CDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy.

Liver kinase B1 (LKB1) mutation is prevalent and a driver of resistance to immune checkpoint blockade (ICB) therapy for lung adenocarcinoma. Here leveraging single cell RNA sequencing data, we demonstrate that trafficking and adhesion process of activated T cells are defected in genetically engineered Kras-driven mouse model with Lkb1 conditional knockout. LKB1 mutant cancer cells result in marked suppression of intercellular adhesion molecule-1 (ICAM1). Ectopic expression of Icam1 in Lkb1-deficient tumor increases homing and activation of adoptively transferred SIINFEKL-specific CD8+ T cells, reactivates tumor-effector cell interactions and re-sensitises tumors to ICB. Further discovery proves that CDK4/6 inhibitors upregulate ICAM1 transcription by inhibiting phosphorylation of retinoblastoma protein RB in LKB1 deficient cancer cells. Finally, a tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies promotes ICAM1-triggered immune response in multiple Lkb1-deficient murine models. Our findings renovate that ICAM1 on tumor cells orchestrates anti-tumor immune response, especially for adaptive immunity.

Paraneoplastic neurological syndrome with positive anti-Hu and anti-Yo antibodies: A case report.

BACKGROUND: Paraneoplastic neurological syndrome (PNS) is a rare complication in patients with cancer. PNS can affect the central, peripheral, autonomic nervous system, neuromuscular junction, or muscles and cause various neurological symptoms. Anti-Yo antibody-positive neurological paraneoplasms and anti-Hu antibody-positive neurological paraneoplasms are common, but coexistence of both types has not been described in the literature. CASE SUMMARY: Here we present a rare case of paraneoplastic neuropathy occurring in both breast and lung cancers. A 55-year-old woman was admitted to our hospital with unsteadiness while walking. The patient had a history of breast cancer two years previously. Chest computed tomography revealed a 4.6 cm × 3.6 cm mass in the right lung, which was diagnosed as small-cell lung cancer (SCLC). Blood test was positive for anti-Yo antibodies, and the cerebrospinal fluid was positive for both anti-Yo and anti-Hu antibodies, and the neurological symptoms were considered to be related to the paraneoplasm. The patient was treated with a course of intravenous immunoglobulin, without noticeable improvement. After being discharged from hospital, the patient underwent regular chemotherapy for SCLC and periodic reviews. The patient's neurological symptoms continued to deteriorate at the follow-up visit in April 2021. CONCLUSION: This case suggests the possibility of two types of tumors appearing simultaneously with two paraneoplastic antibodies. The clinical appearance of two or more paraneoplastic tumors requires additional attention.

Diabetes-Induced H3K9 Hyperacetylation Promotes Development of Alzheimer's Disease Through CDK5.

The connection between diabetes and Alzheimer's disease (AD) is not fully determined. Hyperphosphorylation of tau protein is mediated by binding and stabilization of truncated p25 with cyclin-dependent kinase-5 (CDK5) in AD. We recently showed that diabetes-associated hyperglycemia increased the CDK5 levels to promote development of AD. Here, we examined the underlying mechanisms. Hyperglycemia and glucose intolerance were induced in rats that had received a low dose of streptozotocin (STZ) and a high fat diet (HFD). Compared to the control rats that received no STZ and normal diet-fed, the STZ + HFD rats exhibited poorer performance in the behavioral test and showed hyperacetylation of H3K9 histone on CDK5 promoter, likely resulting from upregulation of a histone acetyltransferase, GCN5. Inhibition of acetylation of H3K9 histone by a specific GCN5 inhibitor, MB3, attenuated activation of CDK5, resulting in decreased tau phosphorylation in rat brain and improved performance of the rats in the behavior test. Thus, these data suggest that diabetes may promote future development of AD through hyperacetylation of H3K9 histone on CDK5 promoter.

Epigenetic Control of CDK5 Promoter Regulates Diabetes-Associated Development of Alzheimer's Disease.

Cyclin-dependent kinase-5 (CDK5) is activated by p35 and then binds to both p35 and its truncated form p25 to promote hyperphosphorylation of tau protein, thereby facilitating the pathological progression of Alzheimer's disease (AD). However, it is unknown whether a patient's diabetic status promotes the later onset of AD in a CDK5-dependent manner. Here, we induced pro-diabetic insulin resistance and glucose intolerance in rats using a combined high fat and high glucose diet. Compared to normal diet-fed rats, these pro-diabetic rats exhibited poorer behavioral performance in the Morris water maze test and the novel object recognition test. Increased phosphorylation of tau protein was detected in the hippocampal CA1 region of the rat brain, suggesting neurodegeneration. Moreover, CDK5 transcriptional activity was significantly increased in the HFGD-rat brain, likely resulting from an increase in acetylation and a decrease in methylation of the CDK5 promoter. Together, these data suggest that epigenetic control of the CDK5 promoter by acetylation and methylation may regulate the diabetes-associated development of AD.

[Effect of nitrogen and phosphorus addition on soil enzyme activities: A meta-analysis]. / æ•´åˆåˆ†æžæ°®ç£·æ·»åŠ å¯¹åœŸå£¤é ¶æ´»æ€§çš„å½±å“.

We conducted a meta-analysis to analyze the effects of nitrogen (N) and combined N and phosphorus (N+P) addition on soil enzyme activities, which being involved in soil carbon (C), N, and P cycles as well as oxidative processes. Nitrogen addition significantly increased the activities of soil C acquisition enzymes, N acquisition enzymes, and P acquisition enzymes by 6.9%, 5.6% and 10.7%, respectively, while the enhancement was much stronger under N+P treatment with 13.4%, 37.4% and 13.3%, respectively. In contrast, both N addition and N+P addition decreased the activities of oxidative enzymes by 6.1% and 0.4%, respectively. The effect sizes of N and N+P addition on soil enzyme activities varied with ecosystem types, N fertilizer types, N addition rates, and the duration of fertilization experiments. Our results suggested that the changes in soil microbes and their enzymes under increasing N deposition and P addition would have profound impacts on soil biogeochemical processes and functions.

Effect of TRPV4-p38 MAPK Pathway on Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion.

The aim of this study was to investigate the relationships among TRPV4, p38, and neuropathic pain in a rat model of chronic compression of the dorsal root ganglion. Mechanical allodynia appeared after CCD surgery, enhanced via the intrathecal injection of 4α-phorbol 12,13-didecanoate (4α-PDD, an agonist of TRPV4) and anisomycin (an agonist of p38), but was suppressed by Ruthenium Red (RR, an inhibitor of TRPV4) and SB203580 (an inhibitor of p38). The protein expressions of p38 and P-p38 were upregulated by 4α-PDD and anisomycin injection but reduced by RR and SB203580. Moreover, TRPV4 was upregulated by 4α-PDD and SB203580 and downregulated by RR and anisomycin. In DRG tissues, the numbers of TRPV4- or p38-positive small neurons were significantly changed in CCD rats, increased by the agonists, and decreased by the inhibitors. The amplitudes of ectopic discharges were increased by 4α-PDD and anisomycin but decreased by RR and SB203580. Collectively, these results support the link between TRPV4 and p38 and their intermediary role for neuropathic pain in rats with chronic compression of the dorsal root ganglion.

The Efficacy and Safety of Granulocyte Colony-Stimulating Factor for Patients with Stroke.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) has been shown to reduce lesion volume and improve functional outcome in experimental stroke models. However, whether G-CSF plays a role currently in patients with stroke remains uncertain. Our study aimed at examining the efficacy and safety of G-CSF in patients with acute ischemic stroke. METHODS: A comprehensive search was conducted in 5 online databases up to April 2014, and 10 studies with 711 patients met the criteria. RESULTS: The results showed that G-CSF was beneficial in improving the National Institutes of Health Stroke Scale (standardized mean difference [SMD], .43; 95% confidence interval [CI], .03-.82; P = .04) and modified Rankin Scale (mRS) scores (SMD, .72; 95% CI, .51-.93; P = .01), and elevating CD34(+) count (P < .001). No treatment effects were found in Barthel Index scores (SMD, -.13; 95% CI, -.61 to .35; P = .59), serious adverse events (relative ratio [RR], 1.12; 95% CI, .91-1.38; P = .28), or the death of serious adverse events (RR, 1.25; 95% CI, .82-1.91; P = .30) between groups at day 90. Adverse effect on vascular complications was not detected to be increased although G-CSF produced a marked elevation in the total leukocyte count (SMD, 3.52; 95% CI, 2.54-4.49; P < .001). CONCLUSIONS: In conclusion, G-CSF is effective at mobilizing bone marrow-derived CD34(+) stem cells to the peripheral blood. It also seems to improve the National Institutes of Health Stroke Scale and mRS scores. The administration of G-CSF appears to be safe and well tolerated. Further studies need to be done on a large sample to verify or fully characterize the results.

[Emission characteristics of PM2.5 from blast furnace iron making].

Electrical low pressure impactor (ELPI) was used to online analyze the PM2.5 particle size and mass concentration distribution in the trapping field and ore tank of blast furnace iron-making plant. Results showed that the grain number concentration of PM2.5 in trapping field after dust removal was in the range of 10(5)-10(6)cm-3 , and the particle size was mainly below 0. 1 µm. While the grain number concentration of the PM2.5 in ore tank after dust removal was in the range of 10(4)-10(5) cm-3, the particle size was mainly below 1.0 µm, and the mass concentration distribution showed a single peak. The micro-morphology of PM2.5 monomer was mainly divided into two categories, spherical particles and irregular aggregates. Chemical composition analysis indicated that the concentrations of water soluble SO(2-)(4) , K+ , Ca2+ were higher than other ions in PM2.5, with the percentage of 10. 32% -28.55% , 10. 36% -12. 15% , 3.97% -15. 4% , respectively. The major elements was Fe, Si, Al, with 16. 8% -31. 62% , 2. 24% -8.76% , 1.24% -5. 89% of total mass, respectively; organic carbon and elementary carbon were 2. 7% -4. 6% and 0. 8% -1. 3% , respectively. The emission factors of PM2.5 in trapping field and in ore tank after dust removal were ranged from 0.045 to 0.085 kg t(-1) and 0.042 to 0.071 kg t-1, respectively.

Association between the MMP-9-1562 C>T polymorphism and the risk of stroke: a meta-analysis.

Matrix metalloproteinase (MMP)-9 so far is identified as extremely large and complicated MMP family member. Recently, dozens of studies have explored the association between a promoter polymorphism (-1562 C>T) in MMP-9 and stroke susceptibility. However, the conclusions of these studies still remain equivocal. Therefore, our current meta-analysis was conducted to investigate whether or not the MMP-9 promoter polymorphism is related to the risk of stroke. Electronic databases (PubMed, EMBASE, Web of Science, Cochrane Library and the Chinese Biomedical Literature Database) were searched to obtain all the available studies investigating this polymorphism and stroke from inception to October 2013. Overall and subgroup analyses were rigorously conducted after data extraction. Pooled odds ratio (OR) corresponding to 95 % confidence interval (CI) were estimated. The statistical analysis was performed using Review Manager 5.2. Totally, seven studies involving 1,624 cases and 1,525 controls were identified. The overall results suggested that there was no association of the C-1562T variant on stroke risk under the T allele versus C allele [OR T vs. C 0.98, 95 % CI (0.84, 1.15), P = 0.84], the dominant model [OR TT+TC vs. CC 0.95, 95 % CI (0.81, 1.13), P = 0.59], the recessive model [OR TT vs. TC+CC 1.55, 95 % CI (0.86, 2.81), P = 0.15], the homozygote comparison [OR TT vs. CC 1.48, 95 % CI (0.82, 2.68), P = 0.20] and the heterozygote comparison [OR TC vs. CC 0.93, 95 % CI (0.78, 1.10), P = 0.38]. In the subgroup analyses by ethnicity, age, stroke type and source of controls, no significant relations were observed in any genetic models. Our results indicated that MMP-9-1562 C>T polymorphism was not a risk factor for stroke. Further studies should focus on gene-gene and gene-environment interactions, and provide a more convincing explanation for this association.

Hyperexcitability to electrical stimulation and accelerated muscle fatiguability of taut bands in rats.

OBJECTIVE: Myofascial trigger points contribute significantly to musculoskeletal pain and motor dysfunction and may be associated with accelerated muscle fatiguability. The aim of this study was to investigate the electrically induced force and fatigue characteristics of muscle taut bands in rats. METHODS: Muscle taut bands were dissected out and subjected to trains of electrical stimulation. The electrical threshold intensity for muscle contraction and maximum contraction force (MCF), electrical intensity dependent fatigue and electrical frequency dependent fatigue characteristics were assessed in three different sessions (n=10 each) and compared with non-taut bands in the biceps femoris muscle. RESULTS: The threshold intensity for muscle contraction and MCF at the 10th, 15th and 20th intensity dependent fatigue stimuli of taut bands were significantly lower than those of non-taut bands (all p<0.05). The MCF at the 15th and 20th intensity dependent fatigue stimuli of taut bands were significantly lower than those at the 1st and 5th stimuli (all p<0.01). The MCF in the frequency dependent fatigue test was significantly higher and the stimulus frequency that induced MCF was significantly lower for taut bands than for non-taut bands (both p<0.01). CONCLUSIONS: The present study demonstrates that the muscle taut band itself was more excitable to electrical stimulation and significantly less fatigue resistant than normal muscle fibres.

Effects of colchicine-induced microtubule depolymerization on TRPV4 in rats with chronic compression of the dorsal root ganglion.

The aim of this study was to investigate the effect of colchicine-induced microtubule depolymerization on allodynia in rats with chronic compression of the dorsal root ganglion (DRG) (CCD) and the effect of colchicine on transient receptor potential vanilloid 4 (TRPV4). Intrathecal administration of the anti-microtubule agent, colchicine, resulted in a dose-dependent and partial reduction in CCD-induced mechanical and thermal allodynia. The reduction of allodynia was associated with significant and dose-dependent decreases in the levels of both TRPV4 mRNA and protein expression in CCD rats. In addition, colchicine resulted in reduction and advance of TRPV4 currents in both DRG neurons and HEK293-TRPV4 cells. The current-voltage (IV) relation in HEK293-TRPV4 cells that were exposed to colchicine displayed a typical outward rectification characteristic of TRPV4 with the reversal potential shifted toward a more positive voltage. In conclusion, intrathecal administration of colchicine attenuated allodynia and TRPV4 contributed to the colchicine-induced attenuation of allodynia in CCD rats.