate maize seeds. The inoculated seeds were tried out on the field. A randomized block design was used. PGPB used were in single, consortia of two, and three organisms. The length of the leaves, roots, and stem, plant height, numbers of leaves, and weight of 100 seeds were taken at the fourth and eighth weeks after planting. Microbial consortia increased growth parameters compared to single inoculant treatments. Thus, they can be of advantage in the eradication of low yield. They can also serve as reliable alternatives to chemical fertilizers.
20
Leichman, Lawrence P., Bert H. O'Neil, Jordan Berlin, Colin D. Weekes, Patricia Ames, Marti McKinley, Angela M. Davies, and Steven J. Cohen. "A phase IB study of erlotinib in combination with gemcitabine and nab-paclitaxel in patients with previously untreated advanced pancreatic cancer: An Academic GI Cancer Consortium (AGICC) study." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 4052. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4052.
Анотація:
4052 Background: The combination of gemcitabine (gem) and nab-paclitaxel (nab) has demonstrated promising activity in advanced pancreatic cancer. Erlotinib (erl) adds modest benefit to gemcitabine. We initiated this phase IB study to evaluate the safety of the three drug combination and obtain preliminary evidence of efficacy. Methods: Patients (pts) with previously untreated locally advanced (la) or metastatic (met) pancreatic cancer with ECOG PS 0-1 were treated with gem and nab IV days 1,8,15 and once daily erl days 1-28 Q28 days. Standard 3+3 design was used with dose levels (DL) (gem,nab,erl): 1(1,000, 125, 100), -1 (1,000, 100, 100), -2 (1,000, 75, 100), -3 (1,000,75,75). CT scans were obtained Q 2 cycles. DLT was defined as ≥grade (gr) 3 non-hematologic, febrile neutropenia, ≥gr 3 thrombocytopenia, or missing ≥2 doses gem, nab or >5 doses erl within first cycle (C). Results: Nineteen pts were enrolled and completed a total of 62 cycles (range 0-11). Pt characteristics: M/F (9/10), White/Hispanic/AA (15/2/2), median age 63 (range 54-78), ECOG PS 1=11, met/la (12/7). In DL1, 1/3 pts had gr3 dehydration in C 2 and 1/3 had gr 4 neutropenia/sepsis in C 4. Although not formally DLT, 3 more pts were enrolled. Of the next 3 pts, 1 DLT of gr 3 diarrhea/gr 4 neutropenia in C 1 was noted and 1 other pt DC’d therapy for neutropenia after 2 cycles. Of 3 pts in DL -1, 2 DLTs (gr 3 optic neuropathy, too many missed doses) were observed. Of 3 pts in DL -2, 2/3 had DLT (gr 3 esophagitis/fatigue and gr 3 transaminitis). Of 6 evaluable pts in DL -3, no DLTs were observed. Most common gr 3/4 toxicities were neutropenia (9), dehydration, thrombocytopenia (3 each), and hypotension (2). Of 13 pts evaluable for response, 6 had partial response (46%), 5 stable disease (38%), and 2 progressive disease (15%) as best response. Median PFS and OS of entire cohort were 5.3 and 9.3 months respectively. Conclusions: The combination of erlotinib with gemcitabine and nab-paclitaxel is not tolerable at standard single agent dosing of all drugs. However, significant clinical activity was noted, even at DL -3. Further study of the combination will need to incorporate reduced dosing.
21
Hinrichs, Richard N., and Scott P. McLean. "NLT and extrapolated DLT: 3-D cinematography alternatives for enlarging the volume of calibration." Journal of Biomechanics 28, no. 10 (October 1995): 1219–23. http://dx.doi.org/10.1016/0021-9290(95)00034-f.
22
Somlo, George, Joseph A. Sparano, Tessa Cigler, Gini F. Fleming, Thehang H. Luu, Arti Hurria, Joanne E. Mortimer, et al. "ABT-888 (veliparib) in combination with carboplatin in patients with stage IV BRCA-associated breast cancer. A California Cancer Consortium Trial." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 1010. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.1010.
Анотація:
1010 Background: Platinum and PARP inhibitors have both shown activity in BRCA-associated breast cancer (BC) patients (pts). We have conducted a phase I trial of carboplatin (Carb) and velapirib [V], a PARP inhibitor, to define dose limiting toxicities [(DLT) during cycle (C) 1] and the maximum tolerated dose (MTD). Methods: BRCA 1 or 2 carriers with stage IV BC were eligible. Carb starting at an AUC of 6 was given IV every 21 days (length of planned C) and V was administered orally, BID at dose levels (L) L1 through L5 (highest L planned). Results: 22 pts (21 eligible/evaluable, 20 with measurable BC) carrying BRCA1 (10) or BRCA2 (11), or both (1) mutations were accrued. Median age: 45 years, (32-65); 68% of BCs were ER+, and 10% were HER2+. In the table below are the schema, incidence of DLTs, and # of Cs on study. Toxicities: At L1, grade ¾ DLTs with C 1 were seen in 2/6 evaluable pts (1 pt w/grade 3 hyponatremia, pleural effusion, and dehydration, and 1pt w/grade 4 thrombocytopenia [PLT]), leading to deescalation of carb (AUC 5) for pts treated at Ls 2-5. At L2, 1 of 6 pts had grade 4 PLT. There were no DLTs at Ls 3 and L4. L5 is currently being expanded to 6 pts (3 currently enrolled, 1 pt with grade 4 granulocytopenia (Gr) and grade PLT reached DLT). Non-DLT dose delays mostly due ≥ grade 2 Gr or PLT were needed at 60%, 53%, 53%, and 43% of Cs in pts treated on Ls 1-4. Response: In 12 eligible pts treated at Ls 1 and 2, 2 complete and 6 partial responders (67%) and a clinical benefit (CB) of 75% were seen. All pts at Ls 3-5 are still being treated, and in pts treated at Ls 3 and 4, 2 unconfirmed PRs, and 4 cases of stable disease were seen, with L5 too early to assess. Conclusions: The combination of Carb at an AUC of 5 and daily V at doses 150 to 200 mg BID is feasible and the MTD is being defined. In preliminary analysis, response and CB rates are better than expected with the individual agents alone, providing justification to proceed with a planned phase II randomized single agent versus combination trial. [Table: see text]
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Ledwaba, Lehlogonolo P. I., Gerhard P. Hancke, Sherrin J. Isaac, and Hein S. Venter. "Smart Microgrid Energy Market: Evaluating Distributed Ledger Technologies for Remote and Constrained Microgrid Deployments." Electronics 10, no. 6 (March 18, 2021): 714. http://dx.doi.org/10.3390/electronics10060714.
Анотація:
The increasing strain on ageing generation infrastructure has seen more frequent instances of scheduled and unscheduled blackouts, rising reliability on fossil fuel based energy alternatives and a slow down in efforts towards achieving universal access to electrical energy in South Africa. To try and relieve the burden on the National Grid and still progress electrification activities, the smart microgrid model and secure energy trade paradigm is considered—enabled by the Industrial IoT (IIoT) and distributed ledger technologies (DLTs). Given the high availability requirements of microgrid operations, the limited resources available on IIoT devices and the high processing and energy requirements of DLT operations, this work aims to determine the effect of native DLT algorithms when implemented on IIoT edge devices to assess the suitability of DLTs as a mechanism to establish a secure, energy trading market for the Internet of Energy. Metrics such as the node transaction time, operating temperature, power consumption, processor and memory usage are considered towards determining possible interference on the edge node operation. In addition, the cost and time required for mining operations associated with the DLT-enabled node are determined in an effort to predict the cost to end users—in terms of fees payable and mobile data costs—as well as predicting the microgrid’s growth and potential blockchain network slowdown.
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Wagner, L. M., J. P. Perentesis, J. M. Reid, M. M. Ames, S. L. Safgren, M. D. Nelson, A. M. Ingle, S. M. Blaney, and P. C. Adamson. "Phase I trial and pharmacokinetic study of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with refractory solid tumors: A Children's Oncology Group Phase I Consortium study." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 10017. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.10017.
Анотація:
10017 Background: In preclinical models, temozolomide (TMZ) and vincristine (VCR) are synergistic with irinotecan (IRN). We sought to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of orally administered IRN given on two different schedules together with TMZ and VCR in children with refractory solid tumors, using cefixime to reduce IRN-associated diarrhea. Methods: Schedule A: Oral IRN daily for 5 days for 2 weeks (dx5x2), with VCR 1.5 mg/m2 on days 1 and 8 and TMZ 100 mg/m2 on days 1 - 5. Schedule B: Oral IRN daily for 5 days for 1 week (dx5x1) with VCR 1.5 mg/m2 on day 1 and TMZ 100 - 150 mg/m2 on days 1 - 5. Courses were repeated every 3 weeks. A standard cohorts of 3 + 3 design was used. Results: On Schedule A, 18 evaluable patients (median age 15 yrs, range 3 - 21) received 55 courses. At IRN 50 mg/m2/day, 4/12 pts had DLT (hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia). The oral IRN MTD on this dx5x2 schedule was 35 mg/m2/d (1/6 pts with DLT of hypoalbuminemia). On Schedule B, 18 evaluable patients (median age 9 yrs, range 3–21) received 71 courses of oral IRN 70 - 90 mg/m2/d x 5 with TMZ 100 - 150 mg/m2/d x 5. At oral IRN 90 mg/m2/d with TMZ 150 mg/m2/d, 0/6 pts had DLT, and no Grade 4 toxicities were seen. No further doses were explored. First-course and cumulative toxicity appeared worse with Schedule A, including 3 patients with responding or stable tumors who withdrew due to fatigue, nausea, and weight loss. UGT1A1*28genotype did not correlate with DLT. At the oral IRN MTD of 90 mg/m2/d, the median SN-38 AUCinf was 72 ng/ml*h. One patient with osteosarcoma had a confirmed partial response. Unconfirmed complete and partial responses were seen in 2 Ewing sarcoma patients. Eight additional patients received > 6 courses, including 2 each with neuroblastoma and medulloblastoma. Conclusions: The dx5x1 schedule of VOIT was well tolerated, with SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in sarcoma patients. No significant financial relationships to disclose.
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Delgado, Ninoska, Matías Olivera, Fabiola Cádiz, Guillermo Bravo, Iván Montenegro, Alejandro Madrid, Claudia Fuentealba, Romina Pedreschi, Eduardo Salgado, and Ximena Besoain. "Volatile Organic Compounds (VOCs) Produced by Gluconobacter cerinus and Hanseniaspora osmophila Displaying Control Effect against Table Grape-Rot Pathogens." Antibiotics 10, no. 6 (June 1, 2021): 663. http://dx.doi.org/10.3390/antibiotics10060663.
Анотація:
Table grapes (Vitis vinifera) are affected by botrytis bunch rot and summer bunch rot, the latter a complex disease caused by Botrytis cinerea, Aspergillus spp., Penicillium expansum and Rhizopus stolonifer. To search for biocontrol alternatives, a new bioproduct composed of Gluconobacter cerinus and Hanseniaspora osmophila, a consortium called PUCV-VBL, was developed for the control of fungal rots in table grapes. Since this consortium presents new biocontrol species, the effect of their VOCs (volatile organic compounds) was evaluated under in vitro and in vivo conditions. The VOCs produced by the PUCV-VBL consortium showed the highest mycelial inhibition against Botrytis cinerea (86%). Furthermore, H. osmophila was able to inhibit sporulation of A. tubingensis and P. expansum. VOCs’ effect in vivo was evaluated using berries from Red Globe, Thompson Seedless and Crimson Seedless grapes cultivars, demonstrating a mycelial inhibition by VOCs greater than 70% for all evaluated fungal species. The VOC identification of the PUCV-VBL consortium was analyzed by solid-phase microextraction coupled to gas chromatography-mass spectrometry (SPME-GCMS). A total 26 compounds were identified, including 1-butanol 3-methyl, propanoic acid ethyl ester, ethyl acetate, phenylethyl alcohol, isobutyl acetate and hexanoic acid ethyl ester. Our results show that VOCs are an important mode of action of the PUCV-VBL biological consortium.
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Goldsmith, Kelly C., Kimberly Kayser, Susan G. Groshen, Marc Chioda, Holger C. Thurm, Joseph Chen, Gerson Peltz, et al. "Phase I trial of lorlatinib in patients with ALK-driven refractory or relapsed neuroblastoma: A New Approaches to Neuroblastoma Consortium study." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 10504. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.10504.
Анотація:
10504 Background: Lorlatinib, a potent ALK inhibitor, exerts unprecedented activity against neuroblastoma (NB) derived xenografts harboring common crizotinib-resistant ALK mutations, leading to a first in child phase I study. Methods: R/R NB patients (pts) > 12 months, with ALK mutations/amplification and prior ALK inhibitor (ALKi) treatment were eligible. Lorlatinib was administered in 28-day courses (C). For pts < 18 years, 5 dose levels (DL) (45, 60, 75, 95, 115 mg/m2/day) were assessed. DL5 (115 mg/m2/day) expansion is enrolling (cohort A1). For patients > 18 years, two DL (DL3a the adult RP2D of 100 mg/day and DL4a at 150mg/day) were assessed (cohort A2). Primary endpoint was dose-limiting toxicity (DLT) during C1 and neurocognitive toxicity through C2. Blood samples for circulating tumor DNA (ctDNA) were matched to radiologic restaging. Results: From 9/2017 to 1/2019, 33 eligible patients enrolled (13 with prior ALKi therapy), with median age (range) 5.5 years (2-17) on A1, 21.5 years (15-50) on A2. In A1, 3 pts each enrolled onto DL1-3, with no DLT’s. 5/10 pts enrolled on DL4, with no DLT’s. 1/3 on DL5 had a DLT of grade 3 diarrhea, with expansion ongoing. In cohort A2, 5 patients enrolled at 100 mg/day with no DLT’s; 6 enrolled at 150 mg/day, with one DLT (grade 4 reversible psychosis). Most common treatment-related adverse events were weight gain (90%, grade 1-3), hyperlipidemia (90%, grade 1-3), concentration/memory impairment (23%, grade 1-2), peripheral neuropathy (13%; grade 1-2, A2 only), and peripheral edema (10%; grade 1, A2 only). Lorlatinib steady state exposure at DL3 and DL4 was in the range of exposures seen in adult lung cancer patients at the 100 mg and 200 mg DLs. In A1, 1/18 had partial response (PR), 3/18 had minor responses (MR), and 4/18 had stable disease (SD). Of pts with MR, 2/3 had PR of soft tissue and 1/3 had complete response (CR) by MIBG. In A2 pts, 1/10 had CR, 3/10 PR, and 3/10 MR; Notably, 2/3 with PR had CR by MIBG. Of the pts with MR, one had PR and one CR by MIBG. Responses occurred across dose levels, ALK mutations, and in ALKi pre-treated pts with median courses of 2 (1-24) on A1 and 10.5 (2-28) on A2. Serial ctDNA results showed mutant ALK variant allele frequency trajectories that correlated with clinical response and emergence of novel ALK mutations in cis that corresponded with disease progression. Conclusions: Inhibition of ALK-driven NB with lorlatinib occurs with manageable toxicity and objective anti-tumor activity. Prospective ctDNA allows for monitoring of disease and evolution of resistance. Clinical trial information: NCT03107988.
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Widemann, B. C., E. Fox, P. C. Adamson, S. Baruchel, A. Kim, A. M. Ingle, J. Glade Bender, D. Stempak, F. M. Balis, and S. M. Blaney. "Phase I study of sorafenib in children with refractory solid tumors: A Children's Oncology Group Phase I Consortium trial." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 10012. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.10012.
Анотація:
10012 Background: Sorafenib, an oral multitargeted kinase inhibitor, is indicated for treatment of adults with refractory renal cell or hepatocelluar carcinoma. We performed a phase I trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of sorafenib in children with refractory solid tumors. Methods: Sorafenib was administered q12h for 28 consecutive day cycles. Cohorts of 3–12 patients were enrolled at 105, 130, 150, 200, and 250 mg/m2/dose dose levels. Results: 34 eligible pts [16M, median age 14.6 yrs, (range, 5–21)] with osteosarcoma (n = 8), rhabdomyosarcoma (n = 3), other sarcomas (n = 13), hepatoblastoma (n = 3), or other solid tumors (n = 7) received 1–22 cycles (median 2). Grade 3 dose-limiting toxicity (DLT) occurred in 4/6 pts at the starting dose (150 mg/m2) and included hypertension (n = 1), rash/urticaria (n = 1), back pain (n = 1), thrombocytopenia (n = 1) and ALT/AST (n = 1). No DLTs were observed at 105 (n = 6) or 130 (n = 3) mg/m2, and the dose was re-escalated to 150 mg/m2 with modified eligibility criteria (normal ALT) and revised guidelines for grading and management of hypertension. Gr 3 DLTs occurred in 1/6 pts (lipase) at 150 mg/m2 and 2/2 pts (hyponatremia, hand-foot syndrome) at 250 mg/m2. At 200 mg/m2 only 1/6 pts experienced DLT (gr 3 ALT). No objective responses were observed, but 2 pts had tumor shrinkage. Sorafenib AUC did not increase proportionally with dose - the mean AUC0–24h was similar at 150 mg/m2 (28±24 μg · h/mL, n = 9) and 200 mg/m2 (28±17 μg · h/mL, n = 4). Tmax was prolonged and variable (10±11 h, n = 19). Plasma VEGFR (n = 13) decreased from 9.9±1.6 ng/mL at baseline to 8.3±1.7 ng/mL by d 28 (p < 0.001). Conclusions: The MTD of sorafenib in children with solid tumors is 200 mg/m2, similar to the adult recommended dose (400 mg). No significant financial relationships to disclose.
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Han, Lei, Andreja Kutnar, Jakub Sandak, Iztok Šušteršič, and Dick Sandberg. "Adhesive- and Metal-Free Assembly Techniques for Prefabricated Multi-Layer Engineered Wood Products: A Review on Wooden Connectors." Forests 14, no. 2 (February 5, 2023): 311. http://dx.doi.org/10.3390/f14020311.
Анотація:
Engineered wood products (EWPs) are being increasingly used as construction materials. EWPs are currently being made using synthetic adhesives or metal fasteners, which lead to poor recyclability and reusability. Therefore, this review paper focused on emerging adhesive- and metal-free assembling techniques including wood dowels, rotary-dowel welding, wooden nails, and dovetail joining as alternative ways of making prefabricated EWPs. This will contribute towards green construction and optimising the building process to minimise its negative impact on the environment and its inhabitants, while maximising the positive aspects of the finished structure. The respective advantages and shortcomings will be compared with those of equivalent EWPs. In general, the dowel-laminated timber (DLT) provides sufficient load-bearing capacity and even better ductility than EWPs of equivalent size, but its relatively low stiffness under a bending load limits its application as a structural element. Optimised manufacturing parameters such as dowel species, dowel spacing, dowel diameter, dowel insertion angle, dowel shape, etc. could be studied to improve the stiffness. The improved mechanical properties and tight fitting due to set-recovery of densified wood support its use as sustainable alternatives to hardwood dowels in DLT to overcome problems such as the loosening of connections over time and dimensional instability. The rotary welding technology could also enhance the strength and long-term performance of dowel-type joints, but its poor water resistance needs further investigation. The main obstacles to implementing DLT products in the market are missing technical information and design guidelines based on national codes.
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Mosse, Yael P., Frank M. Balis, Megan S. Lim, Julie Laliberte, Stephan D. Voss, Elizabeth Fox, Rochelle Bagatell, et al. "Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: A Children's Oncology Group phase I consortium study." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 9500. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.9500.
Анотація:
9500 Background: Genetic aberrations in the anaplastic lymphoma kinase (ALK) gene are found in anaplastic large cell lymphoma (ALCL), neuroblastoma (NB) and other tumors.Crizotinib,a small molecule inhibitor of ALK and c-Met, is active in non-small cell lung cancers (NSCLC) harboring an ALK translocation. We performed a phase 1 dose-escalation and pharmacokinetic (PK) trial of crizotinib in patients (pts) with refractory solid tumors and ALCL. Methods: Crizotinib was administered bid without interruption in 28 day cycles using the rolling-six design. Six dose levels (100, 130, 165, 215, 280, 365 mg/m2/dose) have been evaluated (A1). Pts with confirmed ALK fusion proteins, mutations or amplification (A2) could enroll at one dose level lower than part A1 and those with NB could enroll on a separate stratum (A3). PK studies were performed on day 1 and at steady state (SS). ALK genomic status in tumor tissue was evaluated and qPCR was used to measure NPM-ALK fusion transcript in bone marrow and blood samples of ALCL pts. Results: 70 pts were enrolled, 57 fully evaluable for toxicity, [median (range) age 9.9 yrs (1.1–21.3)]: 29 on A1, 18 on A2, and 10 on A3. In A1, 2/7 pts developed DLT (grade 3 dizziness, grade 5 intra-tumoral hemorrhage) at 215 mg/m2 and 1/6 pts developed DLT (grade 4 liver enzyme elevation) at 365 mg/m2. In A2, 1 grade 4 DLT (neutropenia) occurred at 165 mg/m2; in A3, no DLTs occurred. Mean (±SD) Cave (=AUC0-12h/12h) of crizotinib at SS was 466±114 ng/mL at 215 mg/m2/dose (n=5), 443±121 ng/mL at 280 mg/m2/dose (n=8), and 720±230 ng/mL at 365mg/m2/dose (n=4). Response data for pts with ALCL (six at 165 mg/m2, two at 280 mg/m2) approved for release by the Data Safety Monitoring Committee demonstrates 7/8 (88%) complete response (CR) rate to date. RT-PCR data for 6 of these pts at 57 time points was obtained and will be described. In addition, 2 pts with NB have had CRs, one with a documented ALK mutation. One patient with an inflammatory myofibroblastic tumor and one with NSCLC had PRs. Conclusions: Inhibition of ALK in pediatric pts with ALK-driven tumors occurs with minimal toxicity and is associated with objective anti-tumor activity.
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Morris, Michael J., Justine Yang Bruce, Leonard M. Reyno, Banmeet Anand, Alan Hartford, Kathy Jelaca-Maxwell, Jacqueline Lackey, and Mario A. Eisenberger. "Phase I trial of ASG-5ME in metastatic castration-resistant prostate cancer (CRPC)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 4568. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4568.
Анотація:
4568 Background: SLC44A4 is a 710 amino acid protein that is expressed on prostate, pancreas and other cancers. SLC44A4 is found in 95% of primary prostate tumors (75% express moderate to high levels). ASG-5ME is an antibody drug conjugate (ADC) comprised of a fully human antibody targeting SLC44A4, conjugated to the microtubule-disrupting agent monomethyl auristatin E. ASG-5ME has dose-dependent cytotoxic effects in vitro and significant anti-tumor activity in xenograft models. We report results of a phase I study to establish the maximum tolerated dose (MTD) of ASG-5ME for CRPC, conducted by the Prostate Cancer Clinical Trials Consortium. Methods: Patients (pts) had progressive metastatic CRPC. Prior chemotherapy was allowed. Treatment cohorts were 0.3, 0.6, 1.2, 1.8, 2.4, and 3.0 mg/kg. ASG-5ME was given IV q3 weeks. Safety, pharmacokinetic properties, anti-tumor effects, circulating tumor cell (CTC) enumeration, and CTC molecular profiles were assessed. Pts were treated until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) was defined by cycle 1 toxicity. Results: 20 pts have been treated (3, 3, 3, 3, 6, and 2 pts per respective cohort). Mean age was 69 (range 56-87), median Gleason score 8 (6-10), mean baseline PSA 225 (5-1987). Pts received an average of 4 doses (1-12). 2 DLTs occurred in Cycle 1 in the 3 mg/kg cohort: DLT 1: Grade (Gr) 3 troponin elevation and DLT 2: Gr3 maculopapular rash, hypoxia, constipation, and Gr4 neutropenia. Common Gr 1 and 2 adverse events included fatigue, anorexia, peripheral neuropathy, dyspnea and nausea. Gr3 events included: fatigue (2 pts),peripheral neuropathy (1), dyspnea (1) and nausea (1). Serum concentrations of ASG-5ME decreased multi-exponentially and the exposure was dose-proportional. The half-life of intact drug was calculated as 7.01 days (range-3.93-15.9, n=17) after the first dose and 11.2 days ( range-7.75-19.1 days, n=10) after the last dose. PSA declines of >50% were seen in 3/8 pts treated in the last two cohorts and one unconfirmed >50% decrease in retroperitoneal nodes. Conclusions: DLT events observed at 3 mg/kg exceeded the MTD; the MTD is 2.4 mg/kg of doses tested in pts with metastatic CRPC. The drug appears to have anti-cancer activity at 2.4 and 3 mg/kg.
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Lim, Michael, Xiaobu Ye, Anna F. Piotrowski, Arati Suvas Desai, Manmeet Singh Ahluwalia, Tobias Walbert, Joy D. Fisher, et al. "Updated phase I trial of anti-LAG-3 or anti-CD137 alone and in combination with anti-PD-1 in patients with recurrent GBM." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2017. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2017.
Анотація:
2017 Background: Preclinical GBM data targeting the checkpoint molecules Lag-3 and CD137 have shown promising anti-tumor immune response with resultant improved survival when combined with anti-PD-1. Here we report our experience from a multi-arm safety study in patients with recurrent GBM treated with anti-Lag-3 and anti-CD137. Methods: The Adult Brain Tumor Consortium (ABTC) 1501 trial is a phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) or anti-CD137 (BMS-663513) alone and in combination with anti-PD-1 in patients at first recurrence of GBM. The primary objective is to define MTD for the mono and combinational treatment. The major secondary objective is to explore for a signal in efficacy. The key inclusion criteria are adults, first recurrence of GBM following RT+TMZ, TLC≥1000/ul, KPS≥ 60%, stable corticosteroid regimen, measurable disease, and written informed consent. Sequential allocation was used for the treatment assignment at starting dose of 80mg for anti-LAG-3 and 8mg for anti-CD137. Anti-PD-1was given at a flat dose of 240 mg in the combination treatment arms. The 3+3 design is used for the dose finding with a target DLT rate < 33%. Results: to date 44 patients were enrolled into the trial with median age at 57, median KPS at 90. Median treatment cycle was 3 and 39% tumors were MGMT methylated. The highest safe dose for Anti-LAG-3 alone is 800 mg without a DLT. The safe dose for anti-CD137 alone arm is 8mg with 1 DLT, and 2 grade 3 elevated serum ALT at end of cycle 2. Combination arms of Anti-LAG-3 +anti-PD-1 (160 mg/240mg as the highest dose combination) had one DLT (hypertension) and no toxicities were seen in the combination arm of Anti-CD137+Anti-PD-1 (3 mg/240 mg). mOS was 14 months for anti-CD137 alone, 8 months for Anti-Lag-3, and 7 months for Anti-Lag-3 + Anti-PD-1. Correlative data will be discussed. Conclusions: The trial is ongoing. The RP2D is 800mg for anti-LAG-3 as a monotherapy and 8mg for anti-CD137. For the combination arms, 160 mg of Anti-LAG-3 and 240 mg of anti-PD-1 and 3 mg of anti-CD137 and 240 mg antiPD-1 were the RP2D. Clinical trial information: NCT02658981.
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Chumsri, Saranya, Sharmila Giri, Andrew Ness, David W. Hillman, Nadine Norton, Davitte Cogen, Edward Famularo, et al. "Safety run-in phase of the multi-epitope HER2 peptide vaccine in combination with trastuzumab emtansine in HER2-positive breast cancer with residual disease after neoadjuvant chemotherapy." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): 550. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.550.
Анотація:
550 Background: Residual disease after neoadjuvant chemotherapy (NAC) in HER2-positive breast cancer (BC) confers poor outcomes. Despite additional trastuzumab emtansine (T-DM1) in the adjuvant setting, a significant number of patients with residual disease still develop recurrence. H2NVAC is a multi-epitope T helper cell-activating peptide vaccine that is composed of 4 degenerate HER2-derived HLA-DR epitopes admixed with GM-CSF. Our previous phase I trial showed that this vaccine was safe and generated robust, long-lasting T and B cell immune responses. Methods: Patients with stage II-III HER2+ BC with any amount of residual disease in the breast /axilla after NAC were enrolled in a safety run-in phase of H2NVAC in combination with T-DM1. Patients were treated with H2NVAC and T-DM1 for 6 cycles, followed by 2 boosters at 3 and 12 months. Dose-limiting toxicity (DLT) was defined as any grade (G) ≥ 3 adverse events (AE) occurring within 21 days after the first vaccination. Results: A total of20 patients were enrolled with a median age of 51 years (range 27-69), 80% were White and 15% were Black. Most patients had hormone receptor-positive disease (90%). 40% were premenopausal, 40% were postmenopausal, and 20% were unknown. 14 patients had ypT1, 3 patients ypT2, 3 patients ypT3, 1 patient ypT4, 8 patients ypN0, 9 patients yp N1, 1 patient ypN1mi, and 2 patients ypN2. H2NVAC, in combination with T-DM1, was well tolerated, with no DLT being observed. Only grades 1 and 2 AEs were observed during the DLT period, with fatigue being the most common (G1 60%, G2 5%), followed by peripheral sensory neuropathy (G1 55%, G2 5%) and injection site reaction (G1 50%). Across all treatment cycles, the top 10 most common AEs that were at least possibly related to treatment include injection site reaction (G1 85%, G2 15%), AST increase (G1 65%), ALT increase (G1 45%), fatigue (G1 35%, G2 10%), peripheral sensory neuropathy (G1 35%, G-tube 10%), alk-phos increase (40% G1), nausea (G1 35%, G2 5%), arthralgia (G1 35%), myalgia (G1 25%, G2 5%), and platelet count decrease (G1 30%). There were four patients with G3 AEs at least possibly related to the vaccine observed after the DLT period, including allergic reaction, myositis/skin infection, urticaria, and pruritus/maculopapular rash. Conclusions: H2NVAC, in combination with T-DM1, was safe without DLT observed. The side effect profile was favorable, with the most common AE being the G1 injection site reaction. A multicenter, randomized, placebo-controlled, phase II trial of H2NVAC vs. placebo in combination with trastuzumab emtansine is currently ongoing through the ACCRU consortium. Clinical trial information: NCT04197687 .
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Mehra, Sameer, Annette M. Harte, Adeayo Sotayo, Zhongwei Guan, and Conan O’Ceallaigh. "Experimental investigation on the effect of accelerated ageing conditions on the pull-out capacity of compressed wood and hardwood dowel type fasteners." Holzforschung 76, no. 1 (January 1, 2021): 89–98. http://dx.doi.org/10.1515/hf-2021-0097.
Анотація:
Abstract The widespread use of adhesives in timber construction has negative implications for the end-of-life disposal or re-use of the structural timber components. To promote the circular bioeconomy, it is preferable to substitute adhesives with more sustainable alternatives such as wood-based connectors. Today, robotic fabrication technologies facilitate the development of dowel-laminated timber (DLT) products whereby hardwood dowels are used to connect timber laminates as a substitute to adhesives. In recent years, thermo-mechanical densification of wood has resulted in significant improvements in the mechanical performance of the wood. This modified product often termed compressed wood (CW) has a shape-recovery effect which may be beneficial for the development of DLT products and timber-timber connections with improved friction fit with time. To test the hypothesis, accelerated ageing tests were carried out on CW-timber and hardwood-timber dowel type connections subjected to variable climate conditions. Finally, the capacity of the connections or friction fit was assessed using pull-out tests. Results show that the shape-recovery effect leads to the continuous expansion of the CW dowels and facilitates a friction fit with the timber substrate yielding higher pull-out loads when compared to hardwood dowels.
34
Cotoras, Davor, Cristian Hurtado, and Pabla Viedma. "Integrated Sulfate Reduction and Biosorption Process for the Treatment of Mine Drainages." Solid State Phenomena 262 (August 2017): 582–86. http://dx.doi.org/10.4028/www.scientific.net/ssp.262.582.
Анотація:
Sulfate is a pollutant present in the mining waste water and acid mine drainage. High levels of sulfate can generate important environmental problems. One of the alternatives proposed for the treatment of water with high levels of sulfate is the use of sulfate-reducing microorganisms. This work describes the synergistic combination of a treatment system for the removal of metals by biosorption with the strain Bacillus sp. NRRL-B-30881 to reduce the inhibiting concentration of metals in waters, followed by a new process of sulfate removal that uses a halotolerant sulfate-reducing microbial consortium. The results show that the sulfate reducing consortium can be cultured and is able to reduce the sulfate concentration using cheaper complex organic substrates like spirulina, cellulose and industrial starch. The sulfate reducing consortium was cultured on a bioreactor with Celite R-635, as support material. Using this bioreactor it was possible to reduce the sulfate concentration in the culture medium in batch or semi-continuous operation. An acid mine drainage was pretreated by lime and treated by biosortion in order to increase the pH and reduce the heavy metals concentration. Subsequently the remaining sulfate was removed by the developed process. This integrated biological process represents a more economical alternative for the removal of metal by biosortion and the removal of sulfate using a sulfate reducing consortium.
35
Hammoud, Obadah, Ivan Tarkhanov, and Artyom Kosmarski. "An Architecture for Distributed Electronic Documents Storage in Decentralized Blockchain B2B Applications." Computers 10, no. 11 (November 4, 2021): 142. http://dx.doi.org/10.3390/computers10110142.
Анотація:
This paper investigates the problem of distributed storage of electronic documents (both metadata and files) in decentralized blockchain-based b2b systems (DApps). The need to reduce the cost of implementing such systems and the insufficient elaboration of the issue of storing big data in DLT are considered. An approach for building such systems is proposed, which allows optimizing the size of the required storage (by using Erasure coding) and simultaneously providing secure data storage in geographically distributed systems of a company, or within a consortium of companies. The novelty of this solution is that we are the first who combine enterprise DLT with distributed file storage, in which the availability of files is controlled. The results of our experiment demonstrate that the speed of the described DApp is comparable to known b2c torrent projects, and subsequently justify the choice of Hyperledger Fabric and Ethereum Enterprise for its use. Obtained test results show that public blockchain networks are not suitable for creating such a b2b system. The proposed system solves the main challenges of distributed data storage by grouping data into clusters and managing them with a load balancer, while preventing data tempering using a blockchain network. The considered DApps storage methodology easily scales horizontally in terms of distributed file storage and can be deployed on cloud computing technologies, while minimizing the required storage space. We compare this approach with known methods of file storage in distributed systems, including central storage, torrents, IPFS, and Storj. The reliability of this approach is calculated and the result is compared to traditional solutions based on full backup.
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DeWire, Mariko, Christine Fuller, Olivia Campagne, Tong Lin, Haitao Pan, Tina Young-Pussaint, Patricia Baxter, et al. "EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIB AND EVEROLIMUS IN CHILDREN WITH RECURRENT OR REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN TUMOR CONSORTIUM INTERIM REPORT." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii307. http://dx.doi.org/10.1093/neuonc/noaa222.139.
Анотація:
Abstract Genomic aberrations in the cell cycle and PI3K pathway are commonly observed in recurrent childhood brain tumors. Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dosage (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus was determined in the Phase I study and ribociclib concentrations were characterized in plasma and tumor in children undergoing neurosurgical procedures. Following resection, eligible patients were enrolled in the Phase I study according to a rolling 6 design and received ribociclib and everolimus once daily for 21 days and 28 days, respectively. Patients undergoing surgery received ribociclib at the pediatric RP2D (350 mg/m2/day) for 7–10 days pre-operatively. Pharmacokinetic samples were collected on both cohorts and analyzed in nine patients on phase I study. Sixteen eligible patients enrolled on phase I study (median age 10.3 years; range: 3.9–20.4) and 5 patients were enrolled on the surgical cohort (median age 11.4 years; range: 7.2–17.1). Six patients enrolled at dose level 1 without dose limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4 ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. Everolimus concentrations following administration of everolimus alone were lower than those following drug combination, suggesting an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus in recurrent CNS tumors is 120 mg/m2 and 1.2 mg/ m2 daily for 21 days and 28 days, respectively.
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Leary, Sarah, Julie R. Park, Joel M. Reid, Andrew T. Ralya, Sylvain Baruchel, Bing Wu, Ashish M. Ingle, Charlotte H. Ahern, Brenda Weigel, and Susan Blaney. "A phase I trial and pharmacokinetic study of trebananib (AMG386) in children with recurrent or refractory solid tumors: A Children’s Oncology Group Phase 1 Consortium report." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2538. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2538.
Анотація:
2538 Background: Trebananib is a first-in-class peptibody (peptide-Fc fusion protein) that selectively inhibits Angiopoietin 1 and Angiopoietin 2 to inhibit interaction with the Tie2 receptor tyrosine kinase and prevent angiogenesis by a VEGF independent mechanism. A pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of trebananib. Methods: Trebananib was administered as a weekly 30 - 60 minute IV infusion. Three dose levels (10, 15 or 30 mg/kg/dose) were evaluated using a rolling-six design. PK sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks of therapy. Results: Fifteen eligible patients (14 evaluable for toxicity) with a median age of 14 yrs (range, 3 to 20) and diagnoses of neuroblastoma (n=4), rhabdomyosarcoma (n=3), Ewing sarcoma (n=3), osteosarcoma (n=2), other soft tissue sarcoma (n=2), or nasopharyngeal carcinoma (n=1) have been enrolled. There were no DLTs observed at either the 10 mg/kg (n=6 pts) or 15 mg/kg (n=3 pts) dose. 1/6 pts receiving 30 mg/kg/dose developed DLT (venous thrombosis at a central line site). Non-dose limiting grade 3 or 4 toxicities included lymphopenia (n=2) hypertension (n=1), and neutropenia (n=1). Response in evaluable patients after eight weeks of therapy included stable disease (n=6 pts) and progressive disease (n=7 pts). PK were linear over the 3 dose levels, with t1/2 and Clpvalues of 69±18 h and 1.6±0.5 ml/h/kg, respectively. Conclusions: Trebananib is well tolerated in pediatric patients with recurrent or refractory solid tumors with recommended Phase 2 dose of 30 mg/kg. Correlative biology studies will be presented. Further study is planned to evaluate tolerability and changes in vascular permeability in patients with primary CNS tumors. Clinical trial information: NCT01538095.
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Matthay, Katherine K., Jessica C. Tan, Judith G. Villablanca, Gregory A. Yanik, Janet Veatch, Benjamin Franc, Eilish Twomey, et al. "Phase I Dose Escalation of Iodine-131–Metaiodobenzylguanidine With Myeloablative Chemotherapy and Autologous Stem-Cell Transplantation in Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy Consortium Study." Journal of Clinical Oncology 24, no. 3 (January 20, 2006): 500–506. http://dx.doi.org/10.1200/jco.2005.03.6400.
Анотація:
Purpose To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131–metaiodobenzylguanidine (131I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma. Patients and Methods Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. 131I-MIBG was administered on day −21, CEM was administered on days −7 to −4, and ASCT was performed on day 0, followed by 13-cis-retinoic acid. 131I-MIBG was escalated in groups of three to six patients, stratified by corrected glomerular filtration rate (GFR). Results The MTD for patients with normal GFR (≥ 100 mL/min/1.73 m2) was 131I-MIBG 12 mCi/kg, carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. In the low-GFR cohort, at the initial dose level using 12 mCi/kg of 131I-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOD). Three more patients in this group had grade 3 or 4 hepatotoxicity, and two had VOD, without meeting DLT criteria. There was only one death as a result of toxicity among all 24 patients. All assessable patients engrafted, with median time for neutrophils ≥ 500/μL of 10 days and median time for platelets ≥ 20,000/μL of 26 days. Six of 22 assessable patients had complete or partial response, and 15 patients had mixed response or stable disease. The estimated probability of event-free survival and survival from the day of MIBG infusion for all patients at 3 years was 0.31 ± 0.10 and 0.58 ± 0.10, respectively. Conclusion 131I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.
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Van Mater, David, Sridharan Gururangan, Sarah Leary, Oren Becher, Joanna Phillips, Jie Huang, Olivia Campagne, et al. "EPCT-05. A PHASE I TRIAL OF THE CDK 4/6 INHIBITOR PALBOCICLIB IN PEDIATRIC PATIENTS WITH PROGRESSIVE OR REFRACTORY CNS TUMORS: A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii304. http://dx.doi.org/10.1093/neuonc/noaa222.129.
Анотація:
Abstract PBTC-042 was a phase I trial of palbociclib to determine the maximum tolerated dose (MTD) and describe toxicities in children. Palbociclib is an oral, selective cyclin dependent kinase 4/6 inhibitor. METHODS: A rolling-6 design was utilized. Eligible patients were children ≥4 and ≤21 years-old with a progressive/refractory CNS tumor with intact retinoblastoma protein, measurable disease, and ability to swallow capsules. Pharmacokinetic studies were performed during the first course. Here, we report on the heavily pretreated stratum, which included patients who received >4 prior treatment regimens (either chemotherapy or biologic agent), and/or craniospinal irradiation, and/or myeloablative chemotherapy plus stem cell rescue. Palbociclib was initiated at 50 mg/m2/day for 21 consecutive days of a 28-day course. This was one dosage level below the MTD for the less heavily pretreated stratum (75 mg/m2). RESULTS: Fourteen eligible patients were enrolled (median age 12.8 years; male 79%). Eleven patients (79%) had either ependymoma or medulloblastoma. Four eligible and evaluable patients were enrolled at 50 mg/m2 with no DLTs. This prompted a dosage increase to 75 mg/m2. Ten eligible subjects were enrolled and 7 were evaluable for DLT assessment. One of 7 evaluable patients experienced a DLT (grade 3 thrombocytopenia). This established 75 mg/m2 as the MTD for more heavily pretreated patients. Mean ± SD palbociclib apparent oral clearance was 34.6 ± 18.4 L/h/m2. CONCLUSION: The MTD for palbociclib on a 3 week on/1 week off schedule in children with brain tumors is 75 mg/m2 and does not appear to be influenced by the degree of prior therapy.
40
Elhalis, Hosam, Xin Yi See, Raffael Osen, Xin Hui Chin, and Yvonne Chow. "Significance of Fermentation in Plant-Based Meat Analogs: A Critical Review of Nutrition, and Safety-Related Aspects." Foods 12, no. 17 (August 27, 2023): 3222. http://dx.doi.org/10.3390/foods12173222.
Анотація:
Plant-based meat analogs have been shown to cause less harm for both human health and the environment compared to real meat, especially processed meat. However, the intense pressure to enhance the sensory qualities of plant-based meat alternatives has caused their nutritional and safety aspects to be overlooked. This paper reviews our current understanding of the nutrition and safety behind plant-based meat alternatives, proposing fermentation as a potential way of overcoming limitations in these aspects. Plant protein blends, fortification, and preservatives have been the main methods for enhancing the nutritional content and stability of plant-based meat alternatives, but concerns that include safety, nutrient deficiencies, low digestibility, high allergenicity, and high costs have been raised in their use. Fermentation with microorganisms such as Bacillus subtilis, Lactiplantibacillus plantarum, Neurospora intermedia, and Rhizopus oryzae improves digestibility and reduces allergenicity and antinutritive factors more effectively. At the same time, microbial metabolites can boost the final product’s safety, nutrition, and sensory quality, although some concerns regarding their toxicity remain. Designing a single starter culture or microbial consortium for plant-based meat alternatives can be a novel solution for advancing the health benefits of the final product while still fulfilling the demands of an expanding and sustainable economy.
41
Argumedo-Delira, Rosalba, Mario J. Gómez-Martínez, and Brenda Joan Soto. "Gold Bioleaching from Printed Circuit Boards of Mobile Phones by Aspergillus niger in a Culture without Agitation and with Glucose as a Carbon Source." Metals 9, no. 5 (May 7, 2019): 521. http://dx.doi.org/10.3390/met9050521.
Анотація:
Hydrometallurgical and pyrometallurgical processes to recover gold (Au) from cell-phone printed circuit boards (PCBs) have the disadvantage of generating corrosive residues and consuming a large amount of energy. Therefore, it is necessary to look for biological processes that have low energy consumption and are friendly to the environment. Among the biological alternatives for the recovery of Au from PCB is the use of cyanogenic bacteria and filamentous fungi in cultures with agitation. Considering that it is important to explore the response of microorganisms in cultures without agitation to reduce energy expenditure in the recovery of metals from PCB, the present investigation evaluated the capacity of Aspergillus niger MXPE6 and a fungal consortium to induce Au bioleaching from PCB in a culture medium with glucose as a carbon source and without agitation (pH 4.5). The results indicate that the treatments with PCB inoculated with the fungal consortium showed a considerable decrease in pH (2.8) in comparison with the treatments inoculated with A. niger MXPE6 (4.0). The fungal consortium showed a significantly higher Au bioleaching (56%) than A. niger MXPE6 (17%). Finally, the use of fungal consortia grown without agitation could be an alternative to recover metals from PCB, saving energy and material resources.
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Mora-Salguero, Daniela, Martha Josefina Vives Florez, Johanna Husserl Orjuela, Miguel Fernández-Niño, and Andrés Fernando González Barrios. "Evaluation of the phenol degradation capacity of microalgae-bacteria consortia from the bay of Cartagena, Colombia." TecnoLógicas 22, no. 44 (January 15, 2019): 149–58. http://dx.doi.org/10.22430/22565337.1179.
Анотація:
The development of new technologies for environmental reparation has allowed the application of inexpensive alternatives such as bioremediation, which has a high potential to treat ecosystems polluted with hydrocarbons. Microalgae-bacteria consortia have been identified as an efficient alternative for the detoxification of organic and inorganic contaminants and the removal of toxic compounds. This work investigates the phenol degradation potential of several alga-microbial consortia, which involved the algae Chlamydomonas reinhardtii and an osmotolerant phenol-resistant bacterial strain isolated from the bay of Cartagena, Colombia. A total of three bacterial strains were tested (i.e. Stenotrophomonas maltophilia, Microbacterium paraoxydans and Paenibacillus lactis) individually and in consortium with C. reinhardtii. Our data indicate a significant increase in the growth rate and a reduction in the lag phase of microorganisms in the consortium as compared to microorganisms growing in isolation. Interestingly, the inoculum ratio 2:1 (bacteria-microalgae) was shown to be the most robust taking into account that both microorganisms improved their growth. Afterward, the phenol degradation capacity of pure cultures and consortia in the presence of different phenol concentrations was evaluated. Our results reveal that such consortia perform better at low phenol concentrations; more specifically, the consortium Microbacterium paraoxydans-Chlamydomonas reinhardtii was the most effective: it reached a 49.89% phenol removal.
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Cairo, Mitchell S., Erin Cooney, Mark Krailo, Richard Belanger, Sherrie L. Perkins, Rashid Fawwaz, Anne Angiolillo, and Peter Adamson. "A Phase I Study of 90Y-Ibritumomab-Tiuxetan (90Y-It) in Children with Recurrent/Refractory CD20 Positive Lymphoma: A Cog Phase I Consortium Study." Blood 106, no. 11 (November 16, 2005): 2448. http://dx.doi.org/10.1182/blood.v106.11.2448.2448.
Анотація:
Abstract More than 98% of newly diagnosed childhood B-NHL expresses CD20 (Perkins/Cairo, Clin Adv Hem/Onc 2003). The prognosis for children and adolescents with recurrent CD20 positive NHL, particularly DLBCL and BL, is dismal (Cairo et al, Am J Hem, 2003, Cairo et al, Br J Hem, 2003). A radiolabeled anti-CD20 antibody, 90Y-IT, has recently received FDA approval for adults with recurrent indolent CD20+ B-NHL. The dose limiting toxicity in adults has been myelosuppression (Witzig et al, JCO, 2003). Through the COG Phase I Consortium, we evaluated the safety of 90Y-IT in Pts with refractory childhood and adolescent CD20+ lymphoma: DLBCL (n=3) 1st relapse (n=1), 2nd relapse (n=2); refractory BL (n=1); refractory PTLD (DLBCL) (n=1); M:F ratio 4:1, median age 12 yrs (5–18). Pts (n=5) had a minimum of 2 x 106 CD34/kg cryopreserved PBSC. Pts (n=5) received Rituximab 250 mg/m2 IV on Days 0 and 7 and Indium 5 mCi IV on Day 0. Gamma imaging scans and peripheral blood dosimetry studies were performed on Days 0, 1, 3, and 6. Immediately following Rituximab on Day 7 (n=4) or approximately 24 hrs post Rituximab on Day 8 (n=1), Pts received 90Y-IT if dosimetry studies demonstrated ≤2000 cGy exposure to all solid organs and ≤300 cGy to red marrow based on a dose escalation schema stratified by marrow reserve and Plt; 0.4 mCi/kg (dose level 1) (n=3), 0.1 mCi/kg (dose level 1) (post BMT) (n=2). One Pt progressed prior to DLT evaluation. No evaluable pts (n=4) experienced non-hematologic DLT defined as any Grade III or IV non-hematologic toxicity attributable to the investigational agent or hematologic DLT defined as Grade IV ANC or Grade IV thrombocytopenia of > 7 days duration, and an ANC that did not reach ≥500 mm3 and/or platelet count that did not recover to ≥20,000/mm3 by Day 35. The incidence of HAMA/HACA was 0% (n=0). Toxicities related to the 90Y-IT included Grade I muscle pain/abdominal cramping (n=2), Grade III Plts (n=1), Hgb (n=1), infection (n=1), and Grade IV ANC (n=2), Plts (n=1). One Pt experienced Grade II infusion related chills associated with Rituximab. Mean organ radiation exposure (cGy) was as follows: kidneys 341 (112–515), liver 345 (83–714), lungs 309 (155–519), red marrow 46 (20–78), spleen 565 (161–816), and total body 3.7 (2.1 – 4.8). Mean serum quantitative immunoglobulins (mg/dl) at Day 35 were as follows: IgA 65, IgG 394, and IgM 32. 5/5 Pts experienced progressive disease and went on to receive further therapy. In conclusion, 90Y-IT appears to be well tolerated in children and adolescents with recurrent/refractory CD20+ lymphoma and associated with low exposure of radiation to solid organs and marrow. Based on these findings, an investigator-initiated limited institutional Phase II study is planned to further evaluate the safety, tolerability, and response rate with dose stratification based on marrow reserve and Plt: 0.4 mCi/kg (no prior BMT and Plt ≥ 150k), 0.3 mCi/kg (no prior BMT and Plt 100-149 k), 0.2 mCi/kg (prior BMT and Plt ≥ 100k).
44
AlSkaif, Tarek, Bart Holthuizen, Wouter Schram, Ioannis Lampropoulos, and Wilfried van Sark. "A Blockchain-Based Configuration for Balancing the Electricity Grid with Distributed Assets." World Electric Vehicle Journal 11, no. 4 (September 30, 2020): 62. http://dx.doi.org/10.3390/wevj11040062.
Анотація:
This paper explores a future perspective to foster the provision of balancing services to the electricity grid by distributed assets. One recent test case, initiated by the Dutch Transmission System Operator (TSO), was to operate an Electric Vehicle (EV) fleet on the automatic Frequency Restoration Reserve (aFRR) market, which entails fast and automated reserves. To achieve that in a decentralised, automated and transparent manner, the role of blockchain technology for this specific application is explored. We propose a novel configuration that can serve as a basis for deploying distributed assets for aFRR markets using blockchain or any alternative Distributed Ledger Technology (DLT). Automation can be achieved via the deployment of smart contracts, which also results in transparency in the system. The blockchain configurations are designed for three phases in the aFRR market, namely: (i) Operational planning and scheduling by a balancing service provider (i.e., formulation and submission of aFRR bid), (ii) Real-time operations (i.e., activation and measurements), and (iii) Verification and settlement (i.e., imbalance correction and financial settlement). The paper concludes that the scalability of distributed assets that can participate in the system, combined with the large transaction times and energy consumption of some consensus mechanisms, could put limitations on the proposed architecture. Future research should address benchmarking studies of other alternatives (e.g., DLTs, such as the ones based on directed acyclic graphs, and non-DLT solutions) with the proposed blockchain solution.
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Varavallo, Giuseppe, Giuseppe Caragnano, Fabrizio Bertone, Luca Vernetti-Prot, and Olivier Terzo. "Traceability Platform Based on Green Blockchain: An Application Case Study in Dairy Supply Chain." Sustainability 14, no. 6 (March 11, 2022): 3321. http://dx.doi.org/10.3390/su14063321.
Анотація:
Recent progress in IoT and software development has simplified data acquisition and immutability of information in the agri-food supply chain. In the last few years, several frameworks and applications were proposed to ensure traceability in the agri-food-sector using distributed ledger technologies (DLT) such as Blockchain technologies. Still, no other study has presented a Blockchain-based traceability platform with a lower impact on the environment and lower cost for each transaction sent by the supply chain. This article presents a traceability platform based on Green Blockchain with low energy consumption and costs savings applied to the Fontina PDO cheese supply chain, part of the project “Typicalp”, funded by the European Union (EU). The proposed traceability system is based on Algorand Blockchain, which uses the Pure Proof-of-Stake mechanism of consensus that requires minimal computational power, is highly scalable and environmentally sustainable. In addition to the environmental and financial benefits, the developed traceability platform has made it possible to digitize the entire production chain, making the data immutable and available in real-time for Fontina consortium operators and final consumers.
46
Netto, G., A. Armstrong, D. Wood, P. Creel, A. Partin, A. Jimeno, M. Rudek, D. George, R. Gurganus, and M. A. Carducci. "Pharmacodynamic (PD) study of pre-prostatectomy rapamycin in men with advanced localized prostate cancer (PC): A DOD Prostate Cancer Clinical Trials Consortium Trial." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 5001. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.5001.
Анотація:
5001 Background: Rapamycin is an orally bioavailable and generic mTOR inhibitor with an MTD of 6 mg daily and anticancer activity in solid tumors. We sought to determine the optimal biologic dose (OBD) in the pre-operative setting in men with PC. Methods: We explored the safety and PD activity of 3 and 6 mg of daily oral rapamycin for 14 days prior to radical prostatectomy (RP) in cohorts of 21 men with intermediate risk localized PC. Ten untreated control subjects were included using identical inclusion criteria. Men had Gleason >6 PC involving multiple cores. PD markers in pre-treatment prostate biopsies and RP specimens included p-S6 and p-Akt, 4EBP-1, PTEN, p27, Ki-67, and cleaved caspase-3. Tissue and whole blood sirolimus levels were measured. A Simon 2-stage design using PD efficacy (tumor S6 inhibition > 60%) was utilized. Results: 32 subjects were accrued to this 2 stage pharmacodynamic trial, including 10 control subjects. Median pre-treatment PSA was 6.4 ng/dl, age 60y, Gleason 7 in 85%. 20 accrued to the 3 mg cohort without DLT. However, 2/2 men enrolled at the 6 mg dose level experienced DLT consisting of thrombocytopenia leading to a delay in surgery (<100K) and fever with grade 3 stomatitis. AEs observed in the 3 mg cohort included stomatitis (2), rash (1), post-operative ileus (2), and mild neutropenia (2). One post-operative ileus was observed among control patients. PD studies demonstrated tumor S6 inhibition in >50% of subjects (median 60% decline, p=0.026 vs. baseline) with no negative effect on the state of Akt phosphorylation (p=0.82) or p27 levels (p=0.10). Prostate sirolimus levels (range 7.1–47.2 ng/g) were two-fold higher than whole blood concentrations (range 3.2–19.2 ng/ml). There was no effect of rapamycin on rates of post-operative wound healing or bleeding. PBMC S6 activity inhibition did not correlate with tumor S6 inhibition. Conclusions: The MTD/OBD of daily rapamycin in the pre-operative or prevention setting is 3 mg. This dose demonstrated downstream mTOR inhibition in tumor tissue and achieved adequate prostate tissue levels. Additional PD and genomic studies will be presented. Conducted through the DOD PCCTC and registered at clinicaltrials.gov as NCT00311623 . [Table: see text]
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Weingart, Jon, Stuart A. Grossman, Kathryn A. Carson, Joy D. Fisher, Shannon M. Delaney, Mark L. Rosenblum, Alessandro Olivi, Kevin Judy, Stephen B. Tatter, and M. Eileen Dolan. "Phase I Trial of Polifeprosan 20 With Carmustine Implant Plus Continuous Infusion of Intravenous O6-Benzylguanine in Adults With Recurrent Malignant Glioma: New Approaches to Brain Tumor Therapy CNS Consortium Trial." Journal of Clinical Oncology 25, no. 4 (February 1, 2007): 399–404. http://dx.doi.org/10.1200/jco.2006.06.6290.
Анотація:
Purpose This phase I trial was designed to (1) establish the dose of O6-benzylguanine (O6-BG) administered intravenously as a continuous infusion that suppresses O6-alkylguanine-DNA alkyltransferase (AGT) levels in brain tumors, (2) evaluate the safety of extending continuous-infusion O6-BG at the optimal dose with intracranially implanted carmustine wafers, and (3) measure the pharmacokinetics of O6-BG and its metabolite. Patients and Methods The first patient cohort (group A) received 120 mg/m2 of O6-BG over 1 hour followed by a continuous infusion for 2 days at escalating doses presurgery. Tumor samples were evaluated for AGT levels. The continuous-infusion dose that resulted in undetectable AGT levels in 11 or more of 14 patients was used in the second patient cohort. Group B received the optimal dose of O6-BG for 2, 4, 7, or 14 days after surgical implantation of the carmustine wafers. The study end point was dose-limiting toxicity (DLT). Results Thirty-eight patients were accrued. In group A, 12 of 13 patients had AGT activity levels of less than 10 fmol/mg protein with a continuous-infusion O6-BG dose of 30 mg/m2/d. Group B patients were enrolled onto 2-, 4-, 7-, and 14-day continuous-infusion cohorts. One DLT of grade 3 elevation in ALT was seen. Other non-DLTs included ataxia and headache. For up to 14 days, steady-state levels of O6-BG were 0.1 to 0.4 μmol/L, and levels for O6-benzyl-8-oxoguanine were 0.7 to 1.3 μmol/L. Conclusion Systemically administered O6-BG can be coadministered with intracranially implanted carmustine wafers, without added toxicity. Future trials are required to determine if the inhibition of tumor AGT levels results in increased efficacy.
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Pedrotti, Carine, Clarissa Franzoi, Rafael Nicolas Sandi, Daniel Santos Grohs, and Joséli Schwambach. "Eucalyptus staigeriana essential oil can control downy mildew in grapevine." Pesquisa Agropecuária Gaúcha 28, no. 1 (December 27, 2021): 1–14. http://dx.doi.org/10.36812/pag.20222811-14.
Анотація:
Downy mildew (Plasmopara viticola) is the primary disease in viticulture worldwide, and your control requires synthetic fungicides applications to avoid quality and yield loss in the grapevines. However, alternatives to reduce synthetic fungicides are needed to ensure the consumer’s health and the environment. Essential oils (EOs) are amongst the most promising natural plant protection alternatives because of their antifungal properties on several crop diseases. The present study objective was to determine the effect of Eucalyptus staigeriana EO in vitro and in vivo against P. viticola. The EO exhibited the highest activity in vitro, inhibiting 90% of the incidence and severity of disease caused by P. viticola in leaves of grapevines in the greenhouse. In the field (in vivo), treatment with EO could not control the disease; however, treatment with EO in consortium with conventional treatment reduced approximately 50% of the incidence and more than 90% of the severity of downy mildew disease in leaves, decreasing the application of synthetic fungicides by 50%.
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Dale, Michael J., and Carl Sanniti. "Litigation as an Instrument for Change in Juvenile Detention: A Case Study." Crime & Delinquency 39, no. 1 (January 1993): 49–67. http://dx.doi.org/10.1177/0011128793039001004.
Анотація:
Litigation is an expensive and contentious means to solve the twin problems of over-crowding and dangerous conditions in juvenile detention centers. However, it is possible to use lawsuits as effective agents for change. Willingness to mediate settlement and develop a common approach to problems causes greater change than through trial and court-imposed injunction or consent decree. This alternative approach obligates litigants to engage a consortium to attack institutional conditions and develop a continuum of alternatives. It also requires sensible population control resulting in decreased costs and a guarantee that children charged with serious and repeated offenses remain in secure detention.
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Holdhoff, Matthias, Stuart A. Grossman, Jeffrey G. Supko, Xiaobu Ye, Joy D. Fisher, Serena Desideri, Richard L. Wahl, and David Schiff. "Sequential therapy with the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas: An Adult Brain Tumor Consortium phase I study (ABTC1101)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): TPS2105. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.tps2105.
Анотація:
TPS2105 Background: Despite recent advances in their treatment, high-grade gliomas (HGG) carry a dismal prognosis. Treatment options at recurrence are particularly limited and a re-challenge with temozolomide (TMZ) frequently appears as the most appropriate systemic treatment option in patients whose progression occurred off TMZ. This study investigates the sequential treatment of mibefradil (MIB), a selective Cav3 calcium channel blocker, and standard dose TMZ. Preclinical data showed that Cav3 inhibitors such as MIB can slow tumor growth without significant effect on normal tissues and can induce cell cycle arrest in cancer cells at the G1/S-phase checkpoint. We hypothesize that withdrawal of MIB could synchronize and release cells into S-phase, thereby potentiating the cytotoxic effect of TMZ. Methods: This trial is an open-label, multicenter phase I study, structured into a dose escalation phase to determine the maximum tolerated dose of MIB (MTD; Primary Objective) and an expansion cohort of 10 patients at the MTD level. Adults with recurrent HGG (WHO grade 3 or 4) who have previously received standard adjuvant therapy with radiation (RT) and TMZ (last dose ≥ 3 months prior to enrollment) and who have not received other cytotoxic therapy (except for carmustine wafers) are eligible. Patients receive oral MIB for 7 days on a 4 x/day (QID) schedule, followed by standard dose TMZ at 150-200 mg/m2 for 5 days each 28-day cycle. Dose finding uses a modified 3+3 design, starting at MIB 25 mg po QID (100 mg/day) with dose increases of 25 mg/dose per dose level. The target dose-limiting toxicity (DLT) rate is ≤ 33%. Secondary Objectives: (1) safety and adverse event analysis (incl. cardiac monitoring during cycle 1), (2) pharmacokinetic profile of MIB, (3) response assessment (RANO criteria), and (4) assessment of the potential effect of MIB on tumor DNA synthesis as determined by fluorothymidine positron emission tomography (FLT PET; extension cohort). Enrollment status as of January 2013: cohort 1 completed without DLT; cohort 2 enrolling at MIB 200 mg/day. Clinical trial information: NCT01480050.