Apelin receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling

The apelin receptor (APJ) belongs to family A of the G protein-coupled receptors (GPCRs) and is a potential pharmacotherapeutic target for heart failure, hypertension, and other cardiovascular diseases. There is evidence APJ heterodimerizes with other GPCRs; however, the existence of APJ homodimers and oligomers remains to be investigated. Here, we measured APJ monomer-homodimer-oligomer interconversion by monitoring APJ dynamically on cells and compared their proportions, spatial arrangement, and mobility using total internal reflection fluorescence microscopy, resonance energy transfer, and proximity biotinylation. In cells with <0.3 receptor particles/μm2, approximately 60% of APJ molecules were present as dimers or oligomers. APJ dimers were present on the cell surface in a dynamic equilibrium with constant formation and dissociation of receptor complexes. Furthermore, we applied interference peptides and MALDI-TOF mass spectrometry to confirm APJ homo-dimer and explore the dimer-interfaces. Peptides corresponding to transmembrane domain (TMD)1, 2, 3, and 4, but not TMD5, 6, and 7, disrupted APJ dimerization. APJ mutants in TMD1 and TMD2 also decreased bioluminescence resonance energy transfer of APJ dimer. APJ dimerization resulted in novel functional characteristics, such as a distinct G-protein binding profile and cell responses after agonist stimulation. Thus, dimerization may serve as a unique mechanism for fine-tuning APJ-mediated functions

Clinical features and prognosis of lung cancer in patients with connective tissue diseases: a retrospective cohort study

BackgroundStudies have demonstrated a close association between connective tissue diseases (CTDs) and lung cancer (LC). Evidence supports that poor survival may be associated with the presence of CTDs in patients with LC.MethodsThis retrospective cohort study investigated 29 patients with LC with CTDs, and 116 patients with LC without CTDs were enrolled as case-matched control cohorts. Medical records, therapeutic efficacy of cancer, and outcomes were analyzed.ResultsThe median duration from the diagnosis of CTDs to LC was 17 years. The Eastern Cooperative Oncology Group (ECOG) performance score for LC-CTD patients was worse than that for matched non-CTD LC patients. The median progression-free survival (mPFS) and overall survival (mOS) of first-line chemotherapy did not differ between patients with lung adenocarcinoma (AC) with and without CTDs. A significant difference was observed in mPFS [4 months vs. 17 months; hazard ratio (HR), 9.987; p = 0.004] and mOS (6 months vs. 35 months; HR, 26.009; p &lt; 0.001) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment between patients with AC with and without CTDs. The presence of CTD, sex, ECOG performance status, and tumor-node-metastasis clinical stage were the independent prognostic factors in all patients with non–small cell LC (NSCLC). ECOG performance status was determined to be an independent prognostic factor in patients with LC-CTD. In patients with NSCLC with CTD (n = 26), sex (male) and worse ECOG score were the independent poor prognostic factors.ConclusionsCTDs were associated with poor survival in patients with LC. The therapeutic efficacy of first-line EGFR-TKI therapy was significantly worse in patients with lung AC with CTDs than in those without CTDs. ECOG performance status was determined as an independent prognostic factor for patients with LC and CTDs

Meta-analysis of the effect of PGM on survival prognosis of tumor patients

ObjectiveA systematic evaluation of the impact of phosphoglucose translocase PGM on the survival prognosis of tumor patients was conducted to understand its impact on tumors so as to improve the quality of survival and to find effective therapeutic targets for tumor patients.MethodsThe following were searched in the databases China National Knowledge Infrastructure (CNKI), Wanfang, Wipu, PubMed, EMBASE, ScienceDirect, Web of Science, and Cochrane Library: “PGM1”, “PGM2”, “PGM3”, “PGM4”, and “PGM5” as Chinese keywords and “PGM1”, “PGM2”, “PGM3”, “PGM4”, “PGM5”, “PGM1 cancer”, “PGM2 cancer”, “PGM3 cancer”, “PGM4 cancer”, “PGM5 cancer”, and “phosphoglucomutase”. Relevant studies published from the database establishment to April 2022 were collected. Studies that met the inclusion criteria were extracted and evaluated for quality with reference to the Cochrane 5.1.0 systematic evaluation method, and quality assessment was performed using RevMan 5.3 software.ResultsThe final results of nine articles and 10 studies with a total of 3,806 patients were included, including 272 patients in the PGM1 group, 541 patients in the PGM2 group, 1,775 patients in the PGM3 group, and 1,585 patients in the PGM5 group. Results of the meta-analysis: after determining the results of the nine articles, it was found that the difference was statistically significant with a p-value &lt;0.05 (hazard ratio (HR) = 0.89, 95% CI 0.69–1.09, p = 0.000). To find the sources of heterogeneity, the remaining eight papers were tested after removing the highly sensitive literature, and the results showed I2 = 26.5%, p &lt; 0.001, a statistically significant difference. The HR for high expression of PGM1 and PGM2 and PGM5 was &lt;1, while the HR for high expression of PGM3 was &gt;1.ConclusionAlthough PGM1, PGM2, PGM3, and PGM5 are enzymes of the same family, their effects on tumors are different. High expression of PGM1, PGM2, and PGM5 can effectively prolong the overall survival of patients. In contrast, high expression of PGM3 reduced the overall survival of patients. This study of PGM family enzymes can assist in subsequent tumor diagnosis, treatment, and prognostic assessment

Research progress on the role of lncRNA–miRNA networks in regulating adipogenic and osteogenic differentiation of bone marrow mesenchymal stem cells in osteoporosis

Osteoporosis (OP) is characterized by a decrease in osteoblasts and an increase in adipocytes in the bone marrow compartment, alongside abnormal bone/fat differentiation, which ultimately results in imbalanced bone homeostasis. Bone marrow mesenchymal stem cells (BMSCs) can differentiate into osteoblasts and adipocytes to maintain bone homeostasis. Several studies have shown that lncRNAs are competitive endogenous RNAs that form a lncRNA–miRNA network by targeting miRNA for the regulation of bone/fat differentiation in BMSCs; this mechanism is closely related to the corresponding treatment of OP and is important in the development of novel OP-targeted therapies. However, by reviewing the current literature, it became clear that there are limited summaries discussing the effects of the lncRNA–miRNA network on osteogenic/adipogenic differentiation in BMSCs. Therefore, this article provides a review of the current literature to explore the impact of the lncRNA–miRNA network on the osteogenic/adipogenic differentiation of BMSCs, with the aim of providing a new theoretical basis for the treatment of OP

Experimental Design and Study of Micro-nano Wood Fiber Processed by Nanosecond Pulse Laser

A new processing technology using a nanosecond pulse laser to process micro-nano wood fiber is proposed in this paper. A test bench was designed and manufactured for the technology. The digital design process, experimental methods, and general layout principle of the test bench are introduced. When the factors that affected the results of the experiment were analyzed, it was found that cutting width and cutting depth were affected by cutting direction, cutting speed, and cutting power. The wood underwent thermal degradation near the point of processing. The results of the experiment showed that the technology is feasible

Molecular analysis of phosphomannomutase (PMM) genes reveals a unique PMM duplication event in diverse Triticeae species and the main PMM isozymes in bread wheat tissues

BACKGROUND: Phosphomannomutase (PMM) is an essential enzyme in eukaryotes. However, little is known about PMM gene and function in crop plants. Here, we report molecular evolutionary and biochemical analysis of PMM genes in bread wheat and related Triticeae species. RESULTS: Two sets of homoeologous PMM genes (TaPMM-1 and 2) were found in bread wheat, and two corresponding PMM genes were identified in the diploid progenitors of bread wheat and many other diploid Triticeae species. The duplication event yielding PMM-1 and 2 occurred before the radiation of diploid Triticeae genomes. The PMM gene family in wheat and relatives may evolve largely under purifying selection. Among the six TaPMM genes, the transcript levels of PMM-1 members were comparatively high and their recombinant proteins were all enzymatically active. However, PMM-2 homoeologs exhibited lower transcript levels, two of which were also inactive. TaPMM-A1, B1 and D1 were probably the main active isozymes in bread wheat tissues. The three isozymes differed from their counterparts in barley and Brachypodium distachyon in being more tolerant to elevated test temperatures. CONCLUSION: Our work identified the genes encoding PMM isozymes in bread wheat and relatives, uncovered a unique PMM duplication event in diverse Triticeae species, and revealed the main active PMM isozymes in bread wheat tissues. The knowledge obtained here improves the understanding of PMM evolution in eukaryotic organisms, and may facilitate further investigations of PMM function in the temperature adaptability of bread wheat

Serial Monitoring of Circulating Tumor DNA in Patients With Metastatic Colorectal Cancer to Predict the Therapeutic Response

Early biomarkers of therapeutic responses can help optimize the treatment of metastatic colorectal cancers (mCRC). In this prospective exploratory study, we examined serial changes of plasma-circulating tumor DNA (ctDNA) in 41 mCRC patients receiving first-line chemotherapies and tested its association with treatment outcomes according to radiological assessments. Using next-generation sequencing technologies, we profiled somatic mutations in 50 cancer-related genes in ctDNA before each of the first four treatment cycles. We observed mutations in 95.7% of pre-treatment ctDNA samples. Using mutations of the maximal frequency in each pre-treatment plasma ctDNA sample as the candidate targets, we computed log2 fold changes of ctDNA levels between adjacent treatment cycles. We found that ctDNA reductions as early as prior to cycle 2 predicted responses after cycle 4. Log2 fold changes of ctDNA after cycle 1 (ctDNA log2 (C1/C0)) &gt; −0.126 predicted progressive disease, with an accuracy of 94.6%. These patients also showed significantly worse progression-free survival than those with ctDNA log2 (C1/C0) ≤ −0.126 (median 2.0 vs. 9.0 months; P = 0.007). Together, the present exploratory study suggests that early changes in ctDNA levels detected via targeted sequencing are potential biomarkers of future treatment responses in mCRCs

First-line treatment with chemotherapy plus cetuximab in Chinese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Efficacy and safety results of the randomised, phase III CHANGE-2 trial.

Abstract Background The EXTREME regimen (chemotherapy [CT; cisplatin/carboplatin and 5-fluorouracil]) plus cetuximab is a standard-of-care first-line (1L) treatment for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), as supported by international guidelines. The phase III CHANGE-2 trial assessed the efficacy and safety of a modified CT regimen (with a reduced dose of both components) and cetuximab versus CT for the 1L treatment of Chinese patients with R/M SCCHN. Methods Patients were randomised to receive up to six cycles of CT plus cetuximab followed by cetuximab maintenance until progressive disease or CT alone. The primary end-point was the progression-free survival (PFS) time assessed by the independent review committee (IRC). Results Overall, 243 patients were randomised (164 to CT plus cetuximab; 79 to CT). The hazard ratios for PFS by IRC and overall survival (OS) were 0.57 (95% CI: 0.40–0.80; median: 5.5 versus 4.2 months) and 0.69 (95% CI: 0.50–0.93; median: 11.1 versus 8.9 months), respectively, in favour of CT plus cetuximab. The objective response rates (ORR) by IRC were 50.0% and 26.6% with CT plus cetuximab and CT treatment, respectively. Treatment-emergent adverse events of maximum grade 3 or 4 occurred in 61.3% (CT plus cetuximab) and 48.7% (CT) of patients. Conclusions CHANGE-2 showed an improved median PFS, median OS and ORR with the addition of cetuximab to a modified platinum/5-fluorouracil regimen, with no new or unexpected safety findings, thereby confirming CT plus cetuximab as an effective and safe 1L treatment for Chinese patients with R/M SCCHN. Clinical trial registration number NCT02383966