A prospective study of zanubrutinib, a Bruton tyrosine kinase inhibitor, in relapsed/refractory idiopathic multicentric Castleman disease.

Relapsed and refractory (R/R) idiopathic multicentric Castleman disease (iMCD) is a clinical challenge with no standard treatment. In this preliminary clinical trial, we investigated the efficacy and safety profiles of a Bruton tyrosine kinase inhibitor (BTKi), zanubrutinib, in patients with R/R iMCD. The primary endpoint was the overall response rate at Week 12 according to the Castleman Disease Collaborative Network (CDCN) response criteria. The trial was terminated early due to a lack of treatment response in the first enrolled 5 patients. Although 3 patients achieved symptomatic response, none of the 5 patients had an overall response by Week 12. One patient had progressive disease and the other 4 had stable disease. The study drug was well tolerated without grade 2 or higher adverse events. Our findings suggest that BTKi therapy is not effective for iMCD, and further attempts at single-agent therapy with zanubrutinib or other BTKis for iMCD should be considered with caution and probably avoided. This trial was registered at www.clinialtrials.gov as #NCT04743687.

Idiopathic multicentric Castleman disease (iMCD)-idiopathic plasmacytic lymphadenopathy: A distinct subtype of iMCD-not otherwise specified with different clinical features and better survival.

Idiopathic multicentric Castleman disease (iMCD) is subclassified into iMCD-thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly (TAFRO) and iMCD-not otherwise specified (NOS) according to the Castleman Disease Collaborative Network (CDCN) consensus criteria. With a deeper understanding of iMCD, a group of patients with iMCD-NOS characterised by polyclonal hypergammaglobulinaemia, plasmacytic/mixed-type lymph node histopathology and thrombocytosis has attracted attention. This group of patients has been previously described as having idiopathic plasmacytic lymphadenopathy (IPL). Whether these patients should be excluded from the current classification system lacks sufficient evidence. This retrospective analysis of 228 patients with iMCD-NOS identified 103 (45.2%) patients with iMCD-IPL. The clinical features and outcomes of patients with iMCD-IPL and iMCD-NOS without IPL were compared. Patients with iMCD-IPL showed a significantly higher inflammatory state but longer overall survival. No significant difference in overall survival was observed between severe and non-severe patients in the iMCD-IPL group according to the CDCN severity classification. Compared with lymphoma-like treatments, multiple myeloma-like and IL-6-blocking treatment approaches in the iMCD-IPL group resulted in significantly higher response rates and longer time to the next treatment. These findings highlight the particularities of iMCD-IPL and suggest that it should be considered a new subtype of iMCD-NOS.

Comprehensive genomic profiling of breast cancers characterizes germline-somatic mutation interactions mediating therapeutic vulnerabilities.

Germline-somatic mutation interactions are universal and associated with tumorigenesis, but their role in breast cancer, especially in non-Caucasians, remains poorly characterized. We performed large-scale prospective targeted sequencing of matched tumor-blood samples from 4079 Chinese females, coupled with detailed clinical annotation, to map interactions between germline and somatic alterations. We discovered 368 pathogenic germline variants and identified 5 breast cancer DNA repair-associated genes (BCDGs; BRCA1/BRCA2/CHEK2/PALB2/TP53). BCDG mutation carriers, especially those with two-hit inactivation, demonstrated younger onset, higher tumor mutation burden, and greater clinical benefits from platinum drugs, PARP inhibitors, and immune checkpoint inhibitors. Furthermore, we leveraged a multiomics cohort to reveal that clinical benefits derived from two-hit events are associated with increased genome instability and an immune-activated tumor microenvironment. We also established an ethnicity-specific tool to predict BCDG mutation and two-hit status for genetic evaluation and therapeutic decisions. Overall, this study leveraged the large sequencing cohort of Chinese breast cancers, optimizing genomics-guided selection of DNA damaging-targeted therapy and immunotherapy within a broader population.

Spinal-Specific Super Enhancer in Neuropathic Pain.

Dysfunctional gene expression in nociceptive pathways plays a critical role in the development and maintenance of neuropathic pain. Super enhancers (SEs), composed of a large cluster of transcriptional enhancers, are emerging as new players in the regulation of gene expression. However, whether SEs participate in nociceptive responses remains unknown. Here, we report a spinal-specific SE (SS-SE) that regulates chronic constriction injury (CCI)-induced neuropathic pain by driving Ntmt1 and Prrx2 transcription in dorsal horn neurons. Peripheral nerve injury significantly enhanced the activity of SS-SE and increased the expression of NTMT1 and PRRX2 in the dorsal horn of male mice in a bromodomain-containing protein 4 (BRD4)-dependent manner. Both intrathecal administration of a pharmacological BRD4 inhibitor JQ1 and CRISPR-Cas9-mediated SE deletion abolished the increased NTMT1 and PRRX2 in CCI mice and attenuated their nociceptive hypersensitivities. Furthermore, knocking down Ntmt1 or Prrx2 with siRNA suppressed the injury-induced elevation of phosphorylated extracellular-signal-regulated kinase (p-ERK) and glial fibrillary acidic protein (GFAP) expression in the dorsal horn and alleviated neuropathic pain behaviors. Mimicking the increase in spinal Ntmt1 or Prrx2 in naive mice increased p-ERK and GFAP expression and led to the genesis of neuropathic pain-like behavior. These results redefine our understanding of the regulation of pain-related genes and demonstrate that BRD4-driven increases in SS-SE activity is responsible for the genesis of neuropathic pain through the governance of NTMT1 and PRRX2 expression in dorsal horn neurons. Our findings highlight the therapeutic potential of BRD4 inhibitors for the treatment of neuropathic pain.SIGNIFICANCE STATEMENT SEs drive gene expression by recruiting master transcription factors, cofactors, and RNA polymerase, but their role in the development of neuropathic pain remains unknown. Here, we report that the activity of an SS-SE, located upstream of the genes Ntmt1 and Prrx2, was elevated in the dorsal horn of mice with neuropathic pain. SS-SE contributes to the genesis of neuropathic pain by driving expression of Ntmt1 and Prrx2 Both inhibition of SS-SE with a pharmacological BRD4 inhibitor and genetic deletion of SS-SE attenuated pain hypersensitivities. This study suggests an effective and novel therapeutic strategy for neuropathic pain.

Effect of high-frequency oscillation on reduction of atelectasis in perioperative patients: a prospective randomized controlled study.

BACKGROUND: Atelectasis affects approximately 90% of anaesthetized patients, with laparoscopic surgery and pneumoperitoneum reported to exacerbate this condition. High-frequency oscillation therapy applies continuous positive pressure pulses to oscillate the airway, creating a pressure difference in small airways obstructed by secretions. This process helps reduce peak airway pressure, open small airways, and decrease atelectasis incidence, while also facilitating respiratory tract clearance. This study examines the efficacy of high-frequency oscillation on reduction of atelectasis in laparoscopic cholecystectomy (LC) patients under general anaesthesia, evaluated using lung ultrasound. METHODS: Sixty-four patients undergoing laparoscopic cholecystectomy were randomly divided into a control group and a high-frequency oscillation (HFO) group. Both groups underwent total intravenous anaesthesia under invasive arterial monitoring. The HFO group received a 10-minute continuous high-frequency oscillation therapy during surgery, while the control group received no intervention. Lung ultrasound evaluations were performed three times: five minutes post-intubation (T1), at the end of the surgery (T2), and before leaving the Post-Anaesthesia Care Unit (PACU; T3). Blood gas analysis was performed twice: prior to induction with no oxygen supply and before PACU discharge (oxygen supply off). RESULTS: The HFO group displayed a significantly lower incidence of atelectasis at T3 (57.5% vs. 90.3%, OR 6.88, 95%CI (1.74 to 27.24)) compared to the control group. Moreover, the HFO group's PaO2 levels remained consistent with baseline levels before PACU discharge, unlike the control group. Although there was no significant difference in LUS scores between the groups at T1 (8.56 ± 0.15 vs. 8.19 ± 0.18, p = 0.1090), the HFO group had considerably lower scores at T2 (13.41 ± 0.17 vs.7.59 ± 0.17, p < 0.01) and T3 (13.72 ± 0.14 vs.7.25 ± 0.21, p < 0.01). CONCLUSION: Our study indicates that high-frequency oscillation effectively reduces atelectasis in patients undergoing laparoscopic cholecystectomy. Additionally, it can mitigate the decline in oxygen partial pressure associated with atelectasis.

Tumor Cell-derived Extracellular Vesicles in Modulating Phenotypes and Immune Functions of Macrophages: Mechanisms and Therapeutic Applications.

Tumor tissues consist of tumor cells and tumor stroma, which is structured by non-tumor cells and the extracellular matrix. Macrophages are the predominant immune cells in the tumor microenvironment (TME). Based on the intimate interaction between macrophages and tumor cells, macrophages are closely involved in tumor initiation and progression, playing a key role in tumor formation, angiogenesis, metastasis, and immune escape. Extracellular vesicles (EVs) are a group of membrane-enclosed structures secreted by almost all cell types. As crucial mediators of cell-to-cell communication, EVs play a role in various physiological processes and the development of diseases including cancer. According to numerous studies, tumor cell-derived extracellular vesicles (T-EVs) could highly modulate the phenotypes and functions of macrophages, thus promoting tumor development. Herein, we comprehensively introduce the role of T-EVs in regulating the M1/M2 phenotypes and immune functions of macrophages, including cytokine secretion, expression of immune regulatory molecules on the membrane, phagocytosis, and antigen presentation. More importantly, based on the regulatory effects of T-EVs on macrophages, we propose several potential therapeutic approaches that may guide future attempts to increase the effectiveness of cancer therapy.

Anti-Tumor Strategies by Harnessing the Phagocytosis of Macrophages.

Macrophages are essential for the human body in both physiological and pathological conditions, engulfing undesirable substances and participating in several processes, such as organism growth, immune regulation, and maintenance of homeostasis. Macrophages play an important role in anti-bacterial and anti-tumoral responses. Aberrance in the phagocytosis of macrophages may lead to the development of several diseases, including tumors. Tumor cells can evade the phagocytosis of macrophages, and "educate" macrophages to become pro-tumoral, resulting in the reduced phagocytosis of macrophages. Hence, harnessing the phagocytosis of macrophages is an important approach to bolster the efficacy of anti-tumor treatment. In this review, we elucidated the underlying phagocytosis mechanisms, such as the equilibrium among phagocytic signals, receptors and their respective signaling pathways, macrophage activation, as well as mitochondrial fission. We also reviewed the recent progress in the area of application strategies on the basis of the phagocytosis mechanism, including strategies targeting the phagocytic signals, antibody-dependent cellular phagocytosis (ADCP), and macrophage activators. We also covered recent studies of Chimeric Antigen Receptor Macrophage (CAR-M)-based anti-tumor therapy. Furthermore, we summarized the shortcomings and future applications of each strategy and look into their prospects with the hope of providing future research directions for developing the application of macrophage phagocytosis-promoting therapy.

Morphological change and differential proteomics analysis of gill in Mytilus coruscus under starvation.

Mytilus coruscus is a dominant shellfish in the Yangtze estuary and its adjacent sea area. Food deprivation often occurs during their growth due to fluctuations in algal abundance caused by seasonal freshwater flushing and high-density aquaculture mode. To investigate the coping strategies of M. coruscus to starvation stress, electron microscopy and differential proteomic analysis were performed on the critical feeding organ gill of the mussels after 9 days of starvation. The electron microscopy results showed that the cilia of the mussel gills were dissolved, and the gaps between gill filaments widened under starvation. Differential proteomic analysis revealed that phagocytosis-related proteins such as ATPeV1E, ATPeV1C, LAMP1_2 and CTSL were significantly upregulated, and the phagocytosis pathway was significantly enriched (p < 0.05). In addition, the corin content in gill and myeloperoxidase level as well as the number of dead cells in blood were both significantly increased (p < 0.05). What's more, proteomic data suggested that immune maintenance, cellular transport and metabolism related pathways were significantly enriched, which illustrated an immune and metabolism responses under starvation. This study reveals for the first time that phagocytosis functions as an essential strategy for M. coruscus to cope with starvation, which provides new scientific knowledge and a theoretical basis for understanding the adaptation mechanisms of mussel to starvation and for rational optimization of mussel culture patterns.

DHX9/DNA-tandem repeat-dependent downregulation of ciRNA-Fmn1 in the dorsal horn is required for neuropathic pain.

Circular RNAs (ciRNAs) are emerging as new players in the regulation of gene expression. However, how ciRNAs are involved in neuropathic pain is poorly understood. Here, we identify the nervous-tissue-specific ciRNA-Fmn1 and report that changes in ciRNA-Fmn1 expression in spinal cord dorsal horn neurons play a key role in neuropathic pain after nerve injury. ciRNA-Fmn1 was significantly downregulated in ipsilateral dorsal horn neurons after peripheral nerve injury, at least in part because of a decrease in DNA helicase 9 (DHX9), which regulates production of ciRNA-Fmn1 by binding to DNA-tandem repeats. Blocking ciRNA-Fmn1 downregulation reversed nerve-injury-induced reductions in both the binding of ciRNA-Fmn1 to the ubiquitin ligase UBR5 and the level of ubiquitination of albumin (ALB), thereby abrogating the nerve-injury-induced increase of ALB expression in the dorsal horn and attenuating the associated pain hypersensitivities. Conversely, mimicking downregulation of ciRNA-Fmn1 in naïve mice reduced the UBR5-controlled ubiquitination of ALB, leading to increased expression of ALB in the dorsal horn and induction of neuropathic-pain-like behaviors in naïve mice. Thus, ciRNA-Fmn1 downregulation caused by changes in binding of DHX9 to DNA-tandem repeats contributes to the genesis of neuropathic pain by negatively modulating UBR5-controlled ALB expression in the dorsal horn.

Simple and Versatile Nitrooxylation: Noncyclic Hypervalent Iodine Nitrooxylating Reagent.

Organic nitrates are broadly applied as pharmaceuticals (acting as efficient nitric oxide donor), energetic materials, building blocks in organic synthesis, etc. However, practical and direct methods to access organic nitrates efficiently are still rare, mainly due to the lack of powerful nitrooxylating reagents. Herein, we report bench-stable and highly reactive noncyclic hypervalent iodine nitrooxylating reagents, oxybis(aryl-λ3 -iodanediyl) dinitrates (OAIDNs, 2), which are prepared just by using aryliodine diacetate and HNO3 . The reagents are used to achieve a mild and operationally simple protocol to access diverse organic nitrates. By employing of 2, zinc-catalyzed regioselective nitrooxylation of cyclopropyl silyl ethers is realized efficiently to access the corresponding ß-nitrooxy ketones with high functional-group tolerance. Moreover, a series of direct and catalyst-free nitrooxylations of enolizable C-H bonds are carried out smoothly to afford the desired organic nitrates within minutes by just mixing the substrates with 2 in dichloromethane.

Analytical method for calculating internal stray radiation from an IR spectrometer based on the view factor.

Optomechanical components such as the lens barrels and frames of IR spectrometers produce strong internal stray radiation, which reduces the instrument's SNR and dynamic range. An IR internal stray radiation calculation method based on an analytical model of the view factor is proposed. The mathematical model of the view factor calculation method of typical optomechanical components is established. For any IR optical systems, the internal stray radiation can be quickly and accurately calculated by adjusting the coordinate systems in the calculation method. Based on the proposed method, the internal stray radiation of a double-pass long-wave IR spectrometer was calculated. The calculation results are consistent with the simulation results. The RMS value of the relative error between the calculated value and the simulated value is around 11%. To verify the proposed method, an experiment was conducted to test the internal stray radiation of the long-wave IR spectrometer. The internal stray radiation test results agree with the calculated and simulated results, and the relative error between the test results and the calculation results is within 9%.

Prinsepia utilis Royle leaf extract: Ameliorative effects on allergic inflammation and skin lesions in allergic contact dermatitis and polyphenolic profiling through UPLC-MS/MS coupled to chemometric analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Allergic contact dermatitis (ACD) is a common allergic inflammatory disease that is concomitant with skin swelling, redness, dry itching, and relapses. Prinsepia utilis Royle, a Chinese and Indian folk medicine, is rich in polyphenols with potential anti-inflammatory and skin-protective activities. However, the underlying mechanism of P. utilis leaf (PUL) in the treatment of ACD and its functional basis remains unclear. AIM OF THE STUDY: This study is aimed to explore and reveal the active substances and mechanism of PUL against ACD. MATERIALS AND METHODS: Hyaluronidase inhibitory assay and fluorescein isothiocyanate (FITC)-induced ACD mouse model were performed to assess the antiallergic effects of PUL in vitro and in vivo. Different solvents were applied to obtain multiple PUL extracts. The extracts were further tested for total phenolic content (TPC) and total flavonoid content (TFC) by using spectrophotometric assays. Polyphenolic profiles were analyzed by using ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-QTOF-MS/MS), and a simultaneous quantification method was established using UPLC-QTrap-MS/MS through multiple reaction monitoring (MRM) and applied to analyze the pharmacokinetics of the multiple major polyphenols of PUL in mice. RESULTS: The water extract of PUL with the highest TPC/TFC exhibited the strongest antihyaluronidase effect (IC50 = 231.93 µg/mL). In vivo assays indicated that the oral administration of PUL water extract dose-dependently attenuated ACD-like symptoms by decreased interleukin (IL)-4, IL-5, IL-13, IL-33, thymic stromal lymphopoietin, and IgE production, suppressed eosinophil and basophil secretion, and increasing the expression of tight junction (TJ) proteins (claudin-1 [CLDN-1] and occludin). Concomitantly, UPLC-QTOF-MS/MS analysis enabled the identification of 60 polyphenols and the pharmacokinetic parameters of seven quantified constituents of PUL were characterized. Four compounds, trans-p-coumaric acid 4-O-ß-D-glucopyranoside (11), vicenin-2 (21), isoschaftoside (31), and kaempferol 3-O-(2″,6″-di-O-α-L-rhamnopyransoyl)-ß-D-glucopyranoside (38) which displayed satisfactory pharmacokinetic features, were considered as potential effective substances in PUL. CONCLUSIONS: PUL water extract ameliorated the allergic inflammation of ACD by repairing the epithelial barrier and alleviating Th2-type allergic inflammation. The anti-allergic effect of PUL is closely related to its phenolic substances, and compounds 11, 21, 31, and 38 were the active substances of PUL. It revealed that P. utilis could be developed as a new source of antiallergic agents for ACD therapy.

Identification of a novel signature with prognostic value in triple-negative breast cancer through clinico-transcriptomic analysis.

Background: Although perceived as a highly aggressive disease, triple-negative breast cancer (TNBC) constitutes heterogeneous features with various outcomes. In this study, we aimed to establish a prognostic signature for patients with TNBC to improve risk stratification. Methods: Gene expression data were obtained from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) were detected pairwise between TNBC and other subtypes of samples. Then, TNBC-correlated modules were determined using coexpression network analysis. A gene signature was established based on the prognostic genes in the intersection between DEGs and selected gene modules using least absolute shrinkage and selection operator (LASSO) Cox regression. Finally, a clinico-transcriptomic signature was developed to predict overall survival (OS). Model performance was quantified, and the bootstrap resampling method was used for validation. Results: The gene signature included 6 messenger RNAs (mRNAs) and a clinical score indicating an increased likelihood of death when used as continuous or categorical predictors. A nomogram was built by integrating the pathological stage and gene signature to predict 2-, 3-, and 5-year OS. The addition of pathological stage increased the concordance index (C-index) compared with pathological stage alone and the gene signature alone. Bootstrap resampling revealed a stable performance of the nomogram. Conclusions: A 6-mRNA signature was established to inform prognosis for patients with TNBC. Its combination with pathological stage can contribute to improving performance and provide additional supporting evidence for clinical decision-making.

[Investigating the Pollutants of Marine Shipping Emissions Along the East China Sea by Combining in-situ Measurements and Automatic Identification System].

Marine shipping emissions have important impacts on air quality and climate. This type of anthropogenic emission remains largely unclear due to complex vessel types and activities. A coastal site near the Ningbo-Zhoushan port along the East China Sea was selected for this study, representing one of the hotspot regions globally with the most intensive shipping activities, in combination with vessels for both domestic and international transportation. Long-term temporal variations in key gaseous and particulate pollutants were obtained at the site using in-situ measurements, and the vessel speed associated with each classified vessel type was obtained according to the automatic identification system (AIS). In combination of backward trajectories, we were able to identify the periods predominated by the surrounding vessel emissions (in warm seasons, dominated by vessels in full operation or idle mode) or influenced by continental outflow (in cold season). We found that emissions of sulphur dioxide (SO2), nitrogen oxides (NOx), and black carbon (BC) aerosol were highly correlated with high-speed vessels, whereas carbon monoxide (CO) was likely related to lower operation speed. The total particulate matter (PM) was not directly linked to vessel activities. The enhancement factor in operation mode compared to that in idle mode was approximately 1-4 for most pollutants. This direct ambient observation of the emissions from a range of mixed vessel types may provide a basis for evaluating the shipping emission inventory.

Structural-visual functional relationships detected by optical coherence tomography in varying age-cohorts' patients with optic neuritis.

AIM: To assess the relationships of final best-corrected visual acuity (BCVA) and the optic nerve structural loss in varying age-cohorts of optic neuritis (ON) patients. METHODS: This is a retrospective, cross-sectional study. Totally 130 ON subjects (200 eyes) without ON onset within 6mo were included, who underwent BCVA assessment, peripapillary retinal nerve fibre layer (pRNFL) and macular segmented layers evaluation by optical coherence tomography (OCT). RESULTS: For the 0-18y cohort, the final BCVA (logMAR) was significantly better and less frequent recurrences than adult cohorts (P=0.000). The final BCVA (logMAR) in all age-cohorts of the ON patients had negative and linear correlations to the pRNFL thicknesses and macular retinal ganglion cell layer (mRGCL) volumes, when the pRNFL thicknesses were reduced to the thresholds of 57.2-67.5 µm or 0.691-0.737 mm3 in mRGCL volumes, respectively, with the strongest interdependence in the 19-40y cohort. The ON patients from varying age cohorts would be threatened by blindness when their pRNFL thicknesses dropped 36.7-48.3 µm or the mRGCL volumes dropped to 0.495-0.613 mm3. CONCLUSION: The paediatric ON has best prognosis and young adult ON exhibits perfectly linear correlations of final vision and structural loss. The pRNFL and the mRGCL could be potential structural markers to predict the vision prognosis for varying-age ON patients.

Utility of Provocative Testing in the Diagnosis and Genotyping of Congenital Long QT Syndrome: A Systematic Review and Meta-Analysis.

Background Diagnosis is particularly challenging in concealed or asymptomatic long QT syndrome (LQTS). Provocative testing, unmasking the characterization of LQTS, is a promising alternative method for the diagnosis of LQTS, but without uniform standards. Methods and Results A comprehensive search was conducted in PubMed, Embase, and the Cochrane Library through October 14, 2021. The fixed effects model was used to assess the effect of the provocative testing on QTc interval. A total of 22 studies with 1137 patients with LQTS were included. At baseline, QTc interval was 40 ms longer in patients with LQTS than in controls (mean difference [MD], 40.54 [95% CI, 37.43-43.65]; P<0.001). Compared with the control group, patients with LQTS had 28 ms longer ΔQTc upon standing (MD, 28.82 [95% CI, 23.05-34.58]; P<0.001), nearly 30 ms longer both at peak exercise (MD, 27.31 [95% CI, 21.51-33.11]; P<0.001) and recovery 4 to 5 minutes (MD, 29.85 [95% CI, 24.36-35.35]; P<0.001). With epinephrine infusion, QTc interval was prolonged both in controls and patients with QTS, most obviously in LQT1 (MD, 68.26 [95% CI, 58.91-77.60]; P<0.001) and LQT2 (MD, 60.17 [95% CI, 50.18-70.16]; P<0.001). Subgroup analysis showed QTc interval response to abrupt stand testing and exercise testing varied between LQT1, LQT2, and LQT3, named Type Ⅰ, Type Ⅱ, and Type Ⅲ. Conclusions QTc trend Type Ⅰ and Type Ⅲ during abrupt stand testing and exercise testing can be used to propose a prospective evaluation of LQT1 and LQT3, respectively. Type Ⅱ QTc trend combined epinephrine infusion testing could distinguish LQT2 from control. A preliminary diagnostic workflow was proposed but deserves further evaluation.

Prediction of axillary lymph node metastasis in triple-negative breast cancer by multi-omics analysis and an integrated model.

Background: To avoid unnecessary postoperative complications, it is essential to select breast cancer patients without axillary lymph node (LN) metastasis who might be eligible for exemption from sentinel lymph node biopsy (SLNB). However, the lymph node metastasis (LNM) of triple-negative breast cancer (TNBC) is difficult to predict if only considering clinical parameters. Hence, by investigating the difference between LN positive and LN negative patients, we aimed to build a multi-omics model able to better predict LNM in TNBC. Methods: A total of 445 TNBC patients with lymph node status and multi-omics data were enrolled and divided into training and validation sets. We analyzed both clinicopathological characteristics and multi-omics data to search for robust biomarkers, which were used to establish a multi-omics model. Results: Compared with LN negative patients, LN positive patients had an increasing number of mutational events, while the frequencies of both amplification and deletion in somatic copy number alterations (SCNAs) were lower in LN positive cases. After analyzing upregulated gene-related pathways, neutrophil-related pathways were found to be enriched in LN positive patients. Based on these omics analyses, 5 predictors were utilized to build a multi-omics model, and the area under the receiver operating characteristic curve was 0.790 in the training set and 0.807 in the validation set, showing a better performance than models using individual omics data. Conclusions: After analyzing the largest TNBC multi-omics cohorts, we identified the potential clinical and molecular characteristics that are related to LNM. A multi-omics model was developed and performed robustly in predicting LNM, with the potential assistance of tailoring unnecessary axillary LN management among TNBC patients.

Garnet secondary ion mass spectrometry oxygen isotopes reveal crucial roles of pulsed magmatic fluid and its mixing with meteoric water in lode gold genesis.

SignificanceThere is a common consensus that lode gold deposits mostly precipitated from metamorphic fluids via fluid boiling and/or fluid-rock interaction, but whether magmatic hydrothermal fluids and the mixing of such fluids with an external component have played a vital role in the formation of lode gold deposits remains elusive. We use garnet secondary ion mass spectrometry oxygen isotope analysis to demonstrate that the world-class Dongping lode gold deposit has been formed by multiple pulses of magmatic hydrothermal fluids and their mixing with large volumes of meteoric water. This study opens an opportunity to tightly constrain the origin of lode gold deposits worldwide and other hydrothermal systems that may have generated giant ore deposits in the Earth's crust.

Two New Xanthones from the Twigs of Calophyllum membranaceum and Their Anti-Inflammatory Activities in HESC Cells.

Two new xanthones, calmemxanthone A (1) and calmemxanthone B (2), along with eleven known compounds were isolated from the dried twigs of Calophyllum membranaceum Gardn. et Champ. The structures of compounds 1 and 2 were established by analysis of spectra and mass spectrometry data. The absolute configuration of compound 1 was confirmed by electronic circular dichroism (ECD) spectral analysis. The anti-inflammation action of these compounds were evaluated on lipopolysaccharide (LPS)-induced inflammatory damage to human endometrial stromal cells (HESCs), and the structure-activities of 1-13 were also discussed. Compound 10 presented the anti-inflammation action with an IC50 value of 20.3 µM, that might be relevant to the regulation of NF-κB signaling pathway via the suppression of TRIF, IKKα, and IκBα.

Pyranochromones with Anti-Inflammatory Activities in Arthritis from Calophyllum membranaceum.

Eleven new pyranochromones, calomembranone A-K (1-11), two new pyranocoumarins, calopolyanolide E and F (12 and 13), together with six known analogues (14-19) were isolated from the leaves of Calophyllum membranaceum. Their structures and absolute configurations were elucidated by analysis of spectroscopic data, computational calculations, as well as X-ray crystallography of 4 and 9. The anti-inflammatory activities of all the isolates were evaluated by measuring their NO inhibitory effects in LPS-stimulated RAW 264.7 cells. Structure-activity relationships are also discussed. Compound 7 showed the strongest NO inhibition (IC50 = 0.92 µM). Oral administration of 7 dose-dependently reduced the paw swelling and downregulated neutrophil-to-lymphocyte ratio in the carrageenan-induced acute arthritis mice model. Molecular dynamics simulation and cellular thermal shift assay results indicated that 7 participated in a robust and stable interaction with the active site of TLR4. Compound 7 also suppressed the inflammation in arthritis through the regulation of TLR4 mediated signal transduction via IKK/NF-κB signaling pathway and the consequent reduction of IL-2, IL-4, and IL-5.