First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-ß receptor I inhibitor, in patients with advanced solid tumors.

BACKGROUND: Transforming growth factor-ß (TGF-ß) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-ß pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-ß signal transduction, inhibits the progression and/or metastasis of advanced cancers. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of GFH018 monotherapy in patients with advanced solid tumors. METHODS: This phase I, open-label, multicenter study used a modified 3+3 dose escalation and expansion design. Adult patients with advanced solid tumors failing the standard of care were enrolled. Starting at 5 mg, eight dose levels up to 85 mg were evaluated. Patients received GFH018 BID (14d-on/14d-off) starting on the 4th day after a single dose on cycle 1, day 1. Subsequent cycles were defined as 28 days. The study also explored the safety of 85 mg BID 7d-on/7d-off. Adverse events were graded using NCI criteria for adverse events (NCI-CTCAE v5.0). PK was analyzed using a noncompartmental method. Efficacy was evaluated using RECIST 1.1. Blood samples were collected for biomarker analysis. RESULTS: Fifty patients were enrolled and received at least one dose of GFH018. No dose-limiting toxicity occurred, and the maximum tolerated dose was not reached. Forty-three patients (86.0%) had at least one treatment-related adverse event (TRAE), and three patients (6.0%) had ≥ G3 TRAEs. The most common TRAEs (any grade/grade ≥3) were AST increased (18%/0%), proteinuria (14%/2%), anemia (14%/2%), and ALT increased (12%/0%). No significant cardiotoxicity or bleeding was observed. GFH018 PK was linear and dose-independent, with a mean half-life of 2.25-8.60 h from 5 - 85 mg. Nine patients (18.0%) achieved stable disease, and one patient with thymic carcinoma achieved tumor shrinkage, with the maximum target lesion decreased by 18.4%. Serum TGF-ß1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off. CONCLUSIONS: GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies. TRIAL REGISTRATION: ClinicalTrial. gov ( https://www. CLINICALTRIALS: gov/ ), NCT05051241. Registered on 2021-09-02.

Low-level photodynamic therapy in chronic wounds.

BACKGROUND: Chronic wounds refer to those that can't reconstruct anatomical and physical functional integrity, and are usually associated with signs of microbial infection. Current therapies include debridement and dressing change, local or systemic application of antibiotics, and medical dressing care, which are not ideal for the healing of chronic wounds. OBJECTIVE: To explore the efficacy and safety of photodynamic therapy (ALA-PDT) for the treatment of chronic infectious wounds. MATERIALS AND METHODS: ALA-PDT was used in ten patients with persistent wound infections and systemic complications who did not respond to conventional treatment. 5 % ALA solution was applied to the wound surface after debridement, incubated for 3 h with light protection, and then irradiated with red light for 20 min. This procedure was repeated every two weeks, and any adverse reactions were recorded. After the end of three treatments, the patients were followed up for 3 months. RESULTS: Patients who exhibit resistance to traditional therapies demonstrate a favorable therapeutic outcome with ALA-PDT, although complications may impede wound healing. All participants successfully underwent ALA-PDT treatment and subsequent monitoring, with 90 % achieving complete healing. Common adverse reactions to ALA-PDT encompass treatment-related pain, temporary erythema, and swelling, all of which are well-tolerated by patients without enduring severe consequences. CONCLUSIONS: ALA-PDT proves to be an efficacious intervention for managing chronic wounds, irrespective of the presence of localized infections or systemic complications.

Targeting PRMT9-mediated arginine methylation suppresses cancer stem cell maintenance and elicits cGAS-mediated anticancer immunity.

Current anticancer therapies cannot eliminate all cancer cells, which hijack normal arginine methylation as a means to promote their maintenance via unknown mechanisms. Here we show that targeting protein arginine N-methyltransferase 9 (PRMT9), whose activities are elevated in blasts and leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic type I interferon (IFN)-associated immunity. PRMT9 ablation in AML cells decreased the arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cyclic GMP-AMP synthase, which underlies the type I IFN response. Genetically activating cyclic GMP-AMP synthase in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-programmed cell death protein 1 in eradicating AML. Overall, we conclude that PRMT9 functions in survival and immune evasion of both LSCs and non-LSCs; targeting PRMT9 may represent a potential anticancer strategy.

Multi-centers experience using therapeutic plasma exchange for corticosteroid/tocilizumab-refractory cytokine release syndrome following CAR-T therapy.

The chimeric antigen receptor T (CAR-T) cell therapy significantly enhances the prognosis of various hematologic malignancies; however, the systemic expansion of CAR-T cells also gives rise to severe cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Despite the successful application of corticosteroids and tocilizumab in alleviating severe CRS in most patients, there are still individuals who experience life-threatening CRS without responding to the aforementioned therapies. In our retrospective cohort, we conducted an analysis of clinical and laboratory parameters, including inflammatory cytokines, in 17 patients from three centers who underwent therapeutic plasma exchange (TPE) for refractory CRS with or without ICANS following CAR-T products treatment. Our findings demonstrate a significant improvement in both clinical symptoms and laboratory parameters subsequent to TPE treatment. The rapid decrease in temperature and levels of inflammatory indexes indicates the remarkable scavenging efficacy of TPE against cytokine storm following CAR-T therapy. In conclusion, TPE may serve as a valuable and safe adjunct to corticosteroids and tocilizumab in the management of severe CRS resulting from CAR-T cell infusion. We eagerly await further prospective studies to validate this finding.

Association of frailty with mortality in cancer survivors: results from NHANES 1999-2018.

Cancer survivors are vulnerable to frailty. While few studies have focused on the association of frailty with mortality risk among cancer survivors, the current study aimed to reveal this association. In this cohort study, 4723 cancer survivors were enrolled from the National Health and Nutrition Examination Surveys (NHANES, 1999-2018). Frailty status was quantified using the 53-item frailty index. Death outcomes were linked to National Death Index mortality data (as of December 31, 2019). Cox proportional hazard models were used to estimate HRs (95% CIs). The median (IQR) frailty score was 0.190 (0.132, 0.277). During the median follow-up of 6.7 years, 1775 all-cause deaths (including 581 cancer deaths and 385 cardiac deaths) were documented. Compared to the lowest tertile of frailty scores, the adjusted HRs (95% CIs) for the highest tertile were 2.698 (2.224, 3.272) for all-cause mortality (P trend < 0.001), 2.145 (1.547, 2.973) for cancer mortality (P trend < 0.001), and 3.735 (2.231, 6.251) for cardiac mortality (P trend < 0.001). Moreover, a positive dose‒response association between the frailty score and mortality risk was determined. Each per-unit increase in the frailty score (natural logarithm transformed) was found to increase all-cause mortality by 159% (P < 0.001), cancer mortality by 103% (P < 0.001), and cardiac mortality by 256% (P < 0.001). A consistent result was shown when stratifying by age, sex, race, body mass index, and type of cancer. This study suggested that the frailty index was positively associated with all-cause mortality and cause-specific mortality (including cancer and cardiac deaths) among cancer survivors.

A large-scale microRNA transcriptome-wide association study identifies two susceptibility microRNAs, miR-1307-5p and miR-192-3p, for colorectal cancer risk.

Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting miRNA expression. We applied these models and data from genome-wide association studies (GWAS) including 23 942 cases and 217 267 controls of East Asian ancestry to investigate associations of predicted miRNA expression with CRC risk. Perturbation experiments separately by promoting and inhibiting miRNAs expressions and further in vitro assays in both SW480 and HCT116 cells were conducted. At a Bonferroni-corrected threshold of P < 4.5 × 10-4, we identified two putative susceptibility miRNAs, miR-1307-5p and miR-192-3p, located in regions more than 500 kb away from any GWAS-identified risk variants in CRC. We observed that a high predicted expression of miR-1307-5p was associated with increased CRC risk, while a low predicted expression of miR-192-3p was associated with increased CRC risk. Our experimental results further provide strong evidence of their susceptible roles by showing that miR-1307-5p and miR-192-3p play a regulatory role, respectively, in promoting and inhibiting CRC cell proliferation, migration, and invasion, which was consistently observed in both SW480 and HCT116 cells. Our study provides additional insights into the biological mechanisms underlying CRC development.

Autophagy in colitis-associated colon cancer: exploring its potential role in reducing initiation and preventing IBD-Related CAC development.

ABBREVIATIONS: A. muciniphila: Akkermansia muciniphila; AIEC: adherent invasive Escherichia coli; AOM/DSS: azoxymethane-dextran sodium sulfate; ATG: autophagy related; BECN1: beclin1, autophagy related; CAC: colitis-associated colon cancer; CCDC50: coiled-coil domain containing 50; CLDN2: claudin 2; CoPEC: colibactin-producing Escherichia coli; CRC: colorectal cancer; DAMPs: danger/damage-associated molecular patterns; DC: dendritic cell; DSS: dextran sulfate sodium; DTP: drug-resistant persistent; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; IKK: IkappaB kinase; IL: interleukin; IRGM1: immunity-related GTPase family M member 1; ISC: intestinal stem cell; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MDP: muramyl dipeptide; MELK: maternal embryonic leucine zipper kinase; MHC: major histocompatibility complex; miRNA: microRNA; MTOR: mechanistic target of rapamycin kinase; NLRP3: NLR family, pyrin domain containing 3; NOD2: nucleotide-binding oligomerization domain containing 2; NRBF2: nuclear receptor binding factor 2; PAMPs: pathogen-associated molecular patterns; PI3K: class I phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PYCARD/ASC: PYD and CARD domain containing; RALGAPA2/RalGAPα2: Ral GTPase activating protein protein, alpha subunit 2 (catalytic); RIPK2/CARD3: receptor (TNFRSF)-interacting serine-threonine kinase 2; RIPK3: receptor-interacting serine-threonine kinase 3; ROS: reactive oxygen species; sCRC: sporadic colorectal cancer; SMARCA4/BRG1: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; TNF/TNFA: tumor necrosis factor; ULK1: unc-51 like autophagy activating kinase 1; UPR: unfolded protein response; WT: wild-type.

Post-transcriptional regulation of myeloid cell-mediated inflammatory responses.

Myeloid cells, particularly macrophages, act as the frontline responders to infectious agents and initiate inflammation. While the molecular mechanisms driving inflammatory responses have primarily focused on pattern recognition by myeloid cells and subsequent transcriptional events, it is crucial to note that post-transcriptional regulation plays a pivotal role in this process. In addition to the transcriptional regulation of innate immune responses, additional layers of intricate network of post-transcriptional mechanisms critically determine the quantity and duration of key inflammatory products and thus the outcome of immune responses. A multitude of mechanisms governing post-transcriptional regulation in innate immunity have been uncovered, encompassing RNA alternative splicing, mRNA stability, and translational regulation. This review encapsulates the current insights into the post-transcriptional regulation of inflammatory genes within myeloid cells, with particular emphasis on translational regulation during inflammation. While acknowledging the advancements, we also shed light on the existing gaps in immunological research pertaining to post-transcriptional levels and propose perspectives that controlling post-transcriptional process may serve as potential targets for therapeutic interventions in inflammatory diseases.

Outcomes and risk factors of SARS-CoV-2 omicron variant in B-cell lymphoma patients following CD19 targeted CAR-T therapy.

BACKGROUND: Little was known on infection and mortality rates, still less the risk factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant in B-cell lymphoma patients following CD19 targeted chimeric antigen receptor T cell (CAR-T). AIMS: We performed a retrospective multicenter study and analyzed the details of relapsed/refractory (R/R) B-cell lymphoma patients who received CD19 targeted CAR-T heretofore in five cellular immunotherapy centers in China during the omicron wave. MATERIALS & METHODS: One hundred fifty-four patients were enrolled in this study. RESULTS: Among them, 52 patients (33.8%) were uninfected, 74 patients (48.1) had ambulatory mild disease (including nine patients of asymptomatic infection), 22 patients (14.3%) had moderate disease and six patients (3.9%) had severe disease when data collected up. Three patients with severe disease died from COVID-19, the death rate was 1.9% for all enrolled patients, and 2.9% for infected patients. We also found that patients over 60 years old or with diabetes mellitus (DM) tend to develop severe disease (p = 0.0057 and p = 0.0497, respectively). Patients had CAR-T infusion within 6 months also tend to have severe disease (p = 0.0011). In multivariate logistic regression model, CAR-T infusion within 6 months (relative risk (RR) 40.92; confidence interval (CI) 4.03-415.89; p = 0.002) were associated with significantly higher risk of severe disease. CONCLUSION: Through this study, we conclude that the outcome for B-cell lymphoma patients following CD19 targeted CAR-T therapy when facing omicron infection was improved, but aggressive precautionary measures were particularly crucial for patients with high risk factors.

Long-term complete remission and peripheral biomarkers in Hodgkin lymphoma patients after decitabine-plus-camrelizumab epi-immunotherapy and treatment cessation.

Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine-plus-camrelizumab therapy, while long-term outcome especially after treatment discontinuation remains unclear. We present a retrospective analysis of 87 relapsed/refractory cHL patients who acquired CR after decitabine-plus-camrelizumab. Patients were divided into two groups and received consolidation treatment every 3-4 or 6-12 weeks, and 1-year of continuous CR was guaranteed for treatment cessation. At a median follow-up of 5.3 years, the median relapse-free survival (RFS) after achieving CR with decitabine-plus-camrelizumab therapy was 4.5 years, and patients underwent consolidation per 3-4 weeks might have longer RFS. The baseline percentage of peripheral central memory T cells was not associated with RFS, while patients with higher pretreatment serum levels of interleukin-6 (IL-6) and lactate dehydrogenase (LDH) had significantly shorter RFS and increased risk for disease recurrence. Fifty-seven patients completed and discontinued decitabine-plus-camrelizumab, and their median RFS had not been reached. The 2-year RFS rate after treatment cessation was 78% (95% CI, 67-90%). Patients in the high-risk subgroup with higher pretreatment IL-6 and LDH levels showed poor treatment-free remission. Moreover, decitabine-plus-camrelizumab therapy was safe and cost-effective. In conclusion, patients who obtained CR with decitabine-plus-camrelizumab and received consolidation per 3-4 weeks can achieve long-term remission after treatment discontinuation.

Characteristics of premanufacture CD8+T cells determine CAR-T efficacy in patients with diffuse large B-cell lymphoma.

Although chimeric antigen receptor (CAR) T cells have become an important treatment option for patients with relapsed/refractory B-cell malignancies, more than 60% of patients with diffuse large B-cell lymphoma (DLBCL) treated with CAR-T cell therapies fail to achieve a durable response. To reveal changes in CAR-T cell therapy and identify response biomarkers, we conducted a retrospective analysis of pre-manufacture source T cells and CAR-T cell products and their association with outcome in 58 patients with r/rDLBCL who received tandem CD19/CD20 CAR-T cell therapy. We performed bulk RNA-Seq, single-cell RNA-Seq, and paired T cell receptor sequencing on CAR-T cell products and pre-manufacture T cells from DLBCL patients. We note that a CD8+ stem cell-like memory T cell population with a higher proportion and enhanced activating capacity of the CAR-T cell products was key to achieving durable clinical response. By analysing autologously-derived, pre-manufacture T cells, our data suggest that heterogeneity in the cellular and molecular features of pre-manufacture T cells contribute to the variation in efficacy after CAR-T cell therapy in DLBCL. The differences in anti-tumour efficacy of CAR-T cells among patients with different clinical outcomes appear to be due to the loss of CCR7 gene expression, coupled with increased expression of activation- and inhibitor-related genes in the CD8+ naïve-T cell populations among the apheresis T cells from patients with a poor molecular response. These findings significantly advance our understanding of the underlying molecular determinants of pre-manufacture T cell function.

Construction of a predictive model for osteoporosis risk in men: using the IOF 1-min osteoporosis test.

OBJECTIVE: To construct a clinical prediction nomogram model using the 1-min IOF osteoporosis risk test as an evaluation tool for male osteoporosis. METHODS: The 1-min test results and the incidence of osteoporosis were collected from 354 patients in the osteoporotic clinic of our hospital. LASSO regression model and multi-factor logistic regression were used to analyze the risk factors of osteoporosis in patients, and the risk prediction model of osteoporosis was established. Verify with an additional 140 objects. RESULTS: We used logistic regression to construct a nomogram model. According to the model, the AUC value of the training set was 0.760 (0.704-0.817). The validation set has an AUC value of 0.806 (0.733-0.879). The test set AUC value is 0.714 (0.609-0.818). The calibration curve shows that its advantage is that the deviation correction curve of the nomogram model can maintain a good consistency with the ideal curve. In terms of clinical applicability, compared with the "total intervention" and "no intervention" schemes, the clinical net return rate of the nomogram model showed certain advantages. CONCLUSION: Using the 1-min osteoporosis risk test provided by IOF, we built a male osteoporosis risk prediction model with good prediction effect, which can provide greater reference and help for clinicians.

IL-6 translation is a therapeutic target of human cytokine release syndrome.

Chimeric antigen receptor (CAR) T therapies have achieved remarkable success for treating hematologic malignancies, yet are often accompanied by severe cytokine release syndrome (CRS). Here, an accidental clinical observation raised the possibility that metoprolol, an FDA-approved ß1 adrenergic receptor blocker widely used for cardiovascular conditions, may alleviate CAR T-induced CRS. Metoprolol effectively blocked IL-6 production in human monocytes through unexpected mechanisms of action of targeting IL-6 protein translation but not IL6 mRNA expression. Mechanistically, metoprolol diminished IL-6 protein synthesis via attenuating eEF2K-eEF2 axis-regulated translation elongation. Furthermore, an investigator-initiated phase I/II clinical trial demonstrated a favorable safety profile of metoprolol in CRS management and showed that metoprolol significantly alleviated CAR T-induced CRS without compromising CAR T efficacy. These results repurposed metoprolol, a WHO essential drug, as a potential therapeutic for CRS and implicated IL-6 translation as a mechanistic target of metoprolol, opening venues for protein translation-oriented drug developments for human inflammatory diseases.

Integrated Analysis Identifies DPP7 as a Prognostic Biomarker in Colorectal Cancer.

Colorectal cancer has a poor prognosis and is prone to recurrence and metastasis. DPP7, a prolyl peptidase, is reported to regulate lymphocyte quiescence. However, the correlation of DPP7 with prognosis in CRC remains unclear. With publicly available cohorts, the Wilcoxon rank-sum test and logistic regression were employed to analyze the relationship between DPP7 expression and the clinicopathological features of CRC patients. Specific pathways of differentially expressed genes were determined through biofunctional analysis and gene set enrichment analysis (GSEA). qPCR and immunohistochemical staining were used to determine DPP7 expression levels in surgical specimens. The public dataset and analysis of the biospecimens of CRC patients revealed that DPP7, in the CRC samples, was expressed significantly higher than in non-tumor tissues. Moreover, increased DPP7 was significantly associated with a higher N stage, lymphatic invasion, and shorter overall survival. Functionally, DPP7 is involved in neuroactive ligand-receptor interaction and olfactory transduction signaling. We identified a series of targeted drugs and small-molecule drugs with responses to DPP7. To conclude, DPP7 is a valuable diagnostic and prognostic biomarker for CRC and considered as a new therapeutic target.

Intelligent biogenic pH-sensitive and amine-responsive color-changing label for real-time monitoring of shrimp freshness.

BACKGROUND: This study developed an intelligent, pH-sensitive and amine-responsive colorimetric label based on chitosan, whey protein and thymol blue by controlling the pH value of the film-forming solution. The obtained label was used to monitor shrimp freshness in real time. The results of this study offer a new approach for developing highly intelligent biogenic labels for freshness monitoring during seafood preservation and processing. RESULTS: The pH 2.0 chitosan-whey protein-thymol blue (CWT-pH 2.0) label exhibited remarkable properties, including the highest tensile strength (5.90 MPa), excellent thermal stability, low water solubility (27.80%) and highly sensitive color responsiveness. The characterization techniques of scanning electron microscopy, X-ray diffraction and Fourier transform infrared spectroscopy confirmed the effective immobilization of thymol blue within the film-forming matrix through hydrogen bonding. Furthermore, the CWT-pH 2.0 label demonstrated visible color changes in the presence of volatile ammonia concentrations ranging from 25 to 25 000 ppm. Consequently, the label successfully facilitated real-time monitoring of shrimp freshness during storage at 4 °C. Importantly, the release rate of thymol blue from the label in food simulants was minimal, measuring only 2.53%. CONCLUSION: The CWT-pH 2.0 label exhibits significant potential as a highly intelligent biogenic label for freshness monitoring in seafood preservation and processing. © 2023 Society of Chemical Industry.

Efficacy and safety of PD­1 inhibitor plus antiangiogenic treatment in patients with unresectable biliary tract cancer: A multicenter retrospective study.

Immunotherapy and antiangiogenic therapy have shown promising clinical activity in patients with advanced biliary tract cancer (BTC) in clinical trials. As the combination of these two treatments for BTC is not well studied in the real world, the present study retrospectively analyzed the clinical outcomes of patients with unresectable BTC who received immunotherapy-antiangiogenesis combination therapy in a real-world setting. A three-center, retrospective study was performed on patients with unresectable BTC who received a combination of programmed death 1 inhibitor and antiangiogenic agent between March 26, 2019 and November 1, 2021 in China. In total, 68 patients were enrolled in the cohort. The objective response rate and disease control rate were 13.2 and 75.0%, respectively. The median time to progression, progression-free survival and overall survival were 8.2, 5.5 and 10.7 months, respectively. Adverse events of all grades occurred in 58 patients (85.3%). In conclusion, the present study demonstrated that immunotherapy-antiangiogenesis combination therapy may be considered a therapeutic option for patients with unresectable BTC. Further prospective investigations are needed.