Discovery of novel nitrofuran PROTAC-like compounds as dual inhibitors and degraders targeting STING.

Aberrant activation of the innate immune molecule STING can initiate inflammation and autoimmune diseases. Small molecule inhibitors targeting STING have demonstrated therapeutic efficacy against these conditions. Moreover, employing degradants to target STING represents a novel approach to drug design strategy. Consequently, we have designed and synthesized a series of covalent degradants targeting STING. Among them, compound P8 exhibited the highest degradation capacity, with a 24-h DC50 of 2.58 µM in THP-1 cells. In THP-1 cells, P8 specifically degraded STING proteins through the lysosomal pathway, acting as dual a degrader and inhibitor to manifest anti-inflammatory effects. Conversely, in RAW264.7 cells, P8 solely acted as an inhibitor without exhibiting degradative capacity towards the STING protein level. Additionally, P8 displayed renal-protective properties in a cisplatin-induced acute kidney injury model. These results highlight the significant potential of further investigating compound P8.

Clinical outcomes and microenvironment profiling in relapsed/refractory multiple myeloma patients with extramedullary disease receiving anti-BCMA CAR T-cell-based therapy.

Relapsed/refractory multiple myeloma patients with extramedullary disease (EMD) have unfavorable prognosis and lack effective therapy. Chimeric antigen receptor (CAR) T-cell activities in EMD have yet to be determined; how EMD-specific microenvironment influences the clinical outcomes of CAR T-cell therapy remains of great interest. In this prospective cohort study, patients with histologically confirmed extra-osseous EMD were enrolled and treated with combined anti-BCMA and anti-CD19 CAR T-cell therapy from May 2017 to September 2023. Thirty-one patients were included in the study. Overall response occurred in 90.3% of medullary disease and 64.5% of EMD (p = .031). Discrepancies in treatment response were noted between medullary and extramedullary diseases, with EMD exhibiting suboptimal and delayed response, as well as shortened response duration. With a median follow-up of 25.3 months, the median progression-free and overall survival were 5.0 and 9.7 months, respectively. Landmark analysis demonstrated that progression within 6 months post-infusion is strongly associated with an increased risk of death (HR = 4.58; p = .029). Compared with non-EMD patients, patients with EMD showed inferior survival outcomes. Unique CAR-associated local toxicities at EMD were seen in 22.6% patients and correlated with the occurrence and severity of systemic cytokine release syndrome. To the cutoff date, 65% treated patients experienced EMD progression, primarily in the form of BCMA+ progression. The pretherapy EMD immunosuppressive microenvironment, characterized by infiltration of exhausted CD8+ T cells, was associated with inferior clinical outcomes. CAR T cells have therapeutic activity in relapsed/refractory EMD, but the long-term survival benefits may be limited. EMD-specific microenvironment potentially impacts treatment. Further efforts are needed to extend EMD remission and improve long-term outcomes.

Anti-BCMA/GPRC5D bispecific CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, single-centre, phase 1 trial.

BACKGROUND: Some challenges still exist with single-target B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapies due to variable or negative BCMA expression, although they have yielded remarkable efficacy in relapsed or refractory multiple myeloma. We developed anti-BCMA/GPRC5D bispecific CARs to mitigate the limitations and potentiate the functions of CAR T cells. METHODS: This single-arm, phase 1 trial was conducted at the Affiliated Hospital of Xuzhou Medical University (Xuzhou, China). The trial enrolled patients aged 18-75 years with relapsed or refractory multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-3. Anti-BCMA/GPRC5D bispecific CAR T cells were administered at 0·5 × 106, 1·0 × 106, 2·0 × 106, and 4·0 × 106 CAR T cells per kg in the dose-escalation phase, with additional patients included at the dose selected for the dose-expansion phase. The primary endpoint was safety, which included dose-limiting toxicity and maximum tolerated dose. Activity was also evaluated as a secondary endpoint. The maximum tolerated dose was chosen for the dose-expansion phase. Safety and activity analyses were done in all patients who received anti-BCMA/GPRC5D bispecific CAR T cells as defined in the protocol. This trial is registered with ClinicalTrials.gov (NCT05509530) and is complete. FINDINGS: Between Sept 1, 2022, and Nov 3, 2023, 24 patients were enrolled and underwent apheresis. Three patients were excluded after apheresis (two patients discontinued due to rapid disease progression and one patient was withdrawn because of failed manufacture of CAR T cells), so 21 patients were infused with anti-BCMA/GPRC5D bispecific CAR T cells. Median follow-up was 5·8 months (IQR 5·2-6·7). Median age was 62 years (IQR 56-67). Eight (38%) patients were male, and 13 (62%) female. All patients were Chinese. At the 4·0 × 106 CAR T cells per kg dose, two patients had dose-limiting toxicities, of whom one died of subarachnoid haemorrhage (which was not considered to be related to the study treatment). The maximum tolerated dose was identified as 2·0 × 106 CAR T cells per kg. The most common grade 3 or worse adverse events were haematological toxicities in 19 (90%) patients (except lymphopenia). 15 (71%) patients had cytokine release syndrome, of which all cases were grade 1 or 2. One case of grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in a patient who received 4·0 × 106 CAR T cells per kg. No ICANS or grade 3 or worse organ toxicities were observed in patients who received 0·5-2·0 × 106 CAR T cells per kg. The overall response rate was 86% (18 of 21 patients), with 13 (62%) patients having a complete response or better, and 17 (81%) patients having measurable residual disease negativity. Of the 12 patients who received 2·0 × 106 CAR T cells per kg (three in the dose-escalation phase and an addition nine in the dose-expansion phase), the overall response rate was 92% (11 of 12 patients) with nine (75%) patients having a complete response or better. INTERPRETATION: Anti-BCMA/GPRC5D bispecific CAR T cells show a good safety profile and encouraging activity in patients with relapsed or refractory multiple myeloma. FUNDING: National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A complex metabolic network and its biomarkers regulate laccase production in white-rot fungus Cerrena unicolor 87613.

BACKGROUND: White-rot fungi are known to naturally produce high quantities of laccase, which exhibit commendable stability and catalytic efficiency. However, their laccase production does not meet the demands for industrial-scale applications. To address this limitation, it is crucial to optimize the conditions for laccase production. However, the regulatory mechanisms underlying different conditions remain unclear. This knowledge gap hinders the cost-effective application of laccases. RESULTS: In this study, we utilized transcriptomic and metabolomic data to investigate a promising laccase producer, Cerrena unicolor 87613, cultivated with fructose as the carbon source. Our comprehensive analysis of differentially expressed genes (DEGs) and differentially abundant metabolites (DAMs) aimed to identify changes in cellular processes that could affect laccase production. As a result, we discovered a complex metabolic network primarily involving carbon metabolism and amino acid metabolism, which exhibited contrasting changes between transcription and metabolic patterns. Within this network, we identified five biomarkers, including succinate, serine, methionine, glutamate and reduced glutathione, that played crucial roles in co-determining laccase production levels. CONCLUSIONS: Our study proposed a complex metabolic network and identified key biomarkers that determine the production level of laccase in the commercially promising Cerrena unicolor 87613. These findings not only shed light on the regulatory mechanisms of carbon sources in laccase production, but also provide a theoretical foundation for enhancing laccase production through strategic reprogramming of metabolic pathways, especially related to the citrate cycle and specific amino acid metabolism.

A systematic review on the appropriate discounting rates for the economic evaluation of gene therapies: whether a specific approach is justified to tackle the challenges?

OBJECTIVES: Discounting the cost and effect for health intervention is a controversial topic over the last two decades. In particular, the cost-effectiveness of gene therapies is especially sensitive to the discount rate because of the substantial delay between the upfront cost incurred and long-lasing clinical benefits received. This study aims to investigate the influence of employing alternative discount rates on the incremental cost-effectiveness ratio (ICER) of gene therapies. METHODS: A systematic review was conducted to include health economic evaluations of gene therapies that were published until April 2023. RESULTS: Sensitivity or scenario analysis indicated that discount rate represented one of the most influential factors for the ICERs of gene therapies. Discount rate for cost and benefit was positively correlated with the cost-effectiveness of gene therapies, that is, a lower discount rate significantly improves the ICERs. The alternative discount rate employed in some cases could be powerful to alter the conclusion on whether gene therapies are cost-effective and acceptable for reimbursement. CONCLUSIONS: Although discount rate will have substantial influence on the ICERs of gene therapies, there lacks solid evidence to justify a different discounting rule for gene therapies. However, it is proposed that the discount rate in the reference case should be updated to reflect the real-time preference, which in turn will affect the ICERs and reimbursement of gene therapies more profoundly than conventional therapies.

Transrectal contrast-enhanced ultrasound-guided transperineal core-needle biopsy versus endoscopic forceps biopsy in the diagnosis of complex rectal lesions.

Background: The preoperative pathological diagnosis of rectal lesions is crucial for formulating treatment plans. For subepithelial lesions (SELs) and larger lesions with necrosis of the rectum, endoscopic forceps biopsy (EFB) cannot provide an accurate pathological diagnosis in most cases. By comparing the efficacy and safety of transrectal contrast-enhanced ultrasound-guided transperineal core-needle biopsy (TRCEUS-TP-CNB) and EFB, this study explored the value of TRCEUS-TP-CNB in the diagnosis of complex rectal lesions, such as SELs. Methods: A retrospective, cross-sectional study was conducted with 32 consecutive patients with complex rectal lesions admitted to our hospital from May 2016 to June 2022. Clinical, ultrasound, and pathological data were collected from these patients who underwent EFB followed by TRCEUS-TP-CNB. Results: The success rate of EFB was 21.88% (7/32) and that of TRCEUS-TP-CNB was 93.75% (30/32). No significant complications were observed for either biopsy method. Factors affecting the success rate of EFB included the lesion width (cm) (1.90±0.62 vs. 4.26±2.40, P<0.001) and lesion thickness (cm) (1.29±0.51 vs. 2.96±1.75, P<0.001). The success rate of TRCEUS-TP-CNB was not affected by these factors. In the paired study of TRCEUS-TP-CNB and EFB, the times of samples per person (1 vs. 2.14±0.90, P=0.015), number of specimens per sample (8.27±1.93 vs. 3.31±1.67, P<0.001), lesion width (cm) (3.79±2.42 vs. 1.90±0.62, P=0.001), and lesion thickness (cm) (2.64±1.75 vs. 1.29±0.51, P=0.001) were the factors affecting the difference of the sampling success rate. In the SELs, the success rate of EFB was 10% (1/10) and that of TRCEUS-TP-CNB was 100% (10/10), and the difference between the two groups was statistically significant (P=0.004). Conclusions: TRCEUS-TP-CNB is an effective biopsy method for complex rectal lesions. The success rate of EFB is lower in the larger lesions. Compared with EFB, TRCEUS-TP-CNB required fewer times of samples be taken and obtained more specimens. For larger lesions and SELs of the rectum, TRCEUS-TP-CNB is expected to become one of the preferred biopsy methods.

Synthesis, structural characterization, analytical profiling, and application to authentic samples of synthesized Phase I metabolites of the synthetic cannabinoid 5F-MDMB-PICA.

5F-MDMB-PICA, an indole-type synthetic cannabinoid (SC), was classified illicit globally in 2020. Although the extensive metabolism of 5F-MDMB-PICA in the human body warrants the development of robust analytical methods for metabolite detection and quantification, a current lack of reference standards for characteristic metabolites hinders such method creation. This work described the synthesis of 18 reference standards for 5F-MDMB-PICA and its possible Phase I metabolites, including three hydroxylated positional isomers R14 to R16. All the compounds were systematic characterized via nuclear magnetic resonance, Fourier transform infrared spectroscopy, and high-resolution mass spectrometry. Furthermore, two methods were developed for the simultaneous detection of all standards using liquid chromatography-tandem mass spectrometry and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. By comparison with authentic samples, R17 was identified as a suitable urine biomarker for 5F-MDMB-PICA uptake.

Transcriptomic and metabolomic analysis unveils a negative effect of glutathione metabolism on laccase activity in Cerrena unicolor 87613.

The white rot fungus Cerrena unicolor 87613 has been previously shown to be a promising resource in laccase production, an enzyme with significant biotechnological applications. Conventional methods face technical challenges in improving laccase activity. Attempts are still being made to develop novel approaches for further enhancing laccase activity. This study aimed to understand the regulation of laccase activity in C. unicolor 87613 for a better exploration of the novel approach. Transcriptomic and metabolomic analyses were performed to identify key genes and metabolites involved in extracellular laccase activity. The findings indicated a strong correlation between the glutathione metabolism pathway and laccase activity. Subsequently, experimental verifications were conducted by manipulating the pathway using chemical approaches. The additive reduced glutathione (GSH) dose-dependently repressed laccase activity, while the GSH inhibitors (APR-246) and reactive oxygen species (ROS) inducer (H2O2) enhanced laccase activity. Changes in GSH levels could determine the intracellular redox homeostasis in interaction with ROS and partially affect the expression level of laccase genes in C. unicolor 87613 in turn. In addition, GSH synthetase was found to mediate GSH abundance in a feedback loop. This study suggests that laccase activity is negatively influenced by GSH metabolism and provides a theoretical basis for a novel strategy to enhance laccase activity by reprogramming glutathione metabolism at a specific cultivation stage.IMPORTANCEThe production of laccase activity is limited by various conventional approaches, such as heterologous expression, strain screening, and optimization of incubation conditions. There is an urgent need for a new strategy to meet industrial requirements more effectively. In this study, we conducted a comprehensive analysis of the transcriptome and metabolome of Cerrena unicolor 87613. For the first time, we discovered a negative role played by reduced glutathione (GSH) and its metabolic pathway in influencing extracellular laccase activity. Furthermore, we identified a feedback loop involving GSH, GSH synthetase gene, and GSH synthetase within this metabolic pathway. These deductions were confirmed through experimental investigations. These findings not only advanced our understanding of laccase activity regulation in its natural producer but also provide a theoretical foundation for a strategy to enhance laccase activity by reprogramming glutathione metabolism at a specific cultivation stage.

Novel endomorphin analogues CEMR-1 and CEMR-2 produce potent and long-lasting antinociception with a favourable side effect profile at the spinal level.

BACKGROUND AND PURPOSE: Endomorphins have shown great promise as pharmaceutics for the treatment of pain. We have previously confirmed that novel endomorphin analogues CEMR-1 and CEMR-2 behaved as potent µ agonists and displayed potent antinociceptive activities at the supraspinal and peripheral levels. The present study was undertaken to evaluate the antinociceptive properties of CEMR-1 and CEMR-2 following intrathecal (i.t.) administration. Furthermore, their antinociceptive tolerance and opioid-like side effects were also determined. EXPERIMENTAL APPROACH: The spinal antinociceptive effects of CEMR-1 and CEMR-2 were determined in a series of pain models, including acute radiant heat paw withdrawal test, spared nerve injury-induced neuropathic pain, complete Freund's adjuvant-induced inflammatory pain, visceral pain and formalin pain. Antinociceptive tolerance was evaluated in radiant heat paw withdrawal test. KEY RESULTS: Spinal administration of CEMR-1 and CEMR-2 produced potent and prolonged antinociceptive effects in acute pain. CEMR-1 and CEMR-2 may produce their antinociception through distinct µ receptor subtypes. These two analogues also exhibited significant analgesic activities in neuropathic, inflammatory, visceral and formalin pain at the spinal level. It is noteworthy that CEMR-1 showed non-tolerance-forming analgesic properties, while CEMR-2 exhibited substantially reduced antinociceptive tolerance. Furthermore, both analogues displayed no or reduced side effects on conditioned place preference response, physical dependence, locomotor activity and gastrointestinal transit. CONCLUSIONS AND IMPLICATIONS: The present investigation demonstrated that CEMR-1 and CEMR-2 displayed potent and long-lasting antinociception with a favourable side effect profile at the spinal level. Therefore, CEMR-1 and CEMR-2 might serve as promising analgesic compounds with minimal opioid-like side effects.

Diagnosis of liver fibrosis and liver function reserve through non-invasive multispectral photoacoustic imaging.

Liver function reserve (LFR) is the sum of remnant functional hepatic cells after liver injury. In the pathologic process of liver fibrosis (LF), LFR is impaired. LFR assessment can help determine the safe scope of liver resection or drug regimen and predict prognosis of patients with liver disease. Here, we used a photoacoustic imaging (PAI) system to assess LF and LFR in rabbit models. We performed PAI, ultrasound elastography and biopsy for 21 rabbits developing none (n = 6) and LF (n = 15). In vivo indocyanine green (ICG) measurements by PAI showed that LF group presented a significantly attenuated ICG clearance compared to control group, indicating LFR impairment of LF. Another finding was a significantly higher collagen photoacoustic signal intensity value was observed in LF both in vivo and in vitro. Our findings demonstrated that PAI was potentially effective to evaluate LFR and collagen accumulation of LF.

Genome-wide study of Cerrena unicolor 87613 laccase gene family and their mode prediction in association with substrate oxidation.

BACKGROUND: Laccases are green biocatalysts with wide industrial applications. The study of efficient and specific laccase producers remains a priority. Cerrena species have been shown to be promising basidiomycete candidates for laccase production. Although two sets of Cerrena genome data have been publicly published, no comprehensive bioinformatics study of laccase gene family in C. unicolor has been reported, particularly concerning the analysis of their three-dimensional (3D) structures and molecular docking to substrates, like ABTS and aflatoxin B1 (AFB1). RESULTS: In this study, we conducted a comprehensive genome-wide analysis of laccase gene family in C. unicolor 87613. We identified eighteen laccase genes (CuLacs) and classified them into three clades using phylogenetic analysis. We characterized these laccases, including their location in contig 5,6,9,12,15,19,26,27, gene structures of different exon-intron arrangements, molecular weight ranging from 47.89 to 141.41 kDa, acidic pI value, 5-15 conserved protein motifs, signaling peptide of extracellular secretion (harbored by 13 CuLacs) and others. In addition, the analysis of cis-acting element in laccase promoters indicated that the transcription response of CuLac gene family was regulatable and complex under different environmental cues. Furthermore, analysis of transcription pattern revealed that CuLac8, 12 and CuLac2, 13 were the predominant laccases in response to copper ions or oxidative stress, respectively. Finally, we focused on the 3D structure analysis of CuLac proteins. Seven laccases with extra transmembrane domains or special sequences were particularly interesting. Predicted structures of each CuLac protein with or without these extra sequences showed altered interacting amino acid residues and binding sites, leading to varied affinities to both ABTS and AFB1. As far as we know, it is the first time to discuss the influence of the extra sequence on laccase's affinity to substrates. CONCLUSIONS: Our findings provide robust genetic data for a better understanding of the laccase gene family in C. unicolor 87613, and create a foundation for the molecular redesign of CuLac proteins to enhance their industrial applications.

Pathophysiology of obesity and its associated diseases.

The occurrence of obesity has increased across the whole world. Many epidemiological studies have indicated that obesity strongly contributes to the development of cancer, cardiovascular diseases, type 2 diabetes, liver diseases and other disorders, accounting for a heavy burden on the public and on health-care systems every year. Excess energy uptake induces adipocyte hypertrophy, hyperplasia and formation of visceral fat in other non-adipose tissues to evoke cardiovascular disease, liver diseases. Adipose tissue can also secrete adipokines and inflammatory cytokines to affect the local microenvironment, induce insulin resistance, hyperglycemia, and activate associated inflammatory signaling pathways. This further exacerbates the development and progression of obesity-associated diseases. Although some progress in the treatment of obesity has been achieved in preclinical and clinical studies, the progression and pathogenesis of obesity-induced diseases are complex and unclear. We still need to understand their links to better guide the treatment of obesity and associated diseases. In this review, we review the links between obesity and other diseases, with a view to improve the future management and treatment of obesity and its co-morbidities.

Cytopenia after CAR­T cell therapy: Analysis of 63 patients with relapsed and refractory B­cell non­Hodgkin lymphoma.

The present study aimed to determine the clinical characteristics of cytopenia in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (B-NHL) who were treated with chimeric antigen receptor T-cell (CAR-T) therapy. Thus, a total of 63 patients with relapsed and refractory B-NHL who underwent CAR-T therapy between March 2017 and October 2021 were retrospectively selected for analysis. Neutropenia, anemia and thrombocytopenia at grade ≥3 occurred in 48 (76.19%), 16 (25.39%) and 15 (23.80%) cases, respectively. The results of a multivariate analysis demonstrated that the baseline absolute neutrophil count (ANC) and hemoglobin concentration were independent risk factors for grade ≥3 cytopenia. A total of 3 patients died early and were therefore excluded from the present study. Furthermore, cell recovery was examined at day +28 after infusion; 21 patients (35%) did not recover from cytopenia and 39 patients (65%) recovered. A multivariate analysis demonstrated that the baseline ANC <2.29×109/l, baseline hemoglobin <114.50 g/l and baseline IL-6 >21.43 pg/l were independent risk factors affecting hemocyte recovery. In conclusion, patients with relapsed and refractory B-NHL exhibited an increased incidence of grade ≥3 hematologic toxicity following CAR-T cell therapy, while baseline blood cell and IL-6 levels are independent risk factors for hemocyte recovery.

Pediatric Rheumatology Care and Outcomes Improvement Network's Quality Measure Set to Improve Care of Children With Juvenile Idiopathic Arthritis.

OBJECTIVE: To describe the selection, development, and implementation of quality measures (QMs) for juvenile idiopathic arthritis (JIA) by the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN), a multihospital learning health network using quality improvement methods and leveraging QMs to drive improved outcomes across a JIA population since 2011. METHODS: An American College of Rheumatology-endorsed multistakeholder process previously selected initial process QMs. Clinicians in PR-COIN and parents of children with JIA collaboratively selected outcome QMs. A committee of rheumatologists and data analysts developed operational definitions. QMs were programmed and validated using patient data. Measures are populated by registry data, and performance is displayed on automated statistical process control charts. PR-COIN centers use rapid-cycle quality improvement approaches to improve performance metrics. The QMs are revised for usefulness, to reflect best practices, and to support network initiatives. RESULTS: The initial QM set included 13 process measures concerning standardized measurement of disease activity, collection of patient-reported outcome assessments, and clinical performance measures. Initial outcome measures were clinical inactive disease, low pain score, and optimal physical functioning. The revised QM set has 20 measures and includes additional measures of disease activity, data quality, and a balancing measure. CONCLUSION: PR-COIN has developed and tested JIA QMs to assess clinical performance and patient outcomes. The implementation of robust QMs is important to improve quality of care. PR-COIN's set of JIA QMs is the first comprehensive set of QMs used at the point-of-care for a large cohort of JIA patients in a variety of pediatric rheumatology practice settings.

Predicting prognosis, immunotherapy and distinguishing cold and hot tumors in clear cell renal cell carcinoma based on anoikis-related lncRNAs.

Background: Clear cell renal cell carcinoma (ccRCC) is the most frequently occurring malignant tumor within the kidney cancer subtype. It has low sensitivity to traditional radiotherapy and chemotherapy, the optimal treatment for localized ccRCC has been surgical resection, but even with complete resection the tumor will be eventually developed into metastatic disease in up to 40% of localized ccRCC. For this reason, it is crucial to find early diagnostic and treatment markers for ccRCC. Methods: We obtained anoikis-related genes (ANRGs) integrated from Genecards and Harmonizome dataset. The anoikis-related risk model was constructed based on 12 anoikis-related lncRNAs (ARlncRNAs) and verified by principal component analysis (PCA), Receiver operating characteristic (ROC) curves, and T-distributed stochastic neighbor embedding (t-SNE), and the role of the risk score in ccRCC immune cell infiltration, immune checkpoint expression levels, and drug sensitivity was evaluated by various algorithms. Additionally, we divided patients based on ARlncRNAs into cold and hot tumor clusters using the ConsensusClusterPlus (CC) package. Results: The AUC of risk score was the highest among various factors, including age, gender, and stage, indicating that the model we built to predict survival was more accurate than the other clinical features. There was greater sensitivity to targeted drugs like Axitinib, Pazopanib, and Sunitinib in the high-risk group, as well as immunotherapy drugs. This shows that the risk-scoring model can accurately identify candidates for ccRCC immunotherapy and targeted therapy. Furthermore, our results suggest that cluster 1 is equivalent to hot tumors with enhanced sensitivity to immunotherapy drugs. Conclusion: Collectively, we developed a risk score model based on 12 prognostic lncRNAs, expected to become a new tool for evaluating the prognosis of patients with ccRCC, providing different immunotherapy strategies by screening for hot and cold tumors.

Comorbidity of Anxiety and Hypertension: Common Risk Factors and Potential Mechanisms.

Anxiety is more common in patients with hypertension, and these two conditions frequently coexist. Recently, more emphasis has been placed on determining etiology in patients with comorbid hypertension and anxiety. This review focuses on the common risk factors and potential mechanisms of comorbid hypertension and anxiety. Firstly, we analyze the common risk factors of comorbid hypertension and anxiety including age, smoking, alcohol abuse, obesity, lead, and traffic noise. The specific mechanisms underlying hypertension and anxiety were subsequently discussed, including interleukin (IL)-6 (IL-6), IL-17, reactive oxygen species (ROS), and gut dysbiosis. Increased IL-6, IL-17, and ROS accelerate the development of hypertension and anxiety. Gut dysbiosis leads to hypertension and anxiety by reducing short-chain fatty acids, vitamin D, and 5-hydroxytryptamine (5-HT), and increasing trimethylamine N-oxide (TAMO) and MYC. These shared risk factors and potential mechanisms may provide an effective strategy for treating and preventing hypertension and comorbid anxiety.

ICG clearance test based on photoacoustic imaging for assessment of human liver function reserve: An initial clinical study.

Liver function reserve (LFR) plays an extensive and important role in patients with liver disease. Indocyanine green (ICG) clearance test is the standard diagnostic approach for LFR evaluation which was performed by spectrophotometry or pulse dye densitometry (PDD). Spectrophotometry is the gold standard, it's invasive and not real-time. PDD is non-invasive, but accuracy of PDD is controversial. Taken spectrophotometry as the reference standard, this study investigated the accuracy of photoacoustic imaging (PAI) method for LFR assessment and compared to PDD in healthy volunteers. The results demonstrated a strong correlation between PAI method and spectrophotometry (r = 0.9649, p < 0.0001). No significant difference was shown in ICG clearance between PAI and spectrophotometry method (rate constant k1 vs. k2, 0.001158 +-0.00042 vs. 0.001491 +- 0.00045, p = 0.0727; half-life t1 vs. t2, 601.2 s vs. 474.4 s, p = 0.1450). These results indicated that PAI may be valuable as a noninvasive, accurate diagnostic tool for LFR assessment in human.

Usefulness of the lupus low disease activity state as a treatment target in childhood-onset SLE.

OBJECTIVE: Treat-to-target (T2T) strategies are advocated to improve prognosis in childhood-onset SLE (cSLE). Proposed T2T states include SLEDAI score of <4 (SLEDAI-LD), limited corticosteroid use (low-CS), and lupus low disease activity state (LLDAS). We sought to compare T2T states for their association with cSLE prognosis under consideration of relevant disease characteristics such as pre-existing damage, race and lupus nephritis (LN). METHODS: Longitudinal data from 165 patients enrolled in the Cincinnati Lupus Registry were included. LN presence was based on renal biopsy, and patients were followed up until 18 years of age. RESULTS: The 165 patients (LN: 45, white: 95) entered the registry within a median of 0 (IQR: 0-1) year post diagnosis and were followed up for a median of 4 (IQR: 2-5) years during which 80%, 92% and 94% achieved LLDAS, low-CS and SLEDAI-LD. Patients with LN were significantly less likely to achieve any T2T state (all p<0.03) and required a significantly longer time to reach them (all p<0.0001). Over the study period, patients maintained low-CS, SLEDAI-LD or LLDAS for a median of 76% (IQR: 48%-100%), 86% (IQR: 55%-100%) or 39% (IQR: 13%-64%) of their follow-up. Significant predictors of failure to maintain LLDAS included LN (p≤0.0062), pre-existing damage (p≤0.0271) and non-white race (p≤0.0013). There were 22%, 20% and 13% of patients who reached SLEDAI-LD, CS-low and LLDAS and nonetheless acquired new damage. Patients with LN had a higher risk of new damage than patients without LN even if achieving low-CS (p=0.009) or LLDAS (p=0.04). CONCLUSIONS: Patients with LN and pre-existing damage are at higher risk of increased future damage acquisition, even if achieving a T2T state such as LLDAS. Among proposed common T2T states, the LLDAS is the hardest to achieve and maintain. The LLDAS may be considered the preferred T2T measure as it conveys the highest protection from acquiring additional disease damage.