Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity.

T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8+ tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10-Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8+ tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10-Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.

Tf2O-Mediated Tandem Reaction of Enaminones for the Synthesis of Functionalized Conjugated-Enals/ß-Naphthalaldehydes.

A highly efficient and regioselective method for constructing functionalized conjugated enals via the Tf2O-mediated tandem reaction of enaminones with thiophenols has been described. Chain products with excellent stereoselectivity could be obtained through substrate regulation. Additionally, a feasible method for synthesizing ß-naphthalaldehydes through PhSO2Na/DABCO promoting hydrogen atom transfer process has also been reported here. Mechanism studies have shown that 2-formyl vinyl triflate 8 and sulfonylated enal 9 were the key intermediates in this process.

Heart Rot Disease of Walnut Caused by Nothophoma juglandis sp. nov. and Its Endophytic Biocontrol Agent.

English walnut (Juglans regia L.) is an economically important hardwood tree species cultivated worldwide. Walnut heart rot disease leading to heartwood decay of trees has been frequently observed in a number of plantations in China. To identify the causal agent, 29 diseased stem samples were collected from walnut plantations in Beijing, and 54 fungal isolates were obtained. Koch's postulates were developed, and the results showed that Nothophoma juglandis, a species new to science, was the causal agent of walnut heart rot disease. Granulobasidium vellereum, a notable biocontrol agent, was coisolated with N. juglandis. An antagonistic assay on dual culture and walnut stems (both in the field and detached branches) proved that G. vellereum acted as a potential biocontrol agent against N. juglandis, as it could significantly inhibit the expansion of N. juglandis. The optimal temperature for mycelial growth and pathogenicity of N. juglandis was 26.6 and 27.0°C, respectively, which frequently occur in the summer of the walnut-growing regions in China.

Effect mechanism of capsaicin and dihydrocapsaicin in chili on the oxidative stability of myoglobin in duck meat.

BACKGROUND: Myoglobin (Mb) in duck meat is commonly over-oxidized when heated at high temperatures, which may worsen the color of the meat. Enhancing the oxidative stability of Mb is essential for improving the color of duck meat. Capsaicin and dihydrocapsaicin (CA-DI) in chili exhibit antioxidant properties. This study investigated the effects of CA-DI on the structure and oxidative damage of Mb by fluorescence spectroscopy, differential scanning calorimetry analysis and particle size in duck meat during heat treatment. RESULTS: When the ratio of CA-DI to Mb was 10:1 g kg-1 and heat-treated for 36 min, oxymyoglobin significantly increased, and metmyoglobin significantly decreased compared with the control group (P < 0.05). In parallel, the carbonyl content of Mb in the CA-DI group decreased by 43.40 ± 0.10%, the sulfhydryl content increased by 188 ± 0.21%, and the free radical scavenging activity of Mb was significantly enhanced (P < 0.05). Moreover, the addition of CA-DI resulted in a significant decrease in the particle size of the Mb surface (P < 0.05). When the ratio of CA-DI to Mb was 10:1 g kg-1, CA-DI enhanced the thermal stability and significantly increased the thermal denaturation temperature of Mb. The molecular docking results indicated that hydrophobic interactions and hydrogen bonds were involved in the binding of CA-DI to Mb. CONCLUSION: CA-DI could combine with Mb and improve the oxidation stability of Mb in duck meat. This suggested that CA-DI could be a potential natural antioxidant that improves the color of meat products. © 2024 Society of Chemical Industry.

The imbalance between NKG2A and NKG2D expression is involved in NK cell immunosuppression and tumor progression of patients with hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: Immunosuppression in a tumor microenvironment is associated with enhanced tumor progression. Natural killer group 2 (NKG2) family proteins, including inhibitory receptors and activators, can be used as attractive targets for immunotherapy of immune checkpoint inhibition. We further explore the expression level prognostic value of NKG2A and NKG2D in hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). METHODS: This study was a prospective study involving 92 patients with HBV-HCC, 16 patients with HBV-related liver cirrhosis, 18 patients with CHB, and 38 healthy donors. We analyzed the expression and related functions of NKG2A, NKG2D, and the NKG2A/NKG2D ratio in the peripheral blood of patients with HBV-HCC and analyzed tumor progression. The tissue samples from patients with HBV-HCC were further used for multiple immunofluorescence and immunohistochemistry. RESULTS: In patients with HBV-HCC with tumor progression, the ratio of NKG2A/NKG2D is higher in NK cells and T cells. The Kaplan-Meier survival curve showed that the NKG2A/NKG2D ratio on NK cells could predict tumor progression in patients with HBV-HCC, and that an increase in this ratio was associated with inhibition of NK cell function. The Cancer Genome Atlas (TCGA) database was further used to verify that the higher the NKG2A/NKG2D ratio, the shorter the progression-free survival of patients with HCC, and the more likely the immune function was suppressed. CONCLUSIONS: The imbalance between NKG2A and NKG2D of NK cells is involved in NK cell immunosuppression, and the increase of the NKG2A/NKG2D ratio is related to the tumor progression of HBV-HCC.

Nitratireductor luteus sp. nov. isolated from saline-alkali land.

The Gram-staining negative, oxidase and catalase negative strain KC-ST17T, isolated from saline-alkali land, was characterized using a polyphasic approach to determine its taxonomic position. Using 16S rRNA gene sequence analysis, the highest similarity of strain KC-ST17T was found with Nitratireductor pacificus CCTCC AB 209302T (97.2%). Cells are aerobic, non-motile, and rod-shaped. The isolate was found to be able to grow in NaCl concentrations of 0-4.0%. The assembled genome of strain KC-ST17T had a total length of 4.9 Mb with a G + C content of 62.7%. According to genome analysis, strain KC-ST17T encodes genes involved in the reduction of nitrate to nitrite, which may play a role in the utilization of nitrogenous compounds from the soil as an immediate source of energy. Based on the phenotypic characteristics and phylogenetic analysis, strain KC-ST17T was confirmed to represent a novel species in the Nitratireductor genus; thus, the name Nitratireductor luteus sp. nov. was proposed. The type strain of this species was KC-ST17T (= KCTC 92119T = MCCC 1K07309T).

Flexible trajectory control of Bessel beams with pure phase modulation.

Spatial phase modulation has become an important method for the design of new self-accelerating light beams. Based on the transverse-longitudinal mapping of Bessel beam, we propose a method of pure phase modulation to directly convert a zero-order Bessel beam into a self-accelerating beam, of which the propagation trajectories can be flexibly predesigned. We experimentally demonstrate three typical types of curves that the modulated Bessel beam propagates along, and the parabolic, spiral, and teleporting self-accelarating beams are realized. The experimental results match the expected trajectory well. This method is simple to operate, and imposes fewer restrictions on the beam trajectory.

Molecular identification and efficacy of entomopathogenic fungi isolates against larvae of the Asian corn borer Ostrinia furnacalis (Lepidoptera: Crambidae) in Xinjiang, China.

AIMS: This study aimed to isolate and identify entomopathogenic fungi (EPF) from fungus-infected Ostrinia furnacalis larvae, screen their bio-efficacy against O. furnacalis, and select the most suitable virulent native EPF for biocontrol agent development. METHODS AND RESULTS: The occurrence of EPF isolated from various maize production regions in Xinjiang was investigated. Of 13,864 O. furnacalis cadavers surveyed, 536 were selected, and of 136 fungal specimens collected, 14 species were identified. Four fungal isolates were highly pathogenic to O. furnacalis: Aspergillus sp., Lecanicillium attenuatum, Beauveria bassiana and Penicillium polonicum. The Aspergillus sp. was the most abundant (42.25% distribution frequency). Bioassay results revealed that it was as pathogenic as B. bassiana (positive control), with 96.58% lethality against O. furnacalis (LC50 : 1.40 × 104 conidia ml-1 , LT50 : 3.41 days). Through morphological examination and rDNA-benA and rDNA-CaM homogeneity analyses, the isolate was identified as Aspergillus nomius. CONCLUSIONS: Four EPF species were highly pathogenic, with A. nomius being the most prevalent in Xinjiang. A. nomius is a potential biocontrol agent. SIGNIFICANCE AND IMPACT OF STUDY: For sustainable prevention and control of O. furnacalis infestation, identifying biocontrol agents with high virulence against O. furnacalis is crucial. The findings of this study support the development of EPF-based biocontrol approaches.

Lysobacter chinensis sp. nov., a cellulose-degrading strain isolated from cow dung compost.

A novel bacterial strain, TLK-CK17T, was isolated from cow dung compost sample. The strain was Gram-staining negative, non-gliding rods, aerobic, and displayed growth at 15-40 °C (optimally, 35 °C), with 0-5.0% (w/v) NaCl (optimally, 0.5) and at pH 6.5-8.5 (optimally, 7.0-7.5). The assembled genome of strain TLK-CK17T has a total length of 4.3 Mb with a G + C content of 68.2%. According to the genome analysis, strain TLK-CK17T encodes quite a few glycoside hydrolases that may play a role in the degradation of accumulated plant biomass in compost. On the basis 16S rRNA gene sequence analysis, strain TLK-CK17T showed the highest sequence similarity (98.9%) with L. penaei GDMCC 1.1817 T, followed by L. maris KCTC 42381 T (98.3%). Cells contained iso-C16:0, iso-C15:0, and summed feature 9 (comprising C17:1 ω9c and/or 10-methyl C16:0), as its major cellular fatty acids (> 10.0%) and ubiquinone-8 as the exclusively respiratory quinone. Diphosphatidylglycerol, phosphatidylethanolamine, and phosphatidylglycerol prevailed among phospholipids. Based on the phenotypic, genomic and phylogenetic data, strain TLK-CK17T represents a novel species of the genus Lysobacter, for which the name Lysobacter chinensis sp. nov. is proposed, and the type strain is TLK-CK17T (= CCTCC AB2021257T = KCTC 92122 T).

Nomogram for prediction of long-term survival with hepatocellular carcinoma based on NK cell counts.

INTRODUCTION: Among all immune cells, natural killer (NK) cells play an important role as the first line of defense against tumor. The purpose of our study is to observe whether the NK cell counts can predict the overall survival of patients with hepatocellular carcinoma (HCC). METHODS: To develop a novel model, from January 2010 to June 2015, HCC patients enrolled in Beijing Ditan hospital were divided into training and validation cohort. Cox multiple regression analysis was used to analyze the independent risk factors for 1-year, 3-year and 5-year overall survival (OS) of patients with HCC, and the nomogram was used to establish the prediction model. In addition, the decision tree was established to verify the contribution of NK cell counts to the survival of patients with HCC. RESULTS: The model used in predicting overall survival of HCC included six variables (namely, NK cell counts, albumin (ALB) level, alpha-fetoprotein (AFP) level, portal vein tumor thrombus (PVTT), tumor number and treatment). The C-index of nomogram model in HCC patients predicting 1-year, 3-year and 5-year overall survival was 0.858, 0.788 and 0.782 respectively, which was higher than tumor-lymph node-metastasis (TNM) staging system, Okuda, model for end-stage liver disease (MELD), MELD-Na, the Chinese University Prognostic Index (CUPI) and Japan Integrated Staging (JIS) scores (p < 0.001). The decision tree showed the specific 5-year OS probability of HCC patients under different risk factors, and found that NK cell counts were the third in the column contribution. CONCLUSIONS: Our study emphasizes the utility of NK cell counts for exploring interactions between long-term survival of HCC patients and predictor variables.

Development and evaluation of a Mycobacterium bovis interferon-γ enzyme-linked immunospot (ELISpot) assay for detection of bovine tuberculosis.

Bovine tuberculosis (bTB) caused by Mycobacterium bovis is an important zoonotic disease. This infection is difficult to control because of the limited ability of the tuberculin skin test (TST) and ancillary IFN-γ release assay to detect all infected animals. In this study, we aimed to develop an efficient assay based on the enzyme-linked immunospot (ELISpot) technique for the diagnosis of bTB, with IFN-γ monoclonal antibodies 3E9 and Bio-labeled 6F8 used as capture and detection antibodies, respectively. As expected, there were significantly more M. bovis-specific spot-forming units (SFU) in bTB-infected cattle than in healthy cattle when an M. bovis-specific antigen, CFP-10-ESAT-6 fusion protein (CE protein), was used. The M. bovis IFN-γ ELISpot assay demonstrated a high level of agreement (90.83%) with the BOVIGAM ELISA test (Thermo Fisher Scientific) for detecting bTB. Furthermore, 3 of 109 cattle tested negative by both the TST and the BOVIGAM ELISA tests, but positive by the ELISpot assay (TST- ELISA- ELISpot+). During subsequent long-term monitoring, these 3 cattle became TST+ ELISA+ ELISpot+. These results suggest that the M. bovis IFN-γ ELISpot assay we established could detect infected cattle earlier than the BOVIGAM ELISA test.

Effects of the C/N ratio on the microbial community and lignocellulose degradation, during branch waste composting.

Aerobic composting is an efficient and environmentally friendly method of converting organic waste into nontoxic fertilizers or soil quality enhancers. The quality of the resultant compost depends greatly upon the composition of the substrate used. The initial carbon-to-nitrogen (C/N) ratio of the substrate is an important factor affecting the composting process. This study elucidated how initial C/N ratios affect the biodegradation of lignocellulose, due to changes in microbial community structure. Four different C/N ratios (20:1, 25:1, 30:1, and 35:1) were examined during a 35-day composting process. The degradation of cellulose, hemicellulose, and lignin was highest (35.7%, 30.6%, and 19.1% respectively) at a 30:1 C/N ratio; after 30 days, the 25:1 C/N ratio ranked second in terms of lignocellulosic degradation rate. The 30:1 C/N ratio further promoted the growth of functional microorganisms responsible for lignocellulose degradation (Luteimonas, Sphingobium, Trichoderma, Chaetomium, and Rosellinia), while the growth of dominant pathogenic microbes (Erwinia and Ulocladium) decreased significantly. These results confirm that the initial C/N ratio of the substrate has a significant effect on the microbial community and degradation of organic matter, during walnut branch composting. This process could therefore offer an alternative means of efficient recycling and recovery of waste branches.

Molecular targets of Yangyin Fuzheng Jiedu Prescription in the treatment of hepatocellular carcinoma based on network pharmacology analysis.

BACKGROUND: Yangyin Fuzheng Jiedu Prescription (YFJP) is a traditional Chinese medicine (TCM) indicated for the treatment of hepatocellular carcinoma (HCC). Its potential targets and molecular mechanisms are not clear. Therefore, this study intends to explore the molecular mechanism of YFJP based on network pharmacology analysis and in vitro validation. METHODS AND RESULTS: Through univariate and multivariate analyses and survival analysis in HCC patients with or without YFJP treatment we found that drinking alcohol, alfafeto protein ≥ 400 ng/l, baseline portal vein tumor thrombus and total bilirubin level ≥ 18.8 µM) were independent risk factors for poor prognosis, while red blood cell count ≥ 4 × 109/l and TCM treatment were independent protective factors. Besides, YFJP prolonged the cumulative survival of HCC patients. Using online pharmacological methods, we obtained 58 relevant compounds and molecular 53 targets. By using scratch test, Transwell assay, EdU assay, and TUNEL staining, we found that YFJP-containing serum repressed the migration, invasion and proliferation of HCC cells in vitro, and induced cell apoptosis. Moreover, YFJP diminished the gene expression of TP53, CCND1, p-EGFR, EGF, VEGFA, JUN, IL6, COX-2, AKT1, and MAPK1 in HCC cells, but elevated the expression of ESR1 and CASP3. CONCLUSIONS: Taken together, results showed that YFJP attenuated HCC progression through mediating effects on HCC-related genes.

Rapid loss of early antigen-presenting activity of lymph node dendritic cells against Ag85A protein following Mycobacterium bovis BCG infection.

BACKGROUND: Control of Mycobacterium tuberculosis (Mtb) infection requires CD4+ T-cell responses and major histocompatibility complex class II (MHC II) presentation of Mtb antigens (Ags). Dendritic cells (DCs) are the most potent of the Ag-presenting cells and are central to the initiation of T-cell immune responses. Much research has indicated that DCs play an important role in anti-mycobacterial immune responses at early infection time points, but the kinetics of Ag presentation by these cells during these events are incompletely understood. RESULTS: In the present study, we evaluated in vivo dynamics of early Ag presentation by murine lymph-node (LN) DCs in response to Mycobacterium bovis bacillus Calmette-Guérin (BCG) Ag85A protein. Results showed that the early Ag-presenting activity of murine DCs induced by M. bovis BCG Ag85A protein in vivo was transient, appearing at 4 h and being barely detectable at 72 h. The transcription levels of CIITA, MHC II and the expression of MHC II molecule on the cell surface increased following BCG infection. Moreover, BCG was found to survive within the inguinal LN DC pool, representing a continuing source of mycobacterial Ag85A protein, with which LN DCs formed Ag85A peptide-MHCII complexes in vivo. CONCLUSIONS: Our results demonstrate that a decrease in Ag85A peptide production as a result of the inhibition of Ag processing to is largely responsible for the short duration of Ag presentation by LN DCs during BCG infection in vivo.

CD8+ T cells and IFN-γ induce autoimmune myelofibrosis in mice.

Myelofibrosis usually occurs either as a part of a myelodysplastic syndrome or in conjunction with neoplasia. It is not commonly thought of an autoimmune disease. We reported that p40-/-IL-2Rα-/- (interleukin-12p40 and interleukin-2 receptor alpha double knockout) mice, a mouse model of human primary biliary cholangitis, exhibited features consistent with autoimmune myelofibrosis, including anemia associated with bone marrow fibrosis, and extramedullary hematopoiesis (EMH) including LSK (Lineage-c-Kit+Sca-1+) cells in spleen, liver and peripheral blood. There were also increased LSK cells in bone marrow but they demonstrated impaired hematopoiesis. Importantly effector memory T cells that infiltrated the bone marrow of p40-/-IL-2Rα-/- mice manifested a higher ability to produce IFN-γ. CD8+ T cells, already known to play a dominate role in portal inflammation, were also key for bone marrow dysregulation and EMH. IFN-γ was the key cytokine that induced bone marrow fibrosis, bone marrow failure and EMH. Finally anti-CD8α antibody therapy fully protected p40-/-IL-2Rα-/- mice from autoimmune myelofibrosis. In conclusion, our results demonstrate that CD8+ T cells and IFN-γ are associated with autoimmune myelofibrosis, a finding that may allow targeting of CD8+ T cells and IFN-γ as a therapeutic targets.

Paenibacillus wulumuqiensis sp. nov. and Paenibacillus dauci sp. nov., two novel species of the genus Paenibacillus.

Two Gram-staining-positive, aerobic, motile, endospore-forming, rod-shaped bacteria, designated strains Y24(T) and H9(T) were isolated from cold spring and carrot (Daucus L.) samples, respectively, in Xinjiang Uyghur Autonomous Region, north-western China. The taxonomic positions of the two new isolates were determined by using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences and DNA-DNA hybridizations showed that strains Y24(T) and H9(T) were two different novel species belonging to the genus Paenibacillus, with Paenibacillus hunanensis FeL05(T) as their closest relative. The genomic DNA G + C contents of the two isolates Y24(T) and H9(T) were 48.1 and 46.6 mol %, respectively. The cell wall peptidoglycan contained meso-diaminopimelic acid. The predominant menaquinone was both as MK-7. The major cellular fatty acids were anteiso-C15:0, C16:0, iso-C16:0, anteiso-C17:0 and iso-C15:0. The polar lipid profiles consisted of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine and two glycolipids as the major components. On the basis of their phenotypic characteristics, the two isolates represent two different novel species of the genus Paenibacillus, for which the names Paenibacillus wulumuqiensis sp. nov. (type strain Y24(T) = CPCC 100602(T) = JCM 30284(T)) and Paenibacillus dauci sp. nov. (type strain H9(T) = CPCC 100608(T) = JCM 30283(T)) are proposed.

Rufibacter roseus sp. nov., isolated from radiation-polluted soil.

A rose, Gram-stain-negative, aerobic, rod-shaped bacterium that was motile by gliding, and designated strain H359(T), was isolated from radiation-polluted soil (with high Cs(137)) from the Xinjiang Uygur Autonomous Region of PR China and subjected to a polyphasic taxonomic analysis. The isolate grew optimally at 30 °C and pH 7.0. It grew with NaCl up to 4% (w/v). 16S rRNA gene sequence analysis indicated that strain H359(T) belonged to the genus Rufibacter, a member of the family Cytophagaceae, with Rufibacter tibetensis CCTCC AB 208084(T) as its closest phylogenetic relative, having 96.1% 16S rRNA gene sequence similarity to the type strain. Strain H359(T) contained menaquinone-7 (MK-7) as the predominant menaquinone, and the major fatty acids were iso-C15 : 0, summed feature 4 (iso-C17 : 1 I and/or anteiso-C17 : 1 B), summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c) and C16 : 1ω5c. The polar lipid profile had phosphatidylethanolamine as the major component. The DNA G+C content was 43.9 mol%. Based on phenotypic, genotypic and phylogenetic evidence, strain H359(T) represents a novel species of the genus Rufibacter, for which the name Rufibacter roseus sp. nov. is proposed. The type strain is H359(T) ( =CPCC 100615(T) =KCTC 42217(T)).

Apolipoprotein A1, B levels, and their ratio and the risk of a first stroke: a meta-analysis and case-control study.

The associations of levels of apolipoprotein A1 (ApoA1) and apolipoprotein B and ApoB/A1 ratio and risk of a first stroke have not been reliably documented. We performed a meta-analysis to summarize the relationships and confirmed them in a case-control study. We identified relevant publications in PubMed and Embase databases up to June 1, 2015. A Dersimonian-Laird random effects model was used to compute summary relative risks (RRs) and 95 % confidence intervals (CIs). A case-control study was conducted in a southern Chinese population. We included 8 cohort and 4 case-control studies (222,774 subjects; 10,032 first stroke events) in the meta-analysis. Reduced ApoA1 level and increased ApoB level and ApoB/A1 ratio was associated with a first stroke in cohort studies (RR 0.86 [95 % CI 0.79-0.94], 1.66 [1.62-1.69], and 1.66 [1.63-1.70], respectively) and reduced ApoA1 level and increased ApoB/A1 ratio in case-control studies (0.68 [0.47-0.99] and 1.76 [1.50-2.06], respectively). When stratified by stroke type in cohort studies, the RR for ischemic stroke was 0.83 (0.76-0.90), 1.36 (1.32-1.40), and 1.38 (1.35-1.42) for the 3 factors, respectively. In our case-control study (1013 cases; 1029 controls), the OR for a first ischemic stroke was 0.83 (0.74-0.92), 1.33 (1.18-1.48) and 2.10 (1.76-2.51), respectively, with increased ApoA1 level associated with hemorrhagic stroke (1.37 [1.06-1.78]). Meta-analysis suggests that reduced ApoA1 level and increased ApoB level and ApoB/A1 ratio are risk factors for a first ischemic but not hemorrhagic stroke. Elevated ApoA1 level may be a risk factor for a first hemorrhagic stroke.

Ultrashort-Peptide-Responsive Gene Switches for Regulation of Therapeutic Protein Expression in Mammalian Cells.

Despite the array of mammalian transgene switches available for regulating therapeutic protein expression in response to small molecules or physical stimuli, issues remain, including cytotoxicity of chemical inducers and limited biocompatibility of physical cues. This study introduces gene switches driven by short peptides comprising eight or fewer amino acid residues. Utilizing a competence regulator (ComR) and sigma factor X-inducing peptide (XIP) from Streptococcus vestibularis as the receptor and inducer, respectively, this study develops two strategies for a peptide-activated transgene control system. The first strategy involves fusing ComR with a transactivation domain and utilizes ComR-dependent synthetic promoters to drive expression of the gene-of-interest, activated by XIP, thereby confirming its membrane penetrability and intracellular functionality. The second strategy features an orthogonal synthetic receptor exposing ComR extracellularly (ComREXTRA), greatly increasing sensitivity with exceptional responsiveness to short peptides. In a proof-of-concept study, peptides are administered to type-1 diabetic mice with microencapsulated engineered human cells expressing ComREXTRA for control of insulin expression, restoring normoglycemia. It is envisioned that this system will encourage the development of short peptide drugs and promote the introduction of non-toxic, orthogonal, and highly biocompatible personalized biopharmaceuticals for gene- and cell-based therapies.

Development and Validation of a Novel Prognostic Nomogram Based on Platelet and CD8+T Cell Counts in Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombosis.

Purpose: Portal vein tumor thrombosis (PVTT) is one of the hallmarks of advanced Hepatocellular carcinoma (HCC). Platelet (PLT) function parameters and CD8+T cells (CD8+Ts) play an important role in HCC progression and metastasis. This study is committed to establishing an efficient prognosis prediction model and exploring the combined effect of PLT and CD8+Ts on PVTT prognosis. Patients and Methods: This retrospective study collected 932 HCC patients with PVTT from 2007 to 2017 and randomly divided them into a training cohort (n = 656) and a validation cohort (n = 276). We performed multivariable Cox and Elastic-net regression analysis, constructed a nomogram and used Kaplan-Meier survival curves to compare overall survival and progression-free survival rates in different substrata. Relationships between indicators involved were also analyzed. Results: We found tumor number, size, treatment, PLT, γ-glutamyl transferase, alpha-fetoprotein, mean platelet volume, and CD8+Ts were related to the 5-year OS of patients with PVTT, and established a nomogram. The area under the receiver operating characteristic curve (AUCs) for predicting the 1-year OS rates were 0.767 and 0.794 in training and validation cohorts. The calibration curve and decision curve indicated its predictive consistency and strong clinical utility. We also found those with low PLT (<100*10^9/L) and high CD8+Ts (>320 cells/µL) had a better prognosis. Conclusion: We established a well-performing prognostic model for PVTT based on platelet functional parameters and CD8+Ts, and found that PT-8 formed by PLT and CD8+Ts was an excellent predictor of the prognosis of PVTT.