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Changa Manga forest is a man-made forest in Pakistan. The soil properties of this forest serve an ideal habitat for a vast variety of entomopathogenic fungi. A number of entomopathogenic fungi were isolated from the soil samples collected from the Changa Manga Forest using Galleria bait method during this investigation. Among these isolated fungi, Aspergillus pakistanicus was found to be morphologically and phylogenetically different from closely related Aspergillus species thus described as a new species. The fungal species was identified on the basis of colony morphology; light microscopy; scanning electron microscopy and by molecular analysis. Macroscopic and microscopic comparison with other species of the respective genus along with sequencing of 18S rRNA genes confirmed its uniqueness and supports its recognition as a novel species. Its angular ornamented conidia and separate clade in the phylogenetic tree support it as a new taxa. A detailed description, microscopic images, and comparison with morphologically and phylogenetically similar species are presented. [ABSTRACT FROM AUTHOR]

ABSTRACT: Present work was focused on the removal of reactive dyes involving management of agro-waste(chickpea pods, pea pods, potato peels, onion peels and eucalyptus leaves) directly and their conversion to green biosorbents. Dye removal efficiency was monitored by UV-Visible spectrophotometer and the adsorption process was evaluated by scanning electron microscopy(SEM) as well. Maximum dye removal(99%) was obtained from chickpea and pea pods while as a natural biosrbents they remove selected dye up to 24.5% and 28.5% respectively. Continuous monitoring showed that decolorization efficiency of selected biosorbent has a direct relationship with contact time. Synergistic effect was observed between green biosorbent and chitosan. Overall findings of present work confirmed that activated carbon of chickpea and pea pods could be an effective and environment benign(green) adsorbent to remove reactive dyes from industrial effluents. [ABSTRACT FROM AUTHOR]

Green synthesis is gaining huge significance because of its environmentally harmonious nature and low cost. This is an important technique to synthesize metal oxide nanoparticles. In the current study, iron oxide nanoparticles (Fe2O3-NPs) were formulated by using Populus ciliata leaf extract and ferrous sulphate (FeSO4.7H2O). These NPs were analyzed by X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Fourier Transform Spectroscopy (FT-IR), and Energy Dispersive X-ray (EDX). The synthesized NPs were used against Gram positive and negative bacteria to find their bactericidal potential. These NPs were found active against Klebsiella pneumonia, Escherichia coli, Bacillus (B) lichenifermis and B. subtilis. B. licheniformis showed the highest antibacterial activity (zone of inhibition) up to 29.1±0.5 mm at 8 mg/mL concentration. This study concludes that Populus ciliata conjugated Iron oxides NPs could be used a potential antibacterial agent. [ABSTRACT FROM AUTHOR]

Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas., (© 2024 UICC.)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy of the dendritic cell lineage that affects patients of all ages, though the incidence appears to be highest in patients over the age of 60 years. Diagnosis is based on the presence of plasmacytoid dendritic cell precursors expressing CD123, the interleukin-3 (IL-3) receptor alpha, and a distinct histologic appearance. Timely diagnosis remains a challenge, due to lack of disease awareness and overlapping biologic and clinical features with other hematologic malignancies. Prognosis is poor with a median overall survival of 8 to 14 months, irrespective of disease presentation pattern. Historically, the principal treatment was remission induction therapy followed by a stem cell transplant (SCT) in eligible patients. However, bridging to SCT is often not achieved with induction chemotherapy regimens. The discovery that CD123 is universally expressed in BPDCN and is considered to have a pathogenetic role in its development paved the way for the successful introduction of tagraxofusp, a recombinant human IL-3 fused to a truncated diphtheria toxin payload, as an initial treatment for BPDCN. Tagraxofusp was approved in 2018 by the United States Food and Drug Administration for the treatment of patients aged 2 years and older with newly diagnosed and relapsed/refractory BPDCN, and by the European Medicines Agency in 2021 for first-line treatment of adults. The advent of tagraxofusp has opened a new era of precision oncology in the treatment of BPDCN. Herein, we present an overview of BPDCN biology, its diagnosis, and treatment options, illustrated by clinical cases., Competing Interests: Disclosures Naveen Pemmaraju: Pacylex Pharmaceuticals, Astellas Pharma US, ImmunoGen, Inc, Bristol-Myers Squibb Co., Cimeio Therapeutics AG, EUSA Pharma, Menarini Group, Blueprint Medicines, CTI BioPharma, ClearView Healthcare Partners, Novartis Pharmaceutical, Neopharm, Celgene Corporation, AbbVie Pharmaceuticals, Pharma Essentia, Curio Science, DAVA Oncology, Imedex, Intellisphere, CancerNet, Harborside Press, Aptitude Health, Medscape, Magdalen Medical Publishing, OncLive, CareDx, Patient Power, Physician Education Resource (PER): Consultancy/Scientific Advisory Board/Speaking; United States Department of Defense, National Institute of Health/National Cancer Institute (NIH/NCI): Research (Grant); Affymetrix: Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors/Management; ASH Committee on Communications, ASCO Cancer.Net Editorial Board: Leadership; Karger Publishers: Licences; HemOnc Times/Oncology Times: Uncompensated. Eric Deconinck: Stemline Therapeutics: Consultancy, honoraria; ImmunoGen: Consultancy, honoraria; Chugai: Research funding; Novartis: Research funding. Priyanka Mehta: Pfizer, AbbVie, Celgene, Daiichi Sankyo, Jazz Pharmaceuticals, Stemline Therapeutics: Advisory board/honoraria. Irwin Walker: Sanofi: Research funding. Marco Herling: AbbVie, BeiGene, Jazz, Janssen, Stemline Therapeutics, Takeda: Consultancy; Mundipharma EDO, Janpix, Novartis, Roche: Funding of preclinical research. Francine Garnache-Ottou: Stemline Therapeutics, LFB: Consultancy. Nadia Gabarin: Declarations of interest: none. Clinton Campbell: Declarations of interest: none. Johannes Duell: Stemline: Lecturing Yakir Moshe: AbbVie: Advisory board, research funding, speaker; Astellas, Medison: Advisory board, speaker; Gilead, Novartis, Stemline: Advisory board Tariq Mughal: Informa Publishing, Oxford University Press: Royalties. Consultant: Stemline Therapeutics Inc, New York, NY, USA. Mohamad Mohty: Jazz Pharmaceuticals: Research funding, honoraria. Emanuele Angelucci: Menarini/Stemline, Novartis: Honoraria; bluebird bio, Glaxo, Gilead, Roche: Board of Directors or advisory committees; Vifor Pharma, BMS, Vertex Inc.: Participation DMC., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: CD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the antiapoptotic molecule BCL-2. Here, we report a phase 1b study in 56 adults with CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining TAG with AZA in AML/MDS, and subsequently TAG, AZA, and the BCL-2 inhibitor venetoclax (VEN) in AML. Adverse events with 3-day TAG dosing were as expected, without indication of increased toxicity of TAG or AZA+/-VEN in combination. The recommended phase 2 dose of TAG was 12 μg/kg/day for 3 days, with 7-day AZA +/- 21-day VEN. In an expansion cohort of 26 patients (median age 71) with previously untreated European LeukemiaNet adverse-risk AML (50% TP53 mutated), triplet TAG-AZA-VEN induced response in 69% (n=18/26; 39% complete remission [CR], 19% complete remission with incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 patients with TP53 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi = 2, MLFS = 1). Twelve of 17 (71%) tested responders had no flow measurable residual disease. Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations. The study was registered on ClinicalTrials.gov as #NCT03113643., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The main purpose was to elucidate the potential anti-aging impact of sericin, due to its anti-oxidant potential in D-galactose induced mice model. To induce natural aging in mice, a solution of 0.9 % saline containing D-galactose (250 mg/kg b.w.) was injected intraperitoneally for a period of 60 days. In this experiment, 56 male mice were arbitrarily categorized into 8 groups (1: control; 2: D-Galactose (250 mg/kg b.w), Group 3: Sericin (150 mg/kg b.w), Group 4: Metformin (150 mg/kg), Group 5: sericin (P), Group 6; sericin (T), Group 7; Met (P), Group 8; Met (T). The level of Glutathione reductase (2.1 ± 0.2 µmol/L), CAT (0.5 ± 0.0 mmol/mL), Superoxide dismutase (65.4 ± 1.7 U/mL), GSHPx (69.2 ± 1.7 U/l), T3 (3.1 ± 0.7 ng/mL), IL-2 (68.8 ± 1.5 Pg/mL), IL-4 (71.4 ± 4.2 Pg/mL), IgG (0.6 ± 0.0 mg/mL) and IgM (0.6 ± 0.0 mg/mL) were significantly (P < 0.05) decreased whereas the cortisol (22.0 ± 1.5 µg/L), and total cholesterol (229.4 ± 4.2 mg/dL)) were significantly elevated in D-galactose-treated /aged mice. However, administration of sericin significantly reduced the level of oxidative stress in aged mice. Real-time qPCR data showed that the level of telomere length- gene TERT significantly downregulated (10.43 ± 0.1) in the D-Gal-treated mice with respect to control (21.97 ± 0.5). The highest significant upregulation was found in the TERT gene when D-Gal-induced aged mice were treated with sericin (24.74 ± 0.3). Our outcomes showed that sericin gradually recovered the organ indices, and improved the histological changes of the brain, kidney, and liver in D-Gal-induced aging mice. Therefore, concluded that sericin possesses anti-aging effect against D-Gal-induced aging by diminishing oxidative stress, restoring the immune system, and enhancing the antioxidant defense system., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Hexavalent chromium induces oxidative stress in the liver and kidney. Therefore an in vivo study was designed to investigate the modulatory effect of biosynthesized AgNP against Cr (VI) induced hepatotoxicity and nephrotoxicity. The organs index, serum level of ALT, AST, ALP, MDA, total protein and creatinine were measured. The histopathology and micrometry of the liver and kidney were examined. The liver index was significantly increased (0.098 ± 0.13 g) with slight increase in kidney index in Cr exposed group. The serum level of ALT (163.0 ± 5.5 U/L), AST (484.0 ± 10.7 U/L), ALP (337.6 ± 9.6 U/L), MDA (641.2 ± 29.2 U/L), and creatinine (2.9 ± 0.2 mg/dL) were significantly increased ( P  ≤ 0.05) with significant decrease in total protein level (2.9 ± 0.2 g/dL) ( P  ≤ 0.05) in chromium treated group. In histopathology, distorted hepatic cords, necrosis, damaged glomerulus and Bowman's capsule were observed. Micrometric studies of the liver and kidney showed significant increase in size of hepatocytes (1188.2 ± 467.7 µ 2 ) and their nuclei (456.4 ± 206.7 µ 2 ), ACSA of Bowman's capsule (11835.5 ± 336.7 µ 2 ) and glomerulus (9051.8 ± 249.8 µ 2) in Cr (VI) treated group. The size of brush border (10.1 ± 3.0 µ) was significantly reduced in Cr (VI) treated group however the ACSA of lumen was not significantly changed. With the administration of NSSE and Nigella sativa AgNPs, decreased the oxidative damage caused by Cr (V)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Hexavalent chromium, toxic heavy metal, among the top-rated environmental contaminants, is declared a potent endocrine disruptor in humans and animals. The present study was planned to find harmful effects on the reproductive system caused by Cr (VI) and the ameliorative effect of Nigella sativa and Nigella sativa -mediated AgNP on male mice ( Mus musculus ). In the present study, known infertility medicine, clomiphene citrate is also used as a positive control. The main objective of the present study was to assess the ameliorative potential of oral administration of a dose of 50 mg/kg BW clomiphene citrate (control), AgNP via chemical synthesis, Nigella sativa seed extract, and Nigella sativa -mediated AgNP against the Cr (VI) at the dose of 1.5 mg/kg BW from K 2 Cr 2 O 7 orally induced toxicity over eight weeks on the reproductive performance of male albino mice. Nigella sativa mediated AgNPs were characterized by UV, SEM, FTIR, and XRD. The histological analysis, smear study, antioxidant capacity test, and hormone analysis were conducted by blood samples of albino mice. Cr exposed groups showed a significant decrease in sperm head breadth (5.29 ± 0.54 µ) and length (19.54 ± 1.18 µ), middle piece length, tail length, LH (1.65 ± 0.15 ng/mL), testosterone (2.63 ± 0.29 ng/mL), SOD (61.40 ± 2.48 mmol/mL), CAT (87.40 ± 6.01 mmol/mL), GSH (1.54 ± 0.09 µmol/mL), and no of spermatogonia (1.22 ± 0.25), and spermatocytes (2.33 ± 0.943). However, FSH level (160.00 ± 4.98 ng/mL), seminiferous tubule CSA (1094.69 ± 49.76 mm 2 ), size of spermatogonia (41.30 ± 1.24 µ), and spermatocytes (26.07 ± 1.34 µ) were significantly increased. Administration of Nigella sativa and Nigella sativa -mediated AgNPs reduced the toxicity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Antioxidants are materials that scavenge or remove free radicals from living systems. The oxidation process ends in the production of free radicals. These free radicals are the chief birthplace of cancerous cells. Antioxidizing agents remove free radical intermediates by terminating oxidation processes by being oxidized themselves. On the other hand, infectious diseases affect the world on a large scale. To fight these diseases several synthetic compounds have been used. Plant based medications play important role in this regard. So, the current research aimed to investigate the antibacterial and antioxidant effect of Berberis lycium Royle root bark (BLR) extract. Berberis lycium Royle was used for phytochemical analysis and also as antimicrobial and antioxidant agents. The antimicrobial activity was evaluated by the agar well diffusion method. Current study revealed that BLR was rich in phytochemicals and toxic against tested pathogenic bacteria. BLR showed the highest activity against S. pyogenes (13.3±0.8 mm). The lowest antibacterial activity was reported against E. coli (0±0 mm). In case of minimum inhibitory concentration, it was observed that BLR with 10 μg/mL concentration showed the highest activity while 2.5 μg/mL of BLR showed the least inhibitory activity. The highest In vitro antioxidant activity was recorded as 65% at 100 µg/mL. In case of in vivo antioxidant activity level of CAT, GSH and SOD were decreased while that of MDA was enhanced in groups treated with CCl4 as compared to the control group. BLR extract treatment reversed all these changes significantly. Current results indicate that BLR is effective against bacterial pathogens and also has antioxidant potential.

Glioblastoma (GB), an aggressive primary tumor of the central nervous system, represents about 60% of all adult primary brain tumors. It is notorious for its extremely low (~5%) 5-year survival rate which signals the unsatisfactory results of the standard protocol for GB therapy. This issue has become, over time, the impetus for the discipline of bringing novel therapeutics to the surface and challenging them so they can be improved. The cell-based approach in treating GB found its way to clinical trials thanks to a marvelous number of preclinical studies that probed various types of cells aiming to combat GB and increase the survival rate. In this review, we aimed to summarize and discuss the up-to-date preclinical studies that utilized stem cells or immune cells to treat GB. Likewise, we tried to summarize the most recent clinical trials using both cell categories to treat or prevent recurrence of GB in patients. As with any other therapeutics, cell-based therapy in GB is still hampered by many drawbacks. Therefore, we highlighted several novel techniques, such as the use of biomaterials, scaffolds, nanoparticles, or cells in the 3D context that may depict a promising future when combined with the cell-based approach.

Now a day's multidrug resistance phenomenon has become the main cause for concern and there has been an inadequate achievement in the development of novel antibiotics to treat the bacterial infections. Therefore, there is an unmet need to search for novel adjuvant. Vitamin C is one such promising adjuvant. The present study was aimed to elucidate the antibacterial effect of vitamin C at various temperatures (4°C, 37°C and 50°C) and pH (3, 8, and 11), against Gram-positive and Gram-negative bacteria at various concentrations (5-20 mg/ml) through agar well diffusion method. Growth inhibition of all bacterial strains by vitamin C was concentration-dependent. Vitamin C significantly inhibited the growth of Gram-positive bacteria: Bacillus licheniformis (25.3 ± 0.9 mm), Staphylococcus aureus (22.0 ± 0.6 mm), Bacillus subtilis (19.3 ± 0.3 mm) and Gram-negative bacteria: Proteus mirabilis (27.67 ± 0.882 mm), Klebsiella pneumoniae (21.33±0.9 mm), Pseudomonas aeruginosa (18.0 ± 1.5 mm) and Escherichia coli (18.3 ± 0.3 mm). The stability of vitamin C was observed at various pH values and various temperatures. Vitamin C showed significant antibacterial activity at acidic pH against all bacterial strains. Vitamin C remained the stable at different temperatures. It was concluded that vitamin C is an effective and safe antibacterial agent that can be used in the future as an adjunct treatment option to combat infections in humans.

During the past few years, our understanding of molecular mechanisms and cellular interactions relevant to malignant blood cell disorders has improved substantially. New insights include a detailed knowledge about disease-initiating exogenous factors, endogenous (genetic, somatic, epigenetic) elicitors or facilitators of disease evolution, and drug actions and interactions that underlie efficacy and adverse event profiles in defined cohorts of patients. As a result, precision medicine and personalized medicine are rapidly growing new disciplines that support the clinician in making the correct diagnosis, in predicting outcomes, and in optimally selecting patients for interventional therapies. In addition, precision medicine tools are greatly facilitating the development of new drugs, therapeutic approaches, and new multiparametric prognostic scoring models. However, although the emerging roles of precision medicine and personalized medicine in hematology and oncology are clearly visible, several questions remain. For example, it remains unknown how precision medicine tools can be implemented in healthcare systems and whether all possible approaches are also affordable. In addition, there is a need to define terminologies and to relate these to specific and context-related tools and strategies in basic and applied science. To discuss these issues, a working conference was organized in September 2019. The outcomes of this conference are summarized herein and include a proposal for definitions, terminologies, and applications of precision and personalized medicine concepts and tools in hematologic neoplasms. We also provide proposals aimed at reducing costs, thereby making these applications affordable in daily practice., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that preferentially affects the spinal cord and optic nerve. Most patients with NMOSD experience severe relapses that lead to permanent neurologic disability; therefore, limiting frequency and severity of these attacks is the primary goal of disease management. Currently, patients are treated with immunosuppressants. Interleukin-6 (IL-6) is a pleiotropic cytokine that is significantly elevated in the serum and the CSF of patients with NMOSD. IL-6 may have multiple roles in NMOSD pathophysiology by promoting plasmablast survival, stimulating the production of antibodies against aquaporin-4, disrupting blood-brain barrier integrity and functionality, and enhancing proinflammatory T-lymphocyte differentiation and activation. Case series have shown decreased relapse rates following IL-6 receptor (IL-6R) blockade in patients with NMOSD, and 2 recent phase 3 randomized controlled trials confirmed that IL-6R inhibition reduces the risk of relapses in NMOSD. As such, inhibition of IL-6 activity represents a promising emerging therapy for the management of NMOSD manifestations. In this review, we summarize the role of IL-6 in the context of NMOSD., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Sustainability assessments have revealed that integration of CO 2 from coal-fired flue gas with microalgae cultivation systems could reduce greenhouse gas emissions. The technical goal of this integration is to utilize exhaust from coal power plants to enhance microalgae cultivation processes by capturing and recycling of carbon dioxide from a more toxic to a less toxic form. However, heavy metals are also introduced along with CO2 to the cultivation system which could contaminate biomass and have deleterious effects on products derived from such systems. The present study aimed at shedding some light on capability of microalgae to sustain their diversity and propagate them under different CO 2 concentrations from coal-fired flue gas. Mixed microalgal culture was grown in nutrient rich medium and heavy metals (Al, Cu, Fe, Mn and Zn) are expected to be introduced from flue gas. Three concentrations (1%, 3% and 5.5%) of CO 2 were evaluated (reference concentrations from flue gas). Comparative studies were carried out by flue gas and control systems in photobioreactors. Under the 3% CO 2 (30% flue gas), the highest fraction of B, Mn and Zn were found to be internalized by the cells (46.8 ±9.45 gL-1, 253.66 ± 40.62 gL-1 and 355.5 ±50.69 gL-1 respectively) during their cultivation period into biomass. Hence, microalgae may offer solution to two major challenges: providing potential biofuel feedstock for energy security and reducing heavy metal pollution to the air., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Genomic analyses of chronic lymphocytic leukemia (CLL) identified somatic mutations and associations of clonal diversity with adverse outcomes. Clonal evolution likely has therapeutic implications but its dynamic is less well studied. We studied clonal composition and prognostic value of seven recurrently mutated driver genes using targeted next-generation sequencing in 643 CLL patients and found higher frequencies of mutations in TP53 (35 vs. 12%, p < 0.001) and SF3B1 (20 vs. 11%, p < 0.05) and increased number of (sub)clonal (p < 0.0001) mutations in treated patients. We next performed an in-depth evaluation of clonal evolution on untreated CLL patients (50 "progressors" and 17 matched "non-progressors") using a 404 gene-sequencing panel and identified novel mutated genes such as AXIN1, SDHA, SUZ12, and FOXO3. Progressors carried more mutations at initial presentation (2.5 vs. 1, p < 0.0001). Mutations in specific genes were associated with increased (SF3B1, ATM, and FBXW7) or decreased progression risk (AXIN1 and MYD88). Mutations affecting specific signaling pathways, such as Notch and MAP kinase pathway were enriched in progressive relative to non-progressive patients. These data extend earlier findings that specific genomic alterations and diversity of subclones are associated with disease progression and persistence of disease in CLL and identify novel recurrently mutated genes and associated outcomes.

Chromosomal rearrangements that result in oncogenic kinase activation are present in many solid and hematological malignancies, but none have been reported in multiple myeloma (MM). Here we analyzed 1421 samples from 958 myeloma patients using a targeted assay and detected fusion genes in 1.5% of patients. These fusion genes were in-frame and the majority of them contained kinase domains from either receptor tyrosine kinases (ALK, ROS1, NTRK3, and FGFR1) or cytoplasmic kinases (BRAF, MAP3K14, and MAPK14), which would result in the activation of MEK/ERK, NF-κB, or inflammatory signaling pathways. Fusion genes were present in smoldering MM, newly diagnosed MM, and relapse patient samples indicating they are not solely late events. Most fusion genes were subclonal in nature, but one EML4-ALK fusion was clonal indicating it is a driver of disease pathogenesis. Samples with fusions of receptor tyrosine kinases were not found in conjunction with clonal Ras/Raf mutations indicating a parallel mechanism of MEK/ERK pathway activation. Fusion genes involving MAP3K14 (NIK), which regulates the NF-κB pathway, were detected as were t(14;17) rearrangements involving NIK in 2% of MM samples. Activation of kinases in myeloma through rearrangements presents an opportunity to use treatments existing in other cancers.

Genomic profiling of circulating tumor DNA derived from cell-free DNA (cfDNA) in blood can provide a noninvasive method for detecting genomic biomarkers to guide clinical decision making for cancer patients. We developed a hybrid capture-based next-generation sequencing assay for genomic profiling of circulating tumor DNA from blood (FoundationACT). High-sequencing coverage and molecular barcode-based error detection enabled accurate detection of genomic alterations, including short variants (base substitutions, short insertions/deletions) and genomic re-arrangements at low allele frequencies (AFs), and copy number amplifications. Analytical validation was performed on 2666 reference alterations. The assay achieved >99% overall sensitivity (95% CI, 99.1%-99.4%) for short variants at AF >0.5%, >95% sensitivity (95% CI, 94.2%-95.7%) for AF 0.25% to 0.5%, and 70% sensitivity (95% CI, 68.2%-71.5%) for AF 0.125% to 0.25%. No false positives were detected in 62 samples from healthy volunteers. Genomic alterations detected by FoundationACT demonstrated high concordance with orthogonal assays run on the same clinical cfDNA samples. In 860 routine clinical FoundationACT cases, genomic alterations were detected in cfDNA at comparable frequencies to tissue; for the subset of cases with temporally matched tissue and blood samples, 75% of genomic alterations and 83% of short variant mutations detected in tissue were also detected in cfDNA. On the basis of analytical validation results, FoundationACT has been approved for use in our Clinical Laboratory Improvement Amendments-certified/College of American Pathologists-accredited/New York State-approved laboratory., (Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD), which can be detected by evaluating genome-wide loss of heterozygosity (LOH). Multiple myeloma (MM) is a genetically unstable tumor and we hypothesized that HRD-related LOH (HRD-LOH) could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Using results from targeted next-generation sequencing studies (FoundationOne ® Heme), we analyzed HRD-LOH in patients at all disease stages (MGUS (n = 7), smoldering MM (SMM, n = 30), newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64), and relapsed MM (RLMM, n = 234)) using an algorithm to identify HRD-LOH segments. We demonstrated HRD-LOH in MM samples, increasing as disease progresses. The extent of genomic HRD-LOH correlated with high-risk disease markers. Outcome of RLMM patients, the biggest clinical group, was analyzed and patients with HRD-LOH above the third quartile (≥5% HRD-LOH) had significantly worse progression-free and overall survival than those with lower levels (p < 0.001). Mutations in key homologous recombination genes account for some, but not all, of the cases with an excess of HRD-LOH. These data support the further evaluation of PARP inhibitors in MM patients, particularly in the relapsed setting with a high unmet need for new treatments.

We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma). Median number of GAs per case was 6, with 97% of patients harboring at least one alteration. Recurrent GAs were detected in genes with established roles in DLBCL pathogenesis (e.g. MYD88, CREBBP, CD79B, EZH2), as well as notable differences compared to prior studies such as inactivating mutations in TET2 (5%). Less common GAs identified potential targets for approved or investigational therapies, including BRAF, CD274 (PD-L1), IDH2, and JAK1/2. TP53 mutations were more frequently observed in relapsed/refractory DLBCL, and predicted for lack of response to first-line chemotherapy, identifying a subset of patients that could be prioritized for novel therapies. Overall, 90% (n = 169) of the patients harbored a GA which could be explored for therapeutic intervention, with 54% (n = 107) harboring more than one putative target.

Large scale comprehensive genomic profiling (CGP) has led to an improved understanding of oncogenic mutations in acute myeloid leukemia (AML), as well as identification of alterations that can serve as targets for potential therapeutic intervention. We sought to gain insight into age-associated variants in AML through comparison of extensive DNA and RNA-based GP results from pediatric and adult AML. Sequencing of 932 AML specimens (179 pediatric (age 0-18), 753 adult (age ≥ 19)) from diagnostic, relapsed, and refractory times points was performed. Comprehensive DNA (405 genes) and RNA (265) sequencing to identify a variety of structural and short variants was performed. We found that structural variants were highly prevalent in the pediatric cohort compared to the adult cohort (57% vs. 30%; p < 0.001), with certain structural variants detected only in the pediatric cohort. Fusions were the most common structural variant and were highly prevalent in AML in very young children occurring in 68% of children < 2 years of age. We observed an inverse trend in the prevalence of fusions compared to the average number of mutations per patient. In contrast to pediatric AML, adult AML was marked by short variants and multiple mutations per patient. Mutations that were common in adult AML were much less common in the adolescent and young adult cohort and were rare or absent in the pediatric cohort. Clinical CGP demonstrates the biologic differences in pediatric vs. adult AML that have significant therapeutic impacts on prognosis, therapeutic allocation, disease monitoring, and the use of more targeted therapies., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest in this article.

Increasing incidents of colorectal cancer have shifted researchers' attention to the production and improvement of anti-cancer drugs by the scientific investigation of vast pool of synthetic, biological and natural products. Thymoquinone and thymohydroquinone are considered the ideal compounds for the cancer therapy as they are economically and environmental friendly and have less toxicity level to the survival and diseased model up to increased dosage level. For colorectal cancer, researches are shifting towards the oral drug delivery instead of injection, as administering drugs through oral route shows maximum absorption of drugs, improves patient life quality and is cost-effective. Naturally occurring polysaccharides as oral drug carriers, such as pectin, have the ability to break down completely in colon, making it suitable for targeted drug delivery against cancer cells. Pectin with polymeric base is an efficient nano drug carrier. The current study reviews the delivery of thymoquinone/thymohydroquinone through pectin nano carriers to treat colorectal cancer.

Castleman disease (CD) is a rare lymphoproliferative disorder subclassified as unicentric CD (UCD) or multicentric CD (MCD) based on clinical features and the distribution of enlarged lymph nodes with characteristic histopathology. MCD can be further subtyped based on human herpes virus 8 (HHV8) infection into HHV8-associated MCD, HHV8 - /idiopathic MCD (iMCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS)-associated MCD. In a subset of cases of UCD, an associated follicular dendritic cell sarcoma (FDCS) may be seen. Although numerous reports of the clinical and histologic features of UCD, MCD, and FDCS exist, an understanding of the genetic and epigenetic landscape of these rare diseases is lacking. Given this paucity of knowledge, we analyzed 15 cases of UCD and 3 cases of iMCD by targeted next-generation sequencing (NGS; 405 genes) and 3 cases of FDCS associated with UCD hyaline vascular variant (UCD-HVV) by whole-exome sequencing. Common amplifications of ETS1 , PTPN6 , and TGFBR2 were seen in 1 iMCD and 1 UCD case; the iMCD case also had a somatic DNMT3A L295Q mutation. This iMCD patient also showed clinicopathologic features consistent with a specific subtype known as Castleman-Kojima disease (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly [TAFRO] clinical subtype). Additionally, 1 case of UCD-HVV showed amplification of the cluster of histone genes on chromosome 6p. FDCS associated with UCD-HVV showed mutations and copy number changes in known oncogenes, tumor suppressors, and chromatin structural-remodeling proteins., (© 2018 by The American Society of Hematology.)