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BackgroundRectal cancer has a high risk of recurrence and metastasis, with median survival ranging from 24 months to 36 months. K-RAS mutation is a predictor of poor prognosis in rectal cancer. Advanced rectal cancer can be stopped in its tracks by pelvic exenteration.Case summaryA 51-year-old woman was diagnosed with advanced rectal cancer (pT4bN2aM1b, stage IV) with the KRAS G12D mutation due to a change in bowel habits. The patient had experienced repeated recurrences of rectal cancer after initial radical resection, and the tumor had invaded the ovaries, sacrum, bladder, vagina and anus. Since the onset of the disease, the patient had undergone a total of seven surgeries and long-term FOLFIRI- or XELOX-based chemotherapy regimens, with the targeted agents bevacizumab and regorafenib. Fortunately, the patient was able to achieve intraoperative R0 resection in almost all surgical procedures and achieve tumor-free survival after pelvic exenteration. The patient has been alive for 86 months since her diagnosis.ConclusionsPatients with advanced rectal cancer can achieve long-term survival through active multidisciplinary management and R0 surgery.

BackgroundLeft subclavian artery (LSA) revascularization during thoracic endovascular aortic repair (TEVAR) is necessary to reduce postoperative complications in patients with Stanford type B aortic dissection and an insufficient proximal anchoring area. However, the efficacy and safety of different LSA revascularization strategies remain unclear. Here, we compared these strategies to provide a clinical basis for selecting an appropriate LSA revascularization method.MethodsIn this study, we included 105 patients with type B aortic dissection who were treated using TEVAR combined with LSA reconstruction in the Second Hospital of Lanzhou University from March 2013 to 2020. They were divided into four groups according to the method used for LSA reconstruction, namely, carotid subclavian bypass (CSB; n = 41), chimney graft (CG; n = 29), single-branched stent graft (SBSG; n = 21), and physician-made fenestration (PMF; n = 14) groups. Finally, we collected and analyzed the baseline, perioperative, operative, postoperative, and follow-up data of the patients.ResultsThe treatment success rate was 100% in all the groups, and CSB + TEVAR was the most commonly used procedure in emergency settings compared with the other three procedures (P 0.05) The median follow-up time of CSB, CG, SBSG, and PMF groups was significantly different (P

A 10-year-old girl presented with obvious cyanosis, and the saturation of arterial blood oxygen (SpO2) was decreased to 60.5% in the outpatient examination. Computed tomography angiography (CTA) and echocardiography suggested congenitally corrected transposition of the great arteries (ccTGAs), membranous ventricular septal aneurysm (MVSA), atrial septal defect (ASD), severe pulmonary stenosis (PS), and severe tricuspid regurgitation (TR). Due to the complex pathological anatomical structures, the three-dimensional printed model was used for preoperative assessment. After a comprehensive evaluation was completed, the operation was performed by physiological correction under cardiopulmonary bypass, including the resection of MVSA, repair using the bovine pericardial patch for ASD, and linear valvuloplasty of the tricuspid valve. Due to the special anatomical structures of ccTGA, PS was treated by extracardiac pipe technique. After the operation, the patient recovered well, cyanosis disappeared, SpO2 was up to 96%, and the extracardiac pipe was well-functioning without regurgitation or obstruction.

Bacteriophages, which are viruses infecting bacteria, are the most ubiquitous and diverse entities in the biosphere. There is accumulating evidence revealing their important roles in shaping the structure of various microbiomes. Thanks to (viral) metagenomic sequencing, a large number of new bacteriophages have been discovered. However, lacking a standard and automatic virus classification pipeline, the taxonomic characterization of new viruses seriously lag behind the sequencing efforts. In particular, according to the latest version of ICTV, several large phage families in the previous classification system are removed. Therefore, a comprehensive review and comparison of taxonomic classification tools under the new standard are needed to establish the state-of-the-art. In this work, we retrained and tested four recently published tools on newly labeled databases. We demonstrated their utilities and tested them on multiple datasets, including the RefSeq, short contigs, simulated metagenomic datasets, and low-similarity datasets. This study provides a comprehensive review of phage family classification in different scenarios and a practical guidance for choosing appropriate taxonomic classification pipelines. To our best knowledge, this is the first review conducted under the new ICTV classification framework. The results show that the new family classification framework overall leads to better conserved groups and thus makes family-level classification more feasible.

BackgroundLumbar intervertebral disc degeneration (IVDD) is an important cause of low back pain or sciatica, and metabolic factors play an important role. However, little is known about the relationship of dyslipidemia to the risk of intervertebral disc degeneration (IVDD). This study aimed to assess the impact of serum lipid levels on the severity of lumbar disc degeneration and to investigate its association with endplate inflammation.MethodsWe conducted a case retrospective study in which a total of 302 hospitalized Chinese patients were recruited, of whom 188 (112 males and 76 females; mean age: 51.66 years) were without underlying disease, while the remaining 114 patients (51 males and 63 females; mean age: 62.75 years) had underlying diseases. We examined fasting serum lipid levels for total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Magnetic resonance imaging (MRI) was used to determine endplate inflammation. Pfirrmann grading and Weishaupt grading were used to evaluate the severity of intervertebral disc degeneration and facet joint degeneration, respectively.ResultsThere was no difference in age, gender, and general BMI between the two groups (P > 0.05), but there were significantly high levels in TC, LDL-C, and LDL-C/HDL-C (P = 0.04, P = 0.013, P = 0.01, respectively). TG and HDL-C showed no significant difference (P = 0.064, P = 0.336, respectively). The multivariate logistic regression model showed that age was a risk factor for the occurrence of endplate inflammation. In the group without underlying diseases, age, but not other indicators, was a risk factor for the occurrence of endplate inflammation (P < 0.01), In the group with underlying diseases, none of the patient indicators was directly related to the occurrence of endplate inflammation (P > 0.05). A nonlinear machine learning model was used to measure the contribution of each factor to the disease outcome and to analyze the effect between the top three contributing factors and the outcome variables. In patients without underlying diseases, the top three factors contributing to the severity grading of intervertebral disc degeneration were age (32.9%), high-density lipoproteins (20.7%), and triglycerides (11.8%). For the severity grading of facet joint degeneration, the top three contributing factors were age (27.7%), high-density lipoproteins (19.4%), and triglycerides (14.6%). For patients with underlying diseases, the top three factors contributing to intervertebral disc degeneration were age (25.4%), BMI (15.3%), and low-density lipoprotein/high-density lipoprotein ratio (13.9%). In terms of degree classification for facet joint degeneration, the top three contributing factors were age (17.5%), BMI (17.2%), and total cholesterol (16.7%).ConclusionThis study shows that age, high-density lipoprotein, and triglycerides affect the degree of degeneration in patients with symptomatic lumbar degeneration without underlying diseases. Age and BMI are two major factors affecting the severity of degeneration in patients with underlying diseases, and dyslipidemia is a secondary factor. However, there is no clear association between dyslipidemia and the occurrence of endplate inflammation in either group.

BackgroundAarskog–Scott syndrome, a rare X-linked genetic disorder, is identified by combined clinical manifestations of short stature, facial, skeletal, and genital anomalies. Annually, two or three new cases are diagnosed with Aarskog–Scott syndrome, which is associated with FGD1 variants. However, there is no specific treatment for Aarskog–Scott syndrome due to its unclear mechanism.MethodsClinical data were collected when the patient first visited the hospital. Trio whole-exome sequencing and Sanger sequencing were performed for the genetic cause of disease. To evaluate the pathogenicity of the variants in vitro, stable cell lines were constructed using lentivirus infection in 143B cell. Furthermore, Western blot was used to verify the expression of signaling pathway-related proteins, and the transcription levels of osteogenic-related genes were verified by luciferase reporter gene assay.ResultsA 7-year-old boy was manifested with facial abnormalities, intellectual disability, and short stature (−3.98 SDS) while the growth hormone level of stimulation test was normal. Trio whole-exome sequencing and Sanger sequencing identified a variant (c.1270A>G, p.Asn424Asp) in FGD1 gene. The Asn424 residue was highly conserved and the hydrogen bond in the FGD1 variant protein has changed, which led to decrease in the interaction with CDC42 protein. In vitro study showed that the Asn424Asp variant significantly decreased the transcription levels of OCN, COL1A1, and ALP activity, and it activated the phosphorylation of JNK1.ConclusionMolecular biological mechanisms between abnormal expression of FGD1and Aarskog–Scott syndrome remain poorly understood. In our study, c.1270A>G variant of FGD1 resulted in Aarskog–Scott syndrome, and the analysis of pathogenicity supports the deleterious effect of the variant. Furthermore, we demonstrated the weakened affinity of the mutant FGD1 and CDC42. Decreased expression of osteogenic-related gene and abnormal activation of JNK1 were also shown in this work.

Background: 46,XY disorders/differences of sex development (46,XY DSD) are congenital conditions that result from abnormal gonadal development (gonadal dysgenesis) or abnormalities in androgen synthesis or action. During early embryonic development, several genes are involved in regulating the initiation and maintenance of testicular or ovarian-specific pathways. Recent reports have shown that MAP3K1 genes mediate the development of the 46,XY DSD, which present as complete or partial gonadal dysgenesis. Previous functional studies have demonstrated that some MAP3K1 variants result in the gain of protein function. However, data on possible mechanisms of MAP3K1 genes in modulating protein functions remain scant.Methods: This study identified a Han Chinese family with the 46,XY DSD. To assess the history and clinical manifestations for the 46,XY DSD patients, the physical, operational, ultra-sonographical, pathological, and other examinations were performed for family members. Variant analysis was conducted using both trio whole-exome sequencing (trio WES) and Sanger sequencing. On the other hand, we generated transiently transfected testicular teratoma cells (NT2/D1) and ovary-derived granular cells (KGN), with mutant or wild-type MAP3K1 gene. We then performed functional assays such as determination of steady-state levels of gender related factors, protein interaction and luciferase assay system.Results: Two affected siblings were diagnosed with 46,XY DSD. Our analysis showed a missense c.556A > G/p.R186G variant in the MAP3K1 gene. Functional assays demonstrated that the MAP3K1R186G variant was associated with significantly decreased affinity to ubiquitin (Ub; 43–49%) and increased affinity to RhoA, which was 3.19 ± 0.18 fold, compared to MAP3K1. The MAP3K1R186G led to hyperphosphorylation of p38 and GSK3β, and promoted hyperactivation of the Wnt4/β-catenin signaling. In addition, there was increased recruitment of β-catenin into the nucleus, which enhanced the expression of pro-ovarian transcription factor FOXL2 gene, thus contributing to the 46,XY DSD.Conclusion: Our study identified a missense MAP3K1 variant associated with 46,XY DSD. We demonstrated that MAP3K1R186G variant enhances binding to the RhoA and improves its own stability, resulting in the activation of the Wnt4/β-catenin/FOXL2 pathway. Taken together, these findings provide novel insights into the molecular mechanisms of 46,XY DSD and promotes better clinical evaluation.

BackgroundKidney involvement is common in antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). It tends to be aggressive, and in some patients, the kidney involvement may reach the criteria of acute kidney injury (AKI). Here, we aim to describe the clinical characteristics of these patients and find risk factors for poor outcomes.MethodsPatients diagnosed with AAV in our hospital from February 2003 to February 2017 were included. Those who reached the KDIGO AKI criteria were reclassified according to the KDIGO AKI stage. The clinical features of these patients were analyzed. Also, according to the variation of serum creatinine 3 months after AKI episode, patients were further divided into two groups: patients whose serum creatinine (Scr) level at the third month decreased by 30% or more from the peak Scr level was classified into G1 and others were classified into G2. Long-term renal and survival outcomes of these patients were analyzed with a Cox model. The renal endpoint was reaching end-stage renal disease (ESRD), and the survival endpoint was death. Nomograms were built based on cox models.ResultsOf 141 AAV patients included, during the median follow-up period of 64.0 (IQR 34.8, 85.4) months, 36 (25.5%) patients reached renal endpoints, and 22 (15.6%) patients died. The median renal survival time was 35.9 (IQR 21.3, 72.6) months and the median survival time was 48.4 (IQR 26.8, 82.8) months. Multivariate analysis showed that poor recovery of Scr level at 90 days (P < 0.001, RR = 9.150, 95%CI 4.163–20.113), BVAS score (P = 0.014, RR = 1.110, 95% CI1.021–1.207), and AKI stage 3 (P = 0.012 RR = 3.116, 95%CI 1.278–7.598) were independent risk factors for renal endpoints; poor recovery of Scr level at 90 days (P = 0.010, RR = 3.264, 95%CI 1.326–8.035), BVAS score (P = 0.010, RR = 1.171, 95%CI 1.038–1.320) and age (P = 0.017, RR = 1.046, 95%CI 1.008–1.086) were independent risk factors for all-cause death. The c-index of nomograms is 0.830 for the renal outcome and 0.763 for the survival outcome.ConclusionKDIGO AKI stage 3 is the risk factor for ESRD in AAV patients with AKI. The BVAS score and level of kidney function recovery at 90 days are the independent risk factors for both ESRD and all-cause death and are of predictive value for the outcome.

Background: Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive diseases characterized by enzyme deficiencies, within steroid hormone anabolism, which lead to disorders in cortisol synthesis. The 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is an uncommon form of CAH caused by variants in the CYP17A1 gene.Aims: We report a novel compound heterozygous CYP17A1 variant and its association with the pathogenesis of 17-OHD.Methods: The patient was assessed for medical history, clinical manifestations, physical examination, laboratory examination, karyotype analysis, and adrenal computed tomography. Mutation screening was conducted using whole-exome sequencing (WES) and Sanger sequencing. The wild-type and mutant CYP17A1 complementary DNAs (cDNAs) were amplified and cloned into a pcDNA3.1(+) vector. These plasmids were transfected transiently into HEK-293T cells. Quantitative PCR and Western blotting analysis were performed to measure the expression level of P450c17. An enzymatic activity assay was conducted to measure the content of 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone (DHEA) in medium using liquid chromatography–tandem mass spectrometry (LC-MS/MS).Results: The proband was characterized by 17-OHD with rhabdomyolysis, hypokalemia, and adrenal insufficiency. Novel compound heterozygous variants of the CYP17A1 gene (c.1304T > C/p.Phe435Ser and c.1228delG/p.Asp410Ilefs*9) were identified. The enzymatic activity assay revealed that this variant resulted in a complete deficiency of 17α-hydroxylase and 17,20-lyase activity. This was consistent with the hormonal characteristics of the proband’s blood.Conclusions: These results suggest that the compound heterozygous variant of c.1304T > C and c.1228delG of the CYP17A1 gene can lead to 17-OHD. Our findings thus provide a novel insight into the clinical evaluations and molecular basis of 17-OHD.

Background: Tanshinone IIA (Tan IIA), a lipophilic constituent from Salvia miltiorrhiza Bunge, has shown a promising cardioprotective effect including anti-atherosclerosis. This study aims at exploring Tan IIA’s anti-inflammatory and immune-regulating roles in stabilizing vulnerable atherosclerotic plaque in ApoE-deficient (ApoE−/−) mice.Methods: Male ApoE−/− mice (6 weeks) were fed with a high-fat diet for 13 weeks and then randomized to the model group (MOD) or Tan IIA groups [high dose: 90 mg/kg/day (HT), moderate dose: 30 mg/kg/day (MT), low dose: 10 mg/kg/day (LT)] or the atorvastatin group (5 mg/kg/day, ATO) for 13 weeks. Male C57BL/6 mice (6 weeks) were fed with ordinary rodent chow as control. The plaque stability was evaluated according to the morphology and composition of aortic atherosclerotic (AS) plaque in H&E staining and Movat staining sections by calculating the area of extracellular lipid, collagenous fiber, and foam cells to the plaque. The expression of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor88 (MyD88)/nuclear factor-kappa B (NF-κB) signal pathway in aorta fractions was determined by immunohistochemistry. Serum levels of blood lipid were measured by turbidimetric inhibition immunoassay. The concentrations of tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were detected by cytometric bead array.Results: Tan IIA stabilized aortic plaque with a striking reduction in the area of extracellular lipid (ATO: 13.15 ± 1.2%, HT: 12.2 ± 1.64%, MT: 13.93 ± 1.59%, MOD: 18.84 ± 1.46%, P < 0.05) or foam cells (ATO: 16.05 ± 1.26%, HT: 14.88 ± 1.79%, MT: 16.61 ± 1.47%, MOD: 22.08 ± 1.69%, P < 0.05) to the plaque, and an evident increase in content of collagenous fiber (ATO: 16.22 ± 1.91%, HT: 17.58 ± 1.33%, MT: 15.71 ± 2.26%, LT:14.92 ± 1.65%, MOD: 9.61 ± 0.7%, P < 0.05) to the plaque than that in the model group, concomitant with down-regulation of the protein expression of TLR4, MyD88, and NF-κB p65, and serum level of MCP-1 and TNF-α in a dose-dependent manner. There were no differences in serum TC, LDL, HDL, or TG levels between ApoE–/– mice and those treated with atorvastatin.Conclusions: These results suggest that Tan IIA could stabilize vulnerable AS plaque in ApoE−/− mice, and this anti-inflammatory and immune-regulating effect may be achieved via the TLR4/MyD88/NF-κB signaling pathway.

Hierarchical buckling is a novel phenomenon observed in elastic fibers subjected to transverse confinement; however, the deformation mechanisms and modal transitions of this unique phenomenon remain to be elucidated. This paper investigates the hierarchical buckling of elastic fibers with elliptical (circular) cross-sections under transverse confinement through analytical derivations and numerical simulations. Various magnitudes of hierarchical buckling of fibers are observed with the variation of the controlled elastic matrix stiffness. An analytical solution is first derived for the fiber's buckling phenomenon, and the hierarchical buckling is accomplished through the superposition of buckling at various modes. The theoretical results are validated against the finite element simulations with good agreement. It is demonstrated from the parametric results that the hierarchical buckling phenomenon is primarily influenced by the stiffness of the external transverse confinement (matrix), which is defined as a dimensionless parameter. It is thus illustrated from the computational results that the buckling of elastic fibers within a solid or fluid matrix can be controlled and customized. The present work provides theoretical guidance for the application of elastic fibers in stretchable conductor fibers and flexible electronic devices. [ABSTRACT FROM AUTHOR]