Targeting the tumor microenvironment in primary central nervous system lymphoma: Implications for prognosis.

Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma, and there is limited research on its tumor microenvironment (TME). Nevertheless, more and more studies have evidence that TME has essential effects on tumor cell proliferation, immune escape, and drug resistance. Thus, it is critical to elucidate the role of TME in PCNSL. The understanding of the PCNSL TME is gradually unfolding, including factors that distinguish it from systemic diffuse large B-cell lymphoma (DLBCL). The TME in PCNSL exhibits both transcriptional and spatial intratumor heterogeneity. Cellular interactions between tumor cells and stroma cells reveal immune evasion signaling. The comparative analysis between PCNSL and DLBCL suggests that PCNSL is more likely to be an immunologically deficient tumor. In PCNSL, T cell exhaustion and downregulation of macrophage immune function are accompanied by suppressive microenvironmental factors such as M2 polarized macrophages, endothelin B receptor, HLA depletion, PD-L1, and TIM-3. MMP-9, Integrin-ß1, and ICAM-1/LFA-1 play crucial roles in transendothelial migration towards the CNS, while CXCL13/CXCR5, CD44, MAG, and IL-8 are essential for brain parenchymal invasion. Further, macrophages, YKL-40, CD31, CD105, PD-1/PD-L1 axis, osteopontin, galectin-3, aggregative perivascular tumor cells, and HLA deletion may contribute to poor outcomes in patients with PCNSL. This article reviews the effect of various components of TME on the progression and prognosis of PCNSL patients to identify novel therapeutic targets.

METTL3 Promotes Osteogenic Differentiation of Human Periodontal Ligament Stem Cells through IGF2BP1-Mediated Regulation of Runx2 Stability.

N6-Methyladenosine (m6A) has been reported to play a dynamic role in osteoporosis and bone metabolism. However, whether m6A is involved in the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) remains unclear. Here, we found that methyltransferase-like 3 (METTL3) was up-regulated synchronously with m6A during the osteogenic differentiation of hPDLSCs. Functionally, lentivirus-mediated knockdown of METTL3 in hPDLSCs impaired osteogenic potential. Mechanistic analysis further showed that METTL3 knockdown decreased m6A methylation and reduced IGF2BP1-mediated stability of runt-related transcription factor 2 (Runx2) mRNA, which in turn inhibited osteogenic differentiation. Therefore, METTL3-based m6A modification favored osteogenic differentiation of hPDLSCs through IGF2BP1-mediated Runx2 mRNA stability. Our study shed light on the critical roles of m6A on regulation of osteogenic differentiation in hPDLSCs and served novel therapeutic approaches in vital periodontitis therapy.

Utility of contrast-enhanced MRI radiomics features combined with clinical indicators for predicting induction chemotherapy response in primary central nervous system lymphoma.

PURPOSE: To assess the utility of combining contrast-enhanced magnetic resonance imaging (CE-MRI) radiomics features with clinical variables in predicting the response to induction chemotherapy (IC) for primary central nervous system lymphoma (PCNSL). METHODS: A total of 131 patients with PCNSL (101 in the training set and 30 in the testing set) who had undergone contrast-enhanced MRI scans were retrospectively analyzed. Pyradiomics was utilized to extract radiomics features, and the clinical variables of the patients were gathered. Radiomics prediction models were developed using different combinations of feature selection methods and machine learning models, and the best combination was ultimately chosen. We screened clinical variables associated with treatment outcomes and developed clinical prediction models. The predictive performance of radiomics model, clinical model, and combined model, which integrates the best radiomics model and clinical characteristics, was independently assessed and compared using Receiver Operating Characteristic (ROC) curves. RESULTS: In total, we extracted 1598 features. The best radiomics model we selected as the best utilized T-test and Recursive Feature Elimination (RFE) for feature selection and logistic regression for model building. Serum Interleukin 2 Receptor (IL-2R) and Eastern Cooperative Oncology Group (ECOG) Score were utilized to develop a clinical predictive model for assessing the response to induction chemotherapy. The results of the testing set revealed that the combined prediction model (radiomics and IL-2R) achieved the highest area under the ROC curve at 0.868 (0.683, 0.967), followed by the radiomics model at 0.857 (0.681, 0.957), and the clinical prediction model (IL-2R and ECOG) at 0.618 (0.413, 0.797). The combined model was significantly more accurate than the clinical model, with an AUC of 0.868 compared to 0.618 (P < 0.05). While the radiomics model had slightly better predictive power than the clinical model, this difference was not statistically significant (AUC, 0.857 vs. 0.618, P > 0.05). CONCLUSIONS: Our prediction model, which combines radiomics signatures from CE-MRI with serum IL-2R, can effectively stratify patients with PCNSL before high-dose methotrexate (HD-MTX) -based chemotherapy.

LncRNA urothelial cancer associated 1 promotes the osteogenic differentiation of human periodontal ligament stem cells by regulating the miR-96-5p/Osx axis.

OBJECTIVES: To investigate the expression of long non-coding RNA (lncRNA) urothelial cancer associated 1 (UCA1) in human periodontal ligament stem cells (hPDLSCs), its effect on osteogenic differentiation of hPDLSCs and its mechanism. DESIGN: The expression of osteogenic genes Osx, Runx2, Ocn and Opn was explored by qPCR. Protein expression in hPDLSCs was estimated by Western blot. The osteogenic differentiation of hPDLSCs was detected by Alizarin red staining assays. The interaction between UCA1 and miR-96-5p was explored by RNA pulldown assay and dual luciferase assay. The interaction between miR-96-5p and Osx 3'-UTR was measured by dual luciferase assay. RESULTS: The expression of UCA1 and miR-96-5p was negatively correlated in hPDLSCs. During the osteogenic differentiation of hPDLSCs, the expression of UCA1 was increased, while the expression of miR-96-5p was decreased. Knockdown of UCA1 in hPDLSCs inhibited osteogenic differentiation but induced upregulation of miR-96-5p expression, and vice versa. In addition, miR-96-5p partially reversed the positive effect of UCA1 on osteogenic differentiation of hPDLSCs. Notably, UCA1 was identified as a miR-96-5p sponge, and miR-96-5p targeted Osx. CONCLUSIONS: Our results demonstrated that the novel UCA1/miR-96-5p/Osx pathway regulates osteogenic differentiation of hPDLSCs and sheds new insights and targets for periodontitis therapeutics.

Relationship between driver gene mutations and clinical pathological characteristics in older lung adenocarcinoma.

Objectives: Lung adenocarcinoma (LUAD) is the most common newly diagnosed malignant tumor in older people. As older patients age, organ function decreases, leading to increased adverse reactions to treatment. The epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase tyrosine (ALK) tyrosine kinase inhibitors (TKIs) therapy are more effective and well-tolerated than chemotherapy, while the rate of genetic testing and subsequent targeted treatment among older patients remains relatively low, the clinical benefit limitation for those patients. This study aims to investigate the mutation characteristics of LUAD diver gene and its relationship with clinicopathological features in older LUAD. Materials and methods: A total of 275 patients were diagnosed as LUAD and were over sixty years old. We utilized next-generation sequencing technology to detect and analyze gene mutations in postoperative tissue specimens, including EGFR, KRAS, ALK, ROS1, RET, MET, BRAF, HER2, PIK3CA and NRAS. Results: A total of 90.18% (248/275) of older LUAD patients experienced genetic mutations. The EGFR (192, 69.82%) had the highest mutation rate among ten genes, followed by KRAS (21, 7.64%), MET (21, 7.64%), ERBB2 (15, 5.45%), RET (9, 3.27%), ALK (8, 2.91%), ROS1 (8, 2.91%), PIK3CA (6, 2.18%), BRAF (5, 1.82%) and NRAS (1, 0.36%). We also found thirty patients (15.63%) with EGFR mutations also having other gene mutations. The L858R mutation and exon19 deletion were the predominant EGFR mutations, accounting for 84.90% of EGFR-mutated patients. In addition, fifty-one kinds of EGFR mutations were detected, distributed in the protein tyrosine kinase catalytic domain (43, 84.31%), cysteine enriched domain (4, 7.84%), receptor binding domain (3, 5.88%), and EGFR transmembrane domain (1,1.96%). Ten cases of gene fusion mutation were detected. Two rare partner genes, PKHD1 (P60:R34) and STK39 (R33:S11), were detected by ROS1 gene fusion. RET gene fusion revealed a rare companion gene KCND2 (R11:K2). The EGFR mutations were more prevalent in female, non-smoking patients (p < 0.05), and the KRAS mutations were more common in male and smoking patients (p < 0.01). In addition, the BRAF mutations were more likely to occur in the right lung (p < 0.05). Conclusion: Older LUAD populations exhibit diverse genetic mutations, which may also exist simultaneously. Simultaneous detection of multiple genes by NGS can accelerate and enhance targeted treatment benefits for older LUAD patients, ultimately improving their quality of life.

Effect of non-surgical periodontal treatment on cytokines/adipocytokines levels among periodontitis patients with or without obesity: a systematic review and meta-analysis.

BACKGROUND: The objective of this systematic review and meta-analysis was to evaluate the effects of non-surgical periodontal therapy (NSPT) on inflammatory-related cytokines/adipocytokines in periodontitis patients with or without obesity. METHODS: We followed the preferred reporting items for systematic reviews and meta-analyses statement and registered the study (CRD42022375331) in the Prospective International Register of Systematic Reviews. We screened randomized-controlled trials and controlled clinical trials from six databases up to December 2022. Quality assessment was performed with RoB-2 and ROBINS-I tools for randomized trials and non-randomized trials, respectively. Meta-analysis was carried out using a random-effect model. RESULTS: We included seventeen references in the systematic analysis, and sixteen in the meta-analysis. Baseline results of pro-inflammatory biomarkers, including serum interleukin (IL)-6, serum and gingival crevicular fluid (GCF), tumor necrosis factor (TNF)-a, serum C-reactive protein (CRP)/hs-CRP, and serum and GCF resistin, were higher in obesity subjects than in normal weight subjects. The effect of NSPT with respect to levels of cytokines/adipocytokines, including IL-6, TNF-a, CRP/hs-CRP, resistin, adiponectin, leptin and retinol binding protein 4 (RBP4), were then analyzed in the systematic and meta-analysis. After three months of NSPT, serum (MD = -0.54, CI = -0.62 - -0.46), and GCF (MD = -2.70, CI = -4.77 - -0.63) levels of IL-6, along with the serum RBP4 (MD = -0.39, CI = -0.68-0.10) decreased in periodontitis individuals with obesity. NSPT also improved GCF adiponectin levels after three months (MD = 2.37, CI = 0.29 - 4.45) in periodontitis individuals without obesity. CONCLUSIONS: Obese status altered the baseline levels of cytokines/adipocytokines (serum IL-6, serum and GCF TNF-a, serum CRP/hs-CRP, and serum and GCF resistin). Then NSPT can shift the levels of specific pro-inflammatory mediators and anti-inflammatory mediators in biological fluids, both in obesity and non-obesity individuals. NSPT can reduce serum and GCF IL-6 levels together with serum RBP4 level in individuals with obesity after 3 months, besides, there is no sufficient evidence to prove that obese patients have a statistically significant decrease in the levels of other cytokines compared to patients with normal weight. NSPT can also increase GCF adiponectin level in normal weight individuals after 3 months. Our findings imply the potential ideal follow-up intervals and sensitive biomarkers for clinical bioanalysis in personalized decision-making of effect of NSPT due to patients' BMI value.

Challenges in the management of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma. Stereotactic biopsy remains the gold standard for the pathological diagnosis of PCNSL. However, certain new auxiliary diagnostic methods are considered to have good application prospects; these include cytokine and tumor circulating DNA, among others. Although new drugs such as immunomodulators, immune checkpoint inhibitors, chimeric antigen receptor T-cells, and Bruton tyrosine kinase inhibitors have brought hope owing to their improved efficacy, the high recurrence rate and subsequent high mortality remain barriers to long-term survival. Increasing emphasis is therefore being placed on consolidation treatments. Consolidation treatment strategies include whole brain radiotherapy, autologous hematopoietic stem cell transplantation, and non-myeloablative chemotherapy. As studies directly comparing the effectiveness and safety of different consolidation treatment schemes are lacking, the optimal consolidation strategy remains uncertain. This article will review the diagnosis and treatment of PCNSL, focusing on the progress in research pertaining to consolidation therapy.

Robust self-cleaning membrane with superhydrophilicity and underwater superoleophobicity for oil-in-water separation.

The discharge of oily wastewater has increased dramatically and will bring serious environmental problems. In this work, a self-cleaning and anti-fouling g-C3N4/TiO2/PVDF composite membrane was fabricated via the layer-by-layer approach. The surface of as-prepared composite membrane displayed a superhydrophilic and underwater superoleophobic behavior under irradiation with visible light. Also, upon irradiation with visible light, the fabricated g-C3N4/TiO2/PVDF composite membrane displayed enhanced permeation flux and improved oil removal efficiency as a result of the generation of hydroxyl free radicals during the photocatalytic filtration process. Significantly, irradiation with visible light remarkably improved reusability of the composite membrane by initiating photocatalytic decomposition of deposited oil foulants, which enabled removal of over 99.75% of oils, thus reaching a nearly 100% flux recovery ratio. Furthermore, the g-C3N4/TiO2/PVDF composite membrane exhibited great anti-fouling behavior in photocatalysis-assisted filtration. The mechanistic study revealed that underwater superhydrophobicity and the generation of free hydroxyl radicals jointly contributed to membrane anti-fouling. The greatest advantages of this g-C3N4/TiO2/PVDF composite membrane are that not only does it degrades the oil pollutants, but it also makes the membrane less vulnerable to fouling.

Efficacy and safety of chimeric antigen receptor T-cells treatment in central nervous system lymphoma: a PRISMA-compliant single-arm meta-analysis.

BACKGROUND: Chimeric antigen receptor (CAR) T cells are used to treat refractory and recurrent B-cell lymphoma. When administered intravenously, CAR T cells can be detected in cerebrospinal fluid, and thus represent a promising method for the treatment of central nervous system lymphoma (CNSL). This meta-analysis aimed to clarify the effectiveness and safety of CAR T-cell therapy in the treatment of CNSL. METHODS: Studies involving patients with CNSL who received CAR T-cell therapy that reported overall response (OR), complete response (CR), and partial response (PR) were included. A random-effects or fixed-effects model with double arcsine transformation was used for the pooled analysis and 95% confidence intervals (CI) were determined for all outcomes. RESULTS: Eight studies, comprising 63 patients, were identified and were included in the meta-analysis. The pooled OR and CR rates after treatment with CAR T cells were 69% (95% CI, 56-81%) and 51% (95% CI, 37-64%), respectively. The pooled rate of progressive disease after remission was 38% (95% CI, 21-55%). The pooled rate for neurotoxicity grade 3 or above was 12% (95% CI, 3-24%, I2 = 0.00%, p = 0.53). No treatment-related deaths were reported. CONCLUSIONS: CAR T-cell therapy is a promising option for the treatment of CNSL owing to a high short-term remission rate and controllable side effects. However, the high recurrence rate after remission must be addressed. Long-term follow-up data with large sample sizes are also needed to better assess the effectiveness and safety of CAR T-cell therapy. REGISTRATION: This meta-analysis was registered in the international prospective register of systematic reviews (PROSPERO) (CRD42022301332).

[Safety and efficacy of different doses of tranexamic acid in posterior cervical laminectomy with lateral mass screw fixation and bone graft fusion].

Objective: To investigate the safety and efficacy of different doses of tranexamic acid (TXA) in posterior cervical laminectomy with lateral mass screw fixation and bone graft fusion by a prospective clinical study. Methods: The middle-aged and elderly patients with cervical spondylotic myelopathy, who were admitted between January 2020 and January 2022 and scheduled to undergo posterior cervical laminectomy with lateral mass screw fixation and bone graft fusion, were studied as the research subjects. Among them, 165 patients met the selection criteria and were included in the study. The patients were allocated into 3 groups ( n=55) by random double-blind lottery. Groups A and B were given intravenous infusion of TXA at 30 minutes before operation according to the standards of 15 and 30 mg/kg, respectively; and group C was given normal saline in the same way. There was no significant difference in gender, age, body mass index, and preoperative D-dimer, hemoglobin (Hb), and hematocrit (HCT) between groups ( P>0.05). The intraoperative bleeding, intraoperative blood transfusion, postoperative drainage volume, drainage days, and postoperative hospital stay were recorded. The Hb, HCT, and D-dimer were compared before operation and at 3 days after operation. Venous ultrasonography of the lower extremities was taken after operation to assess thrombosis; and the postoperative hematoma and epilepsy were also observed. Results: All operations were successfully completed, and the incisions healed by first intention. The differences in intraoperative bleeding volume, postoperative drainage volume, drainage days, and postoperative hospital stay between groups were significant ( P<0.05). The above indexes were significantly less in group B than in groups A and C. During operation, 14 patients in group A and 23 patients in group C were transfused, and no patient in group B had blood transfusions. Compared with groups A and C, the blood transfusion volume in group B significantly decreased ( P<0.05), and the difference between groups A and C was not significant ( P>0.05). There was no significant difference in the differences of D-dimer, Hb, and HCT before and after operation between groups ( P>0.05). At 5 days after operation, the venous ultrasonography of the lower extremities showed that the 2 cases of intermuscular venous thrombosis occurred in groups A, B, and C, respectively. No hematoma or epilepsy occurred after operation. Conclusion: The application of 15 and 30 mg/kg TXA in posterior cervical laminectomy with lateral mass screw fixation and bone graft fusion can reduce intraoperative bleeding and postoperative drainage volume, postoperative drainage days, and postoperative hospital stay. And application of 30 mg/kg TXA can reduce intraoperative blood transfusion, without increasing the risk of lower extremity venous thrombosis, hematoma, and epilepsy.

Exploration of interaction property between nonylphenol and G protein-coupled receptor 30 based on molecular simulation and biological experiments.

Nonylphenol (NP), a representative of environmental hormones, can cause extensive biological effects in the human body. In this study, we first analyzed the mutual binding modes of NP and G protein coupled estrogen receptor 30 (GPR30) by molecular simulation. The 3D structure of GPR30 was successfully constructed. We found that the binding sites of NP on GPR30 are similar to that of 17ß-Estradiol (E2) on GPR30. The GPR30-E2 bond complex is more stable than GPR30-NP bond complex. Next CCK-8 assay was used to detect the regulatory effect of NP on SKBR-3 cell proliferation. When NP and E2 were used alone, low concentration could promote cell proliferation, while high concentration was the opposite. The presence of E2 can promote the cell proliferation effect of NP, and inhibit the inhibitory intensity. NP could promote both the cell proliferation effect and inhibition intensity of E2. Based on our results, we conclude that the binding modes of NP and GPR30 is similar to that of E2 and GPR30. In biology, NP can play estrogen role by activating GPR30 receptor, but it can also produce cytotoxicity at higher concentration.

Non-Myeloablative Chemotherapy as Consolidation Strategy After High-Dose Methotrexate-Based Chemoimmunotherapy in Patients With Primary CNS Lymphoma: A Retrospective Single Center Study in China.

Primary central nervous system lymphoma (PCNSL) remains a disease with poor outcome and high recurrence rate. We retrospectively analyzed the clinical data of 243 immunocompetent patients with PCNSL in Beijing Tiantan Hospital. The median age of PCNSL patients was 57 years (range 10-95 years). For induction therapy, 94.7% of patients received high-dose methotrexate (HD-MTX) containing regimens, and 59.3% received rituximab, which increased over time. The overall response rate was 72.8%, with 58.8% achieving complete response. With a median follow-up of 27.0 months (95% confidence interval 23.6-30.4), the median progression-free survival (PFS) time was 14.0 months (95% CI 9.45-18.55), and the 2-year PFS rate was 33.2%. The median overall survival (OS) was not reached (NR), with an estimated overall survival rate at 4 years of 61.6%. Among 95 patients who completed sequential consolidation chemotherapy with either pemetrexed or etoposide plus cytarabine, the median PFS was 28 months (95% CI 17.11-38.89), and the estimated overall survival at 4 years was 78.7%. In conclusion, HD-MTX based induction chemotherapy with non-myeloablative sequential consolidation chemotherapy is an alternative feasible treatment option.

The PI3K/AKT/mTOR signaling pathway is aberrantly activated in primary central nervous system lymphoma and correlated with a poor prognosis.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a specific subtype of non-Hodgkin lymphoma that is highly invasive and confined to the central nervous system (CNS). The vast majority of PCNSLs are diffuse large B-cell lymphomas (DLBCLs). PCNSL is a highly heterogeneous disease, and its pathogenesis has not yet been fully elucidated. Further studies are needed to guide individualized therapy and improve the prognosis. METHODS: In this study, we detected 1) the expression of p-AKT, p-mTOR, p-S6 and p-4E-BP1 by immunohistochemistry (IHC) and Western blotting, 2) the mRNA expression by real-time qPCR and 3) the deletion of PTEN gene by immunofluorescence in situ hybridization (FISH) in order to investigate the activation status of the PI3K/AKT/mTOR signaling pathway in PCNSL. Samples of reactive hyperplasia lymphnods were used as the control group. The correlations between the clinical characteristics and prognosis of PCNSL patients and the expression of p-AKT, p-mTOR, p-S6 and p-4E-BP1 and the deletion of PTEN were assessed. RESULTS: The IHC results showed that the positive expression rates of p-AKT, p-mTOR, p-S6 and p-4E-BP1 in PCNSL were significantly higher in the PCNSL group than in the control group (P < 0.05). The relative mRNA expression level of MTOR in PCNSL samples was significantly increased (P = 0.013). Correlation analysis revealed that the expression of p-mTOR was correlated with that of p-AKT, p-S6, p-4E-BP1. PTEN deletion was found in 18.9% of PCNSL samples and was correlated with the expression of p-AKT (P = 0.031). Correlation analysis revealed that the PCNSL relapse rate in the p-mTOR-positive group was 64.5%, significantly higher than that in the negative group (P = 0.001). Kaplan-Meier survival analysis showed inferior progression-free survival (PFS) in the p-mTOR- and p-S6-positive groups (P = 0.002 and 0.009, respectively), and PTEN deletion tended to be related to shorter overall survival (OS) (P = 0.072). Cox regression analysis revealed p-mTOR expression as an independent prognostic factor for a shorter PFS (hazard ratio (HR) =7.849, P = 0.046). CONCLUSIONS: Our results suggest that the PI3K/AKT/mTOR signaling pathway is aberrantly activated in PCNSL and associated with a poor prognosis, which might indicate new therapeutic targets and prognostic factors.

PIEZO1 Ion Channels Mediate Mechanotransduction in Odontoblasts.

INTRODUCTION: Odontoblasts, terminally differentiated dentin-forming cells with their processes that penetrate into dentin, have been considered potential sensory cells. Current research suggests that odontoblasts sense external stimuli and transmit pain signals. PIEZO1, as a specific mechanically activated ion channel, may play an important role in mechanical transduction in odontoblasts. In this study, we devoted to investigating the functions and underlying molecular mechanisms of PIEZO1 ion channels in odontoblast mechanotransduction. METHODS: Human dental pulp stem cells were cultured in vitro and induced to differentiate into odontoblast-like cells (OLCs). The expression of PIEZO1 protein in pulp, dental pulp stem cells, and OLCs was detected by immunohistochemistry or immunofluorescence. The mechanical sensitivity of OLCs was detected by a constructed fluid shear stress model and examined by calcium fluorescence intensity. A single-cell mechanical stimulation model was used to detect the PIEZO1 electrophysiological properties of OLCs. Yoda1 (a PIEZO1-specific agonist), GsMTx4 (a PIEZO1 antagonist), and non-calcium ion extracellular solution were utilized to confirm PIEZO1 mechanotransduction in OLCs in both fluid shear stress and single-cell mechanical stimulation assays. The amount of ATP released by OLCs was measured under stimulation with Yoda1 and GsMTx4. Rat trigeminal ganglion neurons were cultured in vitro and detected by whole-cell patch-clamp recording under ATP stimulation. RESULTS: PIEZO1 ion channels were positively expressed in OLCs and odontoblastic bodies and processes but weakly expressed in dental pulp cells. After the treatment of OLCs with shearing stress or Yoda1, the fluorescence intensity of intracellular calcium ions increased rapidly but did not noticeably change after treatment with GsMTx4 or the non-calcium ion extracellular solution. When single-cell mechanical stimuli were applied to OLCs, the evoked inward currents were recorded by patch-clamp electrophysiology. The inward currents increased and current inactivation became slower after Yoda1 treatment, but these currents almost completely disappeared after the addition of GsMTx4. The amount of ATP released by OLCs increased significantly after Yoda1 stimulation, while GsMTx4 reversed the release of ATP. Whole-cell patch-clamp detection showed that ATP evoked slow inward currents and increased the frequency of action potentials of trigeminal ganglion neurons. CONCLUSIONS: Taken together, these findings indicated that odontoblasts evoked a fast inward current via PIEZO1 ion channels after the application of external mechanical stimuli and released ATP to transmit signals to adjacent cells. Thus, PIEZO1 ion channels in odontoblasts mediate mechanotransduction under various pathophysiological conditions in dentin.

miR-23b mediates TNF-α-Inhibited Osteogenic Differentiation of Human Periodontal Ligament Stem Cells by Targeting Runx2.

Periodontitis is the most prevalent oral infection disease, which causes the destruction of periodontal supporting tissues and eventual tooth loss. This study aimed to investigate the molecular mechanism of miRNA-23b (miR-23b) in regulating the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) in an inflammatory environment. Results revealed that tumor necrosis factor-α (TNF-α), a notoriously inflammatory cytokine, remarkably attenuated the osteogenic differentiation of hPDLSCs, which were partially rescued by SKL2001 (Wnt/ß-catenin agonist). We further explored the underlying roles of miRNAs involved in TNF-α-inhibited osteogenesis of hPDLSCs. The miR-23b significantly increased with TNF-α stimulation, which was abolished by SKL2001. Similar to the effect of TNF-α, miR-23b agonist (agomir-23b) dramatically reduced the expression of runt-related transcription factor 2 (Runx2) and suppressed the osteogenic differentiation of hPDLSCs. The inhibition of miR-23b significantly increased Runx2, which is the major transcription factor during osteogenesis, thereby indicating that miR-23b was an endogenous regulator of Runx2 in hPDLSCs. Bioinformatic analysis and dual luciferase reporter assays confirmed that Runx2 was a target gene of miR-23b. Furthermore, the gain function assay of Runx2 revealed that the Runx2 overexpression efficiently reversed the suppression of the osteogenic differentiation of hPDLSCs with miR-23b agonist, suggesting that the suppressing effect of miR-23b on osteogenesis was mediated by Runx2 inhibition. Our study clarified that miR-23b mediated the TNF-α-inhibited osteogenic differentiation of hPDLSCs by targeting Runx2. Therefore, the expanded function of miR-23b in the osteogenesis of hPDLSCs under inflammatory conditions. This study might provide new insights and a novel therapeutic target for periodontitis.

Efficacy and Safety of Ibrutinib in Central Nervous System Lymphoma: A PRISMA-Compliant Single-Arm Meta-Analysis.

BACKGROUND: Central nervous system lymphoma (CNSL) is an aggressive lymphoma. Studies investigating primary CNSL determined that the Bruton tyrosine kinase (BTK) played an important role in pathogenesis. Ibrutinib, an oral BTK inhibitor, is a new treatment strategy for CNSL. The purpose of this meta-analysis was to clarify the effectiveness and safety of ibrutinib in the treatment of CNSL. METHODS: A systematic search of PubMed, Embase, Cochrane library, Wanfang Data Knowledge Service Platform, and China National Knowledge Infrastructure databases was conducted through to 31 October 2019. Studies involving patients with CNSL who received ibrutinib that reported the overall response (OR), complete remission (CR), and partial response (PR) were included. The random-effects or fixed-effects model with double arcsine transformation was used for the pooled rates and 95% confidence intervals (CI) were determined for all outcomes. RESULTS: Eight studies including 162 patients were identified and included in the meta-analysis. The pooled OR rate after treatment with ibrutinib was 69% (95% CI, 61-79%, I2 = 47.57%, p = 0.06), while the pooled CR and PR was 52% (95% CI, 35-68%, I2 = 74.95%, p = 0.00) and 17% (95% CI, 7-30%, I2 = 67.85%, p = 0.00), respectively. Among PCNSL patients, including new diagnoses PCNSL and R/R PCNSL, the pooled OR rate was 72% (95% CI, 63-80%, I2 = 49.20%, p = 0.06) while the pooled CR and PR rates were 53% (95% CI, 33-73%, I2 = 75.04%, p = 0.00) and 22% (95% CI, 14-30%, I2 = 46.30%, p = 0.07), respectively. Common adverse events above grade 3 included cytopenia and infections. CONCLUSIONS: The ibrutinib-containing therapy was well tolerated and offered incremental benefit to patients with CNSL. However, randomized-controlled studies that directly compare efficacy and adverse events of ibrutinib are still needed. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42020218974.

Treatment of secondary central nervous system involvement in systemic aggressive B cell lymphoma using R-MIADD chemotherapy: a single-center study.

BACKGROUND: Secondary central nervous system lymphoma (SCNSL) is defined as lymphoma involvement within the central nervous system (CNS) that originated elsewhere, or a CNS relapse of systemic lymphoma. Prognosis of SCNSL is poor and the most appropriate treatment is still undetermined. METHODS: We conducted a retrospective study to assess the feasibility of an R-MIADD (rituximab, high-dose methotrexate, ifosfamide, cytarabine, liposomal formulation of doxorubicin, and dexamethasone) regimen for SCNSL patients. RESULTS: Nineteen patients with newly diagnosed CNS lesions were selected, with a median age of 58 (range 20 to 72) years. Out of 19 patients, 11 (57.9%) achieved complete remission (CR) and 2 (10.5%) achieved partial remission (PR); the overall response rate was 68.4%. The median progression-free survival after CNS involvement was 28.0 months (95% confidence interval 11.0-44.9), and the median overall survival after CNS involvement was 34.5 months. Treatment-related death occurred in one patient (5.3%). CONCLUSIONS: These single-centered data underscore the feasibility of an R-MIADD regimen as the induction therapy of SCNSL, further investigation is warranted.

Efficacy and Safety of Autologous Stem-Cell Transplantation as Part of First-Line Treatment for Newly Diagnosed Primary Central Nervous System Lymphoma: A Systematic Review and Meta-Analysis.

OBJECTIVE: The reviewed literature supports a treatment regimen for primary central nervous system lymphoma (PCNSL) that includes induction chemotherapy, followed by one consolidation therapy. High-dose chemotherapy supported by autologous stem-cell transplantation (ASCT) is the most studied option, but its effects are controversial. The aim of this study was to evaluate the efficacy and safety of ASCT for newly diagnosed PCNSL by means of a meta-analysis. METHODS: The PubMed, Embase, and Cochrane Library databases were systematically searched for studies published until May 20, 2021. Included studies were prospective studies of patients with newly diagnosed PCNSL treated with ASCT. The pooled rates and 95% confidence intervals (CIs) were determined for all outcomes. Subgroup analysis was conducted to compare the relative risk (RR) with 95% CIs for the complete remission (CR) rate and the hazard ratios (HRs) with 95% CIs for progression-free survival (PFS) and overall survival (OS). RESULTS: Thirteen prospective studies including 348 patients were analyzed. The pooled CR rate, overall response rate, and relapse rate were 80% (95% CI, 71-88%, I2 = 67.06%, p = 0.00), 95% (95% CI, 87-100%, I2 = 73.65%, p= 0.00), and 19% (95% CI, 15-24%, I2 = 76.18%, p = 0.00), respectively. The pooled 2- and 5-year PFS and OS rates were 74% (95% CI, 68-80%, I2 = 3.90%), 65% (95% CI, 51-77%, I2 = 74.61%), 80% (95% CI, 72-88%, I2 = 57.54%), and 69% (95% CI, 53-83%, I2 = 83.89%), respectively. Hematological toxicity and infections were more common adverse events above grade 3. The pooled treatment-related mortality was 3% (95% CI, 1-6%, I2 = 28.18%, p = 0.16). In the group analysis of ASCT compared with whole-brain radiotherapy, there were no significant differences in the CR rate (RR, 1.00, 95% CI, 0.88-1.14, p = 0.971), relapse rate (RR, 0.44, 95% CI, 0.06-3.10, p = 0.408), PFS (HR, 1.28, 95% CI, 0.81-2.01, p = 0.29), or OS (HR, 1.62, 95% CI, 0.97-2.69, p = 0.06). Cognitive functions were preserved or improved after ASCT. CONCLUSIONS: ASCT is a feasible approach for consolidation with good tolerability for newly diagnosed PCNSL patients. High-quality randomized controlled trials are still needed to confirm the effects of ASCT. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42021268422.

Spatial assessment models to evaluate human health risk associated to soil potentially toxic elements.

Quantifying source apportionment of potentially toxic elements (PTEs) in soils and associated human health risk (HHR) is essential for soil environment regulation and pollution risk mitigation. For this purpose, an integrated method was proposed, and applied to a dataset consisting of As, Cd, Cr, Cu, Hg, Ni, Pb, Se, and Zn in 273 soil surface samples. Positive matrix factorization (PMF) was used to quantitatively examine sources contributions of PTEs in soils; and the HHR arising from the identified source was determined by combining source profiles and health risk assessment; at last, sequential Gaussian simulation (SGS) was used to identify the areas with high HHR. Four sources were identified by PMF. Natural and agricultural sources affected all 9 PTEs contents with contributions ranging from 19.2% to 62.9%. 41.9% of Cd, 40.8% of Pb, 58.6% of Se, and 29.8% of Zn were controlled by industrial and traffic emissions. Metals smelting and mining explained 35.5%, 30.5%, and 24.9% of Cr, Cu, and Ni variations, respectively. Hg was dominated by atmospheric deposition from coal combustion and coking (58.7%). The mean values of the total non-carcinogenic risks of PTEs were 1.55 × 10-1 and 9.40 × 10-1 for adults and children, and the total carcinogenic risk of PTEs had an average value of 8.86 × 10-5. Based on source-oriented HHR calculation, natural and agricultural sources were the most important factor influencing HHR, explaining 51.0% and 49.1% of non-carcinogenic risks for children and adults, and 44.2% of carcinogenic risk. SGS indicated that 1.1% of the total area was identified as hazardous areas with non-carcinogens risk for children.

Dynamic contrast-enhanced magnetic resonance imaging biomarkers predict chemotherapeutic responses and survival in primary central-nervous-system lymphoma.

OBJECTIVES: To evaluate the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting the response of chemotherapy and clinical outcomes in primary central-nervous-system lymphoma (PCNSL) patients. METHODS: DCE-MRI in 56 patients enrolled in a prospective study was performed at baseline and 30 days after treatment from 2016 to 2019. Multivariate logistic regression analyses were performed to assess risk factors for tumor responses. The predictive values of related parameters derived from DCE were analyzed via receiver operating characteristic (ROC) curve analysis. To evaluate prognostic factors, the Kaplan-Meier survival analysis with log-rank tests and Cox regression tests were analyzed. RESULTS: Ktrans and Ve were higher in the non-response group than in the response group (p < 0.05). The Ktrans and the percentage of Ktrans decreased after 30 days of treatment were independent predictors of chemotherapy responses (p = 0.034 and p = 0.019). ROC analysis indicated that the cut-off point of Ktrans for predicting chemotherapeutic responses was 0.353 min-1 (AUC, 0.941; 95% CI, 0.87-1; p < 0.001) and percentage of Ktrans decreased after 30 days of treatment was 15.2% (AUC, 0.858; 95% CI, 0.742-0.970; p < 0.001). The greater decrease in Ktrans correlated with a longer progression-free survival (PFS) (χ2 = 13.203, p < 0.001). The higher Ktrans was an independent predictor for shorter PFS (hazard ratio, 10.182; 95% CI, 2.510-41.300; p = 0.001). CONCLUSIONS: Ktrans and Ktrans change measured by DCE-MRI were reliable biomarkers for predicting chemotherapy responses in PCNSL patients. KEY POINTS: • Baseline Ktrans and greater decrease in Ktrans can predict chemotherapeutic efficacy. • DCE-MRI provides quantitative parameters reflecting the tumor microenvironment. • Targeted treatment therapy can be given with more evidence in the future.