Hyperactivation of mTOR/eIF4E Signaling Pathway Promotes the Production of Tryptophan-To-Phenylalanine Substitutants in EBV-Positive Gastric Cancer.

Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon-γ (IFN-γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine-2,3-dioxygenase (IDO)- kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan-to-phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV-positive GC continuously secreted IFN-γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV-positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV-positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti-tumor immunotherapy.

Complete mitochondrial genome of Devario shanensis (Cypriniformes: Danionidae: Danioninae): genome characterization and phylogenetic consideration.

In this study, a comprehensive analysis is presented on the complete mitochondrial genome and phylogenetic relationships of Devario shanensis, an endemic species to the Irrawaddy drainage in southwestern China. The complete mitogenome sequence of D. shanensis was sequenced to be 16,860 bp long and encompassed 13 protein-coding genes, 22 tRNA genes, two rRNA genes and a non-coding control region. The overall AT content (61.1%) was much higher than GC content (38.9%). Phylogenetic analyses employing maximum-likelihood and Bayesian inference methods on the complete mitogenomes, including D. shanensis and 13 other species, unveiled a close genomic relationship between D. shanensis and Devario interruptus. This work will contribute to the genetic resource enrichment and phylogenetic researches on genus Devario.

The residues and health risk assessment of polychlorinated biphenyls (PCBs) in Pheretima (an earthworm-derived traditional medicine) from southeastern China.

Minimal research exists on polychlorinated biphenyl (PCB) exposure from traditional Chinese medicines (TCMs), despite their significant contributions to domestic and international health protection. This study is the first to investigate the levels, profiles, and health risks of PCB residue in Pheretima, a typical TCM produced from earthworm. Seventy-seven Pheretima samples from different regions of China were analyzed for 45 PCB congeners. PCBs were found in all samples exhibiting species-dependent discrepancies. ∑45PCBs was ranging from 0.532 to 25.2 µg/kg (mean 4.46 µg/kg), with CB-11 being the most abundant congener contributing 71.8% ± 10.8% to ∑45PCBs, followed by CB-47, which were all non-Aroclor congeners called unintentionally produced PCBs (UP-PCBs). The average estimated daily intake of ∑45PCBs, ∑7ID-PCBs (indicative polychlorinated biphenyls), and CB-11 were 0.71, 0.04, and 0.51 ng/kg bw/d, respectively. The ∑HQ of PCBs in Pheretima samples was 2.97 × 10-4-2.46 × 10-2 (mean 2.77 × 10-3, 95th 4.21 × 10-3), while the ∑RQ ranged from 1.19 × 10-8 to 2.88 × 10-6 (mean 4.87 × 10-7, 95th 2.31 × 10-6). These findings indicate that Pheretima ingestion does not pose significant non-carcinogenic risks. However, certain individual samples exhibit an acceptable level of potential risks, particularly when considering that PCBs are recognized as endocrine disruptors and classified as probable carcinogens. These results contribute to the safety evaluation of traditional medicines and suggest the potential use of Pheretima as a bioindicator for PCB pollution. It is advisable to monitor UP-PCBs as indicator congeners and gather additional toxicological data.

Complete mitochondrial genome of Eonemachilus longidorsalis (Cypriniformes: Nemacheilidae): genome characterization and phylogenetic consideration.

For the first time, this study presents the complete mitochondrial genome and phylogenetic analysis of Eonemachilus longidorsalis, an endemic species in southwest China. The mitogenome is a circular molecule of 16,569 bp in length with a base composition of 30.2% A, 27.3% T, 16.6% G, and 25.9% C. The phylogenetic analysis based on the complete mitogenomes shows that E. Longidorsalis clusters with Yunnanilus jiuchiensis, Yunnanilus pleurotaenia and Eonemachilus niger. This contribution may provide a valuable framework for completely resolving phylogenetic relationships of the family Nemacheilidae in future research.

Prognostic Significance of PD-L1 Expression in Gastric Cancer Patients with Peritoneal Metastasis.

BACKGROUND: Recently, many studies have explored the relationship between the expression of programmed death ligand 1 (PD-L1) and prognosis in gastric cancer, but there is still controversy. Additionally, few studies have specifically investigated the expression of PD-L1 in patients with peritoneal metastasis. METHODS: Immunohistochemistry was used to analyze the expression of PD-L1 in gastric cancer patients with peritoneal metastasis. The combined positive score (CPS) was calculated to evaluate the expression of PD-L1, and the clinicopathological data were analyzed to explore prognostic significance. RESULTS: In total, 147 gastric cancer patients with peritoneal metastasis were enrolled. The negative PD-L1 expression was defined as a CPS < 1, and high PD-L1 expression was defined as a CPS ≥ 10. PD-L1 expression with CPS ≥ 1 and CPS-negative was detected in 67 (45.58%) and 80 (54.42%) patients, respectively. High PD-L1 expression at PD-L1 CPS ≥ 10 was detected in 21(14.29%) patients. The median overall survival (OS) was 18.53 months in the CPS < 10 group and 27.00 months in the CPS ≥ 10 group; the OS difference between the two groups was significant (p = 0.015). Multivariate analysis demonstrated that a poor Eastern Cooperative Oncology Group performance score (ECOG PS) (p = 0.002) and severe peritoneal metastasis (p = 0.033) were significantly associated with poor survival, while palliative chemotherapy (p = 0.002) and high PD-L1 expression (p = 0.008) were independent and significantly favorable prognostic factors. CONCLUSIONS: Our study demonstrated that PD-L1 expression was widely presented in gastric cancer patients with peritoneal metastasis, while a CPS no less than 10 predicted better prognosis.

Complete mitochondrial genome sequence and annotation of Rhinogobius lentiginis (Gobiiformes: Gobiidae: Gobionellinae).

We report the complete mitochondrial genome of Rhinogobius lentiginis, which was found to be a circular molecule of 16,633 bp in length and included 13 protein-coding genes (PCGs), 2 rRNA genes, 22 tRNA genes, and a non-coding control region. The overall base composition was 28.44% A, 26.21% T, 16.33% G, and 29.02% C. Phylogenetic analyses using maximum-likelihood and Bayesian inference methods revealed a close genome relationship among R. lentiginis, R. niger, R. shennongensis and R. maculagenys. The complete mitogenome of R. lentiginis will provide a valuable resource for species classification and conservation.

First complete mitochondrial genome of the endemic goby, Rhinogobius davidi (Gobiiformes: Gobiidae: Gobionellinae), in China.

The first complete mitochondrial genome of the freshwater goby Rhinogobius davidi was determined by high-throughput sequencing. This genome was 16,627 bp in length and consisted of 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 2 non-coding control regions. Phylogenetic analysis based on the amino acid sequences of 13 mitochondrial protein-coding genes from R. davidi and 23 relatives suggested that R. davidi had a close mitogenome relationship with Rhinogobius giurinus. This complete genome of R. davidi will provide basal molecular data for future studies on taxonomy, comparative genomics, and adaptive evolution in Rhinogobius.

The complete mitochondrial genome of Rhinogobius szechuanensis (Gobiiformes: Ggobiidae: Gobionellinae).

Here, we sequenced the complete mitogenome of Rhinogobius szechuanensis using the Illumina HiSeq platform and submitted the genome to Genbank with accession number OM617727. Assembly circular mitogenome (16,492 bp) consisted of 54.4% AT content, 13 protein-coding genes, 22 tRNA genes, two rRNA genes, an origin of light-strand replication, and a control region. Phylogenetic analysis supported that R. szechuanensis was grouped with R. rubromaculatus and clustered with other Rhinogobius species. The basal molecular data will be essential for further genetics studies such as evolution, taxonomy, DNA barcoding, and population genetics of Rhinogobius.

Assembly and phylogenetic analysis of the complete mitogenome of Devario interruptus (Teleostei, Cypriniformes, Danionidae).

The complete mitochondrial DNA genome of Devario interruptus was sequenced on the Illumina HiSeq platform and found to be 16,735 bp and included 37 genes encoding 13 proteins, 22 tRNAs, two rRNAs, and two non-coding regions. The proportion of nucleotides in mitochondrial genome was T (27.9%), C (23.7%), A (33%), G (15.4%), and the deviation of AT was 60.9%. A Maximum-Likelihood phylogenetic tree was reconstructed using the concatenated mitochondrial protein-coding genes of D. interruptus and other 18 species of fishes. Phylogenetic analysis results supported that D. interruptus was closely related to Devario shanensis. Fundamental genetic data of D. interruptus will be essential for further genetic studies.

Adjuvant Chemotherapy for Patients with Adenocarcinoma of the Esophagogastric Junction: A Retrospective, Multicenter, Observational Study.

BACKGROUND: Although the incidence of adenocarcinoma of the esophagogastric junction (AEG) has been increasing since the past decade, the proportion of AEG cases in two previous clinical trials (ACTS-GC and CLASSIC) that investigated the efficacy of adjuvant chemotherapy was relatively small. Therefore, whether AEG patients can benefit from adjuvant chemotherapy remains unclear. METHODS: Patients who were diagnosed with pathological stage II/III, Siewert II/III AEG, and underwent curative surgery at three high-volume institutions were assessed. Clinical outcomes were analyzed by using Kaplan-Meier curves, log-rank test, and Cox regression model. Propensity score matching (PSM) was used to reduce the selection bias. RESULTS: A total of 927 patients were included (the chemotherapy group: 696 patients; the surgery-only group: 231 patients). The median follow-up was 39.0 months. The 5-year overall survival was 63.1% (95% confidence interval [CI]: 59.0-67.6%) for the chemotherapy group and 50.2% in the surgery-only group (hazard ratio [HR] = 0.69, 95% CI: 0.54-0.88; p = 0.003). The 5-year, disease-free survival was 35.4% for the chemotherapy group and 16.6% for the surgery-only group (HR = 0.66, 95% CI: 0.53-0.83; p < 0.001). After PSM, the survival benefit of adjuvant chemotherapy for AEG was maintained. Multivariate analysis for overall survival and disease-free survival further demonstrated the survival benefit of adjuvant chemotherapy, with HRs of 0.63 (p < 0.001) and 0.52 (p < 0.001), respectively. CONCLUSIONS: Postoperative adjuvant chemotherapy was associated with improved overall survival and disease-free survival in patients with operable stage II or III AEG after D2 gastrectomy.

Phylogenetic relationship and characterization of the complete mitochondrial genome sequence of Opsarius caudiocellatus (Cypriniformes: Danionidae: Chedrinae).

In this paper, we first report the complete mtDNA sequence of Opsarius caudiocellatus with the main aim of providing a basis for further researches of this species. Assembly circular mitogenome was 16,534 bp long encoded 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and one control region. The gene nucleotide composition was estimated to be 28.1% A, 25.2% T, 18.6% G, 28.1% C. A maximum-likelihood (ML) phylogenetic tree was reconstructed using the 13 concatenated mitochondrial protein-coding genes of O. caudiocellatus and other 19 species of the subfamily Chedrinae. Result of the phylogenetic analysis revealed that O. caudiocellatus was well grouped with Barilius barila. This study could enrich genetic resources and be helpful to studies on evolution and conservation genetics for O. caudiocellatus.

Determination and analysis of the complete mitochondrial genome of Barilius barila (Cypriniformes: Danionidae: Chedrinae).

Cyprinid fish Barilius barila found in the Irrawaddy water system is a valuable fishery resource and has been listed as Least Concern by the IUCN. This study determined the complete mitochondrial genome of B. barila from Yunnan, China, for the first time. Circular molecule of B. barila mitogenome was sequenced to be 16,560 bp in length, with the typical gene structure of 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and two noncoding areas (control region and the origin of L-strand replication). Overall nucleotides composition appeared to be 27.5% A, 24.8% T, 19.2% G, and 28.6% C, with a slight AT (52.3%) bias. The topology of the phylogenetic tree showed that B. barila was well grouped with Opsarius caudiocellatus, and clustered together with the genus Opsarius instead of Barilius, revealing that it was more reasonable for Barilius barila to belong to Opsarius rather than Barilius.

Characteristic and phylogenetic analyses of mitochondrial genome for Rhinogobius filamentosus (Teleostei: Gobiidae: Gobionellinae), an endemic species in China.

This study sequenced and annotated the complete mitochondrial genome sequence of Rhinogobius filamentosus, an endemic species in China. The complete mitochondrial genome was 16,510 base pairs long and contained 13 protein-coding genes (PCGs, 11,414 bp), 22 tRNA genes (1,555 bp), two rRNA genes (2,615 bp), two non-coding regions (D-loop: control region displacement loop, 478 bp; OL: origin of L-strand replication, 30 bp). The overall base composition of the genome was estimated to be T (25.4%), C (30.2%), A (27.6%) and G (16.7%), showing an AT bias (53%). Phylogenetic analyses revealed that the genus Rhinogobius included two clades. For one clade, R. filamentosus clustered with R. duospilus, and they formed a sister-group relationship with other ten Rhinogobius species. This work would be essential in revealing the evolutionary relationships in Gobionellinae.

LAG3-PD1 or CTLA4-PD1 Inhibition in Advanced Melanoma: Indirect Cross Comparisons of the CheckMate-067 and RELATIVITY-047 Trials.

Objective: To compare the inhibition of LAG3-PD1 versus the inhibition of CTLA-4-PD1 in patients with previously untreated advanced melanoma. Methods: The individual participant data (IPD) were extracted from the KM plots using a graphical reconstructive algorithm. Log-rank, Cox proportional hazard model, Bayesian hierarchical model with time-varying hazard ratio (HR) effect, and restricted mean survival time (RMST) were performed to estimate survival benefits. Results: The CheckMate-067 (n = 630) and RELATIVITY-047 (n = 714) trials were included for analysis. The graphical reconstructive algorithm showed that IPD had similar HRs and log-rank values as the original plots. The HR of nivolumab plus relatlimab (LAG3 inhibitor) versus nivolumab plus ipilimumab (CTLA4 inhibitor) was 1.19 (95% confidence interval [CI] 0.96 to1.48). The 24-months RMST of nivolumab plus relatlimab versus nivolumab was 2.35 (95% CI 0.77-3.94) months, compared with 1.87 (95% CI, 0.25-3.49) months for nivolumab plus ipilimumab versus nivolumab. The Bayesian hierarchical model showed that patients treated with nivolumab plus relatlimab had earlier PFS benefits than those with nivolumab plus ipilimumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients using nivolumab plus relatlimab and 55.0% of patients using nivolumab plus ipilimumab. Conclusions: These findings suggest that the PFS of LAG3-PD1 and CTLA4-PD1 inhibition were similar and LAG3-PD1 inhibition exhibited earlier survival benefit and lesser TRAEs.

Complete mitochondrial genome of Devario kakhienensis (Cypriniformes: Danionidae: Danioninae): genome characterization and phylogenetic consideration.

Complete mitochondrial genome and phylogenetic analysis of Devario kakhienensis, endemic minnow from southwest China, for the first time was presented. It was determined to be a 16,777 bp long circular molecule and the genome organization was consistent with that of Danioninae species published previously. Based on PCGs, the maximum likelihood phylogenetic analysis supported the close genetic relationship between D. kakhienensis and Devario interruptus. These data would contribute toward the genetic resource enrichment, and provide a valuable framework for future research in completely resolving phylogenetic relationships with the family Danionidae.

The complete mitochondrial genome of the freshwater fish Traccatichthys pulcher (Cypriniformes: Nemacheilidae) from China.

This study aimed to sequence and annotate the complete mitochondrial DNA genome sequence of Traccatichthys pulcher. The mitochondrial genome comprised 16,583 bp, harboring 13 protein-coding genes (PCGs), 22 tRNA genes, two rRNA genes, and a control region. The whole genome contained T (25.8%), C (26.9%), A (31.4%), and G (15.9%), showing an obvious AT bias (57.2%). Based on the concatenated protein sequences of 13 PCGs, a phylogenetic tree was reconstructed by the maximum likelihood method, and the topology revealed the monophyly of Traccatichthys, and the gathering of T. pulcher and M. pulcher. The mitochondrial DNA of T. pulcher (MZ853162.1) and M. pulcher (NC_031581.1) were aligned by the BLAST 2 sequences tool, which showed 97% similarity.

Characterization and phylogenetic analysis of the complete mitochondrial genome of Rhinogobius wuyanlingensis (Gobiiformes: Gobiidae: Gobionellinae).

Rhinogobius wuyanlingensis is endemic to the upper reaches of Feiyunjiang river basin. In this article, the complete mitochondrial genome (mtDNA) for this freshwater goby was first determined. Sequence analysis showed the genome consisted of 13 protein-coding genes, 22 tRNA genes, two ribosomal RNA genes, and two main non-coding regions (the control region and the origin of the light strand replication). This circular molecule was 16,491 bp in length with a slight AT bias of 53.5%. In the phylogenetic tree, R. wuyanlingensis was closer to Rhinogobius brunneus, Rhinogobius yonezawai, Rhinogobius flumineus, and Rhinogobius cliffordpopei. The mitochondrial genome of R. wuyanlingensis reported here would provide basal molecular data for evolution, taxonomy, and population genetics of Rhinogobius.

Complete mitochondrial genome and phylogenetic analysis of Mystacoleucus lepturus (Teleostei, Cypriniformes, Cyprinidae).

In this study, we aimed to sequence and annotate the complete mtDNA genome sequence of Mystacoleucus lepturus, which were collected from Luosuojiang River in Menglun area, Yunnan Province, China. The mitochondrial genome was 16,592 bp in length, comprising 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNAs), and two non-coding regions (origin of L-strand replication and control region). The whole genome contained C (26.5%), A (32.5%), T (25.3%), and G (15.7%), with an obvious A + T bias (57.8%). Based on the concatenated amino acids sequences of 13 PCGs of M. lepturus and other 22 fishes, a phylogenetic tree was reconstructed using the maximum-likelihood method. The result of phylogenetic analysis supported a close relationship between M. lepturus and M. marginatus. The fundamental genetic data of M. lepturus would be useful for conservation and phylogeny.

Characterization of the complete mitochondrial genome and phylogenetic analysis of Opsarius pulchellus (Cypriniformes, Danionidae, Chedrinae).

This study aimed to sequence and annotate the complete mitochondrial DNA genome sequence of Opsarius pulchellus. Complete mitochondrial genome is a circular molecule of 16,552 bp in length, including 13 protein-coding genes (PCGs), 22 tRNA genes, two rRNA genes, and a displacement loop region. Proportion of nucleotides in mitochondrial genome is 26.8% T, 26.9% C, 27.6% A, and 18.8% G, with an AT bias of 54.4%. Maximum-likelihood phylogenetic tree was reconstructed using the connected protein sequences of 13 PCGs of O. pulchellus and other 18 fishes. Result of phylogenetic analysis supports a close relationship between O. pulchellus and Barilius bendelisis (Hamilton, 1807). Fundamental genetic data of O. pulchellus would be beneficial for further studies on genetic diversity and phylogeny.