Clinical phenotype and genetic function analysis of a family with hypomyelinating leukodystrophy-7 caused by POLR3A mutation.

Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.

Potential regulatory role of the Nrf2/HMGB1/TLR4/NF-κB signaling pathway in lupus nephritis.

OBJECTIVES: Systemic lupus erythematosus is an autoimmune disease that involves multiple organ systems. One of its major complications, lupus nephritis (LN), is associated with a high mortality rate, and children-onset LN have a more severe course and worse prognosis than adults. Oxidative stress and inflammatory responses are involved in LN development and pathogenesis. Thus, this study aimed to explore the role of signaling regulation of the Nrf2/HMGB1/TLR/NF-κB pathway in LN pathogenesis and unravel the expression of TLR4+CXCR4+ plasma cells subset (PCs) in LN. METHODS: C57BL/6 and MRL/lpr mice were divided into four groups: control, model, vector control, and Nrf2 overexpression groups. The vector control and Nrf2 overexpression groups were injected with adenoviral vectors into the kidney in situ. Pathological changes in kidney tissues were observed by hematoxylin-eosin staining. The expression of Nrf2, HMGB1, TLR4, NF-κB, and downstream inflammatory factors in kidney samples was analyzed by quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The ratios of TLR4+CXCR4+ PC subsets in the blood and kidneys of mice were determined by flow cytometry. RESULTS: In MRL/lpr mice, Nrf2 was downregulated while HMGB1/TLR4/NF-κB pathway proteins were upregulated. Nrf2 overexpression decreased the expression of HMGB1, TLR4, NF-κB, and its downstream inflammatory cytokines (IL-1ß and TNFα). These cytokines were negatively correlated with an increase in Nrf2 content. PC and TLR4 + CXCR4 + PCs in the blood and kidney samples were significantly increased in MRL/lpr mice; however, they were decreased upon Nrf2 overexpression. CONCLUSION: This study showed severe kidney injury in an LN mouse model and an increased ratio of TLR4 + CXCR4 + PCs. Furthermore, we observed that Nrf2 regulates LN immune response through the Nrf2/HMGB1/TLR4/NF-κB pathway, which can be considered an important target for LN treatment. The clinical value of the findings of our study requires further investigation.

Pharmarcomechanical thrombectomy combined with transluminal balloon angioplasty for treating transplant renal vein thrombosis.

Renal vein thrombosis (RVT) is a rare vascular complication that occurs after renal transplantation and usually results in irreversible kidney damage and graft loss. We report the case of a patient who underwent right iliac fossa allogeneic kidney transplantation and developed RVT combined with ipsilateral thrombosis from the popliteal to the femoral veins, with extension to the common iliac veins, 4 months after transplantation. Under unfractionated heparin anticoagulation, an Aegisy (Life Tech Scientific Co., Ltd., Shenzhen, China) vena cava filter was placed to prevent pulmonary embolism. Percutaneous mechanical thrombectomy combined with balloon angioplasty was performed to aspirate the thrombus and successfully dilate the narrow venous lumen. The patient's renal function was restored postoperatively. Ultrasonography showed the allograft and ipsilateral lower extremity deep veins to be fluent and patent. To conclude, in patients with RVT after renal transplantation, percutaneous mechanical thrombectomy in conjunction with balloon angioplasty can be performed with desirable outcomes and no severe adverse effects. This method reduces the risk of bleeding from exposure to systemic intravenous thrombolysis and avoids surgery-associated trauma.

CDK13 promotes lipid deposition and prostate cancer progression by stimulating NSUN5-mediated m5C modification of ACC1 mRNA.

Cyclin-dependent kinases (CDKs) regulate cell cycle progression and the transcription of a number of genes, including lipid metabolism-related genes, and aberrant lipid metabolism is involved in prostate carcinogenesis. Previous studies have shown that CDK13 expression is upregulated and fatty acid synthesis is increased in prostate cancer (PCa). However, the molecular mechanisms linking CDK13 upregulation and aberrant lipid metabolism in PCa cells remain largely unknown. Here, we showed that upregulation of CDK13 in PCa cells increases the fatty acyl chains and lipid classes, leading to lipid deposition in the cells, which is positively correlated with the expression of acetyl-CoA carboxylase (ACC1), the first rate-limiting enzyme in fatty acid synthesis. Gain- and loss-of-function studies showed that ACC1 mediates CDK13-induced lipid accumulation and PCa progression by enhancing lipid synthesis. Mechanistically, CDK13 interacts with RNA-methyltransferase NSUN5 to promote its phosphorylation at Ser327. In turn, phosphorylated NSUN5 catalyzes the m5C modification of ACC1 mRNA, and then the m5C-modified ACC1 mRNA binds to ALYREF to enhance its stability and nuclear export, thereby contributing to an increase in ACC1 expression and lipid deposition in PCa cells. Overall, our results disclose a novel function of CDK13 in regulating the ACC1 expression and identify a previously unrecognized CDK13/NSUN5/ACC1 pathway that mediates fatty acid synthesis and lipid accumulation in PCa cells, and targeting this newly identified pathway may be a novel therapeutic option for the treatment of PCa.

Theoretical Exploration of Properties of Iron-Silicon Interface Constructed by Depositing Fe on Si(111)-(7×7).

Exploring the properties of magnetic metal on the semiconductor surface is of great significance for the application of magnetic recording materials. Herein, DFT calculations are carried out to explore the properties of the iron-silicon interface structures (nFe/DASF) formed by depositing n Fe atoms on the reconstructed Si(111)-(7×7) surface (DASF). The stable nFe/DASF structures are studied in the cases of the adsorption and permeation of Fe atoms on the DASF. In both cases, Fe atoms are not very dispersed and prefer binding with Si atoms rather than the adsorbed Fe atoms, because the Fe-Si interaction is stronger than the Fe-Fe interaction. As the n value increases, the average binding energy (Eb_ave) of Fe generally firstly becomes more negative and then becomes less negative, with the presence of a 7Fe wheel as a stable geometry on the upmost surface. The presence of the 7Fe wheel is attributed to the enhanced Fe-Si interaction in this wheel compared to other geometries. CO adsorption occurs at the central Fe site of the 7Fe wheel which is greatly influenced by the surrounding Si atoms but is little influenced by the additional Fe atoms in the interlayer.

Differences in Pathogenicity and Vaccine Resistance Discovered between Two Epidemic Strains of Marek's Disease Virus in China.

Despite highly effective vaccines, Marek's disease (MD) causes great economic loss to the poultry industry annually, largely due to the continuous emergence of new MD virus (MDV) strains. To explore the pathogenic characteristics of newly emerged MDV strains, we selected two strains (AH/1807 and DH/18) with clinically different pathotypes. We studied each strain's infection process and pathogenicity and observed differences in immunosuppression and vaccine resistance. Specific pathogen-free chickens, unvaccinated or vaccinated with CVI988, were challenged with AH/1807 or DH/18. Both infections induced MD damage; however, differences were observed in terms of mortality (AH/1807: 77.8%, DH/18: 50%) and tumor rates (AH/1807: 50%, DH/18: 33.3%). The immune protection indices of the vaccine also differed (AH/1807: 94.1, DH/18: 61.1). Additionally, while both strains caused interferon-ß and interferon-γ expression to decline, DH/18 infection caused stronger immunosuppression than AH/1807. This inhibition persisted even after vaccination, leading to increased replication of DH/18 that ultimately broke through vaccine immune protection. These results indicate that both strains have different characteristics, and that strains such as DH/18, which cause weaker pathogenic damage but can break through vaccine immune protection, require further attention. Our findings increase the understanding of the differences between epidemic strains and factors underlying MD vaccination failure in China.

Multiple bioinformatics analysis identifies IGFBP1 as associated with the prognosis of stomach adenocarcinoma.

This study aimed to screen the hub gene for predicting the prognosis of patients with stomach adenocarcinoma (STAD). The RNA-sequencing expression data and clinical data of STAD were collected from the cancer genome atlas. The R package "limma" was performed to ascertain the differentially expressed genes (DEGs) between the relapse group and non-relapse group, and the DEGs between the survival dead status group and survival alive status group were screened. The overlapping genes between 2 DEGs sets were identified by the Venn diagram. Many different bioinformatics analysis methods were performed to analyze the importance of hub genes. One gene signature, IGFBP1, was extracted. The KM plot indicated that STAD patients with low IGFBP1 mRNA expression have a shorter overall survival time. The top 100 co-expression genes of IGFBP1 were mainly enriched in complement and coagulation cascades, epithelial cell signaling in Helicobacter pylori infection, and Wnt signaling pathway. Immune infiltration analysis indicated IGFBP1 may inhibit immune cell infiltration in tumors by infiltration and immune escape, leading to tumor metastasis and progression. The bioinformatics analysis results indicate that IGFBP1 can be used as a tool to evaluate the mortality risk of patients with STAD.

Eighteen cases of renal aneurysms: Clinical retrospective analysis and experience of endovascular interventional treatment.

Background: Development of endovascular interventional techniques gradually replaced traditional open surgery and has become the preferred treatment for renal aneurysms. This study aimed to analyze the clinical characteristics of renal artery aneurysm (RAA) and the safety and efficacy of intravascular interventional treatment. Materials and Methods: We retrospectively analyzed the clinical characteristics and imaging data of 23 aneurysms in 18 patients with RAA. The technical success rate, complication rate, mortality rate, reintervention rate, and use of embolization materials were evaluated. Results: In 18 patients with RAA (age, 32-72 years, average age, 52.2 ± 11.2 years), a total of 23 aneurysms were found (diameter 0.5-5.5 cm, average diameter 2.2 ± 1.4 cm). Among them, 11 cases (61.1%) were discovered accidentally, and the remaining patients were diagnosed due to the following major complaints: four cases (22.2%) presented low back pain, two (11.1%) were due to high blood pressure, and one (5.5%) had low back pain with gross hematuria. A total of 14 aneurysms in 13 patients received endovascular interventional therapy. The technical success rate of 13 patients with renal aneurysms was 100%. Three of the 18 patients were lost to follow-up, and the remaining were followed up for 4-89 months. There was no recurrence of the aneurysm or displacement of the stent or coil. Conclusion: Endovascular treatment for RAA has a high success rate, low complication rate, and low reintervention rate. It has the advantage of less trauma and is flexible and more targeted for different types of renal aneurysms.

Han family with essential tremor caused by the P421L variant of the TENM4 gene in China.

BACKGROUND: Essential tremor (ET) is an autosomal dominant inheritance disorder. Mutations in fusion sarcoma (FUS), mitochondrial serine peptidase 2 (HTRA2), teneurin transmembrane protein 4 (TENM4), sortilin1 (SORT1), SCN11A, and notch2N-terminal-like (NOTCH2NLC) genes are associated with familial ET. METHODS: A proband with ET was tested using whole-exome sequencing and repeat-primed polymerase chain reaction. Subsequently, the family members were screened for the suspected mutation, and the results were verified using Sanger sequencing. The relationship between pedigree and phenotype was also analyzed, and structural and functional changes in the variants were predicted using bioinformatics analysis. RESULTS: In a family with ET, the proband (III4) and the proband's father (II1), grandfather (I1), uncle (II2), and cousin (III5) all presented with involuntary tremors of both upper limbs. The responsible mutation was identified as TENM4 c.1262C > T (p.P421L), which showed genetic co-segregation in the family survey. AlphaFold predicted a change in the spatial position of TENM4 after the P421L mutation, which may have affected its stability. AlphaFold also predicted P421L to be a deleterious variation, which would lead to lower degrees of freedom of the TENM4 protein, thereby affecting the protein's structure and stability. According to the bioinformatics analysis, TENM4 (p.P421L) may reduce the signal reaching the nucleus by affecting the expression of TENM4 messenger RNA (mRNA), thereby impairing the normal oligodendrocyte differentiation process and leading to impaired myelination. CONCLUSION: This study revealed that the TENM4 (p.P421L) pathogenic missense variation was responsible for ET in the proband.

Comprehensive analysis of immune ferroptosis gene in renal clear cell carcinoma: prognosis and influence of tumor microenvironment.

OBJECTIVE: We conducted an in-depth study of the immune system and ferroptosis to identify prognostic biomarkers and therapeutic targets for renal clear cell carcinoma. METHODS: Immune ferroptosis-related differentially expressed genes (IFR-DEGs) were selected from The Cancer Genome Atlas (TCGA). A lasso-Cox risk scoring model was established; its prognostic value was determined using prognostic analysis and single multivariate Cox analysis. Model genes were subjected to subcellular fluorescence localization, mRNA and protein expression analyses, and single-cell RNA sequencing localization analysis. Risk score was analyzed using the immune score, immune infiltrating cell correlation, immune checkpoint, TIDE, and drug sensitivity. RESULTS: A total of 103 IFR-DEGs were identified; a risk model comprising ACADSB, CHAC1, LURAP1L, and PLA2G6 was established. The survival curve, single multivariate Cox regression, and receiver operating characteristic (ROC) curve analysis showed that the model had good predictive ability (p < 0.05). It was also validated using the validation set and total cohort. Subcellular fluorescence localization revealed that ACADSB, CHAC1, and PLA2G6 were distributed in the cytoplasm and LURAP1L in the nucleus. The mRNA and protein expression trends were consistent. Single-cell RNA sequencing mapping revealed that ACADSB was enriched in distal tubule cell clusters. In the Kidney renal clear cell carcinoma (KIRC) mutation correlation analysis, 1.56% of the patients were found to have genetic alterations; The Spearman correlation analysis of model gene mutations showed that ACADSB was positively correlated with LURAP1L, which may have a synergistic effect; it was negatively correlated with CHAC1 and PLA2G6, and CHAC1 was negatively correlated with LURAP1L, which may have an antagonistic effect. Model and immune correlation analyses found that high-risk patients had significantly higher levels of CD8+ T cells, regulatory T cells (Tregs), immune checkpoints, immune scores, and immune escape than those in low-risk patients. High-risk patients had a higher susceptibility to small-molecule drugs. CONCLUSION: A novel prognostic model of immune ferroptosis-related genes (ACADSB, CHAC1, LURAP1L, and PLA2G6), which plays an important role in immune infiltration, microenvironment, and immune escape, was constructed. It effectively predicts the survival of patients with KIRC.

Retrospective Analysis of the Effect of Lidocaine Combined with Methylprednisolone on Pain Control After Uterine Artery Embolization.

Background: The analgesic effect produced by the intra-arterial injection of lidocaine in patients undergoing uterine artery embolization has been proven to be safe and effective. Nevertheless, a significant degree of pain is typically experienced after the operation, and pain management is crucial. Methylprednisolone, which provides an anti-inflammatory effect, is widely used in the treatment of several diseases. To date, methylprednisolone has not been used after uterine artery embolization. Methods: A total of 131 patients with uterine leiomyoma were retrospectively enrolled. Forty-five patients (control group) were treated with embolized microspheres for bilateral uterine artery embolization. Fifty (study group) and 36 (lidocaine group) patients were administered lidocaine mixed with embolized microspheres during embolization, and in addition, the study group was administered methylprednisolone. Completed pain scales at different time points during surgery were obtained from patients undergoing uterine artery embolization. Efficacy against pain was evaluated by comparing the pain score, inflammatory index, and use of sufentanil within 24 h followed by a Kruskal-Wallis Test and a least significant difference post-hoc analysis. Results: The postoperative pain scores at 1, 4, and 7 h after uterine artery embolization in the study group (3.08 ± 2.09, 2.46 ± 1.93, and 2.38 ± 1.85, respectively) were significantly lower than those in the control group (4.84 ± 2.36, 4.16 ± 1.87, and 3.56 ± 1.93, respectively) and the lidocaine group (3.50 ± 2.10, 3.30 ± 1.88, and 3.28 ± 1.89, respectively). At the first 24 h after embolization, the total usage of sufentanil in the study group (31.4 ± 4.16) was significantly lower than those in the control group (45.7 ± 6.51) and the lidocaine group (38.3 ± 6.25). At 1 and 4 h, the pain scores of the lidocaine group were significantly lower than those of the control group. In addition, at the first 24 h after embolization, the total usage of sufentanil in the lidocaine group was significantly lower than that in the control group. Conclusion: Lidocaine in combination with methylprednisolone can significantly alleviate pain and reduce the usage of sufentanil after bilateral uterine artery embolization. Thus, methylprednisolone is a recommended addition to the therapeutic regimen after embolization.

Clinical and Genetic Analysis of a Family With Sitosterolemia Caused by a Novel ATP-Binding Cassette Subfamily G Member 5 Compound Heterozygous Mutation.

Sitosterolemia (OMIM ##210250), also known as phytosterolemia, is a rare autosomal recessive disorder caused by mutations in the ATP-binding cassette subfamily G member 5 (ABCG5) or member 8 (ABCG8) genes. This leads to abnormal functions of the transporter sterolin-1 protein encoded by ABCG5 and sterolin-2 protein encoded by ABCG8, respectively, which can hinder the formation of stable ABCG5/G8 heterodimers, decreasing its ability to transport sterols. As a result, phytosterols in tissue or plasma are significantly increased, leading to early onset atherosclerosis-related diseases and xanthelasma of tendons and skin. In this study, whole exome sequencing was performed on a Chinese Han proband with sitosterolemia to capture the target gene and screen for suspected pathogenic mutations. Sanger sequencing of the family members was performed to verify the relationship between family genetics and phenotypes. The structural and functional changes in the transporter sterolin-1 protein after the responsible mutation were predicted using bioinformatics analysis. A novel compound heterozygous mutation in the ABCG5 gene (NM_022436) was identified in a proband with sitosterolemia, one of which was inherited from the father: c.296T >G (p.M99R), and one from the mother: c.-76 C >T. SIFT, Polyphen2, and Mutation Taster software predicted that p.M99R may be the responsible variant and a novel variant. RNAFold software predicts that c.-76 C >T may affect the transcriptional information or the binding of RNA binding proteins by regulating the structure of RNA, and ultimately affect gene transcription or RNA stability and translation. Swiss model software predicts that the amino acid sequence around p.M99R is highly conserved, and p.M99R leads to instability of the tertiary structure of the ABCG5/ABCG8 heterodimer. GPS 5.0 predicted that M99R affects the phosphorylation of nearby amino acid sequences, and DUET and VarSite software predicted that M99R affects the stability of sterolin-1 and cause disease. The p.M99R and c.-76 C >T mutations led to the formation of unstable heterodimers, which disturbed sterol absorption and excretion in vivo. The compound heterozygous variants c.296 T >G (p.m99r) and C.-76 C >T on exon 3 of ABCG5 in this family may be the molecular genetic basis of sitosterolemia.

Effects of electroacupuncture on pain sensation in a rat model of hyperalgesia with nicotine dependence.

Tobacco smoking is considered to be one of the main risk factors in the development of chronic pain. Long-term chronic exposure to nicotine and other forms of tobacco have been shown to be associated with an increased incidence of pain. Studies have shown that acupuncture can help smokers to reduce their desire to smoke, reduce their withdrawal symptoms, and avoid a relapse after treatment. However, little has been reported about the effects of acupuncture on pain sensitivity caused by long-term smoking. Models of hyperalgesia were established in rats exposed to nicotine for 6 weeks. After 6 weeks of continuous nicotine exposure, electroacupuncture at bilateral acupoints Zusanli (ST36) and Taichong (LR3) was performed 20 minutes per day for 6 days at a continuous wave with a frequency of 2 Hz and a stimulus intensity of 1 mA. The results revealed that electroacupuncture treatment increased the mechanical response threshold of hind paw of nicotine-dependent rats with hyperalgesia and up-regulated the protein expression of pain-related factors µ-opioid receptor, ß-endorphin and glutamic acid decarboxylase 65 in the spinal cord and midbrain periaqueductal gray and the protein expression of glutamic acid decarboxylase 67 in the spinal cord. These findings suggest that electroacupuncture treatment has positive analgesic effects on pain sensitivity caused by long-term chronic nicotine exposure. One possible mechanism for the improved analgesia is that electroacupuncture increases the expression of pain-related factors in the spinal cord and midbrain periaqueductal gray. This study was approved by Institutional Animal Care and Use Committee (IACUC) of the University of Miami (#18-167) on December 12, 2018.

Different phenotypes of neurological diseases, including alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism, caused by de novo ATP1A3 mutation in a family.

BACKGROUND: The spectrum of neurological diseases related to ATP1A3 gene mutations is highly heterogeneous and exhibits different phenotypes. Phenotype overlaps, including alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy, and rapid-onset dystonia-parkinsonism (RDP), can also occur at extremely low incidences. Currently, over 90 types of pathogenic mutations have been identified in ATP1A3. PATIENTS AND METHODS: The family of a 2-year-11-month-old proband with AHC was recruited for this clinical investigation. The proband was screened for candidate mutation gene sites using next-generation sequencing and target-region capture technology. Sanger sequencing was used to identify carriers among family members. RESULTS: The mother of the proband with AHC was diagnosed with dystonia (later diagnosed as RDP). The biochemical and immune indices of the proband and the mother were not abnormal. Moreover, brain imaging of the proband revealed no significant abnormalities. However, the electroencephalogram of the mother was mildly abnormal, with no spike wave discharge. Brain MRI revealed slight cerebellar atrophy. Electromyography revealed neurogenic damage, with a decrease in the conduction velocity of the left ulnar and radial nerves. Based on the sequencing data, both the proband and her mother carried c.823G > C p. (Ala275Pro) heterozygotes; other family members were not identified as carriers. With a PolyPhen-2 score of 0.997 and SIFT score of 0.001, this mutation can be considered damaging. CONCLUSION: Family genotype-phenotype correlation analysis revealed that the phenotype and gene mutation were co-segregated, suggesting that it may be a pathogenic mutation.

The Melastoma dodecandrum genome and the evolution of Myrtales.

Melastomataceae has abundant morphological diversity with high economic and ornamental merit in Myrtales. The phylogenetic position of Myrtales is still contested. Here, we report the chromosome-level genome assembly of Melastoma dodecandrum in Melastomataceae. The assembled genome size is 299.81 Mb with a contig N50 value of 3.00 Mb. Genome evolution analysis indicated that M. dodecandrum, Eucalyptus grandis, and Punica granatum were clustered into a clade of Myrtales and formed a sister group with the ancestor of fabids and malvids. We found that M. dodecandrum experienced four whole-genome polyploidization events: the ancient event was shared with most eudicots, one event was shared with Myrtales, and the other two events were unique to M. dodecandrum. Moreover, we identified MADS-box genes and found that the AP1-like genes expanded, and AP3-like genes might have undergone subfunctionalization. The SUAR63-like genes and AG-like genes showed different expression patterns in stamens, which may be associated with heteranthery. In addition, we found that LAZY1-like genes were involved in the negative regulation of stem branching development, which may be related to its creeping features. Our study sheds new light on the evolution of Melastomataceae and Myrtales, which provides a comprehensive genetic resource for future research.

A clinical analysis of intestinal mucosal necrosis and exfoliation induced by superior mesenteric vein thrombosis: A case report.

Background: Superior mesenteric vein (SMV) thrombosis is a rare intestinal ischemic disease. The clinical manifestations of patients differ, and most experience gastrointestinal symptoms. Case summary: A 45-year-old female patient presented with persistent abdominal pain and abnormal vaginal bleeding for 7 days. A physical examination revealed significant abdominal tenderness with positive rebound tenderness. A laboratory examination revealed a white blood cell count of 27 × 109/l, hemoglobin level of 52 g/L, and D-dimer of 4.54 mg/l. Enhanced computed tomography revealed a thickening and swelling of the jejunum and ileum in the left upper quadrant and portal vein. Filling defects in the main lumen and branch lumen suggested the possibility of portal vein and superior mesenteric vein thrombosis. Symptoms improved after treatment with low-molecular-weight heparin and warfarin. One month later, the patient developed occasional dull pain in the left lower quadrant, with long strips of discharge. An electronic colonoscopy revealed avascular necrosis and tissue exfoliation of the intestinal mucosa. After the continuation of warfarin therapy, the abdominal pain resolved. Five months later, the patient experienced recurrent abdominal pain and vomiting. A physical examination revealed a blood pressure of 75/49 mm Hg. An incomplete ileus with the portal and superior mesenteric vein thrombosis was diagnosed, partial jejunectomy and gastrointestinal bypass anastomosis were performed, and warfarin was continued postoperatively. Conclusion: The intestinal mucosal shedding observed, in this case, was caused by SMV thrombosis, which enriched the clinical manifestations of the disease and provided a new basis for the clinical diagnosis of SMV thrombosis.

Neutrophil extracellular traps-associated modification patterns depict the tumor microenvironment, precision immunotherapy, and prognosis of clear cell renal cell carcinoma.

Background: Neutrophil extracellular traps (NETs) are web-like structures formed by neutrophils, and their main function is antimicrobial defense. Moreover, NETs have numerous roles in the pathogenesis and progression of cancers. However, the potential roles of NET-related genes in renal cell carcinoma remain unclear. In this study, we comprehensively investigated the NETs patterns and their relationships with tumor environment (TME), clinicopathological features, prognosis, and prediction of therapeutic benefits in the clear cell renal cell carcinoma (ccRCC) cohort. Methods: We obtained the gene expression profiles, clinical characteristics, and somatic mutations of patients with ccRCC from The Cancer Genome Atlas database (TCGA), Gene Expression Omnibus (GEO), and ArrayExpress datasets, respectively. ConsensusCluster was performed to identify the NET clusters. The tumor environment scores were evaluated by the "ESTIMATE," "CIBERSORT," and ssGSEA methods. The differential analysis was performed by the "limma" R package. The NET-scores were constructed based on the differentially expressed genes (DEGs) among the three cluster patterns using the ssGSEA method. The roles of NET scores in the prediction of immunotherapy were investigated by Immunophenoscores (TCIA database) and validated in two independent cohorts (GSE135222 and IMvigor210). The prediction of targeted drug benefits was implemented using the "pRRophetic" and Gene Set Cancer Analysis (GSCA) datasets. Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed to identify the reliability of the core genes' expression in kidney cancer cells. Results: Three NET-related clusters were identified in the ccRCC cohort. The patients in Cluster A had more metabolism-associated pathways and better overall survival outcomes, whereas the patients in Cluster C had more immune-related pathways, a higher immune score, and a poorer prognosis than those in Cluster B. Based on the DEGs among different subtypes, patients with ccRCC were divided into two gene clusters. These gene clusters demonstrated significantly different immune statuses and clinical features. The NET scores were calculated based on the ten core genes by the Gene Set Variation Analysis (GSVA) package and then divided ccRCC patients into two risk groups. We observed that high NET scores were associated with favorable survival outcomes, which were validated in the E-MTAB-1980 dataset. Moreover, the NET scores were significantly associated with immune cell infiltration, targeted drug response, and immunotherapy benefits. Subsequently, we explored the expression profiles, methylation, mutation, and survival prediction of the 10 core genes in TCGA-KIRC. Though all of them were associated with survival information, only four out of the 10 core genes were differentially expressed genes in tumor samples compared to normal tissues. Finally, RT-PCR showed that MAP7, SLC16A12, and SLC27A2 decreased, while SLC3A1 increased, in cancer cells. Conclusion: NETs play significant roles in the tumor immune microenvironment of ccRCC. Identifying NET clusters and scores could enhance our understanding of the heterogeneity of ccRCC, thus providing novel insights for precise individual treatment.

Chemical Degradation of Intravenous Chemotherapy Agents and Opioids by a Novel Instrument.

Purpose: To assess chemical degradation of various liquid chemotherapy and opioid drugs in the novel RxDestruct™ instrument. Methods: Intravenous (IV) drug solutions for chemotherapy and pain management were prepared using 0.9% normal saline in Excel® bags to a final volume of 500 mL. We investigated duplicate IV solutions of methotrexate (0.1 mg/mL), etoposide (0.4 mg/mL), doxorubicin (0.25 mg/mL), cladribine (12.4 µg/mL), fentanyl (1.0 µg/mL), and hydromorphone (12.0 µg/mL) in this study. Solutions were poured into an automated instrument to undergo pulsatile chemical treatment (Fenton reactions) for 20 minutes, and then discharged from the instrument through a waste outlet. Extent of intact drug degradation was determined by measuring concentrations of drugs before entry into the instrument and after chemical treatment in the filtrate using high-performance liquid-chromatography with ultraviolet detection (HPLC-UV). Results: Following chemical reactions (Fenton processes) in the automated instrument, infusion solutions containing methotrexate, etoposide, doxorubicin, and cladribine had levels below the HPLC-UV limit of quantification (LOQ), indicating <50 ppb of each. This equated to >99.5%, 99.99%, 99.9%, and 99.8% intact drug loss, respectively. Likewise, processed samples of fentanyl and hydromorphone contained levels below the LOQ (78 and 98 ng/mL, respectively), indicating extensive degradation (>92.2% and 99.2% intact drug loss, respectively). Conclusion: The novel instrument was capable of degrading intact chemotherapy and opioid drugs prepared in infusion solutions to undetectable quantities by HPLC-UV. RxDestruct™ is a possible alternative for disposal of aqueous medication waste.

[Clinical Characteristics and Prognostic Factors of Primary FL Patients with Grade 3 or Large B Cell Transformation].

OBJECTIVE: To investigate the clinical characteristics and prognostic factors of primary follicular lymphoma (FL) patients with grade 3 or large B cell transformation, so as to provide more reference for the subsequent clinical diagnosis and treatment. METHODS: Forty-seven primary FL patients with grade 3 or large B cell transformation from March 2010 to March 2018 were selected, the clinical characteristics and survival of patients were analyzed. Cox regression model were used to evaluate the related prognostic factors. RESULTS: The cumulative progression-free survival rate and cumulative overall survival rate of 47 patients in 3-year follow-up reached to 55.32% (26/47) and 80.85% (38/47) respectively. There were significant differences in cumulative progression-free survival rate and cumulative overall survival rate among different subgroups of IPI, FLIPI-1 and FLIPI-2 in 3-year follow-up (P<0.05). The cumulative progression-free survival rate during follow-up for 3-year in the patients with Ann Arbor staging for III-IV stage, lymph node-involved site≥5, lymph node-involved site with diameter more than 3 cm≥3 and extranodal lesions≥3 was significantly lower than other subgroups (P<0.05). The cumulative overall survival rate in 3-year follow-up of patients with LDH levels≥240 U/ml was significantly lower than patients with LDH levels < 240 U/ml (P<0.05). Univariate analysis showed that Ann Arbor stage for III-IV, lymph node-involved site number≥5, >3 cm lymph node-involved site number≥3, extranodal lesion site number≥2, IPI score=2-3, FLIPI-1 score and FLIPI-2 score≥3 were the risk factors for progression-free survival (P<0.05); LDH≥240 U/ml, IPI score=2-3 and FLIPI-2 score≥3 were risk factors for overall survival (P<0.05). Cox regression model multivariate analysis showed that IPI score=2-3 was the independent risk factor for progression-free survival and overall survival (P<0.05). FLIPI-2 score≥3 was the independent risk factor for overall survival (P<0.05). CONCLUSION: Primary FL patients with grade 3 or large B cell transformation by using the existing treatment regimen might be possibly curable, and the current treatment strategies and IPI score can be used to predict the clinical prognosis of patients.

[Clinical features of very preterm small-for-gestational-age infants born due to severe preeclampsia].

OBJECTIVE: To study the clinical features of very preterm small-for-gestational-age infants born by cesarean section due to severe preeclampsia. METHODS: Forty-two small-for-gestational-age infants who were admitted from August 2017 to July 2018 and were born due to severe preeclampsia were enrolled as the observation group. Forty very preterm infants who were born to healthy mothers since uterine contractions could not be suppressed were enrolled as the control group. Perinatal features, clinical manifestations of infection, complications, and clinical outcomes were analyzed for the two groups. RESULTS: Within 6 hours and 2-3 days after birth, the observation group had significantly lower white blood cell count (WBC), absolute neutrophil count (ANC), and platelet count (PLT) than the control group (P < 0.05). At 5-7 days after birth, there was no significant difference in WBC between the two groups (P > 0.05), while the observation group still had significantly lower ANC and PLT than the control group (P < 0.05). The observation group had a significantly higher C-reactive protein (CRP) level than the control group at 2-3 days and 5-7 days after birth (P < 0.05). The observation group had a significantly higher proportion of infants with severe infections than the control group (P < 0.05). The observation group had a significantly higher hemoglobin level than the control group within 6 hours after birth (P < 0.05). The observation group had a significantly higher incidence rate of bronchopulmonary dysplasia than the control group (P < 0.05). There was no significant difference between the two groups in the rate of pulmonary hemorrhage, intracranial hemorrhage, neonatal necrotizing enterocolitis, retinopathy of prematurity, and the rate of use of invasive ventilation, and clinical outcomes (P > 0.05). CONCLUSIONS: Very preterm small-for-gestational-age infants born due to severe preeclampsia have a high incidence rate of infection and severe conditions. Early manifestations include reductions in the infection indicators WBC, ANC, and PLT, and CRP does not increase significantly in the early stage and gradually increases at 2-3 days after birth. Most of these infants require invasive ventilation after birth, with bronchopulmonary dysplasia as the main complication. Clinical changes should be closely observed and inflammatory indicators should be monitored for early identification of infection, timely diagnosis, and timely adjustment of antibiotic treatment, so as to improve the outcome.