The Mg–Ca alloy system has been proposed as a potential new kind of degradable biomaterial with possible application within bone. Here microarc oxidation (MAO) coatings were fabricated on top of a ...Mg–Ca alloy using different applied voltages and the effect of applied voltage on the surface morphology and phase constitution, hydrogen evolution, pH variation in the immersion solution and in vitro biocompatibility of the MAO coating on the Mg–Ca alloy were extensively studied. It was found that the thickness and pore size of the MAO coating increased with the increasing applied voltage, whereas some micro-pores could be seen inside the 400V treated MAO coating. The 360V treated MAO coating gave the best long-term corrosion resistance during a 50days immersion test. All the MAO coatings could promote MG63 cell adhesion, proliferation and differentiation in comparison with the uncoated Mg–Ca alloy sample, due to significantly reduced Mg ion release and pH value variations in the culture medium. After 5days culture well-spread and elongated MG63 cells could be seen on the surface of the 360V and 400V MAO coatings, in contrast to no cells on the uncoated Mg–Ca alloy sample. In summary, MAO showed beneficial effects on the corrosion resistance of, and thus improved cell adhesion to, the Mg–Ca alloy, and should be a good surface modification method for other biomedical magnesium alloys.
We examined whether mucosal melanomas are different in their clinical course and patterns of metastases when arising from different anatomic sites. Our hypothesis was that metastatic behavior would ...differ from primary mucosal melanomas at different anatomical sites.
Clinical and pathological data from 706 patients were compared for their stage distribution, patterns of metastases, CKIT/BRAF mutation status, and overall survival for different anatomical sites.
The anatomic sites of the primary mucosal melanomas were from the lower GI tract (26.5%), nasal cavity and paranasal sinuses (23%), gynecological sites (22.5%), oral cavity (15%), urological sites (5%), upper GI tract (5%), and other sites (3.0%). At initial diagnosis, 14.5% were stage I disease, 41% Stage II, 21.5% Stage III, and 23.0% stage IV. Predominant metastatic sites were regional lymph nodes (21.5%), lung (21%), liver (18.5%), and distant nodes (9%). Oral cavity mucosal melanoma had a higher incidence of regional nodal metastases (31.7% versus 19.8%,P = 0.009), and a higher incidence of lung metastases (32.5% versus 18.5%,P = 0.007) compared to other primary mucosal melanomas. There was a 10% incidence of CKIT mutation and 12% BRAF mutation. Mucosal melanomas from nasal pharyngeal and oral, gastrointestinal, gynecological, and urological had a similar survival with a 1-year survival rate (88%, 83%, 86%), 2-year survival rate (66%, 57%, 61%), 5-year survival rate (27%, 16%, 20%), respectively.
The largest sample size allows, for the first time, a comparison of primary melanoma stage and patterns of metastases across anatomical sites. With few exceptions, the presenting stages, incidence of nodal and distant metastases, the site of predilection of distant metastases, or overall survival were similar despite different primary anatomic sites. These findings suggest that clinical trials involving mucosal melanomas and the administration of systemic therapy can be applied equally to mucosal melanomas regardless of their primary anatomic site.
Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the ...purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM.
Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled.
A total of 28 patients were enrolled in this cohort; CSF and plasma were available in 26 patients, respectively. Driver genes were detected in 100% (26/26), 84.6% (22/26), and 73.1% (19/26) of samples comprising CSF cell-free DNA (cfDNA), CSF precipitates, and plasma, respectively; 92.3% (24/26) of patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were mainly identified in CSF cfDNA, and MET copy number gain identified in 47.8% (11/23) of patients was the most frequent one, while other CNVs included ERBB2, KRAS, ALK, and MYC. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 73.1% (19/26) CSF cfDNA, which was much higher than that in plasma (2/26, 7.7%; P<0.001). There was a trend towards a higher frequency of concomitant resistance mutations in patients with TP53 LOH than those without (70.6% versus 33.3%; P=0.162). EGFR T790M was identified in CSF cfDNA of 30.4% (7/23) of patients who experienced TKI progression.
CSF cfDNA could reveal the unique genetic profiles of LM and should be considered as the most representative liquid biopsy medium for LM in EGFR-mutant NSCLC.
Abstract Acid-sensing ion channels (ASICs), the members of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily, are proton-gated voltage-insensitive cation channels. Six ASIC subunits have ...been identified and characterized in the mammalian nervous system so far. Of these subunits, ASIC3 has been shown to be predominantly expressed in the peripheral nervous system of rodents and implicated in mechnosensation, chemosensation and pain perception. Little is known on ASIC3 in the brain. We thus employed reverse transcription–polymerase chain reaction (RT-PCR) and Western blot to examine the expression of ASIC3 in various rat brain regions, including hippocampus, amygdala, caudate putamen, prefrontal cortex, and hypothalamus. Specific attention was paid to the distribution of ASIC3 in the hypothalamus of rats by using immunohistochemistry. ASIC3 immunoreactivity showed a widespread pattern throughout the hypothalamus, with the highest density in paraventricular nucleus, supraoptic nucleus, suprachiasmatic nucleus, arcuate nucleus, dorsomedial nucleus, median preoptic nucleus, ventromedial preoptic nucleus, and dorsal tuberomammillary nucleus. This study may contribute to the understanding of ASIC3 functions in the CNS.
Spin-orbit coupling (SOC), the interaction between the electron spin and the orbital angular momentum, can unlock rich phenomena at interfaces, in particular interconverting spin and charge currents. ...Conventional heavy metals have been extensively explored due to their strong SOC of conduction electrons. However, spin-orbit effects in classes of materials such as epitaxial 5d-electron transition-metal complex oxides, which also host strong SOC, remain largely unreported. In addition to strong SOC, these complex oxides can also provide the additional tuning knob of epitaxy to control the electronic structure and the engineering of spin-to-charge conversion by crystalline symmetry. Here, we demonstrate room-temperature generation of spin-orbit torque on a ferromagnet with extremely high efficiency via the spin-Hall effect in epitaxial metastable perovskite SrIrO₃. We first predict a large intrinsic spin-Hall conductivity in orthorhombic bulk SrIrO₃ arising from the Berry curvature in the electronic band structure. By manipulating the intricate interplay between SOC and crystalline symmetry, we control the spin-Hall torque ratio by engineering the tilt of the corner-sharing oxygen octahedra in perovskite SrIrO₃ through epitaxial strain. This allows the presence of an anisotropic spin-Hall effect due to a characteristic structural anisotropy in SrIrO₃ with orthorhombic symmetry. Our experimental findings demonstrate the heteroepitaxial symmetry design approach to engineer spin-orbit effects. We therefore anticipate that these epitaxial 5d transition-metal oxide thin films can be an ideal building block for low-power spintronics.
SOX2 (Sry-related high-mobility box SOX-2) is a transcription factor, which is essential for maintaining the cancer cell stemness. However, the role of microRNAs targeting SOX2 in cancer cell ...stemness remains unclear. We examined the effect of miR-590-5p, which targeted SOX2, on the breast cancer cell stemness and metastasis.
We predicted and screened microRNA targeting SOX2, and further investigated the regulatory role of miR-590-5p on the level of SOX2 with Western blot, luciferase reporting assay and qRT-PCR analysis. Flow cytometry was performed to detect the effect of miR-590-5p on the breast cancer stem cell population with ALDEFLUOR Assay. We inoculated the breast cancer cells transfected with or without miR-590-5p to NOD/SCID mice to detect the tumorigenicity in vivo. Finally, forty-nine pairs of breast cancer samples and adjacent noncancerous tissues were obtained, and immunohistochemistry (IHC) with SOX2 antibody and qRT-PCR assay were used to quantify the expression of miR-590-5p in breast cancer samples.
miR-590-5p significantly downregulated the SOX2 protein expression, and inhibition of miR-590-5p increased SOX2 expression. The luciferase reporter assay indicated that miR-590-5p decreased the SOX2 3'UTR (3' untranslated region) reporter activity but not the luciferase activity of the mutant reporter, in which the binding sites for miR-590-5p were mutated. ALDEFLUOR Assay showed that miR-590-5p significantly decreased breast cancer stem cells population. NOD/SCID nude mice experiments indicated that miR-590-5p significantly inhibited tumorigenicity of breast cancer cells. IHC assay and qRT-PCR suggested that miR-590-5p expression was downregulated in breast cancer patients, and negatively correlated with SOX2.
miR-590-5p inhibited breast cancer cell stemness through targeting SOX2. Our study indicated that miR-590-5p might be a useful strategy for breast cancer treatment.
Recent studies have shown that the ambient plasma in the near-Earth magnetotail can be compressed by the arrival of a dipolarization front (DF). In this paper we study the variations in the ...characteristics of currents flowing in this compressed region ahead of the DF, particularly the changes in the cross-tail current, using observations from the THEMIS satellites. Since we do not know whether the changes in the cross-tail current lead to a field-aligned current formation or just form a current loop in the magnetosphere, we thus use redistribution to represent these changes of local current density. We found that (1) the redistribution of the cross-tail current is a common feature preceding DFs; (2) the redistribution of cross-tail current is caused by plasma pressure gradient ahead of the DF and (3) the resultant net current redistributed by a DF is an order of magnitude smaller than the typical total current associated with a moderate substorm current wedge (SCW). Moreover, our results also suggest that the redistributed current ahead of the DF is closed by currents on the DF itself, forming a closed current loop around peaks in plasma pressure, what is traditionally referred to as a banana current.
Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the ...efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC.
Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib 50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle). The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety.
A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028. The median PFS was 18.0 months in the toripalimab–axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab–axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab–axitinib group and 58.6% of patients in the sunitinib group.
In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile
ClinicalTrials.gov NCT04394975
•Toripalimab plus axitinib provided significantly better PFS than sunitinib as a first-line treatment for advanced RCC.•A significantly higher ORR was found in patients who received toripalimab plus axitinib than those who received sunitinib.•The combination of toripalimab plus axitinib was generally well tolerated.•No new safety signals were identified in the combination outside the known safety profile of toripalimab or axitinib.
A phase III trial was conducted to compare the safety and efficacy of erlotinib with that of gefitinib in advanced non-small cell lung cancer harbouring epidermal growth factor receptor mutations in ...exon 19 or 21.
Eligible patients were randomised to receive erlotinib (150 mg per day) or gefitinib (250 mg per day) orally until disease progression or unacceptable toxicity. We aimed to determine whether erlotinib is superior to gefitinib in efficacy. The primary end point was progression-free survival.
A total of 256 patients were randomised to receive erlotinib (N=128) or gefitinib (N=128). Median progression-free survival was not better with erlotinib than with gefitinib (13.0 vs 10.4 months, 95% confidence interval (CI) 0.62-1.05, P=0.108). The corresponding response rates and median overall survival were 56.3% vs 52.3% (P=0.530) and 22.9 vs 20.1 months (95% CI 0.63-1.13, P=0.250), respectively. There were no significant differences in grade 3/4 toxicities between the two arms (P=0.172).
The primary end point was not met. Erlotinib was not significantly superior to gefitinib in terms of efficacy in advanced non-small cell lung cancer with epidermal growth factor receptor mutations in exon 19 or 21, and the two treatments had similar toxicities.
Although genetic diversity is very important for alien species, which have to cope with new environments, little is known about the role that genetic diversity plays in their invasive success. In ...this study, we set up a manipulation experiment including three levels of genotypic diversity to test whether genotypic diversity can enhance the invasive ability of alien species, in our case the invasive Spartina alterniflora in China, and to infer the underlying mechanisms. There was no significant relationship between genotypic diversity and parameters of performance in the first year; however, from the summer of the second year onwards, genotypic diversity enhanced four of the six parameters of performance. After two growing seasons, there were significant positive relationships between genotypic diversity and maximum spread distance, patch size, shoot number per patch, and aboveground biomass. Moreover, abundance of the native dominant species Scirpus mariqueter was marginally significantly decreased with genotypic diversity of S. alterniflora, suggesting that enhanced invasive ability of S. alterniflora may have depressed the growth of the native species. There was no significant difference in most measures of performance among six genotypes, but we observed a transgressive over performance in four measures in multiple‐genotype patches. At the end of the experiment, there were significant nonadditive effects of genotypic diversity according to Monte Carlo permutations, in six‐genotype, but not three‐genotype plots. Our results indicated that both additive and nonadditive effects played roles in the positive relationship between genetic diversity and invasion success, and nonadditive effects were stronger as duration increased.
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