An analysis of conventional and modern packaging approaches for cut flowers: a review article.

Fresh-cut flowers are considered to be one of the most delicate and challenging commercial crops. It is important to take into consideration how to minimize loss during storage and transportation when preserving cut flowers. Many impinging (bad effect) forces can interact to shorten the flowers' vase life. In the flower industry, effective methods need to be developed to extend freshly cut flowers' life. Fresh-cut flowers' vase life can be shortened by a variety of interlocking causes. The flower industry must develop new techniques to extend the flowers' vase lifespan. This review provides comprehensive, up-to-date information on classical, modified atmosphere packaging (MAP), and controlled atmosphere packaging (CAP) displays. According to this review, a promising packaging technique for fresh flowers can be achieved through smart packaging. A smart package is one that incorporates new technology to increase its functionality. This combines active packaging, nanotechnology, and intelligence. This technology makes it easier to keep an eye on the environmental variables that exist around the packaged flowers to enhance their quality. This article offers a comprehensive overview of creative flower-saving packaging ideas that reduce flower losses and assist growers in handling more effectively their flower inventory. To guarantee the quality of flowers throughout the marketing chain, innovative packaging techniques and advanced packaging technologies should be adopted to understand various package performances. This will provide the consumer with cut flowers of standard quality. Furthermore, sustainable packaging is achieved with circular packaging. We can significantly reduce packaging waste's environmental impact by designing reused or recyclable packaging.

Ameliorative Effect of Quercetin against Abamectin-Induced Hemato-Biochemical Alterations and Hepatorenal Oxidative Damage in Nile Tilapia, Oreochromis niloticus.

Abamectin (ABM) is a common agricultural pesticide and veterinary anthelmintic drug. It can discharge from the sites of application to aquatic systems via surface run-off or spray drift, causing harmful effects to aquatic organisms. The present study investigated the protective effect of dietary quercetin supplementation on hemato-biochemical parameters and hepato-renal oxidative stress biomarkers in Nile tilapia (Oreochromis niloticus) exposed to a sublethal dose of ABM. Fish were allocated into six equal groups. The first group was kept as a control group. The second and third groups (Q400, and Q800) were fed diets supplemented with two quercetin levels (400 and 800 mg/kg diet), respectively. The fourth group (ABM) was intoxicated with 20.73 µg/L of ABM. The fifth and sixth groups (ABM + Q400, and ABM + Q800) were fed diet supplemented with two quercetin levels (400 and 800 mg/kg diet) and simultaneously intoxicated with ABM for 60 days. The results showed that ABM significantly decreased RBCs, hemoglobin content, hematocrit, total protein, albumin levels, and acetylcholinesterase activity activities compared to the control. Meanwhile, ABM significantly increased white blood cells, glucose, total lipids, cholesterol, and alanine and aspartate aminotransferase activities. Liver and kidney levels of lipid peroxidation was significantly increased, while hepato-renal antioxidant biomarkers (reduced glutathione, super oxide dismutase, catalase, and total antioxidant capacity) were significantly decreased upon ABM exposure. On the other hand, quercetin dietary supplementation improved the hemato-biochemical alterations and alleviated oxidative stress induced by ABM exposure. Fish supplemented with quercetin at a level of 800 mg/kg diet showed better alleviating effects against ABM compared to 400 mg/kg diet. Based on these study findings, we suggest that quercetin dietary supplementation (800 mg/kg) offered direct protection against ABM-induced physiological disturbance and oxidative stress in Nile tilapia.

Humic Acid-Coated Fe3O4 Nanoparticles Confer Resistance to Acremonium Wilt Disease and Improve Physiological and Morphological Attributes of Grain Sorghum.

Acremonium wilt disease affects grain quality and reduces sorghum yield around the globe. The present study aimed to assess the efficacy of humic acid (HA)-coated Fe3O4 (Fe3O4/HA) nanoparticles (NPs) in controlling acremonium wilt disease and improving sorghum growth and yields. During the season 2019, twenty-one sorghum genotypes were screened to assess their response to Acremonium striticum via artificial infection under field conditions and each genotype was assigned to one of six groups, ranging from highly susceptible to highly resistant. Subsequently, over the two successive seasons 2020 and 2021, three different concentrations of 10, 40 and 80 mg L-1 of Fe3O4/HA NPs were tested against A. striticum. The concentrations of 40 and 80 mg L-1 were found to be highly effective in controlling acremonium wilt disease on different sorghum genotypes: LG1 (highly susceptible), Giza-3 (susceptible), and Local 119 (resistant) genotypes. After harvest, the physiological (growth and yield) and biochemical (peroxidase, catalase, and gibberellic acid) attributes of sorghum plants were determined, and the results demonstrated that concentrations of 40 and 80 mg L-1 increased peroxidase and catalase activities in healthy (uninoculated) sorghum genotypes compared to inoculated sorghum genotypes. Additionally, the toxicity of Fe3O4/HA NPs on male albino rats was investigated via hematological (CBC), chemical (ALT and AST) and histopathological analyses. The concentration 80 mg L-1 of Fe3O4/HA NPs caused a marked increase in ALT and creatinine level after 51 days of feeding. Severe pathological alterations were also observed in liver and kidney tissues of rats administered with grain sorghums treated with 80 mg L-1. In comparison with the untreated control plants, a concentration of 40 mg L-1 significantly increased the growth, yield and gibberellic acid levels (p ≤ 0.05) and was found to be safe in male albino rats. Conclusively, a concentration of 40 mg L-1 of Fe3O4/HA NPs showed promising results in curtailing A. striticum infections in sorghum, indicating its great potential to substitute harmful fertilizers and fungicides as a smart agriculture strategy.

Green Synthesis of Zinc Oxide Nanoparticles Using Red Seaweed for the Elimination of Organic Toxic Dye from an Aqueous Solution.

This study aims to produce green zinc oxide nanoparticles (ZnO-NPs) derived from red seaweed (Pterocladia Capillacea) and evaluate their potential to absorb Ismate violet 2R (IV2R) ions from an aqueous solution. UV-vis spectrophotometry, Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and a Brunauer-Emmett-Teller surface area analysis (BET) were used to analyze the structural, morphological, and optical features of the synthesized nanoparticles. The change in color of the chemical solution revealed the formation of zinc oxide nanoparticles. The FTIR examination confirmed the synthesis of both Zn and ZnO nanoparticle powder, with a BET surface area of 113.751 m2 g-1 and an average pore size of 2.527 nm for the synthesized adsorbent. Furthermore, the maximum removal effectiveness of IV2R was 99% when 0.08 g ZnO-NPs was applied at a pH of 6, a temperature of 55 °C, and a contact time of 120 min. The dye adsorption capacity of the ZnO-NPs was 72.24 mg g-1. The adsorption process was also controlled by the Freundlich adsorption model and pseudo-second-order reaction kinetics. The adsorption of IV2R ions onto the ZnO-NPs could be represented as a nonideal and reversible sorption process of a nonuniform surface, according to Freundlich adsorption isotherms. In addition, the constant values of the model parameters were determined using various nonlinear regression error functions. Moreover, thermodynamic parameters such as entropy change, enthalpy change, and free energy change were investigated; the adsorption process was spontaneous and endothermic. The high capacity of the ZnO-NPs synthesized by red seaweed promotes them as promising substances for applications in water treatment for the removal of IV2R dye from aqueous systems.

Genetic and Morphological Diversity Assessment of Five Kalanchoe Genotypes by SCoT, ISSR and RAPD-PCR Markers.

Determining the appropriate parents for breeding programs is the most important decision that plant breeders must make to maximize the genetic variability and produce excellent recombinant genotypes. Several methods are used to identify genotypes with desirable phenotypic features for breeding experiments. In this study, five kalanchoe genotypes were morphologically characterized by assessing plant height, number of inflorescences, number of flowers, flower length, flower diameter and number of petals. The analysis showed the distinction of yellow kalanchoe in the plant height trait, while the orange kalanchoe was distinguished in the number of inflorescences, the number of flowers and flower length traits, whereas the violet kalanchoe possessed the largest flower diameter and the highest number of petals. The molecular profiling was performed by random amplified polymorphism DNA (RAPD), inter-simple sequence repeats (ISSR) and start codon targeted (SCoT)-polymerase chain reaction (PCR) tools. Genomic DNA was extracted from young leaves and the PCR reactions were performed using ten primers for each SCoT, ISSR and RAPD marker. Only four out of ten primers showed amplicon profiles in all PCR markers. A total of 70 bands were generated by SCoT, ISSR and RAPD-PCR with 35 polymorphic bands and 35 monomorphic bands. The total number of bands of RAPD, ISSR and SCoT was 15, 17 and 38, respectively. The polymorphism percentages achieved by RAPD, ISSR and SCoT were 60.25%, 15% and 57%, respectively. The cluster analysis based on morphological data revealed two clusters. Cluster I consisted of violet and orange kalanchoe, and cluster II comprised red, yellow and purple kalanchoe. Whereas the cluster analysis based on molecular data revealed three clusters. Cluster I included only yellow kalanchoe, cluster II comprised orange and violet kalanchoe while cluster III comprised red, and purple kalanchoe. The study concluded that orange, violet and yellow kalanchoe are distinguished parents for breeding economically valued traits in kalanchoe. Also, the study concluded that SCoT and RAPD markers reproduced reliable banding patterns to assess the genetic polymorphism among kalanchoe genotypes that consider the basis stone for genetic improvements in ornamental plants.

Exogenous Postharvest Application of Calcium Chloride and Salicylic Acid to Maintain the Quality of Broccoli Florets.

The importance of broccoli (Brassica oleracea var. italica) consumption has increased in recent years due to its significant amount of anticarcinogenic and antioxidant compounds, as well as its many vitamins. However, broccoli florets are a highly perishable product which rapidly senesce and turn yellow after harvest, resulting in losses in nutritional and bioactive compounds. Thus, in this study, we evaluated the effect of postharvest exogenous of salicylic acid (SA) and calcium chloride (CaCl2) and their combination on the quality of broccoli florets stored at 5 °C for 28 days to minimize the rapid senescence of broccoli florets. Samples treated with 2 mM SA alone or in combination with 2% CaCl2 showed lower weight loss and lower losses of chlorophyll content, vitamin C, phenolic compounds, carotenoids, flavonoids, and glucosinolates compared with the control samples. Additionally, antioxidant activity was maintained by either SA or SA + CaCl2 treatments while peroxidase activity was decreased. For higher quality and lower losses in antioxidant compounds of broccoli florets during refrigerated storage at 5 °C, SA + CaCl2 treatment could be helpful for up to 21 days.

Phytochemical Characterization and Utilization of Dried Red Beetroot (Beta vulgaris) Peel Extract in Maintaining the Quality of Nile Tilapia Fish Fillet.

Phytochemicals derived from agro-industrial waste materials could be employed as functional food additives and natural antioxidants to replace their synthetic counterparts, which are increasingly being rejected. The current study aims to assess total phenolic compound (TPC), flavonoids, betalain contents, and antiradical scavenging using DPPH and IC50% of dried red beetroot peel (DRBP) extract at different concentrations of 50, 80, 100, 150, and 200 mg/100 mL t. In addition, a characterization of phenols and flavonoids was conducted using HPLC. The second part of this study aims to utilize aqueous DRBP extract in preserving Nile Talipia fish fillet at two concentrations of 80 and 100 mg/100 mL water, compared with 200 ppm of BHT (butylated hydroxytoluene) and control at 5 °C for 10 days. The DRBP aqueous extract was found to have a high concentration of TPC (832 mg/100 g), flavonoids (234 mg/100 g) and betalains (535 mg/100 g) compounds, resulting in a potential antioxidant activity. The IC50% for the extract was detected at 80 mg/100 mL extract. DRBP aqueous extract showed an excellent preservative effect on the fish fillet. Fish fillet samples treated with DRBP extract at a concentration of 100 mg/100 mL were superior in reducing TBA (thiobarbituric acid) increase compared with other treatments at the end of cold storage. Overall, the study showed that red beetroot extracts can act as a natural preservative agent due to their significant antioxidant activity, providing healthy and safe food to consumers.

Can Grafting Manage Fusarium Wilt Disease of Cucumber and Increase Productivity under Heat Stress?

Cucumber production is considered a crucial problem under biotic and abiotic stress, particularly in arid and semi-arid zones. The current study investigated the impact of grafted cucumber plants on five cucurbit rootstocks under infection with Fusarium oxysporum f. sp. cucumerinum alone and in combination with heat stress in two different locations (i.e., Kafr El-Sheikh and Sidi Salem) during the year of 2021. The rootstock of VSS-61 F1 displayed the highest level of resistance with values 20.8 and 16.6% for wilt incidence and 79.2 and 83.4% for the wilt reduction, respectively for both locations. This rootstock showed the lowest disease severity of fusarium wilt (15.3 and 12%), and high grafting efficiency (85 and 88%), respectively in both locations. Grafting also improved plant vigor and cucumber production under heat stress (40-43 °C). The rootstocks VSS-61 F1, Ferro and Super Shintoza significantly increased the total yield of cucumber plants compared to non-grafted cucumber and the rootstock Bottle gourd in both locations. Further studies are needed on grafted plants under multiple stresses in terms of plant biological levels, including physiological, biochemical and genetic attributes.

Republication: Targeting PI3KC2ß Impairs Proliferation and Survival in Acute Leukemia, Brain Tumours and Neuroendocrine Tumours.

BACKGROUND: Eight human catalytic phosphoinositide 3-kinase (PI3K) isoforms exist which are subdivided into three classes. While class I isoforms have been well-studied in cancer, little is known about the functions of class II PI3Ks. MATERIALS AND METHODS: The expression pattern and functions of the class II PI3KC2ß isoform were investigated in a panel of tumour samples and cell lines. RESULTS: Overexpression of PI3KC2ß was found in subsets of tumours and cell lines from acute myeloid leukemia (AML), glioblastoma multiforme (GBM), medulloblastoma (MB), neuroblastoma (NB), and small cell lung cancer (SCLC). Specific pharmacological inhibitors of PI3KC2ß or RNA interference impaired proliferation of a panel of human cancer cell lines and primary cultures. Inhibition of PI3KC2ß also induced apoptosis and sensitised the cancer cells to chemotherapeutic agents. CONCLUSION: Together, these data show that PI3KC2ß contributes to proliferation and survival in AML, brain tumours and neuroendocrine tumours, and may represent a novel target in these malignancies.

Alpha Lipoic Acid as a Protective Mediator for Regulating the Defensive Responses of Wheat Plants against Sodic Alkaline Stress: Physiological, Biochemical and Molecular Aspects.

Recently, exogenous α-Lipoic acid (ALA) has been suggested to improve the tolerance of plants to a wide array of abiotic stresses. However, there is currently no definitive data on the role of ALA in wheat plants exposed to sodic alkaline stress. Therefore, this study was designed to evaluate the effects of foliar application by ALA at 0 (distilled water as control) and 20 µM on wheat seedlings grown under sodic alkaline stress (50 mM 1:1 NaHCO3 & Na2CO3; pH 9.7. Under sodic alkaline stress, exogenous ALA significantly (p ≤ 0.05) improved growth (shoot fresh and dry weight), chlorophyll (Chl) a, b and Chl a + b, while Chl a/b ratio was not affected. Moreover, leaf relative water content (RWC), total soluble sugars, carotenoids, total soluble phenols, ascorbic acid, K and Ca were significantly increased in the ALA-treated plants compared to the ALA-untreated plants. This improvement was concomitant with reducing the rate of lipid peroxidation (malondialdehyde, MDA) and H2O2. Superoxide dismutase (SOD) and ascorbate peroxidase (APX) demonstrated greater activity in the ALA-treated plants compared to the non-treated ones. Conversely, proline, catalase (CAT), guaiacol peroxidase (G-POX), Na and Na/K ratio were significantly decreased in the ALA-treated plants. Under sodic alkaline stress, the relative expression of photosystem II (D2 protein; PsbD) was significantly up-regulated in the ALA treatment (67% increase over the ALA-untreated plants); while Δ pyrroline-5-carboxylate synthase (P5CS), plasma membrane Na+/H+ antiporter protein of salt overly sensitive gene (SOS1) and tonoplast-localized Na+/H+ antiporter protein (NHX1) were down-regulated by 21, 37 and 53%, respectively, lower than the ALA-untreated plants. These results reveal that ALA may be involved in several possible mechanisms of alkalinity tolerance in wheat plants.

Paclobutrazol Improves the Quality of Tomato Seedlings to Be Resistant to Alternaria solani Blight Disease: Biochemical and Histological Perspectives.

The production and quality of tomato seedlings needs many growth factors and production requirements besides controlling the phytopathogens. Paclobutrazol (PBZ) has benefit applications in improving crop productivity under biotic stress (Alternaria solani, the causal agent of early blight disease in tomatoes). In the current study, the foliar application of PBZ, at rates of 25, 50, and 100 mg L-1, was evaluated against early blight disease in tomatoes under greenhouse conditions. The roles of PBZ to extend tomato seedling lives and handling in nurseries were also investigated by measuring different the biochemical (leaf enzymes, including catalase and peroxidase) and histological attributes of tomato seedlings. Disease assessment confirmed that PBZ enhanced the quality of tomato seedlings and induced resistance to early blight disease post inoculation, at 7, 14, and 21 days. Higher values in chlorophyll content, enzyme activities, and anatomical features of stem (cuticle thickness) and stomata (numbers and thickness) were recorded, due to applied PBZ. This may support the delay of the transplanting of tomato seedlings without damage. The reason for this extending tomato seedling life may be due to the role of PBZ treatment in producing seedlings to be greener, more compact, and have a better root system. The most obvious finding to emerge from this study is that PBZ has a distinguished impact in ameliorating biotic stress, especially of the early blight disease under greenhouse conditions. Further studies, which consider molecular variables, will be conducted to explore the role of PBZ in more detail.

Nano-biofortification of different crops to immune against COVID-19: A review.

Human health and its improvement are the main target of several studies related to medical, agricultural and industrial sciences. The human health is the primary conclusion of many studies. The improving of human health may include supplying the people with enough and safe nutrients against malnutrition to fight against multiple diseases like COVID-19. Biofortification is a process by which the edible plants can be enriched with essential nutrients for human health against malnutrition. After the great success of biofortification approach in the human struggle against malnutrition, a new biotechnological tool in enriching the crops with essential nutrients in the form of nanoparticles to supplement human diet with balanced diet is called nano-biofortification. Nano biofortification can be achieved by applying the nano particles of essential nutrients (e.g., Cu, Fe, Se and Zn) foliar or their nano-fertilizers in soils or waters. Not all essential nutrients for human nutrition can be biofortified in the nano-form using all edible plants but there are several obstacles prevent this approach. These stumbling blocks are increased due to COVID-19 and its problems including the global trade, global breakdown between countries, and global crisis of food production. The main target of this review was to evaluate the nano-biofortification process and its using against malnutrition as a new approach in the era of COVID-19. This review also opens many questions, which are needed to be answered like is nano-biofortification a promising solution against malnutrition? Is COVID-19 will increase the global crisis of malnutrition? What is the best method of applied nano-nutrients to achieve nano-biofortification? What are the challenges of nano-biofortification during and post of the COVID-19?

Nano-selenium, silicon and H2O2 boost growth and productivity of cucumber under combined salinity and heat stress.

The production of cucumber under combined salinity and heat stress is a crucial challenge facing many countries particularly in arid environments. This challenge could be controlled through exogenous foliar application of some bio-stimulants or anti-stressors. This study was carried out to investigate the management and improving cucumber production under combined salinity and heat stress. Nano-selenium (nano-Se, 25 mg L-1), silicon (Si, 200 mg L-1) and hydrogen peroxide (H2O2, 20 mmol L-1) were foliar applied on cucumber plants as anti-stress compounds. The results revealed that studied anti-stressors improved growth and productivity of cucumber grown in saline soil regardless the kind of anti-stressor under heat stress. The foliar application of nano-Se (25 mg L-1) clearly improved cucumber growth parameters (plant height and leaf area) compared to other anti-stressor and control. Foliar Si application showed the greatest impact on enzymatic antioxidant capacities among the other anti-stressor treatments. This applied rate of Si also showed the greatest increase in marketable fruit yield and yield quality (fruit firmness and total soluble solids) compared to untreated plants. These increases could be due to increasing nutrient uptake particularly N, P, K, and Mg, as well as Se (by 40.2% and 43%) in leaves and Si (by 11.2% and 22.1% in fruits) in both seasons, respectively. The potential role of Si in mitigating soil salinity under heat stress could be referred to high Si content found in leaf which regulates water losses via transpiration as well as high nutrient uptake of other nutrients (N, P, K, Mg and Se). The distinguished high K+ content found in cucumber leaves might help stressed plants to tolerate studied stresses by regulating the osmotic balance and controlling stomatal opening, which support cultivated plants to adapt to soil salinity under heat stress. Further studies are needed to be carried out concerning the different response of cultivated plants to combined stresses.

Tropomyosin receptor kinase C (TrkC) expression in medulloblastoma: relation to the molecular subgroups and impact on treatment response.

PURPOSE: High messenger RNA (mRNA) expression of the tropomyosin receptor kinase C gene (TrkC) has been associated with favorable survival in medulloblastoma patients. Untested is whether it plays a role through modulating the response to therapy or whether it might be a surrogate marker for a favorable molecular subgroup. METHODS: The medulloblastoma-derived cell line DAOY was stably transfected to overexpress TrkC (clone DAOY-TrkC) and compared to a control (clone DAOY-EV, empty vector transfected). Cell viability (MTS assay) was tested after irradiation or incubation with chemotherapeutic drugs. Neuroradiologic response to postoperative chemotherapy or craniospinal irradiation (CSI) of medulloblastoma patients aged 3-21 years with postoperative residual disease treated within the consecutive trials HIT'91/HIT2000 was compared to TrkC mRNA expression in their tumor samples. Five well-characterized independent expression-profiling studies covering together 686 medulloblastoma patients were analyzed for TrkC levels according to the molecular subgroups. RESULTS: Cell viability of DAOY-TrkC compared to DAOY-EV was not different after exposure to increasing doses of irradiation, cisplatin, etoposide, or vincristine. While TrkC mRNA expression tended to be higher in non-responders (n = 5/19) to postoperative CSI (p = 0.03, ratio 15.5, 95% CI 9-267), this was the case in responders (n = 23/43) to chemotherapy (p = 0.04, ratio 6.1, 95% CI 1.1-35), both analyzed with Mann-Whitney U test (not significant after Bonferroni adjustment). The highest TrkC mRNA levels were found in the SHH subgroup across all expression-profiling studies. CONCLUSIONS: High TrkC mRNA expression appears to be frequent in the SHH subgroup and seems not to have a major effect on therapy responsiveness in medulloblastoma patients.

Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

BACKGROUND: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. FINDINGS: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084). INTERPRETATION: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection. FUNDING: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.

Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes.

Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed 192 ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.

MYC as Therapeutic Target for Embryonal Tumors: Potential and Challenges.

The MYC family plays essential roles during brain development and their oncogenic deregulation is implicated in the formation of embryonal neural tumors such as medulloblastomas (MB) and neuroblastoma (NB). Amplification of the MYCN is the predominant marker for aggressive NB and correlates with poor prognosis, while c-MYC overexpression is a defining feature of MB subgroups inflected with aggressive biological behavior and increased likelihood of metastasis. Not surprisingly MYC has emerged as an attractive target for pediatric neural cancer therapy. However despite three decades of intensive research in MYC biology and an impressive number of 30,000 publications, inhibition of MYC as therapeutic strategy remains an elusive goal in cancer medicine. This review discusses the potential and challenges of targeting the oncogenic effects of MYC as therapeutic strategy for MYC over-expressing embryonal neural tumors where current therapies are inadequate.

Tumor-Associated CSF MicroRNAs for the Prediction and Evaluation of CNS Malignancies.

Cerebrospinal fluid (CSF) is a readily reachable body fluid that is reflective of the underlying pathological state of the central nervous system (CNS). Hence it has been targeted for biomarker discovery for a variety of neurological disorders. CSF is also the major route for seeding metastases of CNS malignancies and its analysis could be informative for diagnosis and risk stratification of brain cancers. Recently, modern high-throughput, microRNAs (miRNAs) measuring technology has enabled sensitive detection of distinct miRNAs that are bio-chemicallystable in the CSF and can distinguish between different types of CNS cancers. Owing to the fact that a CSF specimen can be obtained with relative ease, analysis of CSF miRNAs could be a promising contribution to clinical practice. In this review, we examine the current scientific knowledge on tumor associated CSF miRNAs that could guide diagnosis of different brain cancer types, or could be helpful in predicting disease progression and therapy response. Finally, we highlight their potential applications clinically as biomarkers and discuss limitations.

The Ser/Thr kinase MAP4K4 drives c-Met-induced motility and invasiveness in a cell-based model of SHH medulloblastoma.

Medulloblastoma (MB) comprises four molecularly and genetically distinct subgroups of embryonal brain tumors that develop in the cerebellum. MB mostly affects infants and children and is difficult to treat because of frequent dissemination of tumor cells within the leptomeningeal space. A potential promoter of cell dissemination is the c-Met proto-oncogene receptor tyrosine kinase, which is aberrantly expressed in many human tumors including MB. Database analysis showed that c-Met is highly expressed in the sonic hedgehog (SHH) subgroup and in a small subset of Group 3 and Group 4 MB tumors. Using a cell-based three-dimensional cell motility assay combined with live-cell imaging, we investigated whether the c-Met ligand HGF could drive dissemination of MB cells expressing high levels of c-Met, and determined downstream effector mechanisms of this process. We detected variable c-Met expression in different established human MB cell lines, and we found that in lines expressing high c-Met levels, HGF promoted cell dissemination and invasiveness. Specifically, HGF-induced c-Met activation enhanced the capability of the individual cells to migrate in a JNK-dependent manner. Additionally, we identified the Ser/Thr kinase MAP4K4 as a novel driver of c-Met-induced invasive cell dissemination. This increased invasive motility was due to MAP4K4 control of F-actin dynamics in structures required for migration and invasion. Thus, MAP4K4 couples growth factor signaling to actin cytoskeleton regulation in tumor cells, suggesting that MAP4K4 could present a promising novel target to be evaluated for treating growth factor-induced dissemination of MB tumors of different subgroups and of other human cancers.

MicroRNA signatures as biomarkers and therapeutic target for CNS embryonal tumors: the pros and the cons.

Embryonal tumors of the central nervous system represent a heterogeneous group of childhood cancers with an unknown pathogenesis; diagnosis, on the basis of histological appearance alone, is controversial and patients' response to therapy is difficult to predict. They encompass medulloblastoma, atypical teratoid/rhabdoid tumors and a group of primitive neuroectodermal tumors. All are aggressive tumors with the tendency to disseminate throughout the central nervous system. The large amount of genomic and molecular data generated over the last 5-10 years encourages optimism that new molecular targets will soon improve outcomes. Recent neurobiological studies have uncovered the key role of microRNAs (miRNAs) in embryonal tumors biology and their potential use as biomarkers is increasingly being recognized and investigated. However the successful use of microRNAs as reliable biomarkers for the detection and management of pediatric brain tumors represents a substantial challenge. This review debates the importance of miRNAs in the biology of central nervous systemembryonal tumors focusing on medulloblastoma and atypical teratoid/rhabdoid tumors and highlights the advantages as well as the limitations of their prospective application as biomarkers and candidates for molecular therapeutic targets.