Oncolytic Newcastle disease virus induced degradation of YAP through E3 ubiquitin ligase PRKN to exacerbate ferroptosis in tumor cells.

Ferroptosis, a form of programmed cell death characterized by iron-dependent lipid peroxidation, has recently gained considerable attention in the field of cancer therapy. There is significant crosstalk between ferroptosis and several classical signaling pathways, such as the Hippo pathway, which suppresses abnormal growth and is frequently aberrant in tumor tissues. Yes-associated protein 1 (YAP), the core effector molecule of the Hippo pathway, is abnormally expressed and activated in a variety of malignant tumor tissues. We previously proved that the oncolytic Newcastle disease virus (NDV) activated ferroptosis to kill tumor cells. NDV has been used in tumor therapy; however, its oncolytic mechanism is not completely understood. In this study, we demonstrated that NDV exacerbated ferroptosis in tumor cells by inducing ubiquitin-mediated degradation of YAP at Lys90 through E3 ubiquitin ligase parkin (PRKN). Blocking YAP degradation suppressed NDV-induced ferroptosis by suppressing the expression of Zrt/Irt-like protein 14 (ZIP14), a metal ion transporter that regulates iron uptake. These findings demonstrate that NDV exacerbated ferroptosis in tumor cells by inducing YAP degradation. Our study provides new insights into the mechanism of NDV-induced ferroptosis and highlights the critical role that oncolytic viruses play in the treatment of drug-resistant cancers.IMPORTANCEThe oncolytic Newcastle disease virus (NDV) is being developed for use in cancer treatment; however, its oncolytic mechanism is still not completely understood. The Hippo pathway, which is a tumor suppressor pathway, is frequently dysregulated in tumor tissues due to aberrant yes-associated protein 1 (YAP) activation. In this study, we have demonstrated that NDV degrades YAP to induce ferroptosis and promote virus replication in tumor cells. Notably, NDV was found to induce ubiquitin-mediated degradation of YAP at Lys90 through E3 ubiquitin ligase parkin (PRKN). Our study reveals a new mechanism by which NDV induces ferroptosis and provides new insights into NDV as an oncolytic agent for cancer treatment.

Machine Learning-Based Integrated Analysis of PANoptosis Patterns in Acute Myeloid Leukemia Reveals a Signature Predicting Survival and Immunotherapy.

Objective: We conducted a meticulous bioinformatics analysis leveraging expression data of 226 PANRGs obtained from previous studies, as well as clinical data from AML patients derived from the HOVON database. Methods: Through meticulous data analysis and manipulation, we were able to categorize AML cases into two distinct PANRG clusters and subsequently identify differentially expressed genes (PRDEGs) with prognostic significance. Furthermore, we organized the patient data into two corresponding gene clusters, allowing us to investigate the intricate relationship between the risk score, patient prognosis, and the immune landscape. Results: Our findings disclosed significant associations between the identified PANRGs, gene clusters, patient survival, immune system, and cancer-related biological processes and pathways. Importantly, we successfully constructed a prognostic signature comprising nineteen genes, enabling the stratification of patients into high-risk and low-risk groups based on individually calculated risk scores. Furthermore, we developed a robust and practical nomogram model, integrating the risk score and other pertinent clinical features, to facilitate accurate patient survival prediction. Our comprehensive analysis demonstrated that the high-risk group exhibited notably worse prognosis, with the risk score proving to be significantly correlated with infiltration of most immune cells. The qRT-PCR results revealed significant differential expression patterns of LGR5 and VSIG4 in normal and human leukemia cell lines (HL-60 and MV-4-11). Conclusions: Our findings underscore the potential utility of PANoptosis-based molecular clustering and prognostic signatures as predictive tools for assessing patient survival in AML.

Vitamin B complex blocks the dust fall PM2 .5 -induced acute lung injury through DNA methylation in rats.

This study aimed to explore whether vitamin B complex (folic acid, B6 , and B12 ) could avert DNA methylation changes associated with inflammation induced by acute PM2.5 exposure. Sprague-Dawley rats were administered by gavage with different concentrations of vitamin B complex once a day for 28 days, and then by intratracheal instillation with saline or PM2.5 once every 2 days for three times. Vitamin B continued to be taken during the PM2.5 exposure. Rats were sacrificed 24 h after the last exposure. The results showed that vitamin B complex could block the pathological changes and injury in lungs induced by PM2.5 . Meanwhile, vitamin B complex could prevent the abnormal DNA methylation of IL-4 and IFN-γ to antagonize the imbalance of IL-4/IFN-γ associated with inflammation. It was further found that vitamin B complex could regulate DNA methyltransferases (DNMTs) and increase the S-adenosylmethionine (SAM)/S-Adenosyl-L-homocysteine (SAH) ratio to reverse the hypomethylation of genomic DNA and the abnormal DNA methylation of IL-4 and IFN-γ. In conclusion, vitamin B complex has a protective effect on acute lung injury by attenuating abnormal DNA methylation induced by PM2.5 in rats. This study may provide a new insight into the physiological function of vitamin B to prevent the health effects induced by PM2.5 .

Pitavastatin stimulates retinal angiogenesis via HMG-CoA reductase-independent activation of RhoA-mediated pathways and focal adhesion.

BACKGROUND: Excessive angiogenesis of the retina is a key component of irreversible causes of blindness in many ocular diseases. Pitavastatin is a cholesterol-lowering drug used to reduce the risk of cardiovascular diseases. Various studies have shown the effects of pitavastatin on angiogenesis but the conclusions are contradictory. The effects of pitavastatin on retinal angiogenesis have not been revealed. This study investigated the effects of pitavastatin at clinically relevant concentrations on retinal angiogenesis and its underlying mechanisms using retinal microvascular endothelial cells (RMECs). METHODS: The effects of pitavastatin on retinal angiogenesis were determined using in vitro model of retinal angiogenesis, endothelial cell migration, adhesion, proliferation, and apoptosis assays. The mechanism studies were conducted using immunoblotting and stress fiber staining. RESULTS: Pitavastatin stimulated capillary network formation of RMECs in a similar manner as vascular endothelial growth factor (VEGF) and lipopolysaccharide (LPS). Pitavastatin also increased RMEC migration, adhesion to Matrigel, growth, and survival. The combination of pitavastatin with VEGF or LPS was more effective than VEGF or LPS alone in stimulating biological activities of RMECs, suggesting that pitavastatin can enhance the stimulatory effects of VEGF and LPS on retinal angiogenesis. Pitavastatin acted on RMECs in a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-independent manner. In contrast, pitavastatin activated pro-angiogenic microenvironment via promoting the secretion of VEGF and stimulated retinal angiogenesis via multiple mechanisms including activation of RhoA-mediated pathways, induction of focal adhesion complex formation, and activation of ERK pathway. CONCLUSION: Our work provides a preclinical evidence on the pro-angiogenic effect of pitavastatin in retina via multiple mechanisms that are irrelevant to mevalonate pathway.

Membrane ion Channels and Receptors in Animal lifespan Modulation.

Acting in the interfaces between environment and membrane compartments, membrane ion channels, and receptors transduce various physical and chemical cues into downstream signaling events. Not surprisingly, these membrane proteins play essential roles in a wide range of cellular processes such as sensory perception, synaptic transmission, cellular growth and development, fate determination, and apoptosis. However, except insulin and insulin-like growth factor receptors, the functions of membrane receptors in animal lifespan modulation have not been well appreciated. On the other hand, although ion channels are popular therapeutic targets for many age-related diseases, their potential roles in aging itself are largely neglected. In this review, we will discuss our current understanding of the conserved functions and mechanisms of membrane ion channels and receptors in the modulation of lifespan across multiple species including Caenorhabditis elegans, Drosophila, mouse, and human.

[Recurrent pulmonary infection and oral mucosal ulcer].

An 8-year-old girl who had experienced intermittent cough and fever over a 3 year period, was admitted after experiencing a recurrence for one month. One year ago the patient experienced a recurrent oral mucosal ulcer. Physical examination showed vitiligo in the skin of the upper right back. Routine blood tests and immune function tests performed in other hospitals had shown normal results. Multiple lung CT scans showed pulmonary infection. The patient had recurrent fever and cough and persistent presence of some lesions after anti-infective therapy. The antitubercular therapy was ineffective. Routine blood tests after admission showed agranulocytosis. Gene detection was performed and she was diagnosed with dyskeratosis congenita caused by homozygous mutation in RTEL1. Patients with dyskeratosis congenita with RTEL1 gene mutation tend to develop pulmonary complications. Since RTEL1 gene sequence is highly variable with many mutation sites and patterns and can be inherited via autosomal dominant or recessive inheritance, this disease often has various clinical manifestations, which may lead to missed diagnosis or misdiagnosis. For children with unexplained recurrent pulmonary infection, examinations of the oral cavity, skin, and nails and toes should be taken and routine blood tests should be performed to exclude dyskeratosis congenita. There are no specific therapies for dyskeratosis congenita at present, and when bone marrow failure and pulmonary failure occur, hematopoietic stem cell transplantation and lung transplantation are the only therapies. Androgen and its derivatives are effective in some patients. Drugs targeting the telomere may be promising for patients with dyskeratosis congenita.

Inhibition of the oxidative stress response by heat stress in Caenorhabditis elegans.

It has long been recognized that simultaneous exposure to heat stress and oxidative stress shows a synergistic interaction that reduces organismal fitness, but relatively little is known about the mechanisms underlying this interaction. We investigated the role of molecular stress responses in driving this synergistic interaction using the nematode Caenorhabditis elegans To induce oxidative stress, we used the pro-oxidant compounds acrylamide, paraquat and juglone. As expected, we found that heat stress and oxidative stress interact synergistically to reduce survival. Compared with exposure to each stressor alone, during simultaneous sublethal exposure to heat stress and oxidative stress the normal induction of key oxidative-stress response (OxSR) genes was generally inhibited, whereas the induction of key heat-shock response (HSR) genes was not. Genetically activating the SKN-1-dependent OxSR increased a marker for protein aggregation and decreased whole-worm survival during heat stress alone, with the latter being independent of HSF-1. In contrast, compared with wild-type worms, inactivating the HSR by HSF-1 knockdown, which would be expected to decrease basal heat shock protein expression, increased survival during oxidative stress alone. Taken together, these data suggest that, in C. elegans, the HSR and OxSR cannot be simultaneously activated to the same extent that each can be activated during a single stressor exposure. We conclude that the observed synergistic reduction in survival during combined exposure to heat stress and oxidative stress is due, at least in part, to inhibition of the OxSR during activation of the HSR.

[Shang Ring scissor circumcision versus electrotome circumcision for redundant prepuce].

OBJECTIVE: To compare the clinical effects of Shang Ring scissor circumcision (SC) and electrotome circumcision (EC) in the treatment of redundant prepuce or phimosis.Methods: Results: Conclusion. METHODS: This retrospective study included 524 patients with redundant prepuce or phimosis, 422 treated by SC and 120 by EC. We made comparisons between the two groups of patients in the operation time, intra- and post-operative pain scores, pain scores before, at and after ring removal, wound healing time, and incidence rates of postoperative edema and incision dehiscence. RESULTS: The operation time was longer in the SC than in the EC group (ï¼»59.99±5.39ï¼½ vs ï¼»39.94±4.94ï¼½ sec, P<0.05), but there were no significant differences between the two groups in the intraoperative pain scores (1.02±0.74 vs 1.08±0.59, P>0.05) or the pain scores within 24 h after operation (6.74±1.01 vs 6.56±1.06, P>0.05), 24 h prior to ring removal (1.14±0.69 vs 1.10±0.64, P>0.05), and after ring removal (2.73±0.74 vs 2.85±0.75, P>0.05) except at ring removal, which was remarkably lower in the SC than in the EC group (3.56±0.47 vs 4.77±0.58, P<0.05). The wound healing time was markedly shorter in the former than in the latter (ï¼»14.11±1.26ï¼½ vs ï¼»39.78±7.55ï¼½ d, P<0.05), but the incidence rate of incision dehiscence showed no significant difference between the two groups (4.03% ï¼»17/422ï¼½ vs 9.17% ï¼»11/120ï¼½, P>0.05). The rate of postoperative satisfaction with the external penile appearance was 100% in both of the two groups. CONCLUSIONS: Shang Ring scissor circumcision is preferred to electrotome circumcision for its advantages of less pain at ring removal and shorter healing time despite its longer operation time.

ω-3PUFAs Inhibit Hypoxia-Induced Retinal Neovascularization via Regulating Microglial Pyroptosis through METTL14-Mediated m6A Modification of IFNB1 mRNA.

Retinal neovascular disease is the leading reason of vision impairment in all ages. Here, we figured out the function and mechanism of omega-3 polyunsaturated fatty acids (ω-3PUFAs) in hypoxia-induced retinal neovascularization by focusing on microglial pyroptosis. Microglia BV-2 cells were given ω-3PUFAs treatment and co-cultured with mouse retinal microvascular endothelial cells (MRMECs) under hypoxia. Tube formation assay, transwell assay and wound healing assay were utilized to monitor the MRMEC angiogenesis. Cell counting kit-8, western blot, lactate dehydrogenase assay, and enzyme-linked immunosorbent assay were used to assess pyroptosis of BV-2 cells. RNA sequencing and methylated RNA immunoprecipitation-polymerase chain reaction were utilized to identify the target gene of methyltransferase-like 14 (METTL14) and its N6-methyladenosine (m6A) level in BV-2 cells. BV-2 cells prominently enhanced MRMEC angiogenesis under hypoxia, but this effect was abolished after ω-3PUFAs treatment. ω-3PUFAs inhibited pyroptosis in hypoxia-induced BV-2 cells, and BV-2 cell pyroptosis boosted angiogenesis of MRMECs. Additionally, ω-3PUFAs markedly augment the expression of MELLL14 in BV-2 cells, and METTL14 knockdown promoted BV-2 cell pyroptosis and BV-2 cell-mediated angiogenesis in MEMECs. Mechanistically, interferon beta 1 (IFNB1) was a target of METTL14, and METTL14 silencing increased the mRNA expression and decreased the m6A modification of IFNB1 in BV-2 cells. Our results uncovered that ω-3PUFAs diminished hypoxia-induced retinal neovascularization through controlling microglial pyroptosis via METTL14-mediated m6A modification. This study offers a novel potential target for the treatment of retinal neovascular diseases.

TXNDC12 inhibits lipid peroxidation and ferroptosis.

Ferroptosis is a type of regulated cell death characterized by lipid peroxidation and subsequent damage to the plasma membrane. Here, we report a ferroptosis resistance mechanism involving the upregulation of TXNDC12, a thioredoxin domain-containing protein located in the endoplasmic reticulum. The inducible expression of TXNDC12 during ferroptosis in leukemia cells is inhibited by the knockdown of the transcription factor ATF4, rather than NFE2L2. Mechanistically, TXNDC12 acts to inhibit lipid peroxidation without affecting iron accumulation during ferroptosis. When TXNDC12 is overexpressed, it restores the sensitivity of ATF4-knockdown cells to ferroptosis. Moreover, TXNDC12 plays a GPX4-independent role in inhibiting lipid peroxidation. The absence of TXNDC12 enhances the tumor-suppressive effects of ferroptosis induction in both cell culture and animal models. Collectively, these findings demonstrate an endoplasmic reticulum-based anti-ferroptosis pathway in cancer cells with potential translational applications.

[The protective function and mechanism of notoginsenoside Rb1 against hypoxia hypercapnia-induced pulmonary vasoconstriction].

OBJECTIVE: To explore the protective function and mechanism of notoginsenoside Rb1 against hypoxia hypercapnia-induced pulmonary vasoconstriction (HHPV). METHODS: The pulmonary artery smooth muscle cells of healthy male SD rats were primarily cultured and the second to the fifth subcultured cells were incubated with 8, 40, and 100 mg/L notoginsenoside Rb1 respectively under the hypoxia-hypercapnia condition (1% O2 and 6% CO2). The cells were harvested for 24 h. The phosphated extracellular signal-regulated kinase (p-ERK) protein expression of the cells was detected by Western blot. The mRNA expressions of ERK1 and ERK2 were detected using half quantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The expression of p-ERK protein, the mRNA expressions of ERK1 and ERK2 were weakly positive in the control group. Their expressions in the hypoxia-hypercapnia group were obviously enhanced (P < 0.01). After intervention of Rb1 at different concentrations, their expressions were obviously lowered (P < 0.05, P < 0.01) in a dose-dependent manner. The optimal effects were obtained at the dose of 100 mg/L. The expression of p-ERK protein was significantly positively correlated with mRNA expressions of ERK1 and ERK2 in notoginsenoside Rbl-treated groups (r = 0.500, P < 0.01; r = 0.977, P < 0.01). CONCLUSIONS: ERK1/2 pathway might play a role in the rat HHPV. Notoginsenoside Rb, could alleviate HHPV by inhibiting the ERK1/2 pathway.

mTOR inhibition by TAK-228 is effective against growth, survival and angiogenesis in preclinical retinoblastoma models.

We and others have shown that aberrant activation of the mammalian target of rapamycin (mTOR) signalling is essential for retinoblastoma progression and has potential therapeutic value. TAK-228 is a potent inhibitor of mTOR1 and 2 with preclinical activity in a variety of cancers. In this study, we report that TAK-228 is a dual inhibitor of retinoblastoma and angiogenesis. TAK-228 inhibits growth and induces apoptosis in a panel of retinoblastoma cell lines, with IC50 at ~0.2 µM. Under the same experimental conditions, TAK-228 was less effective in inhibiting growth and survival in normal retinal and fibroblast cells than retinoblastoma cells. In addition, TAK-228 inhibited retinal endothelial cell capillary network formation, migration, growth and survival. We further demonstrate that TAK-228 inhibits retinoblastoma and retinal angiogenesis through inhibiting mTOR signalling. Rescue studies confirm that mTOR is the target of TAK-228 in both retinoblastoma and retinal endothelial cells. Finally, we confirm the inhibitory effects of TAK-228 on tumor and angiogenesis in retinoblastoma xenograft mouse model. Our findings provide a preclinical rationale to explore TAK-228 as a strategy to treat retinoblastoma and highlight the therapeutic value of targeting mTOR in retinoblastoma.

Case report: Application of metagenomic next-generation sequencing in the diagnosis of visceral leishmaniasis and its treatment evaluation.

Visceral leishmaniasis is a vector-borne infection by the Leishmania spp., a parasite. Although the overall incidence of visceral leishmaniasis is low, the disease still occurs frequently in some high-risk areas. In our study, two patients were admitted to the hospital with an unprovoked and recurrent high fever, and the condition was not improved after antibiotics administration. Meanwhile, bone marrow aspiration smears failed to find out any pathogen. Finally, Leishmania-specific nucleic acid sequences were successfully detected in the peripheral blood of two patients through metagenomic next-generation sequencing (mNGS), which was further confirmed by bone marrow smear microscopy and antibody tests. After targeted treatment for visceral leishmaniasis in the patients, mNGS reported a decrease in the reads number of Leishmania sequence. The results indicate the feasibility of mNGS in detecting Leishmania spp. in peripheral blood samples. Its therapeutic effect evaluation may be achieved through a comparative analysis of the number of reads before and after the treatment.

Correlation of Glucose Metabolism with Cancer and Intervention with Traditional Chinese Medicine.

Cancer is a complex disease with several distinct characteristics, referred to as "cancer markers" one of which is metabolic reprogramming, which is a common feature that drives cancer progression. Over the last ten years, researchers have focused on the reprogramming of glucose metabolism in cancer. In cancer, the oxidative phosphorylation metabolic pathway is converted into the glycolytic pathway in order to meet the growth requirements of cancer cells, thereby creating a microenvironment that promotes cancer progression. The precise mechanism of glucose metabolism in cancer cells is still unknown, but it is thought to involve the aberrant levels of metabolic enzymes, the influence of the tumor microenvironment (TME), and the activation of tumor-promoting signaling pathways. It is suggested that glucose metabolism is strongly linked to cancer progression because it provides energy to cancer cells and interferes with antitumor drug pharmacodynamics. Therefore, it is critical to unravel the mechanism of glucose metabolism in tumors in order to gain a better understanding of tumorigenesis and to lay the groundwork for future research into the identification of novel diagnostic markers and therapeutic targets for cancer treatment. Traditional Chinese Medicine (TCM) has the characteristics of multiple targets, multiple components, and less toxic side effects and has unique advantages in tumor treatment. In recent years, researchers have found that a variety of Chinese medicine monomers and compound recipes play an antitumor role by interfering with the reprogramming of tumor metabolism. The underlying mechanisms of metabolism reprogramming of tumor cells and the role of TCM in regulating glucose metabolism are reviewed in this study, so as to provide a new idea for antitumor research in Chinese medicine.

TRPV1 Receptor-Mediated Hypoglycemic Mechanism of Capsaicin in Streptozotocin-Induced Diabetic Rats.

Our previous research showed that capsaicin exhibits hypoglycemic effects by activating the transient receptor potential vanilloid 1 (TRPV1) channel in diabetic rats. Interestingly, capsiate was also able to activate the TRPV1 channel, but with a non-significant hypoglycemic effect. This study aimed to investigate the effect of capsaicin on the glycometabolism of streptozotocin (STZ)-induced diabetic rats by blocking the TRPV1 channel. After a 4-week capsaicin treatment (6 mg/kg·bw), the serum insulin level of STZ-induced diabetic rats increased from 15.2 to 22.1 mIU/L, the content of hepatic glycogen and muscle glycogen increased by 81.2 and 20.2%, respectively, and the blood glucose level decreased significantly from 19.3 to 14.7 mmol/L. When the TRPV1 channel was blocked, capsaicin lost the above-mentioned effects, and the hypoglycemic effect was no longer significant. It was concluded that a combined up-regulation of both TRPV1 receptors and pancreatic duodenal homeobox-1 (PDX-1) led to the hypoglycemic effect of capsaicin, which partially explains our previous observation: capsiate activating TRPV1 without showing a significant hypoglycemic effect was due to the lack of a significant up-regulation of PDX-1. Based on the experimental results, we speculated that two signaling pathways [TRPV1-(PDX1)-(GLUT2/GK) and TRPV1-(PDX-1)-(IRS1/2)] exist in the pancreas of STZ-induced diabetic rats.

Elevated P-Element-Induced Wimpy-Testis-Like Protein 1 Expression Predicts Unfavorable Prognosis for Patients with Various Cancers.

Increasing evidence has shown that overexpression of P-element-induced wimpy-testis (PIWI)-like protein 1 (PIWIL1) was associated with unfavorable prognosis of patients with various types of cancers. Herein, we conducted this meta-analysis to identify the clinicopathological and prognostic value of the PIWIL1 expression in cancers. Three electronic databases (PubMed, Web of Science, and Embase) were comprehensively retrieved for relevant studies up to August 4th, 2019. RevMan 5.3 and STATA 12.0 statistical software programs were used to explore the relationships between PIWIL1 expression and the prognosis and clinicopathological features in cancer patients. A total of 13 studies recruiting 2179 patients with 9 types of solid tumors were finally included in the meta-analysis. The results indicated that patients with high PIWIL1 expression tended to have a shorter survival, and additionally deeper tumor invasion, higher clinical stage, and more lymph node metastasis. PIWIL1 could serve as a biomarker for prognosis and clinicopathological characteristics in various cancers.

[Involvement of metallothionein in the protection of lung ischemic preconditioning].

The aim of the present study was to investigate whether metallothionein was involved in the protection of lung ischemic preconditioning (IP) against lung ischemia-reperfusion (I/R) injury. Adult male Sprague-Dawley rats were randomly divided into 3 groups based upon the intervention (n=8): control group (C), lung I/R group (I/R), lung I/R+IP group (IP). At the end of the experiment, the content of metallothionein was tested in lung tissue. Blood specimens collected from the arteria carotis were tested for the contents of malondialdehyde (MDA), the activities of superoxide dismutase (SOD) and myeloperoxidase (MPO). The pneumocyte apoptosis index (AI) was determined by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL). Ultrastructural changes of lung tissue were observed by using transmission electron microscope. The results showed that in I/R group, the content of metallothionein was decreased (P<0.05), the content of MDA and MPO activity were increased (P<0.01), and SOD activity was decreased (P<0.01), compared with those in control group. IP treatment significantly increased the content of metallothionein (P<0.01), attenuated the MDA level (P<0.05) and MPO activity (P<0.01), and improved SOD activity (P<0.01) in blood serum. The number of TUNEL-positive cells in IP group was significantly reduced compared with that in I/R group (P<0.01). There were abnormal ultrastructural changes in I/R group, which were markedly reversed in IP group. In conclusion, IP may protect lung against I/R injury by inducing the expression of metallothionein.

Intravenous leiomyomatosis: molecular analysis of 17 cases.

Intravenous leiomyomatosis (IVL) is a rare smooth muscle tumour with a benign histology but with a quasi-malignant intravascular growth. In this study, we investigated the molecular alterations in 17 IVL cases composed of concurrent uterine leiomyoma (n=12), uterine IVL (n=17) and extra-uterine IVL (n=12). We found that eight tumours had a somatic MED12 mutation (c.130G>A, p.G44S, n=7; c.131G>C, p.G44A, n=1). The frequency of MED12 mutations was significantly higher in concurrent uterine leiomyoma (6/12, 50%) than in uterine (0/17, 0%) and extra-uterine IVL (2/12, 16.7%). The frequency of HMGA2 over-expression or MED12 low-expression was not significantly different among uterine leiomyoma, IVL and extra-uterine IVL (p>0.05). Short tandem repeat (STR) analysis indicated that one uterine and two extra-uterine IVL tumours from three patients were microsatellite instability positive (MSI+) whereas loss of heterozygosity (LOH) was found in one uterine leiomyoma, three uterine and three extra-uterine IVL tumours from five patients. LOH was more frequently seen in uterine/extra-uterine IVL tumours (6/20, 30%) than in the concurrent leiomyomas (1/7, 14.3%) (p<0.05). MED12 mutation, MSI and LOH were discordant between uterine and extra-uterine IVL in all patients. These findings suggest that IVL harbours distinct molecular pathogenesis from common uterine leiomyomas. Uterine IVL and extra-uterine tumours may represent an independent origin rather than uniclonal dissemination from a single tumour. Further investigations are warranted to explore the underlying key molecular events in the pathogenesis of IVL.

Long non-coding RNA SNHG5 regulates chemotherapy resistance through the miR-32/DNAJB9 axis in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a common hematopoietic malignancy with invasive activity. Drug resistance greatly contributes to the poor efficacy of chemotherapy in AML treatment. Recent research indicates that long non-coding RNAs (LncRNAs) regulates chemotherapy resistance in malignancy. METHODS: Microarray analysis was used to screen out AML related genes, and interaction between small nucleolar RNA host gene 5(SNHG5) and miR-32, as well as that between miR-32 and DNAJB9. Quantitative real-time PCR (qRT-PCR) and In situ hybridization(ISH) were used to determine the expression levels of SNHG5, miR-32 and DNAJB9 mRNA in AML cell lines and clinic samples. Western blot was performed to detect protein expression levels. After being treated with varying concentrations of Adriamycin(ADM), cell viability was evaluated using a cell counting kit-8(CCK8). RESULTS: We carried out a genome-wide LncRNA expression study and found SNHG5 aberrantly overexpressed in AML comparing to the donors. Knock-down of SNHG5 promoted sensitivity of AML cells to chemotherapy. In addition, miR-32 was identified as the downstream target of SNHG5 and miR-32 inhibitor abrogated the inhibiting effects of downregulated SNHG5 on AML cell viability. Furthermore, inhibited SNHG5 decreased DNAJB9 expression levels by sponging miR-32. The SNHG5/miR-32/DNAJB9 axis targeted autophagy to regulate chemotherapy resistance. CONCLUSION: SHNG5 regulates chemotherapy resistance by targeting the miR-32/DNAJB9 axis in acute myeloid leukemia, which provided a novel potential target for AML and revealed an important mechanism of chemotherapy resistance.

Oxidative effects of lungs in Wistar rats caused by long-term exposure to four kinds of China representative chrysotile.

Chrysotile accounts for some 90% to 95% of all the asbestos used worldwide. Scientific evidences have shown that asbestos (including chrysotile) exposure is associated with increased rates of lung cancer, asbestosis, and mesothelioma. However, molecular mechanisms underlying the toxicity effects of chrysotile are not clear. This study evaluated the oxidative stress in chronic lung toxicity caused by the intratracheal instillation (IT) of four kinds China representative chrysotile once a month for 12 months in Wistar rats. These results indicated that chrysotile exposure led to an obvious increase in lung mass and slowed the growth of body mass. Inflammation and fibrosis were observed by hematoxylin-eosin (HE) staining. Exposure to chrysotile significantly increased the accumulation of reactive oxygen species (ROS) and the level of lipid peroxidation and decreased antioxidant capacity in lung tissues. Furthermore, 1-6-month chrysotile exposure activated heme oxygenase-1 (HO-1) and heat shock protein 70 (HSP70) expression, whereas 12-month exposure caused significant decreases of two-factor expression levels in XK and MN groups when compared to negative control group. Therefore, our results suggested that chronic chrysotile pulmonary injury in Wistar rats is triggered by oxidative damage. Meanwhile, the oxidative damage of MN and XK was stronger than that of SSX and AKS, and the difference of oxidative damage in four chrysotile could have been brought by its properties, morphology, chemical composition, and particle size. With all the above mentioned in view, we hope that the revealed data in the experiment could contribute to the progress of further researches on the toxicity and mechanism of chrysotile.