The interplay between metal ions and immune cells in glioma: pathways to immune escape.

This review explores the intricate roles of metal ions-iron, copper, zinc, and selenium-in glioma pathogenesis and immune evasion. Dysregulated metal ion metabolism significantly contributes to glioma progression by inducing oxidative stress, promoting angiogenesis, and modulating immune cell functions. Iron accumulation enhances oxidative DNA damage, copper activates hypoxia-inducible factors to stimulate angiogenesis, zinc influences cell proliferation and apoptosis, and selenium modulates the tumor microenvironment through its antioxidant properties. These metal ions also facilitate immune escape by upregulating immune checkpoints and secreting immunosuppressive cytokines. Targeting metal ion pathways with therapeutic strategies such as chelating agents and metalloproteinase inhibitors, particularly in combination with conventional treatments like chemotherapy and immunotherapy, shows promise in improving treatment efficacy and overcoming resistance. Future research should leverage advanced bioinformatics and integrative methodologies to deepen the understanding of metal ion-immune interactions, ultimately identifying novel biomarkers and therapeutic targets to enhance glioma management and patient outcomes.

Adsorption Properties of Diatomite Minerals on Glyceryl Monostearate for Antifogging of the Plastic Film.

Adding an appropriate amount and the stable precipitation of surfactant on the inner surface of agricultural plastic greenhouse films can prevent the formation of water droplets on the inner surface of the film to reduce its harmful effects in the process of plant cultivation and production. In this work, for the stable precipitation of the surfactant glycerol monostearate, diatomite minerals from three origins in China were compared through structural analysis and adsorption performance. The effects of acid treatments and alkali treatments on the mineral structure were studied, and the adsorption mechanism of glycerol monostearate was further investigated. The results show that the structural characteristics of Jilin diatomite are more suitable as adsorbents for glyceryl monostearate adsorption. Because diatomite is resistant to acids but not alkalis, when diatomite is treated with an alkali, impurities on its surface can be removed and the hydroxyl group and specific surface area can be greatly increased. The adsorption capacity of glycerol stearate was increased to 218.4 mg/g, or 32.08%, over its pretreatment level. The results show that this is mainly the result of physical adsorption caused by van der Waals force imbalance and chemisorption caused by a small number of hydrogen bonds. In addition, the dripping performance of this composite dripping film with mineral diatomite was better than that of the commercial dripping film, which provided a theoretical basis for efficient mineral slow-release drip irrigation composite film.

Adaptation of the anammox process for high ammonium photovoltaic wastewater treatment.

Tunnel Oxide Passivating Contacts (TOPcon) battery in the photovoltaic industry generates high ammonium wastewater during the production process, the adaptability of using the anaerobic ammonia oxidation (Anammox) process for photovoltaic wastewater (PVW) treatment is a research hotspot. Based on the analysis of photovoltaic wastewater quality, the effectiveness of nitrogen removal, sludge characteristics and microbial communities were examined. The results showed that when the influent NH4+-N concentration of PVW was lower than 150 mg·L-1, the nitrogen removal efficiency (NRE) was almost 100 %. In addition, the NRE decreased from 74 % sharply to 20 % when the NH4+-N concentration was increased from 175 mg·L-1 to 200 mg·L-1. The extracellular polymeric substances (EPS) content increased with elevated ammonium concentration in the influent, indicating that microorganisms secreted more EPS to resist elevated nitrogen loading. The main functional populations were Candidatus Kuenenia (0-24 %). The influent ammonium concentration is recommended to be < 200 mg·L-1.

Preliminary study on the active substances and cellular pathways of lactic acid bacteria for colorectal cancer treatment.

Colorectal cancer (CRC) is a common malignant tumor and is one of the three most common cancers worldwide. Traditional surgical treatment, supplemented by chemotherapy and radiotherapy, has obvious side effects on patients. Immunotherapy may lead to some unpredictable complications. Low introduction rate and high cost are some of the problems of gene therapy, so finding a safe, reliable and least toxic treatment method became the main research direction for this study. Lactic acid bacteria and their metabolites are widely used in functional foods or as adjuvant therapies for various diseases because they are safe to eat and have no adverse reactions. Research has shown that lactic acid bacteria and their metabolites play an auxiliary therapeutic role in colorectal cancer mainly by improving the intestinal flora composition, inhibiting the growth of pathogenic bacteria and inhibiting the proliferation of cancer cells. It is now widely believed that the substances that probiotics such as lactic acid bacteria exert anti-cancer effects are mainly secondary metabolites such as butyric acid. Lb. plantarum AY01 isolated from fermented food has good anti-cancer ability, and its main anti-cancer substance is 2'-deoxyinosine. Through flow cytometry detection, it was found that Lb. plantarum AY01 can block cell proliferation in the S phase. In addition, Lb. plantarum AY01 culture reduces the sensitivity of mice to colitis-associated CRC induced by azoxymethane (AOM)/dextran sulfate sodium salt (DSS) and exhibits the occurrence and promotion of tumors. According to transcriptome analysis, Lb. plantarum AY01 may induce apoptosis of colorectal cancer cells by activating the p38 MAPK pathway. This experiment provided possibilities for the treatment of CRC.

Anti-signal recognition particle antibodies induce cardiac diastolic dysfunction via oxidative stress injury.

Objectives: Anti-signal recognition particle (SRP) antibodies, markers of immune-mediated necrotising myopathy, are reportedly related to cardiac involvement; however, whether they are pathogenic to the myocardium remains unclear. We aimed, therefore, to explore the pathogenicity of anti-SRP antibodies against the myocardium through in vivo and in vitro studies. Methods: Total immunoglobulin G (IgG), purified from patients with positive anti-SRP antibodies, was passively transferred into C57BL/6 mice. Cardiac function was evaluated via echocardiography and the ventricular pressure-volume loop; cardiac histological changes were analysed using haematoxylin-eosin staining, picrosirius red staining, immunofluorescence and immunohistochemistry. Additionally, reactive oxygen species (ROS) formation was evaluated by dihydroethidium (DHE) staining; mitochondrial morphology and function were evaluated using transmission electron microscopy and seahorse mitochondrial respiration assay, respectively. The myositis cohort at our centre was subsequently reviewed in terms of cardiac assessments. Results: After the passive transfer of total IgG from patients with positive anti-SRP antibodies, C57BL/6 mice developed significant left ventricular diastolic dysfunction (LVDD). Transcriptomic analysis and corresponding experiments revealed increased oxidative stress and mitochondrial damage in the hearts of the experimental mice. Cardiomyocytes exposed to anti-SRP-specific IgG, however, recovered normal mitochondrial metabolism after treatment with N-acetylcysteine, an ROS scavenger. Moreover, patients positive for anti-SRP antibodies manifested worse diastolic but equivalent systolic function compared to their counterparts after propensity score matching. Conclusion: Anti-SRP antibodies may play a pathogenic role in the development of LVDD by promoting ROS production and subsequent myocardial mitochondrial impairment. The inhibition of oxidative stress was effective in reversing anti-SRP antibody-induced LVDD.

High Spatial-Resolution and Acquisition-Efficiency Cardiac MR T1 Mapping Based on Radial bSSFP and a Low-Rank Tensor Constraint.

BACKGROUND: Cardiac T1 mapping is valuable for evaluating myocardial fibrosis, yet its resolution and acquisition efficiency are limited, potentially obscuring visualization of small pathologies. PURPOSE: To develop a technique for high-resolution cardiac T1 mapping with a less-than-100-millisecond acquisition window based on radial MOdified Look-Locker Inversion recovery (MOLLI) and a calibrationless space-contrast-coil locally low-rank tensor (SCC-LLRT) constrained reconstruction. STUDY TYPE: Prospective. SUBJECTS/PHANTOM: Sixteen healthy subjects (age 25 ± 3 years, 44% females) and 12 patients with suspected cardiomyopathy (age 57 ± 15 years, 42% females), NiCl2-agar phantom. FIELD STRENGTH/SEQUENCE: 3-T, standard MOLLI, radial MOLLI, inversion-recovery spin-echo, late gadolinium enhancement. ASSESSMENT: SCC-LLRT was compared to a conventional locally low-rank (LLR) method through simulations using Normalized Root-Mean-Square Error (NRMSE) and Structural Similarity Index Measure (SSIM). Radial MOLLI was compared to standard MOLLI across phantom, healthy subjects, and patients. Three independent readers subjectively evaluated the quality of T1 maps using a 5-point scale (5 = best). STATISTICAL TESTS: Paired t-test, Wilcoxon signed-rank test, intraclass correlation coefficient analysis, linear regression, Bland-Altman analysis. P < 0.05 was considered statistically significant. RESULTS: In simulations, SCC-LLRT demonstrated a significant improvement in NRMSE and SSIM compared to LLR. In phantom, both radial MOLLI and standard MOLLI provided consistent T1 estimates across different heart rates. In healthy subjects, radial MOLLI exhibited a significantly lower mean T1 (1115 ± 39 msec vs. 1155 ± 36 msec), similar T1 SD (74 ± 14 msec vs. 67 ± 23 msec, P = 0.20), and similar T1 reproducibility (28 ± 18 msec vs. 22 ± 15 msec, P = 0.34) compared to standard MOLLI. In patients, the proposed method significantly improved the sharpness of myocardial boundaries (4.50 ± 0.65 vs. 3.25 ± 0.43), the conspicuity of papillary muscles and fine structures (4.33 ± 0.74 vs. 3.33 ± 0.47), and artifacts (4.75 ± 0.43 vs. 3.83 ± 0.55). The reconstruction time for a single slice was 5.2 hours. DATA CONCLUSION: The proposed method enables high-resolution cardiac T1 mapping with a short acquisition window and improved image quality. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Optimizing the placement of medical wastewater outlets in sewer systems to reduce chemical consumption at wastewater treatment plants.

The severely low influent chemical oxygen demand (COD) concentration at wastewater treatment plants (WWTPs) has become a critical issue. A key factor is the excessive biodegradation of organic matter by microbial communities within sewer systems. Intense disinfection commonly adopted for medical wastewater leads to abundant residual chlorine entering sewers, likely causing significant changes in microbial communities and sewage quality in sewers, yet our understanding is limited. Through long-term sewer simulation batch tests, this study revealed the response mechanism of microbial communities to residual chlorine and its impact on organic matter concentration in sewage. Under residual chlorine stress, microbial community structure rapidly changed, and more complex microbial interactions were observed. Besides, pathways related to stress response such as two-component system were significantly enriched; pathways related to energy metabolism (such as carbon fixation in prokaryotes and citrate cycle) in microbial communities were inhibited, and carbon metabolism shifted from the Embden-Meyerhof pathway to the pentose phosphate pathway to enhance cellular reducing power, reduce oxidative stress, and consequently decrease organic matter degradation. Therefore, compared to sewers with normal disinfection, concentrations of COD and dissolved organic carbon in sewage under chlorine stress increased by 12.6 % and 7.4 %, respectively. Besides, the decay and transformation of residual chlorine in sewers were explored. These findings suggest a new approach to medical wastewater discharge management: placing the medical wastewater outlet at the upstream in sewer systems, which ensures that residual chlorine consumption reaches maximum during long-distance transportation, mitigating its harmful effects on WWTPs, and increases the influent organic matter concentration, thereby reducing the need for additional carbon sources.

SpatialCTD: A Large-Scale Tumor Microenvironment Spatial Transcriptomic Dataset to Evaluate Cell Type Deconvolution for Immuno-Oncology.

Recent technological advancements have enabled spatially resolved transcriptomic profiling but at a multicellular resolution that is more cost-effective. The task of cell type deconvolution has been introduced to disentangle discrete cell types from such multicellular spots. However, existing benchmark datasets for cell type deconvolution are either generated from simulation or limited in scale, predominantly encompassing data on mice and are not designed for human immuno-oncology. To overcome these limitations and promote comprehensive investigation of cell type deconvolution for human immuno-oncology, we introduce a large-scale spatial transcriptomic deconvolution benchmark dataset named SpatialCTD, encompassing 1.8 million cells and 12,900 pseudo spots from the human tumor microenvironment across the lung, kidney, and liver. In addition, SpatialCTD provides more realistic reference than those generated from single-cell RNA sequencing (scRNA-seq) data for most reference-based deconvolution methods. To utilize the location-aware SpatialCTD reference, we propose a graph neural network-based deconvolution method (i.e., GNNDeconvolver). Extensive experiments show that GNNDeconvolver often outperforms existing state-of-the-art methods by a substantial margin, without requiring scRNA-seq data. To enable comprehensive evaluations of spatial transcriptomics data from flexible protocols, we provide an online tool capable of converting spatial transcriptomic data from various platforms (e.g., 10× Visium, MERFISH, and sci-Space) into pseudo spots, featuring adjustable spot size. The SpatialCTD dataset and GNNDeconvolver implementation are available at https://github.com/OmicsML/SpatialCTD, and the online converter tool can be accessed at https://omicsml.github.io/SpatialCTD/.

Cyy-272, an indazole derivative, effectively mitigates obese cardiomyopathy as a JNK inhibitor.

Obesity has shown a global epidemic trend. The high-lipid state caused by obesity can maintain the heart in a prolonged low-grade inflammatory state and cause ventricular remodeling, leading to a series of pathologies, such as hypertrophy, fibrosis, and apoptosis, which eventually develop into obese cardiomyopathy. Therefore, prolonged low-grade inflammation plays a crucial role in the progression of obese cardiomyopathy, making inflammation regulation an essential strategy for treating this disease. Cyy-272, an indazole derivative, is an anti-inflammatory compound independently synthesized by our laboratory. Our previous studies revealed that Cyy-272 can exert anti-inflammatory effects by inhibiting the phosphorylation and activation of C-Jun N-terminal kinase (JNK), thereby alleviating lipopolysaccharide (LPS)-induced acute lung injury (ALI). The current study aimed to evaluate the potential of Cyy-272 to mitigate the occurrence and progression of obese cardiomyopathy through the inhibition of the JNK signaling pathway. Our results indicate that the compound Cyy-272 has encouraging therapeutic effects on obesity-induced cardiac injury. It significantly inhibits inflammation in cardiomyocytes and heart tissues induced by high lipid concentrations, further alleviating the resulting hypertrophy, fibrosis, and apoptosis. Mechanistically, the protective effect of Cyy-272 on obese cardiomyopathy can be attributed to its direct inhibition of JNK protein phosphorylation. In conclusion, we identified a novel compound, Cyy-272, capable of alleviating obese cardiomyopathy and confirmed that its effect is achieved through direct inhibition of JNK.

Paeoniflorin suppresses ferroptosis after traumatic brain injury by antagonizing P53 acetylation.

BACKGROUND: Traumatic brain injury (TBI) could induce multiple forms of cell death, ferroptosis, a novel form of cell death distinct from apoptosis and autophagy, plays an important role in disease progression in TBI. Therapies targeting ferroptosis are beneficial for recovery from TBI. Paeoniflorin (Pae) is a water-soluble monoterpene glycoside and the active ingredient of Paeonia lactiflora pall. It has been shown to exert anti-inflammatory and antioxidant effects. However The effects and mechanisms of paeoniflorin on secondary injury after TBI are unknown. PURPOSE: To investigate the mechanism by which Pae regulates ferroptosis after TBI. METHODS: The TBI mouse model and cortical primary neurons were utilized to study the protective effect of paeoniflorin on the brain tissue after TBI. The neuronal cell ferroptosis model was established by treating cortical primary neurons with erastin. Liproxstatin-1(Lip-1) was used as a positive control drug. Immunofluorescence staining, Nissl staining, biochemical analyses, pharmacological analyses, and western blot were used to evaluate the effects of paeoniflorin on TBI. RESULTS: Pae significantly ameliorated neuronal damage after TBI, inhibited mitochondrial damage, increased glutathione peroxidase 4 (GPX4) activity, decreased malondialdehyde (MDA) production, restored neurological function and inhibited cerebral edema. Pae promotes the degradation of P53 in the form of proteasome, promotes its ubiquitination, and reduces the stability of P53 by inhibiting its acetylation, thus alleviating the P53-mediated inhibition of cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) by P53. CONCLUSION: Pae inhibits ferroptosis by promoting P53 ubiquitination out of the nucleus, inhibiting P53 acetylation, and modulating the SLC7A11-GPX4 pathway.

Epicardial adipose tissue volume and density are associated with heart failure with improved ejection fraction.

BACKGROUND: Heart failure (HF) with improved ejection fraction (EF, HFimpEF) is a distinct HF subtype, characterized by left ventricular (LV) reverse remodeling and myocardial functional recovery. Multiple cardiometabolic factors are implicated in this process. Epicardial adipose tissue (EAT), emerging as an endocrine and paracrine organ, contributes to the onset and progression of HF. However, the relation between EAT and the incidence of HFimpEF is still unclear. METHODS: A total of 203 hospitalized HF patients with reduced EF (HFrEF, LVEF ≤ 40%) who underwent coronary CT angiography (CCTA) during index hospitalization were consecutively enrolled between November 2011 and December 2022. Routine follow-up and repeat echocardiograms were performed. The incidence of HFimpEF was defined as (1) an absolute LVEF improvement ≥ 10% and (2) a second LVEF > 40% (at least 3 months apart). EAT volume and density were semiautomatically quantified on non-enhanced series of CCTA scans. RESULTS: During a median follow-up of 8.6 (4.9 ~ 13.3) months, 104 (51.2%) patients developed HFimpEF. Compared with HFrEF patients, HFimpEF patients had lower EAT volume (115.36 [IQR 87.08 ~ 154.78] mL vs. 169.67 [IQR 137.22 ~ 218.89] mL, P < 0.001) and higher EAT density (-74.92 ± 6.84 HU vs. -78.76 ± 6.28 HU, P < 0.001). Multivariate analysis showed lower EAT volume (OR: 0.885 [95%CI 0.822 ~ 0.947]) and higher density (OR: 1.845 [95%CI 1.023 ~ 3.437]) were both independently associated with the incidence of HFimpEF. Subgroup analysis revealed that the association between EAT properties and HFimpEF was not modified by HF etiology. CONCLUSIONS: This study reveals that lower EAT volume and higher EAT density are associated with development of HFimpEF. Therapies targeted at reducing EAT quantity and improving its quality might provide favorable effects on myocardial recovery in HF patients.

Case report: A case with atypical presentation oftesticular choriocarcinoma.

Testicular choriocarcinoma is a relatively rare malignancy with a highly aggressive nature. Timely diagnosis and treatment can help prolong the survival of patients and even cure them. This case reports a 29-year-old male who presented to the clinic for a month with epigastric pain. On examination, a massive mass of approximately 9*10 cm could be palpated in the upper abdomen. When asked about his previous history, the patient only described a history of a right inguinal hernia that had been repaired 12 years earlier. The admission diagnosis was considered the retroperitoneal tumor, which was found to have metastasized to the liver and lungs after the completion of relevant tests. We then performed a CT-guided lune puncture biopsy on day 8 of admission. The biopsy pathology suggested metastatic cancer was considered. As the symptoms of tumor compression gradually worsened, we performed surgical treatment (retroperitoneal tumor resection + partial duodenal resection + enteroanastomosis) on day 13 of admission. The postoperative pathology was choriocarcinoma. We subsequently conducted a detailed inquiry with the patient's family about his medical history and found a history of inguinal testicle. Through testicular ultrasound examination, it was preliminarily determined to be testicular choriocarcinoma (not yet pathologically confirmed). We wanted to start salvage chemotherapy as soon as possible after surgery. However, the patient's postoperative condition was poor, with rapid progression of hepatopulmonary metastases and gradually increased thyrotoxicosis, and we started salvage chemotherapy (EP regimen: etoposide and cisplatin) on postoperative day 12. However, the patient was forced to stop due to a severe chemotherapy reaction and died of respiratory and cardiac arrest in the hospital. For male patients with retroperitoneal mass, the possibility of germ-cell neoplasm should first be excluded. By inquiring in detail about a history of cryptorchidism and in the initial days of hospitalization, testicular exploration, ultrasounds, and serum tumor markers (AFP, ß-HCG) tests can be conducted to rule out the possibility of germ-cell neoplasm, thereby preventing misdiagnosis and treatment delays. If the clinical diagnosis is metastatic germ-cell tumor with severe symptoms of metastatic disease, surgery should never be used as the initial treatment.

Investigation of vascular risk factor control and secondary prevention medication compliance in acute ischemic stroke.

Objectives: This study aimed to investigate the management of vascular risk factors, with a specific focus on understanding the various factors affecting risk factor control through an in-depth analysis of clinical data and a longitudinal follow-up of patients who have experienced ischemic strokes. Methods: A total of 1,572 participants were included in the analysis. We assessed thresholds for blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and glycated hemoglobin (HbA1c) levels to uncover the contextual conditions and factors affecting vascular risk factor control. Moreover, the study also scrutinized medication compliance at intervals of 3, 6, and 12 months post-onset. Logistic regression was used to adjust for confounding factors. Results: At 3, 6, and 12 months, BP,LDL, hemoglobin control targets were achieved in 50.7, 51.8, and 50.6%; 51.5, 59.4, and 50.6%; 48.1, 44.0, and 48.4%,respectively. Notably, age was associated with the achievement of BP control (odds ratio [OR], 0.96; 95% confidence intervals [CI], 0.94-0.98; p < 0.0001). Ethnic minorities (OR, 4.23; 95% CI, 1.19-15.09; p = 0.02) and individuals with coronary heart disease (OR, 0.5; 95% CI, 0.3-1.0; p = 0.05) experienced decreased BP control ratios. A previous history of stroke (OR, 1.7; 95% CI, 1.0-2.8; p = 0.03) and unrestricted alcohol consumption (OR, 3.3; 95% CI, 1.0-11.1; p = 0.05) was significantly associated with the achievement of lipid control. Furthermore, lifestyle modifications were significantly correlated with the achievement of BP control (OR, 0.19; 95% CI, 0.12-0.30; p < 0.01), blood glucose control (OR, 0.03; 95% CI, 0.01-0.08; p < 0.01), and blood lipid control (OR, 0.26; 95% CI, 0.16-0.42; p < 0.01). The absence of regular physical activity was associated with lower rates of glycemic (OR, 0.14; 95% CI, 0.06-0.36; p < 0.01) and lipid controls (OR, 0.55; 95% CI, 0.33-0.90; p = 0.01). Over time, overall medication compliance declined. Conclusion: Within the cohort of patients under medication, the compliance rate concerning vascular risk factors remains unsatisfactory. Attention should be paid to compliance with secondary prevention medications and enhance the control of vascular risk factors, as compliance emerges as the key to effective prevention.

Metal nanozymes modulation of reactive oxygen species as promising strategies for cancer therapy.

Nanozymes, nanostructured materials emulating natural enzyme activities, exhibit potential in catalyzing reactive oxygen species (ROS) production for cancer treatment. By facilitating oxidative reactions, elevating ROS levels, and influencing the tumor microenvironment (TME), nanozymes foster the eradication of cancer cells. Noteworthy are their superior stability, ease of preservation, and cost-effectiveness compared to natural enzymes, rendering them invaluable for medical applications. This comprehensive review intricately explores the interplay between ROS and tumor therapy, with a focused examination of metal-based nanozyme strategies mitigating tumor hypoxia. It provides nuanced insights into diverse catalytic processes, mechanisms, and surface modifications of various metal nanozymes, shedding light on their role in intra-tumoral ROS generation and applications in antioxidant therapy. The review concludes by delineating specific potential prospects and challenges associated with the burgeoning use of metal nanozymes in future tumor therapies.

Theoretical study of electronic structures, magnetic properties, and ultrafast spin manipulation in transition metal adsorbed polycyclic-aromatic-hydrocarbon molecules.

We present a first-principles study of the structural, electronic, and magnetic properties of TM(PAH)0/+ (TM = Fe, Co, Ni; PAH = C10H8, C16H10, C24H12, C32H14) complexes and explore the laser-induced spin dynamics as well as their stability with respect to various laser parameters. For each complex, the most stable configuration shows that the TM atom prefers to adsorb at the hollow site of the carbon ring with a slight deviation from the center. The electronic structure and spin localization of the complexes are found to be largely affected by the TM type. Driven by various laser pulses, spin-crossover scenarios are achieved in all structures, while spin-transfer between TM and PAH is achieved in Ni(C10H8), Ni(C16H10), and Ni(C24H12). The influence of the laser energy and chirp on the dynamics is also investigated, providing important information regarding the stability and sensitivity of the dynamical process. All results are believed to reveal the physics nature of the TM-PAH systems, to guide the experimental realization of their ultrafast spin dynamics and thus to promote their applications in future spintronics.

Prognostic value of plasma big endothelin-1 in patients with light chain cardiac amyloidosis.

BACKGROUND: Light chain cardiac amyloidosis (AL-CA) is associated with a high incidence of mortality. Big endothelin-1 (ET-1), the precursor of endothelial-vasoconstrictive ET-1, is closely related to the concentration of bioactive ET-1. Association between big ET-1 and prognosis of AL-CA has not yet been documented. The purpose of this study was to evaluate the prognostic value of big ET-1 for poor outcomes in moderate to severe AL-CA. METHODS: Big ET-1 levels were determined on admission in patients with newly diagnosed AL-CA with modified Mayo 2004 stage II or III. Primary outcome was all-cause mortality. The secondary outcomes included death from cardiac cause and the composite of the primary outcome or hospitalisations due to worsening heart failure. RESULTS: Overall, 141 patients were retrospectively included (57 stage II, 34 stage IIIa, 50 stage IIIb). During a median follow-up time of 25.7 months, 84 (59.6%) patients died. Patients with big ET-1 levels of ≤0.88 pmol/L had longer survival than those with >0.88 pmol/L (median survival time: 34.1 months vs 15.3 months, log-rank p<0.001), which was also observed in the validation cohort (log-rank p=0.026). Higher big ET-1 levels were predictive for all-cause mortality after multivariable adjustment (HR 1.91, 95% CI 1.05 to 3.49, p=0.035). Big ET-1 levels added an incremental prognostic value over modified Mayo 2004 stage (C-index: from 0.671 to 0.696, p=0.025; integrated discrimination improvement 0.168, p=0.047). CONCLUSIONS: Big ET-1 is a strong and independent predictor of mortality in patients with moderate to severe AL-CA, which may indicate a possible role for risk stratification in patients with this disease.

Extrachromosomal circular DNA promotes prostate cancer progression through the FAM84B/CDKN1B/MYC/WWP1 axis.

BACKGROUND: Extrachromosomal circular DNA (eccDNA), a kind of circular DNA that originates from chromosomes, carries complete gene information, particularly the oncogenic genes. This study aimed to examine the contributions of FAM84B induced by eccDNA to prostate cancer (PCa) development and the biomolecules involved. METHODS: The presence of eccDNA in PCa cells and the FAM84B transcripts that eccDNA carries were verified by outward and inward PCR. The effect of inhibition of eccDNA synthesis on FAM84B expression in PCa cells was analyzed by knocking down Lig3. The impact of FAM84B on the growth and metastases of PCa cells was verified by Cell Counting Kit-8 (CCK8), EdU, transwell assays, and a xenograft mouse model. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) and dual-luciferase reporter assays were carried out to examine the effect of FAM84B/MYC on WWP1 transcription, and a co-immunoprecipitation (Co-IP) assay was conducted to verify the modification of CDKN1B by WWP1. The function of this molecular axis in PCa was explored by rescue assays. RESULTS: The inhibited eccDNA synthesis significantly downregulated FAM84B in PCa cells, thereby attenuating the growth and metastasis of PCa. FAM84B promoted the transcription of WWP1 by MYC by activating the expression of MYC coterminous with the 8q24.21 gene desert in a beta catenin-dependent approach. WWP1 transcription promoted by MYC facilitated the ubiquitination and degradation of CDKN1B protein and inversely attenuated the repressive effect of CDKN1B on MYC expression. Exogenous overexpression of CDKN1B blocked FAM84B-activated MYC/WWP1 expression, thereby inhibiting PCa progression. CONCLUSIONS: FAM84B promoted by eccDNA mediates degradation of CDKN1B via MYC/WWP1, thereby accelerating PCa progression.

Combination of manual lymphatic drainage and Kinesio taping for treating pigmented villonodular synovitis: A case report.

BACKGROUND: Pigmented villonodular synovitis (PVNS) is a benign proliferative disorder that affects the synovial joints, bursae, and tendon sheaths. To date, few studies have reported on the treatment of postoperative pain and edema in patients with PVNS. Herein, we present the case of a woman who developed pain and edema in the left lower limb 1 wk after synovectomy and arthroscopic partial meniscectomy and was unable to walk due to limited flexion and extension of the left knee. CASE SUMMARY: A 32-year-old woman underwent synovectomy and arthroscopic partial meniscectomy successively and was treated with a combination of manual lymphatic drainage (MLD) and kinesio taping (KT) in our hospital to alleviate postoperative pain and edema. The following parameters were assessed at 2 wk post-treatment and 1 wk post-discharge follow up: suprapatellar circumference, infrapatellar circumference, visual analog scale score, knee range of motion, pittsburgh sleep quality index score, hamilton anxiety rating scale (HAMA) score, and hamilton depression rating scale (HAMD) score. After treatment, the postoperative pain and edema in the patient's left knee were effectively relieved, resulting in improved sleep quality and remarkably attenuated HAMA and HAMD scores. CONCLUSION: Combined MLD and KT may be an effective approach for relieving postoperative pain and edema in patients with PVNS.

Novel OX40 and 4-1BB derived spacers enhance CD30 CAR activity and safety in CD30 positive lymphoma models.

The chimeric antigen receptor (CAR) derived from the CD30 specific murine antibody, HRS-3, has produced promising clinical efficacy with a favorable safety profile in the treatment of relapsed or refractory CD30-positive lymphomas. However, persistence of the autologous CAR-T cells was brief, and many patients relapsed a year after treatment. The lack of persistence may be attributed to the use of a wild-type immunoglobulin (Ig)G1 spacer that can associate with Fc receptors. We first identified the cysteine-rich domain (CRD) 5 of CD30 as the primary binding epitope of HRS-3 and armed with this insight, attempted to improve the HRS-3 CAR functionality with a panel of novel spacer designs. We demonstrate that HRS-3 CARs with OX40 and 4-1BB derived spacers exhibited similar anti-tumor efficacy, circumvented interactions with Fc receptors, and secreted lower levels of cytokines in vitro than a CAR employing the IgG1 spacer. Humanization of the HRS-3 scFv coupled with the 4-1BB spacer preserved potent on-target, on-tumor efficacy, and on-target, off-tumor safety. In a lymphoma mouse model of high tumor burden, T cells expressing humanized HRS-3 CD30.CARs with the 4-1BB spacer potently killed tumors with low levels of circulating inflammatory cytokines, providing a promising candidate for future clinical development in the treatment of CD30-positive malignancies.

The Association Between Frailty Evaluated by Clinical Frailty Scale and Mortality of Older Patients in the Emergency Department: A Prospective Cohort Study.

Background: Frailty epitomizes the most complex consequence of an aging population. This study aimed to evaluate the impact of frailty, measured using the Clinical Frailty Scale (CFS), on outcomes of older people in an emergency department (ED). Methods: We conducted a prospective observational study enrolling patients aged 65 years and older in a medical center of Taiwan between March 8, 2021, and November 30, 2021. The primary outcome was 90-day mortality rate. Individuals were categorized into three groups based on the CFS scores. Logistic regression was employed to examine the influence of frailty on clinical outcomes following covariate adjustment. Survival analysis was conducted using Kaplan-Meier curves and Log rank tests. Results: A total of 473 individuals were included in the study, with a mean age of 82.1 years, and 60.5% of them were males. The 90-day mortality rate was 10.6%. Among these groups, the CFS score 7-9 group had the highest 90-day mortality rate (15.9%), followed by the CFS score 4-6 group (8.0%) and the CFS score 1-3 group (7.1%). The multiple logistic regression analyses demonstrated a significant impact of CFS score on prognosis, with adjusted odd ratios of 1.24 (95% CI 1.06-1.47) for 90-day mortality, 1.18 (95% CI 1.06-1.31) for hospitalization, and 1.30 (95% CI 1.12-1.52) for 180-day mortality. The Kaplan-Meier curves revealed a significantly higher 90-day mortality rate for patients with high CFS scores (Log rank tests, p = 0.019). Conclusion: In the older ED population, the severity of frailty assessed by the CFS emerged as a significant and important prognostic factor for hospitalization, 90-day mortality, and 180-day mortality.