Epidemiological features and a survival nomogram for primary lymphoma of the male genital tract.

Primary lymphoma of the male genital tract (PLMGT) is rare, and data on its epidemiology and prognosis are lacking. Our study aimed to estimate the incidence and develop a predictive nomogram for PLMGT. We pooled the incidence and survival data of PLMGT over the last 20 years from the Surveillance, Epidemiology, and End Results (SEER) database. Incidence rates were calculated by year of diagnosis, age, race, and histology. Independent prognostic factors selected by Cox regression analysis were used to develop a nomogram for predicting overall survival (OS). Our study enrolled 1312 patients with PLMGT. The overall incidence rate of PLMGT was 0.437/1,000,000 during 2000-2019. OS was associated with age, marital status, histological subtype, Ann Arbor stage, and therapeutic strategy, which were used to construct nomograms to predict 1-, 3-, and 5-year OS rates. Receiver operating characteristic curves, calibration plots, and decision curve analysis showed good performance of the nomogram. Based on the total score of each patient from the nomogram, the patients were clustered into three risk groups, and the risk stratification model was more successful in predicting clinical outcomes than the traditional Ann Arbor staging system. The incidence rate of PLMGT has remained relatively stable over the past two decades. For the OS of patients with PLMGT, we established a novel predictive nomogram involving all independent risk factors obtained from the SEER database and developed a corresponding risk classification system that showed better predictive performance than the Ann Arbor staging system.

Improving the safety of CAR-T-cell therapy: The risk and prevention of viral infection for patients with relapsed or refractory B-cell lymphoma undergoing CAR-T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy, an innovative immunotherapeutic against relapsed/refractory B-cell lymphoma, faces challenges due to frequent viral infections. Despite this, a comprehensive review addressing risk assessment, surveillance, and treatment management is notably absent. This review elucidates immune response compromises during viral infections in CAR-T recipients, collates susceptibility risk factors, and deliberates on preventive strategies. In the post-pandemic era, marked by the Omicron variant, new and severe threats to CAR-T therapy emerge, necessitating exploration of preventive and treatment measures for COVID-19. Overall, the review provides recommendations for viral infection prophylaxis and management, enhancing CAR-T product safety and recipient survival.

Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial.

BACKGROUND: Accumulating evidence proposed Janus-associated kinase (JAK) inhibitors as therapeutic targets warranting rapid investigation. OBJECTIVE: This study evaluated the efficacy and safety of ruxolitinib, a JAK1/2 inhibitor, for coronavirus disease 2019. METHODS: We conducted a prospective, multicenter, single-blind, randomized controlled phase II trial involving patients with severe coronavirus disease 2019. RESULTS: Forty-three patients were randomly assigned (1:1) to receive ruxolitinib plus standard-of-care treatment (22 patients) or placebo based on standard-of-care treatment (21 patients). After exclusion of 2 patients (1 ineligible, 1 consent withdrawn) from the ruxolitinib group, 20 patients in the intervention group and 21 patients in the control group were included in the study. Treatment with ruxolitinib plus standard-of-care was not associated with significantly accelerated clinical improvement in severe patients with coronavirus disease 2019, although ruxolitinib recipients had a numerically faster clinical improvement. Eighteen (90%) patients from the ruxolitinib group showed computed tomography improvement at day 14 compared with 13 (61.9%) patients from the control group (P = .0495). Three patients in the control group died of respiratory failure, with 14.3% overall mortality at day 28; no patients died in the ruxolitinib group. Ruxolitinib was well tolerated with low toxicities and no new safety signals. Levels of 7 cytokines were significantly decreased in the ruxolitinib group in comparison to the control group. CONCLUSIONS: Although no statistical difference was observed, ruxolitinib recipients had a numerically faster clinical improvement. Significant chest computed tomography improvement, a faster recovery from lymphopenia, and favorable side-effect profile in the ruxolitinib group were encouraging and informative to future trials to test efficacy of ruxolitinib in a larger population.

NOV/CCN3 induces cartilage protection by inhibiting PI3K/AKT/mTOR pathway.

Osteoarthritis (OA), an age-related degenerative joint disease, is pathologically characterized by articular cartilage degeneration and synovial inflammation. Nephroblastoma overexpressed (NOV or CCN3), a matricellular protein, is a primary member of the CCN family (Cyr61, Ctgf, NOV) of proteins and is involved in various inflammatory disorders. Previous studies reported that CCN3 might play a therapeutic role in OA. However, the underlying mechanism remains unclear. In this study, we confirmed the expression of CCN3 was decreased in human and rat OA articular cartilage. Recombinant CCN3 ameliorated the IL-1ß-induced matrix catabolism, as demonstrated by MMP1, MMP3, MMP13, ADAMTS5 and iNOS expression, in vitro. In addition, the degradation of cartilage matrix such as collagen 2 and aggrecan could be reversed by CCN3. Furthermore, we found CCN3 promoted autophagy as Atg5, Beclin1 and LC3-II expression were increased. High-mobility group box 1 was negatively correlated with CCN3 in IL-1ß-induced osteoarthritis responses, and HMGB1 is involved in the protective effect of CCN3 in OA. Moreover, CCN3 overexpression decreased the expression of HMGB1 and reversed the IL-1ß induced MMPs production. Additionally, recombinant CCN3 or CCN3 overexpression attenuated the activation of PI3K/AKT/mTOR pathway induced by IL-1ß. Our study presents new mechanisms of CCN3 in osteoarthritis and indicates that CCN3 can serve as a novel potential therapeutic target for osteoarthritis.

Chondrogenic effect of cell-based scaffold of self-assembling peptides/PLGA-PLL loading the hTGFß3 plasmid DNA.

With the application of tissue engineering to tissue regeneration, additional new complexes have been made in response to the challenge of cartilage-injury repair. This study was performed to construct a rat precartilaginous stem cells-based scaffold of self-assembling peptides RADA16-I/PLGA-PLL (poly-L-lysine coated PLGA) as extracellular matrix loading the NLS-TAT as a peptide-based carrier for a plasmid DNA containing hTGFß3. After composites were cultured for 1, 2, 3 and 4 weeks, respectively, the results showed that the levels of chondrogenic-related gene expression were higher in the experimental group with and hTGFß3 gene by reverse transcription-polymerase chain reaction, and with higher histochemical and immunohistochemical expression. hTGFß3 protein expression had increased at 4 weeks based on western blot analysis. The results of this study show that a complex may be a suitable scaffold for cartilage repair and offer a strategy for tissue regeneration through the use of tissue engineering.

Outcome of aggressive B-cell lymphoma with TP53 alterations administered with CAR T-cell cocktail alone or in combination with ASCT.

TP53 gene alteration confers inferior prognosis in refractory/relapse aggressive B-cell non-Hodgkin lymphoma (r/r B-NHL). From September 2016 to September 2020, 257 r/r B-NHL patients were assessed for eligibility for two trials in our center, assessing anti-CD19 and anti-CD22 chimeric antigen receptor (CAR19/22) T-cell cocktail treatment alone or in combination with autologous stem cell transplantation (ASCT). TP53 alterations were screened in 123 enrolled patients and confirmed in 60. CAR19/22 T-cell administration resulted in best objective (ORR) and complete (CRR) response rate of 87.1% and 45.2% in patients with TP53 alterations, respectively. Following a median follow-up of 16.7 months, median progression-free survival (PFS) was 14.8 months, and 24-month overall survival (OS) was estimated at 56.3%. Comparable ORR, PFS, and OS were determined in individuals with or without TP53 alterations, and in individuals at different risk levels based on functional stratification of TP53 alterations. CAR19/22 T-cell treatment in combination with ASCT resulted in higher ORR, CRR, PFS, and OS, but reduced occurrence of severe CRS in this patient population, even in individuals showing stable or progressive disease before transplantation. The best ORR and CRR in patients with TP53 alterations were 92.9% and 82.1%, respectively. Following a median follow-up of 21.2 months, 24-month PFS and OS rates in patients with TP53 alterations were estimated at 77.5% and 89.3%, respectively. In multivariable analysis, this combination strategy predicted improved OS. In conclusion, CAR19/22 T-cell therapy is efficacious in r/r aggressive B-NHL with TP53 alterations. Combining CAR-T cell administration with ASCT further improves long-term outcome of these patients.

Autologous stem cell transplantation in tandem with Anti-CD30 CAR T-cell infusion in relapsed/refractory CD30+ lymphoma.

BACKGROUND: Long-term outcome is unfavourable for relapsed/refractory (r/r) lymphoma patients who are resistant to salvage chemotherapy, even after subsequent autologous stem-cell transplantation (ASCT). Although anti-CD30 chimeric antigen receptor (CAR30) T-cell therapy induces high response rates in these patients, the duration of response is relatively limited. METHODS: This open-label, single-center and single-arm pilot study investigated the safety and efficacy of ASCT in tandem with CAR30 T-cell infusion in r/r CD30+ lymphoma. The primary endpoint was safety and key secondary endpoint was overall response rate, overall survival, progression-free survival, and duration of response. RESULTS: Five classical Hodgkin lymphoma (cHL) patients and 1 anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) patient were enrolled. The median age was 24 years. No patient had prior ASCT. Three patients (50.0%) relapsed for ≥ 2 times and 3 patients (50.0%) had primary refractory diseases. All had a Deauville score of 4 or 5, and 5 patients (83.3%) had a stable or progressive disease (SD/PD) at enrollment. All patients received myeloablative chemotherapy and infused CD34-positive hematopoietic stem cells (HSCs) and CAR30 T cells in tandem, with a median dose of 3.9 × 106/kg and 7.6 × 106/kg, respectively. Five paitents presented with cytokine release syndrome (CRS), all of which were grade 1. No neurotoxicity was observed. All patients had successful HSCs engraftment and reached an objective response, including 5 (4 cHL and 1 ALCL, 83.3%) with a complete response (CR) and 1 with a partial response (PR). With a median follow-up of 20.4 (range, 12.1-34.4) months, all remained alive and maintained their responses. CONCLUSION: Our work demonstrates the combined administration of ASCT and CAR30 T-cell therapy is well-tolerate and highly effective in r/r cHL and ALCL, even in PET-positive or chemorefractory patients who are expected to have inferior outcome after ASCT, although further large-scaled validation in prospective clinical trial is warranted. Trial registration The trial was registered with the Chinese Clinical Trial Registry (ChiCTR, number ChiCTR2100053662).

Chondro-Protective Effects of Shikimic Acid on Osteoarthritis via Restoring Impaired Autophagy and Suppressing the MAPK/NF-κB Signaling Pathway.

Osteoarthritis (OA) is a major cause of cartilage pain and limited mobility in middle-aged and elderly individuals. The degeneration of cartilage induced by inflammation and cartilage anabolic and catabolic disorder plays a key role in OA. Shikimic acid (SA), a natural ingredient extracted from Illicium verum, has been shown to exert notable anti-inflammatory effects in previous studies, suggesting its potential effects in the treatment of OA. In this study, we revealed that the pretreatment of SW1353 human chondrocytes with SA before interleukin 1ß (IL-1ß) stimulation effectively decreased the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (Cox)-2, matrix metalloproteinases (MMPs; MMP3 and MMP13), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5, type X collagen, and p62; increased the expression of type II collagen, ATG7, Beclin-1, and LC3; and increased the autophagic flux. Mechanistically, we found that SA suppressed the IL-1ß-induced activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) pathways. Furthermore, the results of safranin O staining and toluidine blue staining of primary rat cartilage chondrocytes and a trauma-induced rat model of OA showed that SA alleviated progression of OA in vivo. Collectively, our research enhances understanding of the mechanism of protective effect of SA against the progression of OA, which involves amelioration of cartilage degeneration, thereby providing new evidence for the use of SA as a therapy to prevent the development of OA.

Neferine Inhibits Expression of Inflammatory Mediators and Matrix Degrading Enzymes in IL-1ß-Treated Rat Chondrocytes via Suppressing MAPK and NF-κB Signaling Pathways.

Osteoarthritis (OA), in which inflammation plays a crucial role, is the most common joint disease characterized by cartilage degradation. Neferine (Nef), a dibenzyl isoquinoline alkaloid, has shown its anti-inflammatory effects on other inflammatory diseases. Therefore, we hypothesized that Nef might also have an anti-inflammatory effect on OA and explored its effect on IL-1ß-treated rat chondrocytes. Sprague Dawley (SD) rat chondrocytes were stimulated with IL-1ß (10 ng/ml) and Nef (1, 5, and 10 µM) or IL-1ß (10 ng/ml) alone for 24 h. Expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), matrix metalloproteinases (MMPs), and thrombospondin motifs-5 (ADAMTS5) was determined by quantitative real-time PCR and Western blotting. Expression of collagen II and aggrecan was examined by Western blotting, immunofluorescence, and safranin O staining. In addition, activation of MAPK and NF-κB signaling pathway was examined by Western blotting, and p65 nuclear translocation was evaluated by immunofluorescence. Nef reduced expression of inflammatory regulators (iNOS and COX-2) in IL-1ß-treated chondrocytes. Expression of IL-1ß-induced major catabolic enzymes (MMP3, MMP13, and ADAMTS5) was inhibited by Nef. Meanwhile, downregulation of collagen II and aggrecan expression was also ameliorated. Furthermore, Nef dampened abnormal activation of MAPK and NF-κB signaling pathway triggered by IL-1ß. Overall, the results above showed that Nef inhibited IL-1ß-induced excess production of inflammatory and catabolic factors in rat chondrocytes via inhibiting the MAPK and NF-κB pathways, suggesting a promising pharmacotherapy for OA.

Vanillic acid attenuates cartilage degeneration by regulating the MAPK and PI3K/AKT/NF-κB pathways.

Osteoarthritis (OA) is a frequently seen arthropathy that features cartilage loss and destruction. Vanillic acid (VA), is a well-known flavonoid, which possesses various pharmacological activities. However, the effects of Vanillic acid on articular cartilage destruction and the pathogenesis of OA remain unknown. The present study observed that VA attenuated OA progression in vivo and vitro. VA inhibited the expression of inflammation responses, including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs) and aggrecanase -2(ADAMTS5). Moreover, the major markers of hypertrophic chondrocytes such as Collagen X, Runt related transcription factor 2 (Runx2) and Vascular endothelial growth factor (VEGFA) were also reduced by VA. In addition, the interleukin-1ß (IL-1ß) -stimulated collagen 2 and aggrecan destruction were suppressed by VA. Moreover, VA concentration -dependently inhibited IL-1ß induced production of High-mobility group box 1 (HMGB1), a classic damage-associated molecular pattern (DAMP) molecule with strong pro-inflammatory effects in OA. Meanwhile, we revealed that VA suppressed the IL-1ß induced activation of MAPK and PI3K/AKT/NF-κB pathways. In vivo, VA alleviated osteoarthritis progression in a rat OA model. Collectively, our results demonstrate that VA could potentially be a new candidate for OA therapy.

Pravastatin alleviates interleukin 1ß-induced cartilage degradation by restoring impaired autophagy associated with MAPK pathway inhibition.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degradation driven by proinflammatory cytokines; meanwhile, statins display anti-inflammatory effects. Here we assessed the effects of pravastatin on inflammatory rat chondrocytes and explored the underlying mechanism. METHODS: Rat articular chondrocytes were pretreated with pravastatin and subsequently stimulated with IL-1ß. Then, the expression levels of OA- and autophagy-related effectors, at the mRNA and protein levels, were examined by real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. Autophagic flux in chondrocytes in different treatment groups was monitored via GFP-mRFP-LC3 adenovirus transfection and confocal microscopy. Activation of MAPK, PI3K/Akt, and NF-κB pathways in chondrocytes with or without pravastatin treatment during IL-1ß stimulation was examined by Western blotting. RESULTS: Our results showed that pravastatin downregulated the degradation related genes MMP3, MMP13 and ADAMTS5, as well as extracellular matrix degeneration induced by IL-1ß. In addition, pravastatin upregulated the autophagy related genes atg7, atg12, Beclin1, and LC3 II in IL-1ß stimulated chondrocytes. GFP-mRFP-LC3 adenovirus transfection also indicated that pravastatin restored impaired autophagy in OA chondrocytes. Furthermore, we demonstrated that regulation of the MAPK signaling pathway may be responsible for autophagy regulation in the articular cartilage. CONCLUSIONS: Taken together, these findings suggested that pravastatin restores impaired autophagic flux by inhibiting MAPK activation and protects the cartilage against inflammatory responses, suggesting a potential role for autophagic flux in pravastatin-mediated cartilage protection.

Kaempferol inhibits interleukin­1ß stimulated matrix metalloproteinases by suppressing the MAPK­associated ERK and P38 signaling pathways.

Osteoarthritis (OA) is a common degenerative joint disease in older adults. A number of previous studies have demonstrated that natural flavonoids can serve as promising therapeutic drugs for OA. Kaempferol, a phytochemical ingredient mainly present in various fruits, has exhibited its prominent anti­inflammatory and antioxidant effects in numerous diseases. However, whether Kaempferol ameliorates the deterioration of arthritis remains to be elucidated. The aim of the present study was to investigate the therapeutic role of Kaempferol on OA in rat chondrocytes. The results revealed that Kaempferol significantly inhibited the interleukin (IL)­1ß­induced protein expression of inflammatory mediators such as inducible nitric oxide synthase and cyclo­oxygenase­2. In addition, the common matrix degrading enzymes [matrix metalloproteinase (MMP)­1, MMP­3, MMP­13 and a disintegrin and metalloproteinase with thrombospondin motif­5] induced by IL­1ß were also suppressed by Kaempferol, and consequently abolished the degradation of collagen II. Furthermore, the anti­inflammatory effect of Kaempferol was mediated by the inhibition of the mitogen activated protein kinase­associated extracellular signal­regulated kinase and P38 signaling pathways. These results collectively indicated that Kaempferol can potentially prevent OA development and serve as a novel pharmacological target in the treatment of OA.

Caffeic acid protects against IL-1ß-induced inflammatory responses and cartilage degradation in articular chondrocytes.

Osteoarthritis (OA) is a common articular disease that features cartilage loss and destruction. It has been confirmed that inflammation plays major roles in the progression of osteoarthritis. Caffeic acid (CA), a key dietary nutrient commonly found in coffee, has shown its anti-inflammatory properties in various inflammation diseases. However, the effects of CA in osteoarthritis remain explored. Here we investigated the effects of CA on IL-1ß induced increased expression of inflammatory factors as well as the degradation of Collagen II and aggrecan in rat chondrocytes. CA prevented the cartilage damage induced by IL-1ß in vivo organ culture of articular cartilage. Besides, the IL-1ß induced increased production of inflammation factors such as iNOS and COX2 could be inhibited by CA. Additionally, CA could also suppress IL-1ß induced expression of cartilage matrix catabolic enzymes such as ADAMTS5 and MMPs. Moreover, CA could prevent IL-1ß induced degradation of Collagen II and aggrecan in chondrocytes. Furthermore, CA inhibited NF-κB activity and the activation of JNK pathway. This study reveals that CA inhibits IL-1ß induced inflammation responses through suppression of NF-κB and MAPK related JNK signaling pathways. These results demonstrate that CA may provide new avenues for osteoarthritis treatment in future.

Histone deacetylase-4 and histone deacetylase-8 regulate interleukin-1ß-induced cartilage catabolic degradation through MAPK/JNK and ERK pathways.

Interleukin-1ß (IL-1ß)-induced inflammatory response is associated with osteoarthritis (OA) and its development. Histone deacetylase (HDAC) may be involved in regulating this pathogenesis, but the mechanism has yet to be elucidated. The aim of the present study was to investigate the mechanism underlying the regulation of IL­1ß­stimulated catabolic degradation of cartilage by HDAC. An in vitro model of OA was generated using rat articular chondrocytes (rACs) treated with IL­1ß. The role of HDAC in IL­1ß­induced gene expression was investigated using HDAC inhibitors and specific small interfering RNAs (siRNAs). The association of diverse mitogen­activated protein kinase (MAPK) pathways was examined. The IL­1ß­induced expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)­4 and ADAMTS­5, and the production of collagen X and cyclooxygenase­2 in rACs was accompanied by the expression of HDAC4 and HDAC8, and were significantly downregulated by HDAC inhibitors and specific siRNAs. IL­1ß­induced activation of extracellular signal­regulated kinase was downregulated by the HDAC inhibitor Trichostatin A, but not significantly by PCI­34051. The activation of c­Jun N­terminal kinase was observably downregulated by the latter, but only slightly by the former. These results suggest that HDAC4 and HDAC8 may serve as key upstream mediators of MAPK in regulating the IL­1ß­induced cartilage catabolic and degradation. Therefore, inhibiting HDAC4 or HDAC8 or both may be a promising therapeutic strategy in preventing and treating OA.

Sinapic Acid Inhibits the IL-1ß-Induced Inflammation via MAPK Downregulation in Rat Chondrocytes.

Osteoarthritis (OA) is a degenerative joint disease frequently seen in the elderly population. Sinapic acid (SA), a commonly found phenolic acid, has been pharmacologically evaluated for its anti-inflammation effects in various studies. To explore its potential therapeutic role for OA, rat chondrocytes were treated with IL-1ß (10 ng/ml) with different concentrations of SA in vitro. Our study revealed that SA could inhibit the IL-1ß-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2). Consistent with these findings, the increased protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (Cox)-2 could also be downregulated by SA. Moreover, SA could also suppress the IL-1ß-induced expression of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) in chondrocytes. Furthermore, our data found that SA could suppress the IL-1ß-induced mitogen-activated protein kinase (MAPK) pathway activation. In general, this paper elucidates that sinapic acid inhibits the IL-1ß-induced inflammation via MAPK pathways and may be a good agent for the treatment of OA.