Impaired humoral responses, as well as an increased propensity for autoimmunity, play an important role in the development of immune system dysfunction associated with aging. Accumulation of a subset ...of atypical B cells, termed age-associated B cells (ABCs), is one of the key age-related changes in B cell compartments. ABCs are characterized by their distinct phenotypes, gene expression profiles, special survival requirements, variations in B cell receptor repertoires, and unique functions. Here, we summarize recent progress in the knowledge base related to the features of ABCs, their potential role in immune senescence, and their relationship with autoimmune diseases.
Abstract
Clinical evidence has established that concomitant traumatic brain injury (TBI) accelerates bone healing, but the underlying mechanism is unclear. This study shows that after TBI, injured ...neurons, mainly those in the hippocampus, release osteogenic microRNA (miRNA)-enriched small extracellular vesicles (sEVs), which targeted osteoprogenitors in bone to stimulate bone formation. We show that miR-328a-3p and miR-150-5p, enriched in the sEVs after TBI, promote osteogenesis by directly targeting the 3′UTR of
FOXO4
or
CBL
, respectively, and hydrogel carrying miR-328a-3p-containing sEVs efficiently repaires bone defects in rats. Importantly, increased fibronectin expression on sEVs surface contributes to targeting of osteoprogenitors in bone by TBI sEVs, thereby implying that modification of the sEVs surface fibronectin could be used in bone-targeted drug delivery. Together, our work unveils a role of central regulation in bone formation and a clear link between injured neurons and osteogenitors, both in animals and clinical settings.
Background
This study evaluated the efficacy and safety of anlotinib combined with programmed cell death protein 1 (PD-1) blockade for the treatment of small-cell lung cancer (SCLC) and ...non-small-cell lung cancer (NSCLC).
Patients and methods
SCLC (
n
= 28) and NSCLC (
n
= 177) patients who received treatment at Hunan Cancer Hospital between June 1, 2019, and July 1, 2020, were retrospectively analyzed. Progression-free survival (PFS) and treatment responses were compared among patients who received combination therapy of anlotinib plus PD-1 inhibitor, or monotherapy of either chemotherapy or PD-1 inhibitor. Independent prognostic factors were identified by Cox regression analysis.
Results
Patients with relapsed SCLC who received anlotinib plus PD-1 inhibitor as a ≥ second-line therapy (
n
= 14) had a significantly longer PFS than those who received PD-1 inhibitor alone (
n
= 14, 5.0 vs. 3.0 months;
P
= 0.005). For patients with previously untreated wild-type NSCLC, the combination therapy in the first-line setting (
n
= 6) provided a marginally longer PFS than mono-chemotherapy (
n =
6, 8.0 vs. 3.0 months;
P
= 0.075). For patients with relapsed NSCLC, the combination therapy in the ≥ second-line setting (
n
= 62) resulted in significantly higher objective response rate (19.3 vs. 5.0 vs. 2.4%;
P
= 0.013) and longer PFS (8.0 vs. 2.0 vs. 2.0 months;
P
<0.001) as compared to monotherapy of either chemotherapy (
n
= 41) or PD-1 inhibitor (
n
= 62). Anlotinib and PD-1 blockade combination therapy was an independent predictive factor of longer PFS (
P
<0.001).
Conclusion
The combination of anlotinib and PD-1 inhibitor has promising efficacy and manageable toxicity as a second- or later-line treatment of relapsed NSCLC and possibly for relapsed SCLC.
The vortex-induced vibration and energy harvesting of two cylinders in side-by-side arrangement with different attack angles are numerically investigated using two-dimensional unsteady ...Reynolds-Averaged Navier–Stokes simulations. The Reynolds number ranges from 1000 to 10,000, and the attack angle of free flow is varied from 0° to 90°. Results indicate that the vortex-induced vibration responses with attack angle range of 0°≤ α ≤ 30° are stronger than other attack angle cases. The parallel vortex streets are clearly observed with synchronized vortex shedding. Relatively large attack angle leads to a phase difference between the wake patterns of the two cylinders. Hydrokinetic energy can be obviously harvested when Re > 4000. Compared with the larger attack angle case, the two side-by-side cylinders with smaller attack angle have better performance on energy conversion. The maximum energy conversion efficiency of 21.7% is achieved. The optimum region for energy conversion is 5000 ≤ Re ≤ 7000 and 0°≤ α ≤ 30°.
Ochratoxin A (OTA), a prevalent nephrotoxic mycotoxin contaminant in food and feedstuff, has been reported to induce renal injury. To disclose the nephrotoxicity of continuous administration of OTA ...and to investigate potential mechanisms related to pyroptosis, male C57BL/6 mice were intraperitoneally injected with 1.0 and 2.0 mg/kg B.W. OTA every other day for 14 days. At 2.0 mg/kg B.W. OTA administration significantly increased histological injury and renal fibrosis molecules (α-SMA, Vimentin, TGF-β) and activated the NOD-like receptor protein 3 (NLRP3) inflammasome and induced pyroptosis compared with control. In the in vitro tests, Madin–Darby canine kidney (MDCK) epithelial cells were exposed to 0–4.0 μg/ml OTA for 24 h in serum-free medium. Data showed that OTA dose-dependently affected cell viability and significantly up-regulated renal fibrosis genes (α-SMA, Vimentin, TGF-β). 2.0 μg/ml OTA significantly induced NLRP3 inflammasome activation and caspase-1-dependent pyroptosis, increasing the expression and secretion of pro-inflammatory cytokines (IL-6, TNF-α) and pyroptosis-related genes (GSDMD, IL-1β, IL-18) in MDCK cells. These outcomes were significantly abrogated after inhibiting NLRP3 activation with inhibitor MCC950 and silencing NLRP3 with small interfering RNA (siRNA). Furthermore, knockdown of caspase-1 also ameliorated OTA-induced renal fibrosis via the inhibition of pyroptosis. Collectively, the chosen doses of OTA-triggered nephrotoxicity through NLRP3 inflammasome activation and caspase-1-dependent pyroptosis both in vitro and in vivo.
•Both first- and third-generation EGFR-TKIs showed therapeutic efficacy with EGFR L747 P.•This is the first clinical evidence describing the clinical efficacy of osimertinib for EGFR L747 P.
EGFR ...mutations, primarily sensitizing mutations such as exon 19 deletion and exon 21 point mutations, have been proven to act as predictive biomarkers for the response to tyrosine kinase inhibitors (TKIs). How patients harboring EGFR L747 P (a rare mutation located in exon 19) respond to EGFR-TKI is controversial. Some studies have described EGFR L747 P as providing intrinsic resistance to EGFR-TKIs, but others support this rare mutation as a sensitive mutation. Hence, we reported a patient with advanced lung adenocarcinoma harboring an EGFR L747 P who benefited from first-line treatment with gefitinib. This patient achieved stable disease (SD) and had a progression-free survival (PFS) of 18 months. After disease progression, this patient was subsequently administered osimertinib and responded, as evidenced by a significant reduction in nodular lesions. This case revealed that EGFR L747 P rendered both gefitinib and osimertinib therapeutically efficacious.
Our study aimed to evaluate the efficacy and resistance mechanisms of first-line epidermal growth factor receptor (EGFR) inhibitor therapy in patients with advanced non–small-cell lung cancer (NSCLC) ...harbouring uncommon EGFR exon 19 deletion-insertion (19delins) variants.
Targeted sequencing data of 2467 treatment-naive patients with NSCLC from January 2015 to August 2018 were retrospectively screened for EGFR exon 19 deletion (19del) variants. Clinical outcomes of 93 patients with uncommon EGFR 19delins and 93 patients with common EGFR 19del were selected through propensity score matching at a ratio of 1:1.
We identified 10 previously unreported EGFR 19delins variants. L747_P753delinsS, L747_A750delinsP and E746_S752delinsV were the most frequent variants, accounting for 33.1% (42/127), 23.6% (30/127) and 12.6% (16/127) of the cases, respectively. Despite similar baseline characteristics, treatment history and response rates, patients with uncommon 19delins had significantly longer median progression-free survival (mPFS) than those with common 19del (19.0 months vs. 13.0 months; p = 0.0016). At progression from first-line EGFR inhibitor therapy, patients with uncommon 19delins and common 19del had similar rates of developing resistance mechanisms including the acquisition of EGFR T790M (45.8% vs 57.8%), small-cell transformation (3.4% vs 3.6%) and MET amplification (5.1% vs 4.8%). For patients whose tumours acquired T790M and who received second-line osimertinib, the mPFS was significantly shorter for patients with uncommon 19delins (n = 27) than those with common 19del (n = 47, 5.0 months vs. 12.0 months; p < 0.0001).
Our results suggest that patients with uncommon EGFR 19delins have improved clinical outcomes with first-generation EGFR inhibitor treatment, but inferior outcomes upon the development of T790M resistance mutations.
•Patients with uncommon epidermal growth factor receptor (EGFR) exon 19 deletion-insertion (19delins) and common EGFR exon 19 deletion had distinct survival outcomes.•Patients with uncommon EGFR 19delins had longer progression-free survival (PFS) with front-line EGFR tyrosine kinase inhibitor therapy.•Patients with 19delins who acquired EGFR T790M had shorter PFS with osimertinib treatment.•Patients with uncommon 19delins had superior response to first-line osimertinib therapy.
to elucidate the correlation between histone demethylase and gastric cancer.
histone demethylase and gastric cancer.
As one of the important regulatory mechanisms in molecular biology and ...epigenetics, histone modification plays an important role in gastric cancer including downstream gene expression regulation and epigenetics effect. Both histone methyltransferase and histone demethylases are involved in the formation and maintaining different of histone methylation status, which in turn through a variety of vital molecules and signaling pathways involved in the recognition of histone methylation modification caused by the downstream biological process, eventually participate in the regulation of chromatin function, and with a variety of important physiological activities, especially closely related to the occurrence of gastric cancer and embryonic development.
This paper intends to review the research progress in this field from the aspects of histone methylation modification and the protein structure, catalytic mechanism and biological function of the important histone demethylases LSD1 and LSD2, in order to provide the theoretical reference for further understanding and exploration of histone demethylases in development and prognosis of gastric cancer.
Fluid-structure interaction of an elastically mounted rigid square cylinder of low non-dimensional mass immersed in fluid flow is investigated numerically in the Reynolds numbers range of 60≤Re≤250. ...The square cylinder is allowed to freely vibrate only in the transverse direction perpendicular to the incoming flow. The two-dimensional incompressible Reynolds-averaged Navier-Stokes equations are solved by the finite volume method for the fluid flow. The equation of motion is solved for the vibration of the square cylinder. The results show that abrupt both the frequency and amplitude ratios curves experience sudden change at Re=90 and 168, which marks the onset of the lock-in and galloping regime, respectively. Thus, four regimes can be divided in the present study and which are the initial regime, the lock-in regime, the lower branch and galloping regime. A local peak value is observed in the force coefficients curve and the maximum value is reached at Re=231. It is found that the peak oscillating amplitude of the lock-in regime is reached at 0.22D and the width of lock-in region with sharp corner is very narrow. In the galloping regime, the peak amplitude of the oscillating square cylinder is close to 0.70D at Re=231. Typical 2S vortex structure is observed in the initial regime, the lock-in regime, and the lower branch. While in the galloping regime, 2P, 2P+2S and more complicated vortex patterns are observed as Re increases.
With the continuous development of the power system, the importance of circuit breakers has gradually emerged, becoming a key link to ensure the normal operation of the power system. However, circuit ...breaker mechanical failure defects often occur in the power system, such as plum blossom contact defects, split closing coil defects, tentacle defects, etc., which inhibits the normal operation of the power system and also increases the operation and maintenance costs of power companies. Based on this, this paper takes the Taiyuan Power Grid as an example to study the harm of spring defects in circuit breaker machinery, aiming to find out an effective method to eliminate the spring defects in order to achieve the purpose of contributing to the normal operation of the power grid.
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