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.

Clinicopathologic Spectrum of Pediatric Posttransplant Lymphoproliferative Diseases Following Solid Organ Transplant.

CONTEXT.­: Posttransplant lymphoproliferative disease (PTLD) remains a significant complication in pediatric patients undergoing solid organ transplant (SOT). The majority involve Epstein-Barr virus (EBV)-driven CD20+ B-cell proliferations, which respond to reduction of immunosuppression and anti-CD20-directed immunotherapy. Owing to the low overall incidence, prospective studies of pediatric PTLD are scarce, leading to a lack of comprehensive understanding of this disorder in pediatric populations. This review aims to bridge this knowledge gap by providing a comprehensive analysis of the clinical, morphologic, and molecular genetic features of PTLD in children, adolescents, and young adults after SOT. OBJECTIVE.­: To examine the clinical features, pathogenesis, and classification of pediatric PTLDs after SOT. DATA SOURCES.­: Personal experiences and published works in PubMed. CONCLUSIONS.­: PTLD includes a broad and heterogeneous spectrum of disorders, ranging from nonmalignant lymphoproliferations to lymphomas. While most pediatric PTLDs are EBV+, an increasing number of EBV- PTLDs have been recognized. The pathologic classification of PTLDs has evolved in recent decades, reflecting advancements in understanding the underlying pathobiology. Nevertheless, there remains a great need for further research to elucidate the biology, identify patients at higher risk for aggressive disease, and establish optimal treatment strategies for relapsed/refractory disease.

Protective effects of Scutellariae Radix Carbonisata-derived carbon dots on blood-heat and hemorrhage rats.

As the charcoal processing product of Scutellariae Radix (SR), SR Carbonisata (SRC) has been clinically used as a cooling blood and hemostatic agent for thousands of years. However, the underlying active ingredients and mechanism of SRC still remained unspecified. In this study, SRC derived carbon dots (SRC-CDs) were extracted and purified from the aqueous solution of SRC, followed by physicochemical property assessment by series of technologies. The cooling blood and hemostatic effects of SRC-CDs were further evaluated via a blood-heat and hemorrhage (BHH) rat model. Results showed that the diameters of obtained fluorescent SRC-CDs ranged from 5.0 nm to 10.0 nm and possessed functional group-rich surfaces. Additionally, the as-prepared SRC-CDs showed remarkable cooling blood and hemostasis effects in BHH model, mainly manifested by significant improvement of elevated rectal temperature, inflammatory cytokines (TNF-α, IL-6, and IL-1ß) levels, as well as protein expressions of myD88 and NF-κB p65, abnormal coagulation parameters (elevated APTT and FIB), hemogram parameters (RBC, HGB, and HCT), and histopathological changes in lung and gastric tissues. This study, for the first time, demonstrated that SRC-CDs were the cooling blood and hemostatic active components of SRC, which could inhibit the release of inflammatory cytokines by regulating myD88/NF-κB signaling pathway, and activating the fibrin system and endogenous coagulation pathway. These results not only provide a new perspective for the study of active ingredients of carbonized herbs represented by SRC, but also lay an experimental foundation for the development of next-generation nanomedicines.

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.

Case report: Tisagenlecleucel for treatment of relapsed B- acute lymphoblastic leukemia in a patient with CHEK2 mutation.

Background: Germline Checkpoint Kinase 2 gene (CHEK2) mutations can increase the risk of solid tumors. Recently, they have been identified as risk factors for hematologic malignancies. However, to the best of our knowledge, B-acute lymphoblastic leukemia (B-ALL) has never been described as a presenting manifestation of germline CHEK2 mutation. Chimeric antigen receptor-T (CAR-T) cell therapy directed against CD19 antigen (tisagenlecleucel) is a novel cellular therapy for treatment of relapsed/refractory (R/R) B-ALL. The use of tisagenlecleucel has not been described in patients with CHEK2 mutation. Case Presentation: We describe a case of a pediatric patient with a heterozygous pathogenic germline CHEK2 mutation (c.1100delC; p.Thr367Metfs*15) successfully treated with tisagenlecleucel for relapsed B-ALL to avoid hematopoietic cell transplant (HCT). The twelve-year-old boy was diagnosed with National Cancer Institute (NCI) high-risk B-ALL (white blood cell count >50,000/mcL), with no extramedullary disease. Cytogenetic analysis revealed normal karyotype but fluorescent in situ hybridization (FISH) showed 93% positivity for CRLF2::P2RY8 rearrangement. He was treated as per Children's Oncology Group (COG) AALL1131 therapy and achieved a complete remission. Seven months after diagnosis, he was found to have papillary thyroid carcinoma with no evidence of metastatic disease. The patient underwent a total thyroidectomy with central lymph node biopsy and radioactive iodine therapy. The patient's biological mother and fraternal twin brother carry the same germline CHEK2 mutation with no history of malignancy. The biological father tested negative for the familial mutation. The patient's genetic panel also identified three variants of unclear significance: CDKN2A (c.37 °C > T; p.Arg124Cys), FLCN (c.62G > A; p.Cys21Tyr) and SDHAF2 (c.139A > G; p.Met47Val). Extended family history also revealed a diagnosis of anaplastic thyroid cancer in maternal uncle at the age of 44 years. Fifteen months after diagnosis the patient had a relapse of B-ALL (both medullary and extramedullary with blasts in CSF), which was successfully treated with tisagenlecleucel. The patient remains in remission 3 years after receiving tisagenlecleucel. Conclusion: As conventional chemotherapy and radiation can potentially increase the risk of DNA damage and development of secondary malignancies, CD19 CAR-T therapy (tisagenlecleucel) can be used as a substitute for intensive re-induction chemotherapy and HCT in patients with a germline CHEK2 mutation.

Pulmonary Manifestations and Vascular Changes in Pediatric Transplantation-Associated Thrombotic Microangiopathy.

Although transplant-associated thrombotic microangiopathy (TA-TMA) commonly complicates pediatric hematopoietic cellular therapy (HCT), pulmonary manifestations and histology of TA-TMA (pTA-TMA) are rarely reported, with scant data available on timing, risk factors, pathogenesis, and outcomes. Pulmonary hypertension (PH) and diffuse alveolar hemorrhage (DAH) are recognized manifestations of pTA-TMA. The objective of this study was to characterize the pathologic findings, outcomes, and coincident diagnoses preceding biopsy-proven pTA-TMA. In Institutional Review Board- approved retrospective studies, available lung tissue was reviewed at 2 institutions between January 2016 and August 2021 to include those with pulmonary vascular pathology. Histologic features of pTA-TMA were present in 10 children with prior respiratory decline after an allogeneic HCT (allo-HCT; n = 9) or autologous HCT (n = 1). Pathologic lesions included muscular medialization, microthrombi, and red cell fragments, in addition to perivasculitis and intimal arteritis. Parenchymal findings included diffuse alveolar damage, organizing pneumonia, and plasmocytic infiltrates. Six children were clinically diagnosed with TA-TMA, and all were treated with eculizumab, at a median of 2.5 days after clinical diagnosis (range, 0 to 11 days). Four were identified postmortem. Coincident pulmonary infection was confirmed in 8 of the 10 patients. Five allo-HCT recipients (56%) experienced graft-versus-host disease (GVHD; 4 acute, 1 chronic) prior to the onset of respiratory symptoms. Two patients (20%) had clinically recognized DAH, although 9 (90%) had evidence of DAH on histology. Although all 10 patients underwent echocardiography at the time of symptom onset and 9 had serial echocardiograms, only 2 patients had PH detected. Treatments varied and included sildenafil (n = 3), steroids (n = 1), and eculizumab (n = 6). One patient was alive at the time of this report; the remaining 9 died, at a median of 52 days after onset of respiratory symptoms (range 4 to 440 days) and a median of 126 days post-HCT (range, 13 to 947 days). pTA-TMA is a heterogeneous histologic disease characterized by arteriolar inflammation, microthrombi, and often DAH. pTA-TMA presented with respiratory decline with systemic TA-TMA in all patients. Clinicians should maintain a high degree of suspicion for DAH in patients with TA-TMA and pulmonary symptoms. Coincident rates of GVHD and pulmonary infections were high, whereas the rate of PH identified by echocardiography was 20%. Outcomes were poor despite early use of eculizumab and other therapies. Our data merit consideration of pTA-TMA in patients with acute respiratory decline in the setting of systemic TA-TMA, GVHD, and infection. Investigation of additional therapies for pTA-TMA is needed as well. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

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.

Clinicopathologic and Molecular Characterization of Epstein-Barr Virus-positive Plasmacytoma.

Epstein-Barr virus (EBV)-positive plasmacytoma is a rare plasma cell neoplasm. It remains unclear whether EBV-positive plasmacytoma represents a distinct entity or a variant of plasmacytoma. It shares morphologic features with plasmablastic lymphoma (PBL) and may cause diagnostic uncertainty. To better understand EBV-positive plasmacytoma and explore diagnostic criteria, this study describes 19 cases of EBV-positive plasmacytoma, compared with 27 cases of EBV-negative plasmacytoma and 48 cases of EBV-positive PBL. We reviewed the clinicopathologic findings and performed immunohistochemistry, in situ hybridization for EBV, fluorescence in situ hybridization for MYC , and next-generation sequencing. We found that 63.2% of patients with EBV-positive plasmacytoma were immunocompromised. Anaplastic features were observed in 7/19 cases. MYC rearrangement was found in 25.0% of them, and extra copies of MYC in 81.3%. EBV-positive and EBV-negative plasmacytomas possessed similar clinicopathologic features, except more frequent cytologic atypia, bone involvement and MYC aberrations in the former group. The survival rate of patients with EBV-positive plasmacytoma was comparable to that of patients with EBV-negative plasmacytoma. In comparison to PBL, EBV-positive plasmacytoma is less commonly associated with a "starry-sky" appearance, necrosis, absence of light chain expression, and a high Ki67 index (>75%). The most recurrently mutated genes/signaling pathways in EBV-positive plasmacytoma are epigenetic regulators, MAPK pathway, and DNA damage response, while the most frequently reported mutations in PBL are not observed. Collectively, EBV-positive plasmacytoma should be regarded as a biological variant of plasmacytoma. Thorough morphologic examination remains the cornerstone for distinguishing EBV-positive plasmacytoma and PBL, and molecular studies can be a valuable complementary tool.

Integrative analysis of network pharmacology and proteomics to identify key targets of Tuomin-Zhiti-Decoction for allergic rhinitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Allergic rhinitis (AR) is one of most prevalent disease and it is urgent need to develop new drug. Tuomin-Zhiti-Decoction (TZD) is a traditional medicinal compound consisting of eleven different herbs and has a significant effect on AR, yet its underlying mechanism is still unknown. AIM OF THE STUDY: The aim of this study was to confirm the anti-AR effects and the underlying mechanism of TZD. Integrative analysis of network pharmacology and proteomics to explore the common mechanism of TZD treating AR. MATERIALS AND METHODS: Mice were subjected to serial intranasal challenge with ovalbumin (OVA), we examinaed the nasal symptoms, histopathology and Th1/Th2-related cytokines after TZD treatments. Active compounds, potential targets and underlying mechanisms of TZD against AR were systematically clarified by integrating network pharmacology and proteomics analysis. Then we validated the binding affinity between the key potential targets and matching active compounds using molecular docking evaluation. RESULTS: TZD controlled allergy by reduction of OVA-specific immunoglobulin E (IgE) and histamine release. In nasal tissue, TZD decreased nasal rubbing, sneezing and reduced AR-induced damage to nasal mucosa, accordingly, the nasal symptoms were also clearly ameliorated. Moreover, TZD modulated the balance of Th1/Th2/Th17. The proteomics analysis recognized 41 differentially expressed proteins (DEPs). Integrative analysis of network pharmacology and proteomics, we found IL-6 and CD40 could be potential protein targets of TZD against AR, quercetin and wogonin may play more effective roles in AR. Active core compounds of TZD could bind closely to the key targets by molecular docking. CONCLUSION: TZD may have therapeutic potential for treating AR, integrating analysis of network pharmacology and proteomics uncovered the underlying mechanism and targets of TZD, which provides a scientific method for the sensible development of traditional Chinese medicine.

Fluorescence Imaging, Metabolism, and Biodistribution of Biocompatible Carbon Dots Synthesized Using Punica granatum L. Peel.

In this study, a green, low-cost strategy is reported for the synthesis of carbon dots (CDs) using Punica granatum L. A systematic metabolic analysis and determination of the biodistribution of the nitrogen-doped carbon dots was conducted in vivo in mice. Fluorescence images of carbon dots in the whole body, in individual organs (kidney, gallbladder, and bladder), and in two cell lines from different tissue sources were observed. The results suggest not only that the carbon dots are fluorescent in solution, as reported previously, but also that they behave well as contrast agents in live mice. Moreover, metabolic process curves of carbon dots in blood and urine were obtained for the first time. Unlike quantum dots, which can persist in the body for more than 7 days, the carbon dots diffused and were excreted very quickly after injection into mice; within 3 min, fluorescence could be observed in blood, tissue and urine, indicating the rapid distribution of CDs. The fluorescence faded by approximately 4 h in organs and by approximately 10 h in urine, indicating that the CDs were excreted completely in half a day. Our results on the absorption, distribution, metabolism, and excretion of carbon dots may have great significance for the application of these CDs in drug delivery, as drug targets, and for biological imaging. We also demonstrated that these CDs have good biocompatibility for use in studies of mother-child barriers and in fluorescence imaging in plants.

Development of a Lateral Flow Immunochromatographic Strip for Rapid and Quantitative Detection of Small Molecule Compounds.

Membrane-based lateral flow immunochromatographic strips (ICSs) are useful tools for low-cost self-diagnosis and have been efficiently applied to toxin, physiological index and clinical biomarker detection. In this protocol, we provide a detailed description of the steps to develop a rapid, sensitive and quantitative lateral-flow immunoassay (using AuNPs as a marker and mAbs as a probe). The procedure describes the preparation and characterization of colloidal gold, synthesis of the AuNP-mAb conjugate, assembly of the immunochromatographic strip, and methodological investigation of the assay. The results showed that the final strips can be further utilized for the rapid and convenient self-diagnosis of a small molecule, which may provide an alternative tool in the rapid and precise analysis of physiological and biological indices.

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.

Gastroprotective effects of Nelumbinis Rhizomatis Nodus-derived carbon dots on ethanol-induced gastric ulcers in rats.

Aim: To evaluate the gastroprotective effects of Nelumbinis Rhizomatis Nodus carbon dots (NRN-CDs) on ethanol-induced gastric ulcers in rats. Materials & methods: NRN-CDs synthesized and characterized by transmission electron microscopy, ultraviolet, fluorescence and Fourier transform infrared spectroscopy, x-ray photoelectron spectroscopy, x-ray diffraction and zeta potential analyzer. Their gastroprotective effects toward ethanol-induced gastric ulcers were evaluated in male Sprague-Dawley rats. Results: NRN-CDs showed an average diameter of 2.33 ± 0.42 nm and a lattice spacing of 0.29 nm. Pretreatment with NRN-CDs significantly decreased the ulcer index and attenuated the severity of gastric mucosal damage, indicating that NRN-CDs exerted potent gastric protective effect. Moreover, the gastroprotection effect was related to the regulation of oxidative stress and inflammatory factors. Conclusion: NRN-CDs could be developed as a potential drug for the treatment of gastric ulcers.

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.

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.