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Acute myeloid leukemia (AML) predominantly affects the elderly, and prognosis declines with age. Induction chemotherapy plus consolidation therapy is standard of care for fit patients; options for unfit patients include hypomethylating agents (HMA), low-dose cytarabine (LDAC), targeted therapies, and best supportive care (BSC). This retrospective chart review evaluated clinical outcomes in unfit patients with AML who initiated first-line treatment or BSC 01/01/2015-12/31/2018. Overall survival (OS), progression-free survival (PFS), time-to-treatment failure (TTF), and response rates were assessed. Of 1762 patients, 1310 received systemic therapies: 809 HMA, 199 LDAC, and 302 other therapies; 452 received BSC. Median OS was 9.9, 7.9, 5.4, and 2.5 months for HMA, LDAC, other, and BSC, respectively. Median PFS was 7.5, 5.3, 4.1, and 2.1 months for HMA, LDAC, other, and BSC, respectively; median TTF was 4.9, 2.1, 2.2, and 2.1 months, respectively. Our findings highlight the unmet need for novel therapies for unfit patients.

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with FLT3-mutant acute myeloid leukemia. Patients and Methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m2; days 1–7/28-day cycle). FLT3 mutation was analyzed centrally on pretreatment bone marrow aspirates. Results: In the biomarker evaluable population, FLT3 mutation was detected in 42 (15%) and 22 (19%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc; complete remission (CR) + CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) for FLT3-mutant patients were 67%/36%, median duration of remission (DoR) was 17.3/5.0 months, and median OS was 12.5/8.6 months. The CRc rates among FLT3 wild-type patients were 67%/25%, median DoR 18.4/13.4 months, and median OS 14.7/10.1 months. In patients treated with venetoclax + azacitidine, CRc in patients with FLT3-ITD and FLT3-TKD was 63% and 77% and median OS was 9.9 and 19.2 months, and in comutated FLT3-ITD + NPM1 patients, CRc was 70%, median DoR was not reached, and median OS was 9.1 months. There were no unexpected toxicities in the venetoclax + azacitidine group. Conclusions: When treated with venetoclax + azacitidine, patients with FLT3 mutations and FLT3 wild-type had similar outcomes. Future analyses in larger patient populations may further define the impact of venetoclax + azacitidine in patients harboring FLT3-ITD. See related commentary by Perl and Vyas, p. 2719

Supplementary Data from Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia

Supplementary Table from Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia

Purpose:To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML).Patients and Methods:Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m2; days 1–7/28-day cycle).Results:In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among patients with IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months. Patients with IDH1/2 WT AML treated with venetoclax + azacitidine with poor-risk cytogenetics had inferior outcomes compared with patients with IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax + azacitidine group.Conclusions:Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut.See related commentary by Perl and Vyas, p. 2719

Adenosine triphosphate (ATP) represents a danger signal that accumulates in injured tissues, in inflammatory sites, and in the tumor microenvironment. ATP promotes tumor growth but also anti-tumor immune responses notably via the P2X7 receptor. ATP can also be catabolized by CD39 and CD73 ecto-enzymes into immunosuppressive adenosine. P2X7, CD39 and CD73 have attracted much interest in cancer as targets offering the potential to unleash anti-tumor immune responses. These membrane proteins represent novel purinergic checkpoints that can be targeted by small drugs or biologics. Here, we investigated nanobody-based biologics targeting mainly P2X7, but also CD73, alone or in combination therapies. Blocking P2X7 inhibited tumor growth and improved survival of mice in cancer models that express P2X7. P2X7-potentiation by a nanobody-based biologic was not effective alone to control tumor growth but enhanced tumor control and immune responses when used in combination with oxaliplatin chemotherapy. We also evaluated a bi-specific nanobody-based biologic that targets PD-L1 and CD73. This novel nanobody-based biologic exerted a potent anti-tumor effect, promoting tumor rejection and improving survival of mice in two tumor models. Hence, this study highlights the importance of purinergic checkpoints in tumor control and open new avenues for nanobody-based biologics that may be further exploited in the treatment of cancer.

Tamsulosin is the most widely used alpha-1 blocker medication for managing benign prostatic hyperplasia (BPH) as indicated in the current practice guideline. The aim of this study was to compare all-cause medical costs and BPH-specific medical costs in older male adults with BPH treated with tamsulosin vs other alpha-1 blockers (i.e., doxazosin, terazosin, and alfuzosin).This was a retrospective propensity-score matched cohort study based on 2006-2012 Medicare claims data. All-cause medical costs and BPH-specific medical costs were compared between tamsulosin and other alpha-1 blockers treatment groups using baseline-adjusted quantile regression analyses. The comparisons were performed at different percentiles of the cost distributions.176,793 older male adults with BPH who used alpha-1 blockers were included in the analysis. All-cause medical costs in 75th and 95th percentiles of the cost distribution are substantially higher in tamsulosin treatment group when compared to other alpha-1 blocker medications (p 0.05 for all). Tamsulosin treatment group had substantially higher BPH-specific medical costs in 99th percentile of the cost distribution when compared to doxazosin and terazosin (p 0.001 for all). Overall, the top 5% of the patients with the highest all-cause medical costs accounted for approximately 45% of the overall all-cause medical costs, and the top 1% of the patients with the highest BPH-specific medical costs accounted for 39-51% of those costs.Older adults with BPH who encountered higher medical expenses had substantially higher medical costs when treated with tamsulosin than other common alpha blockers. Cost-related quality of measures should be assessed to improve health outcomes in older adults with BPH.

BackgroundAlthough most elderly patients with acute myeloid leukemia are ineligible for intensive chemotherapy, treatment options remain limited. CURRENT (UMIN000037786), a real-world, non-interventional, retrospective chart review, evaluated clinical outcomes, clinicopathologic characteristics, and treatment patterns in these patients. We present results from a subanalysis of Korean patients in this study.MethodsPatients were aged ≥18 years with primary or secondary acute myeloid leukemia ineligible for intensive chemotherapy who initiated first-line systemic therapy or best supportive care between 2015 and 2018 across four centers in Korea. Primary endpoint was overall survival from diagnosis. Secondary endpoints included progression-free survival, time to treatment failure, and response rates. Data analyses were primarily descriptive, with time-to-event outcomes estimated using the Kaplan-Meier method, and Cox regression used to determine prognostic factors for survival.ResultsAmong 194 patients enrolled, 84.0% received systemic therapy and 16.0% received best supportive care. Median age at diagnosis was 74 and 78 years, and Eastern Cooperative Oncology Group performance status 0 or 1 was reported in 73.0% and 48.4% of patients, respectively; poor cytogenetic risk was reported in 30.1% and 16.1% of patients. Median overall survival was 7.83 versus 4.50 months, and median progression-free survival was 6.73 versus 4.50 months in the systemic therapy versus best supportive care groups. Prognostic factors (all P ConclusionClinical outcomes are poor in Korean patients with acute myeloid leukemia ineligible for intensive chemotherapy who are prescribed current systemic therapies or best supportive care. There is a substantial unmet need for novel agents (monotherapy or in combination) to improve clinical outcomes in this patient population.

Four hydrogen bond-based macrocyclic and tripodal neutral receptors with increasing conformational complementarity with sulfate were used for the first time as ionophores to develop polymeric membrane sulfate-selective electrodes. Optimizing the membrane composition such as ionophores, lipophilic additives, and plasticizers yielded ISEs which showed Nernstian response to sulfate with the best selectivity so far and improved detection limits (a slope of -29.8 mV/dec in the linear range of 1 X 10(-6) -1 x 10(-1 )M with a detection limit of 5 x 10(-7) M), which led to the success of the determination of sulfate in drinking water samples and neomycine tablets. The anion-ionophore complex constants in the membrane phase were determined and correlated with the selectivity sequence of the ISEs. Studies on the influence of pH of the sample solution demonstrated that the developed ISEs can be operated in a wide pH range of 3-8 with fast response and rapid (in 1 min) and long lifetime. The success of these ionophores represents a feasible strategy for overcoming the "Hofmeister series" by employing a combination of complementarity and hydrogen bonds.

Introduction Chronic kidney disease (CKD) may be associated with overt or subclinical hypothyroidism [SCH; defined as elevated serum thyroid-stimulating hormone (TSH) despite normal free thyroxine levels). Although some studies have demonstrated that thyroid replacement therapy may improve renal function in overt hypothyroidism, there is no consensus on its benefits in SCH. Clinical and limited economic outcomes were evaluated in levothyroxine-treated US veterans with CKD + SCH. Methods Veterans Health Administration claims data from April 2013 to March 2018 for levothyroxine-treated versus nontreated CKD + SCH patients were compared. Eligible patients with CKD + SCH (≥ 2 elevated TSH values recorded; ≥ 2 normal thyroxine values recorded) had ≥ 1 TSH values recorded during 24-month follow-up, and ≥ 1 estimated glomerular filtration rate (eGFR) measurement during baseline and follow-up. Continuous levothyroxine use (treatment cohort) was required during follow-up. The primary endpoint was eGFR at 6, 12, 18, and 24 months; secondary endpoints included eGFR change from baseline, CKD progression, and length of hospital stay (LOS). Propensity score matching (PSM) was performed. Results Of 453 eligible patients, 157 remained in each cohort after PSM. Most were male (96%) and white (88%); mean age was 75 years. No significant differences were observed between cohorts at any time point for eGFR, eGFR change from baseline, or CKD progression. Treated patients had numerically higher mean eGFR at 6 and 12 months, lower proportions of progression to higher CKD stages at 12, 18, and 24 months, and shorter mean all-cause LOS versus nontreated patients (1.92 vs. 3.30 days; P = 0.3483) within the 24-month follow-up period. A significantly shorter mean CKD-related LOS was observed versus nontreated patients (0.11 vs. 1.38 days; P

Background Hidradenitis suppurativa (HS) is a chronic, inflammatory, skin condition associated with many comorbidities and often has a substantial impact on patients’ lives. Objectives To evaluate symptom burden and health‐related quality of life (HRQoL) at baseline in patients with HS in an observational, real‐world, clinical setting using several tools including a validated HS‐specific instrument. Methods This study evaluated HRQoL data from the international UNITE HS disease registry. Administration of patient‐reported outcome (PRO) instruments and collection of data were executed per local regulations. All data were assessed using descriptive statistical methods. Results PRO data from 529 adults and 65 adolescents were evaluated. Most adults (64.5%) and adolescents (73.8%) were classified as Hurley Stage II with substantial disease burden at baseline. HS had a large effect (mean DLQI = 12.6) and moderate effect (mean CDLQI = 6.9) on the lives of adults and adolescents, respectively. Approximately 58% of adults and 41% of adolescents had anxiety scores beyond the normal range; 30% of adults and 16% of adolescents exhibited symptoms of depression. Based on HSSA and HSIA scores, approximately 30% of adults reported a substantial burden of multiple HS clinical symptoms and more than 45% reported a significant emotional impact of HS that adversely affected their intimate relationships. Only 60% of adults were employed and of those, 64% reported at least some degree of impairment while working because of HS. Conclusions Based on PROs collected from patients enrolled in the UNITE registry, a real‐world, clinical setting, HS has a significant negative impact on the everyday lives of patients affected by this disease.

Background Hidradenitis suppurativa (HS), also known as acne inversa, is a recurring, painful, chronic, and sometimes disfiguring inflammatory skin disease. Objectives Our objective was to report the baseline clinical characteristics, natural history, and associated outcomes of patients with HS from the ongoing, prospective, non-interventional UNITE registry that is collecting data regarding the natural history and associated outcomes of HS. Methods Patients with inflammatory HS lesions were enrolled, including adolescents (aged 12 to

This retrospective chart review examined real-world healthcare resource utilization (HRU) in patients with AML ineligible for intensive therapy who received first-line systemic therapy or best supportive care (BSC).Data were collected anonymously on patients with AML who initiated first-line hypomethylating agents (HMA), low-dose cytarabine (LDAC), other systemic therapy, or BSC. HRU endpoints included hospitalizations, outpatient consultations, transfusions, and supportive care.Of 1762 patients included, 46% received HMA, 11% received LDAC, 17% received other systemic therapy, 26% received BSC; median treatment durations were 118, 35, 33, and 57 days, respectively. Most patients were hospitalized, most commonly for treatment administration, transfusion, or infection (HMA 82%, LDAC 93%, other systemic therapy 83%, BSC 83%). A median number of hospitalizations were 2-6 across systemic groups and two for BSC, with median durations of 8-18 days. Transfusion rates and outpatient consultations were highest for HMA (80% and 79%) versus LDAC (57% and 53%), other systemic therapy (57% and 63%), and BSC (71% and 66%). Antivirals/antibiotics and antifungals were used more frequently than growth factors (72-92%, 34-63%, and 7-27%, respectively).Patients with AML ineligible for intensive therapy have high HRU; novel therapies are needed to alleviate this burden.

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML). Patients and Methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m2; days 1–7/28-day cycle). Results: In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among patients with IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months. Patients with IDH1/2 WT AML treated with venetoclax + azacitidine with poor-risk cytogenetics had inferior outcomes compared with patients with IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax + azacitidine group. Conclusions: Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut. See related commentary by Perl and Vyas, p. 2719

Acute myeloid leukemia (AML) predominantly affects elderly adults, and its prognosis worsens with age. Treatment options for patients in Japan ineligible for intensive chemotherapy include cytarabine/aclarubicin ± granulocyte colony-stimulating factor (CA ± G), azacitidine (AZA), low-dose cytarabine (LDAC), targeted therapy, and best supportive care (BSC). The country's aging population and the evolving treatment landscape are contributing to a need to understand treatment pathways and associated outcomes. This retrospective chart review evaluated outcomes in patients across Japan with primary/secondary AML who were ineligible for intensive chemotherapy and began first-line treatment or BSC between 01/01/2015 and 12/31/2018. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and healthcare resource utilization (HRU). Of 199 patients (58% 75 years), 121 received systemic therapy (38 CA ± G, 37 AZA, 7 LDAC, 39 other) and 78 received BSC. Median OS was 5.4, 9.2, 2.2, 3.8, and 2.2 months for CA ± G, AZA, LDAC, other systemic therapy, and BSC, respectively; median PFS was 3.4, 7.7, 1.6, 2.3, and 2.1 months, respectively. HRU rates were uniformly high, with 80% patients hospitalized in each cohort. The poor clinical outcomes and high HRU among Japanese AML patients who are ineligible for intensive chemotherapy highlight an unmet need for novel therapies.

Mouse T cells express the ecto-ADP-ribosyltransferase ARTC2.2, which can transfer the ADP-ribose group of extracellular nicotinamide adenine dinucleotide (NAD+) to arginine residues of various cell surface proteins thereby influencing their function. Several targets of ARTC2.2, such as P2X7, CD8a and CD25 have been identified, however a comprehensive mouse T cell surface ADP-ribosylome analysis is currently missing. Using the Af1521 macrodomain-based enrichment of ADP-ribosylated peptides and mass spectrometry, we identified 93 ADP-ribsoylated peptides corresponding to 67 distinct T cell proteins, including known targets such as CD8a and CD25 but also previously unknown targets such as CD73. We evaluated the impact of ADP-ribosylation on the capability of CD73 to generate adenosine from adenosine monophosphate. Our results show that extracellular NAD+reduces the enzymatic activity of CD73 HEK cells co-transfected with CD73/ARTC2.2. Importantly, NAD+significantly reduced CD73 activity on WT CD8 T cells compared to ARTC2ko CD8 T cells or WT CD8 T cells treated with an ARTC2.2-blocking nanobody. Our study provides a comprehensive list of T cell membrane proteins that serve as targets for ADP-ribosylation by ARTC2.2 and whose function may be therefore affected by ADP-ribosylation.

Seed coat color is an important seed quality trait in sesame. However, the genetic mechanism of seed coat color variation remains elusive in sesame. We conducted a QTL mapping of the seed coat color trait in sesame using an F2 mapping population. With the aid of the newly constructed superdense genetic linkage map comprised of 22,375 bins distributed in 13 linkage groups (LGs), 17 QTLs of the three indices (i.e., L, a, and b values) of seed coat color were detected in seven intervals on four LGs, with a phenotype variance explanation rate of 4.46–41.53%. A new QTL qSCa6.1 on LG 6 and a QTL hotspot containing at least four QTLs on LG 9 were further identified. Variants screening of the target intervals showed that there were 84 genes which possessed the variants that were high-impact and co-segregating with the seed coat color trait. Meanwhile, we performed the transcriptome comparison of the developing seeds of a white- and a black-seeded variety, and found that the differentially expressed genes were significantly enriched in 37 pathways, including three pigment biosynthesis related pathways. Integration of variants screening and transcriptome comparison results suggested that 28 candidate genes probably participated in the regulation of the seed coat color in sesame; of which, 10 genes had been proved or suggested to be involved in pigments biosynthesis or accumulation during seed formation. The findings gave the basis for the mechanism of seed coat color regulation in sesame, and exhibited the effects of the integrated approach of genome resequencing and transcriptome analysis on the genetics analysis of the complex traits.

Background: In the Phase 3 randomized, placebo-controlled VIALE-A study, venetoclax (Ven) + azacitidine (Aza) improved overall survival (OS) and complete response (CR) rates vs Aza + placebo (Pbo; DiNardo et al. N Engl J Med. 2020. In Press). Neutropenia and related infections are common in acute myeloid leukemia (AML) and exacerbated by Ven combinations. Antimicrobial prophylaxis is used variably in patients (pts) with AML receiving low-intensity therapies. Ven dose modifications are required for concomitant use of commonly used antimicrobials that are strong or moderate cytochrome P450 3A inhibitors (CYP3Ai). A previous report's findings showed that Ven dose reductions with CYP3Ai do not affect Ven exposure (Wei et al. Blood. 2020;135:2137). This analysis evaluated the use of prophylactic anti-infective CYP3Ai and these agents' effects on infections and efficacy outcomes in the VIALE-A study (NCT02993523). Methods: Pts with newly diagnosed AML, aged ≥75 y or 18-75 yand ineligible for induction therapy were enrolled. Pts were randomized 2:1 to receive Ven (daily, orally) + Aza (75 mg/m2 d 1-7, subcutaneously/intravenously) or Pbo + Aza in 28-d cycles. Anti-infective prophylaxis was required for pts with absolute neutrophil count Results: In total, 286 pts were randomized to Ven + Aza and 145 to Pbo + Aza. Within the first 2 cycles of therapy, concomitant anti-infective prophylaxis agents considered moderate CYP3Ai were received by 41/286 pts (14%) in the Ven + Aza arm and 18/145 (12%) in the Pbo + Aza arm. Concomitant anti-infective prophylaxis agents considered strong CYP3Ai were received in the first 2 cycles by 22/286 pts (8%) treated with Ven + Aza and 13/145 pts (9%) treated with Pbo + Aza. The median duration of each prophylactic CYP3Ai agent use was 12.5 d (range, 1-614) in the Ven + Aza arm and 15 d (range, 1-731) in the Pbo + Aza arm. The rates of CR+CR with incomplete marrow recovery (CRi) as a best response during the study were similar with concomitant use of moderate (61%; CR, 24%; CRi, 37%) or strong (64%; CR, 27%; CRi, 36%) CYP3Ai with adjusted-dose Ven vs no use of CYP3Ai (67%; CR, 39%; CRi, 27%; Table 1). The relatively lower CR and higher CRi rates appear to be due to delay in recovery of peripheral blood counts in pts who received strong CYP3Ai during the first 2 cycles (Table 2). The median time to first CR+CRi was 1.2 mo (range, 0.6-9.9), 1.4 mo (range 1.0-5.5), and 1.4 mo (range, 0.9-5.4) in those receiving no, moderate, and strong CYP3Ai agents, respectively, in the Ven + Aza arm. Median OS was not statistically different regardless of use of moderate or strong CYP3Ai in both arms, as noted by overlapping CIs (Table 1). The 24-month estimated OS was 26.2% (95% CI, 8.1-48.9) for pts receiving strong CYP3Ai vs 37.9% (95% CI, 30.2-45.6) for those receiving no CYP3Ai. Rates of any-grade or Grade 3/4 infections within the first 2 cycles varied between those with or without use of moderate CYP3Ai reported as being given as prophylaxis in both treatment arms (Table 1). Rates of invasive fungal infections were 3%, 12%, and 9% with Ven + Aza and 0%, 0%, and 15% with Pbo + Aza in pts receiving no, moderate, and strong CYP3Ai agents, respectively. Rates of discontinuation from infections were similar in both arms regardless of CYP3Ai use. Conclusions:Antimicrobial prophylaxis with moderate or strong CYP3Ai was used in neutropenic pts in the VIALE-A study, with overall similar composite remission rates with Ven dose reductions. The use of CYP3Ai did not increase rates of discontinuation from infections. Analysis of differences in baseline characteristics, rates of infections, and efficacy outcomes for pts who began anti-infective prophylaxis at the initiation of therapy is ongoing. Disclosures Jonas: Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Genentech/Roche: Research Funding; Sigma Tau: Research Funding; Hanmi: Research Funding; Pfizer: Research Funding; LP Therapeutics: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding. Dinardo:Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Calithera: Research Funding; Celgene: Research Funding; Agios: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria. Fracchiolla:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Pristupa:Beigene: Honoraria, Research Funding; State Institution of Health of the Ryazan Regional Clinical Hospital: Current Employment; Pfizer: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Research Funding; Paraxel: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Geron: Honoraria, Research Funding. Ishizawa:Takeda: Honoraria; Ono: Honoraria; Chugai: Honoraria; Eizai: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; SymBio: Research Funding; Bayer: Research Funding; AbbVie: Research Funding. Jin:The First Affiliated Hospital of Zhejiang University: Current Employment. Konopleva:Rafael Pharmaceutical: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding; Calithera: Research Funding; Kisoji: Consultancy; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy; Ascentage: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Cellectis: Research Funding; Agios: Research Funding. Ofran:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Rambam Health Care: Current Employment; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy. Kovacsovics:Pfizer: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Jazz: Honoraria; Astella: Honoraria; Agios: Honoraria. Kantarjian:Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oxford Biomedical: Honoraria; Janssen: Honoraria; Delta Fly: Honoraria; BioAscend: Honoraria; Jazz: Research Funding; Abbvie: Honoraria, Research Funding; Sanofi: Research Funding; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Ascentage: Research Funding. Hong:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Ainsworth:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Werner:AbbVie: Current Employment, Current equity holder in publicly-traded company. Svensson:AbbVie: Current Employment, Current equity holder in publicly-traded company. Pratz:Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy; Celgene: Other: Scientific Advisory Board; Boston BioMedical: Consultancy; AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding.

Introduction The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in ~20% of patients (pts) with AML ≥70 years (Schneider et al, 2012). Both FLT3-ITD and FLT3-TKD mutations (mut) are associated with AML proliferation and potentially targetable with small molecule inhibitors. The presence of a FLT3mut, particularly FLT3-ITD, often correlates with high leukemic burden and risk of relapse despite high response rates (Gale et. al, 2008). There is limited evidence of the effect of currently available therapies on treatment-naïve AML pts unfit for intensive treatment with FLT3mut. We evaluated the efficacy and safety of venetoclax (Ven) and Azacitidine (Aza) combination among treatment-naïve AML pts with co-morbidities and/or age ≥ 75 years, unfit for intensive treatment, and with FLT3mut. Methods Data were pooled from pts enrolled in a phase 3 study (NCT02993523, data cut-off: 04Jan2020) that compared pts treated with Ven+Aza or placebo (Pbo)+Aza, and a prior phase 1b study (NCT02203773, data cut-off: 19Jun2019) where pts were treated with Ven+Aza. Pts on Ven+Aza received Ven 400 mg daily orally (days 1-28) and Aza (75 mg/m2; days 1-7/28-day cycle). Disease assessments were performed per the modified International Working Group response criteria for AML. DNA was isolated from bone marrow aspirates collected from pts prior to the first dose of study drug and analyzed centrally. Pts with positive test results for FLT3; [Leukostrate FLT3 CDx for phase 3 study or MyAML panel (Invivoscribe) for Phase 1b study] were counted as mutation "detected"; pts with a negative test result were counted as mutation "not detected." Pts without a result either due to an inconclusive test or missing specimen were not included in the analyses. Results In this pooled analysis, FLT3mut was detected in 40 pts treated with Ven+Aza and 22 pts treated with Pbo+Aza. At baseline (Ven+Aza/Pbo+Aza), the median age was 75 (range: 49-91)/75 (65-85) years. Cytogenetic risks were: intermediate: 88%/96% and poor: 13%/5%, Eastern Co-operative Oncology Group performance scores were: 0-1: 40%/50% and 2-3: 60%/50%. 78%/86% had de novo AML, while 23%/14% had secondary AML. FLT3-ITD was detected in 28/13 and FLT3-TKD in 13/10 pts, respectively. FLT3-ITD allelic ratios were: Complete response (CR)+CR with partial hematologic recovery (CRh) rates in FLT3mut pts (Ven+Aza/Pbo+Aza) were 65% (95% CI:48%-79%)/18% (5%-40%) (Table) with a median duration of response (mDoR) 18.3 [95% CI: 10.1- not reached (NR)]/15.1 (13.9-NR) mos. Median time to first CR/CRh response was 1.0/3.2 months (mos). 43%/0% achieved CR+CRh by initiation of cycle (C) 2. Median overall survival (mOS) was 13.3 (95% CI: 8.4-23.5)/8.6 (5.9-14.7) mos, respectively. Among pts with FLT3-ITD, CR+CRh rates (Ven+Aza/Pbo+Aza) were 61% (95% CI: 41%-79%)/23% (5%-54%) with mDoR 17.4 (95% CI: 3.7-NR)/14.5 (13.9-15.1) mos. The median time to first CR/CRh response was 1.0/3.5 mos and 39%/0% pts achieved CR+CRh by initiation of C2. The mOS was 11.5 (95% CI: 6.4-23.5)/8.5 (6.1-20.3) mos, respectively. CR+CRh rates in pts with FLT3-TKD were 69% (95% CI: 39%-91%)/20% (3%-56%) with mDoR 18.3 (95% CI: 3.0-NR)/NR (15.1-NR) mos. The median time to first CR/CRh response was 1.0/2.7 mos and 46%/0% achieved a response by initiation of C2. The mOS was 19.2 (95% CI:1.8-NR/10.0 (0.2-14.7) mos, respectively. In pts treated with Ven+Aza, CR+CRh rates among pts with FLT3 detected/FLT3 not detected were 65% (95% CI: 48%-79%)/63% (56%-69%) with mDoR 18.3 (95% CI: 10.1-NE)/18.1 (15.3-NR) mos. The mOS was 13.3 (95%CI: 8.4-23.5)/14.1 (10.6-18.7) mos, respectively (Figure). Among pts treated with Ven+Aza, grade 3/4 hematologic adverse events (AEs) in pts with FLT3 detected/FLT3 not detected was 67%/77%, and included anemia (33%/25%), neutropenia (36%/33%), thrombocytopenia (39%/36%), and febrile neutropenia (36%/43%). Grade 3/4 hematologic AEs among pts with FLT3-ITD/FLT3-TKD treated with Ven+Aza was 67%/69%. Conclusion Ven+Aza compared to Aza monotherapy resulted in significantly higher CR+CRh rates among treatment-naïve pts with FLT3mut ineligible for intensive chemotherapy. In this unselected AML population, insufficient pt numbers in various subgroups limit the ability to draw conclusions regarding DoR and mOS for FLT3-ITD and TKD subgroups. There were no unexpected toxicities in the Ven+Aza arm. Future studies with larger sample sizes are warranted. Disclosures Konopleva: Ascentage: Research Funding; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Kisoji: Consultancy; Agios: Research Funding; Calithera: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Sanofi: Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Ablynx: Research Funding. Thirman:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Research Funding; TG Therapeutics: Research Funding; Tolero: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Gilead Sciences: Research Funding. Pratz:Millennium: Research Funding; Celgene: Other: Scientific Advisory Board; AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding; Boston BioMedical: Consultancy; Agios: Other: Scientific Advisory Board, Research Funding; Daiichi Sankyo: Research Funding; Jazz Pharmaceutical: Consultancy. Letai:Flash Therapeutics: Membership on an entity's Board of Directors or advisory committees; Dialectic: Membership on an entity's Board of Directors or advisory committees; Chugai: Other: Lecture Fees; Novartis: Research Funding; AbbVie: Consultancy; Zentalis: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy. Pullarkat:AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kantarjian:Immunogen: Research Funding; Janssen: Honoraria; Sanofi: Research Funding; BioAscend: Honoraria; Abbvie: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aptitute Health: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Delta Fly: Honoraria; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; Adaptive biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; Jazz: Research Funding. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Chyla:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Miller:AbbVie: Current Employment, Current equity holder in publicly-traded company. Dinardo:Takeda: Honoraria; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Agios: Consultancy, Research Funding; Calithera: Research Funding; ImmuneOnc: Honoraria. Wei:AbbVie: Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; Pfizer: Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria; Amgen: Honoraria, Research Funding; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties; Genetech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction Isocitrate dehydrogenase (IDH) mutations occur in ~20% of acute myeloid leukemia (AML) patients (pts) and are frequently identified in older pts. Pre-clinical data showed that cells with IDH1/2 mutation (mut) were susceptible to Venetoclax (Ven) therapy (Chan et.al., 2015). Clinical studies have demonstrated that pts with IDH1/2mut treated with Ven and azacitidine (Aza) achieved high response rates that were durable, and had longer median overall survival (mOS) (DiNardo et. al., 2020; DiNardo et. al., 2019). Herein, we further evaluated the efficacy and safety of Ven+Aza among treatment-naïve AML pts with IDH1/2 mut unfit for intensive treatment either due to comorbidities and/or age ≥ 75 yrs. Methods Data were pooled from pts enrolled in an ongoing phase 3 study (NCT02993523, data cut-off: 04Jan2020) comparing pts treated with Ven+Aza or placebo (Pbo)+Aza, and a phase 1b study (NCT02203773, data cut-off: 19Jun2019) where pts were treated with Ven+Aza. Pts on Ven+Aza received Ven 400 mg daily orally (days 1-28) and Aza (75 mg/m2; days 1-7/28-day cycle). Disease assessments were performed per modified International Working Group response criteria for AML. DNA was isolated from bone marrow aspirates collected from pts prior to the first dose of study drug and analyzed centrally. Pts with positive test results for IDH1 and 2 [RealTime IDH1 or IDH2 assay (Abbott) for phase 3 study, MyAML panel (Invivoscribe) for phase 1b study] were counted as mutation "detected"; pts with a negative test result were counted as mutation "not detected." Pts without a result either due to an inconclusive test or missing specimen were excluded from the analyses. Results IDH1/2 mut was detected in 79 pts treated with Ven+Aza and 28 pts treated with Pbo+Aza. At baseline (Ven+Aza/Pbo+Aza), median age was 76 (range: 64-90)/78 (62-90) yrs. Cytogenetic risks were intermediate: 79%/68%, and poor:21%/32%. ECOG scores were: 0-1: 56%/68% and 2-3: 44%/32%. 73%/86% had de novo AML, and 27%/14% had secondary AML. IDH1 was detected in 32/11, IDH2 in 49/18, IDH2R140 in 36/15, and IDH2R172 were detected in 13/3 pts, respectively. The median number of treatment cycles received (Ven+Aza/Pbo+Aza) by IDH1/2 pts was 8 (range: 1-37)/2.5 (1-18). Complete response (CR)+CR with partial hematologic recovery (CRh) in Ven+Aza/Pbo+Aza were 72% (95% CI: 61%-82%)/7% (1%-24%) (Table). Median time to first CR/CRh response was 1.0/2.6 months (mos), and 51%/0% achieved CR+CRh by initiation of cycle (C) 2. Median duration of response (mDoR) was 29.5 [95% CI: 16.7-not reached(NR)]/15.5 (NR-NR) mos and mOS was 24.5 [15.2- NR/6.2 (2.3-12.7) mos. The separation of 95% CIs for mOS indicate superior treatment effect of Ven+Aza (Figure). In pts with IDH1, CR+CRh (Ven+Aza/Pbo+Aza) was 59%/9%. Median time to first CR/CRh response was 2.3/3.1 mos, and 25%/0% achieved CR+CRh by initiation of C2. Median DoR and OS were 21.9 (7.8-29.5)/NR and 17.5 (6.3-32.7)/2.2(1.1-5.6) mos. In pts with IDH2, CR+CRh rates were 80%/6%. Median time to first CR/CRh response was 1.0/2.1 mos and 67%/0% achieved CR+CRh by initiation of C2. Median DoR was NR (16.7-NR)/15.5 (NR-NR), and mOS was NR (17.6-NR)/13.0 (95% CI: 3.8-15.8) mos. In pts with IDH2R140, CR+CRh were 75%/7%. Median time to first CR/CRh response was 1.0/2.1 mos, and 58%/0% achieved CR+CRh by initiation of C2. Median DoR and mOS were NR (17.8-NR)/15.5 (NR-NR) and NR (15.0-NR)/12.7 (1.7-15.8) mos, respectively. Response rates in pts with IDH2R172 were 92%/0%. Median time to first CR/CRh response was 1.0/NR mos, and 92%/0% achieved response by initiation of C2. Median DoR and mOS were 16.7 (7.5-NR)/3.5 (NR-NR) and NR (12.2-NR)/13.7 (10.6-NR) mos. IDH1/2 mut pts achieved higher CR+CRh rates with Ven+Aza treatment as compared to pts with IDH not detected (72%/60%). Median DoR and mOS were 29.5 (16.7-NR)/17.5 (10.6-23.5) and 24.5 (15.2-NR)/12.3 (9.7-14.8) mos, respectively. In pts treated with Ven+Aza, grade 3/4 hematologic adverse events (AEs) among pts with IDH1/2 detected/IDH not detected were similar (81%/74%) and included grade 3/4 thrombocytopenia (46%/34%), febrile neutropenia (43%/41%), neutropenia (35%/33%) and anemia (29%/24%). Conclusion Ven+Aza compared to Aza monotherapy resulted in higher response rates, longer DoR, and mOS among treatment-naïve pts with IDH1/2mut ineligible for intensive chemotherapy. The safety profile was acceptable. No unexpected toxicities were noted with Ven+Aza combination. Disclosures Pollyea: Pfizer: Consultancy; Glycomimetics: Other; Takeda: Consultancy; Daiichi Sankyo: Consultancy; Abbvie: Consultancy, Research Funding; Syros: Consultancy; Syndax: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Genentech: Consultancy; Amgen: Consultancy; Janssen: Consultancy; 47: Consultancy, Research Funding; Agios: Consultancy; Celgene/BMS: Consultancy. Dinardo:Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Agios: Consultancy, Research Funding; Celgene: Research Funding; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria. Arellano:Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Research Funding; Cephalon Oncology: Research Funding. Fiedler:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; Gilead: Honoraria; BMS: Honoraria; BerGenBio ASA: Research Funding; Servier: Honoraria, Other; Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Daiichi Sankyo Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; Morphosys: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations, support in medical writing, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Konopleva:Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Calithera: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; AstraZeneca: Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Ascentage: Research Funding; Ablynx: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Kisoji: Consultancy; Rafael Pharmaceutical: Research Funding; Forty-Seven: Consultancy, Research Funding. Rizzieri:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shinagawa:AbbVie: Research Funding. Lemoli:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio ASA: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Chyla:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Ridgeway:AbbVie: Current Employment, Current equity holder in publicly-traded company. Kantarjian:Janssen: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Delta Fly: Honoraria; BMS: Research Funding; Aptitute Health: Honoraria; Novartis: Honoraria, Research Funding; BioAscend: Honoraria; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding.

Background: Patients with acute myeloid leukemia (AML) who are older or ineligible for intensive induction chemotherapy have limited treatment options and poor survival. In the VIALE-A study, venetoclax (Ven) + azacitidine (Aza) improved overall survival and response rates compared with placebo (Pbo) + Aza in older or unfit patients with newly diagnosed AML (DiNardo et al. N Engl J Med. 2020). Although cytopenia is common in AML, Ven+Aza was associated with hematologic adverse events in 83% of patients in the VIALE-A study (vs 69% in the Pbo+Aza arm). Here, the frequency and management of cytopenia are analyzed in patients achieving a best response of complete remission (CR) or CR with partial hematologic recovery (CRh) in the VIALE-A study. Methods: This double-blind, Pbo-controlled, multicenter Phase 3 study (NCT02993523) enrolled patients with newly diagnosed AML who were ineligible for intensive chemotherapy due to age ≥75 years or comorbidities. Patients were randomized 2:1 to receive 75 mg/m2 Aza (Days 1-7 of each 28-day cycle) plus either daily 400 mg Ven (Ven+Aza) or Pbo (Pbo+Aza). Disease response was assessed via bone marrow aspirate and biopsy at the end of Cycle 1 and at least every 3 cycles thereafter. After patients achieved blast clearance (bone marrow blasts Results: In total, 186 of 283 (66%) Ven+Aza-treated patients and 33 of 144 (23%) Pbo+Aza-treated patients achieved a best response of CR or CRh (CR/CRh). Of patients with a best response of CR/CRh in the Ven+Aza arm, 77% achieved blast clearance by the end of Cycle 1, 88% by the end of Cycle 2, 92% by the end of Cycle 3, and 98% by the end of Cycle 4. Of patients with a best response of CR/CRh in the Pbo+Aza arm, 33% achieved blast clearance by the end of Cycle 1, 55% by the end of Cycle 2, 76% by the end of Cycle 3, and 91% by the end of Cycle 4. After achieving blast clearance, 75% and 67% of patients in the Ven+Aza and Pbo+Aza arms, respectively, had a delay of the next cycle, with a median duration per cycle delay post-blast clearance (range) of 9.0 (1-39) and 5.5 (1-21) days. Among CR/CRh patients, more patients receiving Ven+Aza versus Pbo+Aza had post-remission cytopenia (87% vs 45%; Table 2). A similar percentage of CR/CRh patients in both arms (Ven+Aza, 26%; Pbo+Aza, 24%) had in-cycle dose interruptions (ie, days without Ven/Pbo exposure between a cycle's first and last Ven/Pbo dose), with a median duration (range) of 2.0 days (1-20) for Ven+Aza and 1.0 (1-13) for Pbo+Aza. A greater proportion of CR/CRh patients experienced post-remission cycle delays due to cytopenia in the Ven+Aza arm (77%) than in the Pbo+Aza arm (30%). Furthermore, a higher percentage of CR/CRh patients had post-remission cycles with a reduction in Ven/Pbo dosing days and/or cycle delays totaling ≥7 days due to cytopenia in the Ven+Aza arm (75%) than in the Pbo+Aza arm (27%). Among these patients, the median percentage of days without Ven/Pbo administration while in remission (out of the total number of days in remission) was 18% (range, 1-69) in the Ven+Aza arm and 13% (3-44) in the Pbo+Aza arm. Ultimately, 129 CR/CRh patients (69%) in the Ven+Aza arm and 10 (30%) in the Pbo+Aza arm received ≤21-day Ven/Pbo dosing post-remission, with a median time from remission to first ≤21-day cycle (range) of 92.0 days (1-480) for Ven+Aza and 74.0 days (6-405) for Pbo+Aza. Conclusion: In the VIALE-A study of older or unfit patients with newly diagnosed AML, the majority of responding patients in the Ven+Aza arm required dosing modifications to manage cytopenia, of which delays between cycles or within-cycle reductions of Ven dosing days were most common. Post-remission cytopenia and dosing modifications were more frequent with Ven+Aza versus Pbo+Aza treatment. The impact of cytopenia and dosing modifications on patient outcomes with Ven+Aza is currently being analyzed and will be reported at a future date. Disclosures Pratz: AbbVie: Other: Scientific Advisory Board, Research Funding; Boston BioMedical: Consultancy; Astellas: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy; Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Celgene: Other: Scientific Advisory Board. DiNardo:MedImmune: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Takeda: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Novartis: Consultancy; Calithera: Research Funding. Selleslag:Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Yamamoto:AbbVie: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Zenyaku: Research Funding; Sumitomo Dainippon: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; Mochida: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria; Kyowa Kirin: Honoraria; Janssen: Honoraria; Gilead Sciences: Research Funding; IQIVA/Incyte: Research Funding; HUYA: Consultancy; IQIVA/HUYA: Honoraria; Daiichi Sankyo: Consultancy; Eisai: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Yakult: Research Funding; Stemline Therapeutics: Consultancy; Solasia Pharma: Research Funding; SymBio: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Bayer: Research Funding; Aichi Cancer Center: Current Employment. Konopleva:AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Agios: Research Funding; Sanofi: Research Funding; Amgen: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ascentage: Research Funding; Eli Lilly: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Ablynx: Research Funding; Rafael Pharmaceutical: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Kisoji: Consultancy; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding. McDonald:venetoclax advisory board in South Africa (in CLL context): Consultancy; Alberts Cellular Therapy: Current Employment. Babu:Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; Novartis: Research Funding; Janssen Oncology: Research Funding; Syndax: Research Funding; Nektar: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Alexion Pharmaceuticals: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Lilly: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Bayer: Honoraria; AstraZeneca: Consultancy, Honoraria; AstraZeneca/MedImmune: Research Funding; Argenx: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Merck: Research Funding; AbbVie: Research Funding; TG Therapeutics: Research Funding; Amgen: Research Funding; Lutheran Hospital: Other; Fort Wayne Medical Oncology & Hematology: Current Employment, Current equity holder in publicly-traded company; Sanofi: Research Funding. Stevens:Amgen, MorphoSys: Consultancy. Kantarjian:BioAscend: Honoraria; Delta Fly: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; Janssen: Honoraria; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Oxford Biomedical: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Traina:University of São Paulo at Ribeirão Preto Medical School: Current Employment; AbbVie: Other: Principal Investigator for Protocol Number M15-656 . Venditti:Jazz: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Mayer:AbbVie: Research Funding; Principia Biopharma: Research Funding. Montez:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Ramsingh:Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Genentech: Current Employment, Current equity holder in publicly-traded company. Jin:Genentech: Current Employment. Ainsworth:AbbVie: Current Employment, Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Svensson:AbbVie: Current Employment, Current equity holder in publicly-traded company. Werner:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Jonas:AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; Genentech/Roche: Research Funding; Hanmi: Research Funding; Incyte: Research Funding; LP Therapeutics: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Sigma Tau: Research Funding.

Seed coat color is an important seed quality trait in sesame. However, the genetic mechanism of seed coat color variation remains elusive in sesame. We conducted a QTL mapping of the seed coat color trait in sesame using an F2 mapping population. With the aid of the newly constructed superdense genetic linkage map comprised of 22,375 bins distributed in 13 linkage groups (LGs), 17 QTLs of the three indices (i.e., L, a, and b values) of seed coat color were detected in seven intervals on four LGs, with a phenotype variance explanation rate of 4.46–41.53%. A new QTL qSCa6.1 on LG 6 and a QTL hotspot containing at least four QTLs on LG 9 were further identified. Variants screening of the target intervals showed that there were 84 genes which possessed the variants that were high-impact and co-segregating with the seed coat color trait. Meanwhile, we performed the transcriptome comparison of the developing seeds of a white- and a black-seeded variety, and found that the differentially expressed genes were significantly enriched in 37 pathways, including three pigment biosynthesis related pathways. Integration of variants screening and transcriptome comparison results suggested that 28 candidate genes probably participated in the regulation of the seed coat color in sesame; of which, 10 genes had been proved or suggested to be involved in pigments biosynthesis or accumulation during seed formation. The findings gave the basis for the mechanism of seed coat color regulation in sesame, and exhibited the effects of the integrated approach of genome resequencing and transcriptome analysis on the genetics analysis of the complex traits.

Four Lewis acidic organo-antimony(V) compounds with strong binding affinity to fluoride were used for the first time as ionophores to fabricate polymeric membrane fluoride-selective electrodes. Improved detection limits and significant anti-Hofmeister selectivity could be achieved by optimizing ionophores, lipophilic additives, and plasticizers. Membrane electrodes fabricated with tetrakis-(pentafluorophenyl)stibonium (ionophore 2) performed best in detection limit, sensitivity, and selectivity. Optimal performance was obtained by fluoride with a slope of -59.5 mV/decade in the linear range of 1 × 10-5 to 4 × 10-2 M and a detection limit of 5 × 10-6 M. Studies on the influence of sample solution pH demonstrate that the best pH for fluoride determination is pH 3.0. All of the electrodes studied respond rapidly (in 1 min) in different concentrations of fluoride solutions. The anion-ionophore complex constants in the membrane phase determined using the segmented sandwich membrane method correlate well with the solution-phase binding data and determined selectivity sequence of the ion-selective electrodes. The possibility of real life application of the optimized electrodes was assessed by determination of fluoride concentrations in tap water.

Among laboratory mouse strains many genes are differentially expressed in the same cell population. As consequence, gene targeting in 129-derived embryonic stem cells (ESCs) and backcrossing the modified mice onto the C57BL/6 (B6) background can introduce passenger mutations in the close proximity of the targeted gene. Here, we demonstrate that several 129-originating transgenic mice in which P2rx7-neighboring genes were targeted carry a P2rx7 passenger mutation that affects the vitality and function of T cells. By the example of P2rx4tm1Rass we demonstrate that CD4+ and CD8+ T cells derived from these mice express higher levels of P2X7 when compared to corresponding cell populations in B6-WT mice. The increased T cell sensitivity towards the P2X7 activators adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD+) rendered these cells more vulnerable towards NAD-induced cell death (NICD) compared to their B6-WT counterparts. The enhanced NICD sensitivity significantly affected the outcome of functional assays e.g. cytokine production and cell migration. For P2rx4tm1Rass, we demonstrate that the expression of P2X7 is diminished in several innate immune cell populations, possibly as a side effect of P2rx4 targeting, and independent of the P2rx7 passenger mutation. These results need to be considered when working with P2rx4tm1Rass mice or other 129-based transgenic strains that target P2rx7 neighboring genes and might have implications for other mouse models.

Summary Calcineurin B‐like interacting protein kinase (CIPKs) has been shown to be required for biotic stress tolerance of plants in plant‐pathogen interactions. However, the roles of CIPKs in immune signalling of cereal crops and an in‐depth knowledge of substrates of CIPKs in response to biotic stress are under debate. In this study, we identified and cloned a CIPK homologue gene TaCIPK10 from wheat. TaCIPK10 was rapidly induced by Puccinia striiformis f. sp. tritici (Pst) inoculation and salicylic acid (SA) treatment. In vitro phosphorylation assay demonstrated that the kinase activity of TaCIPK10 is regulated by Ca2+ and TaCBL4. Knockdown TaCIPK10 significantly reduced wheat resistance to Pst, whereas TaCIPK10 overexpression resulted in enhanced wheat resistance to Pst by the induction of defense response in different aspects, including hypersensitive cell death, ROS accumulation and pathogenesis‐relative genes expression. Moreover, TaCIPK10 physically interacted with and phosphorylated TaNH2, which was homologous to AtNPR3/4. Silencing of TaNH2 in wheat resulted in enhanced susceptibility to the avirulent Pst race, CYR23, indicating its positive role in wheat resistance. Our results demonstrate that TaCIPK10 positively regulate wheat resistance to Pst as molecular links between of Ca2+ and downstream components of defense response and TaCIPK10 interacts with and phosphorylates TaNH2 to regulate wheat resistance to Pst.

This study compared severity of physical violence, intimate partner violence (IPV)-related injury, and lifetime diagnoses of psychiatric disorders among women in relationships with bidirectional, unidirectional, or no IPV. The sample includes 763 low-income women from community-based family planning clinics. Results showed that women in relationships with bidirectional IPV were more likely to experience severe physical violence and severe IPV-related injury compared to women in the unidirectional IPV category. These women were also more likely to be diagnosed with drug abuse and depression than women in relationships without IPV. Similarly, women in the bidirectional IPV category were more likely to be diagnosed with drug abuse when compared to women in the victim-only unidirectional IPV category. Recommendations for health-care providers are discussed.

This study aimed to characterize different natural killer (NK) cell phenotypes on bone marrow and peripheral blood cells from acute myeloid leukemia (AML) patients and healthy donors (HDs). Our data show that CD56dimCD16− and CD56brightCD16− NK cells represent the predominant NK cell subpopulations in AML, while the CD56dimCD16+ NK cells are significantly reduced compared to HDs. Moreover, TIGIT+ and PVRIG+ cells cluster on the CD56dimCD16+ subset whereas CD39+ and CD38+ cells do so on CD56brightCD16− NK cells in AML. Furthermore, functional effects of (co-)blockade of TIGIT and CD39 or A2AR on NK cell functionality were analyzed. These experiments revealed that the single blockade of the TIGIT receptor results in an increased NK-92 cell-mediated killing of AML cells in vitro. Combined targeting of CD39 or A2AR significantly augments the anti-TIGIT-mediated lysis of AML cells. Our data indicate that distinct NK cell subsets in AML exhibit different immunosuppressive patterns (via the TIGIT/PVRIG receptors and the purinergic pathway). In summary, we conclude that TIGIT, CD39, and A2AR constitute relevant inhibitory checkpoints of NK cells in AML patients. A combinatorial blockade synergistically strengthens NK-92 cell-mediated cytotoxicity. As inhibitors of TIGIT, CD39, and A2AR are clinically available, studies on their combined use could be conducted in the near future.

A series of PN-heterocycles and urea based cleft receptors containing hydrogen bond donor/acceptor groups complementary with hydrosulfide/hydrosulfate were used for the first time as ionophores to fabricate polymeric membrane hydrosulfide/hydrosulfate ISEs, while similar potentiometric sensors have rarely been reported. ISEs exhibiting Nernstian or near-Nernstian responses to hydrosulfide/hydrosulfate with improved selectivity over lipophilic anions and halides were obtained by optimizing the membrane component such as lipophilic additives and plasticizers. Selectivity for hydrosulfide or hydrosulfate can be manipulated simply by deploying the hydrogen bond donor/acceptor in a subtle way. For real-life applications, the optimized ISEs with good reversibility and improved detection limits were employed for hydrosulfide/hydrosulfate determination in water samples.

This study involved healthy community-living older adults in an investigation of the association between moderate alcohol consumption (AC) and acute changes in postural stability and whether the association differed according to pre-AC balance skills. Thirty-nine moderate drinkers aged ≥ 65 years (62% women; mean age: 73.9 ± 6.1 years) consumed a moderate dose of alcohol (0.4 g/kg; administered as two drinks). Breath alcohol concentration and postural stability were measured at five time points (pre-AC and 40, 80, 120, and 160 minutes post-AC) using unipedal stance time (UPST) and center of pressure (CoP) displacement. Pre-AC UPST was used to categorize participants into good-balance (≥30 seconds) and poor-balance (

Background: Diagnosis of primary angiitis of the central nervous system (PACNS) and discrimination of PACNS from its mimics, e. g., reversible cerebral vasoconstriction syndrome (RCVS) or moyamoya disease (MMD) as non-inflammatory vasculopathies, still remain challenging. Circulating endothelial cells (CEC) are well-established markers for endothelial damage and potential biomarkers in PACNS. This study aimed to investigate if CECs may also help to distinguish an active PACNS from its important differentials (RCVS, MMD).Methods: CECs were assessed in 47 subjects. Twenty-seven patients with PACNS were included, seven with an active disease (aPACNS), 20 in remission (rPACNS). Seven patients with RCVS/MMD were analyzed. Thirteen healthy subjects served as controls (HC). CECs were measured by immunomagnetic isolation from peripheral venous blood. Mann-Whitney-U-Tests were applied for between-group comparisons. The Benjamini-Hochberg-procedure was applied to adjust for multiple comparisons.Results: In aPACNS, CECs were significantly elevated compared to HC (480 vs. 40 CEC/ml, p < 0.001) and rPACNS (54 CEC/ml, p < 0.001). RCVS/MMD patients showed higher CEC levels (288 CEC/ml) than HC (p < 0.001), but lower than those in aPACNS (p = 0.017). An adjustment for multiple comparisons confirmed prior significant differences. An increased CEC value (cut-off 294 CEC/ml) is indicative for an active PACNS [sensitivity 100%, 95% confidence interval (CI) 63–100%; specificity 93%, CI 81–98%].Conclusions: CECs may serve as biomarkers for diagnosis, treatment monitoring, and also for differential diagnosis of PACNS. CECs seem to be a marker of endothelial injury with higher levels in inflammatory than non-inflammatory vasculopathies. Larger patient samples are required to corroborate these findings.

OBJECTIVE: Compare the likelihood of negative clinical outcomes between continuous users of Synthroid® and patients who switch from Synthroid® to an alternative formulation of A/B rated levothyroxine (LT4). METHODS: Data were obtained from Optum ClinformaticsTM DataMart covering May 1, 2000 to March 30, 2016. Following a 6 month lead-in period of consistent use of Synthroid®, patients were categorized as continuous users of Synthroid® or switchers if they stopped use of Synthroid® and filled a prescription for an alternative LT4. Multivariable logistic analyses on propensity score matched cohorts examined the likelihood of an adverse clinical outcome, defined as a composite of diagnoses of chronic kidney disease (CKD), depression, fatigue, heart failure, hyperlipidemia, hypertension or obesity in the 2 years post identification as a continuous user of Synthroid® or a switcher (i.e., the post-period). The individual components of the composite endpoint and the probability of having a thyroid stimulating hormone (TSH) value out of range recommended by guidelines were also examined. All analyses controlled for patient characteristics, index dose of LT4, index copayment, general health, prior visits to an endocrinologist and prior presence of condition of interest. RESULTS: Propensity score matching resulted in a sample of 19,850 patients - 9,925 continuous uses of Synthroid® and 9,925 switchers. Multivariable analyses revealed that switchers, compared to continuous users, were 23% more likely (P

Additional file 1: Table S1. Pairwise correlation coefficients between thousand seed weight and seed size traits for sesame under two environments. *Significant at P ≤ 0.05, **Significant at P ≤ 0.01; tsw, thousand seed weight; sl, seed length; sw, seed width; lwr, length-to-width ratio; sp., seed perimeter; sd, seed diameter; sa, seed area; sc, seed circularity.

Additional file 3: Table S3. SLAF-seq data for each of the F2 individual and their parents.

Additional file 2: Table S2. Pairwise correlation coefficients of sesame seed coat color traits under two environments. *Significant at P ≤ 0.05, **Significant at P ≤ 0.01.

Additional file 4: Table S4. The candidate genes for the seed-related traits.

Along the line for developing ionophores by deploying hydrogen bond donor/acceptor on arylethynyl acaffold, two tripodal urea receptors were used as ionophores for the first time to fabricate polymeric membrane nitrate-selective electrodes. Replacing the hydrogens with fluorine atoms in the arylethynyl core facilitates the selectivity for nitrate over halides, originating from the additional anion–π interactions electron between nitrate and deficient fluorinated core. By optimizing membrane composition such as plasticizers and lipophilic additives, the proposed ISEs showed Nernstian response to nitrate with superior selectivity to both lipophilic ions and halides. Although the formation constants of anions-ionophore complex in membrane phase did not correlate well with the selectivity pattern of the ISEs, these data were consistent with that in solvent such as binary DMSO/CHCl3. The proposed ISEs could work in wide pH range solutions with short response time, good reversibility and reproducibility, which led to the success of determination of nitrate in real mineral water, tap water, as well as river water samples.

Summary Among laboratory mouse strains many genes are differentially expressed in the same cell population. As consequence, gene targeting in 129-derived embryonic stem cells (ESCs) and backcrossing the modified mice onto the C57BL/6 background can introduce passenger mutations in the close proximity of the targeted gene. Here, we demonstrate that several transgenic mice carry a P2rx7 passenger mutation that affects the function of T cells. By the example of P2rx4tm1Rass we demonstrate that P2X4ko T cells express higher levels of P2X7 and are more sensitive toward the P2X7 activators ATP and NAD+, rendering these cells more vulnerable toward NAD-induced cell death (NICD) compared with wild type (WT). The enhanced NICD sensitivity confounded functional assays e.g. cytokine production and cell migration. Our results need to be considered when working with P2rx4tm1Rass mice or other 129-based transgenic strains that target P2rx7 neighboring genes., Graphical Abstract, Highlights • T cells from 129 mice express higher level of P2X7 compared with T cells from B6 mice • P2rx4tm1Rass T cells express high level of P2X7 due to a P2rx7 passenger mutation • P2rx4tm1Rass T cells are highly susceptible to NAD-induced cell death (NICD) • NICD susceptibility of P2rx4tm1Rass T cells confounds the outcome of functional assays, Genetics; Immunology

7531 Background: Venetoclax (Ven) has synergistic activity with hypomethylating agents (eg, azacitidine [Aza] or decitabine [Dec]) or low-dose cytarabine (LDAC). These Ven-based combinations have demonstrated rapid median response times. This analysis describes the rapidity and likelihood of response to Ven treatments, and its associated characteristics, in older patients with newly diagnosed acute myeloid leukemia (AML). Methods: Included are data from two open-label trials of Ven, at label recommended doses, in combination with Aza, Dec (NCT02203773; phase 1b), or low-dose cytarabine (NCT02287233; phase 1/2) in newly diagnosed patients with AML. Patients were classified based on CR/CRi timing: within 2 cycles of therapy, after 2 cycles, or never achieving CR/CRi. Within each group, baseline and post-baseline characteristics were evaluated to determine impact on response timing. The percentage of patients in each category and duration of response (DOR) in each category were also evaluated. Results: Data cutoff was August 2018. Of 197 patients, 42% (n = 83) had CR/CRi in ≤2 cycles, 22% (n = 44) had CR/CRi in > 2 cycles, and 36% (n = 70) did not achieve CR/CRi. Median DOR was 21.2 mos. (95% CI 14.1-NR) for ≤2 cycle responders and 8.1 mos. (95% CI 5.3-14.9) for > 2 cycle responders. Baseline characteristics are shown in the Table. Patients with baseline IDH1/2 mutation were more likely to have CR/CRi in ≤2 cycles, while those with secondary AML and no response by the end of cycle 2 were more likely to never achieve CR/CRi. Of the patients who achieved CR/CRi after 2 cycles of therapy, 43% (19/44) achieved MLFS within the first two cycles. Of those who never achieved CR/CRi, 17% (12/70) of patients achieved MLFS within 2 cycles. In depth regression analyses of factors predictive of response, including analysis of biomarkers, will be available upon presentation. Conclusions: Over 1/3rd of patients that achieved CR/CRi on Ven combination therapy within these two studies required more than 2 cycles of treatment. Therefore, prior to discontinuing therapy for nonresponders, it is critical to assess key predictive patient characteristics. Clinical trial information: NCT02203773 and NCT02287233 . [Table: see text]

Antibody-based biologics are the corner stone of modern immunomodulatory therapy. Though highly effective in dampening systemic inflammatory processes, their large size and Fc-fragment mediated effects hamper crossing of the blood brain barrier (BBB). Nanobodies (Nbs) are single domain antibodies derived from llama or shark heavy-chain antibodies and represent a new generation of biologics. Due to their small size, they display excellent tissue penetration capacities and can be easily modified to adjust their vivo half-life for short-term diagnostic or long-term therapeutic purposes or to facilitate crossing of the BBB. Furthermore, owing to their characteristic binding mode, they are capable of antagonizing receptors involved in immune signaling and of neutralizing proinflammatory mediators, such as cytokines. These qualities combined make Nbs well-suited for down-modulating neuroinflammatory processes that occur in the context of brain ischemia. In this review, we summarize recent findings on Nbs in preclinical stroke models and how they can be used as diagnostic and therapeutic reagents. We further provide a perspective on the design of innovative Nb-based treatment protocols to complement and improve stroke therapy.

Lower urinary tract symptoms (LUTS) result from age-related changes in detrusor function and prostatic growth that are driven by alterations in the ratio of circulating androgens and estrogens. Alpha-adrenergic receptor blockers are commonly used to treat LUTS because they influence urethral tone and intra-urethral pressure. Molecular cloning studies have identified three α1-adrenergic receptor subtypes (α1A, α1B, and α1D). The α1A subtype is predominant in the human prostate but is also present in many parts of the brain that direct cognitive function. Tamsulosin is the most widely used α1-adrenergic receptor antagonist with 12.6 million prescriptions filled in 2010 alone. When compared to the other common types of α1-adrenergic receptor antagonists (i.e., terazosin, doxazosin, and alfuzosin), tamsulosin is 10- to 38-fold more selective for the α1A versus the α1B subtype. Duan et al. have recently shown that men taking tamsulosin have a higher risk of developing dementia when compared to men taking other α-adrenergic antagonists or no α-adrenergic antagonists at all (HR 1.17; 95% CI 1.14–1.21). Based upon this retrospective analysis, we believe that tamsulosin, because of its unique affinity for α1A-adrenergic receptors, may increase the risk of developing dementia when used for an extended period of time. If these findings are confirmed, they carry significant public health implications for an aging society.

Cyclic nucleotide gated channels (CNGCs) play multifaceted roles in plants, particularly with respect to signaling processes associated with abiotic stress signaling and during host-pathogen interactions. Despite key roles during plant survival and response to environment, little is known about the activity and function of CNGC family in common wheat (Triticum aestivum L.), a key stable food around the globe. In this study, we performed a genome-wide identification of CNGC family in wheat and identified a total 47 TaCNGCs in wheat, classifying these genes into four major groups (I–IV) with two sub-groups (IVa and IVb). Sequence analysis revealed the presence of several conserved motifs, including a phosphate binding cassette (PBC) and a “hinge” region, both of which have been hypothesized to be critical for the function of wheat CNGCs. During wheat infection with Pst, the transcript levels of TaCNGC14 and TaCNGC16, both members of group IVb, showed significant induction during a compatible interaction, while a reduction in gene expression was observed in incompatible interactions. In addition, TaCNGC14 and TaCNGC16 mRNA accumulation was significantly influenced by exogenously applied hormones, including abscisic acid (ABA), methyl jasmonate (MeJA), and salicylic acid (SA), suggesting a role in hormone signaling and/or perception. Silencing of TaCNGC14 and TaCNGC16 limited Pst growth and increased wheat resistance against Pst. The results presented herein contribute to our understanding of the wheat CNGC gene family and the mechanism of TaCNGCs signaling during wheat-Pst interaction.