Enhanced Risk Stratification for Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia: A Children's Oncology Group Report.

Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PICOG) that maximized discrimination of the predictive model. Patients with higher PICOG have higher predicted relapse risk. The PICOG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PICOG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PICOG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PICOG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PICOG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure.

Occurrence, identification and characterization of diazotrophic bacteria from aerial roots of Rhynchostylis retusa (L.) Blume for plant growth-promoting activity.

In this study, the diversity of diazotrophic bacteria of orchid Rhynchostylis retusa (L.) Blume and its potential application in plant growth promotion were evaluated. About 183 nitrogen-fixing bacteria were isolated to screen various plant growth-promoting traits viz. phosphate solubilization,IAA, siderophore, HCN, biofilm and ammonia production. Based on 16S rRNA gene sequencing analysis Achromobacter, Arthrobacter, Acinetobacter, Bacillus, Brevibacterium, Curtobacterium, Erwinia, Kosakonia, Lysinibacillus, Klebseilla, Microbacterium, Mixta, Pantoea, Pseudomonas and Stenotrophomonas isolates were selected and showed positive results for PGP traits. Overall, genus Pantoea, Brevibacterium, Achromobacter, Arthrobacter, Klebsiella, Mixta, Bacillus, and Pseudomonas had the most pronounced PGP characteristics and acetylene reduction among the screened isolates. BOX PCR fingerprinting analysis showed variation in polymorphic banding patterns among diazotrophic strains. PCR amplification of nifH gene and the presence of 37 kDa nitrogenase reductase enzyme band in western blot indicated presence of nitrogenase activity. Our study showed that orchid R. retusa diazotroph interaction helps orchid plant to fix nitrogen, essential nutrients, and control pathogen entry. To the best of our knowledge, this is the first report on characterization of diazotrophic bacterial community from aerial roots of R. retusa.

Auxin biosynthesis by Microbacterium testaceum Y411 associated with orchid aerial roots and their efficacy in micropropagation.

Root-associated bacteria strongly affect plant growth and development by synthesizing growth regulators and stress-relieving metabolites. The present study is mainly focused on assessing aerial root-associated bacteria of Rhynchostylis retusa (L.) Blume is an endemic epiphytic orchid responsible for auxin production and influencing plant growth. A bacterial isolate, Microbacterium testaceum Y411, was found to be the most active producer of indole-3-acetic acid (IAA). The maximum IAA production (170µg/mL) was recorded with the bacterium at optimum process parameters such as pH 7, temperature 30°C, and tryptophan 1000 µg/mL in a culture medium for 48 h. The extracted auxin was purified and analyzed by FT-IR, HPLC, and HR-MS, indicating bacterial auxin has a similar mass value to 4-chloroindole-3-acetic acid auxin. Furthermore, the bacterial auxin was tested on in vitro propagation of orchid, Cymbidium aloifolium, and 90% seed germination was recorded in Murashige and Skoog's medium supplemented with bacterial auxin. The novel results obtained in this study are used for agricultural applications and the Microbacterium testaceum Y411 is a valuable biotechnological resource for a natural auxin.

COVID-19 news and the US equity market interactions: An inspection through econometric and machine learning lens.

This study investigates the impact of COVID-19 on the US equity market during the first wave of Coronavirus using a wide range of econometric and machine learning approaches. To this end, we use both daily data related to the US equity market sectors and data about the COVID-19 news over January 1, 2020-March 20, 2020. Accordingly, we show that at an early stage of the outbreak, global COVID-19s fears have impacted the US equity market even differently across sectors. Further, we also find that, as the pandemic gradually intensified its footprint in the US, local fears manifested by daily infections emerged more powerfully compared to its global counterpart in impairing the short-term dynamics of US equity markets.

Financial modeling, risk management of energy and environmental instruments and derivatives: past, present, and future.

In this preface, we investigate the past, study the present, and look for the future of financial modeling, risk management of energy and environmental instruments, and derivatives based on articles selected in this special issue (SI). We also summarize the significant findings of those articles and identify the research trends.

A residual driven ensemble machine learning approach for forecasting natural gas prices: analyses for pre-and during-COVID-19 phases.

The natural gas price is an essential financial variable that needs periodic modeling and predictive analysis for many practical implications. Macroeconomic euphoria and external uncertainty make its evolutionary patterns highly complex. We propose a two-stage granular framework to perform predictive analysis of the natural gas futures for the USA (NGF-USA) and the UK natural gas futures for the EU (NGF-UK) for pre-and during COVID-19 phases. The residuals of the previous stage are introduced as a new explanatory feature along with standard technical indicators to perform predictive tasks. The importance of the new feature is explained through the Boruta feature evaluation methodology. Maximal Overlap Discrete Wavelet Transformation (MODWT) is applied to decompose the original time-series observations of the natural gas prices to enable granular level forecasting. Random Forest is invoked on each component to fetch the respective predictions. The aggregated component-wise sums lead to final predictions. A rigorous performance assessment signifies the efficacy of the proposed framework. The results show the effectiveness of the residual as a feature in deriving accurate forecasts. The framework is highly efficient in analyzing patterns in the presence of a limited number of data points during the uncertain COVID-19 phase covering the first and second waves of the pandemic. Our findings reveal that the prediction accuracy is the best for the NGF-UK in the pre-COVID-19 period. Also, the prediction accuracy of the NGF-USA is better in the COVID-19 period than the pre-COVID-19 period.

A probabilistic fuzzy goal programming model for managing the supply of emergency relief materials.

The post-disaster humanitarian logistic operations deal with the supply of emergency relief materials to mitigate damages in the affected areas. Immediately after the disaster, it is challenging to estimate the demand for emergency relief materials. As a result, the demand for such materials at the point of demand and the corresponding transportation costs for the entire supply chain network becomes uncertain. This paper proposes a new probabilistic fuzzy goal programming model for making decisions to manage the post-disaster supply of emergency relief materials. A suggested procedure converts the proposed model to its deterministic equivalent when the demands for the relief materials follow uniform distributions. We implement the differential evolution, a metaheuristic technique, for analyzing demand satisfaction for relief materials under various scenarios. A case example based on the Nepal Earthquake in 2015 demonstrates the usefulness of the proposed approach. The solution of the model will help the Disaster Management Agency coordinate with the humanitarian organizations and foreign countries to provide the required emergency relief materials so that an adequate level of supply can be assured to the affected areas with the least possible transportation cost.

Assessing perceptions of oral health related quality of life in dental implant patients. Experience of a tertiary care center in India.

BACKGROUND: Patients perception of treatment outcomes are invaluable assessment tools and are effective indicators for future prognosis. Various tools of measurement have been used to assess the same. The oral health impact profile questionnaire (OHIP 14) has been effectively used to evaluate the oral health-related quality of life (OHRQoL) with regards to individual perceptions. This study was conducted to assess OHRQoL in patients who have had dental implants to replace missing teeth in the Department of Dental Surgery, Unit 1, Christian Medical College and Hospital, Vellore, TN, India by using the OHIP 14 questionnaire. MATERIALS AND METHODS: A total of 107 patients who had treatment with dental implants were sent a modified form of the OHIP 14 questionnaire. An attempt was made to draw an inference by correlating scores of the OHIP 14 with data pertaining to key independent variables. Gamma regression was applied to the results as the outcome score distribution was skewed. All statistical analyses were performed using SPSS Version 21.0. RESULTS: The mean score for the OHIP 14 was 16.82 with the highest score of 30 for a total score of 70. OHIP 14 scores were higher in patients with implant-supported fixed dental prosthesis as compared to patients with single implant supported crowns (P = 0.0069). Patients with no complaints scored 9% lesser than those who reported complaints (P = 0.0438). CONCLUSION: Assessing quality of life with regards to specific treatment interventions may help to draw critical inferences that determine overall success. Results from the study enabled us to delineate and appreciate the success imparted by esthetics and function from the general well being imparted by treatment with dental implants. Social media could be used to positively improve responses in questionnaire based studies. Future studies using implant specific OHRQoL questionnaire may help to elicit unbiased patient perception in dental implant patients.

Inactivation of KLF4 promotes T-cell acute lymphoblastic leukemia and activates the MAP2K7 pathway.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a high incidence of relapse in pediatric ALL. Although most T-ALL patients exhibit activating mutations in NOTCH1, the cooperating genetic events required to accelerate the onset of leukemia and worsen disease progression are largely unknown. Here, we show that the gene encoding the transcription factor KLF4 is inactivated by DNA methylation in children with T-ALL. In mice, loss of KLF4 accelerated the development of NOTCH1-induced T-ALL by enhancing the G1-to-S transition in leukemic cells and promoting the expansion of leukemia-initiating cells. Mechanistically, KLF4 represses the gene encoding the kinase MAP2K7. Our results showed that in murine and pediatric T-ALL, loss of KLF4 leads to aberrant activation of MAP2K7 and of the downstream effectors JNK and ATF2. As a proof-of-concept for the development of a targeted therapy, administration of JNK inhibitors reduced the expansion of leukemia cells in cell-based and patient-derived xenograft models. Collectively, these data uncover a novel function for KLF4 in regulating the MAP2K7 pathway in T-ALL cells, which can be targeted to eradicate leukemia-initiating cells in T-ALL patients.

The TGF-ß/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia.

Natural killer (NK) cells are key components of the innate immune system, providing potent antitumor immunity. Here, we show that the tumor growth factor-ß (TGF-ß)/SMAD signaling pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia (ALL). We characterized NK cells in 50 consecutive children with B-ALL at diagnosis, end induction and during maintenance therapy compared with age-matched controls. ALL-NK cells at diagnosis had an inhibitory phenotype associated with impaired function, most notably interferon-γ production and cytotoxicity. By maintenance therapy, these phenotypic and functional abnormalities partially normalized; however, cytotoxicity against autologous blasts remained impaired. We identified ALL-derived TGF-ß1 to be an important mediator of leukemia-induced NK cell dysfunction. The TGF-ß/SMAD signaling pathway was constitutively activated in ALL-NK cells at diagnosis and end induction when compared with healthy controls and patients during maintenance therapy. Culture of ALL blasts with healthy NK cells induced NK dysfunction and an inhibitory phenotype, mediated by activation of the TGF-ß/SMAD signaling pathway, and abrogated by blocking TGF-ß. These data indicate that by regulating the TGF-ß/SMAD pathway, ALL blasts induce changes in NK cells to evade innate immune surveillance, thus highlighting the importance of developing novel therapies to target this inhibitory pathway and restore antileukemic cytotoxicity.

A review of clinical and radiological features of cleidocranial dysplasia with a report of two cases and a dental treatment protocol.

Cleidocranial dysplasia (CCD) is a rare autosomal dominant condition with generalized dysplasia of bone characterized by delayed closure of cranial sutures, hypoplastic or aplastic clavicles, short stature, dental abnormalities and a variety of other skeletal abnormalities. We report two cases presenting with classical features of CCD because of its rarity.

Selecting suitable solid organ transplant donors: Reducing the risk of donor-transmitted infections.

Selection of the appropriate donor is essential to a successful allograft recipient outcome for solid organ transplantation. Multiple infectious diseases have been transmitted from the donor to the recipient via transplantation. Donor-transmitted infections cause increased morbidity and mortality to the recipient. In recent years, a series of high-profile transmissions of infections have occurred in organ recipients prompting increased attention on the process of improving the selection of an appropriate donor that balances the shortage of needed allografts with an approach that mitigates the risk of donor-transmitted infection to the recipient. Important advances focused on improving donor screening diagnostics, using previously excluded high-risk donors, and individualizing the selection of allografts to recipients based on their prior infection history are serving to increase the donor pool and improve outcomes after transplant. This article serves to review the relevant literature surrounding this topic and to provide a suggested approach to the selection of an appropriate solid organ transplant donor.

Generation of multi-leukemia antigen-specific T cells to enhance the graft-versus-leukemia effect after allogeneic stem cell transplant.

Adoptive immunotherapy with ex vivo expanded T cells is a promising approach to prevent or treat leukemia. Myeloid leukemias express tumor-associated antigens (TAA) that induce antigen-specific cytotoxic T lymphocyte (CTL) responses in healthy individuals. We explored the feasibility of generating TAA-specific CTLs from stem cell donors of patients with myeloid leukemia to enhance the graft-versus-leukemia effect after stem cell transplantation. CTL lines were manufactured from peripheral blood of 10 healthy donors by stimulation with 15mer peptide libraries of five TAA (proteinase 3 (Pr3), preferentially expressed antigen in melanoma, Wilms tumor gene 1 (WT1), human neutrophil elastase (NE) and melanoma-associated antigen A3) known to be expressed in myeloid leukemias. All CTL lines responded to the mix of five TAA and were multi-specific as assessed by interferon-γ enzyme-linked immunospot. Although donors showed individual patterns of antigen recognition, all responded comparably to the TAAmix. Immunogenic peptides of WT1, Pr3 or NE could be identified by epitope mapping in all donor CTL lines. In vitro experiments showed recognition of partially human leukocyte antigen (HLA)-matched myeloid leukemia blasts. These findings support the development of a single clinical grade multi-tumor antigen-specific T-cell product from the stem cell source, capable of broad reactivity against myeloid malignancies for use in donor-recipient pairs without limitation to a certain HLA-type.

Pediatric Hodgkin lymphoma: are we over-scanning our patients?

Despite the favorable outcome of most pediatric patients with Hodgkin lymphoma (HL), there is rising concern about risks of carcinogenesis from both diagnostic and therapeutic radiation exposure for patients treated on study protocols. Although previous studies have investigated radiation exposure during treatment, radiation from post-treatment surveillance imaging may also increase the likelihood of secondary malignancies. All diagnostic imaging examinations involving ionizing radiation exposure performed for surveillance following completion of therapy were recorded for 99 consecutive pediatric patients diagnosed with HL from 2000 to 2010. Cumulative radiation dosage from these examinations and the frequency of relapse detection by these examinations were recorded. In the first 2 years following completion of therapy, patients in remission received a median of 11 examinations (range 0-26). Only 13 of 99 patients relapsed, 11 within 5 months of treatment completion. No relapse was detected by 1- or 2-view chest radiographs (n = 38 and 296, respectively), abdomen/pelvis computed tomography (CT) scans (n = 211), or positron emission tomography (PET) scans alone (n = 11). However, 10/391 (2.6%) of chest CT scans, 4/364 (1.1%) of neck CT scans, and 3/47 (6.4%) of PET/CT scans detected relapsed disease. Thus, only 17 scans (1.3%) detected relapse in a total of 1358 scans. Mean radiation dosages were 31.97 mSv for Stage 1, 37.76 mSv for Stage 2, 48.08 mSv for Stage 3, and 51.35 mSv for Stage 4 HL. Approximately 1% of surveillance imaging examinations identified relapsed disease. Given the very low rate of relapse detection by surveillance imaging stipulated by current protocols for pediatric HL patients, the financial burden of the tests themselves, the high cure rate, and risks of second malignancy from ionizing radiation exposure, modification of the surveillance strategy is recommended.

Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles.

Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-DS (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only 2 NDS cases (3.1%) (Fisher's exact P=0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters and enrichment of highly methylated genes for specific pathways and transcription factor-binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions.

Trismus as a first presenting complaint in a case of myasthenia gravis.

The initial presentation of myasthenia gravis as trismus is very rare and no previous reports have been found in the literature. A 35-year-old male presented to the outpatient unit of our department with inability to clench well and to open his mouth. Physical examination revealed that he had clinical findings consistent with the signs and symptoms of myasthenia gravis. He was immediately referred to a neurologist, who confirmed that he was in an advanced stage of myasthenia gravis with severe deficit to his respiratory muscles and he was promptly treated. He is presently on a maintenance drug therapy. To our knowledge, this is the first reported case of myasthenia gravis whose initial presentation was trismus. This case presents a rare but important diagnosis that should be added to the differential diagnosis of trismus.

A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16.

As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband-sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, approximately 95 cM) and Dutch (LOD>1, approximately 100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.