Effective Treatment of Anlotinib Combined With Chemotherapy in Children With Desmoplastic Small Round Cell Tumor: A Case Series in a Single-center and Literature Review.

INTRODUCTION: Desmoplastic small round cell tumor (DSRCT) is a highly aggressive primitive sarcoma with a 5-year survival rate estimated at only 15% to 30%. Although few curative treatment options exist, patients are most often treated with a combination of aggressive chemotherapy, radiation, and surgery. Targeted therapy inhibitors of platelet-derived growth factor A, insulin-like growth factor receptor 1, and vascular endothelial growth factor receptor-2, which are almost uniformly overexpressed in DSRCT, have largely failed in clinical trials. Anlotinib is a multitarget receptor tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor α/ß, c-Kit, and Met. In this study, we presented 3 cases of DSRCT treated effectively with anlotinib combined with chemotherapy. CASE PRESENTATION: Three children DSRCT patients were enrolled from September 2020 to December 2021 and monitored until August 30, 2022. The clinical data were prospectively studied. The peritoneal cancer index classified all 3 patients as stage IV. After surgery, all 3 patients received anlotinib in combination with chemotherapy and reacted to the medication. For all 3 patients, clinical symptoms were substantially eased, and the size of the masses was reduced. Patient 1 and patient 3's progression-free survival had been extended, and anlotinib was continued as a maintenance medication in the 2 patients who were in good health at the end of the follow-up. Patient 2 died of postoperative complications 1 month after second-stage surgery. The main side effects of anlotinib were fatigue and hypertension. However, its toxicity was controllable and tolerable in children patients. CONCLUSIONS: This is the first report that anlotinib is effective in children with DSRCT. This report may provide an additional option for the treatment of metastatic DSRCT.

Philadelphia chromosome-like acute lymphoblastic leukemia with concomitant rearrangements of CRLF2 and ABL1: a pediatric case report.

BACKGROUND: BCR::ABL1-like or Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) was first reported in 2009. Ph-like ALL is characterized by gene signature similar to Philadelphia chromosome ALL, but without BCR::ABL1 fusions. Molecularly, Ph-like ALL is divided into seven categories, with CRLF2 and ABL-class rearrangements being the two most common subtypes, exhibiting alterations in distinct downstream signaling cascades. CASE PRESENTATION: We report a rare case of pediatric Ph-like ALL with concomitant CRLF2 and ABL1 rearrangements. CRLF2 was fused with P2RY8, its most common fusion partner, whereas ABL1 was fused with MYO18B, a novel fusion partner that has not been previously reported. The 4-year-old female patient was treated using the national multicenter CCCG-ALL-2020 protocol with the addition of dasatinib at the end of induction when ABL1 rearrangement was confirmed by RNA-seq. Morphologically and molecularly, the patient remained in continuous remission until the last follow-up. To the best of our knowledge, this is the first case of Ph-like ALL harboring two distinct rearrangement categories. CONCLUSIONS: Our results identified that ABL1 rearrangement and CRLF2 rearrangement can coexist. The application of FISH, whole transcription sequencing, PCR can help us to have a more comprehensive understanding of ALL cytogenetics and molecular biology. Further studies are needed to explore the role of targeted therapies in such rare clinical scenarios.

"Sandwich" protocol based on modified SMILE regimen for children with newly extranodal NK/T cell lymphoma, nasal type: a single-arm, single-center clinical study.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), which is a rare form of mature T/NK cell lymphoma in children, currently lacks a standardized first-line treatment approach. However, a treatment protocol known as the "sandwich" regimen has been used in children newly diagnosed with ENKTL. This protocol combines the administration of methotrexate, ifosfamide, etoposide, pegaspargase, and dexamethasone (referred to as SMILE) with the addition of radiotherapy (RT). From September 2017 to December 2020, a total of five patients were included in the study, consisting of three males and two females. The median age of onset was 10.6 years (range, 9.8 to 14.0 years). Among the patients, four had nasal/nasopharyngeal disease at stage II, while one patient had extra nasal disease involving the skin at stage IV. The median EBV-DNA level in plasma was 1.68 × 103 copies/ml (range, 0.44 to 21.1 × 103copies/ml). All the patients had good overall response after 2 cycles of chemotherapy and radiotherapy, including 4 of the patients who had a complete response and 1 of the patients with partial remission. The patient with stage IV received allogeneic hematopoietic stem cell transplantation after the EBV-DNA level was elevated again during treatment. One patient in the low-risk group experienced grade 4 oral mucositis, while no other severe complications or treatment-related deaths were observed. The median follow-up period was 22 months (range, 5 to 57 months). All five patients successfully completed their treatment, with four patients achieving event-free survival, and one patient was lost to follow-up. The median OS time and EFS time was 33 months (range: 18-57 months) and 20 months (range: 5-47 months), respectively. The sandwich protocol has demonstrated a high response rate, good tolerance to chemotherapy, and no treatment-related fatalities. However, further confirmation is necessary through additional clinical studies involving larger sample sizes. Clinical trial registration number: Due to modified SMILE regimens with sandwiched radiotherapy yielded promising outcomes in children ENKTL, we have carried out a phase II multicenter clinical trial (ChiCTR220005954) for children ENKTL in China to further verify the efficacy and safety.

Gadd45b prevents autophagy and apoptosis against rat cerebral neuron oxygen-glucose deprivation/reperfusion injury.

Autophagic (type II) cell death has been suggested to play pathogenetic roles in cerebral ischemia. Growth arrest and DNA damage response 45b (Gadd45b) has been shown to protect against rat brain ischemia injury through inhibiting apoptosis. However, the relationship between Gadd45b and autophagy in cerebral ischemia/reperfusion (I/R) injury remains uncertain. The aim of this study is to investigate the effect of Gadd45b on autophagy. We adopt the oxygen-glucose deprivation and reperfusion (OGD/R) model of rat primary cortex neurons, and lentivirus interference used to silence Gadd45b expression. Cell viability and injury assay were performed using CCK-8 and LDH kit. Autophagy activation was monitored by expression of ATG5, LC3, Beclin-1, ATG7 and ATG3. Neuron apoptosis was monitored by expression of Bcl-2, Bax, cleaved caspase3, p53 and TUNEL assay. Neuron neurites were assayed by double immunofluorescent labeling with Tuj1 and LC3B. Here, we demonstrated that the expression of Gadd45b was strongly up-regulated at 24 h after 3 h OGD treatment. ShRNA-Gadd45b increased the expression of autophagy related proteins, aggravated OGD/R-induced neuron cell apoptosis and neurites injury. ShRNA-Gadd45b co-treatment with autophagy inhibitor 3-methyladenine (3-MA) or Wortmannin partly inhibited the ratio of LC3II/LC3I, and slightly ameliorated neuron cell apoptosis under OGD/R. Furthermore, shRNA-Gadd45b inhibited the p-p38 level involved in autophagy, but increased the p-JNK level involved in apoptosis. ShRNA-Gadd45b co-treatment with p38 inhibitor obviously induced autophagy. ShRNA-Gadd45b co-treatment with JNK inhibitor alleviated neuron cell apoptosis. In conclusion, our data suggested that Gadd45b inhibited autophagy and apoptosis under OGD/R. Gadd45b may be a common regulatory protein to control autophagy and apoptosis.

Williams-Beuren syndrome in pediatric T-cell acute lymphoblastic leukemia: A rare case report and review of literature.

BACKGROUND: Williams-Beuren syndrome (WBS) is a rare genetic disorder caused by hemizygous microdeletion of contiguous genes on chromosome 7q11.23. Although the phenotype features extensive heterogeneity in severity and performance, WBS is not considered to be a predisposing factor for cancer development. Currently, hematologic cancers, mainly Burkitt lymphoma, are rarely reported in patients with WBS. Here in, we report a unique case of T-cell acute lymphoblastic leukemia in a male child with WBS. METHODS: This retrospective study analyzed the clinical data of this case receiving chemotherapy were analyzed. This is a retrospective study. RESULTS: The patient, who exhibited a typical WBS phenotype and presented with hemorrhagic spots. Chromosomal genome-wide chip analysis (CMA) revealed abnormalities on chromosomes 7 and 9. The fusion gene STIL-TAL1 and mutations in BCL11B, NOTCH1, and USP7 have also been found and all been associated with the occurrence of T-cell leukemia. The patient responded well to the chemotherapy. CONCLUSION: To the best of our knowledge, this is the first reported case of WBS in T-cell acute lymphoblastic leukemia. We want to emphasize that the occurrence of leukemia in this patient might be related to the loss of 7q11.23 and microdeletion of 9p21.3 (including 3 TSGs), but the relationship between WBS and malignancy remains unclear. Further studies are required to clarify the relationship between WBS and malignancy.

Anti-Hu antibody associated paraneoplastic neurological syndrome in a child with ganglioneuroblastoma: A rare case report and literature review.

RATIONALE: Paraneoplastic neurological syndrome with anti-Hu antibody (Hu-PNS) is a neurological disorder that occur in patients with malignancy. The syndrome has a wide range of presentations and can present before diagnosis of primary malignancy. Familiarity with these paraneoplastic neurological syndromes can help early recognition and take appropriate regimens. PATIENTS CONCERNS: Diagnosis and treatment of Hu-PNS. DIAGNOSES: This is retrospective study that analyzed the clinical data of this case. Through retrospective analysis and targeted antibody screening, serum anti-Hu antibody was detected. Subsequent spinal imaging revealed a mass in the paraspinal region, which was confirmed as ganglioneuroblastoma by pathologic examination. INTERVENTIONS: The child was treated with a course of intravenous immunoglobulin and radical surgical operation without chemotherapy. OUTCOMES: The neurological symptoms were gradually improved and no signs indicate disease progression or tumor recurrence. LESSONS: Hu-PNS has rarely been reported in children with ganglioneuroblastomas. They can mimic non-neoplastic processes, making detection and diagnosis difficult. Serum and/or cerebrospinal fluid onconeural antibody can strongly indicate occult cancers. Early detection of paraneoplastic neurological syndromes can help take appropriate regimens and improve prognosis.

[Association between SNP rs12740374 and acute ischemic stroke in Chinese Han population].

OBJECTIVE: To investigate the association between single nucleotide polymorphism (SNP) rs12740374 and acute ischemic stroke in Chinese Han population. METHODS: All subjects (778 ischemic stroke patients and 602 controls) were genotyped using ligation detection reaction (LDR). We analyzed the differences among all genotypes in two groups, as well as the association between rs12740374 and low-density lipoprotein cholesterol (LDL-C). RESULTS: All three genotypes (GG, GT, TT) of rs12740374 were found in both stroke and control group. After adjusting for risk factors, although there was a trend that participants with a minor allele T of rs12740374 (GT/TT) had lower LDL-C concentration, no significant association was found between rs12740374 and ischemic stroke, and also no significant association between different genotypes and LDL-C was found. CONCLUSION: SNPs of rs12740374 was not significantly associated with ischemic stroke in the Chinese Han population.

Excessive weight gain among preschool children during the COVID-19 lockdown in China: a retrospective observational study.

OBJECTIVES: We aimed to analyse weight change and risk factors associated with excessive weight gain in preschool children during the COVID-19-related lockdown in western China. METHODS: A retrospective observational study of eight randomly selected kindergartens was conducted. Data was collected via online electronic questionnaires during the lockdown. RESULTS: During the COVID-19 lockdown period, the incidence of overweight and obesity among preschool children involved in the study was 7.6 and 14.7 %, respectively. In addition, the incidence of obesity among children aged 3-4 years was 26.3 %, which was higher than that of other age groups. Children with excessive weight gain (weight gain ≥1.0 kg) spent more time on TV and video viewing during lockdown than children with normal gain. Among children with excessive weight gain, weight before lockdown and fathers' BMI were higher than those of children with normal weight gain. Heavier weight before lockdown (OR 1.044, p<0.05), higher father's BMI (OR 1.022, p<0.05), fresh fruit consumption during lockdown (frequently, ≥5 times/week) (OR 5.946, p<0.05), and long touch-screen device time during lockdown (OR 1.259, p<0.05) were found to be risk factors significantly associated with excessive weight gain. Living space (80-100 m2, OR=0.499, p<0.05; 100-150 m2, OR=0.467, 95 % CI 0.26, 0.83) and good mental behavior during the lockdown (OR=0.056, p<0.05) were found to be significant protective factors against excessive weight gain. CONCLUSIONS: There was a clear trend in excessive weight gain among preschool children during the COVID-19 lockdown, especially those who had already had heavier weight before the pandemic. The obesity-promoting environment resulting from the COVID-19 pandemic may lead to a further serious exacerbation of the childhood obesity pandemic. Therefore, child health care providers must pay close attention to this and implement effective preventive measures in a timely manner.

Obesity as a Prognostic Factor of Central Nervous System Relapse in Children with Acute Lymphoblastic Leukemia: A Single-Centre Study and Literature Review.

Relapse as the commonest treatment failure through chemotherapy of child presented with acute lymphoblastic leukemia (ALL) is usually within 3 years of remission. Central nervous system (CNS) is expected as a site of extramedullary relapse in 3-8% of child leukemia, often leading to a poor prognosis. A few patients may have headache and vomiting and can be diagnosed without difficulty. However, most patients present with asymptomatic conditions. Obesity has become one of the greatest reported complications of children ALL survivors. Rarely, obesity presentation can be the first manifestation of CNS leukemia. Here, we present three unusual cases with B-ALL presentation of obesity as the first symptom at the time of CNS relapse after achieving remission. This highly localized presentation is unusual and would hopefully inform clinicians to have a high index of suspicion for relapse in children with ALL.

LINC00461 Regulates the Recurrence of Large B Cell Lymphoma through the miR-411-5p/BNIP3 Pathway.

Objective: To analyze the mechanism of LINC00461 regulating the recurrence of diffuse large B cell lymphoma (DLBCL) through microRNA (miR)-411-5p/BCL2 interacting protein 3 (BNIP3) pathway. Methods: DLBCL samples in TCGA and GSE12453 were used for differential analysis to find long noncoding RNA (lncRNA) related to DLBCL recurrence. The 4 DLBCL data with the highest and lowest expression levels of LINC00461 in the TCGA database were selected for GSEA enrichment analysis. The targeting relationships of miR-411-5p with LINC00461 and BNIP3 were verified by the dual luciferase report. Blood samples from DLBCL patients were used to analyze the correlation between miR-411-5p and LINC00461 or BNIP3. LINC00461, miR-411-5p, or BNIP3 was overexpressed or silenced by transfection, and a tumor-bearing nude mice model was constructed to detect their effects on proliferation and apoptosis. Results: The level of LINC00461 in DLBCL was significantly higher than that in normal cases, and the level in recurrence DLBCL was significantly higher than that in nonrecurrence. The enrichment analysis results showed that the function of LINC00461 was closely related to apoptosis. The results shown that miR-411-5p bound to LINC00461 and BNIP3 and was negatively correlated with LINC00461 and BNIP3 mRNA in blood of DLBCL patients. Suppressing the level of LINC00461 inhibited cell proliferation and induced apoptosis. The inhibition of LINC00461 or overexpression of miR-411-5p reduced the expression of BNIP3 protein, thereby inducing apoptosis at the in vivo and in vitro levels. Conclusion: LINC00461 may induce miR-411-5p to "sponge," thereby increasing the expression of BNIP3 protein, and exerting the function of inhibiting apoptosis and promoting DLBCL recurrence.

A Rare Heterozygous TINF2 Deletional Frameshift Mutation in a Chinese Pedigree With a Spectrum of TBDs Phenotypes.

Telomere biology disorders (TBDs) induced by TINF2 mutations manifest clinically with a spectrum of phenotypes, from silent carriers to a set of overlapping conditions. A rare TINF2 frameshift mutation (c.591delG) encoding a truncated mutant TIN2 protein (p.W198fs) was identified in a 6-years-and-3-month-old Chinese girl with neuroblastoma (NB) by next generation sequencing and confirmed by Sanger sequencing. To explore the possible implications of TINF2 mutations in TBDs development, the TINF2 mutant was transfected into the human embryonic kidney (HEK) 293T cells, and mRNA expression of the shelterin complex components as well as the cellular distribution of mutant TIN2 were examined. The TINF2 mutation was phenotypically associated with short stature in the proband, nail dystrophy and spotted hypopigmentation in her mother, and psoriasis in her older brother. I-TASSER modeling analysis revealed conformational changes of the mutant TIN2 protein and loss of pivotal domains downstream of the 198th amino acid. Additionally, mRNA expression of the shelterin components was downregulated, and TIN2 mutant protein expression was reduced in HEK293T cells transfected with mutant TINF2. Furthermore, instead of being restricted to the nucleus, the mutant TIN2 was identified in both the cytoplasm and the nucleus. The TINF2 gene mutation might impair the function of the shelterin complex and the telomere maintenance mechanisms, both of which are involved in the development of TBDs. TBDs have been associated with increased cancer risk. To the best of our knowledge, this is the first report of NB in patients with TBDs. The relationship between the TINF2 mutation and NB may need to further study.

Early-life weight gain patterns of term small-for-gestational-age infants and the predictive ability for later childhood overweight/obesity: A prospective cohort study.

Objectives: We aimed to identify the weight gain patterns of small-for-gestational age (SGA) infants in early life and to explore the predictive value for later overweight/obesity in childhood. Methods: We obtained data from a prospective cohort including term SGA infants born between January 2006 and November 2015 who received regular health care from birth to 5 years in West China Second University Hospital, Chengdu, China. A latent class growth analysis (LCGA) was applied to group children with similar growth trajectory patterns. Multiple logistic regression was performed to examine the association between weight gain patterns and later overweight/obesity. Results: A total of 296 term SGA infants were finally included. Five weight gain trajectories were identified, including excessive rapid catch-up growth (ERCG) (class 1, 10.9%), rapid catch-up growth (RCG) (class 2, 17.9%), appropriate catch-up growth (ACG) (class 3, 53.0%), slow catch-up growth (SCG) (class 4, 13.4%) and almost no catch growth (NCG) (class 5, 4.8%). SGA infants in class 1 and class 2 had a higher BMI according to age- and sex-specific Z scores from 2-5 years of age. In addition, 25% of SGA infants in class 1 and 13.2% of SGA infants in class 2 were found to be overweight/obese at 2-5 years of age. After adjusting for confounders, we found that extremely rapid weight gain (class 1) in the first 2 years of life increased the risk of overweight/obesity by 2.1 times at 2 to 5 years of age (aOR=2.1, 95% CI: 1.3~4.8; P<0.05). Furthermore, the increment of ΔWAZ between 0 and 4 mo was prominently related to the risk of overweight/obesity at 2 to 5 years for term SGA infants (aOR=3.2, 95% CI: 1.7~8.1; P<0.001). A receiver operating characteristic (ROC) curve showed the area under curve (AUC) was 0.7, with a 95% confidence interval (CI) from 0.6 to 0.8 (P<0.001). Conclusions: The extremely rapid weight gain pattern of term SGA infants in the first 2 years of life increased the risk of overweight/obesity at 2 to 5 years of age. It suggests monitoring weight gain across the infant period represents a first step towards primary prevention of childhood obesity.

Case report: A rare case of pulmonary mucormycosis caused by Lichtheimia ramosa in pediatric acute lymphoblastic leukemia and review of Lichtheimia infections in leukemia.

Mucormycosis caused by Lichtheimia ramosa is an emerging and uncommon opportunistic infection in patients with hematological malignancies, with high mortality rates. Herein, we first report a case of pulmonary mucormycosis with Lichtheimia ramosa in a 3-year-old girl recently diagnosed with B-cell acute lymphoblastic leukemia. The diagnosis was made using computerized tomography of the lung, metagenomic next-generation sequencing (mNGS) of blood and sputum specimens, and microscopic examination to detect the development of Lichtheimia ramosa on the surgical specimen. She was effectively treated after receiving prompt treatment with amphotericin B and posaconazole, followed by aggressive surgical debridement. In our case, the fungal isolates were identified as Lichtheimia ramosa using mNGS, which assisted clinicians in quickly and accurately diagnosing and initiating early intensive treatment. This case also indicated the importance of strong clinical suspicion, as well as aggressive antifungal therapy combined with surgical debridement of affected tissues.

Expression and significance of PD-1 and PD-L1 in patients with recurrent spontaneous abortion: A protocol for systematic review and meta-analysis.

BACKGROUND: Recurrent spontaneous abortion (RSA) accounts for the most common complication of early pregnancy in humans. As an immune checkpoint pathway, programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) can be exploited by tumor cells to evade immuno-surveillance. Many studies have shown that the expression of PD-1/PD-L1 is involved in RSA. However, the correlation between the expression of PD-1/PD-L1 and RSA is still controversial. We conducted meta-analysis to further explore the correlation between the expression of PD-1/PD-L1 and RSA, to provide a basis for clinical prevention and treatment. METHODS: We will search PubMed, Embase, Web of Science, Google Scholar, Chinese National Knowledge Infrastructure, Chinese VIP Information, Wanfang Database, and Chinese Biomedical Literature Database for related published studies before February 2021. Two review authors will search and assess relevant studies independently. Case control studies and cohort studies will be included. The Revman 5.3 software was applied to carry out the meta-analysis for the included literature. RESULTS: The findings of this systematic review will be disseminated in a peer-reviewed publication and/or presented at relevant conferences. CONCLUSION: This study will provide a new theoretical basis for the prevention and treatment of RSA. TRIAL REGISTRATION NUMBER: DOI 10.17605/OSF.IO/CZD23.Ethics and dissemination: Formal ethical approval is not required, as the data are not individualized.

The relationship between polymorphisms of microRNA and preeclampsia: A protocol for meta-analysis and bioinformatics prediction.

BACKGROUND: Preeclampsia has genetic correlation. Many studies have shown that microRNA (miRNA) polymorphism is highly associated with preeclampsia, but the results are inconsistent. The purpose of this study is to systematically evaluate the relationship between miRNA polymorphism and preeclampsia. METHODS: In this study, the search time is set from the establishment of the database on January 2021. The search database include China National Knowledge Infrastructure (CNKI), Wanfang, VIP and China Biology Medicine disc (CBM), PubMed, EMBASE, and Web of Science, and the Cochrane Library. The subjects are case-control studies on the relationship between miRNA polymorphism and preeclampsia. The language is limited to English and Chinese. The data of the included study are extracted and the literature quality is evaluated by 2 researchers independently. The data are statistically analyzed through Stata 16.0 software. We also predicted the miRNA secondary structure and the binding sites of miRNA interaction with its target genes. RESULTS: This review will be disseminated in print by peer-review. CONCLUSION: This study will provide evidence-based medicine to elucidate the genetic tendency of preeclampsia. ETHICS AND DISSEMINATION: Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval will not be required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/MJY2X.

Hypoxia induces inflammatory microenvironment by priming specific macrophage polarization and modifies LSC behaviour via VEGF-HIF1α signalling.

BACKGROUND: Leukemia stem cells (LSCs) play pivotal roles in leukemogenesis, and are closely implicated in leukemia relapse and chemoresistance. LSCs are tightly modulated by hypoxic exposure and macrophage-conditioned microenvironment. Nevertheless, the impacts on the biology of LSCs imposed by the interaction of hypoxia and macrophage polarization remain elusive. METHODS: In the study, LSCs characterized by CD34+CD38- immunophenotype sorted from KG1α and primary AML cells were employed as in vitro and ex vivo cell models. mRNA and protein expressions of cytokine/chemokine of cells under normoxic and hypoxic conditions were determined by RT-PCR and western blot. Macrophage polarization, cell cycle and apoptosis were determined by flowcytometry. Cell viability was assayed by CCK-8. RESULTS: Macrophages preferentially presented with M2 polarization phenotype characterized by upregulated VEGF and CCL17 cytokine/chemokine profile, when stimulated by specific set of cytokines under hypoxic exposure, and induced an anti-inflammatory microenvironment. LSCs exhibited significantly increased cell viability, colony-forming capacity and chemoresistance when co-incubated in hypoxic conditioned medium (H-CM) primed by polarized M1 macrophages. VEGF expression was upregulated in LSCs which in turn activated survivin expression. VEGF-mediated upregulation of survivin could be abolished by inhibition of VEGF receptor, but not blocked by survivin-targeting siRNA. In addition, survivin upregulation exerted antiapoptotic effects and was associated with increased chemoresistance. Finally, VEGF mediated transcriptional induction of HIF-1α of LSCs coincubated in H-CM, and HIF-1α induction in turn enhanced chemoresistance and reduced cell apoptosis. CONCLUSIONS: To our best knowledge, this is the first study that focus to explore molecule players and interacting signal pathways regulating LSC biology under hypoxic exposure. It reveals that hypoxia preferentially skew macrophage M2 polarization with specific cytokine profile and proinflammatory microenvironment, which impacts malignant behavior of LSCs. VEGF-HIF-1α interaction is closely implicated in sustaining LSCs survival under hypoxic exposure and might be of potential target of novel therapy.

Hypoxic exposure activates the B cell-specific Moloney murine leukaemia virus integration site 1/PI3K/Akt axis and promotes EMT in leukaemia stem cells.

Acute myeloid leukemia (AML) is a malignant tumor of the immature myeloid hematopoietic cells in the bone marrow. Disease recurrence driven by leukaemia stem cells (LSCs), a sub-population of leukaemia cells presenting self-renewal capacity and differentiation potential, is a major problem in the treatment of AML. Although a hypoxic microenvironment is considered to promote AML malignant behaviours and is considered a potential therapeutic target, the effect of hypoxic stimulation of LSCs is still largely unknown. Therefore, the present study analysed the effects of hypoxia on the malignant behaviours of LSCs. Hypoxia exposure upregulated hypoxia-inducible factor (HIF)-1α, which upregulated the transcription of B cell-specific Moloney murine leukaemia virus integration site 1 (BMI-1). Hypoxia exposure also activated the PI3K/Akt pathway and promoted the epithelial mesenchymal transition (EMT) in LSCs via hypoxia-mediated activation of HIF-1α. BMI-1 served an important role in the hypoxia-induced activation of the PI3K/Akt pathway and the promotion of EMT. Hypoxia exposure promoted chemoresistance against cytarabine arabinoside by inducing HIF-1α, thus activating the transcriptional activity of HIF-1α. Knockdown of BMI-1 disrupted hypoxia-induced chemoresistance in LSCs, indicating that HIF-1α-induced BMI-1 has a role in hypoxia-promoted malignant behaviours. Furthermore, it was demonstrated that induced BMI-1 inhibits the self-renewal capacity in LSCs under hypoxic conditions. The present study provides in vitro evidence demonstrating that hypoxia exposure regulates LSCs by activating HIF-1α/BMI-1 signalling, in turn modulating PI3K/Akt signalling and EMT. These results highlight potentially novel therapeutic targets of LSCs to improve the treatment of AML.

Co-occurrence of TCF3-PBX1 gene fusion, and chromosomal aberration in a pediatric pre-B cell acute lymphoblastic leukemia with clitoris swelling: A case report and literature review.

RATIONALE: Clitoris swelling as the initial clinical presentation of acute lymphoblastic leukemia (ALL) is extremely rare. These patients may be misdiagnosed with acute myeloid leukemia or solid tumor, and the main treatment can also be delayed. PATIENT CONCERNS: A 2.10-year-old girl was referred to the pediatric surgery clinic with a worsening onset of clitoris swellings. The patient was afebrile and well appearing. Multiple retroperitoneal mass were confirmed by computed tomography (CT) and high serum neuron-specific enolase level was high. She was scheduled for an abdominal biopsy from the retroperitoneal mass suspicious of neuroblastoma. DIAGNOSES: The child was eventually diagnosed as having precursor B cell ALL with central nervous system involved, with TCF3-PBX1 fusion gene and additional chromosomal aberrations, based on examinations of the bone marrow and brain magnetic resonance imaging. INTERVENTIONS: Before the diagnosis of leukemia, the patient was given symptomatic treatment for 1 week. She was treated with chemotherapy in accordance with the Chinese Children's Cancer Group protocol 2015 after confirmed diagnosis. OUTCOMES: After induction chemotherapy for ALL, although the girl had transiently clinical remission, the bone marrow aspirate indicated a poor outcome. Our patient discontinued treatment and discharged. From literature review, there was only 1 case of in acute myeloid leukemia with clitoris swelling as the initial symptom. LESSONS: The clinical symptoms of ALL with clitoris swelling are not typical, with a high rate of misdiagnosis. When the cause of clitoris swelling is unknown, ALL should be considered. Bone marrow aspiration must be done before doing a more invasive investigation like biopsy.

Efficacy and safety of low dose aspirin and magnesium sulfate in the treatment of pregnancy induced hypertension: A protocol for systematic review and meta-analysis.

BACKGROUND: Magnesium sulfate combined with low-dose aspirin can significantly reduce adverse reactions and effectively lower blood pressure in patients with pregnancy induced hypertension, but the overall efficacy and safety of the combination of drugs are not clear. The purpose of this study was to evaluate the efficacy and safety of magnesium sulfate combined with low-dose aspirin in the treatment of pregnancy induced hypertension. METHODS: Randomized controlled trials focusing on the administration of magnesium sulfate combined with low-dose aspirin for pregnancy induced hypertension were searched from PubMed, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang, and the Chongqing VIP Chinese Science and Technology Periodical Database. Two researchers independently screened titles, abstracts, and full texts, and extracted relevant data. The RevMan 5.3 software and Stata 14 software were used for statistical analysis. RESULTS: The effect and safety of magnesium sulfate combined with low-dose aspirin in the treatment of pregnancy induced hypertension were assessed by summarizing the related randomized controlled trials. CONCLUSION: This article provides theoretical support for the clinical application of magnesium sulfate combined with low-dose aspirin in the treatment of pregnancy induced hypertension. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/SZFGB.

Impact of mirna-21 on survival prognosis in patients with pancreatic cancer: A protocol for systematic review and meta-analysis.

BACKGROUND: Previous studies have reported that microRNA-21 (mRNA-21) has an effect on the prognosis of pancreatic cancer. However, the conclusion is still unclear. Therefore, this study will try to explore the effect of high expression of mRNA-21 on the prognosis of pancreatic cancer. METHODS: Retrieved the database, including the China National Knowledge Infrastructure (CNKI), Chinese Biomedical literature Database (CBM), Chinese Scientific and Journal Database (VIP), Wan Fang database, PubMed, and EMBASE. Hazard ratios (HRs) and its 95% confidence intervals (CIs) to assess the prognostic effect of miRNA-21 on overall survival (OS) and disease-free survival (DFS). RevMan 5.3 and STATA 16.0 software were used to perform the meta-analysis. RESULTS: This study will comprehensively review and evaluate the available evidence of high expression of miRNA-21 on the prognosis of patients with pancreatic cancer. CONCLUSION: Our findings will show the effect of high expression of miRNA-21 on the prognosis of patients with pancreatic cancer. Such studies may find a new prognostic marker for patients with pancreatic cancer and help clinicians and health professionals make clinical decisions. ETHICS AND DISSEMINATION: The private information from individuals will not publish. This systematic review also will not involve endangering participant rights. Ethical approval is not available. The results may be published in a peer- reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/2A6KJ.