Elevated serum levels of soluble B-cell maturation antigen as a prognostic biomarker for multiple myeloma.

Serum B-cell maturation antigen (sBCMA) levels can serve as a sensitive biomarker in multiple myeloma (MM). In the research setting, sBCMA levels can be accurately detected by enzyme-linked immunosorbent assay (ELISA), but the approach has not been approved for clinical use. Here, we used a novel chemiluminescence method to assess sBCMA levels in 759 serum samples from 17 healthy donors and 443 patients with plasma cell (PC) diseases including AL amyloidosis, POEMS syndrome and MM. Serum BCMA levels were elevated 16.1-fold in patients with newly diagnosed MM compared to healthy donors and rare PC diseases patients. Specifically, the sBCMA levels in patients with progressive disease were 64.6-fold higher than those who showed partial response or above to treatment. The sBCMA level also correlated negatively with the response depth of MM patients. In newly diagnosed and relapsed MM patients, survival was significantly longer among those subjects whose sBCMA levels are below the median levels compared with those above the median value. We optimized the accuracy of the survival prediction further by integrating sBCMA level into the Second Revised International Staging System (R2-ISS). Our findings provide evidence that the novel chemiluminescence method is sensitive and practical for measuring sBCMA levels in clinical samples and confirm that sBCMA might serve as an independent prognostic biomarker for MM.

Interleukin-4 protects retinal ganglion cells and promotes axon regeneration.

BACKGROUND: The preservation of retinal ganglion cells (RGCs) and the facilitation of axon regeneration are crucial considerations in the management of various vision-threatening disorders. Therefore, we investigate the efficacy of interleukin-4 (IL-4), a potential therapeutic agent, in promoting neuroprotection and axon regeneration of retinal ganglion cells (RGCs) as identified through whole transcriptome sequencing in an in vitro axon growth model. METHODS: A low concentration of staurosporine (STS) was employed to induce in vitro axon growth. Whole transcriptome sequencing was utilized to identify key target factors involved in the molecular mechanism underlying axon growth. The efficacy of recombinant IL-4 protein on promoting RGC axon growth was validated through in vitro experiments. The protective effect of recombinant IL-4 protein on somas of RGCs was assessed using RBPMS-specific immunofluorescent staining in mouse models with optic nerve crush (ONC) and N-methyl-D-aspartic acid (NMDA) injury. The protective effect on RGC axons was evaluated by anterograde labeling of cholera toxin subunit B (CTB), while the promotion of RGC axon regeneration was assessed through both anterograde labeling of CTB and immunofluorescent staining for growth associated protein-43 (GAP43). RESULTS: Whole-transcriptome sequencing of staurosporine-treated 661 W cells revealed a significant upregulation in intracellular IL-4 transcription levels during the process of axon regeneration. In vitro experiments demonstrated that recombinant IL-4 protein effectively stimulated axon outgrowth. Subsequent immunostaining with RBPMS revealed a significantly higher survival rate of RGCs in the rIL-4 group compared to the vehicle group in both NMDA and ONC injury models. Axonal tracing with CTB confirmed that recombinant IL-4 protein preserved long-distance projection of RGC axons, and there was a notably higher number of surviving axons in the rIL-4 group compared to the vehicle group following NMDA-induced injury. Moreover, intravitreal delivery of recombinant IL-4 protein substantially facilitated RGC axon regeneration after ONC injury. CONCLUSION: The recombinant IL-4 protein exhibits the potential to enhance the survival rate of RGCs, protect RGC axons against NMDA-induced injury, and facilitate axon regeneration following ONC. This study provides an experimental foundation for further investigation and development of therapeutic agents aimed at protecting the optic nerve and promoting axon regeneration.

Chronic myeloid leukaemia: Biology and therapy.

Chronic myeloid leukaemia (CML) is caused by BCR::ABL1. Tyrosine kinase-inhibitors (TKIs) are the initial therapy. Several organizations have reported milestones to evaluate response to initial TKI-therapy and suggest when a change of TKI should be considered. Achieving treatment-free remission (TFR) is increasingly recognized as the optimal therapy goal. Which TKI is the best initial therapy for which persons and what depth and duration of molecular remission is needed to achieve TFR are controversial. In this review we discuss these issues and suggest future research directions.

Recreational Marijuana Laws and Teen Marijuana Use, 1993-2021.

This cross-sectional study uses data from the Youth Risk Behavior surveys to assess the association of state-level recreational marijuana laws and youth marijuana use.

Recreational Marijuana Legalization and Workplace Injuries Among Younger Workers.

This case-control study uses state-by-year workplace injury data to assess recreational marijuana legalization adoption and workplace injuries among younger workers aged 20 to 34 years.

Genomic features reveal potential benefit of adding anti-PD-1 immunotherapy to treat non-upper aerodigestive tract natural killer/T-cell lymphoma.

Natural killer/T-cell lymphoma (NKTCL) is a highly heterogeneous disease with a poor prognosis. However, the genomic characteristics and proper treatment strategies for non-upper aerodigestive tract NKTCL (NUAT-NKTCL), a rare subtype of NKTCL, remain largely unexplored. In this study, 1589 patients newly diagnosed with NKTCL at 14 hospitals were assessed, 196 (12.3%) of whom had NUAT-NKTCL with adverse clinical characteristics and an inferior prognosis. By using whole-genome sequencing (WGS) and whole-exome sequencing (WES) data, we found strikingly different mutation profiles between upper aerodigestive tract (UAT)- and NUAT-NKTCL patients, with the latter group exhibiting significantly higher genomic instability. In the NUAT-NKTCL cohort, 128 patients received frontline P-GEMOX chemotherapy, 37 of whom also received anti-PD-1 immunotherapy. The application of anti-PD-1 significantly improved progression-free survival (3-year PFS rate 53.9% versus 17.0%, P = 0.009) and overall survival (3-year OS rate 63.7% versus 29.2%, P = 0.01) in the matched NUAT-NKTCL cohort. WES revealed frequent mutations involving immune regulation and genomic instability in immunochemotherapy responders. Our study showed distinct clinical characteristics and mutational profiles in NUAT-NKTCL compared with UAT patients and suggested adding anti-PD-1 immunotherapy in front-line treatment of NUAT-NKTCL. Further studies are needed to validate the efficacy and related biomarkers for immunochemotherapy proposed in this study.

JAK/STAT in leukemia: a clinical update.

Over the past three decades, considerable efforts have been expended on understanding the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in leukemia, following the identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs). The aim of this review is to summarize the latest progress in our understanding of the involvement of the JAK/STAT signaling pathway in the development of leukemia. We also attempt to provide insights into the current use of JAK/STAT inhibitors in leukemia therapy and explore pertinent clinical trials in this field.

Epstein-Barr virus-based prognostic model in nodular sclerosis classic Hodgkin lymphoma.

The role of Epstein-Barr virus (EBV) in lymphoma cells of nodular sclerosis classic Hodgkin lymphoma (NScHL) is controversial. Our aim was to explore this and establish a clinically feasible model for risk stratification. We interrogated data from 542 consecutive subjects with NScHL receiving ABVD therapy and demonstrated EBV-infection in their lymphoma cells with EBV-encoded small RNAs (EBERs) in situ hybridization. Subjects were divided into training and validation datasets. As data from the training dataset suggested EBERs-positivity was the only independent prognostic factor for both progression-free survival (PFS) and overall survival (OS), we developed corresponding prognostic models based on it. Our models showed excellent performance in both training and validation cohort. These data indicate the close association of EBV infection and the outcomes of persons with NScHL receiving ABVD. Additionally, our newly developed models should help physicians estimate prognosis and select individualized therapy.

Inflammatory response signature score model for predicting immunotherapy response and pan-cancer prognosis.

Background: Inflammatory responses influence the outcome of immunotherapy and tumorigenesis by modulating host immunity. However, systematic inflammatory response assessment models for predicting cancer immunotherapy (CIT) responses and survival across human cancers remain unexplored. Here, we investigated an inflammatory response score model to predict CIT responses and patient survival in a pan-cancer analysis. Methods: We retrieved 12 CIT response gene expression datasets from the Gene Expression Omnibus database (GSE78220, GSE19423, GSE100797, GSE126044, GSE35640, GSE67501, GSE115821 and GSE168204), Tumor Immune Dysfunction and Exclusion database (PRJEB23709, PRJEB25780 and phs000452.v2.p1), European Genome-phenome Archive database (EGAD00001005738), and IMvigor210 cohort. The tumor samples from six cancers types: metastatic urothelial cancer, metastatic melanoma, gastric cancer, primary bladder cancer, renal cell carcinoma, and non-small cell lung cancer.We further established a binary classification model to predict CIT responses using the least absolute shrinkage and selection operator (LASSO) computational algorithm. Findings: The model had high predictive accuracy in both the training and validation cohorts. During sub-group analysis, area under the curve (AUC) values of 0.82, 0.80, 0.71, 0.7, 0.67, and 0.64 were obtained for the non-small cell lung cancer, gastric cancer, metastatic urothelial cancer, primary bladder cancer, metastatic melanoma, and renal cell carcinoma cohorts, respectively. CIT response rates were higher in the high-scoring training cohort subjects (51%) than the low-scoring subjects (27%). The five-year survival rates in the high- and low score groups of the training cohorts were 62% and 21%, respectively, while those of the validation cohorts were 54% and 22%, respectively (P < 0·001 in all cases). Inflammatory response signature score derived from on-treatment tumor specimens are highly predictive of response to CIT in patients with metastatic melanoma. A significant correlation was observed between the inflammatory response scores and tumor purity. Regardless of the tumor purity, patients in the low score group had a significantly poorer prognosis than those in the high score group. Immune cell infiltration analysis indicated that in the high score cohort, tumor-infiltrating lymphocytes were significantly enriched, particularly effector and natural killer cells. Inflammatory response scores were positively correlated with immune checkpoint genes, suggesting that immune checkpoint inhibitors may have benefited patients with high scores. Analysis of signature scores across different cancer types from The Cancer Genome Atlas revealed that the prognostic performance of inflammatory response scores for survival in patients who have not undergone immunotherapy can be affected by tumor purity. Interleukin 21 (IL21) had the highest weight in the inflammatory response model, suggesting its vital role in the prediction mode. Since the number of metastatic melanoma patients (n = 429) was relatively large among CIT cohorts, we further performed a co-culture experiment using a melanoma cell line and CD8 + T cell populations generated from peripheral blood monocytes. The results showed that IL21 therapy combined with anti-PD1 (programmed cell death 1) antibodies (trepril monoclonal antibodies) significantly enhanced the cytotoxic activity of CD8 + T cells against the melanoma cell line. Conclusion: In this study, we developed an inflammatory response gene signature model that predicts patient survival and immunotherapy response in multiple malignancies. We further found that the predictive performance in the non-small cell lung cancer and gastric cancer group had the highest value among the six different malignancy subgroups. When compared with existing signatures, the inflammatory response gene signature scores for on-treatment samples were more robust predictors of the response to CIT in metastatic melanoma.

A Comprehensive Analysis of NRP1 in Malignancies Provide Therapeutic Implication for Treating Cancer Patients Infected with SARS-CoV-2.

COVID-19 (Coronavirus disease 2019) is caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2), which can lead to pneumonia, cytokine storms, and lymphopenia. Patients with cancer are more susceptible to SARS-CoV-2 infection and severe COVID-19 due to immunosuppression. Recent studies have indicated that NRP1 (Neuropilin 1) may act as a novel mediator of SARS-CoV-2 entry into the host cell. As no systematic review has been performed investigating the characteristics of NRP1 in pan-carcinoma, we comprehensively analyzed NRP1 in patients with pan-cancer. Using a bioinformatics approach, we aimed to systematically examine NRP1 expression profiles in both pan-carcinoma and healthy tissues. We found that lung and genitourinary cancers have a relatively higher NRP-1 expression than other cancer patients, suggesting that these patients may be more susceptible to SARS-CoV-2. Our analysis further revealed that NRP1 expression was downregulated in Vero E6 cells, whole blood, lung organoids, testis tissue, and alveolospheres infected with SARS-CoV-2. Notably, NRP1 was associated with immune cell infiltration, immune checkpoint genes, and immune-related genes in most patients with cancer. These findings suggest that, in patients with specific types of cancer, especially lung and genitourinary, high expression of NRP1 contributes to greater susceptibility to SARS-CoV-2 infection and an increased risk of damage due to cytokine storms. Overall, NRP1 appears to play a critical role in regulating immunological properties and metabolism in many tumor types. Specific inhibitors of the NRP1 antigen (pegaptanib, EG00229, or MNRP1685A) combined with other anti-SARS-CoV-2 strategies may aid in treating patients with lung and genitourinary cancers following SARS-CoV-2 infection.

Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial.

BACKGROUND: Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed. METHODS: Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR). RESULTS: A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49-0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors. CONCLUSIONS: Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients. TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.

A tumor-associated endothelial signature score model in immunotherapy and prognosis across pan-cancers.

Background: The tumor-associated endothelial cell (TAE) component plays a vital role in tumor immunity. However, systematic tumor-associated endothelial-related gene assessment models for predicting cancer immunotherapy (CIT) responses and survival across human cancers have not been explored. Herein, we investigated a TAE gene risk model to predict CIT responses and patient survival in a pan-cancer analysis. Methods: We analyzed publicly available datasets of tumor samples with gene expression and clinical information, including gastric cancer, metastatic urothelial cancer, metastatic melanoma, non-small cell lung cancer, primary bladder cancer, and renal cell carcinoma. We further established a binary classification model to predict CIT responses using the least absolute shrinkage and selection operator (LASSO) computational algorithm. Results: The model demonstrated a high predictive accuracy in both training and validation cohorts. The response rate of the high score group to immunotherapy in the training cohort was significantly higher than that of the low score group, with CIT response rates of 51% and 27%, respectively. The survival analysis showed that the prognosis of the high score group was significantly better than that of the low score group (all p < 0·001). Tumor-associated endothelial gene signature scores positively correlated with immune checkpoint genes, suggesting that immune checkpoint inhibitors may benefit patients in the high score group. The analysis of TAE scores across 33 human cancers revealed that the TAE model could reflect immune cell infiltration and predict the survival of cancer patients. Conclusion: The TAE signature model could represent a CIT response prediction model with a prognostic value in multiple cancer types.

Distinct selectivity inside self-assembled coordination cages.

Supramolecular containers have long been applied to regulate organic reactions with distinct selectivity, owing to their diverse functions such as the ability to pose a guest molecule(s) with a certain orientation and conformation. In this review, we try to illustrate how self-assembled coordination cages could achieve this goal. Two representative cage hosts, namely, self-assembled Pd(II)-ligand octahedral coordination cages ([Pd6L4]12+) and self-assembled Ga(III)-ligand tetrahedral coordination cages ([Ga4L6]12-) are selected as the pilot hosts that this mini review covers. Representative works in this area are presented here in brief.

TSC22D3 as an immune-related prognostic biomarker for acute myeloid leukemia.

Acute myeloid leukemia (AML) is the type of hematologic neoplasm most common in adults. Glucocorticoid-induced gene TSC22D3 regulates cell proliferation through its function as a transcription factor. However, there is no consensus on the prognostic and immunoregulatory significance of TSC22D3 in AML. In the present study, we evaluated the correlation between TSC22D3 expression, immunoinfiltration, and prognostic significance in AML. Knockdown of TSC22D3 significantly attenuated the proliferation of Hel cells and increased sensitivity to cytarabine (Ara-c) drugs. Furthermore, TSC22D3 reduced the release of interleukin-1ß (IL-1ß) by inhibiting the NF-κB/NLRP3 signaling pathway, thereby inhibiting macrophage polarization to M1 subtype, and attenuating the pro-inflammatory tumor microenvironment. In conclusion, this study identified TSC22D3 as an immune-related prognostic biomarker for AML patients and suggested that therapeutic targeting of TSC22D3 may be a potential treatment option for AML through tumor immune escape.

Development and Application of nanoPCR Method for Detection of Feline Panleukopenia Virus.

Feline panleukopenia (FP) is a severe viral illness caused by the feline panleukopenia virus (FPV), putting sectors like companion cat breeding and endangered feline conservation at risk. The virus has a high morbidity and fatality rate and is found all over the world. We created a novel FPV assay using nanoPCR technology and assessed the method's specificity and sensitivity. The approach amplified a 345 bp nucleic acid fragment with a minimum detection limit of 7.97 × 102 copies/µL, which is about 100 times greater than traditional PCR. We collected anal swabs from 83 cats suspected of FPV infection for practical application, and the FPV-positive rate determined by the nanoPCR approach was 77.1%. In conclusion, the approach is more sensitive than conventional PCR and more convenient and cost-effective than qPCR methodology and may be utilized for the clinical detection of FPV.

Promotion of axon regeneration and protection on injured retinal ganglion cells by rCXCL2.

BACKGROUND: In addition to rescuing injured retinal ganglion cells (RGCs) by stimulating the intrinsic growth ability of damaged RGCs in various retinal/optic neuropathies, increasing evidence has shown that the external microenvironmental factors also play a crucial role in restoring the survival of RGCs by promoting the regrowth of RGC axons, especially inflammatory factors. In this study, we aimed to screen out the underlying inflammatory factor involved in the signaling of staurosporine (STS)-induced axon regeneration and verify its role in the protection of RGCs and the promotion of axon regrowth. METHODS: We performed transcriptome RNA sequencing for STS induction models in vitro and analyzed the differentially expressed genes. After targeting the key gene, we verified the role of the candidate factor in RGC protection and promotion of axon regeneration in vivo with two RGC-injured animal models (optic nerve crush, ONC; retinal N-methyl-D-aspartate, NMDA damage) by using cholera toxin subunit B anterograde axon tracing and specific immunostaining of RGCs. RESULTS: We found that a series of inflammatory genes expressed upregulated in the signaling of STS-induced axon regrowth and we targeted the candidate CXCL2 gene since the level of the chemokine CXCL2 gene elevated significantly among the top upregulated genes. We further demonstrated that intravitreal injection of rCXCL2 robustly promoted axon regeneration and significantly improved RGC survival in ONC-injured mice in vivo. However, different from its role in ONC model, the intravitreal injection of rCXCL2 was able to simply protect RGCs against NMDA-induced excitotoxicity in mouse retina and maintain the long-distance projection of RGC axons, yet failed to promote significant axon regeneration. CONCLUSIONS: We provide the first in vivo evidence that CXCL2, as an inflammatory factor, is a key regulator in the axon regeneration and neuroprotection of RGCs. Our comparative study may facilitate deciphering the exact molecular mechanisms of RGC axon regeneration and developing high-potency targeted drugs.