Anti-PD-1 plus anti-angiogenesis combined with chemotherapy in patients with HER2-negative advanced or metastatic gastric cancer: a multi-institutional retrospective study.

Background: Immunotherapy plus chemotherapy have been confirmed to be effective in treating advanced or metastatic gastric cancer (GC). Anti- programmed death-1 (PD-1) plus antiangiogenic agents have shown promising activity and tolerant toxicity in subsequent therapy of late-stage gastric cancer. The aim of this study was to assess the efficacy and safety of anti-PD-1 plus anti-angiogenic agents and chemotherapy in advanced or metastatic GC and to explore the potential biomarkers associated with response. Methods: We retrospectively reviewed thirty human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic GC patients who received PD-1 plus anti-angiogenic drugs and chemotherapy. Conversion therapy was defined when the patients could undergo resection post combination therapy. Clinical data were retrieved from medical records. We conducted exploratory biomarker analysis of baseline gene mutations and tumor mutation burden (TMB) using the next-generation sequencing (NGS), PD-L1 by immunohistochemistry (IHC), and the tumor immune microenvironment (TIME) by multiplex immunofluorescence. Results: A total of 30 patients received anti-PD-1plus anti-angiogenic drugs and chemotherapy during the study period. The objective response rate (ORR) was 76.7% [95% confidence interval (CI): 57.7-90.1%] and disease control rate (DCR) was 86.7% (95% CI: 69.3-96.2%). A total of 11 patients (36.7%) achieved conversion therapy and underwent surgery. The R0 resection rate was 90.9%. Of the 11 patients, 9 (81.8%) responded to the treatment, 1 with a pathological complete response (pCR) and 8 with a major pathological response (MPR). No adverse events of grade 3 or higher occurred. Neither PD-L1 expression nor TMB was significantly correlated with treatment response. Analysis of TIME revealed that the fraction of CD8+ T cell in the invasive margin was higher in responders than non-responders before treatment. TAM2 in the tumor center and CD8+ T cell in the invasive margin was significantly increased after combination therapy, which suggested that combination therapy promoted infiltration of CD8+ T cells, thereby exerting an antitumor effect. Conclusions: Immunotherapy plus anti-angiogenic drugs and chemotherapy is a promising treatment strategy for advanced or metastatic GC patients. Tumor infiltration CD8+ T cells may serve as potential predictive biomarker.

α-D-1,3-glucan from Radix Puerariae thomsonii improves NAFLD by regulating the intestinal flora and metabolites.

Radix Puerariae thomsonii, the root of the botanical family Fabaceae species Pueraria montana var. thomsonii (Benth.) MR Almeida, can be used as food or medicine. Polysaccharides are important active constituents of this root. A low molecular weight polysaccharide, RPP-2 having α-D-1,3-glucan as the main chain, was isolated and purified. RPP-2 could promote the growth of probiotics in-vitro. Therefore, the effects of RPP-2 on a high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) C57/BL6J mouse models were investigated. RPP-2 could reduce HFD-induced liver injury by reducing inflammation, glucose metabolism, and steatosis, thereby improving NAFLD. RPP-2 regulated the abundances of intestinal floral genera Flintibacter, Butyricicoccus, and Oscillibacter, and their metabolites Lipopolysaccharide (LPS), bile acids, and short-chain fatty acids (SCFAs), thereby improving inflammation, lipid metabolism, and energy metabolism signaling pathways. These results confirmed that RPP-2 play a prebiotic role by regulating intestinal flora and microbial metabolites, playing a multi-pathway and multi-target role in improving NAFLD.

Nano-Econazole Enhanced PD-L1 Checkpoint Blockade for Synergistic Antitumor Immunotherapy against Pancreatic Ductal Adenocarcinoma.

Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo-phototherapy nanoplatform is designed by which econazole and biliverdin can be co-assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD-L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin-induced PTT/PDT and boost the immunotherapeutic response of PD-L1 blockade. In addition, econazole simultaneously enhances PD-L1 expression to sensitize anti-PD-L1 therapy, leading to suppression of distant tumors, long-term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8+ T lymphocytes. The combined FBE NPs and α-PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo-phototherapy with PD-L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy.

Peroxiredoxin 1 transfer during mating protects eupyrene sperm against oxdative stress in Grapholita molesta.

BACKGROUND: Each Grapholita molesta female only copulates once during its lifetime and thus must maintain the viability of stored eupyrene sperm for male reproductive success. The male ejaculate comprises abundant accessory gland proteins produced by the male accessory gland (AG), and many of which are major effectors for sperm storage and maintenance. RESULTS: Here, we reported that an antioxidant protein, peroxiredoxin 1 (GmolPrx1), secreted by the male AG, is essential for protecting eupyrene sperm from oxidative stress and maintaining their quality during storage in the female bursa copulatrix (BC). Our data showed that GmolPrx1 is highly expressed in the AG of sexually mature males. The GmolPrx1 protein is localized to the cytoplasm of AG cells and delivered to the female BC during mating. Knockdown of GmolPrx1 strongly decreased the fertility of mated females. Additionally, we evaluated oxidative status in the spermatophore of females and found that the content of hydrogen peroxide increased significantly after mating with GmolPrx1 knockdown males. Finally, the quality assessment of eupyrene sperm demonstrated that the plasma membrane integrity, acrosome integrity, and DNA integrity were all severely impaired in the spermatophore of females after mating with GmolPrx1 knockdown males, which may contribute to the fertility decline in males. CONCLUSION: Our current data demonstrated that activities of eupyrene sperm stored in females can be significantly impaired by enhanced oxidative stress through knocking down of GmolPrx1 in males. Our finding thus may further lay new foundations for the control of G. molesta through suppressing their populations by manipulating male reproductive genes. This article is protected by copyright. All rights reserved.

Anemia in pregnancy and sleep of 6-month-old infants: A prospective cohort study.

Objective: Anemia has been reported to adversely influence sleep in infants. However, the association between anemia in pregnancy and infant sleep remains unclear. We aimed to examine the association between maternal anemia in pregnancy and sleep parameters of 6-month-old infants. Methods: We enrolled 2,410 mother-infant pairs between 2018 and 2021 in Hefei. Data on maternal hemoglobin concentration were collected at 24-28 gestational weeks from the electronic medical records of the hospitals. Nocturnal and daytime sleep duration, number of night awakenings, nocturnal wakefulness, and sleep latency of infants aged 6 months were measured using the Brief Infant Sleep Questionnaire with five items. A restricted cubic spline model was used to examine the relationship between maternal hemoglobin concentration and infant nocturnal sleep duration after adjusting for potential confounders. Results: In our study, 807 (33.5%) mothers had anemia during pregnancy. Compared to infants born to mothers without anemia, infants born to mothers with anemia in pregnancy had shorter nocturnal sleep duration [mean (SD), 560.29 (79.57) mins vs. 574.27 (75.36) mins] at the age of 6 months. Subgroup analysis showed consistent significant differences in nocturnal sleep duration between infant born to anemic and non-anemic mothers, except in case of stratification by preterm birth [mean difference (mins), 2.03 (95% CI, -20.01, -24.07)] and pre-pregnancy obesity [mean difference (mins), -0.85 (95% CI, -16.86, -15.16)]. A J-shaped nonlinear correlation curve was observed between maternal hemoglobin concentration and infant nocturnal sleep duration. Compared with mothers without daily iron supplementation, mothers who had daily iron supplementation had higher hemoglobin concentrations [mean (SD), 112.39 (11.33) g/L vs. 110.66 (10.65) g/L] at delivery and their infants had longer nocturnal sleep duration [mean (SD), 565.99 (82.46) mins vs. 553.66 (76.03) mins]. Conclusion: Anemia in pregnancy may have an adverse influence on the sleep of 6-mon-old infants, and the relationship between maternal hemoglobin concentration and nocturnal sleep duration is nonlinear.

Effects of Arbuscular Mycorrhizal Fungi on Alleviating Cadmium Stress in Medicago truncatula Gaertn.

Heavy metal contamination is a global problem for ecosystems and human health. Remediation of contaminated soils has received much attention in the last decade. Aided mitigation of heavy metal phytotoxicity by arbuscular mycorrhizal fungi (AMF) is a cost-effective and environmentally friendly strategy. This study was carried out to investigate the mitigation effect of AMF inoculation on heavy metal toxicity in Medicago truncatula under soil cadmium stress. Therefore, a pot experiment was designed to evaluate the growth, chlorophyll fluorescence, Cd uptake and distribution, malondialdehyde (MDA) content, root soil physicochemical properties, and metabolite profile analysis of M. truncatula with/without AMF inoculation in Cd (20 mg/Kg)-contaminated soil. The results showed that inoculating AMF under Cd stress might enhance photosynthetic efficiency, increase plant biomass, decrease Cd and MDA content, and improve soil physicochemical properties in M. truncatula. Non-targeted metabolite analysis revealed that inoculation with AMF under Cd stress significantly upregulated the production of various amino acids in inter-root metabolism and increase organic acid and phytohormone synthesis. This study provides information on the physiological responses of mycorrhizal plants to heavy metal stress, which could help provide deeper insight into the mechanisms of heavy metal remediation by AMF.

Associations of Lung Function Decline with Risks of Cognitive Impairment and Dementia: A Meta-Analysis and Systematic Review.

BACKGROUND: There are controversies surrounding the effects of lung function decline on cognitive impairment and dementia. OBJECTIVE: We conducted a meta-analysis and systematic review to explore the associations of lung function decline with the risks of cognitive impairment and dementia. METHODS: The PubMed, EMBASE, and the Cochrane Library were searched to identify prospective studies published from database inception through January 10, 2023. We pooled relative risk (RR) and 95% confidence intervals (CI) using random-effects models. The Egger test, funnel plots, meta-regression, sensitivity, and subgroup analyses were conducted to detect publication bias and investigate the source of heterogeneity. RESULTS: Thirty-three articles with a total of 8,816,992 participants were subjected to meta-analysis. Poorer pulmonary function was associated with an increased risk of dementia (FEV: RR = 1.25 [95% CI, 1.17-1.33]; FVC: RR = 1.40 [95% CI, 1.16-1.69]; PEF: RR = 1.84 [95% CI, 1.37-2.46]). The results of the subgroup analyses were similar to the primary results. Individuals with lung diseases had a higher combined risk of dementia and cognitive impairment (RR = 1.39 [95% CI, 1.20-1.61]). Lung disease conferred an elevated risk of cognitive impairment (RR = 1.37 [95% CI, 1.14-1.65]). The relationship between lung disease and an increased risk of dementia was only shown in total study participants (RR = 1.32 [95% CI, 1.11-1.57]), but not in the participants with Alzheimer's disease (RR = 1.39 [95% CI, 1.00-1.93]) or vascular dementia (RR = 2.11 [95% CI, 0.57-7.83]). CONCLUSION: Lung function decline was significantly associated with higher risks of cognitive impairment and dementia. These findings might provide implications for the prevention of cognitive disorders and the promotion of brain health.

Role of narrative medicine-based education in cultivating empathy in residents.

OBJECTIVE: To explore the role of narrative medicine-based education in standardized empathy training for residents. METHODS: Among the 2018-2020 residents at the First Affiliated Hospital of Xinxiang Medical University, 230 receiving neurology training were enrolled in this study and randomly divided into study and control groups. The study group received narrative medicine-based education and standardized routine resident training. The Jefferson Scale of Empathy-Medical Student version (JSE-MS) was used to evaluate empathy in the study group, and the neurological professional knowledge test scores of the two groups were also compared. RESULTS: In the study group, the empathy score was higher than the preteaching score (P < 0.01). The neurological professional knowledge examination score was higher in the study group than in the control group, albeit not significantly. CONCLUSION: The addition of narrative medicine-based education in standardized training improved empathy and may have improved the professional knowledge of neurology residents.

AZU1 (HBP/CAP37) and PRKCG (PKC-gamma) may be candidate genes affecting the severity of acute mountain sickness.

BACKGROUND: Acute Mountain Sickness (AMS) is one of the diseases that predispose to sudden ascent to high altitudes above 2500 m. Among the many studies on the occurrence and development of AMS, there are few studies on the severity of AMS. Some unidentified phenotypes or genes that determine the severity of AMS may be vital to elucidating the mechanisms of AMS. This study aims to explore the underlying genes or phenotypes associated with AMS severity and to provide evidence for a better understanding of the mechanisms of AMS. METHODS: GSE103927 dataset was downloaded from the Gene Expression Omnibus database, and a total of 19 subjects were enrolled in the study. Subjects were divided into a moderate to severe AMS (MS-AMS, 9 subjects) group and a no or mild AMS (NM-AMS, 10 subjects) group based on the Lake Louise score (LLS). Various bioinformatics analyses were used to compare the differences between the two groups. Another dataset, Real-time quantitative PCR (RT-qPCR), and another grouping method were used to validate the analysis results. RESULT: No statistically significant differences in phenotypic and clinical data existed between the MS-AMS and NM-AMS groups. Eight differential expression genes are associated with LLS, and their biological functions are related regulating of the apoptotic process and programmed cell death. The ROC curves showed that AZU1 and PRKCG had a better predictive performance for MS-AMS. AZU1 and PRKCG were significantly associated with the severity of AMS. The expression of AZU1 and PRKCG were significantly higher in the MS-AMS group compared to the NM-AMS group. The hypoxic environment promotes the expression of AZU1 and PRKCG. The results of these analyses were validated by an alternative grouping method and RT-qPCR results. AZU1 and PRKCG were enriched in the Neutrophil extracellular trap formation pathway, suggesting the importance of this pathway in influencing the severity of AMS. CONCLUSION: AZU1 and PRKCG may be key genes influencing the severity of acute mountain sickness, and can be used as good diagnostic or predictive indicators of the severity of AMS. Our study provides a new perspective to explore the molecular mechanism of AMS.

A Novel Prognostic Score Based on Multiple Quantitative Parameters of Chest CT for Patients with Synchronous Multiple Primary Lung Cancer: Is Solid Component Size a Better Prognostic Indicator?

BACKGROUND: There is no simple and definitive way to predict the prognosis of synchronous multiple primary lung cancer (SMPLC). In this study, we developed a clinical prognostic score for predicting the survival of patients with SMPLC. PATIENTS AND METHODS: This study included 206 patients with SMPLC between 2011 and 2020 at three hospitals. Kaplan-Meier analysis was used to determine the optimal cutoff values for the quantitative chest computed tomography (CT) parameters. Multivariable Cox proportional hazards regression was carried out to identify independent prognostic factors for predicting overall survival (OS) and disease-free survival (DFS). The time-dependent receiver operating characteristic curve was analyzed to evaluate the prognostic performance. RESULTS: A CT-based prognostic score (CTPS) comprising six chest CT parameters was developed. Compared with T stage, CTPS had a higher prediction accuracy for OS and DFS. All C-indices of the model reached a satisfactory level in both the development and validation cohorts. Significant differences in the OS and DFS curves were observed when the patients were stratified into different risk groups. The high-risk group (CTPS of 5-6) had poorer survival than the low-risk group (CTPS of 0-4). CONCLUSIONS: The developed CTPS and the corresponding risk stratification system are valid for predicting the survival of patients with SMPLC.

Intraocular Lens Tilt and Decentration after Cataract Surgery with and without Primary Posterior Continuous Curvilinear Capsulorrhexis.

PURPOSE: To evaluate intraocular lens (IOL) tilt and decentration and their effects on high-order aberrations (HOAs) after cataract surgery with and without primary posterior continuous curvilinear capsulorrhexis (PPCCC). SETTING: Fujian Provincial Hospital, Fujian, China. DESIGN: Prospective, intraindividual, randomized, comparative clinical trial. METHODS: This study enrolled 64 eyes of 32 patients with age-related cataract who underwent bilateral cataract surgery and IOL implantation. In randomized order, all patients had phacoemulsification cataract surgery with PPCCC in one eye (PPCCC group) and routine cataract surgery in the contralateral eye (NPCCC group). IOL decentration, tilt, HOAs, modulation transfer function, and point spread function were measured at 1 day, 1 week, 1 month, and 3 months after surgery using OPD-Scan III. RESULTS: 52 eyes of 26 patients were available for analysis. The mean overall decentration in NPCCC group was significantly higher than in PPCCC group at 3 months (0.302±0.157 mm vs 0.187±0.099 mm, P<0.001). Under 3-mm pupil, internal spherical aberration (SA) 1 day after surgery, and coma 1 week after surgery were lower in PPCCC group compared with NPCCC group (0.15±0.10 µm vs 0.30±0.21 µm, P<0.001, and 0.34±0.18 µm vs 0.47±0.31 µm, P=0.03, respectively). IOL decentration was significantly correlated with ocular and internal coma, ocular and internal SA, and internal HOAs at 5-mm pupil (R=0.083 and R=0.099, R=0.650 and R=0.613, R=0.418, respectively, all P<0.01). CONCLUSION: Less IOL decentration was observed in PPCCC group at 3 months after surgery, indicating that PPCCC may result in better IOL centrality.

Proteomic and single-cell landscape reveals novel pathogenic mechanisms of HBV-infected intrahepatic cholangiocarcinoma.

Despite the epidemiological association between intrahepatic cholangiocarcinoma (ICC) and hepatitis B virus (HBV) infection, little is known about the relevant oncogenic effects. A cohort of 32 HBV-infected ICC and 89 non-HBV-ICC patients were characterized using whole-exome sequencing, proteomic analysis, and single-cell RNA sequencing. Proteomic analysis revealed decreased cell-cell junction levels in HBV-ICC patients. The cell-cell junction level had an inverse relationship with the epithelial-mesenchymal transition (EMT) program in ICC patients. Analysis of the immune landscape found that more CD8 T cells and Th2 cells were present in HBV-ICC patients. Single-cell analysis indicated that transforming growth factor beta signaling-related EMT program changes increased in tumor cells of HBV-ICC patients. Moreover, ICAM1+ tumor-associated macrophages are correlated with a poor prognosis and contributed to the EMT in HBV-ICC patients. Our findings provide new insights into the behavior of HBV-infected ICC driven by various pathogenic mechanisms involving decreased cell junction levels and increased progression of the EMT program.

The relevance of serum macrophage migratory inhibitory factor and cognitive dysfunction in patients with cerebral small vascular disease.

Cerebral small vascular disease (CSVD) is a common type of cerebrovascular disease, and an important cause of vascular cognitive impairment (VCI) and stroke. The disease burden is expected to increase further as a result of population aging, an ongoing high prevalence of risk factors (e.g., hypertension), and inadequate management. Due to the poor understanding of pathophysiology in CSVD, there is no effective preventive or therapeutic approach for CSVD. Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that is related to the occurrence and development of vascular dysfunction diseases. Therefore, MIF may contribute to the pathogenesis of CSVD and VCI. Here, reviewed MIF participation in chronic cerebral ischemia-hypoperfusion and neurodegeneration pathology, including new evidence for CSVD, and its potential role in protection against VCI.

The high frequency oscillation in orbitofrontal cortex is susceptible to phenethylamine psychedelic 25C-NBOMe in male rats.

Serotoninergic psychedelics induced extensive alterations in perception and cognition, which has been attributable to its disruptive effect on oscillatory rhythms of prefrontal cortex. However, there is a lack of information how serotoninergic psychedelics affect the intra-prefrontal network, which intrinsically interact to accomplish perceptual processing. Uncovering the altered neural network caused by psychedelics helps to understand the mechanisms of their psychoactive effects and contribute to develop biological markers of psychedelic effects. In present study, we investigated the effects of substituted phenethylamine psychedelic 25C-NBOMe on neural oscillations in the intra-prefrontal and hippocampal-prefrontal network. The effective dose of 25C-NBOMe (0.1 mg/kg) disrupting sensorimotor gating in male Sprague-Dawley rats was used to observe its effects on neural oscillations in the prelimbic cortex, anterior cingulate cortex, orbitofrontal cortex (OFC) and hippocampus CA1. The power of high frequency oscillation (HFO, 120-150 Hz) was potentiated by 25C-NBOMe selectively in the OFC, with peaking at 20-30 min after treatment. 25C-NBOMe strengthened HFO coherence within the intra-prefrontal, rather than hippocampal-prefrontal network. Potentiated HFO in the OFC had a strong positive correlation with the strengthened inter-prefrontal HFO coherence by 25C-NBOMe. The 25C-NBOMe-induced alterations of rhythmic patterns were prevented by pre-treatment with selective serotonin 2A receptor antagonist MDL100,907. These results demonstrate that OFC rhythmic activity in HFO is relatively susceptible to substituted phenethylamine and potentially drives drug-induced rhythmic coherence within intra-prefrontal regions. Our findings provide additional insight into the neuropathophysiology of the psychoactive effects of psychedelics and indicate that the altered HFO might be applied as a potential biological marker of psychedelic effect.

Towards precision medicine based on a continuous deep learning optimization and ensemble approach.

We developed a continuous learning system (CLS) based on deep learning and optimization and ensemble approach, and conducted a retrospective data simulated prospective study using ultrasound images of breast masses for precise diagnoses. We extracted 629 breast masses and 2235 images from 561 cases in the institution to train the model in six stages to diagnose benign and malignant tumors, pathological types, and diseases. We randomly selected 180 out of 3098 cases from two external institutions. The CLS was tested with seven independent datasets and compared with 21 physicians, and the system's diagnostic ability exceeded 20 physicians by training stage six. The optimal integrated method we developed is expected accurately diagnose breast masses. This method can also be extended to the intelligent diagnosis of masses in other organs. Overall, our findings have potential value in further promoting the application of AI diagnosis in precision medicine.

Enhanced secret-key generation from atmospheric optical channels with the use of random modulation: erratum.

An erratum is given to correct two typos of Eq. (28) in [Opt. Express30(25), 45862 (2022)10.1364/OE.476856]. The corrections do not impact on the results and conclusions of the original article.

[Effects of Biochar on Antibiotic Environmental Behaviors in Soil: A Meta-analysis].

Biochar, as a soil amendment for synergizing the reduction of pollution and carbon emissions, shows great potential and future prospects in controlling antibiotic contamination. In order to research the effects of biochar on antibiotic behaviors in soil systematically, a Meta-analysis was conducted based on 20 studies published from 2011 to 2021. The results showed that the adsorption and degradation of antibiotics in the soil were significantly affected by the application rate and property of biochar. A 2% biochar application dose seemed to be the highest effect size (ES) of 0.19 on adsorption, while there was a significant effect (ES=0.23) on the degradation when the application rate was 5%. The specific surface area, polarity, stability, and aromaticity of biochar could increase the partition coefficient significantly, and the ES was 0.11, 0.13, 0.09, and 0.18, respectively, whereas the effects of antibiotic transport on the dose and property of biochar were insignificant. Biochar also indirectly controlled antibiotic behavior by altering the soil environment. However, the response of the coupling mechanism in antibiotic behaviors on biochar application into soil is still unclear. Moreover, the long-term and negative effects of biochar application in the field are still lacking basic data.

Phylogenomics of five Pseudanabaena cyanophages and evolutionary traces of horizontal gene transfer.

BACKGROUND: Along with the fast development and urbanization in developing countries, the waterbodies aside the growing cities become heavily polluted and highly eutrophic, thus leading to the seasonal outbreak of cyanobacterial bloom. Systematic isolation and characterization of freshwater cyanophages might provide a biological solution to control the awful blooms. However, genomic sequences and related investigations on the freshwater cyanophages remain very limited to date. RESULTS: Following our recently reported five cyanophages Pam1~Pam5 from Lake Chaohu in China, here we isolated another five cyanophages, termed Pan1~Pan5, which infect the cyanobacterium Pseudanabaena sp. Chao 1811. Whole-genome sequencing showed that they all contain a double-stranded DNA genome of 37.2 to 72.0 kb in length, with less than half of the putative open reading frames annotated with known functions. Remarkably, the siphophage Pan1 encodes an auxiliary metabolic gene phoH and constitutes, together with the host, a complete queuosine modification pathway. Proteomic analyses revealed that although Pan1~Pan5 are distinct from each other in evolution, Pan1 and Pan3 are somewhat similar to our previously identified cyanophages Pam3 and Pam1 at the genomic level, respectively. Moreover, phylogenetic analyses suggested that Pan1 resembles the α-proteobacterial phage vB_DshS-R5C, revealing direct evidence for phage-mediated horizontal gene transfer between cyanobacteria and α-proteobacteria. CONCLUSION: In addition to the previous reports of Pam1~Pam5, the present findings on Pan1~Pan5 largely enrich the library of reference freshwater cyanophages. The abundant genomic information provides a pool to identify novel genes and proteins of unknown function. Moreover, we found for the first time the evolutionary traces in the cyanophage that horizontal gene transfer might occur at the level of not only inter-species, but even inter-phylum. It indicates that the bacteriophage or cyanophage could be developed as a powerful tool for gene manipulation among various species or phyla.

Site-specific nanomodulator capable of modulation apoptosis for enhanced colorectal cancer chemo-photothermal therapy.

BACKGROUND: Colorectal cancer (CRC) is a common malignancy with the second highest mortality and the third highest morbidity worldwide. However, the overall survival of patients is unsatisfactory, thus requiring more effective clinical strategies. Celastrol (CLT), a natural bioactive compound, has been reported to induce reactive oxygen species (ROS)-mediated apoptosis to exhibit significant antitumor effects against CRC. However, the poor water solubility, low targeting ability, and bioavailability of CLT have limited its application, and CLT-induced protective autophagy weakens its therapeutic efficiency. RESULTS: We designed a targeted chemo-phototherapy nanoplatform (HCR NPs) to improve the application of CLT. The codelivery of IR820 and CLT in HCR NPs solved the water-soluble problem of CLT and enhanced apoptosis via IR820-mediated hyperthermia. In addition, hydroxychloroquine (HCQ) conjugated to hyaluronic acid (HA) not only increased the active targeting of HCR NPs but also inhibited CLT-induced protective autophagy to exacerbate apoptosis, thus achieving an amplified antitumor effect. Importantly, the HCR NPs exhibited an excellent therapeutic effect on CRC both in vitro and in vivo. CONCLUSION: The HCR NPs presented in this study may not merely provide a new reference for the clinical application of CLT but also result in an attractive strategy for CRC treatment.