Seminal plasma S100A8/A9 as a potential biomarker of genital tract inflammation.

ABSTRACT: Infections and inflammatory reactions in the male genital tract are the leading causes of male infertility with a prevalence of 6%-10%, primarily affecting testicular and epididymal function and ultimately compromising sperm quality. However, most infertile patients with genital infection/inflammation are asymptomatic and easily overlooked. Traditional indicators, including white blood cells, elastase, and other components in semen, can reflect inflammation of the genital tract, but there is still a lack of a uniform standard method of detection. Therefore, it is necessary to explore reliable markers in semen that reflect the inflammatory status of the genital tract. Using the experimental autoimmune orchitis (EAO) model to simulate noninfectious chronic orchitis, we successfully collected ejaculated seminal fluid from EAO rats using optimized electrical stimulation devices. Proteomic analysis was performed using isobaric tags for relative and absolute quantification (iTRAQ). Compared to the control group, 55 upregulated and 105 downregulated proteins were identified in seminal plasma samples from the EAO group. In a preliminary screening, the inflammation-related protein S100A8/A9 was upregulated. We further verified that S100A8/A9 was increased in seminal plasma and highly expressed in testicular macrophages of the EAO model. In patients with oligoasthenospermia and genital tract infections, we also found that S100A8/A9 levels were remarkably increased in seminal plasma and testicular macrophages. S100A8/A9 in semen may be a potential biomarker for chronic genital inflammation. Our study provides a new potential biomarker for early diagnosis and further understanding of male infertility caused by genital inflammation.

Long-term efficacy, safety and biocompatibility of a novel sirolimus eluting iron bioresorbable scaffold in a porcine model.

Iron is considered as an attractive alternative material for bioresorbable scaffolds (BRS). The sirolimus eluting iron bioresorbable scaffold (IBS), developed by Biotyx Medical (Shenzhen, China), is the only iron-based BRS with an ultrathin-wall design. The study aims to investigate the long-term efficacy, safety, biocompatibility, and lumen changes during the biodegradation process of the IBS in a porcine model. A total of 90 IBSs and 70 cobalt-chromium everolimus eluting stents (EES) were randomly implanted into nonatherosclerotic coronary artery of healthy mini swine. The multimodality assessments including coronary angiography, optical coherence tomography, micro-computed tomography, magnetic resonance imaging, real-time polymerase chain reaction (PCR), and histopathological evaluations, were performed at different time points. There was no statistical difference in area stenosis between IBS group and EES group at 6 months, 1year, 2 years and 5 years. Although the scaffolded vessels narrowed at 9 months, expansive remodeling with increased mean lumen area was found at 3 and 5 years. The IBS struts remained intact at 6 months, and the corrosion was detectable at 9 months. At 5 years, the iron struts were completely degraded and absorbed in situ, without in-scaffold restenosis or thrombosis, lumen collapse, aneurysm formation, and chronic inflammation. No local or systemic toxicity and abnormal histopathologic manifestation were found in all experiments. Results from real-time PCR indicated that no sign of iron overload was reported in scaffolded segments. Therefore, the IBS shows comparable efficacy, safety, and biocompatibility with EES, and late lumen enlargement is considered as a unique feature in the IBS-implanted vessels.

Rapid evaluation of the quality of Smilax glabra Roxb. using QADS based on FT-NIR combined with multiple intelligent algorithms.

Smilax glabra Roxb. (SGR) is known for its high nutritional and therapeutic value. However, the frequent appearance of counterfeit products causes confusion and inconsistent quality among SGR varieties. Herein, this study collected the proportion of SGR adulteration and used high-performance liquid chromatography (HPLC) to measure the astilbin content of SGR. Then Fourier-transform near-infrared (FT-NIR) technology, combined with multivariate intelligent algorithms, was used to establish partial least squares regression quantitative models for detecting SGR adulteration and measuring astilbin content, respectively. The method conducted a quantitative analysis of dual indicators through single-spectrum data acquisition (QADS) to comprehensively evaluate the authenticity and superiority of SGR. The coefficients of determination (R2) for both the calibration and prediction sets exceeded 0.96, which successfully leverages FT-NIR combined with multivariate intelligent algorithms to considerably enhance the accuracy and reliability of quantitative models. Overall, this research holds substantial value in the comprehensive quality evaluation in functional health foods.

Anti-inflammatory properties and characterization of water extracts obtained from Callicarpa kwangtungensis Chun using in vitro and in vivo rat models.

Callicarpa kwangtungensis Chun (CK) is a common remedy exhibits anti-inflammatory properties and has been used in Chinese herbal formulations, such as KangGongYan tablets. It is the main component of KangGongYan tablets, which has been used to treat chronic cervicitis caused by damp heat, red and white bands, cervical erosion, and bleeding. However, the anti-inflammatory effects of CK water extract remains unknown. This study assessed the anti-inflammatory effects of CK in vivo and in vitro, characterized its main components in the serum of rats and verified the anti-inflammatory effects of serum containing CK. Nitric oxide (NO), tumour necrosis factor α (TNF-α) and interleukin-6 (IL-6) release by RAW264.7 cells was examined by ELISA and Griess reagents. Inflammation-related protein expression in LPS-stimulated RAW264.7 cells was measured by western blotting. Furthermore, rat model of foot swelling induced by λ-carrageenan and a collagen-induced arthritis (CIA) rat model were used to explore the anti-inflammatory effects of CK. The components of CK were characterized by LC-MS, and the effects of CK-containing serum on proinflammatory factors levels and the expression of inflammation-related proteins were examined by ELISA, Griess reagents and Western blotting. CK suppressed IL-6, TNF-α, and NO production, and iNOS protein expression in LPS-stimulated RAW264.7 cells. Mechanistic studies showed that CK inhibited the phosphorylation of ERK, P38 and JNK in the MAPK signaling pathway, promoted the expression of IκBα in the NF-κB signaling pathway, and subsequently inhibited the expression of iNOS, thereby exerting anti-inflammatory effects. Moreover, CK reduced the swelling rates with λ-carrageenan induced foot swelling, and reduced the arthritis score and incidence in the collagen-induced arthritis (CIA) rat model. A total of 68 compounds in CK water extract and 31 components in rat serum after intragastric administration of CK were characterized. Serum pharmacological analysis showed that CK-containing serum suppressed iNOS protein expression and NO, TNF-α, and IL-6 release. CK may be an anti-inflammatory agent with therapeutic potential for acute and chronic inflammatory diseases, especially inflammatory diseases associated with MAPK activation.

The meso-substituent electronic effect of Fe porphyrins on the electrocatalytic CO2 reduction reaction.

We report Fe porphyrins bearing different meso-substituents for the electrocatalytic CO2 reduction reaction (CO2RR). By replacing two and four meso-phenyl groups of Fe tetraphenylporphyrin (FeTPP) with strong electron-withdrawing pentafluorophenyl groups, we synthesized FeF10TPP and FeF20TPP, respectively. We showed that FeTPP and FeF10TPP are active and selective for CO2-to-CO conversion in dimethylformamide with the former being more active, but FeF20TPP catalyzes hydrogen evolution rather than the CO2RR under the same conditions. Experimental and theoretical studies revealed that with more electron-withdrawing meso-substituents, the Fe center becomes electron-deficient and it becomes difficult for it to bind a CO2 molecule in its formal Fe0 state. This work is significant to illustrate the electronic effects of catalysts on binding and activating CO2 molecules and provide fundamental knowledge for the design of new CO2RR catalysts.

Neuropilin-1-Targeted Nanomedicine for Spatiotemporal Tumor Suppression through Photodynamic Vascular Damage and Antiangiogenesis.

Antiangiogenic therapy is an effective way to disrupt nutrient supply and starve tumors, but it is restricted by poor efficacy and negative feedback-induced tumor relapse. In this study, a neuropilin-1 (NRP-1)-targeted nanomedicine (designated as FPPT@Axi) is reported for spatiotemporal tumor suppression by combining photodynamic therapy (PDT) with antiangiogenesis. In brief, FPPT@Axi is prepared by utilizing an NRP-1-targeting chimeric peptide (Fmoc-K(PpIX)-PEG8-TKPRR) to encapsulate the antiangiogenic drug Axitinib (Axi). Importantly, the NRP-1-mediated targeting property enables FPPT@Axi to selectively concentrate at vascular endothelial and breast cancer cells, facilitating the production of reactive oxygen species (ROS) in situ for specific vascular disruption and enhanced cell apoptosis under light stimulation. Moreover, the codelivered Axi can further inhibit vascular endothelial growth factor receptor (VEGFR) to impair the negative feedback of PDT-induced tumor neovascularization. Consequently, FPPT@Axi spatiotemporally restrains the tumor growth through blocking angiogenesis, destroying tumor vessels, and inducing tumor apoptosis. Such an NRP-1-mediated targeting codelivery system sheds light on constructing an appealing candidate with translational potential by using clinically approved PDT and chemotherapy.

Breaking Physical Barrier of Fibrotic Breast Cancer for Photodynamic Immunotherapy by Remodeling Tumor Extracellular Matrix and Reprogramming Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve the photodynamic immunotherapy for fibrotic BRCA. FPC@S combines a tumor ECM-targeting peptide, a photosensitizer (protoporphyrin IX) and an antifibrotic drug (SIS3). After anchoring to the ECM, FPC@S causes ECM remodeling and BRCA cell death by generating reactive oxygen species (ROS) in situ. Interestingly, the ROS-mediated ECM remodeling can normalize the tumor blood vessel to improve hypoxia and in turn facilitate more ROS production. Besides, upon the acidic tumor microenvironment, FPC@S will release SIS3 for reprograming CAFs to reduce their activity but not kill them, thus inhibiting fibrosis while preventing BRCA metastasis. The natural physical barrier formed by the dense ECM is consequently eliminated in fibrotic BRCA, allowing the drugs and immune cells to penetrate deep into tumors and have better efficacy. Furthermore, FPC@S can stimulate the immune system and effectively suppress primary, distant and metastatic tumors by combining with immune checkpoint blockade therapy. This study provides different insights for the development of fibrotic tumor targeted delivery systems and exploration of synergistic immunotherapeutic mechanisms against aggressive BRCA.

Disparities in mortality risk after diagnosis of hematological malignancies in 185 countries: A global data analysis.

This study was to report proxy measures for mortality risk in patients with hematological malignancies across 185 countries globally and explore its association with their socioeconomic status and treatment. The incidence, mortality, and 5-year prevalence data were extracted from the GLOBOCAN database. The data regarding the human development index (HDI), gross national income (GNI), vulnerability index, and concordance with cancer Essential Medicines List (EML) were obtained from open-source reports. The ratio of mortality to 5-year-prevalence (MPR) and that of mortality to incidence (MIR) were calculated and age-standardized using Segi's world standard population. Finally, the possible associations were assessed using Pearson correlation analyses. In 2020, the global incidence, mortality, and 5-year prevalence of HMs were 1,278,362, 711,840, and 3,616,685, respectively. Global age-standardized MPR and MIR were 0.15 and 0.44, respectively; they varied significantly among 6 regions, 185 countries, 4 HM types, and 4 HDI groups worldwide. Older populations always had higher ratios. The correlation of MPRs and MIRs with HDI, GNI, and concordance with cancer EML was negative, whereas it was positive with the vulnerability index (lower was better). Increasing access to cancer drugs in resource-limited regions with a focus on vulnerable children may aid in reducing HM-related mortality risk.

Prediction of 5-year overall survival of diffuse large B-cell lymphoma on the pola-R-CHP regimen based on 2-year event-free survival and progression-free survival.

This study aimed to predict the 5-year overall survival (OS) benefit of pola-R-CHP versus R-CHOP in the POLARIX trial based on the 2-year event-free survival (EFS) and progression-free survival (PFS) rates in diffuse large B-cell lymphoma (DLBCL). We identified randomized controlled trials (RCT) published before 31 May 2023. The correlation between the logarithmic (log) hazard ratio (HR) for EFS (HREFS ) or PFS (HRPFS ) and the HR for OS (HROS ) was estimated at the trial-level. Correlation analysis was performed between 2-year PFS or EFS and 5-year OS rates at the treatment arm-level. Linear regression models were used to calculate the 5-year OS of pola-R-CHP and R-CHOP. In the included 20 RCTs, a linear correlation between HREFS (r = 0.765) or HRPFS (r = 0.534) and HROS was observed at the trial- level. Two-year EFS (r = 0.918) or 2-year PFS (r = 0.865) correlated linearly with 5-year OS. Linear regression analysis between 2-year EFS/PFS and 5-year OS gave estimated 5-year OS rates between pola-R-CHP and R-CHOP of 6.4% and 6.3%, respectively. Two-year EFS and PFS are feasible early endpoints in patients with DLBCL treated primarily with immunochemotherapy. The pola-R-CHP regimen is expected to improve 5-year OS.

Multicenter phase II study of moderate low-dose radiotherapy in indolent non-Hodgkin lymphoma: CLCG-iNHL-01 protocol.

Background: Radiotherapy is an effective treatment for indolent non-Hodgkin lymphoma (iNHL); however, the optimal radiotherapy dose remains to be determined. We hypothesize that a suitable dose may exist between 4 and 24 Gy. Methods: This prospective multicenter phase II trial intends to recruit 73 sites of iNHL patients, who will receive involved-site radiotherapy of 12 Gy in four fractions. The primary objective is the 6-month clinical complete response rate. Tumor tissue, blood and conjunctival specimens will be collected to identify potential predictive biomarkers. Discussion: The CLCG-iNHL-01 trial will evaluate the efficacy and toxicity of 12 Gy in patients with iNHL and provide information on a novel hypofractionation regimen of low-dose radiotherapy. Clinical Trial Registration: NCT05543070 (ClinicalTrials.gov).

Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice.

Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.104T>C, p.L35P) in vivo in mice. We first constructed Mef2cL35P heterozygous mice. Male heterozygous mice exhibited hyperactivity, repetitive behavior and social abnormalities. We then programmed AeCBE to edit the mutated C·G base pairs of Mef2c in the mouse brain through the intravenous injection of blood-brain barrier-crossing adeno-associated virus. This treatment successfully restored Mef2c protein levels in several brain regions and reversed the behavioral abnormalities in Mef2c-mutant mice. Our work presents an in vivo base-editing paradigm that could potentially correct single-base genetic mutations in the brain.

The biomarkers associated with epithelial-mesenchymal transition in human keloids.

INTRODUCTION: A keloid is a type of benign fibrotic disease with similar features to malignancies, including anti-apoptosis, over-proliferation, and invasion. Epithelial-mesenchymal transition (EMT) is a crucial mechanism that regulates the metastatic behavior of tumors. Thus, identifying EMT biomarkers is paramount in comprehensively understanding keloid pathogenesis. METHODS: To identify the differentially expressed genes (DEGs) GSE92566 dataset, with 3 normal skin and 4 keloid tissues, was downloaded from GEO databases to identify the differentially expressed genes (DEGs). Further, EMT-related genes were downloaded from dbEMT 2.0 databases and intersected with GSE92566 DEGs to identify EMT-related-DEGs (ERDEGs). Subsequently, the ERDEGs were used for GO, KEGG, gene set enrichment analysis (GSEA), protein-protein interaction (PPI), and miRNAs-mRNAs network analysis. To predict small molecules for EMT inhibition, the ERDEGs were imported to cMAP databases, whereas hub genes were imported to DGidb databases. Finally, we carried out qRT-PCR and in vitro experiments to validate our findings. RESULTS: A total of 122 ERDEGs were identified, including 59 upregulated and 63 down-regulated genes. Moreover, enrichment analysis revealed that focal adhesion, AMPK signal pathway, Wnt signal pathway, and EMT biological process were significantly enriched. STRING databases and Cytoscape software were used to construct the PPI network and EMT-related hub genes. Further, 3 modules were explored from the PPI network using the Molecular Complex Detection (MCODE) plugin. In the Cytohubba plugin, 10 hub genes were explored, including FN1, EGF, SOX9, CDH2, PROM1, EPCAM, KRT19, ITGB1, CD24, and KRT18. These genes were then enriched for the focal adhesion pathway. We constructed a microRNA (miRNA)-mRNA network, which predicted hsa-miR-155-5p (8 edges), hsa-miR-124-3p (7 edges), hsa-miR-145-5p (5 edges), hsa-miR-20a-5p (5 edges) and hsa-let-7b-5p (4 edges) as the most connected miRNAs regulating EMT. Based on the ERDEGs and 10 hub genes mentioned above, ribavirin demonstrated high drug-targeting relevance. Subsequently, qRT-PCR confirmed that the expression of FN1, ITGB1, CDH2, and EPCAM corroborated with previous findings. qRT-PCR also showed that the expression levels of hsa-miR-124-3p and hsa-miR-145-5p were significantly lower in keloids and hsa-miR-155-5p was upregulated in keloids. Finally, by treating human keloid fibroblasts (HKFs) with ribavirin in vitro, we confirmed that ribavirin could inhibit HKFs proliferation and EMT. CONCLUSION: In summary, this work provides novel EMT biomarkers in keloids and predicts new small target molecules for keloid therapy. Our findings improve the understanding of keloid pathogenesis, providing new treatment options.

Strain-Induced Reversible Motion of Skyrmions at Room Temperature.

Magnetic skyrmions are topologically protected swirling spin textures with great potential for future spintronic applications. The ability to induce skyrmion motion using mechanical strain not only stimulates the exploration of exotic physics but also affords the opportunity to develop energy-efficient spintronic devices. However, the experimental realization of strain-driven skyrmion motion remains a formidable challenge. Herein, we demonstrate that the inhomogeneous uniaxial compressive strain can induce the movement of isolated skyrmions from regions of high strain to regions of low strain at room temperature, which was directly observed using an in situ Lorentz transmission electron microscope with a specially designed nanoindentation holder. We discover that the uniaxial compressive strain can transform skyrmions into a single domain with in-plane magnetization, resulting in the coexistence of skyrmions with a single domain along the direction of the strain gradient. Through comprehensive micromagnetic simulations, we reveal that the repulsive interactions between skyrmions and the single domain serve as the driving force behind the skyrmion motion. The precise control of skyrmion motion through strain provides exciting opportunities for designing advanced spintronic devices that leverage the intricate interplay between strain and magnetism.

Quality assurance in a phase III, multicenter, randomized trial of POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a planning benchmark case.

PURPOSE: To report the planning benchmark case results of the POTENTIAL trial-a multicenter, randomized, phase 3 trial-to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer. METHODS: All participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission. RESULTS: The plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. In the first and final submission, the mean values of PTVim V100% were 79.9% vs. 92.7%; the mean values of heart Dmean were 11.5 Gy vs. 9.7 Gy for hypofractionated radiation therapy and 11.5 Gy vs. 11.0 Gy for conventional fractionated radiation therapy, respectively. CONCLUSION: The major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials.

Decreased lymphoma-related deaths and improved long-term relative survival with radiotherapy for early-stage diffuse large B-cell lymphoma in the rituximab era.

BACKGROUND: We aimed to investigate the incidence of lymphoma-related death (LRD) and the long-term net survival benefit of radiotherapy (RT) for early-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era. METHODS: 10,841 adults diagnosed with early-stage DLBCL between 2002-2015 were retrospectively analyzed using data from the Surveillance, Epidemiology, and End Results database. Primary therapy was categorized into combined-modality treatment (CMT, n = 3,631) and chemotherapy alone (n = 7,210). Competing risk analysis was used to evaluate the cumulative incidence of mortality. Inverse probability of treatment weighting (IPTW) was used to balance groups. The net survival benefit of RT was estimated through relative survival (RS), standardized mortality ratio (SMR), and transformed Cox regression, while controlling for background mortality. RESULTS: Patients initially treated with CMT had a lower cumulative incidence of LRD compared to those who received chemotherapy alone (HR 0.63, 95%CI: 0.57-0.69; P < 0.001). The 10-year overall survival (OS), RS, and SMR for CMT were 66.1%, 85.0%, and 1.71 respectively, which were significantly better than those for chemotherapy alone (53.0%; 69.8%; 2.62; all P < 0.001). IPTW and multivariable analysis revealed that the addition of RT led to better OS (HR 0.67, 95%CI: 0.62-0.71; P < 0.001) and RS (HR 0.69, 95%CI: 0.65-0.74; P < 0.001). Moreover, compared with chemotherapy alone, the benefit of OS and RS for CMT increased over time within 10 years of diagnosis. CONCLUSION: RT reduced LRD and improved the long-term net survival in early-stage DLBCL in the rituximab era. Further prospective studies are warranted to assess the specific patient population that would benefit the most from consolidative RT in early-stage DLBCL.

[Application characteristics and modern research progress of "bone-approaching" acupuncture].

The paper explores the evolution of "bone-approaching" acupuncture, its effect target and mechanism. The concrete operation procedure of "bone-approaching" method is recorded originally in Huangdi Neijing (Inner Canon of Yellow Emperor) as short needling and Shu needling (referring to the category of the five needling technique). The periosteum is the most effective stimulation target of "bone-approaching" acupuncture for analgesia, regaining consciousness and regulating spirit. The "bone-approaching" acupuncture is not only prominently effective on bone bi syndrome, but also has the unique effect on painful, encephalogenic and emotional diseases. The paper summarizes and improves "bone-approaching" acupuncture, i.e. "touching bone surface" with needle tip by slow insertion, "touching bone surface" without pain by swift insertion and "touching bone" with needle body by oblique insertion. It contributes to the inheritance, development and supplementation to the bone needling techniques in Huangdi Neijing and is significant for broadening the clinical application range of acupuncture.

[Rapid characterization and identification of non-volatile constituents in Pogostemonis Herba by UPLC-Q-TOF-MS combined with UNIFI and an in-house library].

This study aimed to characterize and identify the non-volatile components in Pogostemonis Herba by using ultra-perfor-mance liquid chromatography-quadrupole-time of flight-mass spectrometry(UPLC-Q-TOF-MS) combined with UNIFI and an in-house library. The chemical components in 50% methanol extract of Pogostemonis Herba were detected by UPLC-Q-TOF-MS in both positive and negative MS~E continuum modes. Then, the MS data were processed in UNIFI combined with an in-house library to automatically characterize the metabolites. Based on the multiple adduct ions, exact mass, diagnostic fragment ions, and peak intensity of compounds and the fragmentation pathways and retention behaviors of reference substances, the structures identified by UNIFI were further verified and those of the unidentified compounds were tentatively elucidated. A total of 120 compound structures were identified or tentatively identified, including flavonoids, phenylpropanoids, phenolic acids, terpenes, fatty acids, alkaloids, and phenylethanoid glycosides. Sixteen of them were accurately identified by comparison with reference substances, and 53 compounds were reported the first time for Pogostemonis Herba. This study systematically characterized and identified the non-volatile compounds in Pogostemonis Herba for the first time. The findings provide a scientific basis for revealing the pharmacodynamic material basis, establishing a quality control system, and developing products of Pogostemonis Herba.

Combination of Internal Extractive Electrospray Ionization Mass Spectrometry and Statistical Analysis for High-Throughput Molecular Differentiation of Rehmannia glutinosa Samples.

Rehmannia glutinosa (Gaert.) Libosch. ex Fisch. et Mey. is a perennial herb of the Scrophulariaceae family, which has long enjoyed a good reputation in China, and has a wide range of pharmacological effects and clinical applications. The place of origin is an important factor affecting the chemical composition of R. glutinosa, resulting in different pharmacological effects. Herein, internal extractive electrospray ionization mass spectrometry (iEESI-MS) combined with statistical techniques was established for high-throughput molecular differentiation of different R. glutinosa samples. Dried and processed R. glutinosa samples from four different places of origin were analyzed by iEESI-MS with high throughput (>200 peaks) and rapidness (<2 min/sample) without sample pretreatment. Clear separation models created by OPLS-DA were then established for distinguishing the places of origin of dried and processed R. glutinosa by using the obtained MS data. In addition, the molecular differences between the pharmacological effects of dried and processed R. glutinosa were also investigated by OPLS-DA, and 31 different components were screened out. This work provides a promising method for evaluating the quality of traditional Chinese medicines and studying the biochemical mechanism of processing.

Outcome and risk prediction of early progression in patients with extranodal natural killer/T cell lymphoma from the CLCG study.

Recently, progression-free survival at 24 months (PFS24) was defined as clinically relevant for patients with extranodal NK/T cell lymphoma. Herein, the clinical data from two independent random cohorts (696 patients each in the primary and validation datasets) were used to develop and validate a risk index for PFS24 (PFS24-RI), and evaluate its ability to predict early progression. Patients achieving PFS24 had a 5-year overall survival (OS) of 95.8%, whereas OS was only 21.2% in those failing PFS24 (P<0.001). PFS24 was an important predictor of subsequent OS, independent of risk stratification. The proportion of patients achieving PFS24 and 5-year OS rates correlated linearly among risk-stratified groups. Based on multivariate analysis of the primary dataset, the PFS24-RI included five risk factors: stage II or III/IV, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group score ≥2, primary tumor invasion, and extra-upper aerodigestive tract. PFS24-RI stratified the patients into low-risk (0), intermediate-risk (1-2), high-risk (≥3) groups with different prognoses. Harrell's C-index of PFS24-RI for PFS24 prediction was 0.667 in the validation dataset, indicating a good discriminative ability. PFS24-RI calibration indicated that the actual observed and predicted probability of failing PFS24 agreed well. PFS24-RI provided the probability of achieving PFS24 at an individual patient level.

HOXD-AS2-STAT3 feedback loop attenuates sensitivity to temozolomide in glioblastoma.

AIMS: Glioblastoma multiforme (GBM) is the deadliest glioma and its resistance to temozolomide (TMZ) remains intractable. Long non-coding RNAs (lncRNAs) play crucial roles in that and this study aimed to investigate underlying mechanism of HOXD-AS2-affected temozolomide sensitivity in glioblastoma. METHODS: We analyzed and validated the aberrant HOXD-AS2 expression in glioma specimens. Then we explored the function of HOXD-AS2 in vivo and in vitro and a clinical case was also reviewed to examine our findings. We further performed mechanistic experiments to investigate the mechanism of HOXD-AS2 in regulating TMZ sensitivity. RESULTS: Elevated HOXD-AS2 expression promoted progression and negatively correlated with prognosis of glioma; HOXD-AS2 attenuated temozolomide sensitivity in vitro and in vivo; The clinical case also showed that lower HOXD-AS2 sensitized glioblastoma to temozolomide; STAT3-induced HOXD-AS2 could interact with IGF2BP2 protein to form a complex and sequentially upregulate STAT3 signaling, thus forming a positive feedback loop regulating TMZ sensitivity in glioblastoma. CONCLUSION: Our study elucidated the crucial role of the HOXD-AS2-STAT3 positive feedback loop in regulating TMZ sensitivity, suggesting that this could be provided as a potential therapeutic candidate of glioblastoma.