Sparing and enhancing dose protraction effects for radiation damage to the aorta of wild-type mice.

PURPOSE: Our previous work indicated the greater magnitude of damage to the thoracic aorta at 6 months after starting 5 Gy irradiation in descending order of exposure to X-rays in 25 fractions > acute X-rays > acute γ-rays > X-rays in 100 fractions ≫ chronic γ-rays, in which the limitations of the study included a lack of data for fractionated γ-ray exposure. To better understand effects of dose protraction and radiation quality, the present study examined changes after exposure to γ-rays in 25 fractions, and compared its biological effectiveness with five other irradiation regimens. MATERIALS AND METHODS: Male C57BL/6J mice received 5 Gy of 137Cs γ-rays delivered in 25 fractions spread over six weeks. At 6 months after starting irradiation, mice were subjected to echocardiography, followed by tissue sampling. The descending thoracic aorta underwent scanning electron microscopy, immunofluorescence staining and histochemical staining. The integrative analysis of multiple aortic endpoints was conducted for inter-regimen comparisons. RESULTS: Exposure to γ-rays in 25 fractions induced vascular damage (evidenced by increases in endothelial detachment and vascular endothelial cell death, decreases in endothelial waviness, CD31, endothelial nitric oxide synthase and vascular endothelial cadherin), inflammation (evidenced by increases in tumor necrosis factor α, CD68 and F4/80) and fibrosis (evidenced by increases in transforming growth factor ß1, alanine blue stain and intima-media thickness). The integrative analysis revealed biological effectiveness in descending order of exposure to X-rays in 25 fractions > acute X-rays > γ-rays in 25 fractions > acute γ-rays > X-rays in 100 fractions ≫ chronic γ-rays. CONCLUSIONS: The results suggest that dose protraction effects on aortic damage depend on radiation quality, and are not a simple function of dose rate and the number of fractions.

The CGRP Receptor Antagonist MK0974 Induces EVI1high AML Cell Apoptosis by Disrupting ERK Signaling.

BACKGROUND/AIM: Acute myeloid leukemia (AML) with high expression of the oncogenic transcription factor ecotropic viral integration site-1 (EVI1) (EVI1high AML) is refractory, and there is an urgent need to develop treatment for EVI1high AML. We previously showed that calcitonin receptor-like receptor (CRLR)/receptor activity modifying protein 1 (RAMP1) is highly expressed in EVI1high AML and participates in calcitonin gene-related peptide (CGRP)-induced stress hematopoiesis. This study examined whether MK0974 (a CGRP antagonist) acts as a therapeutic agent in CRLR/RAMP1high AML cell lines. MATERIALS AND METHODS: An in vitro experimental system was used to determine the effect of MK0974 on EVI1high AML cell lines. The expression of CRLR and RAMP1-3 in EVI1high and EVI1low AML lines was evaluated by reverse-transcription polymerase chain reaction (RT-PCR). Next, MK0974 was added to the AML cell lines, and cell proliferation, cell cycle and apoptosis assays were carried out using flow cytometry (FCM). Proteins were evaluated using western blot analysis. We also generated AML cell lines with CRLR knockdown and evaluated whether the effect of MK0974 was reduced. RESULTS: Apoptosis was induced by adding MK0974 to the EVI1high AML cell line. In the EVI1high AML cell line, the addition of MK0974 attenuated the phosphorylation of ERK and p38. These effects were also attenuated by CRLR knockdown. CONCLUSION: MK0974, a CGRP receptor antagonist, inhibits the CRLR/RAMP1 complex and induces apoptosis, making it a potential therapeutic agent for CRLR/RAMP1high AML.

Kikuchi-Fujimoto Disease Following COVID-19 Infection in a 7-Year-Old Girl: A Case Report and Literature Review.

The coronavirus disease 2019 (COVID-19) symptoms in children are relatively mild and often do not require treatment. Nonetheless, complications caused by the immune response to COVID-19 in children are possible and diverse. We present the case of a 7-year-old girl with persistent fever and lymphadenopathy arising from SARS-CoV-2 infection, diagnosed with Kikuchi-Fujimoto Disease (KFD) on lymph node biopsy. KFD is a rare benign disease, clinically characterized by fever and tender cervical lymphadenopathy affecting posterior cervical lymph nodes. We also reviewed six previously reported cases of COVID-19-associated KFD that occurred in school-aged children and compared them with the present case. The clinical course of COVID-19-associated KFD was similar to that of previous reports of KFD with a favorable prognosis. This is the first report of a school-aged child developing KFD following SARS-CoV-2 infection. KFD should be considered when approaching patients with hyperinflammatory states who present with prolonged fever and cervical lymphadenopathy after COVID-19.

Polymer Nanoparticles with Uniform Monomer Sequences for Sequence-Specific Peptide Recognition.

Synthetic polymer nanoparticles (NPs) that recognize and neutralize target biomacromolecules are of considerable interest as "plastic antibodies", synthetic mimics of antibodies. However, monomer sequences in the synthetic NPs are heterogeneous. The heterogeneity limits the target specificity and safety of the NPs. Herein, we report the synthesis of NPs with uniform monomer sequences for recognition and neutralization of target peptides. A multifunctional oligomer with a precise monomer sequence that recognizes the target peptide was prepared via cycles of reversible addition-fragmentation chain transfer (RAFT) polymerization and flash chromatography. The oligomer or blend of oligomers was used as a chain transfer agent and introduced into poly(N-isopropyl acrylamide) hydrogel NPs by radical polymerization. Evaluation of the interaction with the peptides revealed that multiple oligomers in NPs cooperatively recognized the sequence of the target peptide and neutralized its toxicity. Effect of sequence, combination, density and molecular weight distribution of precision oligomers on the affinity to the peptides was also investigated.

GHS-R1a deficiency mitigates lipopolysaccharide-induced lung injury in mice via the downregulation of macrophage activity.

Acute respiratory distress syndrome (ARDS) is a critical illness syndrome characterized by dysregulated pulmonary inflammation. Currently, effective pharmacological treatments for ARDS are unavailable. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a), has a pivotal role in regulating energy metabolism and immunomodulation. The role of endogenous ghrelin in ARDS remains unresolved. Herein, we investigated the role of endogenous ghrelin signaling by using GHS-R1a-null (ghsr-/-) mice and lipopolysaccharide (LPS)-induced ARDS model. Ghsr-/- mice survived longer than controls after LPS-induced lung injury. Ghsr-/- mice showed lower levels of pro-inflammatory cytokines and higher oxygenation levels after lung injury. The peritoneal macrophages isolated from ghsr-/- mice exhibited lower levels of cytokines production and oxygen consumption rate after LPS stimulation. Our results indicated that endogenous ghrelin plays a pivotal role in initiation and continuation in acute inflammatory response in LPS-induced ARDS model by modulating macrophage activity, and highlighted endogenous GHS-R1a signaling in macrophage as a potential therapeutic target in this relentless disease.

Mannose and phosphomannose isomerase regulate energy metabolism under glucose starvation in leukemia.

Diverse metabolic changes are induced by various driver oncogenes during the onset and progression of leukemia. By upregulating glycolysis, cancer cells acquire a proliferative advantage over normal hematopoietic cells; in addition, these changes in energy metabolism contribute to anticancer drug resistance. Because leukemia cells proliferate by consuming glucose as an energy source, an alternative nutrient source is essential when glucose levels in bone marrow are insufficient. We profiled sugar metabolism in leukemia cells and found that mannose is an energy source for glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway. Leukemia cells express high levels of phosphomannose isomerase (PMI), which mobilizes mannose to glycolysis; consequently, even mannose in the blood can be used as an energy source for glycolysis. Conversely, suppression of PMI expression or a mannose load exceeding the processing capacity of PMI inhibited transcription of genes related to mitochondrial metabolism and the TCA cycle, therefore suppressing the growth of leukemia cells. High PMI expression was also a poor prognostic factor for acute myeloid leukemia. Our findings reveal a new mechanism for glucose starvation resistance in leukemia. Furthermore, the combination of PMI suppression and mannose loading has potential as a novel treatment for driver oncogene-independent leukemia.

Malignant perivascular epithelioid cell neoplasm in the liver: report of a pediatric case.

BACKGROUND: Perivascular epithelioid cell neoplasm (PEComa) in a child is very rare. We herein report the first malignant case of PEComa developing in the liver of a pediatric patient. CASE PRESENTATION: A 10-year-old boy visited a private clinic with prolonged fever of unknown etiology. Abdominal ultrasonography was performed to evaluate the fever's origin, revealing a large tumor in the liver. He was thus referred to a nearby hospital to investigate the tumor further. Enhanced computed tomography (CT) showed a 6.8 × 5.9 × 10.5-cm solid lesion on S4 and S5. On magnetic resonance imaging (MRI), the tumor had a low signal intensity on T1 imaging and high signal intensity on T2 imaging, with partial diffusion restriction. 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) showed a marked uptake in the mass lesion with no evidence of metastasis. The patient was negative for all tumor markers, including AFP, CEA and PIVKA-II. The results of a needle biopsy suggested hepatocellular carcinoma. The tumor's rapid growth suggested malignancy. Hepatic segmentectomy (S4 + S5 + S8) was performed. The tumor was resected en bloc with a margin. Microscopically, the tumor showed atypical spindle, polygonal or oval-shaped cells with a high nuclear grade, and vascular invasion. Immunohistochemistry was positive for alpha-smooth muscle antigen (α-SMA), human melanin black-45 (HMB-45) and melan A. The pathological diagnosis was malignant PEComa. In the 6 months after surgery, the patient complained of shoulder pain. MRI showed a dumbbell-shaped tumor at the 2nd thoracic vertebrae, which was confirmed to be bone metastasis of PEComa. After chemotherapy, including ifosfamide and doxorubicin, vertebrectomy was performed. Two years later, thoracoabdominal CT showed a 10-cm solid mass occupying the pelvis and a 15-mm nodule in the middle lobe of the right lung. Under a diagnosis of peritoneal and lung metastases, they were surgically removed and metastasis of PEComa was pathologically confirmed. Four months after the 2nd relapse, pelvic metastasis appeared again and mTOR (mammalian target of rapamycin) inhibitor was initiated. To our knowledge, this is the first report of malignant hepatic PEComa in a pediatric patient. CONCLUSION: Although extremely rare, malignant hepatic PEComa can develop in a child.

Catatonia as the Initial Manifestation of Dementia with Lewy Bodies.

BACKGROUND Catatonia can occur in various neuropsychiatric disorders and is usually treated with benzodiazepines. So far, although 1 case of dementia with Lewy bodies (DLB) with catatonia has been reported, there have been no reports on patients with DLB whose initial symptom was a catatonia. Here, we present a patient who developed benzodiazepine-resistant catatonia and was subsequently diagnosed with DLB based on DLB biomarkers. CASE REPORT The patient was a 92-year-old woman who had not been diagnosed with dementia before. At the age of 91, she experienced catatonia and was initially treated with lorazepam, which did not improve her condition. Later, she transferred to our hospital and was treated with amantadine. Amantadine improved her catatonic symptoms; however, a decline in her cognitive function was observed. We therefore explored the cause of cognitive impairment through imaging studies. We found that the patient did not have the core clinical features of DLB (ie, visual hallucinations, parkinsonism, cognitive fluctuations, and rapid eye movement sleep behavior disorder) but had 2 indicative biomarkers on 123I-metaiodobenzylguanidine myocardial scintigraphy and dopamine transporter imaging. Possible DLB was diagnosed according to the diagnostic criteria. CONCLUSIONS Our case study suggests that catatonia can be an initial symptom of DLB. Moreover, considering the plausible pathophysiology of catatonia in DLB, amantadine treatment may be the most rational choice for the condition when benzodiazepine treatment is ineffective.

The efficacy of the submucosal injection of lidocaine during endoscopic submucosal dissection for colorectal neoplasms: a multicenter randomized controlled study.

BACKGROUND: Endoscopic submucosal dissection (ESD) is currently a common procedure although it requires a long procedural time. We conducted a prospective study to determine the efficacy and safety of lidocaine injection for shortening the procedural time and relieving bowel peristalsis during ESD. METHODS: A multicenter randomized controlled study was conducted in three hospitals. Ninety-one patients who underwent colorectal ESD were enrolled. Patients were randomly divided into two groups using the envelope method: the lidocaine group and saline group. The primary endpoint was the procedural time, and the secondary endpoints were the procedural time in each part of the colon and the grade of bowel peristalsis and the incidence and amounts of antispasmodic drugs use and adverse events. RESULTS: The patients' demographics were not markedly different between the two groups. The mean procedural time in the lidocaine group was not markedly different from that in the saline group. In contrast, at the proximal site, the procedural time in the lidocaine group (57 min) was significantly shorter in the saline group (80 min). The grade of bowel peristalsis in the lidocaine group (0.67) was significantly lower than in the saline group (1.17). Antispasmodic drug use was significantly rarer in the lidocaine group than in the saline group. The incidence of adverse events was not markedly different between the two groups. CONCLUSIONS: Local lidocaine injection is a feasible option for preventing bowel peristalsis, particularly in the proximal colon, leading to a reduced procedural time for ESD and decreased antispasmodic drug use. University Hospital Medical Information Network Center (UMIN number: 000022843).

Bioactive Sambong oil-loaded electrospun cellulose acetate nanofibers: Preparation, characterization, and in-vitro biocompatibility.

Blumea balsamifera oil loaded cellulose acetate nanofiber mats were prepared by electrospinning. The inclusion of blumea oil increased the nanofiber diameter. FTIR spectra confirm the addition of blumea oil in the nanofiber mats. The XRD pattern suggests that the inclusion of blumea oil has caused a misalignment in the polymer chains of the cellulose acetate. Thus, a decrease in the tensile strength was observed for the blumea oil loaded nanofibers. The increase in fiber diameter causes a reduction in the porosity of the nanofiber mats. The blumea oil loaded nanofiber mats showed antibacterial efficacy against Escherichia coli and Staphylococcus aureus. The blumea oil showed antioxidant abilities against the DPPH solution. MVTR of the neat and blumea oil loaded nanofiber mats was in the range of 2450-1750 g/m2/day, which is adequate for the transport of air and moisture from the wound surface. Blumea oil loaded mats showed good cell viability ~92% for NIH 3T3 cells in more extended periods of incubation. A biphasic release profile was obtained, and the release followed the first-order kinetics depending upon the highest value of the coefficient of correlation R 2 (88.6%).

An EGFR T790M-mutated lung adenocarcinoma undergoing large-cell neuroendocrine carcinoma transformation after osimertinib therapy: a case report.

BACKGROUND: Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is selective for both epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. Almost all patients who initially respond to an epidermal growth factor receptor tyrosine kinase inhibitor subsequently report disease progression. Epidermal growth factor receptor-dependent resistance mechanisms, bypass pathway activation, and histological transformation have been reported with osimertinib therapy. CASE PRESENTATION: We report a case of a 64-year-old Asian man with epidermal growth factor receptor T790M-positive adenocarcinoma that transformed to epidermal growth factor receptor T790M-negative large-cell neuroendocrine carcinoma after osimertinib therapy. A prompt rebiopsy revealed a rare mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitor, and subsequently treatment with carboplatin and etoposide was effective. CONCLUSIONS: Despite the promising emergence of circulating tumoral DNA testing, this case report emphasizes the importance of rebiopsy of a progressive epidermal growth factor receptor-mutant tumor.

[A Case of Metachronous Anal Metastasis from Rectal Cancer].

A 49-year-old man underwent low anterior resection for rectal cancer with liver and lung metastases. He refused additional systemic chemotherapy. After 10 months, he presented with a painful anal tumor and we performed trans-anal resection of the tumor. Histopathological examination revealed a metastasis of the rectal cancer. Chemotherapy was performed subsequently. He survived 7 months after the second surgery without local recurrence. We reported a rare case of anal metastasis from rectal cancer.

EVI1 triggers metabolic reprogramming associated with leukemogenesis and increases sensitivity to L-asparaginase.

Metabolic reprogramming of leukemia cells is important for survival, proliferation, and drug resistance under conditions of metabolic stress in the bone marrow. Deregulation of cellular metabolism, leading to development of leukemia, occurs through abnormally high expression of transcription factors such as MYC and Ecotropic Virus Integration site 1 protein homolog (EVI1). Overexpression of EVI1 in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. To identify a metabolic inhibitor for EVI1-induced metabolic reprogramming in MLL-r AML, we used an XFp extracellular flux analyzer to examine metabolic changes during leukemia development in mouse models of AML expressing MLL-AF9 and Evi1 (Evi1/MF9). Oxidative phosphorylation (OXPHOS) in Evi1/MF9 AML cells accelerated prior to activation of glycolysis, with a higher dependency on glutamine as an energy source. Furthermore, EVI1 played a role in glycolysis as well as driving production of metabolites in the tricarboxylic acid cycle. L-asparaginase (L-asp) exacerbated growth inhibition induced by glutamine starvation and suppressed OXPHOS and proliferation of Evi1/MF9 both in vitro and in vivo; high sensitivity to L-asp was caused by low expression of asparagine synthetase (ASNS) and L-asp-induced suppression of glutamine metabolism. In addition, samples from patients with EVI1+MF9 showed low ASNS expression, suggesting that it is a sensitive marker of L-asp treatment. Clarification of metabolic reprogramming in EVI1+ leukemia cells may aid development of treatments for EVI1+MF9 refractory leukemia.

Transanal total mesorectal excision of giant villous tumor of the lower rectum with McKittrick-Wheelock syndrome: a case report of a novel surgical approach.

BACKGROUND: McKittrick-Wheelock syndrome (MKWS) is caused by a villous tumor of the rectosigmoid colon with hypersecretion of mucus containing electrolytes. Complete resection of the tumor is needed to cure this disease. Transanal total mesorectal excision (TaTME) is currently a promising treatment for lower rectal tumor because of the reliability of its resection margin especially in bulky tumor. We present this first case report of a TaTME for MKWS with a lower rectal tumor. CASE PRESENTATION: An 81-year-old woman was admitted to our hospital with diarrhea and acute renal failure. Computed tomography and magnetic resonance imaging examinations revealed an 80-mm-sized enhanced tumor located in her lower rectum without lymph node swelling and distant metastasis. A giant villous tumor secreting mucus was seen in the lower rectum to the anal canal during colonoscopy. The result of tumor biopsy was adenocarcinoma. To preserve the anal function and ensure distal margin, we chose TaTME for curative resection. After improving the electrolyte imbalance, TaTME was performed successfully and R0 resection was achieved. There was no sign of recurrence or electrolyte depletion for 1 year after the surgery. CONCLUSION: TaTME could be a promising surgical approach for giant villous tumor with MKWS in the lower rectum.

TAE226, a dual inhibitor of focal adhesion kinase and insulin-like growth factor-I receptor, is effective for Ewing sarcoma.

The outcomes for relapsed and metastatic Ewing sarcoma (EWS) is extremely poor. Therefore, it is important to identify the tumor-specific targets in these intractable diseases. High focal adhesion kinase (FAK) transcript expression levels in EWS cell lines are known. TAE226 is a dual inhibitor of FAK and insulin-like growth factor-I receptor (IGF-IR), while PF-562,271 is a dual inhibitor of FAK and proline-rich tyrosine kinase 2. We compared the cytotoxicity of TAE226 and PF-562,271 toward three EWS cell lines. TAE226 strongly inhibited proliferation of three cell lines when compared with PF-562,271. Furthermore, we investigated the efficacy of TAE226 as well as its mechanism of action against EWS. A stable EWS cell line with FAK and IGF-IR knocked down was established, and microarray analysis revealed dysregulated expression in various pathways. TAE226 treatment of EWS cell lines induced cell cycle arrest, apoptosis, AKT dephosphorylation, and inhibition of invasion. We demonstrated that TAE226 drastically inhibits the local growth of primary tumors and metastasis in EWS using mouse models. Furthermore, the combination of TAE226 and conventional chemotherapy proved to exert synergistic effects. TAE226 may be a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future.

PRDM16s transforms megakaryocyte-erythroid progenitors into myeloid leukemia-initiating cells.

Oncogenic mutations confer on cells the ability to propagate indefinitely, but whether oncogenes alter the cell fate of these cells is unknown. Here, we show that the transcriptional regulator PRDM16s causes oncogenic fate conversion by transforming cells fated to form platelets and erythrocytes into myeloid leukemia stem cells (LSCs). Prdm16s expression in megakaryocyte-erythroid progenitors (MEPs), which normally lack the potential to generate granulomonocytic cells, caused AML by converting MEPs into LSCs. Prdm16s blocked megakaryocytic/erythroid potential by interacting with super enhancers and activating myeloid master regulators, including PU.1. A CRISPR dropout screen confirmed that PU.1 is required for Prdm16s-induced leukemia. Ablating PU.1 attenuated leukemogenesis and reinstated the megakaryocytic/erythroid potential of leukemic MEPs in mouse models and human AML with PRDM16 rearrangement. Thus, oncogenic PRDM16 s expression gives MEPs an LSC fate by activating myeloid gene regulatory networks.

[Acute myeloid leukemia evolving from KIT D816-mutated systemic mastocytosis relapsing two months after completion of chemotherapy].

Here, we report the case of a 9-year-old girl with acute myeloid leukemia (AML) developed from systemic mastocytosis (SM). She experienced bladder and rectal disturbance due to an extramedullary nodule in the paraspinal region of the sacrum. Cytogenetic and genetic analyses of leukemic cells revealed the KIT D816Y mutation besides t (8;21) (q22:q22) /RUNX1-RUNX1T1. Despite receiving proton beam therapy after conventional chemotherapy, the patient relapsed after 2 months. As SM-AML with the KIT D816 mutation in adults exhibits a poor prognosis, hematopoietic stem cell transplantation is recommended. Owing to a few reports of SM-AML in children, the standard therapy for pediatric cases has not been established to date. Based on our experience and the related literature, the prognosis of childhood SM-AML could be as poor as in adults. Hence, further investigation, including mutational analyses of the KIT gene, is warranted to establish a risk-oriented strategy for managing childhood SM-AML.

CGRP-CRLR/RAMP1 signal is important for stress-induced hematopoiesis.

Ecotropic viral integration site-1 (EVI1) has a critical role in normal and malignant hematopoiesis. Since we previously identified high expression of calcitonin receptor like receptor (CRLR) in acute myeloid leukemia (AML) with high EVI1 expression, we here characterized the function of CRLR in hematopoiesis. Since higher expression of CRLR and receptor activity modifying protein 1 (RAMP1) was identified in immature hematopoietic bone marrow (BM) cells, we focused on calcitonin gene-related peptide (CGRP), a specific ligand for the CRLR/RAMP1 complex. To elucidate the role of CGRP in hematopoiesis, Ramp1-deficient (Ramp1-/-) mice were used. The steady-state hematopoiesis was almost maintained in Ramp1-/- mice; however, the BM repopulation capacity of Ramp1-/- mice was significantly decreased, and the transplanted Ramp1-/- BM mononuclear cells had low proliferation capacity with enhanced reactive oxygen species (ROS) production and cell apoptosis. Thus, CGRP is important for maintaining hematopoiesis during temporal exposures with proliferative stress. Moreover, continuous CGRP exposure to mice for two weeks induced a reduction in the number of BM immature hematopoietic cells along with differentiated myeloid cells. Since CGRP is known to be increased under inflammatory conditions to regulate immune responses, hematopoietic exhaustion by continuous CGRP secretion under chronic inflammatory conditions is probably one of the important mechanisms of anti-inflammatory responses.