Comparing molecular signatures of dissolved organic matter (DOM) in four large freshwater lakes differing in hydrological connectivity to the Changjiang River.

Freshwater lakes serve as active conduits for processing terrestrial dissolved organic matter (DOM), playing a crucial role in global carbon cycle. Little attention has been paid to how the hydrological connectivity to a large river would affect the molecular signatures of DOM in lakes. Here, we systematically characterized and compared the molecular signatures of DOM in surface waters of four large freshwater lakes in the middle and lower Changjiang River basin that are directly connected to the river (Lake Dongting and Lake Poyang, referred to as Lakeconnected) or indirectly connected to the river (Lake Chao and Lake Tai, referred to as Lakenonconnected). The DOM in Lakeconnected was found to have similar total organic carbon (TOC)-normalized contents and characteristics of lignin phenols to the DOM in surface waters from the upstream Changjiang river, indicating allochthonous/terrestrial sources from riverine inputs. As indicated by the UV-vis and fluorescence analyses, the DOM in Lakeconnected overall had higher aromaticity and larger average molecular weight as well as stronger allochthonous feature compared to the DOM in Lakenonconnected. Consistently, the FT-ICR MS analysis revealed that the DOM in Lakeconnected had higher molecular diversity, higher unsaturation degree, and larger proportions of highly aromatic compounds. In contrast, the DOM in Lakenonconnected had larger proportions of lipids and peptide-like, but lower proportions of aromatic compounds, which could be ascribed to the enhanced autochthonous production and photodegradation due to pollution and eutrophication as well as longer water residence time. The results highlight the strong impacts of the hydrological connectivity to a large river on the molecular signatures of lake DOM. CAPSULE: The hydrological connectivity of the lakes to the Changjiang River has strong impacts on the molecular signatures of lake DOM.

Moderate expression of CD39 in GPC3-CAR-T cells shows high efficacy against hepatocellular carcinoma.

CD39 serves as a crucial biomarker for neoantigen-specific CD8+ T cells and is associated with antitumor activity and exhaustion. However, the relationship between CD39 expression levels and the function of chimeric antigen receptor T (CAR-T) cells remains controversial. This study aimed to investigate the role of CD39 in the functional performance of CAR-T cells against hepatocellular carcinoma (HCC) and explore the therapeutic potential of CD39 modulators, such as mitochondrial division inhibitor-1 (mdivi-1), or knockdown CD39 through short hairpin RNA. Our findings demonstrated that glypican-3-CAR-T cells with moderate CD39 expression exhibited a strong antitumor activity, while high and low levels of CD39 led to an impaired cellular function. Methods modulating the proportion of CD39 intermediate (CD39int)-phenotype CAR-T cells such as mdivi-1 and CD39 knockdown enhanced and impaired T cell function, respectively. The combination of mdivi-1 and CD39 knockdown in CAR-T cells yielded the highest proportion of infiltrated CD39int CAR-T cells and demonstrated a robust antitumor activity in vivo. In conclusion, this study revealed the crucial role of CD39 in CAR-T cell function, demonstrated the potential therapeutic efficacy of combining mdivi-1 with CD39 knockdown in HCC, and provided a novel treatment strategy for HCC patients in the field of cellular immunotherapy.

Exploring the impact of hydrogen sulfide on hematologic malignancies: A review.

Hydrogen sulfide (H2S) is one of the three most crucial gaseous messengers in the body. The discovery of H2S donors, coupled with its endogenous synthesis capability, has sparked hope for the treatment of hematologic malignancies. In the last decade, the investigation into the impact of H2S has expanded, particularly within the fields of cardiovascular function, inflammation, infection, and neuromodulation. Hematologic malignancies refer to a diverse group of cancers originating from abnormal proliferation and differentiation of blood-forming cells, including leukemia, lymphoma, and myeloma. In this review, we delve deeply into the complex interrelation between H2S and hematologic malignancies. In addition, we comprehensively elucidate the intricate molecular mechanisms by which both H2S and its donors intricately modulate the progression of tumor growth. Furthermore, we systematically examine their impact on pivotal aspects, encompassing the proliferation, invasion, and migration capacities of hematologic malignancies. Therefore, this review may contribute novel insights to our understanding of the prospective therapeutic significance of H2S and its donors within the realm of hematologic malignancies.

Restoration of Range of Motion in the Cervical Spine through Single-Segment Artificial Disc Replacement Using the Baguera®C Prosthesis.

Background: Anterior cervical discectomy and fusion (ACDF) is a standard procedure for degenerative diseases of the cervical spine, providing nerve decompression and spinal stabilization. However, it limits cervical spine motility, restricts fused segment activity, and may lead to adjacent degeneration. Cervical disc arthroplasty (CDA) is an accepted alternative that preserves the structure and flexibility of the cervical spine. This study aimed to explore the dynamic changes in the range of motion (ROM) of the cervical spine after CDA using a viscoelastic artificial disc, as well as the factors affecting mobility restoration. Methods: A retrospective analysis was conducted on 132 patients who underwent single-level anterior cervical discectomy and CDA from January 2015 to June 2022. Result: Analysis of data from 132 patients revealed a significant improvement in clinical outcomes. The mean ROM of C2-C7 and functional spinal unit (FSU) segments significantly increased from 2 to 36 months post-operatively. Cervical spine flexibility was preserved and enhanced after prosthesis implantation. However, it took six months for the cervical spine motility to stabilize. In addition, sex and age were found to impact motility restoration, with female and younger patients exhibiting larger ROMs post-surgery. Additionally, CDA at the C5-C6 level resulted in the greatest increase in ROM, potentially improving overall kinematic ability. Conclusions: Single-segment artificial disc arthroplasty effectively restores the ROM in degenerative cervical spine conditions.

Motif-based community detection in heterogeneous multilayer networks.

Multilayer networks composed of intralayer edges and interlayer edges are an important type of complex networks. Considering the heterogeneity of nodes and edges, it is necessary to design more reasonable and diverse community detection methods for multilayer networks. Existing research on community detection in multilayer networks mainly focuses on multiplexing networks (where the nodes are homogeneous and the edges are heterogeneous), but few studies have focused on heterogeneous multilayer networks where both nodes and edges represent different semantics. In this paper, we studied community detection on heterogeneous multilayer networks and proposed a motif-based detection algorithm. First, the communities and motifs of multilayer networks are defined, especially the interlayer motifs. Then, the modularity of multilayer networks based on these motifs is designed, and the community structure of the multilayer network is detected by maximizing the modularity of multilayer networks. Finally, we verify the effectiveness of the detection algorithm on synthetic networks. In the experiments on synthetic networks, comparing with the classical community detection algorithms (without considering interlayer heterogeneity), the motif-based modularity community detection algorithm can obtain better results under different evaluation indexes, and we found that there exists a certain relationship between motifs and communities. In addition, the proposed algorithm is applied in the empirical network, which shows its practicability in the real world. This study provides a solution for the investigation of heterogeneous information in multilayer networks.

Ultrasound versus palpation-guided corticosteroid injection for de Quervain disease: A randomized controlled trial.

INTRODUCTION: Corticosteroid injection effectively treats de Quervain disease, and due to the high prevalence of the intracompartmental septum in the first extensor compartment, ultrasound guidance improves injection accuracy. OBJECTIVE: To compare the effectiveness, adverse events, and the recurrence rate between ultrasound-guided and palpation-guided injection in patients with de Quervain disease. DESIGN: Prospective, single-blind, randomized controlled trial. SETTING: Rehabilitation department of a private teaching hospital. PARTICIPANTS: We enrolled 49 patients, ≥20 years of age, clinically diagnosed with de Quervain disease based on their medical history and physical examination. INTERVENTIONS: Patients were randomized into two groups: ultrasound-guided and palpation-guided injection. Both groups received a mixture of 10 mg triamcinolone acetonide (10 mg/1 mL) and 0.3 mL 1% lidocaine. MAIN OUTCOME MEASURES: The primary outcome measure was the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) score at 1 week. The secondary outcome measures were visual analog scale for pain (pain VAS) score, patient satisfaction, and adverse events or complications from the interventions at 1 week, 3 months, and 6 months. RESULTS: Both groups showed improvement over time in QuickDASH scores and pain VAS (p < .001); however, no statistically significant differences were noted between the groups for either QuickDASH scores (p = .22) or pain VAS (p = .30). In addition, no statistically significant differences were found between the groups in terms of patient satisfaction (p = .76) and adverse events (p = .47, .33, .58) at the 1-week, 3-month, and 6-month follow-ups. CONCLUSIONS: Both ultrasound-guided and palpation-guided injections effectively treated de Quervain disease. During a 6-month follow-up, there were no statistically significant differences between the groups in pain relief, upper limb function, or patient satisfaction. However, the palpation-guided group showed a tendency for more recurrence and skin side effects.

TRIM67 Promotes Non-Small Cell Lung Cancer Development by Positively Regulating the Notch Pathway through DLK1 Ubiquitination.

Tripartite motif-containing 67 (TRIM67), a member of the TRIM protein family, is an E3 ubiquitin ligase. Our previous study revealed a relationship between TRIM67 expression and carcinogenesis, showing that TRIM67 expression is linked to p-TNM stage, lymph node metastasis, tumour size, cancer cell differentiation, and poor prognosis. Additionally, TRIM67 immunostaining results were associated with clinicopathological features. TRIM67 activated the Notch pathway in a favourable manner to enhance cell invasion, migration, and proliferation. Atypical ligand delta like non-canonical Notch ligand 1 (DLK1) inhibits the function of the Notch1 receptor, which in turn prevents activation of the Notch pathway. In addition, we investigated the mechanism by which TRIM67 influences the Notch pathway. We found that TRIM67 altered the behaviour of non-small cell lung cancer (NSCLC) cells by ubiquitinating DLK1 via its RING domain, which in turn activates the Notch pathway. Taken together, these findings indicate that TRIM67 may be involved in promoting the growth of NSCLC.

The potential role of hydrogen sulfide in cancer cell apoptosis.

For a long time, hydrogen sulfide (H2S) has been considered a toxic compound, but recent studies have found that H2S is the third gaseous signaling molecule which plays a vital role in physiological and pathological conditions. Currently, a large number of studies have shown that H2S mediates apoptosis through multiple signaling pathways to participate in cancer occurrence and development, for example, PI3K/Akt/mTOR and MAPK signaling pathways. Therefore, the regulation of the production and metabolism of H2S to mediate the apoptotic process of cancer cells may improve the effectiveness of cancer treatment. In this review, the role and mechanism of H2S in cancer cell apoptosis in mammals are summarized.

Astrocyte-derived exosomes-transported miRNA-26a-5p ameliorates sevoflurane-induced cognitive dysfunction in aged mice.

Prolonged sevoflurane anesthesia is the primary factor contributing to the development of perioperative neurocognitive disorders (PND). Recent studies have highlighted neuronal apoptosis and abnormal dendritic structures as crucial features of PND. Astrocytes-derived exosomes (ADEs) have been identified as carriers of microRNAs (miRNAs), playing a vital role in cell-to-cell communication through transmitting genetic material. Nevertheless, the specific mechanisms by which miRNAs in ADEs contribute to sevoflurane-induced cognitive deficit are currently unknown. Through a series of in vivo and in vitro experiments, we demonstrated that ADEs contributed to improved neurocognitive outcomes by reducing neuronal apoptosis and promoting dendritic development. Our miRNA microarray analysis revealed a significant increase in the expression level of miR-26a-5p within ADEs. Furthermore, we identified NCAM as the downstream target gene of miR-26a-5p. Subsequent gain- and loss-of-function experiments were conducted to validate the role of the miR-26a-5p/NCAM axis. Finally, we found that the AKT/GSK3-ß/CRMP2 signaling pathway was involved in regulating neurons through exosomal miR-26a-5p. Taken together, our findings suggest that the treatment with miR-26a-5p in ADEs can improve neurocognitive outcomes induced by long-term sevoflurane anesthesia, suggesting a promising approach for retarding the progress of PND.

Efficacy of Combination Therapy (Hydrodilatation and Subdeltoid Bursa Injection With Corticosteroid, Mobilization, and Physical Therapy) vs Physical Therapy Alone for Treating Frozen Shoulder: A Randomized Single-Blind Controlled Trial, Phase I.

OBJECTIVE: To compare the efficacy of combination therapy (hydrodilatation and subdeltoid bursa injection with corticosteroid, mobilization, and physical therapy [PT]) with that of PT alone for treating frozen shoulder. DESIGN: A prospective, 2-arm parallel, single-blinded, randomized controlled trial. SETTING: Rehabilitation clinic of a private academic hospital. PARTICIPANTS: Patients (n=70) with frozen shoulder (freezing stage). INTERVENTIONS: Participants (n=35) in the combination group underwent hydrodilatation and subdeltoid bursa injection with corticosteroid twice, mobilization, and usual-care PT for 8 weeks; participants (n=35) in the PT group received only the usual-care PT for 8 weeks. MAIN OUTCOME MEASURES: The Shoulder Pain and Disability Index (SPADI) was the primary outcome measure. The secondary outcome measures were pain scores on a visual analog scale, range of motion (ROM), the Shoulder Disability Questionnaire (SDQ), quality of life (evaluated using the 36-item Short-Form Health Survey [SF-36]), and self-assessment of the treatment effect. RESULTS: Compared with the PT group, the combination group had significantly better pain (during activity), SPADI, SDQ, active and passive ROM, and self-assessment scores (all P<.001) as well as scores on some parts of the SF-36 (physical function and bodily pain, P<.05). Between-group differences were significant at the 1-, 2-, 4-, and 6-month follow-ups. CONCLUSIONS: A combination of hydrodilatation (with corticosteroid), bursal corticosteroid injection, and joint mobilization with PT was superior to PT alone for treating frozen shoulder, and the effects persisted for at least 6 months.

Sevoflurane suppresses colorectal cancer malignancy by modulating ß-catenin ubiquitination degradation via circSKA3.

BACKGROUND: Sevoflurane (SEV), a commonly used inhalational anesthetic, reportedly inhibits colorectal cancer (CRC) malignancy, but whether SEV can inhibit the malignancy of CRC by regulating circular RNAs (circRNAs) remains unclear. Therefore, we aimed to identify specific circRNAs that may be affected by SEV and to investigate their functional roles in CRC. METHODS: RT-qPCR was employed to detect the expression of circRNAs and mRNAs in CRC cells and tissues. Fluorescence in situ hybridization (FISH) was used to determine the location of circSKA3. Protein expression was assessed by western blot analysis. Function-based in vitro and in vivo experiments, including CCK-8, colony formation, transwell, and apoptosis assays and mouse xenograft tumor models, were conducted using circSKA3-knockdown and circSKA3-overexpression cell lines. RNA immunoprecipitation, RNA pull-down and mass spectrometry analyses were performed to explore the related mechanism. RESULTS: Our findings revealed that SEV could inhibit CRC cell activity, proliferation and migration and promote apoptosis in CRC cells. We found that circSKA3 was upregulated in CRC and associated with poorer survival and that its expression could be reduced by SEV. The overexpression of circSKA3 reversed the effects of SEV on inhibiting cell activity, proliferation and migration and promoting apoptosis. The mechanistic analysis revealed that circSKA3 could bind to the ARM structural domain of ß-catenin and thereby disrupt its interaction with the CK1/GSK3ß/ß-TrCP1 destruction complex, resulting in the ubiquitinated degradation of ß-catenin and the activation of Wnt/ß-catenin signaling. In addition, SEV downregulated circSKA3 in vivo to inhibit tumor growth. CONCLUSIONS: All the results showed that SEV could inhibit CRC progression via circSKA3 by increasing ß-catenin ubiquitination degradation.

Tumor size combined with staging systems for thymoma recurrence prediction: A 28-year experience.

Background: We evaluated a new thymoma prognosis prediction model by combining current staging systems with tumor size. Methods: The clinical records of thymoma patients in a single center between January 1993 and December 2021 were collected, and data on tumor size and stage and recurrence-free survival (RFS) was obtained. The prediction model was designed by combining staging with tumor size. Results: During 28 years, 219 thymoma patients were enrolled. Twenty-seven patients had a median RFS of 8.2 years. Further, 153 patients were categorized into limited stage and 66 patients into advanced stage. The RFS was statistically different between these two groups (P = 0.022). The largest area under the curve (AUC) of receiver operating characteristic (ROC) was the dividing group as 5 cm (AUC: 0.804). Conclusions: Combining tumor staging and size improves thymoma recurrence prediction. Patients with advanced stage and tumor size >5 cm may show a poor prognosis.

Re-Rolling Treatment in the Fermentation Process Improves the Aroma Quality of Black Tea.

Aroma is a vital factor influencing tea quality and value. It is a challenge to produce a kind of black tea with a floral/fruity aroma, good taste, and without a green/grassy odor simultaneously using small- and medium-leaf tea species. In this study, the effect of re-rolling treatment on the aroma quality of small-leaf Congou black tea was investigated using the methods of the equivalent quantification of aroma and gas chromatography-mass spectrometry (GC-MS). Sensory evaluation showed that re-rolling treatment improved the aroma quality of Congou black tea by conferring upon it floral and fruity scents. In total, 179 volatile compounds were identified using GC-MS, of which 97 volatiles showed statistical differences (Tukey s-b(K), p < 0.05). Re-rolling treatment significantly reduced the levels of alcoholic fatty acid-derived volatiles (FADVs) and volatile terpenoid (VTs), but increased the levels of aldehydic and ester FADVs, most amino acid-derived volatiles (AADVs), carotenoid-derived volatiles (CDVs), alkene VTs, and some other important volatile compounds. Based on the odor characteristics and fold changes of differential volatile compounds, hexanoic acid, hexyl formate, cis-3-hexenyl hexanoate, (Z)-3-hexenyl benzoate, hexyl hexanoate, phenylacetaldehyde, benzyl alcohol, ß-ionone, α-ionone, dihydroactinidiolide, ipsenone, ß-farnesene, ß-octalactone, melonal, etc., were considered as the potential key odorants responsible for the floral and fruity scents of re-rolled black tea. In summary, this study provides a novel and simple processing technology to improve the aroma quality of small-leaf Congou black tea, and the results are beneficial to enriching tea aroma chemistry.

The complete mitochondrial genome of Morishitium polonicum (Trematoda, Cyclocoelidae) and its phylogenetic implications.

Trematodes can adversely impact the health and survival of wild animals. The trematode family Cyclocoelidae, which includes large digenean bird parasites, lacks molecular analysis, and reclassifications have not been supported. This study produced the first fully assembled and annotated mitochondrial genome sequence for the trematode Morishitium polonicum. The whole length of the M. polonicum (GenBank accession number: OP930879) mitogenome is 14083 bp, containing 22 transfer ribonucleic acids (tRNAs), 2 ribosomal RNAs (rRNAs, rrnL and rrnS), and a noncoding control section (D-loop) 13777 to 13854 bp in length. The 12 PCG areas have 3269 codons and a total length of 10053 bp, which makes up 71.38% of the mitochondrial genome's overall sequence. Most (10/12) of the PCGs that code for proteins begin with ATG, while the nad4L and nad1 genes have a GTG start codon. Phylogenetic analysis using the concatenated nucleotide sequences of 12 PCGs, and the ML tree analysis results showed that M. polonicum is more closely related to with Echinostomatidae and Fasciolidae, which indicates that the family Cyclocoelidae is more closely associated with Echinochasmidae. This study provides mtDNA information, and analysis of mitogenomic structure and evolution. Moreover, we aimed to understand the phylogenetic relationships of this fluke.

Analysis of complete mitogenomes and phylogenetic relationships of Frontopsylla spadix and Neopsylla specialis.

Fleas represent a group of paramount medical significance, subsisting on blood and acting as vectors for an array of naturally occurring diseases. These pathogens constitute essential elements within the plague biome, exerting deleterious effects on both human and livestock health. In this study, we successfully assembled and sequenced the whole mitochondrial genome of Frontopsylla spadix and Neopsylla specialis using long-range PCR and next-generation sequencing technologies. The mitogenomes of F. spadix and N. specialis both have 37 genes with full lengths of 15,085 bp and 16,820 bp, respectively. The topology of the phylogenetic tree elucidates that species F. spadix is clustered in a branch alongside other members of the family Leptopsyllidae, whereas species N. specialis is a sister taxon to Dorcadia ioffi and Hystrichopsylla weida qinlingensis. It also suggests that Pulicidae form a monophyletic clade, Ctenopthalmidae, Hystrichopsyllidae, Vermipsyllidae form a sister group to Ceratophyllidae/Leptopsyllidae group. The mitochondrial genomes of F. spadix and N. specialis were sequenced for the first time, which will contribute to a more comprehensive phylogenetic analysis of the Siphonaptera order. The foundation for subsequent systematic studies, and molecular biology of fleas was established.

Complete mitochondrial genome of Ctenophthalmus quadratus and Stenischia humilis in China provides insights into fleas phylogeny.

Fleas (Order Siphonaptera) are common blood-feeding ectoparasites, which have important economic significance. Limited mitochondrial genome information has impeded the study of flea biology, population genetics and phylogenetics. The Ctenophthalmus quadratus and Stenischia humilis complete mt genomes are described in this study. The samples were collected from Jianchuan, Yunnan plague foci, China. The mt genomes of C. quadratus and S. humilis were 15,938 bp and 15,617 bp, respectively. The gene arrangement of mt genome was consistent with that of other fleas, which include 22 tRNA genes, 13 protein-coding genes, and two rRNA genes, with a total of 37 genes. The relationship between C. quadratus and S. humilis in fleas was inferred by phylogenetic analysis of mt genome sequence datasets. Phylogenetic analyzes showed that the C. quadratus and S. humilis belonged to different species in the same family, and were closely related to Hystrichopsylla weida qinlingensis in the same family; and revealed that the family Hystrichopsyllidae is paraphyletic, supporting the monophyly of the order Siphonaptera. This study decodes the complete mt genomes of the C. quadratus and S. humilis for the first time. The results demonstrate that the C. quadratus and S. humilis are distinct species, and fleas are monophyletic. Analysis of mt genome provides novel molecular data for further studying the phylogeny and evolution of fleas.

Complete mitogenomes characterization and phylogenetic analyses of Ceratophyllus anisus and Leptopsylla segnis.

Fleas are one of the most common ectoparasites in warm-blooded mammals and an important vector of zoonotic diseases with serious medical implications. We sequenced the complete mitochondrial genomes of Ceratophyllus anisus and Leptopsylla segnis for the first time using high-throughput sequencing and constructed phylogenetic relationships. We obtained double-stranded circular molecules of lengths 15,875 and 15,785 bp, respectively, consisting of 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs, and two control regions. AT-skew was negative in both C. anisus (-0.022) and L. segnis (-0.231), while GC-skew was positive in both (0.024/0.248), which produced significant differences in codon usage and amino acid composition. Thirteen PCGs encoding 3,617 and 3,711 codons, respectively, isoleucine and phenylalanine were used most frequently. The tRNA genes all form a typical secondary structure. Construction of phylogenetic trees based on Bayesian inference (BI) and maximum likelihood (ML) methods for PCGs. The results of this study provide new information for the mitochondrial genome database of fleas and support further taxonomic studies and population genetics of fleas.

Mailuoning oral liquid attenuates convalescent cerebral ischemia by inhibiting AMPK/mTOR-associated apoptosis and promoting CREB/BDNF-mediated neuroprotection.

ETHNOPHARMACOLOGICAL RELEVANCE: Ischemic stroke is divided into acute, subacute and convalescent phases according to the time of onset. Clinically, Mailuoning oral liquid (MLN O) is a traditional Chinese patent medicine for treating ischemic stroke. Previous studies have shown that MLN O could prevent acute cerebral ischemia-reperfusion. However, its underlying mechanism remains unclear. AIM OF THE STUDY: To investigate the relationship between neuroprotection and apoptosis for clarifying MLN O mechanism in the recovery phase of ischemic stroke. MATERIALS AND METHODS: We imitated stroke using middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo and oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro models. The infarct volume, neurological deficit scores, HE staining, Nissl staining, TUNEL staining, immunohistochemistry, and Western blot were correspondingly performed to find pathological changes and detect neuronal apoptosis in rat cerebral cortex. The contents of LDH, Cyt-c, c-AMP and BDNF in rat plasma and cerebral cortex were detected by ELISA. Cell viability was measured by CCK8 assay. Cell morphology, Hoechst 33342 staining and Annexin-V-Alexa Fluor 647/PI staining were performed to assess neuronal apoptosis. The expression levels of proteins were evaluated by western blotting. RESULTS: MLN O obviously reduced brain infarct volume and neurological deficit scores in MCAO rats. MLN O inhibited inflammatory cell infiltration and neuronal apoptosis, but promoted gliosis, neuronal survival, and neuroprotection in the cortical region of MCAO rats. Additionally, MLN O decreased the amount of LDH and cytochrome c, while increasing the expression of c-AMP in the plasma and ischemic cerebral cortex of MCAO rats, and promoting the expression of BDNF in the cortical tissue of MCAO rats. Besides, MLN O improved cell viability, restored cell morphology, while attenuating cell damage, inhibiting neuronal apoptosis following OGD/R in PC-12 cells. Moreover, MLN O inhibited apoptosis by suppressing the expression of pro-apoptotic-associated proteins, including Bax, cytochrome c, Cleaved caspase 3 and HIF-1α, whereas accelerating the expression of Bcl-2 in vivo and in vitro. Furthermore, MLN O inhibited the activity of AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR), but activated the signaling pathway of cAMP-response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) in MCAO rats and OGD/R-stimulated PC-12 cells. CONCLUSIONS: These results demonstrated that MLN O inhibited AMPK/mTOR to affect apoptosis associated with mitochondria, leading to improve CREB/BDNF-mediated neuroprotection in the recovery period of ischemic stroke in vivo and in vitro.

Comparison of corticosteroid injection, physiotherapy and combined treatment for patients with chronic subacromial bursitis - A randomised controlled trial.

OBJECTIVE: To investigate whether combination of corticosteroid subdeltoid injections and physiotherapy was more effective than either treatment alone in chronic subacromial bursitis. DESIGN: Prospective, three-arm randomised controlled trial. SETTING: Rehabilitation department of an academic hospital. SUBJECTS: Patients with chronic subacromial bursitis. INTERVENTIONS: Patients were divided into corticosteroid injection (N = 36), physiotherapy (N = 40) and combined (N = 35) groups. Two corticosteroid subdeltoid injections in corticosteroid group, 8-week physical therapy emphasising on therapeutic exercise in physiotherapy group, and combined both treatments in combined group. MAIN OUTCOME MEASURES: The primary outcome measures were pain visual analogue scale and Shoulder Pain and Disability Index at 8 weeks after finishing treatment. The secondary outcome measures were active range of motion, Shoulder Disability Questionnaire, Western Ontario Rotator Cuff Index, patient's evaluation of treatment effect, and symptom recurrence. RESULTS: Group comparison showed significant statistical difference in shoulder flexion (P < 0.003) and patient's evaluation of treatment effect (P < 0.001). The time and group interactions comparison revealed significant statistical differences in pain score (P < 0.024), external rotation (P < 0.044) and patient's evaluation of treatment effect (P < 0.001). The above statistics were in favour of the corticosteroid and combined groups rather than physiotherapy group. The percentage of recurrence was 36.1, 7.5 and 17.1 in the corticosteroid, physiotherapy and combined groups, respectively (P < 0.001). CONCLUSION: Corticosteroid subdeltoid injection, or combined with physiotherapy, was superior to physiotherapy alone, but the recurrence rate was least in the physiotherapy group.

Anti-PD-L1 antibody enhances curative effect of cryoablation via antibody-dependent cell-mediated cytotoxicity mediating PD-L1highCD11b+ cells elimination in hepatocellular carcinoma.

Cryoablation (CRA) and microwave ablation (MWA) are two main local treatments for hepatocellular carcinoma (HCC). However, which one is more curative and suitable for combining with immunotherapy is still controversial. Herein, CRA induced higher tumoral PD-L1 expression and more T cells infiltration, but less PD-L1highCD11b+ myeloid cells infiltration than MWA in HCC. Furthermore, CRA had better curative effect than MWA for anti-PD-L1 combination therapy in mouse models. Mechanistically, anti-PD-L1 antibody facilitated infiltration of CD8+ T cells by enhancing the secretion of CXCL9 from cDC1 cells after CRA therapy. On the other hand, anti-PD-L1 antibody promoted the infiltration of NK cells to eliminate PD-L1highCD11b+ myeloid cells by antibody-dependent cell-mediated cytotoxicity (ADCC) effect after CRA therapy. Both aspects relieved the immunosuppressive microenvironment after CRA therapy. Notably, the wild-type PD-L1 Avelumab (Bavencio), compared to the mutant PD-L1 atezolizumab (Tecentriq), was better at inducing the ADCC effect to target PD-L1highCD11b+ myeloid cells. Collectively, our study uncovered the novel insights that CRA showed superior curative effect than MWA in combining with anti-PD-L1 antibody by strengthening CTL/NK cell immune responses, which provided a strong rationale for combining CRA and PD-L1 blockade in the clinical treatment for HCC.