Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

Squamous cell carcinoma of the cystic duct: A case report and literature review.

RATIONALE: Pure squamous cell carcinoma (SCC) of the gallbladder is a rare malignant biliary tract tumor predominantly found in the body and neck of the gallbladder. However, its occurrence in the cystic duct is even rarer. Given its rarity, no established guidelines or consensus currently exist regarding the treatment of pure SCC of the gallbladder. We report an unusual case of SCC originating from the cystic duct with the intent of providing insights into the therapeutic approach for this type of malignancy. PATIENT CONCERNS: A male patient presented to our hospital with acute cholecystitis. Unexpectedly, imaging revealed gallbladder malignancy. DIAGNOSES: Pathologic examination after surgery confirmed SCC of the cystic duct. INTERVENTIONS: Despite elevated bilirubin levels, we were able to exclude hilar involvement, enabling radical tumor resection. Intraoperatively, we discovered that the tumor was located in the cystic duct, a site associated with a high likelihood of invasion into neighboring organs. The tumor demonstrated a predominantly exophytic growth pattern, which prompted us to refrain from extending the resection range, thereby striking a balance between complete tumor removal and surgical trauma. We performed liver wedge resection only to ensure a negative resection margin while preserving the anatomical structure to the greatest extent possible. Postoperative recovery was rapid and uncomplicated. Pathological examination confirmed pure SCC, which led us to initiate a regimen of nab-paclitaxel and cisplatin, which is known to be effective in other organ SCCs. Remarkably, the patient experienced a rare and severe posttreatment cardiovascular event. Consequently, we switched the patient to a chemotherapy regimen of gemcitabine and cisplatin, which ultimately yielded positive clinical outcomes. OUTCOMES: no evidence of tumor recurrence was observed within 1 year after surgery. LESSONS: The diagnosis and therapeutic strategy for rare tumors such as gallbladder SCC should be meticulously tailored based on their unique characteristics to optimize postoperative patient outcomes.

EIU-Net: Enhanced feature extraction and improved skip connections in U-Net for skin lesion segmentation.

Skin lesion segmentation is a computer-aided diagnosis method for quantitative analysis of melanoma that can improve efficiency and accuracy. Although many methods based on U-Net have achieved tremendous success, they still cannot handle challenging tasks well due to weak feature extraction. In response to skin lesion segmentation, a novel method called EIU-Net is proposed to tackle the challenging task. To capture the local and global contextual information, we employ inverted residual blocks and an efficient pyramid squeeze attention (EPSA) block as the main encoders at different stages, while atrous spatial pyramid pooling (ASPP) is utilized after the last encoder and the soft-pool method is introduced for downsampling. Also, we propose a novel method named multi-layer fusion (MLF) module to effectively fuse the feature distributions and capture significant boundary information of skin lesions in different encoders to improve the performance of the network. Furthermore, a reshaped decoders fusion module is used to obtain multi-scale information by fusing feature maps of different decoders to improve the final results of skin lesion segmentation. To validate the performance of our proposed network, we compare it with other methods on four public datasets, including the ISIC 2016, ISIC 2017, ISIC 2018, and PH2 datasets. And the main metric Dice scores achieved by our proposed EIU-Net are 0.919, 0.855, 0.902, and 0.916 on the four datasets, respectively, outperforming other methods. Ablation experiments also demonstrate the effectiveness of the main modules in our proposed network. Our code is available at https://github.com/AwebNoob/EIU-Net.

Successful totally laparoscopic right trihepatectomy following conversion therapy for hepatocellular carcinoma: A case report.

BACKGROUND: About 20%-30% of newly diagnosed hepatocellular carcinoma (HCC) patients are surgically feasible due to a variety of reasons. Active conversion therapy may provide opportunities of surgery for these patients. Nevertheless, the choice of surgical procedure is controversial after successful conversion therapy. We report a patient with HCC who underwent successful laparoscopic right trisectionectomy after conversion therapy with portal vein embolization and transarterial chemoembolization. CASE SUMMARY: A 67-year-old male patient presented to our hospital with epigastric distention/ discomfort and nausea/vomiting for more than 1 mo. Contrast-enhanced computed tomography scan of the abdomen demonstrated multiple tumors (the largest was ≥ 10 cm in diameter) located in the right liver and left medial lobe, and the left lateral lobe was normal. The future remnant liver (FRL) of the left lateral lobe accounted for only 18% of total liver volume after virtual resection on the three-dimensional liver model. Conversion therapy was adopted after orally administered entecavir for antiviral treatment. First, the right portal vein was embolized. Then tumor embolization was performed via the variant hepatic arteries. After 3 wk, the FRL of the left lateral lobe accounted for nearly 30% of the total liver volume. Totally laparoscopic right trisectionectomy was performed under combined epidural and general anesthesia. The in situ resection was performed via an anterior approach. The operating time was 240 min. No clamping was required during the surgery, and the intraoperative blood loss was 300 mL. There were no postoperative complications such as bile leakage, and the incision healed well. The patient was discharged on the 8th postoperative day. During the 3-mo follow-up, there was no recurrence and obvious hyperplasia of residual liver was observed. Alpha-fetoprotein decreased significantly and tended to be normal. CONCLUSION: Due to the different biological characteristics of the liver cancer and the pathophysiological features of the liver from other organs, the conversion treatment should take into account both the feasibility of tumor downstaging and the volume and function of the remnant liver. Our case provides a reference for clinicians in terms of both conversion therapy and laparoscopic right trisectionectomy.

LINC00346 promotes hepatocellular carcinoma progression via activating the JAK-STAT3 signaling pathway.

Hepatocellular carcinoma (HCC) remains the most common malignant tumor worldwide. Long noncoding RNAs can modulate various tumorigenic processes. In addition, growing evidence has indicated tha the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is activated in multiple cancers, including HCC. Recently, it was found that LINC00346 can participate in several cancers. Nevertheless, the biological roles of LINC00346 in HCC have been barely investigated. In this study, the function of LINC00346 was specifically concentrated upon. We observed that LINC00346 was obviously elevated in HCC cells (Bel7404, Huh-6, HepG2, and QGY-7703 cells). Then, Bel7404 and HepG2 cells were overexpressed with LINC00346. Overexpression of LINC00346 repressed HCC cell survival and cell proliferation. In addition, apoptosis of Bel7404 and HepG2 cells was triggered by LINC00346 upregulation. Bel7404 and HepG2 cell cycle was arrested in the G1 phase by LINC00346. Meanwhile, we conducted wound-healing assay and Transwell invasion assays. As shown, we observed that the migratory and invasive capacities of Bel7404 and HepG2 cells were remarkably restrained by the increase of LINC00346. Moreover, we showed that LINC00346 overexpression activated the JAK-STAT3 pathway, which is involved in many cancers. Afterward, in vivo experiments were utilized and we proved that LINC00346 was able to induce HCC tumor growth via activating the JAK-STAT3 pathway. To conclude, we revealed the potential possibility of developing LINC00346 as an indicator for HCC.

Poly(3,6-diamino-9-ethylcarbazole) based molecularly imprinted polymer sensor for ultra-sensitive and selective detection of 17-ß-estradiol in biological fluids.

In this work, we reported the synthesis of 3, 6-diamino-9-ethylcarbazole and its application as a new monomer for preparation of molecularly imprinted polymer (MIP) electrochemical sensor. The as prepared MIP sensor exhibited ultrahigh sensitivity and selectivity for the detection of 17-ß-estradiol in attomolar levels (1 × 10-18molL-1). The sensor works by detecting the change of the interfacial impedance that is derived from recognition of 17-ß-estradiol on the MIP layer. The MIP sensor based on 3, 6-diamino-9-ethylcarbazole monomer revealed better performance than that of unmodified carbazole monomer. The monomer/template ratio, electropolymerization scanning cycles, and the incubation pH values were optimised in order to obtain the best detection efficiency. Under the optimised condition, the MIP sensor exhibits a wide linear range from 1aM to 10µM (1 × 10-18 ̶ 1 × 10-5molL-1). A low detection limit of 0.36aM (3.6 × 10-19molL-1) and a good selectivity towards structurally similar compounds were obtained. The proposed MIP sensor also exhibits long-term stability and applicability in human serum samples. These advantages enabled this MIP sensor to be a promising alternative of electrochemical sensor and may be extended to detection of other endogenous compounds.

The Associative Memory, Water Mediated, Structure and Energy Model (AWSEM)-Amylometer: Predicting Amyloid Propensity and Fibril Topology Using an Optimized Folding Landscape Model.

Amyloids are fibrillar protein aggregates with simple repeated structural motifs in their cores, usually ß-strands but sometimes α-helices. Identifying the amyloid-prone regions within protein sequences is important both for understanding the mechanisms of amyloid-associated diseases and for understanding functional amyloids. Based on the crystal structures of seven cross-ß amyloidogenic peptides with different topologies and one recently solved cross-α fiber structure, we have developed a computational approach for identifying amyloidogenic segments in protein sequences using the Associative memory, Water mediated, Structure and Energy Model (AWSEM). The AWSEM-Amylometer performs favorably in comparison with other predictors in predicting aggregation-prone sequences in multiple data sets. The method also predicts well the specific topologies (the relative arrangement of ß-strands in the core) of the amyloid fibrils. An important advantage of the AWSEM-Amylometer over other existing methods is its direct connection with an efficient, optimized protein folding simulation model, AWSEM. This connection allows one to combine efficient and accurate search of protein sequences for amyloidogenic segments with the detailed study of the thermodynamic and kinetic roles that these segments play in folding and aggregation in the context of the entire protein sequence. We present new simulation results that highlight the free energy landscapes of peptides that can take on multiple fibril topologies. We also demonstrate how the Amylometer methodology can be straightforwardly extended to the study of functional amyloids that have the recently discovered cross-α fibril architecture.

Core-shell materials bearing iron(ii) carbonyl units and their CO-release via an upconversion process.

CO-release induced by near infrared (NIR) light, to which body tissues are relatively transparent, from photoactive CO-releasing molecules (PhotoCORMs) has great significance in exploring the clinical potential of CO. In this work, a novel upconversion nanoparticle-based nanoplatform, UCNPs@SiO2-CORMs, has been developed using a one-pot reaction. The materials liberate CO under the irradiation of NIR light. TEM images of the materials showed that this nanoplatform consisted of a core-shell structure. On the surface were incorporated thiol groups through which mono-iron(ii) carbonyl units, "Fe(η5-Cp)(CO)2" were successfully anchored by a ligand exchange reaction between [Fe(η5-Cp)(CO)2I] (1) and the thiol groups. The core of the materials consists of ß-NaYF4:Yb3+/Er3+ upconversion nanoparticles (UCNPs). Strong emission bands around 530 and 550 nm from the materials upon irradiation by NIR fall into the broad band of the electronic spectrum of the materials. Consequently, the constructed nanoplatform steadily released CO upon irradiation with a 980 nm laser (1 W cm-2). Kinetic analysis suggests that CO-release from UCNPs@SiO2-CORMs in DMSO/D2O media fits a zero-order reaction model. Assessment of the cytotoxicity of UCNPs@SiO2-CORMs indicated that they showed excellent biocompatibility and no significant photo-toxicity.

The Aggregation Free Energy Landscapes of Polyglutamine Repeats.

Aggregates of proteins containing polyglutamine (polyQ) repeats are strongly associated with several neurodegenerative diseases. The length of the repeats correlates with the severity of the disease. Previous studies have shown that pure polyQ peptides aggregate by nucleated growth polymerization and that the size of the critical nucleus (n*) decreases from tetrameric to dimeric and monomeric as length increases from Q18 to Q26. Why the critical nucleus size changes with repeat-length has been unclear. Using the associative memory, water-mediated, structure and energy model, we construct the aggregation free energy landscapes for polyQ peptides of different repeat-lengths. These studies show that the monomer of the shorter repeat-length (Q20) prefers an extended conformation and that its aggregation indeed has a trimeric nucleus (n* ∼ 3), while a longer repeat-length monomer (Q30) prefers a ß-hairpin conformation which then aggregates in a downhill fashion at 0.1 mM. For an intermediate length peptide (Q26), there is an equal preference for hairpin and extended forms in the monomer which leads to a mixed inhomogeneous nucleation mechanism for fibrils. The predicted changes of monomeric structure and nucleation mechanism are confirmed by studying the aggregation free energy profile for a polyglutamine repeat with site-specific PG mutations that favor the hairpin form, giving results in harmony with experiments on this system.

Protein Folding and Structure Prediction from the Ground Up: The Atomistic Associative Memory, Water Mediated, Structure and Energy Model.

The associative memory, water mediated, structure and energy model (AWSEM) is a coarse-grained force field with transferable tertiary interactions that incorporates local in sequence energetic biases using bioinformatically derived structural information about peptide fragments with locally similar sequences that we call memories. The memory information from the protein data bank (PDB) database guides proper protein folding. The structural information about available sequences in the database varies in quality and can sometimes lead to frustrated free energy landscapes locally. One way out of this difficulty is to construct the input fragment memory information from all-atom simulations of portions of the complete polypeptide chain. In this paper, we investigate this approach first put forward by Kwac and Wolynes in a more complete way by studying the structure prediction capabilities of this approach for six α-helical proteins. This scheme which we call the atomistic associative memory, water mediated, structure and energy model (AAWSEM) amounts to an ab initio protein structure prediction method that starts from the ground up without using bioinformatic input. The free energy profiles from AAWSEM show that atomistic fragment memories are sufficient to guide the correct folding when tertiary forces are included. AAWSEM combines the efficiency of coarse-grained simulations on the full protein level with the local structural accuracy achievable from all-atom simulations of only parts of a large protein. The results suggest that a hybrid use of atomistic fragment memory and database memory in structural predictions may well be optimal for many practical applications.

Down-regulation of nectin-4 inhibits apoptosis in systemic lupus erythematous (SLE) through targeting Bcl-2/Bax pathway.

PURPOSE: The purpose of this study was to investigate the potential role of nectin-4 in systemic lupus erythematous (SLE) cell apoptosis during the disease development and its potential mechanism. METHODS: Human peripheral blood mononuclear cells (PBMCs) were obtained for the isolation of monocytes and T lymphocytes. siRNA-nectin-4 plasma was constructed for the transfection into T cells using Lipofectamine 2000 reagent. siRNA with no nectin-4 sequence was transfected into T cells for the control group. mRNA expression of nectin-4 in cells was analyzed using RT-PCR method. Effect of netin-4 expression on T cell apoptosis was analyzed with Annexin V-FITC cell apoptosis kit. Moreover, effects of nectin-4 expression on cell apoptotic-related proteins expressions were detected using western blotting analysis. RESULTS: Nectin-4 was significantly overexpressed in cells from SLE group compared with healthy control (HC) group (P<0.05). When T cells were transfected with sinectin-4, nectin-4 slicing increased cell apoptosis in HC group but significantly decreased apoptosis in SLE group (P<0.05). Nectin-4 slicing significantly decreased CD40L and CD17 expressions in SLE (P<0.05), but performed no effect on CD11a expression. Moreover, nectin-4 down-regulation could significantly decrease Bcl-2, Bcl-XL, and caspase-6 expressions but increase Bax level in SLE group. CONCLUSION: The data presented in this study suggested that nectin-4 may be a therapeutic target for SLE through affecting the cell apoptosis.

Successful treatment of refractory gastric antral vascular ectasia by distal gastrectomy: a case report.

Gastric antral vascular ectasia (GAVE) is an uncommon and often neglected cause of gastric hemorrhage. The treatments for GAVE include surgery, endoscopy and medical therapies. Here, we report an unusual case of GAVE. A 72-year-old man with a three-month history of recurrent melena was diagnosed with GAVE. Endoscopy revealed the classical "watermelon stomach" appearance of GAVE and complete pyloric involvement. Melena reoccurred three days after argon plasma coagulation treatment, and the level of hemoglobin dropped to 47 g/L. The patient was then successfully treated with distal gastrectomy with Billroth II anastomosis. We propose that surgery should be considered as an effective option for GAVE patients with extensive and severe lesions upon deterioration of general conditions and hemodynamic instability.

[Clinical application of extracorporeal membrane oxygenation for treatment of adult refractory cardiogenic shock].

OBJECTIVE: To summarize the clinical experience of extracorporeal membrane oxygenation (ECMO) treatment for adult refractory cardiogenic shock. METHODS: From January 2003 to January 2011, patients with refractory cardiogenic shock required veno-arterial ECMO by failure of conventional therapy and intra-aortic balloon pump counterpulsation therapy were retrospectively studied. Patients with severe traumatic brain injury, advanced malignancies and multiple organ failure were excluded. Patients were divided into weaned group (n = 31) and not weaned group (n = 23) according to the ECMO weaning. RESULTS: The duration of ECMO was 24.16 (14.12, 56.75) hours. Twenty-two out of 31 patients in the weaned group survived and were discharged, 9 patients died after successfully weaned from ECMO (5 due to multisystem organ failure, 2 due to reoccurred cardiogenic shock, 1 due to infectious shock and 1 due to disseminated or diffuse intravascular coagulation). Pre-ECMO mean arterial pressure, ejection fraction, the duration of ECMO were significantly higher while pre-ECMO blood lactate [(8.64 ± 3.17) vs. (14.44 ± 2.52) , P < 0.01], the duration of ROSC [ (16.70 ± 5.29) vs. (35.64 ± 5.89), P < 0.01] and multisystem organ failure [0 vs. 17.4% (4/23) , P < 0.05] were lower in weaned group than in not wean group. CONCLUSIONS: ECMO is an effective mechanical assistant therapy strategy for adult refractory cardiogenic shock patients. Timely applying this strategy on suitable patients is crucial for the success of ECMO. Cardiac function and reversibility of heart failure are key factors determine the fate of weaned or not weaned ECMO in adult refractory cardiogenic shock patients.

Kinetic network study of the diversity and temperature dependence of Trp-Cage folding pathways: combining transition path theory with stochastic simulations.

We present a new approach to study a multitude of folding pathways and different folding mechanisms for the 20-residue mini-protein Trp-Cage using the combined power of replica exchange molecular dynamics (REMD) simulations for conformational sampling, transition path theory (TPT) for constructing folding pathways, and stochastic simulations for sampling the pathways in a high dimensional structure space. REMD simulations of Trp-Cage with 16 replicas at temperatures between 270 and 566 K are carried out with an all-atom force field (OPLSAA) and an implicit solvent model (AGBNP). The conformations sampled from all temperatures are collected. They form a discretized state space that can be used to model the folding process. The equilibrium population for each state at a target temperature can be calculated using the weighted-histogram-analysis method (WHAM). By connecting states with similar structures and creating edges satisfying detailed balance conditions, we construct a kinetic network that preserves the equilibrium population distribution of the state space. After defining the folded and unfolded macrostates, committor probabilities (P(fold)) are calculated by solving a set of linear equations for each node in the network and pathways are extracted together with their fluxes using the TPT algorithm. By clustering the pathways into folding "tubes", a more physically meaningful picture of the diversity of folding routes emerges. Stochastic simulations are carried out on the network, and a procedure is developed to project sampled trajectories onto the folding tubes. The fluxes through the folding tubes calculated from the stochastic trajectories are in good agreement with the corresponding values obtained from the TPT analysis. The temperature dependence of the ensemble of Trp-Cage folding pathways is investigated. Above the folding temperature, a large number of diverse folding pathways with comparable fluxes flood the energy landscape. At low temperature, however, the folding transition is dominated by only a few localized pathways.

[Comparison of the clinicopathological characteristics of colorectal cancer between elderly and young patients].

OBJECTIVE: To compare the clinicopathological characteristics between elderly and young patients with colorectal cancer (CRC). METHODS: A total of 727 patients with CRC treated between Jan 2003 and Dec 2005 were divided into elderly group (≥ 60 years old), middle-aged group (36-59 years old), and young group (≤ 35 years old). The clinicopathological characteristics of the 3 groups were analyzed retrospectively. RESULTS: The tumor occurred mainly in the rectum, sigmoid colon and ascending colon of the patients. The major initial symptoms included hemafecia and changes in bowel habits in the elderly and middle-aged cases, as compared to abdominal pain and hemafecia in the young group. The elderly patients had greater ratio of well differentiated neoplasm than the middle-aged and young patients. The ratio of radical operation was markedly higher in the elderly and middle-aged group than in the young group. The elderly patients were more likely to have stage II and III tumors than the middle-aged and young patients, having also significantly higher incidences of such complications as heart and lung diseases upon diagnosis. CONCLUSIONS: Compared with the middle-aged and young patients, elderly patients with CRC are more likely to have well differentiated tumor, multiple complications upon diagnosis, and higher radical operation rate.