Radiomics model based on contrast-enhanced computed tomography imaging for early recurrence monitoring after radical resection of AFP-negative hepatocellular carcinoma.

BACKGROUND: Although radical surgical resection is the most effective treatment for hepatocellular carcinoma (HCC), the high rate of postoperative recurrence remains a major challenge, especially in patients with alpha-fetoprotein (AFP)-negative HCC who lack effective biomarkers for postoperative recurrence surveillance. Emerging radiomics can reveal subtle structural changes in tumors by analyzing preoperative contrast-enhanced computer tomography (CECT) imaging data and may provide new ways to predict early recurrence (recurrence within 2 years) in AFP-negative HCC. In this study, we propose to develop a radiomics model based on preoperative CECT to predict the risk of early recurrence after surgery in AFP-negative HCC. PATIENTS AND METHODS: Patients with AFP-negative HCC who underwent radical resection were included in this study. A computerized tool was used to extract radiomic features from the tumor region of interest (ROI), select the best radiographic features associated with patient's postoperative recurrence, and use them to construct the radiomics score (RadScore), which was then combined with clinical and follow-up information to comprehensively evaluate the reliability of the model. RESULTS: A total of 148 patients with AFP-negative HCC were enrolled in this study, and 1,977 radiographic features were extracted from CECT, 2 of which were the features most associated with recurrence in AFP-negative HCC. They had good predictive ability in both the training and validation cohorts, with an area under the ROC curve (AUC) of 0.709 and 0.764, respectively. Tumor number, microvascular invasion (MVI), AGPR and radiomic features were independent risk factors for early postoperative recurrence in patients with AFP-negative HCC. The AUCs of the integrated model in the training and validation cohorts were 0.793 and 0.791, respectively. The integrated model possessed the clinical value of predicting early postoperative recurrence in patients with AFP-negative HCC according to decision curve analysis, which allowed the classification of patients into subgroups of high-risk and low-risk for early recurrence. CONCLUSION: The nomogram constructed by combining clinical and imaging features has favorable performance in predicting the probability of early postoperative recurrence in AFP-negative HCC patients, which can help optimize the therapeutic decision-making and prognostic assessment of AFP-negative HCC patients.

IBI310 (anti-CTLA-4 antibody) monotherapy or in combination with sintilimab in advanced melanoma or urothelial carcinoma.

IBI310 is a recombinant fully human IgG1 antibody against cytotoxic T lymphocyte antigen 4. This study was conducted to evaluate IBI310 monotherapy or combination therapy with sintilimab in the patients with advanced melanoma or urothelial carcinoma (UC). Patients in phase 1a received IBI310 at 0.3/1/2/3 mg/kg intravenously (IV) every 3 weeks (Q3W) following the accelerated titration and 3 + 3 escalation design. Patients in phase 1b received IBI310 (1/2/3 mg/kg IV, Q3W) plus sintilimab (200 mg IV, Q3W) for four cycles, followed by sintilimab maintenance therapy. The phase 1b expansion of IBI310 plus sintilimab was performed in patients with advanced melanoma or UC. Overall, 53 patients were enrolled, including 10 patients with melanoma in phase 1a, 34 with melanoma, and 9 with UC in phase 1b. Overall, 94.3% of patients (50/53) experienced at least one treatment-related adverse event (TRAE) with most being grade 1-2; 26.4% of patients (14/53) experienced grade 3 or higher TRAEs. In phase 1a, the disease control rate (DCR) was 50.0% (95% confidence interval [CI], 18.7%-81.3%). In phase 1b, the objective response rate (ORR) and DCR were 17.6% (95% CI, 6.8%-34.5%) and 44.1% (95% CI, 27.2%-62.1%), respectively, for melanoma, and were 22.2% (95% CI, 2.8%-60.0%) and 66.7% (95% CI, 29.9%-92.5%), respectively, for UC. IBI310 monotherapy or combination therapy with sintilimab was well tolerated with favorable antitumor activity across patients with advanced melanoma and UC.

Molecular beacon-based detection of circulating microRNA-containing extracellular vesicle as an α-synucleinopathy biomarker.

Early and precise diagnosis of α-synucleinopathies is challenging but critical. In this study, we developed a molecular beacon-based assay to evaluate microRNA-containing extracellular vesicles (EVs) in plasma. We recruited 1203 participants including healthy controls (HCs) and patients with isolated REM sleep behavior disorder (iRBD), α-synucleinopathies, or non-α-synucleinopathies from eight centers across China. Plasma miR-44438-containing EV levels were significantly increased in α-synucleinopathies, including those in the prodromal stage (e.g., iRBD), compared to both non-α-synucleinopathy patients and HCs. However, there are no significant differences between Parkinson's disease (PD) and multiple system atrophy. The miR-44438-containing EV levels negatively correlated with age and the Hoehn and Yahr stage of PD patients, suggesting a potential association with disease progression. Furthermore, a longitudinal analysis over 16.3 months demonstrated a significant decline in miR-44438-containing EV levels in patients with PD. These results highlight the potential of plasma miR-44438-containing EV as a biomarker for early detection and progress monitoring of α-synucleinopathies.

Detection of α-Synuclein in Oral Mucosa by Seed Amplification Assay in Synucleinopathies and Isolated REM Sleep Behavior Disorder.

OBJECTIVE: Evidence of abnormal α-synuclein (α-Syn) deposition in the brain is required for definitive diagnosis of synucleinopathies, which remains challenging. The seed amplification assay (SAA) is an innovative technique that can detect the seeding activity of misfolded α-Syn, enabling the amplification and detection of minute quantities of pathogenic α-Syn aggregates. This study aimed to evaluate oral mucosa α-Syn SAA as possible diagnostic and prodromal biomarkers for synucleinopathies. METHODS: A total of 107 Parkinson's disease (PD) patients, 99 multiple system atrophy (MSA) patients, 33 patients with isolated rapid eye movement sleep behavior disorder (iRBD) and 103 healthy controls (HC) were included. The SAA was applied to detect the seeding activity of α-Syn from oral mucosa. A combination of morphological, biochemical, and biophysical methods was also used to analyze the fibrils generated from the oral mucosa α-Syn SAA. RESULTS: Structured illumination microscopy images revealed the increased α-Syn species in oral mucosa of PD, MSA, and iRBD patients than in HCs. Oral mucosa α-Syn SAA distinguished patients with PD from HC with 67.3% sensitivity and 90.3% specificity. Oral mucosa was α-Syn SAA positive in 53.5% MSA patients and 63.6% iRBD patients. Furthermore, the α-Syn fibrils generated from MSA demonstrated greater resistance to proteinase K digestion and exhibited stronger cytotoxicity compared to those from PD patients. CONCLUSION: Oral mucosa α-Syn seeding activity may serve as novel non-invasive diagnostic and prodromal biomarkers for synucleinopathies. The α-Syn aggregates amplified from the oral mucosa of PD and MSA exhibited distinct biochemical and biophysical properties. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Community coalescence and plant host filtering determine the spread of tetracycline resistance genes from pig manure into the microbiome continuum of the soil-plant system.

The spread of livestock manure-borne antibiotic resistance genes (ARGs) into agroecosystems through manure application poses a potential threat to human health. However, there is still a knowledge gap concerning ARG dissemination in coalescing manure, soil and plant microbiomes. Here, we examined the fate of tetracycline resistance genes (TRGs) originating from pig manure microbiomes and spread in the soil-A thaliana system and explored the effects of microbial functions on TRGs spread at different interfaces. Our results indicate that the TRGs abundances in all microbiome continuum of the soil-A. thaliana system were significantly increased with the application of a living manure microbiome, although the addition of manure with both an active and inactive microbiome caused a shift in the microbial community composition. This was attributed to the increasing relative abundances of tetA, tetL, tetM, tetO, tetW and tolC in the system. The application of living manure with DOX residues resulted in the highest relative abundance of total TRGs (3.30×10-3 copies/16S rRNA gene copies) in the rhizosphere soil samples. Community coalescence of the manure and soil microbiomes increased the abundance of Firmicutes in the soil and root microbiome, which directly explains the increase in TRG abundance observed in these interfaces. In contrast, the leaf microbiome differed markedly from that of the remaining samples, indicating strong plant host filtering effects on Firmicutes and TRGs from pig manure. The random forest machine learning model revealed microbial functions and their significant positive correlation with TRG abundance in the microbiome continuum of the system. Our findings revealed that community coalescence is the main driver of TRG spread from manure to the soil and root microbiomes. Plant host filtering effects play a crucial role in allowing certain microbial groups to occupy ecological niches in the leaves, thereby limiting the establishment of manure-borne TRGs in aboveground plant tissues.

Gut microbiome resilience of green-lipped mussels, Perna canaliculus, to starvation

Host gut microbiomes play an important role in animal health and resilience to conditions, such as malnutrition and starvation. These host-microbiome relationships are poorly understood in the marine mussel Perna canaliculus, which experiences significant variations in food quantity and quality in coastal areas. Prolonged starvation may be a contributory factor towards incidences of mass mortalities in farmed mussel populations, resulting in highly variable production costs and unreliable market supplies. Here, we examine the gut microbiota of P. canaliculus in response to starvation and subsequent re-feeding using high-throughput amplicon sequencing of the 16S rRNA gene. Mussels showed no change in bacterial species richness when subjected to a 14-day starvation, followed by re-feeding/recovery. However, beta bacteria diversity revealed significant shifts (PERMANOVA p-value < 0.001) in community structure in the starvation group and no differences in the subsequent recovery group (compared to the control group) once they were re-fed, highlighting their recovery capability and resilience. Phylum-level community profiles revealed an elevation in dominance of Proteobacteria (ANCOM-BC p-value <0.001) and Bacteroidota (ANCOM-BC p-value = 0.04) and lower relative abundance of Cyanobacteria (ANCOM-BC p-value = 0.01) in the starvation group compared to control and recovery groups. The most abundant genus-level shifts revealed relative increases of the heterotroph Halioglobus (p-value < 0.05) and lowered abundances of the autotroph Synechococcus CC9902 in the starvation group. Furthermore, a SparCC correlation network identified co-occurrence of a cluster of genera with elevated relative abundance in the starved mussels that were positively correlated with Synechococcus CC9902... (AU)

Efficacy and Safety of Postoperative Adjuvant Radiation Therapy in Resected Nasal Cavity and Paranasal Sinus Mucosal Melanoma: A Combined Analysis.

PURPOSE: Mucosal melanoma of the nasal cavity and paranasal sinuses (NPMM) is a highly aggressive disease. The role of postoperative adjuvant radiation therapy is controversial. METHODS AND MATERIALS: A total of 300 patients with NPMM treated between March 2009 and January 2020 were divided into surgery alone (SA; 158 patients) and surgery plus radiation therapy (SR; 142 patients) groups. Postoperative radiation therapy was recommended, with a total dose of 65 to 70 Gy/30 to 35 fractions to the gross tumor volume and 60 Gy/30 fractions to the clinical target volume. The primary endpoint was relapse-free survival. Secondary endpoints included local recurrence-free survival, distant metastasis-free survival, and overall survival. RESULTS: At a median follow-up of 50.0 months, relapse-free survival in the SA and SR groups was 9.8 and 15.2 months (hazard ratio [HR], 0.714; 95% CI, 0.546-0.933; P = .014). Distant metastasis-free survival in the SA and SR groups was 23.8 and 21.3 months (HR, 0.896; 95% CI, 15.7-31.9 vs 13.3-29.3; P = .457). Overall survival in the SA and SR groups was 31.0 and 35.1 months (HR, 0.816; 95% CI, 25.7-36.3 vs 27.1-43.2; P = .178). For patients with stage IVA NPMM, radiation therapy reduced the incidence of relapse by 0.43-fold. CONCLUSIONS: Postoperative radiation therapy played a crucial role in the local control of resected NPMM, especially in patients with stage T4a or IVA disease.

Alterations of Peripheral Lymphocyte Subsets in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Adaptive immune dysfunction may play a crucial role in Parkinson's disease (PD) development. Isolated rapid eye movement sleep behavior disorder (iRBD) represents the prodromal stage of synucleinopathies, including PD. Elucidating the peripheral adaptive immune system is crucial in iRBD, but current knowledge remains limited. OBJECTIVE: This study aimed to characterize peripheral lymphocyte profiles in iRBD patients compared with healthy control subjects (HCs). METHODS: This cross-sectional study recruited polysomnography-confirmed iRBD patients and age- and sex-matched HCs. Venous blood was collected from each participant. Flow cytometry was used to evaluate surface markers and intracellular cytokine production in peripheral blood mononuclear cells. RESULTS: Forty-four iRBD patients and 36 HCs were included. Compared with HCs, patients with iRBD exhibited significant decreases in absolute counts of total lymphocytes and CD3+ T cells. In terms of T cell subsets, iRBD patients showed higher frequencies and counts of proinflammatory T helper 1 cells and INF-γ+ CD8+ T cells, along with lower frequencies and counts of anti-inflammatory T helper 2 cells. A significant increase in the frequency of central memory T cells in CD8+ T cells was also observed in iRBD. Regarding B cells, iRBD patients demonstrated reduced frequencies and counts of double-negative memory B cells compared with control subjects. CONCLUSIONS: This study demonstrated alterations in the peripheral adaptive immune system in iRBD, specifically in CD4+ and INF-γ+ CD8+ T cell subsets. An overall shift toward a proinflammatory state of adaptive immunity was already evident in iRBD. These observations might provide insights into the optimal timing for initiating immune interventions in PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The recent advance and prospect of natural source compounds for the treatment of heart failure.

Heart failure is a continuously developing syndrome of cardiac insufficiency caused by diseases, which becomes a major disease endangering human health as well as one of the main causes of death in patients with cardiovascular diseases. The occurrence of heart failure is related to hemodynamic abnormalities, neuroendocrine hormones, myocardial damage, myocardial remodeling etc, lead to the clinical manifestations including dyspnea, fatigue and fluid retention with complex pathophysiological mechanisms. Currently available drugs such as cardiac glycoside, diuretic, angiotensin-converting enzyme inhibitor, vasodilator and ß receptor blocker etc are widely used for the treatment of heart failure. In particular, natural products and related active ingredients have the characteristics of mild efficacy, low toxicity, multi-target comprehensive efficacy, and have obvious advantages in restoring cardiac function, reducing energy disorder and improving quality of life. In this review, we mainly focus on the recent advance including mechanisms and active ingredients of natural products for the treatment of heart failure, which will provide the inspiration for the development of more potent clinical drugs against heart failure.

Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation.

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2+ macrophages in various disease conditions, and substantial induction of TREM2+ NASH-associated macrophages (NAMs) serves as a hallmark of metabolic liver disease. Despite this, the mechanisms through which NAMs contribute to MASH pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) as a NAM-specific pathogenic factor that exacerbates MASH progression in mice. Hepatic MS4A7 expression was strongly induced in mouse and human MASH and associated with the severity of liver injury. Whole-body and myeloid-specific ablation of Ms4a7 alleviated diet-induced MASH pathologies in male mice. We demonstrate that exposure to lipid droplets (LDs), released upon injury of steatotic hepatocytes, triggered NAM induction and exacerbated MASH-associated liver injury in an MS4A7-dependent manner. Mechanistically, MS4A7 drove NLRP3 inflammasome activation via direct physical interaction and shaped disease-associated cell states within the liver microenvironment. This work reveals the LD-MS4A7-NLRP3 inflammasome axis as a pathogenic driver of MASH progression and provides insights into the role of TREM2+ macrophages in disease pathogenesis.

Natural history of bone-only metastasis in renal cell carcinoma.

BACKGROUND: Bone metastasis (BM) is considered a poor prognostic factor of renal cell carcinoma (RCC). Confusion exists regarding how to deal with RCC patients with bone-only metastasis. PATIENTS AND METHODS: The clinical data of consecutive RCC patients with bone-only metastasis at Peking University Cancer Hospital between 2006 and 2018 were retrospectively collected and analyzed. RESULTS: Fifty-four eligible patients were screened from an RCC database of 1,878 metastatic patients. After a median follow-up of 43.6 m, 61.1% of the patients were presented with progression of prior BM or new BM. The progression-free survival (PFS) and overall survival (OS) was 16.2 m (95%CI: 11.4-21.0) and 65.2 m, respectively. For the 30 patients with oligo-metastasis (≤3 loci) and 24 ones with multiple-metastasis (>3 loci), the median OS was not reached and 42.0m (95%CI: 12.7-71.2) with statistical difference (P < 0.001). In the oligo-metastasis group, the median PFS of the 15 patients treated with local therapy and of the 13 patients treated with systemic therapy was 14.2 m (95%CI: 5.3-23.3) and 18.0 m (95%CI:15.4-20.6), respectively. In the multiple-metastasis group, the median PFS and OS of the 18 patients treated with systemic therapy was 16.6 m (95%CI: 7.5-25.7) and 63.9 m (95%CI: 21.8-106.0), respectively. Univariate analysis and multivariate analysis showed that the number of metastatic sites (oligo/multiple) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score, RCC pathological subtype were significantly associated with prognosis (P < 0.05). CONCLUSION: RCC patients with bone-only metastases have a favorable prognosis. The number of metastatic sites, IMDC, RCC pathological subtype could serve as survival predictors, which might provide clue of treatment modality.

Atractylenolide-III attenuates osteoarthritis by repolarizing macrophages through inactivating TLR4/NF-κB signaling.

BACKGROUND: As a common chronic musculoskeletal condition, osteoarthritis (OA) presently lacks particular treatment strategies. The aim of this study was to examine how AT-III therapies affected macrophage repolarity in order to slow down the advancement of OA. METHODS: RAW264.7 macrophages were polarized to M1 subtypes then administered with different concentrations of AT-III. Immunofluorescence, qRT-PCR and flow cytometry were used to assess the polarization of the macrophages. The mechanism of AT-III repolarize macrophages was evaluated by western blot. Furthermore, the effects of macrophage conditioned media (CM) on the migration, proliferation, and chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) were investigated using CCK-8 assays, the scratch test, and alcian blue staining. The effects of macrophage CM on chondrocyte proliferation and degeneration were investigated using CCK-8 and qRT-PCR. In vivo micro-CT and histological observations were performed on rats with anterior cruciate ligament transection and partial medial meniscectomy, either with or without AT-III treatment. RESULTS: AT-III repolarized M1 macrophages to M2 phenotype. Mechanistically, AT-III reduced the expression of Toll-like receptor(TLR) 4 induced by lipopolysaccharide in RAW264.7 and lowered nuclear factor-κB (NF-κB) signaling molecules p-p65 and p-IκBα. The TLR4 agonist RS09 reversed the effects of AT-III on macrophage repolarization. AT-III-induced macrophages CM stimulated BMSCs migration, proliferation and chondrogenic differentiation. AT-III-treated macrophage CM promoted chondrocyte proliferation while inhibiting chondrocyte degeneration. In vivo, AT-III treatment alleviated the degree of synovitis, inhibited subchondral bone remodeling and reduced cartilage destruction in the rat OA model. CONCLUSIONS: AT-III attenuates OA by repolarizing macrophages through inactivating TLR4/NF-κB signaling. These data suggest that AT-III may be an effective therapeutic candidate for OA treatment.

Oral immunization with recombinant L. lactis expressing GCRV-II VP4 produces protection against grass carp reovirus infection.

The hemorrhagic disease causing by grass carp reovirus (GCRV) infection, is associated with major economic losses and significant impact on aquaculture worldwide. VP4 of GCRV is one of the major outer capsid proteins which can induce an immune response in the host. In this study, pNZ8148-VP4/L. lactis was constructed to express recombinant VP4 protein of GCRV, which was confirmed by the Western-Blot and enzyme-linked immunosorbent assay. Then we performed the oral immunization for rare minnow model and the challenge with GCRV-II. After oral administration, pNZ8148-VP4/L. lactis can continuously reside in the intestinal tract to achieve antigen presentation. The intestinal and spleen samples were collected at different time intervals after immunization, and the expression of immune-related genes was detected by real-time fluorescence quantitative PCR. The results showed that VP4 recombinant L. lactis could induce complete cellular and humoral immune responses in the intestinal mucosal system, and effectively regulate the immunological effect of the spleen. The immunogenicity and the protective efficacy of the oral vaccine was evaluated by determining IgM levels and viral challenge to vaccinated fish, a significant level (P < 0.01) of antigen-specific IgM with GCRV-II neutralizing activity was able to be detected, which provided a effective protection in the challenge experiment. These results indicated that an oral probiotic vaccine with VP4 expression can provide effective protection for grass carp against GCRV-II challenge, suggesting a promising vaccine strategy for fish.

Fatty Infiltration of Multifidus Muscles: An Easily Overlooked Risk Factor for the Severity of Osteoporotic Vertebral Fractures.

OBJECTIVES: Osteoporotic vertebral fractures (OVFs) are a critical public health concern requiring urgent attention, and severe OVFs impose substantial health and economic burdens on patients and society. Analysis of the risk factors for severe OVF is imperative to actively prevent the occurrence of this degenerative disorder. This study aimed to investigate the risk factors associated with the severity of OVF, with a specific focus on changes in the paraspinal muscles. METHODS: A total of 281 patients with a first-time single-level acute OVF between January 2016 and January 2023 were enrolled in the study. Clinical and radiological data were collected and analyzed. The cross-sectional area (CSA) and degree of fatty infiltration (FI) of the paraspinal muscles, including the multifidus muscles (MFMs), erector spinae muscles (ESMs), and psoas major muscles (PSMs), were measured by magnetic resonance imaging (MRI) of the L4/5 intervertebral discs. According to the classification system of osteoporotic fractures (OF classification) and recommended treatment plan, OVFs were divided into a low-grade OF group and a high-grade OF group. Univariate and multivariate logistic regression analyse s were performed to identify risk factors associated with the severity of OVF. RESULTS: Ninety-eight patients were included in the low-grade OF group, and 183 patients were included in the high-grade OF group. Univariate analysis revealed a significantly higher incidence of a high degree of FI of MFMs (OR = 1.71, p = 0.002) and ESMs (OR = 1.56, p = 0.021) in the high-grade OF group. Further multivariate logistic regression analysis demonstrated that a high degree of FI of the MFMs (OR = 1.71, p = 0.002) is an independent risk factor for the severity of OVF. CONCLUSION: A high degree of FI of the MFMs was identified as an independent risk factor for the severity of OVF. Decreasing the degree of FI in the MFMs might lower the incidence of the severity of OVF, potentially reducing the necessity for surgical intervention in OVF patients.

Phase Ib study of anlotinib in combination with anti-PD-L1 antibody (TQB2450) in patients with advanced acral melanoma.

BACKGROUND: Acral melanoma, the most common subtype of melanoma in Asians, is often diagnosed at an advanced stage and responds poorly to current programmed cell death protein 1 (PD-1) inhibitors. OBJECTIVES: To evaluate the safety and efficacy of TQB2450 and anlotinib in patients with advanced acral melanoma in a phase Ib study (NCT03991975). METHODS: Patients received TQB2450 (1200 mg every 3 weeks) and anlotinib (10 mg or 12 mg once daily, 2-week on/1-week off) in the dose-escalation and dose-expansion phases. The primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and objective response rate (ORR). RESULTS: Nineteen patients were enrolled between June 2019 and June 2022. The majority of patients (16 of 19 patients) received anlotinib and TQB2450 as first-line treatment. No DLTs were observed, and MTD was not reached. Eighteen (94.7%) out of 19 patients experienced treatment-related adverse events (TRAEs), but most were grade 1 or 2. Grade 3 or greater TRAEs occurred in seven patients (36.8%). The ORR was 26.3% (two complete responses and three partial responses). The disease control rate was 73.7%. The median duration of response was 30.3 months [95% confidence interval (CI): 5.8-NA]. The median progression-free survival (PFS) was 5.5 months (95% CI: 2.8-NA), and median overall survival was 20.3 months (95% CI: 14.8-NA). Whole-exome sequencing suggested that acquired drug resistance might be attributed to activation of the MAPK signalling pathway and transformation to an immunosuppressive tumour environment. CONCLUSIONS: TQB2450 combined with anlotinib showed favourable tolerance and promising anti-tumour activity with a prolonged PFS compared with anti-PD1 monotherapy in patients with advanced acral melanoma.

Gut microbiome resilience of green-lipped mussels, Perna canaliculus, to starvation.

Host gut microbiomes play an important role in animal health and resilience to conditions, such as malnutrition and starvation. These host-microbiome relationships are poorly understood in the marine mussel Perna canaliculus, which experiences significant variations in food quantity and quality in coastal areas. Prolonged starvation may be a contributory factor towards incidences of mass mortalities in farmed mussel populations, resulting in highly variable production costs and unreliable market supplies. Here, we examine the gut microbiota of P. canaliculus in response to starvation and subsequent re-feeding using high-throughput amplicon sequencing of the 16S rRNA gene. Mussels showed no change in bacterial species richness when subjected to a 14-day starvation, followed by re-feeding/recovery. However, beta bacteria diversity revealed significant shifts (PERMANOVA p-value < 0.001) in community structure in the starvation group and no differences in the subsequent recovery group (compared to the control group) once they were re-fed, highlighting their recovery capability and resilience. Phylum-level community profiles revealed an elevation in dominance of Proteobacteria (ANCOM-BC p-value <0.001) and Bacteroidota (ANCOM-BC p-value = 0.04) and lower relative abundance of Cyanobacteria (ANCOM-BC p-value = 0.01) in the starvation group compared to control and recovery groups. The most abundant genus-level shifts revealed relative increases of the heterotroph Halioglobus (p-value < 0.05) and lowered abundances of the autotroph Synechococcus CC9902 in the starvation group. Furthermore, a SparCC correlation network identified co-occurrence of a cluster of genera with elevated relative abundance in the starved mussels that were positively correlated with Synechococcus CC9902. The findings from this work provide the first insights into the effect of starvation on the resilience capacity of Perna canaliculus gut microbiota, which is of central importance to understanding the effect of food variation and limitation in farmed mussels.

Neuregulin 4 mediates the metabolic benefits of mild cold exposure by promoting beige fat thermogenesis.

Interorgan crosstalk via secreted hormones and metabolites is a fundamental aspect of mammalian metabolic physiology. Beyond the highly specialized endocrine cells, peripheral tissues are emerging as an important source of metabolic hormones that influence energy and nutrient metabolism and contribute to disease pathogenesis. Neuregulin 4 (Nrg4) is a fat-derived hormone that protects mice from nonalcoholic steatohepatitis (NASH) and NASH-associated liver cancer by shaping hepatic lipid metabolism and the liver immune microenvironment. Despite its enriched expression in brown fat, whether NRG4 plays a role in thermogenic response and mediates the metabolic benefits of cold exposure are areas that remain unexplored. Here we show that Nrg4 expression in inguinal white adipose tissue (iWAT) is highly responsive to chronic cold exposure. Nrg4 deficiency impairs beige fat induction and renders mice more susceptible to diet-induced metabolic disorders under mild cold conditions. Using mice with adipocyte and hepatocyte-specific Nrg4 deletion, we reveal that adipose tissue-derived NRG4, but not hepatic NRG4, is essential for beige fat induction following cold acclimation. Furthermore, treatment with recombinant NRG4-Fc fusion protein promotes beige fat induction in iWAT and improves metabolic health in mice with diet-induced obesity. These findings highlight a critical role of NRG4 in mediating beige fat induction and preserving metabolic health under mild cold conditions.

Nickel Single Atom Density-Dependent CO2 Efficient Electroreduction.

The transition metal-nitrogen-carbon (M─N─C) with MNx sites has shown great potential in CO2 electroreduction (CO2RR) for producing high value-added C1 products. However, a comprehensive and profound understanding of the intrinsic relationship between the density of metal single atoms and the CO2RR performance is still lacking. Herein, a series of Ni single-atom catalysts is deliberately designed and prepared, anchored on layered N-doped graphene-like carbon (x Ni1@NG-900, where x represents the Ni loading, 900 refers to the temperature). By modulating the precursor, the density of Ni single atoms (DNi) can be finely tuned from 0.01 to 1.19 atoms nm-2. The CO2RR results demonstrate that the CO faradaic efficiency (FECO) predominantly increases from 13.4% to 96.2% as the DNi increased from 0 to 0.068 atoms nm-2. Then the FECO showed a slow increase from 96.2% to 98.2% at -0.82 V versus reversible hydrogen electrode (RHE) when DNi increased from 0.068 to 1.19 atoms nm-2. The theoretical calculations are in good agreement with experimental results, indicating a trade-off relationship between DNi and CO2RR performance. These findings reveal the crucial role of the density of Ni single atoms in determining the CO2RR performance of M─N─C catalysts.

An iodine­labelled Antibody-drug conjugate PET probe for noninvasive monitoring of Nectin-4 expression in urothelial carcinoma.

BACKGROUND AND PURPOSE: Some kinds of antibody-drug conjugate (ADC) with high affinity to Nectin-4 have demonstrated breakthrough progress in the third-line setting for bladder cancer. However, many patients are still difficult to benefit from treatment based on the heterogeneity of tumour. As the most advanced auxiliary treatment technology, treatment visualization can most intuitively predict the effectiveness of drug treatment, and timely detect the occurrence of drug resistance. Among them, nuclear medicine molecular probes play an important role in this field. METHODS: 124/125I-EV was prepared by labelling Enfortumad Vedetin (EV), an ADC drugs widely used in clinic targeted Nectin-4, with Na124/125I using N-bromine succinimide as oxidant. The radiochemical purity was analyzed via radio-TLC and bioactivity was measured by enzyme-linked immunosorbent assay. Cell uptake assay and small-animal PET imaging were performed to verified the specificity and targeting. KEY RESULTS: 124/125I-EV was prepared with high labeling yield and radiochemical purity. ELISA assays demonstrated that 124I-EV maintained the same high bioactivity as EV with significantly higher uptake in SW780 cells (Nectin-4 positive, 4.05 ± 0.32 %IA/5 × 105 cells at 8 h) than that in T24 cells (Nectin-4 negative, 1.34 ± 0.18 %IA/5 × 105 cells, p < 0.001). In PET imaging, 124I-EV had a significantly higher accumulation in SW780 tumour than that in T24 tumour and the uptake in SW780 tumour could be specifically blocked when co-injected with cold EV. The signal-to-noise ratio at the tumour site gradually increased with time, and peaked at 72 h. CONCLUSION AND IMPLICATIONS: 124I-EV was successfully prepared with high specificity and binding affinity of Nectin-4. This radioactive probe completely simulates the internal circulation of ADC drugs and tumour uptake and retention, which will greatly improve the clinical application of ADC therapy.

Factors Affecting Recurrence and Survival for Patients with High-Risk Stage II Melanoma.

BACKGROUND: In the current era of effective adjuvant therapies and de-escalation of surgery, distinguishing which patients with high-risk stage II melanoma are at increased risk of recurrence after excision of the primary lesion is essential to determining appropriate treatment and surveillance plans. METHODS: A single-center retrospective study analyzed patients with stage IIB or IIC melanoma. Demographic and tumor data were collected, and genomic analysis of formalin-fixed, paraffin-embedded tissue samples was performed via an internal next-generation sequencing (NGS) platform (SNaPshot). The end points examined were relapse-free survival (RFS), distant metastasis-free survival (DMFS), overall survival (OS), and melanoma-specific survival (MSS). Uni- and multivariable Cox regressions were performed to calculate the hazard ratios. RESULTS: The study included 92 patients with a median age of 69 years and a male/female ratio of 2:1. A Breslow depth greater than 4 mm, a higher mitotic rate, an advanced T stage, and a KIT mutation had a negative impact on RFS. A primary lesion in the head and neck, a mitotic rate exceeding 10 mitoses per mm2, a CDH1 mutation, or a KIT mutation was significantly associated with a shorter DMFS. Overall survival was significantly lower with older age at diagnosis and a higher mitotic rate. An older age at diagnosis also had a negative impact on MSS. CONCLUSION: Traditional histopathologic factors and specific tumor mutations displayed a significant correlation with disease recurrence and survival for patients with high-risk stage II melanoma. This study supported the use of genomic testing of high-risk stage II melanomas for prognostic prediction and risk stratification.