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Since 2017, the number of agents for acute myeloid leukemia (AML) has rapidly expanded. Given the increased therapeutic options, better identification of high-risk subsets of AML and more refined approaches to patient fitness assessment, the decisions surrounding selection of intensive chemotherapy versus lower-intensity treatment have grown increasingly more nuanced. In this review, we present available data for both standard and investigational approaches in the initial treatment of AML using an intensive chemotherapy backbone or a lower-intensity approach. We summarize management strategies in newly diagnosed secondary AML, considerations around allogeneic stem-cell transplantation, and the role of maintenance therapy. Finally, we highlight important areas of future investigation and novel agents that may hold promise in combination with standard therapies.

Apart from the anti-GD2 antibody, immunotherapy for neuroblastoma has had limited success due to immune evasion mechanisms, coupled with an incomplete understanding of predictors of response. Here, from bulk and single-cell transcriptomic analyses, we identify a subset of neuroblastomas enriched for transcripts associated with immune activation and inhibition and show that these are predominantly characterized by gene expression signatures of the mesenchymal lineage state. By contrast, tumors expressing adrenergic lineage signatures are less immunogenic. The inherent presence or induction of the mesenchymal state through transcriptional reprogramming or therapy resistance is accompanied by innate and adaptive immune gene activation through epigenetic remodeling. Mesenchymal lineage cells promote T cell infiltration by secreting inflammatory cytokines, are efficiently targeted by cytotoxic T and natural killer cells and respond to immune checkpoint blockade. Together, we demonstrate that distinct immunogenic phenotypes define the divergent lineage states of neuroblastoma and highlight the immunogenic potential of the mesenchymal lineage.

Chronic wounds require suitable treatment and management strategies for proper healing. Among other causes, infection delays the healing of wounds and increases the risk of wound-related complications. In this study, an inherently antibacterial and biocompatible wound dressing is developed to enhance the healing. Chemical modification of a natural polysaccharide, Isabgol with epoxypropyltrimethylammonium chloride, renders antibacterial activity to the material. This is the first report of such chemical modification of this polymer for biomedical applications. The modified material is freeze-dried to obtain porous scaffolds. 13C NMR and FTIR analysis confirmed the modification of the Isabgol polymer chains with EPTMAC. SEM analysis confirmed the porous structure of the scaffold that would allow the exchange of gases and nutrients through the matrix. The material can swell up to 17 times its initial weight, allowing it to absorb wound exudates and maintain a moist environment at the wound site. Thermogravimetric analysis and compression testing showed that the scaffold has suitable thermal and mechanical properties. The material is antibacterial and can potentially prevent infections at the wound site. In vitro studies have confirmed that these scaffolds are cytocompatible and hemocompatible. These properties indicate that the EPTMAC-modified Isabgol scaffolds would be suitable for wound dressing applications.

Neuroblastoma is a common pediatric cancer, where preclinical studies have suggested chemotherapy resistance is driven by a mesenchymal-like gene expression program. However, the poor clinical outcomes imply we need a better understanding of the relationship between patient tumors and preclinical models. Here, we generated single-cell RNA-seq maps of neuroblastoma cell lines, patient-derived xenograft models (PDX), and a genetically engineered mouse model (GEMM). We developed an unsupervised machine learning approach to compare the gene expression programs found in preclinical models to a large cohort of human neuroblastoma tumors. The dominant adrenergic programs were well preserved in preclinical models, but contrary to previous reports do not unambiguously map to an obvious cell of origin. The mesenchymal-like program was less clearly preserved, and primarily restricted to cancer-associated fibroblasts and Schwann-like cellsin vivo. Surprisingly however, we identified a subtle, weakly expressed, mesenchymal-like program in otherwise adrenergic cancer cells in some high-risk tumors. This program appears distinct from mesenchymal cell lines but was maintained in PDX and a similar program could be chemotherapy-induced in our GEMM after only 24 hours, suggesting an uncharacterized therapy-escape mechanism. Collectively, our findings advance the understanding of neuroblastoma heterogeneity and can inform the development of new treatments.

Supplementary Data from EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma

Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HAT) EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeting chimera (PROTAC) compound termed “JQAD1” that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid NB apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Furthermore, JQAD1 activity is critically determined by cereblon (CRBN) expression across NB cells.Significance:EP300, but not CBP, controls oncogenic CRC-driven transcription in high-risk NB by binding TFAP2β. We developed JQAD1, a CRBN-dependent PROTAC degrader with preferential activity against EP300 and demonstrated its activity in NB. JQAD1 has limited toxicity to untransformed cells and is effective in vivo in a CRBN-dependent manner.This article is highlighted in the In This Issue feature, p. 587

Non-Hispanic Black (NHB) and Hispanic patients with acute myeloid leukemia (AML) have higher mortality rates than non-Hispanic White (NHW) patients despite more favorable genetics and younger age. A discrete survival analysis was performed on 822 adult patients with AML from 6 urban cancer centers and revealed inferior survival among NHB (hazard ratio [HR] = 1.59; 95% confidence interval [CI]: 1.15, 2.22) and Hispanic (HR = 1.25; 95% CI: 0.88, 1.79) patients compared with NHW patients. A multilevel analysis of disparities was then conducted to investigate the contribution of neighborhood measures of structural racism on racial/ethnic differences in survival. Census tract disadvantage and affluence scores were individually calculated. Mediation analysis of hazard of leukemia death between groups was examined across 6 composite variables: structural racism (census tract disadvantage, affluence, and segregation), tumor biology (European Leukemia Network risk and secondary leukemia), health care access (insurance and clinical trial enrollment), comorbidities, treatment patterns (induction intensity and transplant utilization), and intensive care unit (ICU) admission during induction chemotherapy. Strikingly, census tract measures accounted for nearly all of the NHB-NHW and Hispanic-NHW disparity in leukemia death. Treatment patterns, including induction intensity and allogeneic transplant, and treatment complications, as assessed by ICU admission during induction chemotherapy, were additional mediators of survival disparities in AML. This is the first study to formally test mediators for observed disparities in AML survival and highlights the need to investigate the mechanisms by which structural racism interacts with known prognostic and treatment factors to influence leukemia outcomes.

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Purpose: Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination (HR)-deficient tumors and ability to enhance the action of certain DNA-damaging agents. Compared with other PARP inhibitors in development, iniparib (4-iodo-3-nitrobenzamide) is notable for its simple structure and the reported ability of its intracellular metabolite 4-iodo-3-nitrosobenzamide to covalently inhibit PARP1 under cell-free conditions. The present preclinical studies were conducted to compare the actions iniparib with the more extensively characterized PARP inhibitors olaparib and veliparib.Experimental Design: The abilities of iniparib, olaparib, and veliparib to (i) selectively induce apoptosis or inhibit colony formation in HR-deficient cell lines, (ii) selectively sensitize HR-proficient cells to topoisomerase I poisons, and (iii) inhibit formation of poly(ADP-ribose) polymer (pADPr) in intact cells were compared.Results: Consistent with earlier reports, olaparib and veliparib selectively induced apoptosis and inhibited colony formation in cells lacking BRCA2 or ATM. Moreover, like earlier generation PARP inhibitors, olaparib and veliparib sensitized cells to the topoisomerase I poisons camptothecin and topotecan. Finally, olaparib and veliparib inhibited formation of pADPr in intact cells. In contrast, iniparib exhibited little or no ability to selectively kill HR-deficient cells, sensitize cells to topoisomerase I poisons, or inhibit pADPr formation in situ. In further experiments, iniparib also failed to sensitize cells to cisplatin, gemcitabine, or paclitaxel.Conclusions: While iniparib kills normal and neoplastic cells at high (>40 μmol/L) concentrations, its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors. Clin Cancer Res; 18(6); 1655–62. ©2012 AACR.

Table S1: Primers for Methylation Analysis. Figure S1: Sensitivity of erythroid and myeloid progenitors to veliparib. Figure S2: Reproducibility of colony forming assays. Figure S3: Veliparib IC50 as a function of BRCA1 Promotor Methylation.

Purpose: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo.Experimental Design: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays.Results: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage–induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes.Conclusions: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894–902. ©2016 AACR.

Supplementary Figure Legends 1-5 from Poly(ADP-Ribose) Polymerase Inhibition Synergizes with 5-Fluorodeoxyuridine but not 5-Fluorouracil in Ovarian Cancer Cells

Rhabdomyosarcomas (RMS) represent a family of aggressive soft tissue sarcomas that present in both children and adults. Pathologic risk stratification for RMS has been based on histologic subtype, with poor outcomes observed in alveolar rhabdomyosarcoma (ARMS) and the adult-type pleomorphic rhabdomyosarcoma (PRMS) compared to embryonal rhabdomyosarcoma (ERMS). Genomic sequencing studies have expanded the spectrum of RMS, with several new molecularly defined entities, including fusion-driven spindle cell/sclerosing rhabdomyosarcoma (SC/SRMS) and MYOD1-mutant SC/SRMS. Comprehensive genomic analysis has previously defined the mutational and copy number spectrum for the more common ERMS and ARMS and revealed corresponding methylation signatures. Comparatively, less is known about epigenetic correlates for the rare SC/SRMS or PRMS histologic subtypes. Herein, we present exome and RNA sequencing, copy number analysis, and methylation profiling of the largest cohort of molecularly characterized RMS samples to date. In addition to ARMS and ERMS, we identify two novel methylation subtypes, one having SC/SRMS histology and defined by MYOD1 p. L122R mutations and the other matching adult-type PRMS. Selected tumors from adolescent patients grouped with the PRMS methylation class, expanding the age range of these rare tumors. Limited follow-up data suggest that pediatric tumors with MYOD1-mutations are associated with an aggressive clinical course.

Purpose Evidence indicates that the Indian economy has grown enormously in recent years. and Lean Six Sigma (LSS) has evolved globally as a structured business improvement strategy with diverse applicability in the last fifteen years. Therefore, this paper aims to investigate the status of LSS implementation in Indian industries using a survey research technique. Design/methodology/approach A survey questionnaire was devised from the literature, containing 25 questions to assess respondents’ awareness of the LSS methodology and gain insights on aspects associated with LSS adoption in Indian industries. The survey questionnaire was validated and was conducted using randomly sampled respondents from the Confederation of Indian Industries membership database. The collected data were statistically analyzed using IBM SPSS and MS Excel. Findings The findings attest that adopting LSS is not so encouraging and extremely poor in small- and medium-scale Indian industries. ISO 9001 emerged as a prominent quality improvement program. It is learnt that consultants play a pivotal role in bringing awareness and skills building while implementing LSS. Results endorse top management commitment and involvement, and resistance to change as leading success factors and challenges, respectively. Further, it is revealed that respondents were highly satisfied after the adoption of LSS. Research limitations/implications The findings of this study were derived from 183 responses and should be generalized cautiously. Originality/value This paper provides valuable insights on the present status covering the issues related to L:SS implementation in India. These results can motivate the managers of Indian industries for wide adoption of the LSS methodology. In addition, the findings of the paper may assist the researchers providing direction to carry out further research in LSS in the Indian context.

Evobrutinib is a highly selective, orally administered Bruton's tyrosine kinase (BTK) inhibitor. The objective of this phase II, multicenter, randomized, double-blind, placebo-controlled trial was to evaluate the efficacy and safety of evobrutinib in patients with active autoantibody-positive systemic lupus erythematosus (SLE).Patients were diagnosed with SLE by either the Systemic Lupus International Collaborating Clinics criteria or at least four American College of Rheumatology criteria 6 months or more prior to screening, had an SLE Disease Activity Index-2000 score of 6 or more, were autoantibody-positive and on standard-of-care therapy. Randomization was 1:1:1:1 to oral evobrutinib 25 mg once daily (QD), 75 mg QD, 50 mg twice daily, or placebo. Primary efficacy endpoints were SLE responder index (SRI)-4 response at week 52 and SRI-6 response at week 52 in the high disease activity subpopulation. Safety endpoints included treatment-emergent adverse events (TEAEs).A total of 469 patients were randomized and received at least one dose of evobrutinib or placebo at the time of primary analysis. Mean (SD) age at baseline was 40.7 (±12.3) years; 94.9% of patients were female. Neither primary efficacy endpoint was met. All doses of evobrutinib were well tolerated, and there was no clear dose effect on the incidence of reported TEAEs, or serious TEAEs, including severe infections.This phase II, dose-ranging trial in SLE failed to show a treatment effect of evobrutinib versus placebo at any dose. Evobrutinib was generally well tolerated, with no dose effect observed for TEAEs. These results suggest that BTK inhibition does not appear to be an effective therapeutic intervention for patients with SLE.

Background: In rapidly growing cities there is increased use of motor vehicles. Bus drivers are exposed to toxic gases from the diesel exhaust and atmospheric pollutants, there is an increased risk of decrease in pulmonary function in bus drivers as well as bus conductors. They have irregular shift patterns; prolonged period of driving in congested areas there is an increased stress level thus an increase in cardiovascular risk factors in bus drivers. Due to prolonged period of sitting during driving and irregular meals there is increased risk of obesity in bus drivers and conductors. Purpose: To conduct an evidence based study to find whether pulmonary function, aerobic capacity, obesity and stress level is increased bus drivers and conductors in Gujarat state. Methodology: The study was conducted according to Preferred Reporting Items for systematic reviews and meta-analysis guidelines. Evidences selected since year 1994-February 2020 from PubMed, Google Scholar, Physiotherapy Evidence Database (PEDro), ResearchGate, ScienceDirect and Cumulative Index of Nursing and Allied Health Literature. Key words used were: Pulmonary function test, Aerobic capacity, Stress level, Obesity, Bus drivers and Bus conductors. Analysis was done using Modified Sackett Scale Version 4.0. Total 30 articles were found, out of which 20 articles were relevant and from those 14 articles were included in the study and other articles were excluded as per eligibility criteria. Results: 8 studies showed high prevalence of reduced lung volumes. 2 studies showed prevalence of high level of stress. 2 studies showed prevalence of Overweight and obesity. Conclusion: Based on evidences from search engines like Google scholar, PubMed, PEDro, ScienceDirect and ResearchGate from the year 1994- 2020, it can be concluded that bus drivers and conductors may suffer from chronic respiratory disease, high stress level and may have obesity and there is no evidence on aerobic capacity. Keywords: Pulmonary function test, Aerobic capacity, Stress level, Obesity, Bus drivers and Bus conductors.

The treatment of acute myeloid leukemia (AML) has been enhanced by the development and regulatory approval of a series of novel agents, including midostaurin and gilteritinib (FLT3 inhibitors), venetoclax (BCL2 inhibitor), ivosidenib (IDH1 inhibitor), and enasidenib (IDH2 inhibitor). A difficulty that has arisen in the era of molecular therapies, however, is determining the efficacy of these agents for patients with AML harboring atypical driver mutations. The non-canonical FLT3 p.N676K variant was initially described as an acquired resistance mechanism in patients with FLT3 internal tandem duplication (ITD) mutations who were treated with midostaurin. Clinical data from patients with the FLT3 N676K mutations are limited. Here, we detail our experience caring for nine different patients with AML harboring FLT3 N676K at the University of Chicago. Seven of nine (78%) individuals received intensive induction chemotherapy, with FLT3 inhibitors utilized in three patients upfront and five patients during subsequent lines of treatment. With the use of FLT3 inhibitors, we noted reduction, and in some instances, complete molecular suppression of detectable FLT3 N676K variant allele fraction (VAF) on NGS, underscoring the activity of FLT3 inhibitors in this population regardless of line of therapy. Individuals with FLT3 N676K-mutated AML who received FLT3 inhibitors had longer median survival (940 days) than those who did not (408 days), however, the difference was not significant likely due to small size of the study (p = 0.2). The presence of concurrent canonical FLT3 mutations was associated with loss of treatment response. In silico visualization models of the FLT3 tyrosine kinase domain in the presence of gilteritinib demonstrate that the mechanism of N676K-mediated resistance is not due to disruption of FLT3 inhibitor binding at the ATP-binding site but rather influenced by other allosteric forces on protein structure. In conclusion, this is the largest study to date demonstrating that the atypical FLT3 N676K driver mutation is sensitive to contemporary FLT3 inhibitors, such as midostaurin and gilteritinib. Our data suggest that FLT3 inhibitors should be included in both the upfront induction setting as well as in the relapsed/refractory setting for patients harboring the FLT3 N676K mutation.

According to the performance requirements, either bulk or nanocrystalline form of the material can be used for different types of device applications. In the present study, zirconium triselenide bulk crystals were grown by direct vapour transport technique. The energy-dispersive X-ray analysis (EDAX) confirms the purity of the grown crystals. The as-grown crystals and powder have been examined under Carl Zeiss optical microscope and scanning electron microscope (SEM) for morphological studies which revealed the evolution of crystalline phases of the material by the layered kind of growth mechanism. The transmission electron microscopy (TEM) with selected area electron diffraction (SAED) pattern analysis showed the grown crystals possess good crystallinity, whereas X-ray diffraction (XRD) analysis confirmed the monoclinic phase of the crystals. To study the effect of different wavelength sources (Blue-470 nm, Green-540 nm, Red-670 nm) on bulk zirconium trisulfide photodetectors, a pulse photo response experiment was carried out. The anisotropic behaviour is also revealed using the same sources. Various device parameters like responsivity, sensitivity, detectivity and external quantum efficiency (EQE%) were calculated. The highest responsivity and detectivity of 81.7 µA/W and 3.56 × 107 Jones were achieved for blue (470 nm) light source, respectively.

This research work consists of the ultrasonically synthesized Cu0.4Sn0.6Se nanoparticles and comprehensive photoresponse investigation of these nanoparticles-based thin film. The chemical composition, lateral morphology, phase structure and band-gap measurements were established by means of EDAX-Elemental Mapping, TEM-SAED, powder XRD and UV-DRS-PL measurements, respectively. The average size of the nanoparticles is determined by particle size analysis. Cu0.4Sn0.6Se ternary alloy nanoparticles-based photodetector is designed. The photoconducting behaviour is investigated under periodic 532 nm lase illumination of power intensity 10 mW/cm2. The device unveiled good photo-responsivity, specific detectivity and fast response. Rise time of 1.3 s and decay time of 2.0 s were reported with excellent photo-responsivity of 13.55 mA/W, detectivity of 1.98 × 1010 Jones and EQE of 2.50% for 1.5 V. The results demonstrated that Cu0.4Sn0.6Se nanoparticles possessed excellent optoelectronic properties and have potential applications for future optoelectronic devices.

Chronic wounds require suitable treatment and management strategies for proper healing. Among other causes, infection delays the healing of wounds and increases the risk of wound-related complications. Healing of chronic wounds requires an ingenious biomaterial that is biocompatible and anti-infective to achieve effective wound management. In this study, a wound dressing with inherent antibacterial and biocompatible properties was developed to assist the healing process. Natural polysaccharide Isabgol was chemically modified with Epoxy propyl trimethyl ammonium chloride to render antibacterial activity to the material. This is the first report of such chemical modification of this polymer for biomedical applications. The modified material was freeze-dried to obtain scaffolds. 13C NMR and FTIR analysis confirmed the modification of the Isabgol polymer chains with EPTMAC. The scaffold exhibits an organized porous structure that allows the exchange of gases and nutrients through the matrix, as confirmed by SEM analysis. The material possesses excellent swelling properties up to 17 times its initial weight that allows it to absorb wound exudates and maintain a moist environment at the wound site. The scaffold is biodegradable, and thermally and mechanically stable. The material is anti-infective and can prevent infections at the wound site, which is one of the major causes of delayed wound healing. The developed scaffolds have been proven to be biocompatible and suitable for use in blood contact applications. Finally, since Isabgol is a low-cost raw material, the quaternary ammonium-modified Isabgol scaffold can be an affordable wound dressing material.