Pediatric lymphoproliferative disorders associated with inborn errors of immunity.

Both non-malignant and malignant lymphoproliferative disorders (LPD) are commonly seen in patients with inborn errors of immunity (IEI), which may be the presenting manifestations or may develop during the IEI disease course. Here we review the clinical, histopathological, and molecular features of benign and malignant LPD associated with IEI and recognize the diagnostic challenges.

An investigation of germline variants of HAVCR2 in subcutaneous panniculitis-like T-cell lymphoma and related lesions in a North American population.

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Pediatric cutaneous T-cell neoplasm and mimics with gamma-delta expression: Not always aggressive.

Pediatric cutaneous T-cell lymphoma with γδ immunophenotype is extremely rare. Only a few cases of γδ T-cell neoplasm have been reported in the literature, and therefore little is known whether γδ T-cell neoplasms in children are distinct from their adult counterparts with respect to the clinicopathological presentation, behavior, and prognosis. In this study, we demonstrate three unique pediatric cutaneous T-cell neoplasm and mimics with increased γδ T cells. All cases showed an indolent clinical course.

Myeloid sarcoma in a newborn: A rare manifestation of congenital acute myeloid leukemia.

Cutaneous myeloid sarcoma is rarely present prior to the diagnosis of congenital acute myeloid leukemia (AML); the former is typically diagnosed with or after the leukemia. We report a 2-day-old male born with multiple cutaneous red to violaceous nodules. Histopathologic and immunohistochemistry findings from a skin nodule were suspicious for myeloid sarcoma. Bone marrow biopsy was initially negative for aberrant blasts; however, at age 4 months, AML with a KMT2A gene rearrangement was identified via bone marrow biopsy.

Gut microbiota induces DNA methylation via SCFAs predisposing obesity-prone individuals to diabetes.

Obesity-prone (OP) individuals have a significant predisposition to obesity and diabetes. Previously, we have found that OP individuals, despite being normal in weight and BMI, have already exhibited diabetes-related DNA methylation signatures. However, the underlying mechanisms remain obscure. Here we determined the effects of gut microbiota on DNA methylation and investigated the underlying mechanism from microbial-derived short-chain fatty acids (SCFAs). Diabetes-related DNA methylation loci were screened and validated in a new OP cohort. Moreover, the OP group was revealed to have distinct gut microbiota compositions, and fecal microbiota transplantation (FMT) demonstrated the role of gut microbiota in inducing diabetes-related DNA methylations and glucolipid disorders. UPLC-ESI-MS/MS analysis indicated a significantly lower level of total fecal SCFAs in the OP group. The gut microbiota from OP subjects yielded markedly decreased total SCFAs, while notably enriched propionate. Additionally, propionate was also identified by variable importance in projection (VIP) score as the most symbolic SCFAs of the OP group. Further cellular experiments verified that propionate could induce hypermethylation at locus cg26345888 and subsequently inhibit the expression of the target gene DAB1, which was crucially associated with clinical vitamin D deficiency and thus may affect the development and progression of diabetes. In conclusion, our study revealed that gut microbiota-derived propionate induces specific DNA methylation, thus predisposing OP individuals to diabetes. The findings partially illuminate the mechanisms of diabetes susceptibility in OP populations, implying gut microbiota and SCFAs may serve as promising targets both for clinical treatment and medication development of diabetes.

Green Phellodendri Chinensis Cortex-based carbon dots for ameliorating imiquimod-induced psoriasis-like inflammation in mice.

BACKGROUND: Carbon dots (CDs) with multifaceted advantages have provided hope for development brand-new nanodrug for treating thorny diseases. This study developed a green and simple calcination method to prepare novel CDs as promising drug for psoriasis treatment. The as-prepared CDs using Phellodendri Chinensis Cortex (PCC) as sole precursor were characterized by a series of methods, mainly including electron microscopy, optical technology and X-ray photoelectron spectroscopy (XPS). RESULTS: Results displayed that fluorescence (Quantum yield = 5.63%) and nontoxic PCC-based CDs (PCC-CDs) with abundant chemical groups exhibited solubility and tiny sizes at average of (1.93 ± 0.53) nm, which may be beneficial for its inherent biological activity. Moreover, by using the typical imiquimod (IMQ)-induced psoriasis-like skin mouse model, we firstly demonstrated the pronounced anti-psoriasis activity of as-prepared PCC-CDs on ameliorating the appearance, psoriasis area and severity index (PASI) scores as well as histopathological morphology of both back skin tissues and right ears in IMQ-induced mouse. Further potential mechanisms behind the anti-psoriasis activities may be related to suppress M1 polarization and relatively promote M2 polarization of macrophage both in vitro and in vivo. CONCLUSION: These results suggested that PCC-CDs have potential to be an anti-psoriasis candidate for clinical applications to treat psoriasis, which not only provided an evidence for further broadening the biological application of CDs, but also provided a potential hope for application nanodrugs to treat thorny diseases.

The neuroprotective effect of pretreatment with carbon dots from Crinis Carbonisatus (carbonized human hair) against cerebral ischemia reperfusion injury.

BACKGROUND: Cerebral infarction and cerebral hemorrhage, also known as "stroke", is one of the leading cause of death. At present, there is no real specific medicine for stroke. Crinis Carbonisatus (named Xue-yu-tan in Chinese), produced from carbonized hair of healthy human, and has been widely applied to relieve pain and treat epilepsy, stroke and other diseases in China for thousands of years. RESULTS: In this work, a new species of carbon dots derived from Crinis Carbonisatus (CrCi-CDs) were separated and identified. And the neuroprotective effect of carbon dots from CrCi were evaluated using the middle cerebral artery occlusion (MCAO) model. Neurological deficit score and infarction volume was assessed, evans blue content of ischemic hemispheres was measured, the concentrations of inflammatory factors, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) in the cortex were measured, and the levels of neurotransmitters in the brain were determined. Preconditioning of CrCi-CDs significantly reduced ischemic lesion volume and blood-brain-barrier (BBB) permeability, improved neurologic deficits, decreased the level of TNF-α and IL-6 in MCAO rats, inhibited excitatory neurotransmitters aspartate (Asp) and glutamate (Glu), and increased the level of 5-hydroxytryptamine (5-HT). The RNA-Sequencing results reveal that further potential mechanisms behind the activities may be related to the anti-inflammation effects and inhibition of neuroexcitatory toxicity. CONCLUSION: CrCi-CDs performs neuroprotective effect on cerebral ischemia and reperfusion injury, and the mechanisms may correlate with its anti-inflammatory action, which suggested that CrCi-CDs have potential value in clinical therapy on the acute apoplexy cases in combination with thrombolytic drugs.

Novel Carbon Dots Derived from Glycyrrhizae Radix et Rhizoma and Their Anti-Gastric Ulcer Effect.

Glycyrrhizae Radix et Rhizoma (GRR) is one of the commonly used traditional Chinese medicines in clinical practice, which has been applied to treat digestive system diseases for hundreds of years. GRR is preferred for anti-gastric ulcer, however, the main active compounds are still unknown. In this study, GRR was used as precursor to synthesize carbon dots (CDs) by a environment-friendly one-step pyrolysis process. GRR-CDs were characterized by using transmission electron microscopy, high-resolution TEM, fourier transform infrared, ultraviolet-visible and fluorescence spectroscopy, X-ray photoelectron spectroscopy, X-ray diffraction and high-performance liquid chromatography. In addition, cellular toxicity of GRR-CDs was studied by using CCK-8 in RAW264.7 cells, and the anti-gastric ulcer activity was evaluated and confirmed using mice model of acute alcoholic gastric ulcer. The experiment confirmed that GRR-CDs were the spherical structure with a large number of active groups on the surface and their particle size ranged from 2 to 10 nm. GRR-CDs had no toxicity to RAW264.7 cells at concentration of 19.5 to 5000 µg/mL and could reduce the oxidative damage of gastric mucosa and tissues caused by alcohol, as demonstrated by restoring expression of malondialdehyde, superoxide dismutase and nitric oxide in serum and tissue of mice. The results indicated the explicit anti-ulcer activity of GRR-CDs, which provided a new insights for the research on effective material basis of GRR.

Haemostatic Nanoparticles-Derived Bioactivity of from Selaginella tamariscina Carbonisata.

High-temperature carbonisation is used to prepare many traditional Chinese medicine charcoal drugs, but the bioactive haemostatic substances of these medicines and their mechanisms are still unknown. This study developed and evaluated nanoparticles (NPs) derived from Selaginella pulvinate Carbonisata (STC) for the first time. The haemostatic effect of STC-NPs prepared at 300, 350, and 400 °C were investigated in mouse tail amputation and liver scratch experiments. STC-NPs obtained at 400 °C had the strongest haemostatic effect, and were accordingly characterised by ultraviolet-visible spectroscopy, fluorescence spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, high resolution transmission electron microscopy, X-ray diffractometry, and X-ray photoelectron spectroscopy. STC-NPs averaged 1.4-2.8 nm and exhibited a quantum yield of 6.06% at a maximum excitation wavelength of 332 nm and emission at 432 nm. STC-NPs displayed low toxicity against mouse monocyte macrophage RAW 264.7 cells by CCK-8 assay, and STC-NP treatment significantly shortened bleeding time in rat and mouse models. Coagulation assays showed that the haemostatic effects of STC-NPs were related to improving the fibrinogen and platelet contents, as well as decreasing the prothrombin time that resulted from stimulating extrinsic blood coagulation and activating the fibrinogen system. The STC-NPs had remarkable haemostatic effects in the tail amputation and liver scratch models; these effects may be associated with the exogenous coagulation pathway and activation of the brinogen system, according to the evaluation of the mouse coagulation parameters. This novel evaluation supports the material basis of STC use in traditional Chinese medicine, and this article is worthy of study by authors of clinical pharmacy.

Peripheral blood flow cytometry for the diagnosis of pediatric acute leukemia: Highly reliable with rare exceptions.

BACKGROUND: Recent data have demonstrated the high sensitivity and specificity of peripheral blood flow cytometry (PBFC) for the diagnosis of pediatric leukemia; however, diagnostically significant immunophenotypic discrepancies between PBFC and bone marrow (BM) evaluation, which result in different lineage assignment and treatment protocols, can rarely occur. Here, we sought to further characterize the performance of PBFC for pediatric leukemia and highlight the exceptions when PBFC can result in misdiagnosis. METHODS: An institutional database was searched between 2012 and 2016 for cases of acute leukemia with concurrent PBFC and BM evaluation. Immunophenotyping results from the peripheral blood and BM using four or eight color flow cytometry, as well as BM cytochemical staining and immunohistochemistry, were compared. RESULTS: Two hundred ninety PBFC samples with concurrent BM evaluation were identified. Based on the final immunophenotypic classification, the cases were distributed as follows: 108 B-lymphoblastic leukemia (B-ALL), 57 T-lymphoblastic leukemia (T-ALL), 116 acute myeloid leukemia (AML), and 9 mixed-phenotype acute leukemia (MPAL). Among all cases, five had a diagnostically significant discrepancy between PBFC and BM evaluation. In three cases, the immunophenotype by PBFC was consistent with early T-cell precursor ALL (ETP-ALL), whereas BM evaluation demonstrated MPAL. Two cases were suspicious for acute megakaryoblastic leukemia (AMKL) and MPAL, T/myeloid by PBFC but were diagnosed as B-ALL and T-ALL in the BM. CONCLUSION: Immunophenotypic classification by PBFC is accurate (>98%) in almost all cases of pediatric leukemia with the rare exceptions of suspected ETP-ALL, MPAL, and AMKL. These PBFC diagnoses should be confirmed with BM immunophenotyping.

Novel Carbon Dots Derived from Puerariae lobatae Radix and Their Anti-Gout Effects.

Gout is a disease with a high incidence and causing great harm, and the current treatment drugs are not satisfactory. In this study, novel water-soluble carbon dots (CDs) with anti-gout effect, named Puerariae lobatae Radix CDs (PLR-CDs), are reported. PLR-CDs were synthesized with an improved pyrolysis method at 300 °C, and their characterization was performed with multifaceted approaches, such as transmission electron microscopy (TEM) and ultraviolet-visible (UV-vis) and Fourier-transform infrared (FTIR) spectroscopy. In addition, the biocompatibility of PLR-CDs was studied using the cell counting kit (CCK)-8 in LO2 cells and RAW264.7 cells, and the anti-gout activity of PLR-CDs was examined on animal models of hyperuricemia and gouty arthritis. The characterization of PLR-CDs indicated that they were nearly spherical, with diameters ranging from 3.0 to 10.0 nm, and the lattice spacing was 0.283 nm. The toxicity experiment revealed that PLR-CDs were non-poisonous for LO2 cells and RAW264.7 cells at concentrations below 250 µg/mL. The results of pharmacodynamic experiments showed that PLR-CDs could lower the blood uric acid level in model rats by inhibiting the activity of xanthine oxidase and reduce the degree of swelling and pathological damage of gouty arthritis. Thus, PLR-CDs with anti-gout biological activity and good biocompatibility have the prospect of clinical application for the treatment of gout.

A Highly Sensitive Immunochromatographic Strip Test for Rapid and Quantitative Detection of Saikosaponin d.

A quantitative lateral-flow immunoassay using gold nanoparticles (AuNPs) conjugated with a monoclonal antibody (MAb) against saikosaponin d (SSd) was developed for the analysis of SSd. The AuNPs were prepared in our laboratory. The AuNPs were polyhedral, with an average diameter of approximately 18 nm. We used the conjugation between AuNPs and MAbs against SSd to prepare immunochromatographic strips (ICSs). For the quantitative experiment, the strips with the test results were scanned using a membrane strip reader, and a detection curve (regression equation, y = -0.113ln(x) + 1.5451, R² = 0.983), representing the averages of the scanned data, was obtained. This curve was linear from 96 ng/mL to 150 µg/mL, and the IC50 value was 10.39 µg/mL. In this study, we bring the concept ofPOCT (point-of-care testing) to the measurement of TCM compounds, and this is the first report of quantitative detection of SSd by an ICS.

Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.

BACKGROUND: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS: Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS: Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).

PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia.

Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark of B-progenitor acute lymphoblastic leukemia (B-ALL) and most commonly involve PAX5, encoding the DNA-binding transcription factor paired-box 5. The majority of PAX5 alterations in ALL are heterozygous, and key PAX5 target genes are expressed in leukemic cells, suggesting that PAX5 may be a haploinsufficient tumor suppressor. To examine the role of PAX5 alterations in leukemogenesis, we performed mutagenesis screens of mice heterozygous for a loss-of-function Pax5 allele. Both chemical and retroviral mutagenesis resulted in a significantly increased penetrance and reduced latency of leukemia, with a shift to B-lymphoid lineage. Genomic profiling identified a high frequency of secondary genomic mutations, deletions, and retroviral insertions targeting B-lymphoid development, including Pax5, and additional genes and pathways mutated in ALL, including tumor suppressors, Ras, and Janus kinase-signal transducer and activator of transcription signaling. These results show that in contrast to simple Pax5 haploinsufficiency, multiple sequential alterations targeting lymphoid development are central to leukemogenesis and contribute to the arrest in lymphoid maturation characteristic of ALL. This cross-species analysis also validates the importance of concomitant alterations of multiple cellular growth, signaling, and tumor suppression pathways in the pathogenesis of B-ALL.