Pan-histone deacetylase inhibitor vorinostat suppresses osteoclastic bone resorption through modulation of RANKL-evoked signaling and ameliorates ovariectomy-induced bone loss.

BACKGROUND: Estrogen deficiency-mediated hyperactive osteoclast represents the leading role during the onset of postmenopausal osteoporosis. The activation of a series of signaling cascades triggered by RANKL-RANK interaction is crucial mechanism underlying osteoclastogenesis. Vorinostat (SAHA) is a broad-spectrum pan-histone deacetylase inhibitor (HDACi) and its effect on osteoporosis remains elusive. METHODS: The effects of SAHA on osteoclast maturation and bone resorptive activity were evaluated using in vitro osteoclastogenesis assay. To investigate the effect of SAHA on the osteoclast gene networks during osteoclast differentiation, we performed high-throughput transcriptome sequencing. Molecular docking and the assessment of RANKL-induced signaling cascades were conducted to confirm the underlying regulatory mechanism of SAHA on the action of RANKL-activated osteoclasts. Finally, we took advantage of a mouse model of estrogen-deficient osteoporosis to explore the clinical potential of SAHA. RESULTS: We showed here that SAHA suppressed RANKL-induced osteoclast differentiation concentration-dependently and disrupted osteoclastic bone resorption in vitro. Mechanistically, SAHA specifically bound to the predicted binding site of RANKL and blunt the interaction between RANKL and RANK. Then, by interfering with downstream NF-κB and MAPK signaling pathway activation, SAHA negatively regulated the activity of NFATc1, thus resulting in a significant reduction of osteoclast-specific gene transcripts and functional osteoclast-related protein expression. Moreover, we found a significant anti-osteoporotic role of SAHA in ovariectomized mice, which was probably realized through the inhibition of osteoclast formation and hyperactivation. CONCLUSION: These data reveal a high affinity between SAHA and RANKL, which results in blockade of RANKL-RANK interaction and thereby interferes with RANKL-induced signaling cascades and osteoclastic bone resorption, supporting a novel strategy for SAHA application as a promising therapeutic agent for osteoporosis.

Efficacy and safety of immune checkpoint inhibitor rechallenge in non-small cell lung cancer: A systematic review and meta-analysis.

BACKGROUND: The aim of the study was to explore the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with non-small cell lung cancer (NSCLC). METHODS: Studies that enrolled NSCLC patients treated with two lines of ICIs were included using four databases. The initial line (1L-) and subsequent lines (2L-) of ICIs were defined as 1L-ICI and 2L-ICI, respectively. RESULTS: A total of 17 studies involving 2100 patients were included. The pooled objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) for 2L-ICIs were 10%, 50%, 3.0 months, and 13.1 months, respectively. The 2L-ICI discontinuation rates caused by toxicities ranged from 0% to 23.5%. Original data were extracted from six studies, covering 89 patients. Patients in whom 1L-ICIs were discontinued following clinical decision (the mPFS of 2L-ICIs was not reach) achieved a more prolonged mPFS of 2L-ICIs than those due to toxicity (5.2 months) and progressive disease (2.1 months) (p < 0.0001). Patients' 1L-PFS for more than 2-years had preferable 2L-ORR (35.0% vs. 9.8%, p = 0.03), 2L-DCR (85.0% vs. 49.0%, p = 0.007), and 2L-mPFS (12.4 vs. 3.0 months, p < 0.0001) than those less than 1-year. Patients administered the same drugs achieved a significantly prolonged mPFS compared with the remaining patients (5.4 vs. 2.3 months, p = 0.0004), and those who did not accept antitumor treatments during the intervals of two lines of ICIs achieved a prolonged mPFS compared to those patients who did accept treatments (7.6 vs. 1.9 months, p < 0.0001). CONCLUSIONS: ICI rechallenge is a useful therapeutic strategy for NSCLC patients, especially suitable for those who achieve long-term tumor remission for more than 2-years under 1L-ICIs.

Impact of body mass index and its change on survival outcomes in patients with early breast cancer: A pooled analysis of individual-level data from BCIRG-001 and BCIRG-005 trials.

INTRODUCTION: The relationships between body mass index (BMI) and survival rates are complex, and have not been thoroughly investigated in breast cancer patients who received adjuvant chemotherapy. METHODS: We collected data on 2394 patients from two randomized, phase III clinical trials that investigated adjuvant chemotherapy in breast cancer identified in Project Data Sphere. The objective was to examine the effect of baseline BMI, BMI after adjuvant chemotherapy, and BMI change from baseline to post-adjuvant chemotherapy on disease-free survival (DFS) and overall survival (OS). Restricted cubic splines were used to examine potential non-linear associations between continuous BMI value and survival. Stratified analyses involved chemotherapy regimens. RESULTS: Severe obesity (BMI≥40.0 kg/m2) at baseline was independently associated with worse DFS (hazard ration [HR] = 1.48, 95% confidence interval [CI] 1.02-2.16, P = 0.04) and OS (HR = 1.79, 95%CI 1.17-2.74, P = 0.007) compared with underweight/normal weight (BMI≤24.9 kg/m2). A BMI loss >10% was also an independent prognostic factor for adverse OS (HR = 2.14, 95%CI 1.17-3.93, P = 0.014). Stratified analyses revealed that severe obesity adversely affected DFS (HR = 2.38, 95%CI 1.26-4.34, P = 0.007) and OS (HR = 2.90, 95%CI 1.46-5.76, P = 0.002) in the docetaxel-based group, but not in the non-docetaxel-based group. Restricted cubic splines revealed a "J-shaped" association of baseline BMI with risk of recurrence or all-cause death, and this relationship was more pronounced in the docetaxel-based group. CONCLUSIONS: In early breast cancer patients treated with adjuvant chemotherapy, baseline severe obesity was significantly linked to worse DFS and OS, and a BMI loss over 10% from baseline to post-adjuvant chemotherapy also negatively affected OS. Moreover, the prognostic role of BMI might differ between docetaxel-based and non-docetaxel-based groups.

Biomarkers predicting clinical outcomes in nasopharyngeal cancer patients receiving immune checkpoint inhibitors: A systematic review and meta-analysis.

Background: Optimal biomarkers to select patients who will benefit most from immunotherapy remain lacking in nasopharyngeal cancer (NPC). This systematic review and meta-analysis aimed to evaluate the association between various biomarkers and clinical outcomes in NPC patients treated with immune checkpoint inhibitors (ICIs). Methods: Systematic searches of PubMed, Embase, Cochrane Library, and Web of Science databases were performed up to October 2022. Studies evaluating the association between biomarkers and intended outcomes of ICIs were included. The pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence intervals (CIs) were calculated, respectively, for the objective response rate (ORR) and progression-free survival (PFS) under fixed or random-effect models. Results: A total of 15 studies involving 1,407 patients were included. The pooled analysis indicated that NPC patients with lower plasma Epstein-Barr virus (EBV) DNA level at baseline (OR = 2.14, 95% CI: 1.46-3.14, P < 0.001), decreased EBV DNA load during immunotherapy (OR = 4.57, 95% CI: 2.24-9.34, P = 0.002) and higher programmed cell death-ligand 1 (PD-L1) expression (OR = 2.35, 95% CI: 1.36-4.09, P = 0.002) had superior ORR than the counterparts. No significant differences of ORR were observed between positive PD-L1 expression and negative PD-L1 expression (OR = 1.50, 95% CI: 0.92-2.45, P = 0.104), as well as higher tumor mutation burden (TMB) and lower TMB (OR = 1.62, 95% CI: 0.41-6.44, P = 0.494). Patients with lower plasma EBV DNA level at baseline obtained a significant benefit on PFS than those with higher plasma EBV DNA level (HR = 0.52, 95% CI: 0.42-0.63, P < 0.001). There were no differences in PFS between decreased EBV DNA load and increased EBV DNA load during immunotherapy (HR = 0.51, 95% CI: 0.22-1.17, P = 0.109), higher PD-L1 expression and lower PD-L1 expression (HR = 0.65, 95% CI: 0.42-1.01, P = 0.054), positive PD-L1 expression and negative PD-L1 expression (HR = 0.90, 95% CI: 0.64-1.26, P = 0.531), lower TMB and higher TMB (HR = 0.84, 95% CI: 0.51-1.38, P = 0.684). Conclusion: Lower baseline plasma EBV DNA level, decreased plasma EBV DNA during immunotherapy, and higher PD-L1 expression are reliable biomarkers predicting better response to ICIs treatment. Lower baseline plasma EBV DNA level was also associated with longer PFS. It is warranted to further explore and better illuminate the utility of these biomarkers in future clinical trials and real-world practice. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022324434.

Efficacy of Chinese medicine in the adjuvant treatment of Hashimoto's thyroiditis with hypothyroidism: a systematic review and meta-analysis.

The quality of the studies was assessed using the Cochrane risk bias assessment tool and the results were analyzed using Review Manager 5.3 software. The evidence was also evaluated for its strength using GRADE. A total of 18 randomized controlled trials were included in the study, involving 1247 patients. The primary outcomes of this study included overall efficacy, effectiveness in treating specific symptoms, and the Traditional Chinese Medicine symptom score. The secondary outcomes included the levels of FT3, FT4, and TSH, the size of the thyroid gland, and any adverse events. The results of the meta-analysis showed that CHM combined with WM has a better curative effect and a more effective reduction in clinical symptoms than WM alone: comprehensive efficacy [OR = 4.83; 95% CI (3.45, 6.76)], syndrome efficacy [OR = 5.95; 95% CI (3.94, 8.99)], TCM symptom score SMD = -1.49; 95% CI (-1.86, -1.11)], FT3 [SMD = 0.59; 95% CI (0.48, 0.71)], FT4 [SMD = 0.59; 95% CI (0.48, 0.71)], TSH SMD = -0.97; 95% CI (-1.35, -0.58)], and thyroid volume SMD = -0.25; 95% CI (-0.34, 0.15)]. The incidence of adverse events between the groups was not significantly different [OR = 1.00; 95% CI (0.14, 7.27)]. Because of the effectiveness of CHM, we support using CHM to improve clinical efficacy in the treatment of HTH. The results of our research suggest that the use of Chinese Herbal Medicine (CHM) in combination with Western Medicine (WM) may result in improved clinical efficacy in the treatment of hypothyroidism (HTH) compared to using WM alone.

Association of immune-related adverse events and efficacy in advanced non-small-cell lung cancer: a systematic review and meta-analysis.

Aim: This study aimed to explore the association of immune-related adverse events (irAEs) with efficacy in advanced non-small-cell lung cancer (NSCLC). Materials & methods: A literature search was conducted under preselected criteria. Primary outcomes were hazard ratio (HR) and 95% CI of irAEs on objective response rate, overall survival (OS) and progression-free survival (PFS). Results: 35 studies covering 8435 patients with advanced NSCLC were included. Patients with irAEs exhibited significantly longer PFS and OS (for PFS, HR: 0.481; 95% CI: 0.370-0.568; p < 0.001 and for OS, HR: 0.470; 95% CI: 0.410-0.539; p < 0.001), and also showed significantly higher objective response rate compared with those without irAEs (pooled OR: 0.023 [95% CI: 0.009-0.590]). Conclusion: This meta-analysis showed that irAEs were associated with efficacy for advanced NSCLC.

Immune-related adverse events (irAEs) are a series of adverse events that occur during the application of immune checkpoint inhibitors. The correlation between irAEs and ICI efficacy is controversial. In this meta-analysis, we analyzed the association of irAEs with the efficacy of immune checkpoint inhibitors in patients with advanced non-small-cell lung cancer (NSCLC). A total of 35 studies covering 8435 patients with NSCLC at advanced stage were included. Pooled analysis demonstrated that patients with irAEs got a significantly higher objective response rate than those without irAEs. Besides this, patients with irAEs had a more favorable survival outcome than those without. This study indicated that the occurrence of irAEs was associated with better survival outcome and higher tumor efficacy for patients with advanced NSCLC.

The clinical features, treatment, and prognostic factors for peripheral T-cell lymphomas: A single-institution analysis of 240 Chinese patients.

AIM: This study aimed to analyze the clinical features, treatment, survival, and prognostic factors of Chinese patients with peripheral T-cell lymphoma (PTCL) excluding natural killer/T-cell lymphoma (NKTCL). METHODS: Data on patients with newly diagnosed PTCLs between January 1, 2006 and December 31, 2017 at our hospital were retrospectively reviewed. Patients with NKTCL were excluded. RESULTS: A total of 240 patients were included. PTCL, not otherwise specified (PTCL-NOS), was the most frequent subtype (42.5%), followed by angioimmunoblastic T-cell lymphoma (AITL) (21.3%), anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALK-ALCL) (16.7%), ALK-positive ALCL (ALK+ALCL) (10.8%) and others (8.8%). With a median follow-up of 81.1 months, the 5-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 30.4% (95% CI 25.0%-37.0%) and 48.8% (95% CI 42.6%-55.7%), respectively. On multivariate analysis, no consolidative autologous stem cell transplantation (ASCT) and not achieving complete response after first-line chemotherapy retained independently prognostic value for inferior PFS and OS. Besides, bone marrow involvement and serum albumin level were independent factors for PFS, and Eastern Cooperative Oncology Group performance status ≥2 was significantly predictive of inferior OS. Compared with PTCL-NOS, significantly superior PFS and OS were observed for ALK+ALCL and ALK-ALCL. CONCLUSION: The survival outcomes with current treatment for most PTCL subtypes are still unsatisfactory. Prospective randomized studies are needed to establish the value of consolidative ASCT in PTCL, and novel therapeutic approaches should be explored.

Incidence, Survival Outcome, and Prognostic Nomogram of Patients with Angioimmunoblastic T-cell Lymphoma: a Population-based Analysis.

OBJECTIVE: Due to the rarity of angioimmunoblastic T-cell lymphoma (AITL), very limited data concerning its incidence patterns and prognostic factors are available. This study aimed to explore the incidence, characteristics, survival outcomes, and prognostic factors of AITL. METHODS: Age-adjusted incidence and temporal trends were calculated based on 1247 AITL patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-13 database. A total of 1525 AITL patients from the SEER-18 database and 43 patients from our single center were included for survival analysis and nomogram construction. RESULTS: The age-adjusted incidence for overall cohort was 0.123 [95% confidence interval (CI), 0.117-0.131) per 100 000 during 1992-2017. The overall incidence increased steeply at the rate of 15.3% (95%CI 11.0%-19.8%, P<0.001) per year during 1992-2004, but remained stable during 2004-2017 (P=0.200). Similar incidence trends were observed in age, sex, and stage subgroups. The final nomograms consisted of four variables: age at diagnosis, sex, Ann Arbor stage, and primary site. The concordance index (C-index) of the nomogram for 5-year overall survival prediction was 0.717, 0.690 and 0.820 in the training cohort, validation cohort-1 and cohort-2, respectively. Regarding the disease-specific survival (DSS), the nomogram also demonstrated a good discrimination level, with the C-index for predicting the probability of DSS at 5 years of 0.716, 0.682 and 0.813 for the three cohorts, respectively. The calibration displayed good concordance between the nomogram-predicted and actual observed outcomes. CONCLUSION: The age-adjusted incidence for AITL was low during 1992-2017. The incidence continuously increased during 1992-2004, but remained stable during 2004-2017. The nomograms as proposed may provide a favorable and accurate prognostic survival prediction in AITL.

Molecular mechanism of Sishen pills in the treatment of diarrheal diabetic enteropathy based on network pharmacology.

This study aimed to explore the effectiveness and safety of Sishen pills for the treatment of diarrheal diabetic enteropathy (DDE). The Traditional Chinese Medicine (TCM) Systems Pharmacology and BATMAN-TCM databases were used to determine the chemical composition of Sishen pills and thus predict information on protein targets. We searched for potential targets of DDE in the GeneCards, DrugBank, Therapeutic Target (TTD), and DisGeNET databases. Using the intersection of the drug and disease targets, protein-protein interaction (PPI) networks and molecular interaction modules were constructed, and key targets were screened. The intersecting gene targets were imported into the Metascape database to conduct Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The core targets and active ingredients were then docked at the molecular level. Sishen pills contain 70 active ingredients, 463 targets, and 566 disease targets. A module analysis of the targets revealed that the module was mainly related to adrenergic receptor activity, the adenosine phosphate kinase signaling pathway, and the G protein-coupled receptor signaling pathway. The GO and KEGG pathway enrichment results indicated that the protein genes regulated by Sishen pills were mainly enriched in the response to lipopolysaccharides, the AMPK signaling pathway, the JAK-STAT signaling pathway, and other signaling pathways. The molecular docking results showed that the core active compounds exhibited good binding activity with the predicted targets. Sishen pills can regulate the immune function of the body through anti-inflammatory and antibacterial effects for the treatment of DDE.

Brain metastases and immune checkpoint inhibitors in non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: The use of immune checkpoint inhibitors (ICIs) for brain metastases (BMs) from non-small cell lung cancer (NSCLC) remains debatable. This study aimed to explore the efficacy of ICIs for NSCLC with BMs. We also evaluated the effect of BMs on outcomes of ICIs. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane databases was conducted to identify studies where the efficacy of ICIs against BMs from NSCLC, or the association between BMs and outcomes of ICIs were evaluated. Outcomes included intracranial objective response rate (icORR), intracranial disease control rate (icDCR), systemic ORR and DCR. RESULTS: Overall, 33 studies were included in this meta-analysis. The pooled icORR was 13% (95%CI 6-23%) and icDCR was 50% (95%CI 40-63%) for programmed cell death-ligand 1 (PD-L1) unselected patients with any BMs. For active BMs, pooled icORR was 15% (95%CI 6-28%) and icDCR was 47% (95% CI 36-57%). For PD-L1 ≥ 50% patients with any BMs, pooled icORR and icDCR were 68% (95%CI 57-80%) and 82% (95%CI 73-92%), respectively. Additionally, pooled systemic ORR and DCR for any BMs were 22% (95%CI 15-30%) and 41% (95%CI 18-67%), respectively. Patients with BMs had inferior progression-free survival (HR 1.19, 95%CI 1.07-1.33, P = 0.0016) and overall survival (HR 1.14, 95%CI 1.03-1.25, P = 0.011) when applying ICIs compared to those without BMs. However, no significant difference in systemic ORR between patients with and without BMs was observed (OR 0.94, 95%CI 0.72-1.20, P = 0.629). CONCLUSION: ICIs may be clinically active in NSCLC patients with BMs. More effective treatments for BMs from NSCLC are needed.

Gut Metabolite Urolithin A Inhibits Osteoclastogenesis and Senile Osteoporosis by Enhancing the Autophagy Capacity of Bone Marrow Macrophages.

Senile osteoporosis (SOP) is a systemic bone disease that is significantly associated with age and eventually leads to deteriorated bone strength and increased fracture risk. Urolithin A (Uro-A) is a gut microbiome-derived compound that is mainly produced from pomegranates and some nuts. Uro-A has attracted great attention in recent years in view of its protective effects on aging-related diseases, including muscle dysfunction, kidney disease and knee injury. However, its protective influence and possible mechanisms in senile osteoporosis remain unclear. Our study describes the beneficial effect of Uro-A on bone marrow macrophages (BMMs). The in vitro results demonstrated that Uro-A inhibited receptor activator for nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in BMMs in a concentration-dependent manner. Uro-A significantly reduced the expression of osteoclast-related genes and bone resorption. Mechanistically, we found that the autophagy ability of BMMs was significantly enhanced in the early stage of Uro-A treatment, accompanied by the activation of LC3 and Beclin 1. At the same time, this enhanced autophagy activity was maintained until the later stage after stimulation with RANKL. Furthermore, we found that the MARK signaling pathway was blocked by Uro-A treatment. In a mouse model of aging, Uro-A effectively inhibited bone loss in the proximal femur, spine and tibia of aging mice. These results indicated that Uro-A is a robust and effective treatment for preventing senile osteoporosis bone loss.

NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway.

Periprosthetic osteolysis (PPO) triggered by wear particles is the most severe complication of total joint replacement (TJR) surgeries, representing the major cause of implant failure, which is public health concern worldwide. Previous studies have confirmed the specialized role of osteoclast-induced progressive bone destruction in the progression of PPO. Additionally, the reactive oxygen species (ROS) induced by wear particles can promote excessive osteoclastogenesis and bone resorption. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), a cellular enzyme, is considered to be responsible for the production of ROS and the formation of mature osteoclasts. However, NOX4 involvement in PPO has not yet been elucidated. Therefore, we investigated the mechanism by which NOX4 regulates osteoclast differentiation and the therapeutic effects on titanium nanoparticle-induced bone destruction. We found that NOX4 blockade suppressed osteoclastogenesis and enhanced the scavenging of intracellular ROS. Our rescue experiment revealed that nuclear factor-erythroid 2-related factor 2 (Nrf2) silencing reversed the effects of NOX4 blockade on ROS production and osteoclast differentiation. In addition, we found increased expression levels of NOX4 in PPO tissues, while NOX4 inhibition in vivo exerted protective effects on titanium nanoparticle-induced osteolysis through antiosteoclastic and antioxidant effects. Collectively, these findings suggested that NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway and that NOX4 blockade may be an attractive therapeutic approach for preventing PPO.

Toxicity profile of anaplastic lymphoma kinase tyrosine kinase inhibitors for patients with non-small cell lung cancer: A systematic review and meta-analysis.

Anaplastic lymphoma kinase (ALK) inhibitors are commonly used for patients harboring ALK-positive non-small cell lung cancer (NSCLC). This meta-analysis was conducted to evaluate the toxicity profile of ALK inhibitors. Pubmed, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials databases were systematically searched for clinical trials conducted in advanced NSCLC treated with ALK inhibitors. The incidences of pooled adverse events (AEs) were conducted using the random effects model. We included 30 studies in the meta-analysis. Almost all patients receiving ALK inhibitor monotherapy occurred at least one AE. The pooled incidences of grade ≥ 3 AEs were 71.3% for ceritinib 750 mg, 44.6% for crizotinib, 37.4% for alectinib, and 35.3% for ensartinib. Only one study each reported the incidence of grade ≥ 3 AEs for brgatinib (72.8%), lorlatinib (72.4%), and ceritinib 450 mg (64.8%), respectively. The rates of dose reduction due to AEs ranking from high to low were ceritinib 750 mg, brigatinib, ceritinib 450 mg, lorlatinib, crizotinib, ensartinib, and alectinib. The rates of treatment discontinuation due to AEs were low, ranging from 3.8% to 10.5%. Gastrointestinal AEs were most common for ceritinib 750 mg. Hepatic transaminases elevation was mostly observed in ceritinib and brigatinib. Rash frequently occurred for ensartinib. Lorlatinib had a high incidence of hypertriglyceridemia and hypercholesterolemia, which were rarely reported in other ALK inhibitors. The incidences of grade ≥ 3 AEs for individual ALK inhibitor were moderately high yet manageable. Different toxicity spectrums were found in each ALK inhibitor.

GSK-3ß suppression upregulates Gli1 to alleviate osteogenesis inhibition in titanium nanoparticle-induced osteolysis.

Wear particle-induced periprosthetic osteolysis (PPO) have become a major reason of joint arthroplasty failure and secondary surgery following joint arthroplasty and thus pose a severe threat to global public health. Therefore, determining how to effectively suppress particle-induced PPO has become an urgent problem. The pathological mechanism involved in the PPO signaling cascade is still unclear. Recently, the interaction between osteogenic inhibition and wear particles at the implant biological interface, which has received increasing attention, has been revealed as an important factor in pathological process. Additionally, Hedgehog (Hh)-Gli1 is a crucial signaling cascade which was regulated by multiple factors in numerous physiological and pathological process. It was revealed to exert a crucial part during embryonic bone development and metabolism. However, whether Hh-Gli1 is involved in wear particle-induced osteogenic inhibition in PPO remains unknown. Our present study explored the mechanism by which the Hh-Gli1 signaling cascade regulates titanium (Ti) nanoparticle-induced osteolysis. We found that Hh-Gli1 signaling was dramatically downregulated upon Ti particle treatment. Mechanistically, glycogen synthesis kinase 3ß (GSK-3ß) activation was significantly increased in Ti particle-induced osteogenic inhibition via changes in GSK-3ß phosphorylation level and was found to participate in the posttranslational modification and degradation of the key transcription factor Gli1, thus decreasing the accumulation of Gli1 and its translocation from the cytoplasm to the nucleus. Collectively, these findings suggest that the Hh-Gli1 signaling cascade utilizes a GSK3ß-mediated mechanism and may serve as a rational new therapeutic target against nanoparticle-induced PPO.

A new prognostic model including platelet/lymphocyte ratio and International Prognostic Score 3 for freedom from progression in patients with previously untreated advanced classical Hodgkin lymphoma.

PURPOSE: We aimed to develop a new risk stratification tool to predict freedom from progression (FFP) for newly diagnosed advanced classical Hodgkin lymphoma (cHL). METHODS: We collected data from 386 patients with advanced cHL diagnosed between December 8, 2000 and October 29, 2018, and treated with curative intent with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or an ABVD-equivalent regimen. Cases were randomly divided into training and validation cohorts at a ratio of 7:3. The new model was constructed based on the results of Cox proportional hazards model in the training cohort. Comparisons of discrimination between the new model and other models in the training and validation cohorts for FFP prediction were measured by time-dependent area under curve (tAUC) and Harrell's C-index. Calibration plots were constructed to compare the consistency between the predicted and observed estimates of survival probability for the new model in the training and validation cohorts. RESULTS: The new model (IPSPLR) composed of International Prognostic Score (IPS)-3 and platelet/lymphocyte ratio (PLR) provided four distinct risk groups. The IPSPLR showed better discriminative ability when compared with IPS-3 and IPS-7. The AUC of IPSPLR was consistently higher than that of IPS-3 and IPS-7 between 12 and 120 months. The C-index of the IPSPLR was higher than that of IPS-7 and IPS-3. The calibration plots showed an excellent agreement between the IPSPLR-predicted and observed estimates of 5-year FFP. CONCLUSION: The IPSPLR is an easily used tool for FFP prediction for newly diagnosed advanced cHL. Validation of this tool in other large datasets is needed.

Prognostic role of red blood cell distribution width and platelet/lymphocyte ratio in early-stage classical Hodgkin lymphoma.

Background: To investigate the prognostic role of red blood cell distribution width (RDW) and platelet/lymphocyte ratio (PLR) in early-stage classical Hodgkin lymphoma (cHL). Materials & methods: Data from 402 patients with newly diagnosed early-stage cHL were retrospectively collected. The impact of factors on complete response (CR) rate and freedom from progression (FFP) was analyzed. Results: High PLR was associated with lower CR, but high RDW was not. The univariate analysis showed that RDW and PLR were predictive of FFP. On multivariate analysis, high PLR was an independent risk factor for inferior FFP. Subgroup analysis and a prognostic model for FFP based on PLR validated the prognostic role of PLR. Conclusion: PLR was a robust prognostic factor for newly diagnosed early-stage cHL.

Low CCL19 expression is associated with adverse clinical outcomes for follicular lymphoma patients treated with chemoimmunotherapy.

BACKGROUND: This study aimed to recognize the hub genes associated with prognosis in follicular lymphoma (FL) treated with first-line rituximab combined with chemotherapy. METHOD: RNA sequencing data of dataset GSE65135 (n = 24) were included in differentially expressed genes (DEGs) analysis. Weighted gene co-expression network analysis (WGCNA) was applied for exploring the coexpression network and identifying hub genes. Validation of hub genes expression and prognosis were applied in dataset GSE119214 (n = 137) and independent patient cohort from Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (n = 32), respectively, by analyzing RNAseq expression data and serum protein concentration quantified by ELISA. The Gene Set Enrichment Analysis (GSEA), gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments analysis were performed. CIBERSORT was applied for tumor-infiltrating immune cells (TIICs) subset analysis. RESULTS: A total of 3260 DEGs were obtained, with 1861 genes upregulated and 1399 genes downregulated. Using WGCNA, eight hub genes, PLA2G2D, MMP9, PTGDS, CCL19, NFIB, YAP1, RGL1, and TIMP3 were identified. Kaplan-Meier analysis and multivariate COX regression analysis indicated that CCL19 independently associated with overall survival (OS) for FL patients treated with rituximab and chemotherapy (HR = 0.47, 95% CI [0.25-0.86], p = 0.014). Higher serum CCL19 concentration was associated with longer progression-free survival (PFS, p = 0.014) and OS (p = 0.039). TIICs subset analysis showed that CCL19 expression had a positive correlation with monocytes and macrophages M1, and a negative correlation with naïve B cells and plasma cells. CONCLUSION: CCL19 expression was associated with survival outcomes and might be a potential prognostic biomarker for FL treated with first-line chemoimmunotherapy.

Survival among patients with composite and sequential lymphoma between primary mediastinal lymphoma/diffuse large B-cell lymphoma and classical Hodgkin lymphoma: A population-based study.

BACKGROUND: Data on composite and sequential lymphoma between primary mediastinal lymphoma/diffuse large B-cell lymphoma (LBCL) and classical Hodgkin lymphoma (cHL) are rare. METHODS: We identified 25 cases with composite lymphoma (CL), 116 cases developing LBCL as a second primary cancer after cHL (cHL-LBCL), and 74 cases developing cHL as a second primary cancer after LBCL (LBCL-cHL) from the Surveillance, Epidemiology, and End Results (SEER) 18 database. Comparisons of overall survival (OS) and lymphoma cause-specific survival (CSS) between patients with cHL-LBCL or cHL-LBCL and their de novo counterparts were performed. RESULTS: The 5-year OS of patients with CL was 74.8 %. No significant difference in unadjusted OS and lymphoma CSS were observed between patients with de novo LBCL (LBCL-1 group) and patients with cHL-LBCL. However, the age- and stage-adjusted cHL-LBCL group had inferior OS and lymphoma CSS compared with that in the LBCL-1 group. The unadjusted and adjusted OS and lymphoma CSS in the LBCL-cHL group were significantly worse than patients with de novo cHL. CONCLUSIONS: CL between LBCL and cHL may have good outcomes. cHL survivors had poorer outcomes after a LBCL diagnosis versus patients with LBCL-1. Significantly poor outcomes were observed in patients with LBCL-cHL compared with patients with de novo cHL.

Low platelet/platelet distribution width and high platelet/lymphocyte ratio are adverse prognostic factors in patients with newly diagnosed advanced Hodgkin lymphoma.

We conducted a retrospective study in 274 previously untreated advanced Hodgkin lymphoma (HL) patients to investigate the prognostic value of baseline platelet (PLT) count, platelet distribution width (PDW), mean platelet volume (MPV), and platelet/lymphocyte ratio (PLR). The median follow-up time was 89 (range 0.3-240) months. By univariate analysis, PLT/PDW <24.5, PLR ≥245, and MPV <8fl were all associated with worse freedom from progression (FFP), progression-free survival (PFS), and overall survival (OS). By multivariate analysis, PLT/PDW <24.5 was a risk factor for FFP (HR 2.02, p = 0.002) and PFS (HR 2.36, p < 0.001). PLR ≥245 was independently associated with inferior FFP (HR 2.04, p = 0.003) and PFS (HR 1.93, p = 0.002). Due to the limited number of death events, multivariate analysis was not conducted for OS. Propensity score matching analysis and subgroup analysis further validated the prognostic value for PLT/PDW and PLR. In conclusion, PLT/PDW and PLR are promising prognostic indicators for newly diagnosed advanced HL.

The changing landscape of anti-lung cancer drug clinical trials in mainland China from 2005 to 2020.

BACKGROUND: In recent years, new drug development on lung cancer is in full swing in China. The aim of this study was to overview the changing landscape of anti-lung cancer drug clinical trials in mainland China from 2005 to 2020. METHODS: We analysed anti-lung cancer drug clinical trials registered on three websites including the China National Medical Products Administration Centre for Drug Evaluation platform, the Chinese Clinical Trial Registry and ClinicalTrials.gov. FINDINGS: A total of 1595 anti-lung cancer drug clinical trials from Jan 1st, 2005 to Dec 31st, 2020 were extracted, which included 630 (39•5%) investigator-initiated trials (IITs), 698 (43•8%) domestic industry-sponsored trials (ISTs), and 267 (16•7%) international ISTs. During the past 16 years, the number of anti-lung cancer clinical trials including IITs and domestic ISTs had a remarkable growth, however, the number of international ISTs increased slowly. The number of principal clinical trial units also increased significantly over time. Of the 1595 trials, the largest growth was observed in phase I trials during 2013-2020, with an average annual growth rate of 38•6%. 278 trials were led by principal investigators (PI) from Guangdong, followed by Beijing (n=273) and Shanghai (n=257). Among the 965 ISTs, clinical trials involving targeted drugs (588, 60•9%) accounted for the largest proportion, followed by immunotherapeutic drugs (284, 29•4%), cytotoxic drugs (75, 7•8%), and traditional Chinese medicine (18, 1•9%). In terms of targeted drugs, EGFR-TKIs remained the most studied drugs (225/588, 38•27%). As for immunotherapy, 125 out of 284 (44•01%) trials involved PD-1 inhibitors, 60 (21•13%) trials involved PD-L1 inhibitors, and seven (2•46%) trials involved CTLA-4 inhibitors. INTERPRETATION: In the past 16 years, the development of anti-lung cancer drug clinical trials has achieved much progress in mainland China. The most progress lied in targeted therapy and immunotherapy. FUNDING: This work was financially supported in part by China National Major Project for New Drug Innovation (2017ZX09304015) and Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001).