Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.

Senescent fibroblast facilitates re-epithelization and collagen deposition in radiation-induced skin injury through IL-33-mediated macrophage polarization.

BACKGROUND: The need for radiotherapy among the elderly rises with increasing life expectancy and a corresponding increase of elderly cancer patients. Radiation-induced skin injury is one of the most frequent adverse effects in radiotherapy patients, severely limiting their life quality. Re-epithelialization and collagen deposition have essential roles in the recovery of skin injuries induced by high doses of ionizing radiation. At the same time, radiation-induced senescent cells accumulate in irradiated tissues. However, the effects and mechanisms of senescent cells on re-epithelialization and collagen deposition in radiation-induced skin injury have not been fully elucidated. RESULTS: Here, we identified a role for a population of senescent cells expressing p16 in promoting re-epithelialization and collagen deposition in radiation-induced skin injury. Targeted ablation of p16+ senescent cells or treatment with Senolytics resulted in the disruption of collagen structure and the retardation of epidermal coverage. By analyzing a publicly available single-cell sequencing dataset, we identified fibroblasts as a major contributor to the promotion of re-epithelialization and collagen deposition in senescent cells. Notably, our analysis of publicly available transcriptome sequencing data highlighted IL-33 as a key senescence-associated secretory phenotype produced by senescent fibroblasts. Neutralizing IL-33 significantly impedes the healing process. Finally, we found that the effect of IL-33 was partly due to the modulation of macrophage polarization. CONCLUSIONS: In conclusion, our data suggested that senescent fibroblasts accumulated in radiation-induced skin injury sites participated in wound healing mainly by secreting IL-33. This secretion regulated the local immune microenvironment and macrophage polarization, thus emphasizing the importance of precise regulation of senescent cells in a phased manner.

Factors influencing diffusion tensor imaging of knee cartilage in children ages 6-12 years: a prospective study.

BACKGROUND: Magnetic resonance diffusion tensor imaging (DTI) has recently been used to evaluate the developing cartilage of children, but the influencing factors have not been well studied. OBJECTIVE: The objective of this study was to investigate the influence of the diffusion gradient strength (b value), diffusion gradient direction, age and sex on knee cartilage DTI in healthy children aged 6-12 years. MATERIALS AND METHODS: A total of 30 healthy child volunteers, with an average age of 8.9 ± 1.6 (mean ± standard deviation) years, were enrolled in this study. They were categorized into three groups according to their age range: 6-8 years, 8-10 years and 10-12 years, ensuring equal sex distribution in each group (5 boys and 5 girls). These volunteers underwent routine left knee joint magnetic resonance imaging (MRI) and serial DTI scans. DTI parameters were altered as follows: when b value = 600 s/mm2, diffusion gradient direction was set to 6, 15, 25, 35 and 45; and when diffusion gradient direction = 25, b value was set to 300, 600, 900 and 1200 s/mm2. The values of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were separately acquired using image post-processing techniques. The correlation between various b values, diffusion gradient directions, age and sex on the one hand and FA and ADC values on the other, was investigated. RESULTS: (1) When diffusion gradient direction was fixed and the b value was varied, both FA and ADC exhibited a decreasing trend as the b value increased (P < 0.001). (2) When the b value was fixed and diffusion gradient direction was varied, the FA of knee cartilage showed a decreasing trend with increasing diffusion gradient direction (P < 0.001). (3) The FA value increased with age (P < 0.05). CONCLUSION: The b value, diffusion gradient direction value and age exert a significant impact on both FA and ADC values in MR DTI of knee cartilage in children aged 6-12 years. In order to obtain a stable DTI, it is recommended to select a b value ≥ 600 s/mm2 and a diffusion gradient direction ≥ 25 during scanning.

Simultaneous Reconstruction of Gas Concentration and Temperature Using Acoustic Tomography.

Acoustic tomography utilizes sensor arrays to collect sound wave signals, enabling non-contact measurement of physical parameters within an area of interest. Compared to optical technologies, acoustic tomography offers the advantages of low cost, low maintenance, and easy installation. Current research in acoustic tomography mainly focuses on reconstruction algorithms for temperature fields, while monitoring the composition and concentration of gases is significant for ensuring safety and improving efficiency, such as in scenarios like boiler furnaces and aviation engine nozzles. In excitable gases, the speed of sound exhibits an S-shaped curve that changes with frequency, a characteristic that could be potentially useful for acoustic tomography. Therefore, this study primarily discusses the quantitative calculation of gas concentration and temperature based on the dispersion of the speed of sound. By employing graphic processing and pattern matching methods, a coupled relationship of the dispersion of the speed of sound with gas concentration and temperature is established. The projection intersection method is used to calculate the concentration and temperature of binary and ternary gas mixtures. Combined with the inversion method, a joint reconstruction method for gas concentration fields and temperature fields based on the dispersion of the speed of sound is developed. The feasibility of the proposed simultaneous reconstruction method for temperature and concentration fields is validated using numerical simulations. Additionally, an acoustic tomography experimental system was set up to conduct reconstruction experiments for binary gas concentration fields and temperature fields, confirming the effectiveness of the proposed method.

Serum indoleamine 2, 3-dioxygenase and tryptophan-2, 3-dioxygenase: potential biomarkers for the diagnosis of major depressive disorder.

OBJECTIVE: The objective of this study was to observe the changes in the levels of indoleamine 2, 3-dioxygenase (IDO) and tryptophan-2, 3-dioxygenase (TDO) in patients with major depressive disorder (MDD) and investigate their potential role as novel biomarkers for diagnosing MDD. METHODS: A total of 55 MDD patients and 55 healthy controls (HC) were enrolled in the study. The severity of MDD was assessed using the 24-item Hamilton Depression Rating Scale (HAMD-24) before and after treatment. The serum concentrations of IDO and TDO were measured at baseline and after treatment. The correlations between the serum levels of IDO and TDO and HAMD-24 scores were evaluated using Pearson's correlation test. Receiver operating characteristic (ROC) curve analysis was used to evaluate the area under the curve (AUC) of serum levels of IDO and TDO for discriminating MDD patients from HC. RESULTS: The serum IDO and TDO concentrations were significantly higher in patients with MDD at baseline than in healthy controls, and decreased significantly after 2 weeks or 1 month of treatment. The levels of IDO and TDO were significantly positively correlated with HAMD-24 scores. Furthermore, the AUC values for IDO and TDO were 0.999 and 0.966, respectively. CONCLUSION: The study suggests that serum IDO and TDO may serve as novel biomarkers for diagnosing MDD. These findings may lead to a better understanding of the pathogenesis of MDD and the development of new therapeutic targets.

Ethnobotanical uses, phytochemistry and bioactivities of Cymbopogon plants: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Cymbopogon (Poaceae) plants have been used for various purposes by many indigenous peoples in all continents. In particular, almost all species in the genus have traditionally been used as folk medicine to treat ailments. Traditional application records indicated that Cymbopogon might be used extensively to treat cold, dizziness, headache, loss of appetite, abdominal pain, rheumatism, diarrhea, whole grass for cold, sore throat, tracheitis and others. AIMS OF THE REVIEW: Despite several research confirmed that Cymbopogon includes a range of active components, no review has been undertaken to consolidate information on its traditional uses, phytochemistry, pharmacology, and/or quality control. Thus this article aims to update a comprehensive review about the traditional uses, phytochemistry, pharmacology, cultivation techniques, economic benefits, trade, threats, and future conservation implications of Cymbopogon species. It may provide informative data for future development and further investigation of this important plant group. MATERIALS AND METHODS: Traditional medicinal books and ethnomedicinal publications related to Cymbopogon from 1992 to 2023 were collated to investigate its ethnobotanical, phytochemical and pharmacological information. The online databases including Google Scholar, SciFinder, Web of Science, Scopus, Springer Link, PubMed, Wiley, China National Knowledge Infrastructure (CNKI), Baidu Scholar, and WanFang Database were screened. RESULTS: Cymbopogon (Gramineae or Poaceae) plants have been grown worldwide. Traditional Chinese medicine and other medicinal systems believes that Cymbopogon has the effect of relieve a cough, analgesia, treating dizziness, traumatic injury and can relieve abdominal pain. A total of 153 compounds, including flavonoids, terpenoids, fatty acid and other compounds were isolated or identified from Cymbopogon species by phytochemical studies. The extracts or compounds from Cymbopogon have exhibited numerous biological activities such as antibacterial, antiinflammatory, antiviral, antineoplastic, antiarrhythmic, antidiabetic and other activities. The rich contents of citronellal, citronellol and geraniol found in Cymbopogon also provide significant nutritional benefits. CONCLUSION: Based on their traditional uses, phytochemicals, and pharmacological activities, Cymbopogon plants are potential medicinal and edible resources with diverse pharmacological effects. Due to various advantages of this group, they possess huge application potential in food and pharmaceutical industries, and animal husbandry. Among them, citronella is very important in terms of economic development. Further comprehensive research to evaluate the medicinal properties of Cymbopogon species will be necessary for future development.

Potential Role of SdiA in Biofilm Formation and Drug Resistance in Avian Pathogenic Escherichia coli.

Avian pathogenic Escherichia coli (APEC) constitutes a significant cause of colibacillosis, a localized or systemic inflammatory disorder in avian species, resulting in considerable economic losses within the global poultry industry. SdiA (suppressor of division inhibitor) is a transcription factor recognized as a LuxR homolog in Escherichia coli, regulating various behaviors, including biofilm formation, multidrug resistance, and the secretion of virulence factors. However, the function of SdiA in APEC strains and its correlation with virulence and multidrug resistance remains unknown. This study probed into the function of SdiA by analyzing the effect of sdiA deletion on the transcription profile of an APEC strain. The microarray data revealed that SdiA upregulates 160 genes and downregulates 59 genes, exerting a particularly remarkable influence on the transcription of multiple virulence genes. A series of antibiotic sensitivity tests, biofilm formation assays, motility assays, and transcriptome analyses were performed, while a Normality test and t-test were conducted on the datasets. This research confirmed that SdiA inhibits biofilm formation by 1.9-fold (p-value < 0.01) and motility by 1.5-fold (p-value < 0.01). RT-qPCR revealed that SdiA positively regulates multidrug resistance by upregulating the expression of yafP, cbrA, and eamB. Collectively, the results of this study indicate the role of SdiA in the pathogenesis of APEC by controlling biofilm formation, motility, and multidrug resistance.

Coptisaustrogaoligongensis (Ranunculaceae), a new species from West Yunnan, China.

Based on morphological and plastid data, we have described and confirmed that Coptisaustrogaoligongensis distributed in Tongbiguan Provincial Nature Reserve, Yingjiang County, Yunnan Province, is a new species of Coptis. It is distinctly different from C.teetasubsp.teeta and C.teetasubsp.lohitensis with differences mainly reflected in the following features: former leaf segment lobes contiguous to each other, and lateral segments equal to central one; plants without developed stolons; inflorescences with only 1-3 flowers; petals have short claws. Phylogenetic analysis indicated that C.austrogaoligongensis is a sister to C.teetasubsp.teeta and C.teetasubsp.lohitensis.

Simultaneous enhancement of strength and ductility via microband formation and nanotwinning in an L12-strengthened alloy.

Metallic alloys with high strength and large ductility are required for extreme structural applications. However, the achievement of ultrahigh strength often results in a substantially decreased ductility. Here, we report a strategy to achieve the strength-ductility synergy by tailoring the alloy composition to control the local stacking fault energy (SFE) of the face-centered-cubic (fcc) matrix in an L12-strengthened superlattice alloy. As a proof of concept, based on the thermodynamic calculations, we developed a non-equiatomic CoCrNi2(Al0.2Nb0.2) alloy using phase separation to create a near-equiatomic low SFE disordered CoCrNi medium-entropy alloy matrix with in situ formed high-content coherent Ni3(Al, Nb)-type ordered nanoprecipitates (∼ 12 nm). The alloy achieves a high tensile strength up to 1.6 GPa and a uniform ductility of 33%. The low SFE of the fcc matrix promotes the formation of nanotwins and parallel microbands during plastic deformation which could remarkably enhance the strain hardening capacity. This work provides a strategy for developing ultrahigh-strength alloys with large uniform ductility.

Structure, thermal stability, physicochemical and functional characteristics of insoluble dietary fiber obtained from rice bran with steam explosion treatment: Effect of different steam pressure and particle size of rice bran.

Rice bran was modified by steam explosion (SE) treatment to investigate the impact of different steam pressure (0.4, 0.8, 1.2, 1.6, and 2.0 MPa) with rice bran through 60 mesh and rice bran pulverization (60, 80, and 100 mesh) with the steam pressure of 1.2 MPa on the structure, thermal stability, physicochemical and functional characteristics of insoluble dietary fiber (IDF) extracted from rice bran. IDF with SE treatment from scanning electron microscopy images showed a porous honeycomb structure, and lamellar shape in IDF became obvious with the increase of steam pressure. The relative crystallinity and polymerization degree of crystalline regions in IDF from rice bran with SE treatment from X-ray diffraction analysis were decreased. Differential scanning calorimetry results showed that thermal stability of IDF with SE treatment increased with the increase of crushing degree. The results of FT-IR also suggested that some glycosidic and hydrogen bonds in IDF could be broken, and some cellulose and hemicellulose were degraded during SE process. The physicochemical and functional characteristics of IDF, including water-holding capacity, oil-holding, glucose adsorption capacity, α-amylase and pancreatic lipase inhibition capacity were decreased with the increase of steam pressure and crushing degree. The swelling and nitrite adsorption capacities of IDF were increased first and then decreased with the increase of steam pressure. The physicochemical and functional characteristics of IDF from rice bran were improved after SE treatment, which might provide references for the utilization of IDF from rice bran with SE treatment.

Ethnobotanical studies on rice landraces under on-farm conservation in Xishuangbanna of Yunnan Province, China.

BACKGROUND: A complex interaction and mutual influence exists among landscapes, cultures, and landraces, with rice culture being a typical embodiment of this relationship. The conservation of landraces operates alongside preserving traditional practices. The Xishuangbanna region stands out as a hub for the genetic diversity of landraces, boasting rich genetic resources. Despite the diverse rice resources in this region, a comprehensive and systematic study has not been undertaken. METHODS: From October to November 2023, we collected rice landraces under the on-farm conservation in 18 townships including Menghai, Mengla and Jinghong in Xishuangbanna. Employing semi-structured interviews and various methods, we investigated factors influencing the preservation and loss of rice landraces in the region. Statistical analysis was applied to the agronomic traits of collected local rice, encompassing indica or japonica, glutinous or non-glutinous, grain shape, and hull color as second category traits. The second category included quantitative traits like thousand grain weight and grain length. Rice diversity among different regions, traits, and ethnic groups was assessed using the Shannon-Wiener index. Additionally, clustering analysis via the UPGMA method depicted the distribution characteristics of the resources. RESULTS: A total of 70 rice landraces were collected in the Xishuangbanna region, each exhibiting distinct characteristics. Differences were observed across regions, trait, naming, and ethnic groups. Diversity analysis revealed that Mengla had the highest diversity, followed by Menghai, while Jinghong exhibited the lowest diversity. The second category of traits displayed broader diversity than the first, with the Dai people's glutinous rice showcasing greater diversity than other ethnic groups. Cluster analysis categorized the 70 samples into seven groups at a genetic distance of 1.15. Ethnobotanical interviews emphasized the rapid loss of rice landraces resources in Xishuangbanna, with indigenous ethnic cultures playing a vital role in the conservation of rice landraces. Dai traditions, in particular, played a crucial role in protecting glutinous rice resources, showcasing a mutual dependence between Dai culture and glutinous rice. CONCLUSIONS: The rich natural environment and diverse ethnic cultures in Xishuangbanna have given rise to various rice landraces. The Dai, primary cultivators of glutinous rice with higher diversity, intertwine their traditional ethnic culture with the conservation of glutinous rice resources. At the same time, the preserving glutinous rice resources promotes the inheritance of Dai ethnic culture. However, rice landraces are facing the risk of loss. Hence, collecting and documenting rice landraces is crucial. Encourage local communities to sustain and expand their cultivation, promoting on-farm conservation. These measures contribute valuable germplasm and genes for rice breeding and serve as a means of cultural preservation.

Study on medicinal food plants in the Gaoligongshan Biosphere Reserve, the richest biocultural diversity center in China.

BACKGROUND: Traditional knowledge associated with medicinal food plants (MFPs) plays a vital role in fighting hidden hunger and safeguarding the health of local people. MFPs resources are abundant in the Gaoligongshan area, a biosphere reserve with the richest biocultural diversity in China. Local people of different linguistic groups also have rich traditional botanical knowledge. However, there are still few comprehensive and systematic studies on MFPs there. METHODS: Ethnobotanical investigation including market survey, semi-structured interviews, free listing and key informant interviews was conducted in the Gaoligongshan area, Western Yunnan, Southwest China. A total of 13 local farmers' markets were selected and information about medicinal food plants, including food categories, medicinal and edible parts, modes of consumption, medicinal effects, and distribution were collected. The relative occurrence frequency (RFO) and cultural food significance index (CFSI) were calculated to identify the culturally significant MFPs. RESULTS: A total of 184 species of MFPs, belonging to 83 families, were collected in the Gaoligongshan area, including vegetables (77), medicinal diets (26), fruits (25), spices (18), herbal tea (13), tea substitutes (11), substitutes for staple food (8), nuts (5), oils and fats (4), and dye material (1). The most frequently used families were Fabaceae, Asteraceae and Apiaceae, with 11, 10, and 9 species, respectively. The most frequently used plant parts were the stems, followed by fruits and leaves. Based on the evaluation results of the CFSI and RFO indices, 18 species of MFPs with magnificent local cultural importance have been screened out, such as Houttuynia cordata, Eryngium foetidum, Sechium edule, Centella asiatica and Pseudocydonia sinensis. CONCLUSION: These findings have guiding significance for conservation of traditional knowledge associated with MFPs and facilitation of scientific utilization of MFPs to meet local people's needs for a healthy life.

Carbamoylation at C-8 position of natural 3-arylcoumarin scaffold for the discovery of novel PARP-1 inhibitors with potent anticancer activity.

Structural modification based on natural privileged scaffolds has proven to be an attractive approach to generate potential antitumor candidates with high potency and specific targeting. As a continuation of our efforts to identify potent PARP-1 inhibitors, natural 3-arylcoumarin scaffold was served as the starting point for the construction of novel structural unit for PARP-1 inhibition. Herein, a series of novel 8-carbamyl-3-arylcoumarin derivatives were designed and synthesized. The antiproliferative activities of target compounds against four BRCA-mutated cancer cells (SUM149PT, HCC1937, MDA-MB-436 and Capan-1) were evaluated. Among them, compound 9b exhibited excellent antiproliferative effects against SUM149PT, HCC1937 and Capan-1 cells with IC50 values of 0.62, 1.91 and 4.26 µM, respectively. Moreover, 9b could significantly inhibit the intracellular PARP-1/2 activity in SUM149PT cells with IC50 values of 2.53 nM and 6.45 nM, respectively. Further mechanism studies revealed that 9b could aggravate DNA double-strand breaks, increase ROS production, decrease mitochondrial membrane potential, arrest cell cycle at G2/M phase and ultimately induce apoptosis in SUM149PT cells. In addition, molecular docking study demonstrated that the binding mode of 9b with PARP-1 was similar to that of niraparib, forming multiple hydrogen bond interactions with the active site of PARP-1. Taken together, these findings suggest that 8-carbamyl-3-arylcoumarin scaffold could serve as an effective structural unit for PARP-1 inhibition and offer a valuable paradigm for the structural modification of natural products.

Gallium complex K6 inhibits colorectal cancer by increasing ROS levels to induce DNA damage and enhance phosphatase and tensin homolog activity.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. In the clinical realm, platinum-based drugs hold an important role in the chemotherapy of CRC. Nonetheless, a multitude of patients, due to tumor protein 53 (TP53) gene mutations, experience the emergence of drug resistance. This phenomenon gravely impairs the effectiveness of therapy and long-term prognosis. Gallium, a metallic element akin to iron, has been reported that has the potential to be used to develop new metal anticancer drugs. In this study, we screened and established the gallium complex K6 as a potent antitumor agent in both in vitro and in vivo. K6 exhibited superior efficacy in impeding the growth, proliferation, and viability of CRC cells carrying TP53 mutations compared to oxaliplatin. Mechanistically, K6 escalated reactive oxygen species levels and led deoxyribonucleic acid (DNA) damage. Furthermore, K6 effectively suppressed the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/glycogen synthase kinase 3 beta (GSK3ß) pathway, leading to the degradation of its downstream effectors myelocytomatosis (c-Myc) and Krueppel-like factor 5 (KLF5). Conversely, K6 diminished the protein expression of WW domain-containing protein 1 (WWP1) while activating phosphatase and tensin homolog (PTEN) through c-Myc degradation. This dual action further demonstrated the potential of K6 as a promising therapeutic compound for TP53-mutated CRC.

Predicting pharmacodynamic effects through early drug discovery with artificial intelligence-physiologically based pharmacokinetic (AI-PBPK) modelling.

A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model links the concentration-time profile of a drug with its therapeutic effects based on the underlying biological or physiological processes. Clinical endpoints play a pivotal role in drug development. Despite the substantial time and effort invested in screening drugs for favourable pharmacokinetic (PK) properties, they may not consistently yield optimal clinical outcomes. Furthermore, in the virtual compound screening phase, researchers cannot observe clinical outcomes in humans directly. These uncertainties prolong the process of drug development. As incorporation of Artificial Intelligence (AI) into the physiologically based pharmacokinetic/pharmacodynamic (PBPK) model can assist in forecasting pharmacodynamic (PD) effects within the human body, we introduce a methodology for utilizing the AI-PBPK platform to predict the PK and PD outcomes of target compounds in the early drug discovery stage. In this integrated platform, machine learning is used to predict the parameters for the model, and the mechanism-based PD model is used to predict the PD outcome through the PK results. This platform enables researchers to align the PK profile of a drug with desired PD effects at the early drug discovery stage. Case studies are presented to assess and compare five potassium-competitive acid blocker (P-CAB) compounds, after calibration and verification using vonoprazan and revaprazan.

Bortezomib in previously treated phosphatase and tension homology-deficient patients with advanced intrahepatic cholangiocarcinoma: An open-label, prospective and single-centre phase II trial.

INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) is characterized by a dismal prognosis with limited therapeutic alternatives. To explore phosphatase and tension homolog (PTEN) as a biomarker for proteasome inhibition in ICC, we conducted a phase II trial to assess the second-line efficacy of bortezomib in PTEN-deficient advanced ICC patients. METHODS: A total of 130 patients with advanced ICC in our centre were screened by PTEN immunohistochemical staining between 1 July 2017, and 31 December 2021, and 16 patients were ultimately enrolled and treated with single-agent bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. RESULTS: The median follow-up was 6.55 months (95% confidence interval [CI]: 0.7-19.9 months). Among the 16 enrolled patients, the ORR was 18.75% (3/16) and the disease control rate was 43.75% (7/16). The median progress-free survival was 2.95 months (95% CI: 2.1-5.1 months) and the median overall survival (mOS) was 7.2 months (95% CI: 0.7-21.6 months) in the intent-to-treat-patients. Treatment-related adverse events of any grade were reported in 16 patients, with thrombopenia being the most common toxicity. Patients with PTEN staining scores of 0 were more likely to benefit from bortezomib than those with staining scores > 0. CONCLUSIONS: Bortezomib yielded an encouraging objective response and a favourable OS as a second-line agent in PTEN-deficient ICC patients. Our findings suggest bortezomib as a promising therapeutic option for patients with PTEN-deficient ICC. HIGHLIGHTS: There is a limited strategy for the second-line option of intrahepatic cholangiocarcinoma (ICC). This investigator-initiated phase 2 study evaluated bortezomib in ICC patients with phosphatase and tension homology deficiency. The overall response rate was 18.75% and the overall survival was 7.2 months in the intent-to-treat cohort. These results justify further developing bortezomib in ICC patients with PTEN deficiency.

Rule-based omics mining reveals antimicrobial macrocyclic peptides against drug-resistant clinical isolates.

Antimicrobial resistance remains a significant global threat, driving up mortality rates worldwide. Ribosomally synthesized and post-translationally modified peptides have emerged as a promising source of novel peptide antibiotics due to their diverse chemical structures. Here, we report the discovery of new aminovinyl-(methyl)cysteine (Avi(Me)Cys)-containing peptide antibiotics through a synergistic approach combining biosynthetic rule-based omics mining and heterologous expression. We first bioinformatically identify 1172 RiPP biosynthetic gene clusters (BGCs) responsible for Avi(Me)Cys-containing peptides formation from a vast pool of over 50,000 bacterial genomes. Subsequently, we successfully establish the connection between three identified BGCs and the biosynthesis of five peptide antibiotics via biosynthetic rule-guided metabolic analysis. Notably, we discover a class V lanthipeptide, massatide A, which displays excellent activity against gram-positive pathogens, including drug-resistant clinical isolates like linezolid-resistant S. aureus and methicillin-resistant S. aureus, with a minimum inhibitory concentration of 0.25 µg/mL. The remarkable performance of massatide A in an animal infection model, coupled with a relatively low risk of resistance and favorable safety profile, positions it as a promising candidate for antibiotic development. Our study highlights the potential of Avi(Me)Cys-containing peptides in expanding the arsenal of antibiotics against multi-drug-resistant bacteria, offering promising drug leads in the ongoing battle against infectious diseases.

HECTD3 inhibits NLRP3 inflammasome assembly and activation by blocking NLRP3-NEK7 interaction.

The NLRP3 inflammasome plays an important role in protecting the host from infection and aseptic inflammation, and its regulatory mechanism is not completely understood. Dysregulation of NLRP3 can cause diverse inflammatory diseases. HECTD3 is a E3 ubiquitin ligase of the HECT family that has been reported to participate in autoimmune and infectious diseases. However, the relationship between HECTD3 and the NLRP3 inflammasome has not been well studied. Herein, we show that HECTD3 blocks the interaction between NEK7 and NLRP3 to inhibit NLRP3 inflammasome assembly and activation. In BMDMs, Hectd3 deficiency promotes the assembly and activation of NLRP3 inflammasome and the secretion of IL-1ß, while the overexpression of HECTD3 inhibits these processes. Unexpectedly, HECTD3 functions in an E3 activity independent manner. Mechanically, the DOC domain of HECTD3 interacts with NACHT/LRR domain of NLRP3, which blocks NLRP3-NEK7 interaction and NLRP3 oligomerization. Furthermore, HECTD3 inhibits monosodium urate crystals (MSU)-induced gouty arthritis, a NLRP3-related disease. Thus, we reveal a novel regulatory mechanism of NLRP3 by HECTD3 and suggest HECTD3 could be a potential therapeutic target for NLRP3-dependent pathologies.

The first complete chloroplast genome sequence of Pentaphragma spicatum Merr. (Pentaphragmataceae) and phylogenetic analysis.

Pentaphragma spicatum Merr. is an endemic wild edible plant of China belonging to the Pentaphragmataceae family. It is widely consumed by Shangsi County resident in Guangxi Fangchenggang. Initially, Pentaphragma was classified as a genus within the Campanulaceae family, but, later it was treated as part of the Pentaphragmataceae family. However, the chloroplast genome of Pentaphragmataceae has not yet been reported. In this study, we sequenced the first complete chloroplast (cp) genome of P. spicatum from Guangxi, China. The whole genome was 154,229 bp in length, consisting of a pair of inverted repeats (IR each 25,572 bp), a large single-copy region (LSC 84,884 bp), and a small single-copy region (SSC 18,201 bp). The complete genome contained 129 genes, including 87 protein-coding genes, 34 tRNA, and 8 rRNA genes. The overall GC content of the whole genome was 37.71%. Based on a maximum-likelihood phylogenetic analysis, it has been determined that P. spicatum is not phylogenetically related to Campanulaceae and supports the decision to classify it as a separate family, Pentaphragmataceae. The complete chloroplast genome of P. spicatum will help enhance and integrate the existing genome data of Asterales. This will provide insights into the phylogenetic relationship within Campanulaceae.