Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

LncRNA DYNLRB2-AS1 promotes gemcitabine resistance of nasopharyngeal carcinoma by inhibiting the ubiquitination degradation of DHX9 protein.

Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.

The Anterior Cingulate Cortex Promotes Long-Term Auditory Cortical Responses through an Indirect Pathway via the Rhinal Cortex in Mice.

Sensory cortical areas are robustly modulated by higher-order cortices. Our previous study shows that the anterior cingulate cortex (ACC) can immediately and transiently enhance responses in the mouse auditory cortex (ACx). Here, we further examined whether strong activation of ACC neurons can induce long-term effects in mice of both sexes. To our surprise, only stimulation of cell bodies in the ACC, but not ACC-to-ACx terminal activation, induced long-term enhancement of auditory responses in the ACx. Anatomical examination showed that the ACC indirectly projects to the ACx via the rhinal cortex (RCx). High-frequency stimulation of ACC-projecting terminals to the RCx or RCx-projecting terminals to the ACx induced a similar effect as the cell body activation of ACC neurons, whereas silencing the RCx blocked this long-term enhancement. High-frequency stimulation of ACC projections to the RCx also induced long-term augmentation of sound-evoked flight behavior in male mice. These results show that the ACC promotes the long-term enhancement of auditory responses in the ACx through an indirect pathway via the RCx.SIGNIFICANCE STATEMENT In this study, we demonstrate that the anterior part of the anterior cingulate cortex (ACC) evokes long-term enhancement of auditory responses in the auditory cortex (ACx) when it is strongly activated. Importantly, instead of a direct projection, we show that the ACC implements this effect via an indirect pathway through the lateral rhinal cortex using a series of physiological, optogenetic, anatomic, and behavioral experiments. Along with a short-term effect, this long-term enhancement induced by an indirect ACC-to-ACx projection could increase the odds of survival when animals are faced with threats after a significant event.

VIRMA promotes nasopharyngeal carcinoma, tumorigenesis, and metastasis by upregulation of E2F7 in an m6A-dependent manner.

The N6-methyladenosine (m6A) modification possesses new and essential roles in tumor initiation and progression by regulating mRNA biology. However, the role of aberrant m6A regulation in nasopharyngeal carcinoma (NPC) remains unclear. Here, through comprehensive analyses of NPC cohorts from the GEO database and our internal cohort, we identified that VIRMA, an m6A writer, is significantly upregulated in NPC and plays an essential role in tumorigenesis and metastasis of NPC, both in vitro and in vivo. High VIRMA expression served as a prognostic biomarker and was associated with poor outcomes in patients with NPC. Mechanistically, VIRMA mediated the m6A methylation of E2F7 3'-UTR, then IGF2BP2 bound, and maintained the stability of E2F7 mRNA. An integrative high-throughput sequencing approach revealed that E2F7 drives a unique transcriptome distinct from the classical E2F family in NPC, which functioned as an oncogenic transcriptional activator. E2F7 cooperated with CBFB-recruited RUNX1 in a non-canonical manner to transactivate ITGA2, ITGA5, and NTRK1, strengthening Akt signaling-induced tumor-promoting effect.

m6A-enriched lncRNA LINC00839 promotes tumor progression by enhancing TAF15-mediated transcription of amine oxidase AOC1 in nasopharyngeal carcinoma.

Dysregulation of long noncoding RNAs (lncRNAs) contributes to tumorigenesis by modulating specific cancer-related pathways, but the roles of N6-methyladenosine (m6A)-enriched lncRNAs and underlying mechanisms remain elusive in nasopharyngeal carcinoma (NPC). Here, we reanalyzed the previous genome-wide analysis of lncRNA profiles in 18 pairs of NPC and normal tissues as well as in ten paired samples from NPC with or without post-treatment metastases. We discerned that an oncogenic m6A-enriched lncRNA, LINC00839, which was substantially upregulated in NPC and correlated with poor clinical prognosis, promoted NPC growth and metastasis both in vitro and in vivo. Mechanistically, by using RNA pull-down assay combined with mass spectrometry, we found that LINC00839 interacted directly with the transcription factor, TATA-box binding protein associated factor (TAF15). Besides, chromatin immunoprecipitation and dual-luciferase report assays demonstrated that LINC00839 coordinated the recruitment of TAF15 to the promoter region of amine oxidase copper-containing 1 (AOC1), which encodes a secreted glycoprotein playing vital roles in various cancers, thereby activating AOC1 transcription in trans. In this study, potential effects of AOC1 in NPC progression were first proposed. Moreover, ectopic expression of AOC1 partially rescued the inhibitory effect of downregulation of LINC00839 in NPC. Furthermore, we showed that silencing vir-like m6A methyltransferase-associated (VIRMA) and insulin-like growth factor 2 mRNA-binding proteins 1 (IGF2BP1) attenuated the expression level and RNA stability of LINC00839 in an m6A-dependent manner. Taken together, our study unveils a novel oncogenic VIRMA/IGF2BP1-LINC00839-TAF15-AOC1 axis and highlights the significance and prognostic value of LINC00839 expression in NPC carcinogenesis.

Presence, Subtypes, and Prognostic Significance of Tertiary Lymphoid Structures in Urothelial Carcinoma of the Bladder.

OBJECTIVE: To evaluate the presence and subtypes of tertiary lymphatic structures (TLSs) in urothelial carcinoma of the bladder (UCB) and to analyze their associated clinicopathological characteristics and prognostic significance. METHODS: The study enrolled 580 patients with surgically treated UCB, including 313 non-muscle invasive bladder cancer (NMIBC) and 267 muscle-invasive bladder cancer (MIBC). The presence and subtypes of TLSs were identified by immunohistochemistry (CD20, CD3, Bcl-6, and CD21). TLSs were classified into non-GC (nGC) TLS and GC TLS subtypes based on germinal center (GC) formation. Disease-free survival (DFS) was used as an endpoint outcome to evaluate the prognostic significance of TLS and its subtypes in UCB. RESULTS: TLSs were more common in MIBC than in NMIBC (67.8% vs 48.2%, P < .001), and the tumor-infiltrating lymphocyte (TIL) mean density was significantly higher in MIBC than in NMIBC (24.0% vs 17.5%, P < .001). Moreover, a positive correlation was found between TLS presence and GC structure formation and TIL infiltration in UCB. Endpoint events occurred in 191 patients. Compared to patients with endpoint events, patients without disease progression exhibited higher TIL density and more TLSs (P < .05). Kaplan-Meier curves showed that TLS was associated with better DFS in NMIBC (P = .041) and MIBC (P = .049). However, the Cox multivariate analysis did not demonstrate the prognostic significance of TLS. CONCLUSIONS: TLS is heterogeneous in UCB, and that TLS and GC structures are related to TIL density and prognostic events. However, TLS as a prognostic indicator remains unclear, warranting further investigation.

Toxic effects of combined exposure to homoyessotoxin and nitrite on the survival, antioxidative responses, and apoptosis of the abalone Haliotis discus hannai.

Homoyessotoxin (homo-YTX) and nitrite (NO2-N), released during harmful dinoflagellate cell lysis adversely affect abalones. However, their toxicity mechanisms in shellfish remain unclear. This study investigated the economic abalone species Haliotis discus hannai exposed to varying concentrations of homo-YTX (0, 2, 5, and 10 µg L-1) and NO2-N (0, 3, and 6 mg L-1) on the basis of their 12 h LC50 values (5.05 µg L-1 and 4.25 mg L-1, respectively) and the environmentally relevant dissolved concentrations during severe dinoflagellate blooms, including mixtures. The test abalones were exposed to homo-YTX and NO2-N for 12 h. The mortality rate (D), reactive oxygen species (ROS) levels, antioxidant defense capabilities, and expression levels of antioxidant-related, Hsp-related, and apoptosis-related genes in abalone gills were assessed. Results showed that the combined exposure to homo-YTX and NO2-N increased the D and ROS levels and upregulated B-cell lymphoma-2 (BCL2)-associated X (BAX) and caspase3 (CASP3) expression levels while reducing glutathione peroxidase (GPx) activity and GPx, CuZnSOD, and BCL2 expression levels. High concentrations of homo-YTX (10 µg L-1) and NO2-N (6 mg L-1) solutions and the combinations of these toxicants inhibited the activities of superoxide dismutase (SOD) and catalase (CAT) and downregulated the expression levels of MnSOD, CAT, Hsp70, and Hsp90. The ROS levels were negatively correlated with the activities of SOD, CAT, and GPx and the expression levels of MnSOD, CuZnSOD, CAT, GPx, Hsp70, Hsp90, and BCL2. These results suggest that homo-YTX, in conjunction with NO2-N, induces oxidative stress, disrupts antioxidant defense systems, and triggers caspase-dependent apoptosis in the gills of abalone. ROS-mediated antioxidative and heat-shock responses and apoptosis emerge as potential toxicity mechanisms affecting the survival of H. discus hannai due to homo-YTX and NO2-N exposure.

Integrating Self-Partitioned Pore Space and Amine Functionality into an Aromatic-Rich Coordination Framework with Ph Stability for Effective Purification of C2 Hydrocarbons.

A great demand for high-purity C2 hydrocarbons calls for the development of chemically stable porous materials for the effective isolation of C2 hydrocarbons from CH4 and CO2. However, such separations are challenged by their similar physiochemical parameters and have not been systematically studied to date. In this work, we reported a cadmium-based rod-packing coordination framework compound ZJNU-140 of a new 5,6,7-c topology built up from a custom-designed tricarboxylate ligand. The metal-organic framework (MOF) features an aromatic-abundant pore surface, uncoordinated amine functionality, and self-partitioned pore space of suitable size. These structural characteristics act synergistically to provide the MOF with both selective recognition ability and the confinement effect toward C2 hydrocarbons. As a result, the MOF displays promising potential for adsorptive separation of C2-CH4 and C2-CO2 mixtures. The IAST-predicted C2/CH4 and C2/CO2 adsorption selectivities, respectively, fall in the ranges of 7.3-10.2 and 2.1-2.9 at 298 K and 109 kPa. The real separation performance was also confirmed by dynamic breakthrough experiments. In addition, the MOF can maintain skeleton intactness in aqueous solutions with a wide pH range of 3-11, as confirmed by powder X-ray diffraction (PXRD) and isotherm measurements, showing no loss of framework integrity and porosity. The excellent hydrostability, considerable uptake capacity, impressive adsorption selectivity, and mild regeneration make ZJNU-140 a promising adsorbent material applied for the separation and purification of C2 hydrocarbons.

Ligand Conformation Fixation Strategy for Expanding the Structural Diversity of Copper-Tricarboxylate Frameworks and C2H2 Purification Performance Studies.

Structural and functional expansion of metal-organic frameworks (MOFs) is fundamentally important because it not only enriches the structural chemistry of MOFs but also facilitates the full exploration of their application potentials. In this work, by employing a dual-site functionalization strategy to lock the ligand conformation, we designed and synthesized a pair of biphenyl tricarboxylate ligands bearing dimethyl and dimethoxy groups and fabricated their corresponding framework compounds through coordination with copper(II) ions. Compared to the monofunctionalized version, introduction of two side groups can significantly fix the ligand conformation, and as a result, the dual-methoxy compound exhibited a different network structure from the mono-methoxy counterpart. Although only one almost orthogonal conformation was observed for the two ligands, their coordination framework compounds displayed distinct topological structures probably due to different solvothermal conditions. Significantly, with a hierarchical cage-type structure and good hydrostability, the dimethyl compound exhibited promising practical application value for industrially important C2H2 separation and purification, which was comprehensively demonstrated by equilibrium/dynamic adsorption measurements and the corresponding Clausius-Clapeyron/IAST/DFT theoretical analyses.

Different reoxygenation rates induce different metabolic, apoptotic and immune responses in Golden Pompano (Trachinotus blochii) after hypoxic stress.

Dissolved oxygen (DO) is essential for teleosts, and fluctuating environmental factors can result in hypoxic stress in the golden pompano (Trachinotus blochii). However, it is unknown whether different recovery speeds of DO concentration after hypoxia induce stress in T. blochii. In this study, T. blochii was subjected to hypoxic conditions (1.9 ± 0.2 mg/L) for 12 h followed by 12 h of reoxygenation at two different speeds (30 mg/L per hour and 1.7 mg/L per hour increasing). The gradual reoxygenation group (GRG), experienced DO recovery (1.9 ± 0.2 to 6.8 ± 0.2 mg/L) within 3 h, and the rapid reoxygenation group (RRG), experienced DO recovery (1.9 ± 0.2 to 6.8 ± 0.2 mg/L) within 10 min. Physiological and biochemical parameters of metabolism (glucose, glycegon, lactic acid (LD), lactate dehydrogenase (LDH), pyruvic acid (PA), phosphofructokinase (PFKA), and hexokinase (HK), triglyceride (TG), lipoprotein lipase (LPL), carnitine palmitoyltransferase 1 (CPT-1)) and transcriptome sequencing (RNA-seq of liver) were monitored to identify the effects of the two reoxygenation speeds. Increased LD content and increased activity of LDH, PA, PFKA, and HK suggested enhanced anaerobic glycolysis under hypoxic stress. LD and LDH levels remained significantly elevated during reoxygenation, indicating that the effects of hypoxia were not immediately alleviated during reoxygenation. The expressions of PGM2, PFKA, GAPDH, and PK were increased in the RRG, which suggests that glycolysis was enhanced. The same pattern was not observed in the GRG. Additionally, In the RRG, reoxygenation may promote glycolysis to guarantee energy supply. However, the GRG may through the lipid metabolism such as steroid biosynthesis at the later stage of reoxygenation. In the aspect of apoptosis, differentially expressed genes (DEGs) in the RRG were enriched in the p53 signaling pathway, which promoted cell apoptosis, while DEGs in the GRG seem to activate cell apoptosis at early stage of reoxygenation but was restrained latterly. DEGs in both the RRG and the GRG were enriched in the NF-kappa B and JAK-STAT signaling pathways, the RRG may induce cell survival by regulating the expression of IL-12B, COX2, and Bcl-XL, while in the GRG it may induce by regulating the expression of IL-8. Moreover, DEGs in the RRG were also enriched in the Toll-like receptor signaling pathway. This research revealed that at different velocity of reoxygenation after hypoxic stress, T. blochii would represent different metabolic, apoptotic and immune strategies, and this conclusion would provide new insight into the response to hypoxia and reoxygenation in teleosts.

CYP27A1 inhibits proliferation and migration of clear cell renal cell carcinoma via activation of LXRs/ABCA1.

Cholesterol homeostasis plays an important role in the maintenance of normal body functions. CYP27A1 is a key enzyme known to regulate cholesterol homeostasis, which catalyzes the conversion of cholesterol to 27-HC and has been implicated in the occurrence and metastasis of various cancer types. The present study aimed to explore the regulatory role of CYP27A1 in the development of clear cell renal cell carcinoma (ccRCC). In particular, the effect of CYP27A1 on the proliferation and migration of ccRCC cells was investigated. The construction of a stable 786-O cell line overexpressing CYP27A1/pLVX was mediated by lentiviral infection. The proliferative capacity was assessed using MTT and colony formation. Wound healing assay was used to measure cell migration. Production of intracellular cholesterol and 27-HC was detected by enzyme-linked immunosorbent assay. The LXRs/ABCA1 pathway of cholesterol metabolism regulation was studied by RT-qPCR and Western blotting analysis after cells were treated with stimulation agents of 27-HC or T0901317 and inhibition agents of siRNA or GSK2033. The results revealed that overexpression of CYP27A1 could increase the intracellular production of 27-HC and inhibit the proliferation and migration of 786-O cells. And the treatment of 786-O cells with 27-HC induced a similar effect. CYP27A1/27HC mediated activation of the liver X receptors (LXRs) could up-regulate the expression of ATP-binding cassette transporter A1 (ABCA1), further resulting in the reduction of intracellular cholesterol contents. All of these findings indicated a regulatory role of CYP27A1 in the proliferation and migration of ccRCC, via activating LXRs/ABCA1 to regulate cholesterol homeostasis.

Dinoflagellate Karenia mikimotoi on the growth performance, antioxidative responses, and physiological activities of the rotifer Brachionus plicatilis.

The harmful dinoflagellate Karenia mikimotoi is responsible for the mortality of aquatic animals. However, the mechanism behind these toxic effects has not been fully determined. Herein, the toxic effects of K. mikimotoi on the growth performance, antioxidative responses, physiological activities, and energetic substance contents of rotifer Brachionus plicatilis were assessed. Rotifers were exposed to Nannochloropsis salina (Eustigmatophyceae), K. mikimotoi, and a mixture of N. salina and K. mikimotoi with biomass ratio proportions of 3:1, 1:1, and 1:3, respectively. Results indicated that K. mikimotoi negatively affected the population growth, survival, and specific growth rates of rotifers within 24 h. The level of reactive oxygen species (ROS), the content of malondialdehyde, and the activity of amylase increased. However, the total antioxidant capacity level, pepsase, cellulase, alkaline phosphatase, xanthine oxidase, and lactate dehydrogenase activities, and glycogen and protein contents decreased with increasing proportions of K. mikimotoi. The mixture of 50% N. salina and 50% K. mikimotoi promoted the increase in glutamic-pyruvic transaminase activity and triglyceride content. These findings underscore ROS-mediated antioxidative responses, physiological responses, and energetic substance content changes in B. plicatilis work together to affect population dynamics inhibition of rotifers by K. mikimotoi.

Comparison of the efficacy and safety of total laparoscopic hysterectomy without and with uterine manipulator combined with pelvic lymphadenectomy for early cervical cancer.

OBJECTIVE: Some studies have reported that the prognosis of total laparoscopic hysterectomy (TLH) for early-stage cervical cancer (CC) is worse than that of open surgery. And this was associated with the use of uterine manipulator or not. Therefore, this study retrospectively analyzes the efficacy and safety of TLH without uterine manipulator combined with pelvic lymphadenectomy for early-stage CC. METHODS: Fifty-eight patients with CC (stage IB1-IIA1) who received radical hysterectomy from September 2019 to January 2020 were divided into no uterine manipulator (n = 26) and uterine manipulator group (n = 32). Then, clinical characteristics were collected and intraoperative/postoperative related indicators were compared. RESULTS: Patients in the no uterine manipulator group had significantly higher operation time and blood loss than in the uterine manipulator group. Notably, there was no significant difference in hemoglobin change, blood transfusion rate, number of pelvic nodules, anal exhaust time, complications and recurrence rate between the two groups. Additionally, patients in the uterine manipulator group were prone to urinary retention (15.6%) and lymphocyst (12.5%), while the no uterine manipulator group exhibited high probability of bladder dysfunction (23.1%) and urinary retention (15.4%). Furthermore, the 1-year disease-free survival rate and the 1-year overall survival rate were not significantly different between the two groups. CONCLUSION: There was no significant difference in the efficacy and safety of TLH with or without uterine manipulator combined with pelvic lymphadenectomy in the treatment of patients with early-stage CC. However, the latter requires consideration of the negative effects of high operation time and blood loss.

Vaginal microecological changes of different degrees of cervical lesions in Hakka women in Meizhou City.

Research shows an association between vaginal microbiota and the development of cervical cancer, but the role of altered microbiota in cancer development remains controversial. In this study, we attempted to reveal the vaginal microecological changes in cervical lesions by 16S rRNA gene sequencing. Vaginal secretions were collected from Hakka women in Meizhou City, Guangdong Province, China. The diversity, composition and the correlations among species of the vaginal microbiota were determined by sequencing the bacterial 16S rRNA gene. The microbial functional abundance was detected via KEGG and COG (Clusters of Orthologous Groups). The results showed that the Cancer group was characterised by evident changes in the composition of the vaginal microbiota, increased alpha diversity, and altered community structure distribution and microbial interaction network. Linear discriminant analysis (LDA) effect size showed that 21 bacterial species were abundant in the Cancer group. In addition, the loss of Lactobacillus stimulated other flora proliferation, resulting in a microecological disturbance. KEGG and COG analysis indicated the cancer group is mainly concentrated in energy metabolism. In short, the vaginal microecology of Hakka women in Meizhou City presents with different degrees of cervical lesions, and the flora imbalance is an important factor in the development of cervical cancer.IMPACT STATEMENTWhat is already known on this subject? Cervical cancer is one of the most common gynecological malignancies worldwide and has become a prominent public health problem.What the results of this study add? Our study showed that the type of vaginal community status of Hakka women in Meizhou area was characterised by L. Iners predominates, and the gradual loss of Lactobacillus dominance in vaginal bacteria is key to microecological imbalance.What the implications are of these findings for clinical practice and/or further research? Disturbances in vaginal microecology can stimulate energy metabolism and lipid metabolism to induce cervical cancer development.

TP73-AS1 as a predictor of clinicopathological parameters and prognosis in human malignancies: a meta and bioinformatics analysis.

BACKGROUND: Long non-coding RNA P73 antisense RNA 1 T (non-protein coding), also known as Lnc RNA TP73-AS1, is dysregulated in various tumors but the correlation between its expression and clinicopathological parameters and/or prognoses in cancer patients is inconclusive. Here, we performed a meta-analysis to evaluate the prognostic value of Lnc RNA TP73-AS1 for malignancies. METHODS: We systematically searched four online databases including PubMed, the Web of Science, Embase, and the Cochrane Library for eligible articles published up to June 29/2020. Odds ratios (ORs) and Pooled hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used to assess the association of TP73-AS1 expression with prognostic and clinicopathological parameters. We further validated TP73-AS1 expression in various malignancies and its potential prognostic value using the GEPIA online database. We predicted potential biological processes and relevant signal mechanisms through the public databases. RESULTS: A total of 26 studies examining 14 cancers were analyzed to evaluate the relationship between TP73-AS1 expression, clinicopathological features and prognostic indicators. The results indicated that TP73-AS1 expression markedly correlates with TNM stage (OR = 3.27,95% CI:2.43-4.39, P < 0.00001), tumor size (OR = 3.00, 95%CI:2.08-4.35, P < 0.00001), lymph node metastasis (OR = 2.77, 95%CI:1.42-5.38,P < 0.00001) and distant metastasis (OR = 4.50,95%CI:2. 62-7.73,P < 0.00001). No correlation with age (OR = 1.12,95%CI:0.77-1.64, P > 0.05), gender (OR = 1.08, 95%CI:0.84-1.38, P > 0.05) or differentiation (OR = 1.39, 95%CI:0.71-2.70, P = 0.340) was observed. TP73-AS1 overexpression was a biomarker of poor Overall survival(OS)(HR = 1.85,95%CI:1.53-2.22, P < 0.00001) and Disease-Free-Survival (DFS) (HR = 1.57,95%CI:1.03-2.42, P < 0.05). Dysregulated TP73-AS1 expression and its prognostic value in various cancers was validated based on The Cancer Genome Atlas (TCGA). Further biological function predictions indicated that TP73-AS1 was involved in pro-oncogenic signaling. CONCLUSIONS: The upregulation of Lnc RNA TP73-AS1 was related to detrimental clinicopathological parameters and can be considered an indicator of poor prognosis for cancer malignancies.

Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment.

Metabolic reprogramming and immune escape play a major role in tumorigenesis. Increasing number of studies have shown that reprogramming of glutamine metabolism is a putative determinant of the anti-tumor immune response in the tumor microenvironment (TME). Usually, the predatory uptake of glutamine by tumor cells in the TME results in the limited utilization of glutamine by immune cells and affects the anti-tumor immune response. The cell-programmed glutamine partitioning also affects the anti-tumor immune response. However, the reprogramming of glutamine metabolism in tumors modulates immune escape by regulating tumor PD-L1 expression. Likewise, the reprogramming of glutamine metabolism in the immune cells also affects their immune function. Additionally, different types of glutamine metabolism inhibitors extensively regulate the immune cells in the TME while suppressing tumor cell proliferation. Herein, we discuss how metabolic reprogramming of tumor and immune cells regulates anti-tumor immune responses, as well as functional changes in different immune cells in the context of targeting tumor glutamine metabolism, which can better explain the potential of targeting glutamine metabolism in combination with immunotherapy for cancer. Video abstract.

Degradation of long-chain n-alkanes by a novel thermal-tolerant Rhodococcus strain.

A novel bacterial strain, CH91, was isolated from a high-temperature oil reservoir. Morphological characterization, phylogenetic analyses of 16S rRNA gene sequence and genome relatedness indicated that the strain is a potential new species in the genus Rhodococcus. Strain CH91 could grow in the temperature range of 25-50 °C (optimally at 37 °C) and utilize a broad range of long-chain n-alkanes from hexadecane to hexatriacontane. The utilization of the n-alkanes mixture of strain CH91 revealed that the degradation rate was correlated to the length of the carbon chain. Two novel alkB genes encoding alkane 1-monooxygenase were found in the genome of this strain. The protein sequences of both alkane 1-monooxygenases showed a remarkable phylogenetic distance to other reported AlkB protein sequences. These results would help broaden our knowledge about alkane degradation by Rhodocuccus and its potential ecological role. The ability of the strain in the long-chain alkane degradation and thermal tolerance could also be further exploited for bioremediation of oil contaminations and microbial enhanced oil recovery.

Development and Validation of a Nomogram for Predicting Postoperative Distant Metastasis in Patients with Cervical Cancer.

BACKGROUND Cervical cancer is the fourth most commonly diagnosed malignant neoplasm among women worldwide. Despite improvements in treatment, the rate of postoperative metastasis remains a problem. Nomograms have been used to predict risk of tumor metastasis. We designed a nomogram to predict postoperative distant metastasis among cervical cancer patients, based on the SEER database, and estimated the performance of the nomogram by internal and external validations. MATERIAL AND METHODS We included 6421 participants and divided them into training (n=4495) and testing (n=1926) sets. Multivariate logistic regression was used to explore predictors. The nomogram's predictive value was assessed by internal (testing set) and external (561 Chinese patients) validations. The receiver operating characteristic curve (ROC) was plotted, and the area under the curve (AUC) value was calculated to evaluate the nomogram's discrimination. The nomogram's calibration was assessed via the Hosmer-Lemeshow test and calibration curve. RESULTS Histologic type, T stage, treatment, tumor size, and positive lymph node were identified as independent predictors of postoperative distant metastasis in surgical patients (P<0.05). The developed nomogram had an AUC of 0.866 (95% CI: 0.844 to 0.888). The AUC and the chi-square for the Hosmer-Lemeshow test of the nomogram were 0.847 (95% CI: 0.807 to 0.888) and 11.292, respectively, (P>0.05) in the internal validation, and were 0.626 (95% CI: 0.548 to 0.704) and 316.53, respectively, (P<0.05) in the external validation. CONCLUSIONS Our nomogram showed a good predictive performance for postoperative distant metastasis in cervical cancer patients based on the SEER database. It remains to be determined if it is applicable to other populations.

Cannabinoid receptor 2 plays a central role in renal tubular mitochondrial dysfunction and kidney ageing.

Kidney is one of the most important organs in maintaining the normal life activities. With the high abundance of mitochondria, renal tubular cell plays the vital role in functioning in the reabsorption and secretion of kidney. Reports have shown that mitochondrial dysfunction is of great importance to renal tubular cell senescence and subsequent kidney ageing. However, the underlying mechanisms are not elucidated. Cannabinoid receptor 2 is one of the two receptors responsible for the activation of endocannabinoid system. CB2 is primarily upregulated in renal tubular cells in chronic kidney diseases and mediates fibrogenesis. However, the role of CB2 in tubular mitochondrial dysfunction and kidney ageing has not been clarified. In this study, we found that CB2 was upregulated in kidneys in 24-month-old mice and d-galactose (d-gal)-induced accelerated ageing mice, accompanied by the decrease in mitochondrial mass. Furthermore, gene deletion of CB2 in d-gal-treated mice could greatly inhibit the activation of ß-catenin signalling and restore the mitochondrial integrity and Adenosine triphosphate (ATP) production. In CB2 knockout mice, renal tubular cell senescence and kidney fibrosis were also significantly inhibited. CB2 overexpression or activation by the agonist AM1241 could sufficiently induce the decrease in PGC-1α and a variety of mitochondria-related proteins and trigger cellular senescence in cultured human renal proximal tubular cells. CB2-activated mitochondrial dysfunction and cellular senescence could be blocked by ICG-001, a blocker for ß-catenin signalling. These results show CB2 plays a central role in renal tubular mitochondrial dysfunction and kidney ageing. The intrinsic mechanism may be related to its activation in ß-catenin signalling.

Identification of NTRK3 as a potential prognostic biomarker associated with tumor mutation burden and immune infiltration in bladder cancer.

BACKGROUND: Bladder cancer (BLCA) is a common malignant tumor of urinary system with high morbidity and mortality. In recent years, immunotherapy has played a significant role in the treatment of BLCA. Tumor mutation burden (TMB) has been reported to be a powerful biomarker for predicting tumor prognosis and efficacy of immunotherapy. Our study aimed to explore the relationship between TMB, prognosis and immune infiltration to identify the key genes in BLCA. METHODS: Clinical information, somatic mutation and gene expression data of BLCA patients were downloaded from The Cancer Genome Atlas (TCGA) database. Patients were divided into high and low TMB groups according to their calculated TMB scores. Gene Set Enrichment Analysis (GSEA) was performed to screen for significantly enriched pathways. Differentially expressed genes (DEGs) between the two groups were identified. Univariate Cox analysis and Kaplan-Meier survival analysis were applied for screening key genes. Immune infiltration was performed for TMB groups and NTRK3. RESULTS: Higher TMB scores were related with poor survival in BLCA. After filtering, 36 DEGs were identified. NTRK3 had the highest hazard ratio and significant prognostic value. Co-expressed genes of NTRK3 were mainly involved in several pathways, including DNA replication, basal transcription factors, complement and coagulation cascades, and ribosome biogenesis in eukaryotes. There was a significant correlation among TMB scores, NTRK3 expression and immune infiltration. CONCLUSIONS: Our results suggest that NTRK3 is a TMB-related prognostic biomarker, which lays the foundation for further research on the immunomodulatory effect of NTRK3 in BLCA.