Sequential Treatment of Iliopsoas Tendon Cysts Combined With Medial Hip Snapping by Hip Arthroscopy.

Tendon cysts of the iliopsoas muscle cause pain and snapping of the hip. These cysts are close to the femoral nerve and blood vessels, and the risk of open surgery is high, with cyst recurrence occurring frequently. We describe a method of hip arthroscopy for the orderly excision of iliopsoas cysts. During the operation, the iliopsoas tendon is identified and released, the cyst is excised, and peritendinous osteophytes are formed successively. This technique is a minimally invasive, safe, and highly effective hip arthroscopy technique that addresses both intra- and extra-articular lesions.

The safety and short-term effect of mixed approach in laparoscopic right hemicolectomy for right colon cancer compared with middle approach: a retrospective study.

PURPOSE: To investigate whether the mixed approach is a safe and advantageous way to operate laparoscopic right hemicolectomy. METHODS: A retrospective study was performed on 316 patients who underwent laparoscopic right hemicolectomy in our center. They were assigned to the middle approach group (n = 158) and the mixed approach group (n = 158) according to the surgical approaches. The baseline data like gender、age and body mass index as well as the intraoperative and postoperative conditions including operation time, blood loss, postoperative hospital stay and complications were analyzed. RESULTS: There were no significant differences in age, sex, BMI, ASA grade and tumor characteristics between the two groups. Compared with the middle approach group, the mixed approach group was significantly lower in terms of operation time (217.61 min vs 154.31 min, p < 0.001), intraoperative blood loss (73.8 ml vs 37.97 ml, p < 0.001) and postoperative drainage volume. There was no significant difference in the postoperative complications like postoperative anastomotic leakage, postoperative infection and postoperative intestinal obstruction. CONCLUSIONS: Compared with the middle approach, the mixed approach is a safe and advantageous way that can significantly shorten the operation time, reduce intraoperative bleeding and postoperative drainage volume, and does not prolong the length of hospital stay or increase the morbidity postoperative complications.

Programming viscoelastic properties in a complexation gel composite by utilizing entropy-driven topologically frustrated dynamical state.

Hydrogel composites in an aqueous media with viscoelastic properties and elastic modulus that can be precisely tailored are desirable to mimic many biological tissues ranging from mucus, vitreous humor, and nucleus pulposus as well as build up biosensors. Without altering the chemistry, tuning the physical interactions and structures to govern the viscoelastic properties of the hydrogels is indispensable for their applications but quite limited. Here we design a complexation gel composite and utilize the physical principle of topologically frustrated dynamical state to tune the correlated structures between the guest polycation chains and negatively charged host gels. We precisely quantify the mesh size of the host gel and guest chain size. By designing various topologically correlated structures, a viscoelastic moduli map can be built up, ranging from tough to ultrasoft, and from elastic-like with low damping properties to viscous-like with high damping properties. We also tune the swelling ratio by using entropy effect and discover an Entropy-driven Topologically Isovolumetric Point. Our findings provide essential physics to understand the relationship between entropy-driven correlated structures and their viscoelastic properties of the complexation hydrogel composites and will have diverse applications in tissue engineering and soft biomaterials.

Nonhalogenated Solvent Processable and High-Density Photopatternable Polymer Semiconductors Enabled by Incorporating Hydroxyl Groups in the Side Chains.

Polymer semiconductors hold tremendous potential for applications in flexible devices, which is however hindered by the fact that they are usually processed by halogenated solvents rather than environmentally more friendly solvents. An effective strategy to boost the solubility of high-performance polymer semiconductors in nonhalogenated solvents such as tetrahydrofuran (THF) by appending hydroxyl groups in the side chains is herein presented. The results show that hydroxyl groups, which can be easily incorporated into the side chains, can significantly improve the solubility of typical p- and n-types as well as ambipolar polymer semiconductors in THF. Meanwhile, the thin films of these polymer semiconductors from the respective THF solutions show high charge mobilities. With THF as the processing and developing solvents these polymer semiconductors with hydroxyl groups in the side chains can be well photopatterned in the presence of the photo-crosslinker, and the charge mobilities of the patterned thin films are mostly maintained by comparing with those of the respective pristine thin films. Notably, THF is successfully utilized as the processing and developing solvent to achieve high-density photopatterning with ≈82 000 device arrays cm-2 for polymer semiconductors in which hydroxyl groups are appended in the side chains.

Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes.

Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF. We also performed a large transcriptome-wide association study (TWAS) and Fine-mapping of causal gene sets (FOCUS), leveraging joint-tissue imputation (JTI) prediction models of 22 tissues to identify and prioritize putatively causal genes. We further conducted PWAS, SMR, TWAS, and FOCUS using a multi-trait analysis of GWAS (MTAG) to identify additional PD risk genes to boost statistical power. In this large-scale study, we identified 16 genes whose genetically regulated protein abundance levels were associated with Parkinson's disease risk. We undertook a large-scale analysis of PD and correlated traits, through TWAS and FOCUS studies, and discovered 26 casual genes related to PD that had not been reported in previous TWAS. 5 genes (CD38, GPNMB, RAB29, TMEM175, TTC19) showed significant associations with PD at both the proteome-wide and transcriptome-wide levels. Our study provides new insights into the etiology and underlying genetic architecture of PD.

A Fully Amorphous, Dynamic Cross-Linked Polymer Electrolyte for Lithium-Sulfur Batteries Operating at Subzero-Temperatures.

Solid-state lithium-sulfur batteries have shown prospects as safe, high-energy electrochemical storage technology for powering regional electrified transportation. Owing to limited ion mobility in crystalline polymer electrolytes, the battery is incapable of operating at subzero temperature. Addition of liquid plasticizer into the polymer electrolyte improves the Li-ion conductivity yet sacrifices the mechanical strength and interfacial stability with both electrodes. In this work, we showed that by introducing a spherical hyperbranched solid polymer plasticizer into a Li+ -conductive linear polymer matrix, an integrated dynamic cross-linked polymer network was built to maintain fully amorphous in a wide temperature range down to subzero. A quasi-solid polymer electrolyte with a solid mass content >90 % was prepared from the cross-linked polymer network, and demonstrated fast Li+ conduction at a low temperature, high mechanical strength, and stable interfacial chemistry. As a result, solid-state lithium-sulfur batteries employing the new electrolyte delivered high reversible capacity and long cycle life at 25 °C, 0 °C and -10 °C to serve energy storage at complex environmental conditions.

A 3-Year Survival Update from a Phase 2 Study of Paclitaxel Plus Cisplatin and 5-Fuorouracil Induction Chemotherapy for Locally Advanced Borderline-Resectable Esophageal Squamous Cell Carcinoma: The NEOCRTEC-1601 Clinical Trial.

BACKGROUND: This study updated 3-year analyses to further characterize the impact of docetaxel, cisplatin, and fluorouracil (TPF) chemotherapy followed by surgery. METHODS: This study was a single-center phase 2 clinical trial. Patients with a diagnosis of borderline resectable esophageal squamous cell carcinoma (BR-ESCC) because of the primary tumor or bulky lymph node that potentially invaded adjacent organs were eligible. The treatment started with TPF chemotherapy followed by surgery if the cancer was resectable, or by concurrent chemoradiation if it was unresectable. This updated report presents the 3-year overall survival (OS) and progression-free survival (PFS) rates. RESULTS: Surgery was performed for 27 patients (57.4%), and R0 resection was confirmed in 25 patients (53.2%). Pathologic complete response was confirmed in four patients (8.5%). The median follow-up time for the surviving patients was 44.8 months (range, 3.4-74.6 months). The median OS for all the patients was 41.9 months (95% confidence interval [CI], 18.6-65.3 months), with a median PFS of 38.7 months (95% CI, 23.5-53.9 months). The 3-year survival rate for all the patients was 54.4%. The 3-year survival rate for the R0 patients was 65.4%. CONCLUSION: Long-term follow-up evaluation confirmed that TPF followed by surgery is feasible and promising in terms of survival for BR-ESCC patients. Trial Registration ClinicalTrials.gov identifer: NCT02976909.

Mesenchymal stem cells overexpressing PBX1 alleviates haemorrhagic shock-induced kidney damage by inhibiting NF-κB activation.

Mesenchymal stem cells (MSCs) have favourable outcomes in the treatment of kidney diseases. Pre-B-cell leukaemia transcription factor 1 (PBX1) has been reported to be a regulator of self-renewal of stem cells. Whether PBX1 is beneficial to MSCs in the treatment of haemorrhagic shock (HS)-induced kidney damage is unknown. We overexpressed PBX1 in rat bone marrow-derived mesenchymal stem cells (rBMSCs) and human bone marrow-derived mesenchymal stem cells (hBMSCs) to treat rats with HS and hypoxia-treated human proximal tubule epithelial cells (HK-2), respectively. The results indicated that PBX1 enhanced the homing capacity of rBMSCs to kidney tissues and that treatment with rBMSCs overexpressing PBX1 improved the indicators of kidney function, alleviated structural damage to kidney tissues. Furthermore, administration with rBMSCs overexpressing PBX1 inhibited HS-induced NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and the release of proinflammatory cytokines, and further attenuated apoptosis. We then determined whether NF-κB, an important factor in NLRP3 activation and the regulation of inflammation, participates in HS-induced kidney damage, and we found that rBMSCs overexpressing PBX1 inhibited NF-κB activation by decreasing the p-IκBα/IκBα and p-p65/p65 ratios and inhibiting the nuclear translocation and decreasing the DNA-binding capacity of NF-κB. hBMSCs overexpressing PBX1 also exhibited protective effects on HK-2 cells exposed to hypoxia, as shown by the increase in cell viability, the mitigation of apoptosis, the decrease in inflammation, and the inhibition of NF-κB and NLRP3 inflammasome activation. Our study demonstrates that MSCs overexpressing PBX1 ameliorates HS-induced kidney damage by inhibiting NF-κB pathway-mediated NLRP3 inflammasome activation and the inflammatory response.

GRP78 improves the therapeutic effect of mesenchymal stem cells on hemorrhagic shock-induced liver injury: Involvement of the NF-кB and HO-1/Nrf-2 pathways.

Mesenchymal stem cells (MSCs) are a popular cell source for repairing the liver. Improving the survival rate and colonization time of MSCs may significantly improve the therapeutic outcomes of MSCs. Studies showed that 78-kDa glucose-regulated protein (GRP78) expression improves cell viability and migration. This study aims to examine whether GRP78 overexpression improves the efficacy of rat bone marrow-derived MSCs (rBMSCs) in HS-induced liver damage. Bone marrow was isolated from the femurs and tibias of rats. rBMSCs were transfected with a GFP-labeled GRP78 expression vector. Flow cytometry, transwell invasion assay, scratch assay immunoblotting, TUNEL assay, MTT assay, and ELISA were carried out. The results showed that GRP78 overexpression enhanced the migration and invasion of rBMSCs. Moreover, GRP78-overexpressing rBMSCs relieved liver damage, repressed liver oxidative stress, and inhibited apoptosis. We found that overexpression of GRP78 in rBMSCs inhibited activation of the NLRP3 inflammasome, significantly decreased the levels of inflammatory factors, and decreased the expression of CD68. Notably, GRP78 overexpression activated the Nrf-2/HO-1 pathway and inhibited the NF-κB pathway. High expression of GRP78 efficiently enhanced the effect of rBMSC therapy. GRP78 may be a potential target to improve the therapeutic efficacy of BMSCs.

Tpr Misregulation in Hippocampal Neural Stem Cells in Mouse Models of Alzheimer's Disease.

Nuclear pore complexes (NPCs) are highly dynamic macromolecular protein structures that facilitate molecular exchange across the nuclear envelope. Aberrant NPC functioning has been implicated in neurodegeneration. The translocated promoter region (Tpr) is a critical scaffolding nucleoporin (Nup) of the nuclear basket, facing the interior of the NPC. However, the role of Tpr in adult neural stem/precursor cells (NSPCs) in Alzheimer's disease (AD) is unknown. Using super-resolution (SR) and electron microscopy, we defined the different subcellular localizations of Tpr and phospho-Tpr (P-Tpr) in NSPCs in vitro and in vivo. Elevated Tpr expression and reduced P-Tpr nuclear localization accompany NSPC differentiation along the neurogenic lineage. In 5xFAD mice, an animal model of AD, increased Tpr expression in DCX+ hippocampal neuroblasts precedes increased neurogenesis at an early stage, before the onset of amyloid-ß plaque formation. Whereas nuclear basket Tpr interacts with chromatin modifiers and NSPC-related transcription factors, P-Tpr interacts and co-localizes with cyclin-dependent kinase 1 (Cdk1) at the nuclear chromatin of NSPCs. In hippocampal NSPCs in a mouse model of AD, aberrant Tpr expression was correlated with altered NPC morphology and counts, and Tpr was aberrantly expressed in postmortem human brain samples from patients with AD. Thus, we propose that altered levels and subcellular localization of Tpr in CNS disease affect Tpr functionality, which in turn regulates the architecture and number of NSPC NPCs, possibly leading to aberrant neurogenesis.

Evaluation on the application of conjugate materials in the sound effect and stage effect of modern dance.

The emergence and application of conjugate materials provide a broader space for the performance of sound and presentation effects on the modern music stage. This article compared and analyzed the application of conjugated materials and traditional methods in modern dance sound effects and stage presentation effects through experiments, found that the application of conjugated materials on modern stages had the effect of enhancing visual effects. Its overall reflectivity, color saturation, brightness, transparency, etc. remain in the range of 78%-97%, which is better than traditional methods. In addition, the use of conjugated materials can also improve auditory performance, have greater penetration and durability, and reduce the impact of external noise; in terms of audience experience and dancer experience, the average proportions also reached 87.8893% and 89.3867% respectively. In addition, it also has high temperature resistance and antibacterial effects, with a maximum temperature resistance value of 314.28°C and an antibacterial effect of 95.86%, indicating that it can still maintain stability under high temperature conditions and has a good inhibitory effect on the proliferation of bacteria and viruses. These findings will lay the foundation for further expanding the application of conjugated materials on the modern dance stage.

Bioinformatics identification and integrative analysis of ferroptosis-related key lncRNAs in patients with osteoarthritis.

BACKGROUND: Ferroptosis and dysregulation of long non-coding RNA (lncRNA) have been described to be strictly relevant to the pathogenesis of osteoarthritis (OA). However, the connection between ferroptosis and lncRNA in OA is poorly appreciated. Herein, we investigated the functional contribution of lncRNA markers correlated with the progression of human OA by comprehensive bioinformatics analysis of a panoramic network of competing endogenous RNA (ceRNA) based on ferroptosis-related genes (FRGs). METHODS: FRGs-related competing endogenous RNA (ceRNA) networks were generated using differentially expressed genes based on OA-related whole transcriptome data from the Gene Expression Omnibus (GEO) database via starBase, miRTarBase, and miRWalk databases. The pivotal lncRNAs were ascertained by topological features (degree, betweenness, and closeness) and subceRNA networks were re-visualized. The expression difference of pivotal lncRNAs was verified by quantitative real-time polymerase chain reaction (qRT-PCR). The latent molecular mechanisms of the global ceRNA and subceRNA networks were uncovered by the R package clusterProfiler-based enrichment analysis. RESULTS: A total of 98 dysregulated lncRNA-miRNA-mRNA regulatory relationships were attained in the FRGs-related panoramic ceRNA network of OA, covering 26 mRNAs, 20 miRNAs, and 20 lncRNAs. Three lncRNAs (AC011511.5, AL358072.1, and C9orf139) were ascertained as the central lncRNAs in the panoramic ceRNA network. Functional ensemble analysis illustrated that both the panoramic ceRNA network and the subceRNA network were integrally affiliated with the immune-inflammatory response, oxygen homeostasis, and cell death (apoptosis, autophagy, and ferroptosis). CONCLUSION: Comprehensive bioinformatics analysis of the FRGs-related ceRNA network determined three molecular biomarkers of lncRNAs that might be affiliated with OA progression.

Identifying causal genes for migraine by integrating the proteome and transcriptome.

BACKGROUND: While previous genome-wide association studies (GWAS) have identified multiple risk variants for migraine, there is a lack of evidence about how these variants contribute to the development of migraine. We employed an integrative pipeline to efficiently transform genetic associations to identify causal genes for migraine. METHODS: We conducted a proteome-wide association study (PWAS) by combining data from the migraine GWAS data with proteomic data from the human brain and plasma to identify proteins that may play a role in the risk of developing migraine. We also combined data from GWAS of migraine with a novel joint-tissue imputation (JTI) prediction model of 17 migraine-related human tissues to conduct transcriptome-wide association studies (TWAS) together with the fine mapping method FOCUS to identify disease-associated genes. RESULTS: We identified 13 genes in the human brain and plasma proteome that modulate migraine risk by regulating protein abundance. In addition, 62 associated genes not reported in previous migraine TWAS studies were identified by our analysis of migraine using TWAS and fine mapping. Five genes including ICA1L, TREX1, STAT6, UFL1, and B3GNT8 showed significant associations with migraine at both the proteome and transcriptome, these genes are mainly expressed in ependymal cells, neurons, and glial cells, and are potential target genes for prevention of neuronal signaling and inflammatory responses in the pathogenesis of migraine. CONCLUSIONS: Our proteomic and transcriptome findings have identified disease-associated genes that may give new insights into the pathogenesis and potential therapeutic targets for migraine.

Cryptotanshinone ameliorates hemorrhagic shock-induced liver injury via activating the Nrf2 signaling pathway.

INTRODUCTION: Hemorrhagic shock (HS) is an important cause of high mortality in traumatized patients. Cryptotanshinone (CTS) is a bioactive compound extracted from Salvia miltiorrhiza Bunge (Danshen). The current study aimed to explore the effect and underlying mechanism of CTS on the liver injury induced by HS. MATERIAL AND METHODS: Male Sprague-Dawley rats were used to establish the HS model by hemorrhaging and monitoring mean arterial pressure (MAP). CTS was intravenously administered at concentration of 3.5 mg/kg, 7 mg/kg, or 14 mg/kg 30 minutes before resuscitation. Twenty-four hours after resuscitation, the liver tissue and serum samples were collected for the following examinations. Hematoxylin and eosin (H&E) staining was used to evaluate hepatic morphology changes. The myeloperoxidase (MPO) activity in liver tissue and the serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were examined to reveal the extent of liver injury. The protein expression of Bax and Bcl-2 in liver tissue was detected by western blot. The TUNEL assay determined the apoptosis of hepatocytes. Oxidative stress of liver tissue was assessed by the examination of reactive oxygen species (ROS) generation. The content of malondialdehyde (MDA), glutathione (GSH), and adenosine triphosphate (ATP), the activity of superoxide dismutase (SOD) and oxidative chain complexes (complex I, II, III, IV), as well as cytochrome c expression in cytoplasm and mitochondria, were also used to determine the extent of oxidative injury in the liver. Immunofluorescence (IF) was employed to estimate nuclear factor E2-related factor 2 (Nrf2) expression. The mRNA and protein levels of heme oxygenase 1 (HO-1), NAD(P)H: quinone oxidoreductases 1 (NQO1), cyclooxygenase-2 (COX-2), and nitric oxide synthase (iNOS) were assessed by real-time qPCR, western blot to investigate the mechanism of CTS regulating HS-induced liver injury. RESULTS: H&E staining and a histological score of rat liver suggested that HS induced liver injury. The activity of ALT, AST, and MPO was significantly increased by HS treatment. After CTS administration the ALT, AST, and MPO activities were suppressed, which indicates the liver injury was alleviated by CTS. The HS-induced upregulation of the TUNEL-positive cell rate was suppressed by various doses of CTS. HS-induced ROS production was decreased and the protein expression of Bax and Bcl-2 in the HS-induced rat liver was reversed by CTS administration. In the liver of HS-induced rats, the upregulation of MDA content and the downregulation of GSH content and SOD activitywere suppressed by CTS. Additionally, CTS increases ATP content and mitochondrial oxidative complexes activities and suppressed the release of cytochrome c from mitochondria to the cytoplasm. Moreover, IF and western blot demonstrated that the activation of Nrf2 blocked by HS was recovered by different doses of CTS in liver tissue. The expression of downstream enzymes of the Nrf2 pathway, including HO-1, NQO1, COX-2, and iNOS, was reversed by CTS in the HS rat model. CONCLUSIONS: The current study for the first time revealed the protective effect of CTS in HS-induced liver injury. CTS effectively recovered hepatocyte apoptosis, oxidative stress, and mitochondria damage induced by HS in the rat liver partly via regulating the Nrf2 signaling pathway.

HSF1 enhances the attenuation of exosomes from mesenchymal stem cells to hemorrhagic shock induced lung injury by altering the protein profile of exosomes.

Severe hemorrhagic shock (HS) leads to lung injury, resulting in respiratory insufficiency. Mesenchymal stem cell (MSC)-derived exosomes have therapeutic effects on the organ injury. HSF1 has been reported to protect the lung against injury. In this study, the role of exosomes from HSF1-overexpressed MSCs (HSF1-EVs) in HS-induced lung injury was investigated. We constructed a mouse model of lung injury by induction with HS and pre-treated it with HSF1-EVs. It was clarified that HSF1-EVs manifested better protective effects on HS-induced lung injury compared with the exosomes derived from control MSCs. Inhalation of HSF1-EVs declined the ratio of wet to dry and total protein concentration in bronchoalveolar lavage fluids. Besides, HSF1-EVs greatly inhibited the production of inflammatory cytokines (IL-1ß, IL-6, MCP-1 and HMGB1), and constrained the pulmonary neutrophilic infiltration induced by HS. A reduction of oxidative stress was observed in HSF1-EV-treated mice. HSF1-EVs suppressed the HS-induced apoptosis of lung cell and downregulated Bcl-2 expression, while promoting Bax expression. The key proteins of pulmonary epithelial barrier, E-cadherin, ZO-1 and Occludin, were all upregulated in HS-treated mice after HSF1-EV inhalation, suggesting that HSF1-EVs played a protective role in the epithelial barrier of lung. Additionally, the results of proteomics showed that HSF1 overexpression altered the protein profile of MSC-derived exosomes, which might explain the more significant relief effect of HSF1-EVs on lung injury compared with that of Plasmid-EVs. These new findings demonstrated that the exosomes secreted by HSF1-overexpressed MSCs can be an effective precautionary measure for lung injury induced by HS.

Electrically tuned coupling of lithium niobate microresonators.

Microresonators coupled with integrated waveguides operate stably but usually lack tunability for an optimal coupling state. In this Letter, we demonstrate a racetrack resonator with an electrically modulated coupling on an X-cut lithium niobate (LN) platform by introducing a Mach-Zehnder interferometer (MZI) with two balanced directional couplers (DCs) to realize light exchange. This device provides a wide-range coupling regulation, from under-coupling and critical coupling to deep over-coupling. Importantly, it has a fixed resonance frequency when the DC splitting ratio is 3 dB. The measured optical responses of the resonator exhibit a high extinction ratio, exceeding 23 dB, and an effective half-wave voltage length Vπ·L of 0.77 V·cm, suitable for CMOS compatibility. Microresonators with tunable coupling and a stable resonance frequency are expected to find application in nonlinear optical devices on LN-integrated optical platforms.

Prognostic value of L4 lymph node dissection during video-assisted thoracoscopic surgery in patients with left-sided non-small cell lung cancer: a single-center, retrospective cohort study.

Background: Lymph node dissection (LND) is crucial procedure during radical resection of non-small cell lung cancer (NSCLC), but the prognostic value of L4 LND remains elusive. To investigate the prognostic value of L4 LND in patients with left-side NSCLC who underwent video-assisted thoracoscopic surgery (VATS). Methods: Three hundred twelve patients who underwent VATS between Jan. 2007 and Dec. 2016 were reviewed. Of those, 119 underwent L4 LND (L4D+), whereas the other 193 patients did not (L4D-). The inclusion criteria were as follows: patients diagnosed with primary left-sided NSCLC who underwent VATS lobectomy combined with LND; patients subjected to R0 resection and tumor pathological stage T1-4N0-2M0. The primary endpoint was overall survival (OS). OS was calculated from the operation date to the date of death. The chi-square test was used for categorical variables, and a t test was used for continuous variables. Results: A total of 119 patients underwent L4 LND, and the procedure was more likely to be performed on upper lobe tumors (P=0.019). Patient distributions with respect to age, gender, smoking history, clinical stage, adjuvant therapy, tumor differentiation and tumor size were well balanced between two groups. More lymph nodes (LNs) were dissected in the L4D+ group than in the L4D- group (P<0.001). The rate of metastasis to L4 lymph nodes was 9.2%, which was comparable between patients with upper and lower lobe tumors (8.9% vs. 10.0%, P=1.000). The L4D+ group exhibited a significantly better OS than the L4D- group (median OS: undefined vs. 130 months, HR 0.47; 95% CI: 0.31-0.72; P=0.002). Multivariate analysis showed that L4 LND was an independent factor for OS. However, OS did not significantly differ between the two groups of cT1aN0 and cT1bN0 patients (OS: HR 0.44; 95% CI: 0.18-1.06; P=0.12). Conclusions: L4 LND is recommended for patients with left-sided NSCLC as an essential component of radical resection. The role of L4 LND in cT1a-bN0 disease warrants further study.

Sirtuin3 confers protection against acute pulmonary embolism through anti-inflammation, and anti-oxidative stress, and anti-apoptosis properties: participation of the AMP-activated protein kinase/mammalian target of rapamycin pathway.

An increasing number of studies have suggested that oxidative stress and inflammation play momentous roles in acute pulmonary embolism (APE). Honokiol, a bioactive biphenolic phytochemical substance, is known for its strong anti-oxidative and anti-inflammatory effects, and it served as an activator of sirtuin3 (SIRT3) in the present study. The purposes of the study were to explore the effects of honokiol on APE rats and investigate whether the function of honokiol is mediated by SIRT3 activation. In the study, the rats received a right femoral vein injection of dextran gel G-50 particles (12 mg/kg) to establish the APE model and were subsequently administered honokiol and/or a selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl)pyridine (3-TYP; 5 mg/kg) intraperitoneally. The results showed that SIRT3 activation by honokiol attenuated the loss in lung function, ameliorated the inflammatory response and oxidative damage, and inhibited apoptosis in lung tissues of the rats with APE but that this was reversed by 3-TYP. In addition, we found that the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway might be activated by honokiol but restrained by 3-TYP. These results indicated that honokiol was capable of suppressing the adverse effects of APE and that this was diminished by SIRT3 suppression, implying that activation of SIRT3 might serve as a therapeutic method for APE.

HDAC6 inhibition alleviates acute pulmonary embolism: a possible future therapeutic option.

INTRODUCTION: Acute pulmonary embolism (APE) is a clinical syndrome of pulmonary circulation disorder caused by obstruction of the pulmonary artery or its branches. Histone deacetylase 6 (HDAC6) has been reported to play an important role in lung-related diseases. However, the functional role of HDAC6 in APE remains unclear. MATERIAL AND METHODS: Male Sprague Dawley rats were used. The APE model was constructed by inserting an intravenous cannula into the right femoral vein and injecting Sephadex G-50 microspheres (12 mg/kg; 300 µm in diameter). After 1 h, the control and APE rats were intraperitoneally injected with tubastatin A (TubA) (40 mg/kg, an inhibitor of HDAC6) and sampled at 24 h after modeling. H&E staining, arterial blood gas analysis, and wet/dry (W/D) weight ratio were used to evaluate the histopathological changes and pulmonary function in APE rats. ELISA, Western blot, and immunohistochemistry were used to explore the potential mechanism of HDAC6-mediated inflammation in APE. RESULTS: The results indicated that HDAC6 expression was significantly increased in lungs of APE rats. TubA treatment in vivo decreased HDAC6 expression in lung tissues. HDAC6 inhibition alleviated histopathological damage and pulmonary dysfunction, as evidenced by decreased PaO2/FiO2 ratio and W/D weight ratio in APE rats. Furthermore, HDAC6 inhibition alleviated APE-induced inflammatory response. Specifically, APE rats exhibited increased production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, IL-6, and IL-18, however, this increase was reversed by HDAC6 inhibition. Meanwhile, the activation of the NLRP3 inflammasome was also observed in lungs of APE rats, while HDAC6 inhibition blocked this activation. Mechanically, we demonstrated that HDAC6 inhibition blocked the activation of the protein kinase B (AKT)/extracellular signal-regulated protein kinase (ERK) signaling pathway, a classic pathway promoting inflammation. CONCLUSIONS: These findings demonstrate that the inhibition of HDAC6 may alleviate lung dysfunction and pathological injury resulting from APE by blocking the AKT/ERK signaling pathway, providing new theoretical fundamentals for APE therapy.

GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation.

GGC repeat expansion in the 5' untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific induced pluripotent stem cell (iPSC)-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis and induce ribosomal RNA sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes.