Highly Stable Lithium Metal Batteries Enabled by Tuning the Molecular Polarity of Diluents in Localized High-Concentration Electrolytes.

Electrolyte plays a crucial role in ensuring stable operation of lithium metal batteries (LMBs). Localized high-concentration electrolytes (LHCEs) have the potential to form a robust solid-electrolyte interphase (SEI) and mitigate Li dendrite growth, making them a highly promising electrolyte option. However, the principles governing the selection of diluents, a crucial component in LHCE, have not been clearly determined, hampering the advancement of such a type of electrolyte systems. Herein, the diluents from the perspective of molecular polarity are rationally designed and developed. A moderately fluorinated solvent, 1-(1,1,2,2-tetrafluoroethoxy)propane (TNE), is employed as a diluent to create a novel LHCE. The unique molecular structure of TNE enhances the intrinsic dipole moment, thereby altering solvent interactions and the coordination environment of Li-ions in LHCE. The achieved solvation structure not only enhances the bulk properties of LHCE, but also facilitates the formation of more stable anion-derived SEIs featured with a higher proportion of inorganic species. Consequently, the corresponding full cells of both Li||LiFePO4 and Li||LiNi0.8 Co0.1 Mn0.1 O2 cells utilizing Li thin-film anodes exhibit extended long-term stability with significantly improved average Coulombic efficiency. This work offers new insights into the functions of diluents in LHCEs and provides direction for further optimizing the LHCEs for LMBs.

Articulation-Function-Associated Cortical Developmental Changes in Patients with Cleft Lip and Palate.

Cleft lip and palate (CLP) is one of the most common craniofacial malformations. Overall, 40-80% of CLP patients have varying degrees of articulation problems after palatoplasty. Previous studies revealed abnormal articulation-related brain function in CLP patients. However, the association between articulation disorders and cortical structure development in CLP patients remains unclear. Twenty-six CLP adolescents (aged 5-14 years; mean 8.88 years; female/male 8/18), twenty-three CLP adults (aged 18-35 years; mean 23.35 years; female/male 6/17), thirty-seven healthy adolescents (aged 5-16 years; mean 9.89 years; female/male 5/16), and twenty-two healthy adults (aged 19-37 years; mean 24.41 years; female/male 19/37) took part in the experiment. The current study aims to investigate developmental changes in cortical structures in CLP patients with articulation disorders using both structural and functional magnetic resonance imaging (MRI). Our results reveal the distinct distribution of abnormal cortical structures in adolescent and adult CLP patients. We also found that the developmental pattern of cortical structures in CLP patients differed from the pattern in healthy controls (delayed cortical development in the left lingual gyrus (t = 4.02, cluster-wise p < 0.05), inferior temporal cortex (z = -4.36, cluster-wise p < 0.05) and right precentral cortex (t = 4.19, cluster-wise p < 0.05)). Mediation analysis identified the cortical thickness of the left pericalcarine cortex as the mediator between age and articulation function (partial mediation effect (a*b = -0.48), 95% confident interval (-0.75, -0.26)). In conclusion, our results demonstrate an abnormal developmental pattern of cortical structures in CLP patients, which is directly related to their articulation disorders.

Association of BRCA2 Gene Functional Polymorphisms with Nonsyndromic Cleft Lip With or Without Cleft Palate in a Chinese Population.

Background: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a complex congenital disease affected by genetic and environmental factors however, the specific pathogenic alleles and regulatory mechanisms remain unclear in many cases. Here, we aimed to study the association between eight potentially functional single nucleotide polymorphisms (SNPs) of the BRCA2 and MGMT genes and NSCL/P in a Chinese population through a case-control study. Materials and Methods: To investigate the relationship between potentially functional SNPs of the BRCA2 and MGMT genes and NSCL/P, we selected 200 affected patients and 200 unrelated normal controls in a Chinese population. The BRCA2 gene SNPs (rs11571836, rs144848, rs7334543, rs15869, rs766173 and rs206118) and MGMT gene SNPs (rs12917 and rs7896488) were genotyped using the SNaPshot technique and the resulting data were subjected to statistical and bioinformatic analyses. Results: Our study identified for the first time that alleles of the BRCA2 are associated with NSCL/P in a Chinese population and that the s11571836 G allele was protective against NSCL/P. Under four genetic models, rs11571836 had a significant correlation with NSCL/P. Preliminary bioinformatic analyses revealed four potential miRNA matching sites (miR-1244, miR-1323, miR-562, and miR-633) associated with the rs11571836 which is located in the 3' untranslated region of BRCA2. Conclusions: These results support the role of polymorphisms of BRCA2 gene in affecting susceptibility to NSCL/P and its progression, but further research is necessary to elucidate the mechanism by which the BRCA2 gene polymorphisms affect the penetrance of NSCL/P.

Understanding the origin of the improved sodium ion storage performance of the transition metal oxide@carbon nanocomposite anodes.

Transition metal oxide (TMO) anodes show inferior sodium ion storage performance compared with that of lithium ion storage owing to the larger radium size and heavier elemental mass of Na+ than Li+. Effective strategies are highly desired to improve the Na+ storage performance of TMOs for applications. In this work, using ZnFe2O4@xC nanocomposites as model materials for investigation, we found that by manipulating the particle sizes of the inner TMOs core and the features of outer carbon coating, the Na+ storage performance can be significantly improved. The ZnFe2O4@1C with a diameter of the inner ZnFe2O4 core of around 200 nm coated by a thin carbon layer of around 3 nm shows a specific capacity of only 120 mA h g-1. The ZnFe2O4@6.5C with a diameter of the inner ZnFe2O4 core of around 110 nm embedding in a porous interconnected carbon matrix displays a significantly improved specific capacity of 420 mA h g-1 at the same specific current. Furthermore, the latter shows an excellent cycling stability of 1000 cycles with a capacity retention of 90% of the initial 220 mA h g-1 specific capacity at 1.0 A g-1. TEM, electrochemical impedance spectroscopy, and kinetic analysis show that the inner ZnFe2O4 core with reduced particle size and the outer thicker and interconnected carbon matrix synergistically improve the active reaction sites, integrity, electric conductivity, and pseudocapacitive-controlled contribution of ZnFe2O4@xC nanocomposites, thus leading to an overall enhanced Na+ storage performance. Our findings create a universal, facile, and effective method to enhance the Na+ storage performance of the TMO@C nanomaterials.

DEPDC1B Promotes Melanoma Angiogenesis and Metastasis through Sequestration of Ubiquitin Ligase CDC16 to Stabilize Secreted SCUBE3.

The ability of melanoma to acquire metastasis through the induction of angiogenesis is one of the major causes of skin cancer death. Here, it is found that high transcript levels of DEP domain containing 1B (DEPDC1B) in cutaneous melanomas are significantly associated with a poor prognosis. Tissue microarray analysis indicates that DEPDC1B expression is positively correlated with SOX10 in the different stages of melanoma. Consistently, DEPDC1B is both required and sufficient for melanoma growth, metastasis, angiogenesis, and functions as a direct downstream target of SOX10 to partly mediate its oncogenic activity. In contrast to other tumor types, the DEPDC1B-mediated enhancement of melanoma metastatic potential is not dependent on the activities of RHO GTPase signaling and canonical Wnt signaling, but is acquired through secretion of signal peptide, CUB domain and EGF like domain containing 3 (SCUBE3), which is crucial for promoting angiogenesis in vitro and in vivo. Mechanistically, DEPDC1B regulates SCUBE3 protein stability through the competitive association with ubiquitin ligase cell division cycle 16 (CDC16) to prevent SCUBE3 from undergoing degradation via the ubiquitin-proteasome pathway. Importantly, expression of SOX10, DEPDC1B, and SCUBE3 are positively correlated with microvessel density in the advanced stage of melanomas. In conclusion, it is revealed that a SOX10-DEPDC1B-SCUBE3 regulatory axis promotes melanoma angiogenesis and metastasis, which suggests that targeting secreted SCUBE3 can be a therapeutic strategy against metastatic melanoma.

A Novel Assessment Model Based on Molecular Subtypes of Hypoxia-Related LncRNAs for Prognosis of Bladder Cancer.

Hypoxia is a common feature in various tumors that regulates aggressiveness. Previous studies have demonstrated that some dysregulated long non-coding RNAs (lncRNAs) are correlated with tumor progression, including bladder cancer (BCa). However, the prognostic effect of hypoxia-related lncRNAs (HRLs) and their clinical relevance, as well as their regulatory effect on the tumor immune microenvironment, are largely unknown in BCa. A co-expression analysis between hypoxia genes and lncRNA expression, which was downloaded from the TCGA database, was performed to identify HRLs. Univariate Cox regression analysis was performed to select the most desirable lncRNAs for molecular subtype, and further LASSO analysis was performed to develop a prognostic model. This molecular subtype based on four HRLs (AC104653, AL136084, AL139393, and LINC00892) showed good performance in the tumor microenvironment and tumor mutation burden. The prognostic risk model suggested better performance in predicting BCa patients' prognosis and obtained a close correlation with clinicopathologic features. Furthermore, four of five first-line clinical chemotherapies showed different sensitivities to this model, and nine immune checkpoints showed different expression in the molecular subtypes or the risk model. In conclusion, this study indicates that this molecular subtype and risk model based on HRLs may be useful in improving the prognostic prediction of BCa patients with different clinical situations and may help to find a useful target for tumor therapy.

Phase I clinical trial of EGFR-specific CAR-T cells generated by the piggyBac transposon system in advanced relapsed/refractory non-small cell lung cancer patients.

PURPOSE: This phase I clinical trial is designed to assess the safety and feasibility of the epidermal growth factor receptor (EGFR) chimeric antigen receptor (CAR) T-cell generated by the piggyBac transposon system in advanced relapsed/refractory non-small cell lung cancer (NSCLC) patients. Compared to viral systems, the piggyBac transposon system is a simpler, more economical, and alternative way to introduce chimeric antigen receptor (CAR) transgenes into T cells. METHODS: This study recruited nine patients with advanced relapsed/refractory EGFR-positive NSCLC for two cycles of the piggyBac-generated EGFR-CAR T cells at dose of 1 × 106 cells/kg or 3 × 106 cells/kg of body weight. The patients were monitored for adverse events, clinical response, and persistence of plasma GFR-CAR T cells. RESULTS: Infusions of piggyBac-generated EGFR-CAR T cells were well tolerated in all nine patients. The most common adverse events were grade 1 to 3 fever and there were no patients who experienced grade 4 adverse events or serious cytokine release syndrome. After treatment, eight of nine patients showed detectable EGFR-CAR T cells in their peripheral blood. One patient showed a partial response and lasted for more than 13 months, while six had stable disease, and two had progressed disease. The progression-free survival of these nine patients was 7.13 months (95% CI 2.71-17.10 months), while the median overall survival was 15.63 months (95% CI 8.82-22.03 months). CONCLUSION: This Phase I clinical trial revealed that the non-viral piggyBac transposon system-engineered EGFR-CAR T-cell therapy is feasible and safe in treatment of EGFR-positive advanced relapsed/refractory NSCLC patients. Future study will assess it in more patients or even possibly with a higher dose. Trial registration number NCT03182816.

PDA Got SERious Nerves.

Pancreatic innervation is an important factor in pancreatic cancer etiology and progression. Recent work by Banh et al. has revealed that serine released from the axons of sensory and sympathetic neurons supports pancreatic cancer metabolism during nutrient-deprived conditions. These findings rationalize a therapeutic strategy to combine dietary manipulation and pharmacological denervation to target pancreatic cancer.

Nuclear DLC1 exerts oncogenic function through association with FOXK1 for cooperative activation of MMP9 expression in melanoma.

A Rho GTPase-activating protein (RhoGAP), deleted in liver cancer 1 (DLC1), is known to function as a tumor suppressor in various cancer types; however, whether DLC1 is a tumor-suppressor gene or an oncogene in melanoma remains to be clarified. Here we revealed that high DLC1 expression was detected in most of the melanoma tissues where it was localized in both the nuclei and the cytoplasm. Functional studies unveiled that DLC1 was both required and sufficient for melanoma growth and metastasis. These tumorigenic events were mediated by nuclear-localized DLC1 in a RhoGAP-independent manner. Mechanistically, mass spectrometry analysis identified a DLC1-associated protein, FOXK1 transcription factor, which mediated oncogenic events in melanoma by translocating and retaining DLC1 into the nucleus. RNA-sequencing profiling studies further revealed MMP9 as a direct target of FOXK1 through DLC1-regulated promoter occupancy for cooperative activation of MMP9 expression to promote melanoma invasion and metastasis. Concerted action of DLC1-FOXK1 in MMP9 gene regulation was further supported by their highly correlated expression in melanoma patients' samples and cell lines. Together, our results not only unravel a mechanism by which nuclear DLC1 functions as an oncogene in melanoma but also suggest an unexpected role of RhoGAP protein in transcriptional regulation.

SOX9 is a dose-dependent metastatic fate determinant in melanoma.

BACKGROUND: In this research, we aimed to resolve contradictory results whether SOX9 plays a positive or negative role in melanoma progression and determine whether SOX9 and its closely related member SOX10 share the same or distinct targets in mediating their functions in melanoma. METHODS: Immunofluorescence, TCGA database and qPCR were used to analyze the correlation between the expression patterns and levels of SOX9, SOX10 and NEDD9 in melanoma patient samples. AlamarBlue, transwell invasion and colony formation assays in melanoma cell lines were conducted to investigate the epistatic relationship between SOX10 and NEDD9, as well as the effects of graded SOX9 expression levels. Lung metastasis was determined by tail vein injection assay. Live cell imaging was conducted to monitor dynamics of melanoma migratory behavior. RHOA and RAC1 activation assays measured the activity of Rho GTPases. RESULTS: High SOX9 expression was predominantly detected in patients with distant melanoma metastases whereas SOX10 was present in the different stages of melanoma. Both SOX9 and SOX10 exhibited distinct but overlapping expression patterns with metastatic marker NEDD9. Accordingly, SOX10 was required for NEDD9 expression, which partly mediated its oncogenic functions in melanoma cells. Compensatory upregulation of SOX9 expression in SOX10-inhibited melanoma cells reduced growth and migratory capacity, partly due to elevated expression of cyclin-dependent kinase inhibitor p21 and lack of NEDD9 induction. Conversely, opposite phenomenon was observed when SOX9 expression was further elevated to a range of high SOX9 expression levels in metastatic melanoma specimens, and that high levels of SOX9 can restore melanoma progression in the absence of SOX10 both in vitro and in vivo. In addition, overexpression of SOX9 can also promote invasiveness of the parental melanoma cells by modulating the expression of various matrix metalloproteinases. SOX10 or high SOX9 expression regulates melanoma mesenchymal migration through the NEDD9-mediated focal adhesion dynamics and Rho GTPase signaling. CONCLUSIONS: These results unravel NEDD9 as a common target for SOX10 or high SOX9 to partly mediate their oncogenic events, and most importantly, reconcile previous discrepancies that suboptimal level of SOX9 expression is anti-metastatic whereas high level of SOX9 is metastatic in a heterogeneous population of melanoma.

Laparoscopic Infrapyloric Area Lymph Node Dissection with No. 14v Enlargement for Advanced Lower Gastric Cancer in Middle Colic Vein Approach.

BACKGROUND: We developed a procedure for laparoscopic infrapyloric area lymph node (LN) dissection with No. 14v enlargement, which is complicated for patients with advanced lower gastric cancer (GC) (Xu et al., World J Gastroenterol 13:5133-5138,2007; Masuda et al., Dig Surg 25:351-358,2008; An et al., Br J Surg 98:667-672,2011]. METHODS: From April 2008 to December 2014, 1096 patients with GC underwent laparoscopy-assisted radical distal gastrectomy in our department. According to the Japanese GC treatment guidelines, D2 (+No. 14v) may be beneficial in tumors with apparent metastasis to the No. 6 nodes (Japanese Gastric Cancer Association, Gastric Cancer 14:113-123,2010). Thus, 151 advanced lower GC patients with apparent metastasis to the No. 6 nodes underwent additional No. 14v LN dissection. We dissected infrapyloric area LNs with No. 14v dissection from the left to the right side (i.e., middle colic vein approach). RESULTS: Mean operation time was 22.8 ± 10.0 min, mean blood loss was 17.1 ± 14.6 ml, and mean times to first flatus, fluid diet, and soft diet were 3.7 ± 1.2 days, 5.0 ± 1.7 days, and 8.4 ± 1.6 days, respectively. A mean of 33.7 ± 11.2 LNs were retrieved, including 3.9 ± 2.7 No. 6 LNs and 2.0 ± 1.6 No. 14v LNs. Of 151 patients, 26 had No. 14v metastasis (17.2%), and 43 (28.5%) were accompanied by an extensive infrapyloric area nodal involvement. The overall postoperative morbidity rate was 10.6% (16 of 151). At a median follow-up of 56 months (range 5-84 months), cumulative 3-year overall survival was 56.0%. CONCLUSIONS: Although it remains controversial whether prophylactic No. 14v dissection improves survival, laparoscopic infrapyloric area LN dissection using a middle colic vein approach may be safely achieved and is more convenient for advanced lower GC.

Laparoscopic Suprapancreatic Lymph Node Dissection for Advanced Gastric Cancer Using a Left-Sided Approach.

BACKGROUND: We developed a novel procedure for laparoscopic suprapancreatic lymph node (LN) dissection, which is compulsory and quite difficult for patients with advanced gastric cancer.1 (-) 3 METHODS: We dissected suprapancreatic LNs from the left to the right side. The No. 11p LNs were dissected first, followed by the No. 9, 7, and 8a LNs. Dissection of the No. 5 and 12a LNs was completed last. The above procedure was performed on 814 consecutive patients with stage cT2-3 disease. RESULTS: Mean operation time was 186.9 ± 56.4 min (range 80-480 min), mean blood loss was 76.6 ± 106.8 ml (range 3-500 ml), and mean times to first flatus, fluid diet, and soft diet were 3.7 ± 1.2 days (range 1-9 days), 5.2 ± 1.7 days (range 2-14 days), and 8.3 ± 2.2 days (range 5-20 days), respectively. A mean 34.5 ± 12.9 LNs (range 22-103) were retrieved, including a mean 12.4 ± 5.7 (range 0-35) suprapancreatic area LNs. Overall postoperative morbidity rate was 14.7 % (120/814), including three cases of pancreatic fistula. All of these postoperative complications were successfully treated by conservative methods. At a median follow-up of 27 months (range 1-63), cumulative 3-year overall survival was 59.2 %. CONCLUSION: Laparoscopic suprapancreatic LN dissection using a left-sided approach could be safely achieved and is more convenient for advanced gastric cancer.

Cyclin-dependent kinase 5 decreases in gastric cancer and its nuclear accumulation suppresses gastric tumorigenesis.

PURPOSE: As a cyclin-independent atypical CDK, the role of CDK5 in regulating cell proliferation in gastric cancer remains unknown. EXPERIMENTAL DESIGN: Expression of CDK5 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was measured by Western blotting, immunohistochemistry, and real-time PCR. The subcellular translocation of CDK5 was monitored during gastric cancer cell proliferation. The role of nuclear CDK5 in gastric cancer tumorigenic proliferation and ex vivo xenografts was explored. Furthermore, by screening for compounds in the PubChem database that disrupt CDK5 association with its nuclear export facilitator, we identified a small molecular (NS-0011) that inhibits gastric cancer cell growth. RESULTS: CDK5 level was significantly decreased in the majority of gastric tumor tissues, and the reduction of CDK5 correlated with the severity of gastric cancer based on tumor and lymph node metastasis and patient 5-year fatality rate. Nuclear localization of CDK5 was found to be significantly decreased in tumor tissues and gastric cancer cell lines, whereas exogenously expression of nucleus-targeted CDK5 inhibited the proliferation and xenograft implantation of gastric cancer cells. Treatment with the small molecule NS-0011, which increases CDK5 accumulation in the nucleus, suppressed both cancer cell proliferation and xenograft tumorigenesis. CONCLUSIONS: Our results suggest that low CDK5 expression is associated with poor overall survival in patients with gastric cancer, and nuclear accumulation of CDK5 inhibits the proliferation and tumorigenicity of human gastric cancer cells.

A modified intracorporeal billroth-I anastomosis after laparoscopic distal gastrectomy for gastric cancer: a safe and feasible technique.

BACKGROUND: The delta-shaped gastroduodenostomy, an intracorporeal Billroth-I anastomosis after laparoscopic distal gastrectomy and using only endoscopic linear staplers, has been increasingly adopted by gastrointestinal surgeons.1 (-) 5 We modified this technique to simplify operation procedures and reduce surgical trauma in patients with gastric cancer. METHODS: After the stomach and duodenum were transected in predetermined positions, small incisions were made on the greater curvature of the remnant stomach and the posterior side of the duodenum. The forks of the stapler in each incision were closed and fired following approximation of the posterior walls of the gastric remnant and duodenum. The involution of the common stab incision was accomplished only by the instruments of the surgeon and assistant, and the duodenal cutting edge was completely resected when the common stab incision was closed with the stapler, thus decreasing the anastomotic weak point and avoiding poor blood supply to the duodenal stump. The above procedure was performed for 41 patients with stage cT1-4a disease. RESULTS: Mean operation time was 143.4 ± 23.4 min, mean anastomosis time was 13.9 ± 2.8 min, mean blood loss was 34.6 ± 20.8 ml, and mean times to first flatus, fluid diet, and soft diet were 3.5 ± 1.3, 5.1 ± 1.2, and 8.1 ± 4.3 days, respectively. No patient experienced any anastomosis-related complications, such as anastomotic leakage, anastomotic stricture, or anastomotic hemorrhage. At a median follow-up of 10 months, no patient had died or experienced recurrent or metastatic disease. CONCLUSIONS: The modified technique was technically safe and feasible, with acceptable surgical outcomes, in patients with gastric cancer.

Laparoscopic spleen-preserving no. 10 lymph node dissection for advanced proximal gastric cancer using a left approach.

BACKGROUND: We developed a novel procedure for spleen-preserving No. 10 lymph node (LN) dissection, which is difficult and advocates for patients with advanced proximal gastric cancer, except those with direct tumor extension to the spleen or definite LN metastasis at the splenic hilum. METHODS: The surgeon reveals the splenic vessels (SVs), and the assistant pulls up the lymphatic fatty tissue on the surface of the lower lobar vessels of the spleen (LLVSs). The surgeon then exposes the left gastroepiploic vessels (LGEVs), completely separating the LLVSs from the LGEV roots. After tracking the SV termini, the No. 11d LNs are carefully dissected and the upper lobar vessels of the spleen are exposed from their roots to the upper pole of the spleen. During this process, 2-4 branches of the short gastric vessels are skeletonized and divided at their roots. The LNs behind the SVs in front of Gerota's fascia are then dissected. The above procedure was performed on 118 consecutive patients with stage cT2-3 disease. RESULTS: Mean operation time was 20.4 ± 6.0 min (range 13-41 min), mean blood loss was 13.6 ± 4.0 ml (range 10-40 ml), and mean times to first flatus, fluid diet, and soft diet were 3.3 ± 1.2 days (range 2-8 days), 4.8 ± 1.6 days (range 3-14 days), and 8.1 ± 4.1 days (range 6-20 days), respectively. A mean 44.6 ± 17.3 LNs (range 22-103) were retrieved, including a mean 3.0 ± 2.4 (range 0-11) splenic hilar area LNs. At a median follow-up of 9 months, no patients had died or experienced recurrent or metastatic disease. CONCLUSIONS: This procedure is feasible and simplifies complicated laparoscopic No. 10 LN dissection.