Development and Validation of a Prediction Model for Thyroid Dysfunction in Patients During Immunotherapy.

OBJECTIVE: This study was designed to develop and validate a predictive model for assessing the risk of thyroid toxicity following treatment with immune checkpoint inhibitors. METHODS: A retrospective analysis was conducted on a cohort of 586 patients diagnosed with malignant tumors who received programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors. The patients were randomly divided into training and validation cohorts in a 7:3 ratio. Logistic regression analyses were performed on the training set to identify risk factors of thyroid dysfunction, and a nomogram was developed based on these findings. Internal validation was performed using K-fold cross-validation on the validation set. The performance of the nomogram was assessed in terms of discrimination and calibration. Additionally, decision curve analysis was utilized to demonstrate the decision efficiency of the model. RESULTS: Our clinical prediction model consisted of 4 independent predictors of thyroid immune-related adverse events, namely baseline thyrotropin (TSH, OR = 1.427, 95%CI:1.163-1.876), baseline thyroglobulin antibody (TgAb, OR = 1.105, 95%CI:1.035-1.180), baseline thyroid peroxidase antibody (TPOAb, OR = 1.172, 95%CI:1.110-1.237), and baseline platelet count (platelet, OR = 1.004, 95%CI:1.000-1.007). The developed nomogram achieved excellent discrimination with an area under the curve of 0.863 (95%CI: 0.817-0.909) and 0.885 (95%CI: 0.827-0.944) in the training and internal validation cohorts respectively. Calibration curves exhibited a good fit, and the decision curve indicated favorable clinical benefits. CONCLUSION: The proposed nomogram serves as an effective and intuitive tool for predicting the risk of thyroid immune-related adverse events, facilitating clinicians making individualized decisions based on patient-specific information.

Targeting m6A binding protein YTHDFs for cancer therapy.

N6-methyladenosine (m6A) is the most common mRNA modification in mammalians. The function and dynamic regulation of m6A depends on the "writer", "readers" and "erasers". YT521-B homology domain family (YTHDF) is a class of m6A binding proteins, including YTHDF1, YTHDF2 and YTHDF3. In recent years, the modification of m6A and the molecular mechanism of YTHDFs have been further understood. Growing evidence has shown that YTHDFs participate in multifarious bioprocesses, particularly tumorigenesis. In this review, we summarized the structural characteristics of YTHDFs, the regulation of mRNA by YTHDFs, the role of YTHDF proteins in human cancers and inhibition of YTHDFs.

Effect of boiling and drying process on chemical composition and antioxidant activity of Chaenomeles speciosa.

Chemical composition and antioxidant activity of fresh and boiled Chaenomeles speciosa (CS) slices dried by different drying methods were determined. Data were analyzed by principle component analysis and cluster analysis. All dried boiled CS from dried fresh CS slices form main cluster. The results also demonstrated that both drying methods, freeze drying and hot air drying at 60 °C had good potential in the industrial drying of fresh and boiled CS. Fresh CS dried by hot air drying at 60 °C was more suitable for the industrial production.

Generation and characterization of a human nanobody against VEGFR-2.

AIM: Nanobody is an antibody fragment consisting of a single monomeric variable antibody domain, which can be used for a variety of biotechnological and therapeutic purposes. The aim of this work was to isolate and characterize a human signal domain antibody against VEGFR-2 domain3 (VEGFR D3) from a phage display library. METHODS: To produce antigen-specific recombinant nanobodies with high affinity to VEGFR2 D3, a liquid phase panning strategy was used for all rounds of panning. For nanobody expression and purification, four VEGFR2 D3-blocking clones were subcloned into a pETduet-biotin-MBP expression vector. The recombinant proteins carried an MBP tag to facilitate purification by affinity chromatography. Recombinant NTV(1-4) was obtained after an additional gel filtration chromatography step. The interactions between VEGFR2 D3 and NTV(1-4) were assessed with luminescence-based AlphaScreen assay and SPR assay. Anti-angiogenesis effects were examined in human umbilical vein endothelial cells (HUVECs). RESULTS: In the AlphaScreen assay, NTV1 (100 and 200 nmol/L) elicited the highest binding signal with VEGFR2 D3; NTV2 showed moderate interactions with VEGFR2 D3; NTV3 and NTV4 exhibited little or no interaction with VEGFR2 D3. In the SPR assay, NTV1 displayed a high affinity for VEGFR2 D3 with an equilibrium dissociation constant (KD) of 49±1.8 nmol/L. NTV1 (1-1000 nmol/L) dose-dependently inhibited the proliferation of HUVECs and the endothelial tube formation by the HUVECs. CONCLUSION: The nanobody NTV1 is a potential therapeutic candidate for blocking VEGFR2. This study provides a novel and promising strategy for development of VEGFR2-targeted nanobody-based cancer therapeutics.

Protective effects of PARP inhibitor, PJ34, is related to down-regulation of calpain and NF-κB in a mouse model of TBI.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP), calpain and nuclear factor-κB (NF-κB) are reported to participate in inflammatory reactions in pathological conditions and are involved in traumatic brain injury. The objective of this study was to investigate whether PARP participated in inflammation related to calpain and NF-κB in a mouse model of controlled cortical impact (CCI). MATERIALS AND METHODS: PJ34 (10 mg kg-1), a selective PARP inhibitor, was administered intraperitoneally 5 minutes and 8 hours after experimental CCI. A neurobehavioural evaluation and a histopathological analysis were then performed and the contusion volume, calpain activity and protein levels were measured in all animals. RESULTS: Treatment with PJ34 markedly reduced neurological deficits, decreased contusion volume and attenuated necrotic and apoptotic neuronal cell death 24 hours after CCI. The data showed that the cytosolic and nuclear fractions of calpain and NF-κB were up-regulated in the injured cortex and that these changes were reversed by PJ34. Moreover, PJ34 significantly enhanced the calpastatin and IκB levels and decreased the levels of inflammatory mediators. CONCLUSIONS: PARP inhibition by PJ34 suppresses the over-activation of calpain and the production of inflammatory factors that are caused by NF-κB activation and it improves neurological functioning, decreases the contusion volume and attenuates neuronal cell death in a mouse model of CCI.

Risk factors of stroke in Western and Asian countries: a systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: There has been an increasing trend in the incidence of stroke worldwide in recent years, and the number of studies focusing on the risk factors for stroke has also increased every year. To comprehensively evaluate the risk factors of stroke identified in prospective Western and Asian cohort studies. METHODS: Population-based cohort studies on stroke were searched in databases (PubMed, EMBASE, Web of Science, Google Scholar, etc.), and the library of the Third Military Medical University was manually searched for relevant information. A meta-analysis of Western and Asian studies on risk factors was performed. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to assess the final group of cohort studies. RESULTS: After screening, 22 prospective cohort studies were included in the analyses of this investigation. Two factors, smoking and alcohol consumption, showed statistically significant differences between Western and Asian populations, and the results were as follows (W/A): 2.05 (95% CI, 1.68 ~ 2.49)/1.27 (95% CI, 1.04 ~ 1.55) and 0.89 (95% CI, 0.76 ~ 1.04)/1.28 (95% CI, 1.07 ~ 1.53). The factor BMI = 18.5-21.9 kg/m2 showed statistically significant differences only in Western populations, 0.96 (95% CI, 0.93 ~ 0.99); the factor SBP = 120-139 mm Hg showed statistically significant differences only in Asian populations, 2.29 (95% CI, 1.04 ~ 5.09). CONCLUSIONS: The prevalences of risk factors affect the stroke morbidity in Western and Asian populations, which may be biased by race. The meta-analysis of population-based studies suggests that different preventive measures should be adopted for Western and Asian population groups that are at high risk for stroke.

Identification of differently expressed genes and small molecule drugs for Tetralogy of Fallot by bioinformatics strategy.

This study aimed to screen out differentially expressed genes (DEGs) and explore small molecule drugs for Tetralogy of Fallot (TOF). The gene expression profile of TOF GSE26125 was downloaded from the Gene Expression Omnibus database, including 16 idiopathic TOF samples and five healthy controls. The DEGs were identified by the Limma package in R language and underwent functional enrichment analysis via Database for Annotation, Visualization and Integrated Discovery tools. A protein-protein interaction (PPI) network of DEGs was then constructed and the significant clusters were selected for functional analysis. In addition, the DEGs were mapped to the connectivity map (CMap) database to identify potential small-molecule drugs. As a result, a total of 499 DEGs were selected between TOF and healthy controls. Meanwhile, the functional changes of DEGs related to TOF were mainly associated with cellular respiration and energy metabolism. Furthermore, in the PPI network, two clusters were identified via cluster 1 analysis. And only cluster 1 was significantly enriched into gene ontology terms, including respiratory chain, electron transport chain, and oxidation reduction. The hub gene of cluster 1 was NDUFAB1. Additionally, small molecules, such as harmine, solanine, and testosterone, may have the potential to repair the disordered metabolic pathways of TOF.

Targeting bromodomian-containing protein 8 (BRD8): An advanced tool to interrogate BRD8.

Epigenetic modifications play crucial roles in physiological processes, including cell differentiation, proliferation, and death. Bromodomain/Brd-containing proteins (BCPs) regulate abnormal gene expression in various diseases by recognizing the lysine-ε-N-acetylated residues (KAc) or by acting as transcriptional co-activators. Small molecule inhibitors targeting BCPs offer an attractive strategy for modulating aberrant gene expression. Besides the extensive research on the bromodomain and extra-terminal (BET) domain family proteins, the non-BET proteins have gained increasing attention. Bromodomain containing protein 8 (BRD8), a reader of KAc and co-activator of nuclear receptors (NRs), plays a key role in various cancers. This review provides a comprehensive analysis of the structure, disease-related functions, and inhibitor development of BRD8. Opportunities and challenges for future studies targeting BRD8 in disease treatment are discussed.

Discovery of a brain-permeable bromodomain and extra terminal domain (BET) inhibitor with selectivity for BD1 for the treatment of multiple sclerosis.

Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease and lacks effective therapeutic agents. Dysregulation of transcription mediated by bromodomain and extra-terminal domain (BET) proteins containing two different bromodomains (BD1 and BD2) is an important factor in multiple diseases, including MS. Herein, we identified a series of BD1-biased inhibitors, in which compound 16 showed nanomolar potency for BD1 (Kd = 230 nM) and a 60-fold selectivity for BRD4 BD1 over BD2. The co-crystal structure of BRD4 BD1 with 16 indicated that the hydrogen bond interaction of 16 with BD1-specific Asp145 is important for BD1 selectivity. 16 showed favorable brain distribution in mice and PK properties in rats. 16 was able to inhibit microglia activation and had significant therapeutic effects on EAE mice including improvement of spinal cord inflammatory conditions and demyelination protection. Overall, these results suggest that brain-permeable BD1 inhibitors have the potential to be further investigated as therapeutic agents for MS.

Diagnostic performance of integrated whole-body 18F-FDG PET/MRI for detecting bone marrow involvement in indolent lymphoma: Comparison with 18F-FDG PET or MRI alone.

Purpose: To investigate the diagnostic performance of integrated whole-body 18F-FDG PET/MRI for detecting bone marrow involvement (BMI) in indolent lymphoma compared with 18F-FDG PET or MRI alone. Methods: Patients with treatment-naive indolent lymphoma who underwent integrated whole-body 18F-FDG PET/MRI and bone marrow biopsy (BMB) were prospectively enrolled. Agreement between PET, MRI, PET/MRI, BMB, and the reference standard was assessed using kappa statistics. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of each method were calculated. A receiver operating characteristic (ROC) curve was used to determine the area under the curve (AUC). AUCs of PET, MRI, PET/MRI, and BMB were compared using the DeLong test. Results: Fifty-five patients (24 males and 31 females; mean age: 51.1 ± 10.1 years) were included in this study. Of these 55 patients, 19 (34.5%) had BMI. Two patients were upstaged as extra bone marrow lesions were detected via PET/MRI. 97.1% (33/34) of participants were confirmed as BMB-negative in the PET-/MRI-group. PET/MRI (parallel test) and BMB showed excellent agreement with the reference standard (k = 0.843, 0.918), whereas PET and MRI showed moderate agreement (k = 0.554, 0.577). The sensitivity, specificity, accuracy, PPV, and NPV for identifying BMI in indolent lymphoma were 52.6%, 97.2%, 81.8%, 90.9%, and 79.5%, respectively, for PET; 63.2%, 91.7%, 81.8%, 80.0%, and 82.5%, respectively, for MRI; 89.5%, 100%, 96.4%, 100%, and 94.7%, respectively, for BMB; and 94.7%, 91.7%, 92.7%, 85.7%, and 97.1%, respectively, for PET/MRI (parallel test). According to ROC analysis, the AUCs of PET, MRI, BMB, and PET/MRI (parallel test) for detecting BMI in indolent lymphomas were 0.749, 0.774, 0.947, and 0.932, respectively. The DeLong test showed significant differences between the AUCs of PET/MRI (parallel test) and those of PET (P = 0.003) and MRI (P = 0.004). Regarding histologic subtypes, the diagnostic performance of PET/MRI for detecting BMI in small lymphocytic lymphoma was lower than that in follicular lymphoma, which was in turn lower than that in marginal zone lymphoma. Conclusion: Integrated whole-body 18F-FDG PET/MRI showed excellent sensitivity and accuracy for detecting BMI in indolent lymphoma compared with 18F-FDG PET or MRI alone, demonstrating that 18F-FDG PET/MRI is an optimal method and a reliable alternative to BMB. Trial registration: ClinicalTrials.gov (NCT05004961 and NCT05390632).

A novel prognostic index for diffuse large B-cell lymphoma combined baseline metabolic tumour volume with clinical and pathological risk factors.

OBJECTIVES: This study aimed to develop a novel prognostic index integrating baseline metabolic tumour volume (MTV) along with clinical and pathological parameters for diffuse large B-cell lymphoma (DLBCL). METHODS: This prospective trial enrolled 289 patients with newly diagnosed DLBCL. The predictive value of novel prognostic index was compared with Ann Arbor staging and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI). We used the concordance index (C-index) and a calibration curve to determine its predictive capacity. RESULTS: Multivariate analysis revealed high MTV (>191 cm 3 ), Ann Arbor stage (III-IV) and MYC/BCL2 double expression lymphoma (DEL) to be independently associated with inferior progression-free survival (PFS) and overall survival (OS). Ann Arbor stage and DEL could be stratified by MTV. Our index, combining MTV with Ann Arbor stage and DEL status, identified four prognostic groups: group 1 (no risk factors,), group 2 (one risk factor), group 3 (two risk factors), and group 4 (three risk factors). The 2-year PFS rates were 85.5, 73.9, 53.6, and 13.9%; 2-year OS rates were 94.6, 87.0, 67.5, and 24.2%, respectively. The C-index values of the novel index were 0.697 and 0.753 for PFS and OS prediction, which was superior to Ann Arbor stage and NCCN-IPI. CONCLUSION: The novel index including tumour burden and clinicopathological features may help predict outcome of DLBCL (clinicaltrials.gov identifier: NCT02928861).

A JAK tyrosine kinase and pseudokinase Co-inhibition strategy combines enhanced potency and on-demand activation.

Janus tyrosine kinase (JAK) inhibitors have been on the market for several years, but their use is limited by drug resistance and intolerable side effects. Herein, we propose a novel strategy of JAK tyrosine kinase (TK) and pseudokinase (PK) domain co-inhibition system to consolidate robust JAK inhibition and on-demand activation. A photoexcited prodrug PAT-SIL-TG-1&AT exhibits the synergy effects of TK-PK co-inhibition and enable the spatiotemporal control of JAK2 signaling. The hypoxia-activated prodrug HAT-SIL-TG-1&AT significantly inhibited HEL cells proliferation and downregulated phosphorylated STAT3/5 under hypoxic conditions. Importantly, HAT-SIL-TG-1&AT showed synergistic antitumor effects and selectively inhibited the JAK-STAT signaling in tumor tissues in vivo. This work demonstrates a viable solution to achieve superior JAK2 inhibition, and provides an inspiration for other kinases containing PK domain.

Discovery of 1H-Imidazo[4,5-b]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain.

Neuropathic pain (NP) is an intolerable pain syndrome that arises from continuous inflammation and excitability after nerve injury. Only a few NP therapeutics are currently available, and all of them do not provide adequate pain relief. Herein, we report the discovery of a selective and potent inhibitor of the bromodomain and extra-terminal (BET) proteins for reducing neuroinflammation and excitability to treat NP. Starting with the screening hit 1 from an in-house compound library, iterative optimization resulted in the potent BET inhibitor DDO-8926 with a unique binding mode and a novel chemical structure. DDO-8926 exhibits excellent BET selectivity and favorable drug-like properties. In mice with spared nerve injury, DDO-8926 significantly alleviated mechanical hypersensitivity by inhibiting pro-inflammatory cytokine expression and reducing excitability. Collectively, these results implicate that DDO-8926 is a promising agent for the treatment of NP.

Fibroblast Activation Protein and Glycolysis in Lymphoma Diagnosis: Comparison of 68Ga-FAPI PET/CT and 18F-FDG PET/CT.

Our objective was to compare the diagnostic performance of 68Ga-labeled fibroblast activation protein (FAP) inhibitor (FAPI) and 18F-labeled FDG PET/CT in diagnosing lymphomas and to characterize the influence of FAP and glycolytic markers on tracer uptake by involved lesions. Methods: Participants with different lymphoma subtypes who were prospectively recruited from May 2020 to December 2021 underwent 68Ga-FAPI and 18F-FDG PET/CT. Immunohistochemistry was performed to evaluate FAP, hexokinase 2, and glucose transporter 1 (GLUT1) expression, and the paired-samples t test and Wilcoxon signed-rank test were used to compare parameters. The correlation between the immunochemistry results and tracer uptake was determined by the Spearman rank correlation coefficient. Results: In total, 186 participants (median age, 52 y [interquartile range, 41-64 y]; 95 women) were included. Dual-tracer imaging produced 3 types of imaging profiles. 18F-FDG PET possessed a higher staging accuracy (98.4%) than 68Ga-FAPI PET (86.0%). In 5,980 lymphoma lesions, 18F-FDG PET/CT detected more nodal (4,624 vs. 2,196) and extranodal (1,304 vs. 845) lesions than 68Ga-FAPI PET/CT. Additionally, 52 68Ga-FAPI-positive/18F-FDG-negative lesions and 2,939 68Ga-FAPI-negative/18F-FDG-positive lesions were observed. In many lymphoma subtypes, semiquantitative evaluation revealed no significant differences in SUVmax or target-to-liver ratios between 68Ga-FAPI and 18F-FDG PET/CT (P > 0.05). Interestingly, GLUT1 and hexokinase 2 were overexpressed both in lymphoma cells and in the tumor microenvironment, whereas FAP was expressed only in stromal cells. FAP and GLUT1 expression correlated positively with 68Ga-FAPI SUVmax (r = 0.622, P = 0.001) and 18F-FDG SUVmax (r = 0.835, P < 0.001), respectively. Conclusion: 68Ga-FAPI PET/CT was inferior to 18F-FDG PET/CT in diagnosing lymphomas with low FAP expression. However, the former may supplement the latter and help reveal the molecular profile of lymphomas.

Characterizing Concomitant Follicular Lymphoma and Gastric Carcinoma Using 68Ga-FAPI-04 and 18F-FDG PET/CT.

ABSTRACT: We herein report a case involving a 67-year-old man with concomitant progressive follicular lymphoma and gastric carcinoma. Baseline 18F-FDG PET/CT showed high metabolic activity in multiple nodal stations and a thickened gastric antrum wall, whereas 68Ga-FAPI-04 PET/CT depicted very intense tracer uptake in the gastric lesion but mild uptake in the nodes. After the treatment, complete remission from lymphadenopathy was achieved, whereas the gastric lesion accumulated more radiotracers compared with baseline levels. Despite our incorrect initial assumption of B-cell transformation, molecular imaging was able to profile the characteristics of these 2 diseases.

Physicochemical characteristics and immunoregulatory activities of polysaccharides from five cultivars of Chrysanthemi Flos.

This study compared the physicochemical characteristics and immunomodulatory activities of chrysanthemums' polysaccharides (JPs) from five cultivars. Significant differences were found in the molecular weights, the ratios of monosaccharide compositions, and morphological properties. Polysaccharides of Gongju (GJP) had the lowest molecular weight populations and polysaccharides of Boju (BJP) had the highest. SEM showed that GJP and polysaccharides of Qiju had looser and uniform surface structures, which are beneficial for being developed into instant products. Immunoregulatory assay revealed that JPs enhanced the phagocytosis and proliferation of RAW264.7 cells without obvious cytotoxicity, and upregulated the release level of TNF-α, IFN-γ, and NO. Immune-enhancing activity correlated with their molecular weights, the contents of glucuronic acid and arabinose, and microstructure, which performed differently according to different cultivars. The results suggested that BJP and polysaccharides of Hangbaiju are more suitable to be developed as new functional foods for enhancing immunity, and provided a reference for selection based on the immunization requirements.

Diagnostic value of [68Ga]Ga-FAPI-04 in patients with colorectal cancer in comparison with [18F]F-FDG PET/CT.

Purpose: This study aimed to compare the diagnostic performance of [68Ga]Ga-FAPI-04 PET/CT and [18F]F-FDG PET/CT in primary and metastatic colorectal cancer (CRC) lesions. Methods: This single-center preliminary clinical study (NCT04750772) was conducted at the Peking University Cancer Hospital & Institute and included 61 participants with CRC who underwent sequential evaluation through PET/CT with [18F]F-FDG and [68Ga]Ga-FAPI-04. Their PET/CT images were analysed to quantify the uptake of the two tracers in the form of maximum standardised uptake (SUVmax) values and target-to-background ratio (TBR), which were then compared using Wilcoxon's signed-rank test. The final changes in the tumour-node-metastasis (TNM) stage of all participants were recorded. Results: Of all the participants, 21 were treatment naïve and 40 had been previously treated. In primary CRC lesions, the average TBRs of [68Ga]Ga-FAPI-04 and [18F]F-FDG were 13.3 ± 8.9 and 8.2 ± 6.5, respectively. The SUVmax of [68Ga]Ga-FAPI-04 in signet-ring/mucinous carcinomas (11.4 ± 4.9) was higher than that of [18F]F-FDG (7.9 ± 3.6) (P = 0.03). Both median SUVmax in peritoneal metastases and TBR in liver metastases of [68Ga]Ga-FAPI-04 were higher than those of [18F]F-FDG (5.2 vs. 3.8, P < 0.001; 3.7 vs. 1.9, P < 0.001, respectively). Compared with [18F]F-FDG PET/CT, clinical TNM staging based on [68Ga]Ga-FAPI-04 PET/CT led to upstaging and downstaging in 10 (16.4%) and 5 participants (8.2%), respectively. Therefore, the treatment options were changed in 13 participants (21.3%), including 9 with additional chemo/radiotherapy and/or surgery and others with avoidance or narrowed scope of surgery. Conclusion: [68Ga]Ga-FAPI-04 showed potential as a novel PET/CT tracer to detect lymph nodes and distant metastases, which improved CRC staging, thus prompting the optimisation or adjustment of treatment decisions.

Risk Assessment in Diffuse Large B-Cell Lymphoma by Combining Baseline Metabolic Tumor Volume and Peking Criteria When Evaluating Series 18F-Fluorodeoxyglucose Positron Emission Tomography Scans.

This study aimed to determine the predictive and prognostic value of baseline metabolic tumor volume (MTV) and the Peking criteria from serial positron emission tomography (PET) scans in diffuse large B-cell lymphoma, including 300 newly diagnosed patients who were prospectively treated with 2-4 cycles of standard first-line treatment (clinicaltrials.gov identifier: NCT02928861). PET/computed tomography (CT) examinations were performed at baseline, after two (PET-2) or four cycles (PET-4). PET during the interim was evaluated using Deauville 5-point scales (5-PS), ΔSUVmax criteria, and the Peking criteria which interpreted based on the maximum standard uptake of the liver (SUVmax-liver). Peking criteria had better accuracy, positive predictive value (PPV), and specificity than other two methods. The MTV and Peking criteria both significantly predicted progression-free survival (PFS) and overall survival (OS). An MTV > 191 cm2 and Peking criteria of PET-2 and PET-4 > 1.6-fold SUVmax-liver was used as the cutoff for a positive result. PET-4 achieved higher accuracy, PPV, and specificity for 2-year PFS (83.3%, 86.7%, and 98.4%, respectively) and OS (92.6%, 73.3%, and 97.2%, respectively) than PET-2. Various prognostic models containing different risk factors were established via Cox regression analysis. The MTV and PET-2/PET-4 results were used to categorized patients into low-risk, intermediate-risk, and high-risk prognostic groups (with 0, 1, and 2 risk factors, respectively) (P < 0.0001). High burden MTV and positive PET-2 and PET-4 (>1.6-fold SUVmax-liver) could identify high-risk patients with 2-year PFS and OS of 0.0% and 26.3% (95% confidence interval [CI]: N/A to 54.3%). When PET-2 and PET-4 were evaluated by 5-PS, the 2-year PFS and OS from high risk patients of three-parameters model achieved 31.4% (95%CI: 6.9%-55.9%) and 42.7% (95%CI: 14.6%-70.7%). In conclusion, combining baseline MTV and any regular response on PET/CT evaluated using the Peking criteria can improve prognostic value. Serial PET/CT from baseline MTV to PET-4 may have relatively greater predictive power for poor prognosis in diffuse large B-cell lymphoma. Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT02928861).

Discovery of 2-((2-methylbenzyl)thio)-6-oxo-4-(3,4,5-trimethoxyphenyl)-1,6-dihydropyrimidine-5-carbonitrile as a novel and effective bromodomain and extra-terminal (BET) inhibitor for the treatment of sepsis.

Sepsis has long been a major health problem worldwide. It threatens the lives of hospitalized patients and has been one of the leading causes of death in hospitalized patients over the past decades. BRD4 has been regarded as a potential target for sepsis therapy, for its critical role in the transcriptional expression of NF-κB pathway-dependent inflammatory factors. In this study, compound 1 was obtained through virtual screening, and candidate compound 27 was obtained through several rounds of iterative SAR analysis. 27 decreased LPS-induced NO production and expression of the pro-inflammatory factors IL-6, IL-1ß and TNF-α. In vivo, 27 effectively protected mice from LPS-induced sepsis, increased survival rate and decreased the level of pro-inflammatory factors in serum. Collectively, we reported here 27, a BRD4 inhibitor with a new scaffold, as a potential candidate for the treatment of sepsis.