Time-dependent proteomics and drug response in expanding cancer cells.

Cancer cell line is commonly used for discovery and development of anti-cancer drugs. It is generally considered that drug response remains constant for a certain cell line due to the identity of genetics thus protein patterns. Here, we demonstrated that cancer cells continued dividing even after reaching confluence, in that the proteomics was changed continuously and dramatically with strong relevance to cell division, cell adhesion and cell metabolism, indicating time-dependent intrinsically reprogramming of cells during expansion. Of note, the inhibition effect of most anti-cancer drugs was strikingly attenuated in culture cells along with cell expansion, with the strongest change at the third day when cells were still expanding. Profiling of an FDA-approved drug library revealed that attenuation of response with cell expansion is common for most drugs, an exception was TAK165 that was a selective inhibitor of mitochondrial respiratory chain complex I. Finally, we screened a panel of natural products and identified four pentacyclic triterpenes as selective inhibitors of cancer cells under prolonged growth. Taken together, our findings underscore that caution should be taken in evaluation of anti-cancer drugs using culture cells, and provide agents selectively targeting overgrowth cancer cells.

Prognosis of patients with advanced bile tract carcinoma: assessment using the modified-Gustave Roussy Immune Score (mGRIm-s) as a clinico-immunological tool.

BACKGROUND: The emergence of immune checkpoint inhibitors (ICIs) has enhanced survival outcomes for certain patients with advanced biliary tract carcinoma (BTC). Pinpointing those who would benefit most from immunotherapy remains elusive. We investigated the predictive value of the modified Gustave Roussy Immune Score (mGRIm-s) in BTC patients treated with ICIs. METHODS: Data from 110 patients at Chinese People's Liberation Army General Hospital, spanning September 2015 to April 2021, were analyzed. The median follow-up duration was 38.7 months as of December 2023. Risk factors included low albumin, high lactate dehydrogenase, and an elevated neutrophil-lymphocyte ratio. Patients were stratified into low (patients with no risk factors) and high (patients with at least one risk factor) mGRIm-s groups based on these factors. RESULTS: Survival outcomes post-immunotherapy favored the low mGRIm-s group, with significantly improved progression-free survival (PFS) and overall survival (OS) (8.50 months vs. 3.70 months and 21.60 months vs. 8.00 months). COX regression confirmed an elevated risk in the high mGRIm-s group. Subgroup analysis highlighted a notable survival advantage for low mGRIm-s patients receiving first-line immunotherapy. CONCLUSIONS: This study underscores mGRIm-s's potential in predicting immunotherapy response in BTC, paving the way for more targeted approaches.

Are Current Survival Prediction Tools Useful When Treating Subsequent Skeletal-related Events From Bone Metastases?

BACKGROUND: Bone metastasis in advanced cancer is challenging because of pain, functional issues, and reduced life expectancy. Treatment planning is complex, with consideration of factors such as location, symptoms, and prognosis. Prognostic models help guide treatment choices, with Skeletal Oncology Research Group machine-learning algorithms (SORG-MLAs) showing promise in predicting survival for initial spinal metastases and extremity metastases treated with surgery or radiotherapy. Improved therapies extend patient lifespans, increasing the risk of subsequent skeletal-related events (SREs). Patients experiencing subsequent SREs often suffer from disease progression, indicating a deteriorating condition. For these patients, a thorough evaluation, including accurate survival prediction, is essential to determine the most appropriate treatment and avoid aggressive surgical treatment for patients with a poor survival likelihood. Patients experiencing subsequent SREs often suffer from disease progression, indicating a deteriorating condition. However, some variables in the SORG prediction model, such as tumor histology, visceral metastasis, and previous systemic therapies, might remain consistent between initial and subsequent SREs. Given the prognostic difference between patients with and without a subsequent SRE, the efficacy of established prognostic models-originally designed for individuals with an initial SRE-in addressing a subsequent SRE remains uncertain. Therefore, it is crucial to verify the model's utility for subsequent SREs. QUESTION/PURPOSE: We aimed to evaluate the reliability of the SORG-MLAs for survival prediction in patients undergoing surgery or radiotherapy for a subsequent SRE for whom both the initial and subsequent SREs occurred in the spine or extremities. METHODS: We retrospectively included 738 patients who were 20 years or older who received surgery or radiotherapy for initial and subsequent SREs at a tertiary referral center and local hospital in Taiwan between 2010 and 2019. We excluded 74 patients whose initial SRE was in the spine and in whom the subsequent SRE occurred in the extremities and 37 patients whose initial SRE was in the extremities and the subsequent SRE was in the spine. The rationale was that different SORG-MLAs were exclusively designed for patients who had an initial spine metastasis and those who had an initial extremity metastasis, irrespective of whether they experienced metastatic events in other areas (for example, a patient experiencing an extremity SRE before his or her spinal SRE would also be regarded as a candidate for an initial spinal SRE). Because these patients were already validated in previous studies, we excluded them in case we overestimated our result. Five patients with malignant primary bone tumors and 38 patients in whom the metastasis's origin could not be identified were excluded, leaving 584 patients for analysis. The 584 included patients were categorized into two subgroups based on the location of initial and subsequent SREs: the spine group (68% [399]) and extremity group (32% [185]). No patients were lost to follow-up. Patient data at the time they presented with a subsequent SRE were collected, and survival predictions at this timepoint were calculated using the SORG-MLAs. Multiple imputation with the Missforest technique was conducted five times to impute the missing proportions of each predictor. The effectiveness of SORG-MLAs was gauged through several statistical measures, including discrimination (measured by the area under the receiver operating characteristic curve [AUC]), calibration, overall performance (Brier score), and decision curve analysis. Discrimination refers to the model's ability to differentiate between those with the event and those without the event. An AUC ranges from 0.5 to 1.0, with 0.5 indicating the worst discrimination and 1.0 indicating perfect discrimination. An AUC of 0.7 is considered clinically acceptable discrimination. Calibration is the comparison between the frequency of observed events and the predicted probabilities. In an ideal calibration, the observed and predicted survival rates should be congruent. The logarithm of observed-to-expected survival ratio [log(O:E)] offers insight into the model's overall calibration by considering the total number of observed (O) and expected (E) events. The Brier score measures the mean squared difference between the predicted probability of possible outcomes for each individual and the observed outcomes, ranging from 0 to 1, with 0 indicating perfect overall performance and 1 indicating the worst performance. Moreover, the prevalence of the outcome should be considered, so a null-model Brier score was also calculated by assigning a probability equal to the prevalence of the outcome (in this case, the actual survival rate) to each patient. The benefit of the prediction model is determined by comparing its Brier score with that of the null model. If a prediction model's Brier score is lower than the null model's Brier score, the prediction model is deemed as having good performance. A decision curve analysis was performed for models to evaluate the "net benefit," which weighs the true positive rate over the false positive rate against the "threshold probabilities," the ratio of risk over benefit after an intervention was derived based on a comprehensive clinical evaluation and a well-discussed shared-decision process. A good predictive model should yield a higher net benefit than default strategies (treating all patients and treating no patients) across a range of threshold probabilities. RESULTS: For the spine group, the algorithms displayed acceptable AUC results (median AUCs of 0.69 to 0.72) for 42-day, 90-day, and 1-year survival predictions after treatment for a subsequent SRE. In contrast, the extremity group showed median AUCs ranging from 0.65 to 0.73 for the corresponding survival periods. All Brier scores were lower than those of their null model, indicating the SORG-MLAs' good overall performances for both cohorts. The SORG-MLAs yielded a net benefit for both cohorts; however, they overestimated 1-year survival probabilities in patients with a subsequent SRE in the spine, with a median log(O:E) of -0.60 (95% confidence interval -0.77 to -0.42). CONCLUSION: The SORG-MLAs maintain satisfactory discriminatory capacity and offer considerable net benefits through decision curve analysis, indicating their continued viability as prediction tools in this clinical context. However, the algorithms overestimate 1-year survival rates for patients with a subsequent SRE of the spine, warranting consideration of specific patient groups. Clinicians and surgeons should exercise caution when using the SORG-MLAs for survival prediction in these patients and remain aware of potential mispredictions when tailoring treatment plans, with a preference for less invasive treatments. Ultimately, this study emphasizes the importance of enhancing prognostic algorithms and developing innovative tools for patients with subsequent SREs as the life expectancy in patients with bone metastases continues to improve and healthcare providers will encounter these patients more often in daily practice. LEVEL OF EVIDENCE: Level III, prognostic study.

Efficacy and safety of canakinumab in systemic juvenile idiopathic arthritis, the first Chinese experience.

BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) is a severe form of juvenile arthritis that is characterized by chronic joint inflammation and systemic symptoms such as fever, rash, and organ involvement. Anti-IL-6 receptor monoclonal antibody tocilizumab is an effective treatment. However, some patients still experience persisting or recurrent symptoms and the real-world effectiveness of canakinumab in Chinese patients with sJIA has never been reported. Therefore, this study aimed to assess the efficacy and safety of canakinumab in Chinese patients with sJIA using real-world data. METHODS: We conducted a retrospective study on children with active sJIA. Clinical features, laboratory data, corticosteroid dosage, and adverse events (AEs) were collected at baseline and at 4, 8, 12, and 24 weeks after initiating canakinumab treatment. RESULTS: Seven female and four male patients were included in the study. All patients had previously been treated with tocilizumab and were administered canakinumab for 12.4 ± 3.4 months. Notably, significant improvements were observed in both clinical signs and symptoms as well as laboratory indicators. Four children under corticosteroid treatment were able to successfully discontinue their corticosteroid therapy: one at week 4, two at week 12, and one at week 24. Notably, there was a significant reduction in the number of tender and swollen joints (P = 0.0059) as well as the systemic juvenile arthritis disease activity score (P < 0.0001). The most common AE was infection, but no patients experienced serious AEs. No cases of macrophage activation syndrome or death were reported during the follow-up period. CONCLUSIONS: Canakinumab was found to be potentially efficacious and safe in Chinese patients with sJIA. No new AEs were observed with canakinumab treatment.

Loss and microglia phagocytosis of synaptic proteins in frontotemporal lobar degeneration with TDP-43 proteinopathy.

Cortical synaptic loss has emerged as an early abnormality in Alzheimer's disease (AD) with a strong relationship to cognitive performance. However, the status of synapses in frontotemporal lobar degeneration (FTLD) has received meager experimental attention. The purpose of this study was to investigate changes in cortical synaptic proteins in FTLD with tar DNA binding protein-43 (TDP-43) proteinopathy. A second aim was to study phagocytosis of synaptic proteins by microglia as a surrogate for synaptic pruning. Western blot analysis in frozen tissue from the middle frontal gyrus revealed decreased levels of the presynaptic protein synaptophysin, but slightly increased levels of the postsynaptic density protein 95 (PSD95) in FTLD-TDP. Levels of the dendritic spine protein spinophilin displayed the largest decrease. Double immunofluorescent staining visualized aggregate or punctate synaptic protein immunoreactivity in microglia. Overall, the proportion of microglia containing synaptic proteins was larger in FTLD-TDP when compared with normal controls. The increase in PSD95 levels may represent reactive upregulation of this protein, as suggested in AD. While greater numbers of microglia containing synaptic proteins is consistent with loss of synapses in FTLD-TDP, it may also be an indication of abnormal synaptic pruning by microglia.

A retrospective study of infantile-onset Takayasu arteritis: experience from a tertiary referral center in China.

Objective: Takayasu artery (TAK) is a chronic inflammatory disease that mainly affects the aorta and its major branches and is rarely reported in infants. We aimed to summarize the clinical features of infant TA (I-TA) in a tertiary care center. Methods: We performed a retrospective study involving 10 infants diagnosed with TAK. A comprehensive evaluation of clinical, laboratory, radiographic features, disease activity, treatment and outcomes was carried out. Results: A consecutive cohort was composed of 8 girls and 2 boys, with an age at diagnosis of 11.1 (1.7-36) months. The median time to diagnosis and the average time to follow-up were 9.5 days (2-235 days) and 10.9 (1-21) months, respectively. The most common initial manifestations were malaise (80%), fever (70%), hypertension (50%) and rash (30%). The mean Pediatric Vasculitis Activity Score (PVAS), Takayasu Clinical Activity Score (ITAS-2010) and ITAS-A scores were 2.8/63, 2.6/51, and 5.6/54, respectively. All patients had aberrant laboratory parameters. The most common lesions were in the thoracic aorta (60%) and abdominal aorta (60%). Corticosteroids combined with cyclophosphamide followed by long-term mycophenolate mofetil were initiated in most cases (70%). Biologics were attempted in 5 cases. Mortality was 40%. Conclusions: It is challenging to diagnose TAK in infants in a timely manner. Considering the more vessels involved, more severe inflammation and higher mortality, aggressive treatment is warranted in infants. GCs and CYC treatment seem to be effective.

Long non-coding RNA ENSMUST00000197208 promotes a shift in the Th17/Treg ratio via the P2X7R-NLRP3 inflammasome axis in collagen-induced arthritis.

Recently, long non­coding RNAs (lncRNAs) have been implicated in several human diseases, including arthritis. However, the role of lncRNAs in regulating the Th17/Treg ratio during the progression of collagen-induced arthritis (CIA) is poorly understood. Therefore, the aim of this study was to determine the role of the lncRNA ENSMUST00000197208 and the P2X7R-NLRP3 inflammasome axis in changes in the Th17/Treg ratio in CIA. To achieve this, the distribution of T cell subgroups in the spleen cells of a CIA mouse model and control mice was examined. Additionally, we examined the expression profile of ENSMUST00000197208 in a CIA mouse model and healthy mice. The results showed that ENSMUST00000197208 expression was significantly upregulated in the CIA models compared with the control group. Additionally, the P2X7R-NLRP3 inflammasome axis participated in the pathogenesis of CIA and knockdown of ENSMUST00000197208 inhibited CD4+ T cell differentiation into Th17 cells. Compared with the control group, joint inflammation was less visible in NLRP3 knockout mice. Additionally, the P2X7R-NLRP3 inflammasome axis, which is downstream of ENSMUST00000197208, can be positively targeted and regulated by ENSMUST00000197208 through miR-107. Overall, the findings of this study showed that the "lncRNA ENSMUST00000197208-miR 107-P2X7R/NLRP3" axis plays an important role in CIA and knocking down ENSMUST00000197208 can efficiently inhibit Th17 differentiation by suppressing the P2X7R-NLRP3 inflammasome axis. Therefore, targeting this axis may represent a novel strategy for arthritis treatment.

2,4-Dihydroxybenzoic Acid, a Novel SA Derivative, Controls Plant Immunity via UGT95B17-Mediated Glucosylation: A Case Study in Camellia Sinensis.

The plant hormone salicylic acid (SA) plays critical roles in plant innate immunity. Several SA derivatives and associated modification are identified, whereas the range and modes of action of SA-related metabolites remain elusive. Here, the study discovered 2,4-dihydroxybenzoic acid (2,4-DHBA) and its glycosylated form as native SA derivatives in plants whose accumulation is largely induced by SA application and Ps. camelliae-sinensis (Pcs) infection. CsSH1, a 4/5-hydroxylase, catalyzes the hydroxylation of SA to 2,4-DHBA, and UDP-glucosyltransferase UGT95B17 catalyzes the formation of 2,4-DHBA glucoside. Down-regulation reduced the accumulation of 2,4-DHBA glucosides and enhanced the sensitivity of tea plants to Pcs. Conversely, overexpression of UGT95B17 increased plant disease resistance. The exogenous application of 2,4-DHBA and 2,5-DHBA, as well as the accumulation of DHBA and plant resistance comparison, indicate that 2,4-DHBA functions as a potentially bioactive molecule and is stored mainly as a glucose conjugate in tea plants, differs from the mechanism described in Arabidopsis. When 2,4-DHBA is applied exogenously, UGT95B17-silenced tea plants accumulated more 2,4-DHBA than SA and showed induced resistance to Pcs infection. These results indicate that 2,4-DHBA glucosylation positively regulates disease resistance and highlight the role of 2,4-DHBA as potentially bioactive molecule in the establishment of basal resistance in tea plants.

Long-term complete remission and peripheral biomarkers in Hodgkin lymphoma patients after decitabine-plus-camrelizumab epi-immunotherapy and treatment cessation.

Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine-plus-camrelizumab therapy, while long-term outcome especially after treatment discontinuation remains unclear. We present a retrospective analysis of 87 relapsed/refractory cHL patients who acquired CR after decitabine-plus-camrelizumab. Patients were divided into two groups and received consolidation treatment every 3-4 or 6-12 weeks, and 1-year of continuous CR was guaranteed for treatment cessation. At a median follow-up of 5.3 years, the median relapse-free survival (RFS) after achieving CR with decitabine-plus-camrelizumab therapy was 4.5 years, and patients underwent consolidation per 3-4 weeks might have longer RFS. The baseline percentage of peripheral central memory T cells was not associated with RFS, while patients with higher pretreatment serum levels of interleukin-6 (IL-6) and lactate dehydrogenase (LDH) had significantly shorter RFS and increased risk for disease recurrence. Fifty-seven patients completed and discontinued decitabine-plus-camrelizumab, and their median RFS had not been reached. The 2-year RFS rate after treatment cessation was 78% (95% CI, 67-90%). Patients in the high-risk subgroup with higher pretreatment IL-6 and LDH levels showed poor treatment-free remission. Moreover, decitabine-plus-camrelizumab therapy was safe and cost-effective. In conclusion, patients who obtained CR with decitabine-plus-camrelizumab and received consolidation per 3-4 weeks can achieve long-term remission after treatment discontinuation.

The Prognostic Value of the Prognostic Nutritional Index in Patients with Advanced or Metastatic Gastric Cancer Treated with Immunotherapy.

In recent years, the therapeutic effect of monoclonal antibodies against programmed cell death protein-1 (PD-1) in patients with locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) cancer has been confirmed in many studies. The exploration and discovery of new biomarker combinations based on tumor characteristics and tumor microenvironment help screen superior patients and realize precise immunotherapy. As an evaluation index of immunonutritional status, the prognostic nutritional index (PNI) is low cost, simple and easy to obtain, and effective in determining the prognosis of tumor patients. We selected 268 consecutive AGC patients who were treated with ICI therapy from December 2014 to May 2021. We measured their pretreatment of the PNI levels and performed univariate and multivariate Cox regression analyses of progression-free survival (PFS) or overall survival (OS) after ICI therapy. The low pretreatment PNI level of AGC patients was significantly correlated with shorter PFS (p < 0.001) and OS (p < 0.001) after ICI treatment. In univariate and multivariate analyses of the associations between PNI and OS or PFS, PNI is an independent prognostic factor for PFS (HR = 1.511; 95%CI 1.154-1.977; p = 0.003) and OS (HR = 1.431; 95%CI 1.049-1.951; p = 0.024), respectively. Notably, decreased PNI during treatment with ICIs was associated with early relapse and death. Pretreatment with PNI might help to identify AGC patients who will obtain a survival benefit from ICI therapy.

Determining patients with spinal metastases suitable for surgical intervention: A cost-effective analysis.

BACKGROUND: Both nonoperative and operative treatments for spinal metastasis are expensive interventions. Patients' expected 3-month survival is believed to be a key factor to determine the most suitable treatment. However, to the best of our knowledge, no previous study lends support to the hypothesis. We sought to determine the cost-effectiveness of operative and nonoperative interventions, stratified by patients' predicted probability of 3-month survival. METHODS: A Markov model with four defined health states was used to estimate the quality-adjusted life years (QALYs) and costs for operative intervention with postoperative radiotherapy and radiotherapy alone (palliative low-dose external beam radiotherapy) of spine metastases. Transition probabilities for the model, including the risks of mortality and functional deterioration, were obtained from secondary and our institutional data. Willingness to pay thresholds were prespecified at $100,000 and $150,000. The analyses were censored after 5-year simulation from a health system perspective and discounted outcomes at 3% per year. Sensitivity analyses were conducted to test the robustness of the study design. RESULTS: The incremental cost-effectiveness ratios were $140,907 per QALY for patients with a 3-month survival probability >50%, $3,178,510 per QALY for patients with a 3-month survival probability <50%, and $168,385 per QALY for patients with independent ambulatory and 3-month survival probability >50%. CONCLUSIONS: This study emphasizes the need to choose patients carefully and estimate preoperative survival for those with spinal metastases. In addition to reaffirming previous research regarding the influence of ambulatory status on cost-effectiveness, our study goes a step further by highlighting that operative intervention with postoperative radiotherapy could be more cost-effective than radiotherapy alone for patients with a better survival outlook. Accurate survival prediction tools and larger future studies could offer more detailed insights for clinical decisions.

Volatile compound-mediated plant-plant interactions under stress with the tea plant as a model.

Plants respond to environmental stimuli via the release of volatile organic compounds (VOCs), and neighboring plants constantly monitor and respond to these VOCs with great sensitivity and discrimination. This sensing can trigger increased plant fitness and reduce future plant damage through the priming of their own defenses. The defense mechanism in neighboring plants can either be induced by activation of the regulatory or transcriptional machinery, or it can be delayed by the absorption and storage of VOCs for the generation of an appropriate response later. Despite much research, many key questions remain on the role of VOCs in interplant communication and plant fitness. Here we review recent research on the VOCs induced by biotic (i.e. insects and pathogens) and abiotic (i.e. cold, drought, and salt) stresses, and elucidate the biosynthesis of stress-induced VOCs in tea plants. Our focus is on the role of stress-induced VOCs in complex ecological environments. Particularly, the roles of VOCs under abiotic stress are highlighted. Finally, we discuss pertinent questions and future research directions for advancing our understanding of plant interactions via VOCs.

Effects of C-reactive protein trajectories of critically ill patients with sepsis on in-hospital mortality rate.

Sepsis, a life-threatening condition caused by an inflammatory response to systemic infection, results in a significant social burden and healthcare costs. This study aimed to investigate the relationship between the C-reactive protein (CRP) trajectories of patients with sepsis in the intensive care unit (ICU) and the in-hospital mortality rate. We reviewed 1464 patients with sepsis treated in the ICU of Dongyang People's Hospital from 2010 to 2020 and used latent growth mixture modeling to divide the patients into four classes according to CRP trajectory (intermediate, gradually increasing, persistently high, and persistently low CRP levels). We found that patients with intermediate and persistently high CRP levels had the lowest (18.1%) and highest (32.6%) in-hospital mortality rates, respectively. Multiple logistic regression analysis showed that patients with persistently high (odds ratio [OR] = 2.19, 95% confidence interval [CI] = 1.55-3.11) and persistently low (OR = 1.41, 95% CI = 1.03-1.94) CRP levels had a higher risk of in-hospital mortality than patients with intermediate CRP levels. In conclusion, in-hospital mortality rates among patients with sepsis differ according to the CRP trajectory, with patients with intermediate CRP levels having the lowest mortality rate. Further research on the underlying mechanisms is warranted.

tRF-21-LNK8KEP1B as a potential novel diagnostic biomarker for enthesitis-related arthritis.

OBJECTIVE: tRNA-derived fragments (tRFs) play crucial roles in the progression of various diseases, and widely distribute in human tissues, including blood and urine. The diagnosis of enthesitis-related arthritis (ERA) is based on the observation of clinical manifestations. Therefore, we aimed to investigate whether serum tRFs can be used as diagnostic markers for ERA. METHODS: Serum was collected from children admitted to the Children's Hospital Affiliated with Nanjing Medical University between February 2022 to October 2022. The expression profiles of tRFs in the serum of ERA patients (n = 5) and healthy controls (HCs; n = 5) were investigated using small RNA high-throughput sequencing. The level and diagnostic value of tRF-21-LNK8KEP1B were evaluated by real-time quantitative PCR in serum samples from 30 ERA patients and 31 HCs. The specificity and sensitivity of tRFs were determined using receiver operating characteristic analyses. Bioinformatics analysis was performed to explore and identify the potential biological pathways induced by tRFs. RESULTS: Ninety-eight upregulated and 63 downregulated tRFs were identified in the serum. We selected tRF-21-LNK8KEP1B as a candidate marker using KEGG pathway enrichment and PCR validation. tRF-21-LNK8KEP1B was substantially increased in the serum of ERA patients compared with that in HCs. The area under the curve (AUC) for tRF-21-LNK8KEP1B in the ERA group was 0.7849. CONCLUSIONS: Collectively, we demonstrated the promising role of serum tRF-21-LNK8KEP1B -levels as a diagnostic biomarker for ERA.

Novel Predictive Scoring System for Intravenous Immunoglobulin Resistance Helps Timely Intervention in Kawasaki Disease: The Chinese Experience.

Background: Approximately 10%-20% of patients with Kawasaki disease (KD) are nonresponsive to intravenous immunoglobulin (IVIG) treatment, placing them at higher risk of developing coronary heart lesions. Early detection of nonresponsiveness is crucial to curtail this risk; however, the applicability of existing predictive scoring systems is limited to the Japanese population. Our study aimed to identify a predictive scoring system for IVIG resistance in KD specific to the Chinese population. We aimed to assess the utility of three commonly used risk-scoring systems in predicting IVIG resistance and compare them to the newly developed predictive scoring system. Methods: A total of 895 patients with KD were enrolled in this retrospective review and divided into two groups: IVIG responders and nonresponders. Clinical and laboratory variables were compared between the two groups. Multivariable logistic regression models were used to construct a new scoring system. The utility of the existing and new scoring systems was assessed and compared using the area under the receiver operating characteristic curve. Results: Albumin levels, percentage of neutrophils, and hemoglobin were independent predictors of resistance by logistic regression analysis. The new predictive scoring system was derived with improved sensitivity (60.5%) and specificity (87.8%). The area under the receiver operating characteristic curve was 0.818. Conclusion: This study developed a novel risk-scoring system for predicting resistance to IVIG treatment in KD specific to the Chinese population. Although this new model requires further validation, it may be useful for improving prognostic outcomes and reducing the risk of complications associated with KD.

(Z)-3-Hexenol integrates drought and cold stress signaling by activating abscisic acid glucosylation in tea plants.

Cold and drought stresses severely limit crop production and can occur simultaneously. Although some transcription factors and hormones have been characterized in plants subjected each stress, the role of metabolites, especially volatiles, in response to cold and drought stress exposure is rarely studied due to lack of suitable models. Here, we established a model for studying the role of volatiles in tea (Camellia sinensis) plants experiencing cold and drought stresses simultaneously. Using this model, we showed that volatiles induced by cold stress promote drought tolerance in tea plants by mediating reactive oxygen species and stomatal conductance. Needle trap microextraction combined with GC-MS identified the volatiles involved in the crosstalk and showed that cold-induced (Z)-3-hexenol improved the drought tolerance of tea plants. In addition, silencing C. sinensis alcohol dehydrogenase 2 (CsADH2) led to reduced (Z)-3-hexenol production and significantly reduced drought tolerance in response to simultaneous cold and drought stress. Transcriptome and metabolite analyses, together with plant hormone comparison and abscisic acid (ABA) biosynthesis pathway inhibition experiments, further confirmed the roles of ABA in (Z)-3-hexenol-induced drought tolerance of tea plants. (Z)-3-Hexenol application and gene silencing results supported the hypothesis that (Z)-3-hexenol plays a role in the integration of cold and drought tolerance by stimulating the dual-function glucosyltransferase UGT85A53, thereby altering ABA homeostasis in tea plants. Overall, we present a model for studying the roles of metabolites in plants under multiple stresses and reveal the roles of volatiles in integrating cold and drought stresses in plants.

Effectiveness of tumor necrosis factor inhibitors in children with enthesitis-related arthritis: a single-center retrospective analysis.

Objective: In children with enthesitis-related arthritis (ERA), the hip and sacroiliac joint function might be impaired if not properly treated. We sought to evaluate the effectiveness of anti-tumor necrosis factor-α (TNF-α) therapy using the inflammatory indicators, Juvenile Arthritis Disease Activity Score 27 (JADAS27) and magnetic resonance imaging (MRI). Methods: We conducted a single-center retrospective study of 134 patients with ERA. We evaluated the effect of anti-TNF therapy on the inflammatory indicators, active joint count, MRI quantitative score, and JADAS27 over 18 months. We used the Spondyloarthritis Research Consortium of Canada (SPARCC) and the Hip Inflammation MRI Scoring System (HIMRISS) scoring systems for hip and sacroiliac joints scoring. Results: The average age of onset of children with ERA was 11.62 ± 1.95 years, and they were treated with disease-modifying antirheumatic drugs (DMARDs) combined with biologics (n = 87, 64.93%). There were no differences in HLA-B27 positivity between the biologics and non-biologics treatment groups [66 (49.25%) vs. 68 (50.75%), P > 0.05]. Children who received anti-TNF (71 received etanercept, 13 adalimumab, 2 golimumab, and 1 infliximab) therapy improved significantly. Children with ERA used DMARDs and biologics at baseline (Group A) were followed up to 18 months, and their active joint count (4.29 ± 1.99 vs. 0.76 ± 1.33, P = 0.000), JADAS27 (13.70 ± 4.80 vs. 4.53 ± 4.52, P = 0.000) and MRI quantitative scores (P = 0.001) were significantly lower than those at baseline. Some of the patients (n = 13, 9.70%) were treated with DMARDs at the onset of the disease, but did not show significant improvement (Group B). After 6-18 months of switching to anti-TNF therapy, related indicators of the children were significantly lower than at baseline and 1 month (P < 0.013). At 18 months, a total of 33 patients (n = 74, 44.59%) in Group A and 7 (n = 13, 53.85%) in Group B reached inactive state. Conclusion: Eighteen months after diagnosis, anti-TNF therapy was found to be effective in children diagnosed with ERA. MRI is important for the early diagnosis of juvenile idiopathic arthritis. TNF-α inhibitors can significantly improve the clinical manifestations of sacroiliac joint and hip involvement in patients with ERA. Overall, the real-world study provides more evidence for precision diagnosis and treatment for other hospitals, families and patients.

A Machine Learning Algorithm for Predicting 6-Week Survival in Spinal Metastasis: An External Validation Study Using 2,768 Taiwanese Patients.

INTRODUCTION: There are predictive algorithms for predicting 3-month and 1-year survival in patients with spinal metastasis. However, advance in surgical technique, immunotherapy, and advanced radiation therapy has enabled shortening of postoperative recovery, which returns dividends to the overall quality-adjusted life-year. As such, the Skeletal Oncology Research Group machine learning algorithm (SORG-MLA) was proposed to predict 6-week survival in patients with spinal metastasis, whereas its utility for patients treated with nonsurgical treatment was untested externally. This study aims to validate the survival prediction of the 6-week SORG-MLA for patients with spinal metastasis and provide the measurement of model consistency (MC). METHODS: Discrimination using area under the receiver operating characteristic curve, calibration, Brier score, and decision curve analysis were conducted to assess the model's performance in the Taiwanese-based cohort. MC was also applied to detect the proportion of paradoxical predictions among 6-week, 3-month, and 1-year survival predictions. The long-term prognosis should not be better than the shorter-term prognosis in that of an individual. RESULTS: The 6-week survival rate was 84.2%. The SORG-MLA retained good discrimination with an area under the receiver operating characteristic curve of 0.78 (95% confidence interval, 0.75 to 0.80) and good prediction accuracy with a Brier score of 0.11 (null model Brier score 0.13). There is an underestimation of the 6-week survival rate when the predicted survival rate is less than 50%. Decision curve analysis showed that the model was suitable for use over all threshold probabilities. MC showed suboptimal consistency between 6-week and 90-day survival prediction (78%). CONCLUSIONS: The results of this study supported the utility of the algorithm. The online tool ( https://sorg-apps.shinyapps.io/spinemetssurvival/ ) can be used by both clinicians and patients in informative decision-making discussion before management of spinal metastasis.

Identification of subphenotypes in critically ill thrombocytopenic patients with different responses to therapeutic interventions: a retrospective study.

Introduction: The causes of thrombocytopenia (TP) in critically ill patients are numerous and heterogeneous. Currently, subphenotype identification is a popular approach to address this problem. Therefore, this study aimed to identify subphenotypes that respond differently to therapeutic interventions in patients with TP using routine clinical data and to improve individualized management of TP. Methods: This retrospective study included patients with TP admitted to the intensive care unit (ICU) of Dongyang People's Hospital during 2010-2020. Subphenotypes were identified using latent profile analysis of 15 clinical variables. The Kaplan-Meier method was used to assess the risk of 30-day mortality for different subphenotypes. Multifactorial Cox regression analysis was used to analyze the relationship between therapeutic interventions and in-hospital mortality for different subphenotypes. Results: This study included a total of 1,666 participants. Four subphenotypes were identified by latent profile analysis, with subphenotype 1 being the most abundant and having a low mortality rate. Subphenotype 2 was characterized by respiratory dysfunction, subphenotype 3 by renal insufficiency, and subphenotype 4 by shock-like features. Kaplan-Meier analysis revealed that the four subphenotypes had different in-30-day mortality rates. The multivariate Cox regression analysis indicated a significant interaction between platelet transfusion and subphenotype, with more platelet transfusion associated with a decreased risk of in-hospital mortality in subphenotype 3 [hazard ratio (HR): 0.66, 95% confidence interval (CI): 0.46-0.94]. In addition, there was a significant interaction between fluid intake and subphenotype, with a higher fluid intake being associated with a decreased risk of in-hospital mortality for subphenotype 3 (HR: 0.94, 95% CI: 0.89-0.99 per 1 l increase in fluid intake) and an increased risk of in-hospital mortality for high fluid intake in subphenotypes 1 (HR: 1.10, 95% CI: 1.03-1.18 per 1 l increase in fluid intake) and 2 (HR: 1.19, 95% CI: 1.08-1.32 per 1 l increase in fluid intake). Conclusion: Four subphenotypes of TP in critically ill patients with different clinical characteristics and outcomes and differential responses to therapeutic interventions were identified using routine clinical data. These findings can help improve the identification of different subphenotypes in patients with TP for better individualized treatment of patients in the ICU.

Investigation on Imbibition Mechanism of Tight Core Based on NMR Test.

Seepage is important to improve the postpressure production enhancement effect of tight oil and gas reservoirs. To study the microscopic percolation law of different pores, this paper first characterizes the pore structure of tight cores. High-pressure spontaneous percolation experiments and nuclear magnetic resonance (NMR) tests were combined. The T 2 spectra at different times of percolation were used. The percolation law of different pore types was quantitatively characterized from a microscopic perspective. The effect of different interfacial tensions on the percolation was clarified. Results show that the pore size has a good match with the NMR T 2 relaxation time. The core pore development is dominated by submicrometer pores, which account for more than 70%. The percolation rate is fast at the beginning and then decreases and stabilizes at 48 h. The pore size of the submicropore is small, the capillary force is large, and the recovery rate of percolation is high, followed by those of the micropore and the medium-pore. The higher the porosity and permeability of the core, the greater the overall seepage recovery rate. The sensitivity of submicrometer pores to interfacial tension is great, and the recovery rate increases by 40.9% when the interfacial tension decreases from 17.1 to 1.46 mN/m. Furthermore, as the interfacial tension decreases, the recovery rate of different pores appears to increase first and then decrease. The surfactant formulation must be selected reasonably in practical production.