Metformin induces tolerogenicity of dendritic cells by promoting metabolic reprogramming.

Dendritic cells (DCs) can mediate immune responses or immune tolerance depending on their immunophenotype and functional status. Remodeling of DCs' immune functions can develop proper therapeutic regimens for different immune-mediated diseases. In the immunopathology of autoimmune diseases (ADs), activated DCs notably promote effector T-cell polarization and exacerbate the disease. Recent evidence indicates that metformin can attenuate the clinical symptoms of ADs due to its anti-inflammatory properties. Whether and how the therapeutic effects of metformin on ADs are associated with DCs remain unknown. In this study, metformin was added to a culture system of LPS-induced DC maturation. The results revealed that metformin shifted DC into a tolerant phenotype, resulting in reduced surface expression of MHC-II, costimulatory molecules and CCR7, decreased levels of proinflammatory cytokines (TNF-α and IFN-γ), increased level of IL-10, upregulated immunomodulatory molecules (ICOSL and PD-L) and an enhanced capacity to promote regulatory T-cell (Treg) differentiation. Further results demonstrated that the anti-inflammatory effects of metformin in vivo were closely related to remodeling the immunophenotype of DCs. Mechanistically, metformin could mediate the metabolic reprogramming of DCs through FoxO3a signaling pathways, including disturbing the balance of fatty acid synthesis (FAS) and fatty acid oxidation (FAO), increasing glycolysis but inhibiting the tricarboxylic acid cycle (TAC) and pentose phosphate pathway (PPP), which resulted in the accumulation of fatty acids (FAs) and lactic acid, as well as low anabolism in DCs. Our findings indicated that metformin could induce tolerance in DCs by reprogramming their metabolic patterns and play anti-inflammatory roles in vitro and in vivo.

Pirfenidone suppressed triple-negative breast cancer metastasis by inhibiting the activity of the TGF-ß/SMAD pathway.

Among breast cancer patients, metastases are the leading cause of death. Despite decades of effort, little progress has been made to improve the treatment of breast cancer metastases, especially triple-negative breast cancer (TNBC). The extracellular matrix plays an important role in tumour growth and metastasis by causing its deposition, remodelling, and signalling. As we know, the process of fibrosis results in excessive amounts of extracellular matrix being deposited within the cells. So, it will be interesting to study if the use of anti-fibrotic drugs in combination with conventional chemotherapy drugs can produce synergistic antitumor effects. In this study, we assessed the efficacy of Pirfenidone (PFD), an FDA-approved medication for the treatment of idiopathic pulmonary fibrosis, on TNBC cells as well as its anti-tumour effects in xenograft tumour model. PFD inhibited in a dose-dependent manner breast cancer cell proliferation, migration, and invasion, while promoted their apoptosis in vitro. PFD also suppressed TGF-ß-induced activation of Smad signalling pathway and expression level of EMT-inducing transcription factors (e.g. SNAI2, TWIST1, ZEB1) as well as the mesenchymal genes such as VIMENTIN and N-Cadherin. On the contrary, the expression level of epithelial marker gene E-Cadherin was up-regulated in the presence of PFD. In vivo, PFD alone exerted a milder but significant anti-tumour effect than the chemotherapy drug nanoparticle albumin-bound paclitaxel (nab-PTX) did in the breast cancer xenograft mouse model. Interestingly, PFD synergistically boosted the cancer-killing effect of nab-PTX. Furthermore, Our data suggest that PFD suppressed breast cancer metastasis by inhibiting the activity of the TGFß/SMAD pathway.

Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma.

BACKGROUND: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials. METHODS: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. RESULTS: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group. CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).

Immune infiltration in renal cell carcinoma.

Immune infiltration of tumors is closely associated with clinical outcome in renal cell carcinoma (RCC). Tumor-infiltrating immune cells (TIICs) regulate cancer progression and are appealing therapeutic targets. The purpose of this study was to determine the composition of TIICs in RCC and further reveal the independent prognostic values of TIICs. CIBERSORT, an established algorithm, was applied to estimate the proportions of 22 immune cell types based on gene expression profiles of 891 tumors. Cox regression was used to evaluate the association of TIICs and immune checkpoint modulators with overall survival (OS). We found that CD8+ T cells were associated with prolonged OS (hazard ratio [HR] = 0.09, 95% confidence interval [CI].01-.53; P = 0.03) in chromophobe carcinoma (KICH). A higher proportion of regulatory T cells was associated with a worse outcome (HR = 1.59, 95% CI 1.23-.06; P < 0.01) in renal clear cell carcinoma (KIRC). In renal papillary cell carcinoma (KIRP), M1 macrophages were associated with a favorable outcome (HR = .43, 95% CI .25-.72; P < 0.01), while M2 macrophages indicated a worse outcome (HR = 2.55, 95% CI 1.45-4.47; P < 0.01). Moreover, the immunomodulator molecules CTLA4 and LAG3 were associated with a poor prognosis in KIRC, and IDO1 and PD-L2 were associated with a poor prognosis in KIRP. This study indicates TIICs are important determinants of prognosis in RCC meanwhile reveals potential targets and biomarkers for immunotherapy development.

Vascular endothelial growth factor (VEGF) impairs the motility and immune function of human mature dendritic cells through the VEGF receptor 2-RhoA-cofilin1 pathway.

Dendritic cells (DCs) are potent and specialized antigen presenting cells, which play a crucial role in initiating and amplifying both the innate and adaptive immune responses against cancer. Tumor cells can escape from immune attack by secreting suppressive cytokines that solely or cooperatively impair the immune function of DCs. However, the underlying mechanisms are not fully defined. Vascular endothelial growth factor (VEGF) has been identified as a major cytokine in the tumor microenvironment. To elucidate the effects of VEGF on the motility and immune function of mature DCs (mDCs), the cells were treated with 50 ng/mL VEGF and investigated by proteomics and molecular biological technologies. The results showed that VEGF can impair the migration capacity and immune function of mDCs through the RhoA-cofilin1 pathway mediated by the VEGF receptor 2, suggesting impaired motility of mDCs by VEGF is one of the aspects of immune escape mechanisms of tumors. It is clinically important to understand the biological behavior of DCs and the immune escape mechanisms of tumor as well as how to improve the efficiency of antitumor therapy based on DCs.

Biophysical Properties and Motility of Human Mature Dendritic Cells Deteriorated by Vascular Endothelial Growth Factor through Cytoskeleton Remodeling.

Dendritic cells (DCs), the most potent antigen-presenting cells, play a central role in the initiation, regulation, and maintenance of the immune responses. Vascular endothelial growth factor (VEGF) is one of the important cytokines in the tumor microenvironment (TME) and can inhibit the differentiation and functional maturation of DCs. To elucidate the potential mechanisms of DC dysfunction induced by VEGF, the effects of VEGF on the biophysical characteristics and motility of human mature DCs (mDCs) were investigated. The results showed that VEGF had a negative influence on the biophysical properties, including electrophoretic mobility, osmotic fragility, viscoelasticity, and transmigration. Further cytoskeleton structure analysis by confocal microscope and gene expression profile analyses by gene microarray and real-time PCR indicated that the abnormal remodeling of F-actin cytoskeleton may be the main reason for the deterioration of biophysical properties, motility, and stimulatory capability of VEGF-treated mDCs. This is significant for understanding the biological behavior of DCs and the immune escape mechanism of tumors. Simultaneously, the therapeutic efficacies may be improved by blocking the signaling pathway of VEGF in an appropriate manner before the deployment of DC-based vaccinations against tumors.

WITHDRAWN: Identification of an antimycin gene cluster and characterization of the tryptophan 2,3-dioxygenase from the deep sea-derived Streptomyces somaliensis HND1201.

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[Clinical results of recombinant human endostatin combined with chemoradiotherapy for locally advanced nasopharyngeal carcinoma].

OBJECTIVE: To compare the short-term efficacy and observe the tolerability and safety of recombinant human endostatin combined with induction chemotherapy followed by chemoradiotherapy for locally advanced nasopharyngeal carcinoma. METHODS: Fifty-three patients with locally advanced nasopharyngeal carcinoma, who received recombinant human endostatin combined with induction chemotherapy followed by chemoradiotherapy, treated in our department from December 2011 to March 2013 were included in the study group of this study. Another 48 patients, who received induction chemotherapy followed by chemoradiotherapy alone in the same period, were chosen as a control group. The short-term outcome, overall survival (OS), progression-free survival (PFS), and acute side effects of the two groups were compared. RESULTS: The complete remission rates of nasopharyngeal tumor in the study and control groups were 77.4% and 72.9%, respectively (P=0.154). The complete remission rates of patients with and without cervical lymph node metastasis were 75.5% and 62.6%, respectively, showing a significant difference (P=0.037). The 2-year OS, PFS, and DMFS rates for the study group were 82.3%, 77.2%, and 82.2%, respectively, versus 87.2%, 84.3% and 84.2% for the control group, showing a non-significant differences between the two groups (P=0.938, P=0.551, and P=0.725). CONCLUSIONS: The short-term results of recombinant human endostatin (Endostar) combined with induction chemotherapy followed by concurrent chemoradiotherapy in the treatment of locally advanced nasopharyngeal carcinoma are slightly better than that of induction chemotherapy followed by concurrent chemoradiotherapy alone, with tolerable treatment-related toxicity and no more side effects.

[Phase II clinical trial of two different modes of administration of the induction chemotherapy for locally advanced nasopharyngeal carcinoma].

OBJECTIVE: To compare the therapeutic effects, toxic side effects and influence on the immune function in patients treated with TPF [docetaxel (DOC) + cisplatin (DDP) + 5-fluorouracil (5-Fu)] induction chronochemotherapy and conventional chemotherapy for locally advanced nasopharyngeal (NPC). METHODS: Seventy patients with locally advanced nasopharyngeal carcinoma were treated in our department at their first visit from April 2013 to December 2013. They were divided randomly into two groups: the chronochemotherapy group (38 patients) and conventional chemotherapy group (32 patients). All of the patients were treated with TPF regimen with 2 cycles of induction chemotherapy in a 21-28-days/cycle. The chronochemotherapy group: DOC: 75 mg/m2, i. v. gtt, d1 (03: 30-04: 30); DDP: 75 mg/m2, 10 am-10 pm, c.i.v, d1-d5; 5-Fu: 750 mg·m(-2)·d(-1), 10 pm-10 am, c. i.v., d1-d5, both chemotherapies were administered by intravenous infusion using an automatic electric pump. The conventional chemotherapy group: Both DOC and DDP were administered intravenously at a dose of 75 mg/m2 on d1. 5-Fu was given at a dose of 750 mg/m2 for 24 hours from d1-d5 with continuous infusion in a total of 120 hours. In this procedure, prescribing the conventional intravenous infusion, intensity modulated radiation therapy was used after the induction chemotherapy. The prescribed nasopharyngeal lesion dose (GTVnx) was 69.96 Gy/33 fractions for the T1-T2 nasopharygeal cancer, while 73.92 Gy/33 fractions nasopharynx lesion dose (GTVnx) for the T3-T4 nasopharyngeal cancer. The planning target volume (PTV) of positive lymph node (PTVnd) dose was 69.96 Gy/33 fractions. Concurrent chemoradiotherapy: cisplatin 100 mg/m2, i. v. gtt. d1-d2, and there were two cycles in total and 21 days each cycle. RESULTS: Sixty-six patients were evaluable for the response assessment. There were 36 patients in the chronochemotherapy group and 30 patients in the conventional chemotherapy group. After the induction chemotherapy, no CR case was found in both of the two groups. The PR was 80.6% in the chronochemotherapy group and 50.0% in the conventional chemotherapy group (P=0.009). After concurrent chemoradiotherapy, the CR rate in the chronocheotherapy group was 45.5%, significantly higher than 20.7% in the conventional chemotherapy group (P=0.040). Secondly, the incidence rates of adverse reactions including bone marrow suppression, nausea, vomiting, diarrhea, constipation, oral mucositis, fatigue, anorexia in the chrono-chemotherapy group were significantly lower than that in the conventional group (P<0.05 for all). Finally, compared the two groups, the CD4+ /CD8+ ratio was significantly lower in the chronochemotherapy group than that in the conventional chemotherapy group (P<0.05). The lymphocytes CD19+ and CD4+/CD8+ were decreased and CD3+, CD4+, CD8+, CD16++CD56+ were increased in the chronochemotherapy group, while only CD3+ and CD8+ were increased in the conventional chemotherapy group. CONCLUSIONS: Compared with the conventional chemotherapy, the chronochemotherapy may be more favorable in the treatment of NPC, with a better therapeutic effects and effectiveness than that of conventional chemotherapy after induction chemotherapy, with less side effects, and can improve the immune function in the patients.

Investigations of the functional states of dendritic cells under different conditioned microenvironments by Fourier transformed infrared spectroscopy.

BACKGROUND: Dendritic cells are potent and specialized antigen presenting cells, which play a crucial role in initiating and amplifying both the innate and adaptive immune responses. The dendritic cell-based vaccination against cancer has been clinically achieved promising successes. But there are still many challenges in its clinical application, especially for how to identify the functional states. METHODS: The CD14+ monocytes were isolated from human peripheral blood after plastic adherence and purified to approximately 98% with cocktail immunomagnetic beads. The immature dendritic cells and mature dendritic cells were induced by traditional protocols. The resulting dendritic cells were cocultured with normal cells and cancer cells. The functional state of dendritic cells including immature dendritic cells (imDCs) and mature dendritic cells (mDCs) under different conditioned microenvironments were investigated by Fourier transformed infrared spectroscopy (FTIR) and molecular biological methods. RESULTS: The results of Fourier transformed infrared spectroscopy showed that the gene transcription activity and energy states of dendritic cells were specifically suppressed by tumor cells (P < 0.05 or 0.01). The expression levels of NF-kappa B (NF-κB) in dendritic cells were also specifically inhibited by tumor-derived factors (P < 0.05 or 0.01). Moreover, the ratios of absorption intensities of Fourier transformed infrared spectroscopy at given wave numbers were closely correlated with the expression levels of NF-κB (R2:0.69 and R2:0.81, respectively). CONCLUSION: Our results confirmed that the ratios of absorption intensities of Fourier transformed infrared spectroscopy at given wave numbers were positively correlated with the expression levels of NF-κB, suggesting that Fourier transformed infrared spectroscopy technology could be clinically applied to identify the functional states of dendritic cell when performing dendritic cell-based vaccination. It's significant for the simplification and standardization of dendritic cell-based vaccination clinical preparation protocols.

The complete chloroplast genome sequence of Olea dioica Roxb, 1820 (Oleaceae).

Olea dioica Roxb, 1820 is a very important ethnomedicinal tree because of its medicinal properties and it belongs to the Oleaceae family. It is mainly distributed in evergreen and semi-evergreen forests. However, the chloroplast genome of O. dioica has not yet been reported. In this study, the chloroplast genome sequence of O. dioica was sequenced using next-generation sequencing technologies. The complete chloroplast genome of O. dioica was 155,138 bp in length (GenBank accession no. PP048999), comprising a large single-copy (LSC) region of 86,048 bp, a small single-copy (SSC) region of 17,816 bp, and two inverted repeat (IR) regions 25,637 bp each. The overall GC content was 37.8%. The complete chloroplast genome of O. dioica contains 131 complete genes, which are 88 protein-coding genes, 35 transfer RNA genes, and eight ribosomal RNA genes. A maximum-likelihood (ML) tree of O. dioica and 14 other species in the family Oleaceae suggested that O. dioica showed a close relationship with Olea brachiata.

Long-term survival, toxicities, and the role of chrono-chemotherapy with different infusion rates in locally advanced nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy: a retrospective study with a 5-year follow-up.

Purpose: This study aimed to evaluate 5-year outcomes and the late toxicity profile of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma (NPC). Methods and materials: Our retrospective analysis included 70 patients with locally advanced NPC stages III and IVB (according to the 2010 American Joint Committee on Cancer staging system). Patients were treated with two cycles of induction chemotherapy (IC) before concurrent chemoradiotherapy (CCRT) at Guizhou Cancer Hospital. The IC with docetaxel, cisplatin (DDP) and fluorouracil regimen. Patients were divided into two groups during CCRT. Using a "MELODIE" multi-channel programmed pump, DDP (100 mg/m2) was administered for 12 hours from 10:00 am to 10:00 pm and repeated every 3 weeks for 2-3 cycles. DDP was administered at the peak period of 4:00 pm in the sinusoidal chrono-modulated infusion group (Arm A, n=35). The patients in Arm B received a constant rate of infusion. Both arms received radiotherapy through the same technique and dose fraction. The long-term survival and disease progression were observed. Results: After a median follow-up of 82.8 months, the 5-year progression-free survival rate was 81.3% in Arm A and 79.6% in Arm B (P = 0.85). The 5-year overall survival rate was not significantly different between Arm A and Arm B (79.6% vs 85.3%, P = 0.79). The 5-year distant metastasis-free survival rate was 83.6% in Arm A and 84.6% in Arm B (P = 0.75). The 5-year local recurrence-free survival rate was 88.2% in Arm A and 85.3% in Arm B (P = 0.16). There were no late toxicities of grade 3-4 in either group. Both groups had grade 1-2 late toxicities. Dry mouth was the most common late toxic side effect, followed by hearing loss and difficulty in swallowing. There was no statistically significant difference between Arm A and Arm B in terms of side effects. Conclusion: Long-term analysis confirmed that in CCRT, cisplatin administration with sinusoidal chrono-modulated infusion was not superior to the constant infusion rate in terms of long-term toxicity and prognosis.

A prospective phase II randomized study of docetaxel combined with lobaplatin versus TPF regimen induction chemotherapy followed by concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma.

PURPOSE: To compare the toxicity and clinical efficacy of TL (docetaxel + lobaplatin) induction chemotherapy combined with lobaplatin concurrent chemoradiotherapy and TPF (docetaxel + cisplatin + 5-fluorouracil) induction chemotherapy combined with cisplatin concurrent chemoradiotherapy in the treatment of locally advanced head and neck squamous cell carcinoma. METHODS AND PATIENTS: In total, 128 patients with locally advanced head and neck cancer were prospectively enrolled between August 2016 and April 2021. They were randomly divided into trial group and control group, all using chronological dosage mode. The trial group used TL regimen induction chemotherapy combined with lobaplatin concurrent chemoradiotherapy; the control group used TPF regimen induction chemotherapy and cisplatin concurrent chemotherapy. The endpoints were adverse events and survival rates at 1, 3 and 5 years. RESULTS: Median follow-up was 42 months (20-71 months). (1) Adverse events: During induction chemotherapy, compared with TPF group, grade 3-4 leukocytes and neutrophils, diarrhea, 1-2 hyperbilirubinemia, nausea / vomiting, oral mucositis, fatigue, anorexia, hyponatremia were significantly lower in TL group (p<0. 05): 6% vs. 35%, 14% vs. 53%, 0% vs. 6%, 15% vs. 40%, 9% vs. 56%, 0% vs. 10%, 3% vs. 13%, 2% vs. 23%, 15% vs. 74%. During chemoradiotherapy, the incidence of hyponatremia, hypokalaemia and grade 1-2 nausea was significantly lower in the TL group (p<0. 05), with 24% vs. 69%, 20% vs. 65% and 24% vs. 44%, respectively. However, more grade 3-4 thrombocytopenia were observed in the TL group (15% vs. 3%, p<0. 05). (2) There was no significant difference in the recent objective response rate (ORR) between patients with TL group and TPF group (p=0.961). (3) There was no statistical difference in 1, 3 and 5 years OS between TL group and TPF group, respectively, (71.0% vs. 67.5%, p=0.573), (56.6% vs. 56.9%, p=0.814), (52.5% vs. 52.9%, p=0.841); 1, 3 and 5 years PFS are: (63.4% vs. 64.0%, p=0.883), (51.1% vs. 54.0%, p=0.705) and (47.3% vs. 45.9%, p=0.887), None of them were significantly different. Multivariate analysis of COX regression showed that T stage (p=0.01) and surgery (p=0.046) were independent factors affecting PFS and OS, respectively. OS subgroup analysis shows that people receiving the TL regimen in postoperative and nodal stage N1 and N2 patients tended to survive longer than those receiving the TPF regimen. CONCLUSION: Patients with postoperative, N1 or N2 stage locally advanced head and neck squamous cell carcinoma (HNSCC) may have more significant clinical benefits when treated with TL regimen. TL regimen has advantages in reducing toxic side effects and can be used as one of the first-line treatment options. TRIAL REGISTRATION: ClinicalTrials.gov (No. NCT03117257).

A Genomic Quantitative Study on the Contribution of the Ancestral-State Bases Relative to Derived Bases in the Divergence and Local Adaptation of Populus davidiana.

Identifying alleles associated with adaptation to new environments will advance our understanding of evolution from the molecular level. Previous studies have found that the Populus davidiana southwest population in East Asia has differentiated from other populations in the range. We aimed to evaluate the contributions of the ancestral-state bases (ASBs) relative to derived bases (DBs) in the local adaptation of P. davidiana in the Yunnan-Guizhou Plateau from a quantitative perspective using whole-genome re-sequencing data from 90 P. davidiana samples from three regions across the species range. Our results showed that the uplift of the Qinghai-Tibet Plateau during the Neogene and associated climate fluctuations during the Middle Pleistocene were likely an important factor in the early divergence of P. davidiana. Highly differentiated genomic regions between populations were inferred to have undergone strong linked natural selection, and ASBs are the chief means by which populations of P. davidiana adapt to novel environmental conditions; however, when adapting to regions with high environmental differences relative to the ancestral range, the proportion of DBs was significantly higher than that of background regions, as ASBs are insufficient to cope with these environments. Finally, a number of genes were identified in the outlier region.

Crosstalk Between Four Types of RNA Modification Writers Characterizes the Tumor Immune Microenvironment Infiltration Patterns in Skin Cutaneous Melanoma.

The "writers" of four types of adenosine (A)-related RNA modifications (N6-methyladenosine, N1-methyladenosine, alternative polyadenylation, as well as A-to-inosine RNA editing) are closely related to the tumorigenesis and progression of many cancer types, including skin cutaneous melanoma (SKCM). However, the potential roles of the crosstalk between these RNA modification "writers" in the tumor microenvironment (TME) remain unclear. The RNA modification patterns were identified using an unsupervised clustering method. Subsequently, based on differentially expressed genes responsible for the aforementioned RNA modification patterns, an RNA modification "writer" scoring model (W_Score) was constructed to quantify the RNA modification-associated subtypes in individual patients. Moreover, a correlation analysis for W_Score and the TME characteristics, clinical features, molecular subtypes, drug sensitivities, immune responses, and prognosis was performed. We identified three RNA modification patterns, corresponding to distinct tumor immune microenvironment characteristics and survival outcomes. Based on the W_Score score, which was extracted from the RNA modification-related signature genes, patients with SKCM were divided into high- and low-W_Score groups. The low-W_Score group was characterized by better survival outcomes and strengthened immunocyte infiltration. Further analysis showed that the low-W_Score group was positively associated with higher tumor mutation burden and PD-L1 expression. Of note, two immunotherapy cohorts demonstrated that patients with low W_Score exhibited long-term clinical benefits and an enhanced immune response. This study is the first to systematically analyze four types of A-related RNA modifications in SKCM, revealing that these "writers" essentially contribute to TME complexity and diversity. We quantitatively evaluated the RNA modification patterns in individual tumors, which could aid in developing personalized immunotherapy strategies for patients.

The Treatment Combining Antiangiogenesis with Chemoradiotherapy Impinges on the Peripheral Circulation Vascular Endothelial Cells and Therapeutic Effect in the Patients with Locally Advanced Nasopharyngeal Carcinoma.

This study was implemented for the evaluation on the circulating endothelial cells' (CECs) clinical significance in the locally advanced nasopharyngeal carcinoma treatment with endostatin-combined chemoradiotherapy. This study enrolled 47 patients with locally advanced nasopharyngeal carcinoma who were hospitalized from May 9, 2012 to March 10, 2013. These patients were split up into the observation group (25 patients) and control group (22 patients). Patients in the observation group received the endostatin combined with induction chemotherapy and subsequently with concurrent chemoradiotherapy with endostatin. Patients in the control group were treated with inductive chemotherapy followed by concurrent chemoradiotherapy. CECs in peripheral blood were conducted separately before or after inductive chemotherapy and additionally in the end of concurrent chemoradiotherapy. The CEC values of the observation group showed significant statistical differences (p < 0.05) before or after different therapies, whereas those data in the control group were not statistically different. And, the mostly importantly, the CEC values in the observation group and control group turned out a statistical difference. The combination of endostatin and chemoradiotherapy significantly reduced parameters of peripheral blood CECs in these patients. According to the CEC parameters' variety that we observed in the combined therapies, this study demonstrated that the CECs might be a clinical clue to evaluate this antiangiogenic chemoradiotherapy. And the clinical value of CECs will be further determined along with increasing comparative studies and clinical long-term efficacy observation.

High-Quality Genome Assembly of Olea europaea subsp. cuspidata Provides Insights Into Its Resistance to Fungal Diseases in the Summer Rain Belt in East Asia.

The olive tree (Olea europaea L.) is the most iconic fruit crop of the Mediterranean Basin. Since the plant was introduced to China in the 1960s, the summer rain climate makes it susceptible to pathogens, leading to some olive diseases. Olea europaea L. subsp. cuspidata is natively distributed in the Yunnan province of China. It has a smaller fruit size, lower oil content, and higher resistance compared to subsp. europaea, which makes subsp. cuspidata a critical germplasm resource to be investigated. Here, a high-quality genome of subsp. cuspidata with 1.38 Gb in size was assembled and anchored onto 23 pseudochromosomes with a mounting rate of 85.57%. It represents 96.6% completeness [benchmarking universal single-copy orthologs (BUSCO)] with a contig N50 of 14.72 Mb and a scaffold N50 of 52.68 Mb, which shows a significant improvement compared with other olive genomes assembled. The evaluation of the genome assembly showed that 92.31% of resequencing reads and an average of 96.52% of assembled transcripts could be aligned to the assembled genome. We found that a positively selected gene, evm.model.Chr16.1133, was shared with the results of transcriptome analysis. This gene belongs to the susceptible gene and negatively regulates the disease resistance process. Furthermore, we identified the Cercospora genus which causes the leaf spot disease in the infected leaves. The high-quality chromosome-level genomic information presented here may facilitate the conservation and utilization of germplasm resources of this subspecies and provide an essential genetic basis for further research into the differences in oil content and resistance between subsp. cuspidata and europaea.

Regulation of biomaterial implantation-induced fibrin deposition to immunological functions of dendritic cells.

The performance of implanted biomaterials is largely determined by their interaction with the host immune system. As a fibrous-like 3D network, fibrin matrix formed at the interfaces of tissue and material, whose effects on dendritic cells (DCs) remain unknown. Here, a bone plates implantation model was developed to evaluate the fibrin matrix deposition and DCs recruitment in vivo. The DCs responses to fibrin matrix were further analyzed by a 2D and 3D fibrin matrix model in vitro. In vivo results indicated that large amount of fibrin matrix deposited on the interface between the tissue and bone plates, where DCs were recruited. Subsequent in vitro testing denoted that DCs underwent significant shape deformation and cytoskeleton reorganization, as well as mechanical property alteration. Furthermore, the immune function of imDCs and mDCs were negatively and positively regulated, respectively. The underlying mechano-immunology coupling mechanisms involved RhoA and CDC42 signaling pathways. These results suggested that fibrin plays a key role in regulating DCs immunological behaviors, providing a valuable immunomodulatory strategy for tissue healing, regeneration and implantation.

Final Overall Survival Analysis of Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma: A Multicenter, Randomized Phase III Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported significantly improved failure-free survival using gemcitabine plus cisplatin induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized trial, patients were assigned to be treated with concurrent chemoradiotherapy alone (standard therapy, n = 238) or gemcitabine and cisplatin induction chemotherapy before concurrent chemoradiotherapy (n = 242). With a median follow-up of 69.8 months, the induction chemotherapy group had a significantly higher 5-year OS (87.9% v 78.8%, hazard ratio, 0.51 [95% CI 0.34 to 0.78]; P = .001) and a comparable risk of late toxicities (≥ grade 3, 11.3% v 11.4%). Notably, the depth of the tumor response to induction chemotherapy correlated significantly and positively with survival (complete response v partial response v stable/progressive disease, 5-year OS, 100% v 88.4% v 61.5%, P = .005). Besides, patients with a low pretreatment cell-free Epstein-Barr virus DNA load (< 4,000 copies/mL) might not benefit from induction chemotherapy (5-year OS, 90.6% v 91.4%, P = .77). In conclusion, induction chemotherapy before concurrent chemoradiotherapy improved OS significantly in patients with locally advanced nasopharyngeal carcinoma, without increasing the risk of late toxicities. Tumor response to induction chemotherapy and pretreatment cell-free Epstein-Barr virus DNA might be useful to guide individualized treatment.

A phase II multicenter randomized controlled trial to compare standard chemoradiation with or without recombinant human endostatin injection (Endostar) therapy for the treatment of locally advanced nasopharyngeal carcinoma: Long-term outcomes update.

PURPOSE: This study aimed to observe the feasibility and safety of addition of recombinant human endostatin injection to standard chemoradiation for the locally advanced nasopharyngeal carcinoma. Current follow-up results updated long-term efficacy and late toxicity of the trial. METHODS: Between July 2012 and December 2013, we enrolled 114 patients that are older than 18 years with stage Ⅲ-Ⅳb nasopharyngeal carcinoma from 3 centers in Guizhou, China. Fifty six patients who received standard chemoradiation combined with recombinant human endostatin injection (Endostar) were included in the study group. Another 58 patients were randomly assigned to the control group without using Endostar. Patients in both groups received the same 2 cycles of induction chemotherapy (Docetaxel 75 mg/m2, cisplatin 80 mg/m2), followed by 2 cycles of concurrent intensity-modulated radiation therapy with cisplatin (DDP; 80 mg/m2 on days 1 and 22). The patients in the experimental group received 2 cycles Endostar (7.5 mg/m2 d8-d21 during induction chemotherapy and d1-d14 during concurrent chemoradiation). RESULTS: There were no significant differences of toxicities between the 2 groups. Chemotherapy and radiotherapy compliance between the 2 groups was similar. No hemorrhage and coagulation dysfunction in the experimental group were observed. There was a median follow-up of 67.1 months. Comparing the short-time effect of 3 months to the completion of chemoradiotherapy, there was a little higher objective response rate in the experimental group. Compared with the control group, the experimental group improved in the complete remission rate of cervical lymph node metastasis (91.1% vs 72.4%, χ2 = 3.897, P = 0.048). However, there was no significant difference in the curative effect of nasopharyngeal lesions between the 2 groups. (78.6% vs 74.1%, χ2 = 0.310, P = 0.578). The 5-year overall survival, progression-free of survival, metastasis-free survival, and locoregional failure-free survival rates in the 2 groups were 69.6%, 67.8%, 78.75, and 83.0%, respectively, for the experimental group, these rates were 73.2%, 80.1%, 81.7%, and 91.0%, respectively, and for the control group, no significant difference was found (P > 0.05). CONCLUSIONS: Patients show good tolerance and compliance with a manageable toxicity profile to the regimen of chemoradiation plus Endostar. There was a little higher objective response rate in the study group. A phase 3 randomized study is needed to substantiate our findings.