Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study.

BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.

Up-front autologous stem cell transplant in peripheral T-cell lymphoma patients achieving complete response after first-line treatment: A multicentre real-world analysis.

We conducted a retrospective, multicentre study to compare consolidation therapy with or without first-line autologous stem cell transplant (ASCT) for peripheral T-cell lymphoma (PTCL) patients in a real-world setting. We enrolled 347 PTCL patients who achieved complete response after first-line treatment. Of these, 257 received consolidation chemotherapy (non-ASCT group) and 90 received ASCT (ASCT group). Clinical outcomes were comparable between ASCT and non-ASCT groups. After propensity score matching, the 2-year cumulative incidence of treatment-related mortality and relapse remained similar between groups (1.9% vs. 2.0%, p = 0.985; 24.7% vs. 47.1%, p = 0.021). However, significant differences emerged in progression-free survival and overall survival probabilities. Within the T-cell lymphoma subgroup, ASCT patients exhibited favourable outcomes compared to non-ASCT patients: 2-year progression-free survival (73.4% vs. 50.8%, p = 0.024) and overall survival (92.1% vs. 73.5%, p = 0.021). Notably, no significant differences were observed for patients with NK/T-cell lymphoma. These real-world data suggest that up-front ASCT is a safe and effective consolidation option for PTCL patients in remission, particularly those with T-cell lymphoma.

Precisely Constructing Renal-Clearable and LAP-Activatable Ratiometric Molecular Probes for Early Diagnosis of Acute and Chronic Kidney Injury Via Optimizing Asymmetric DPP Dyes.

Fluorescence analysis is an increasingly important contributor to the early diagnosis of kidney diseases. To achieve precise visualization of the kidneys and early diagnosis of related diseases, an asymmetric pyrrolopyrrolidone (DPP) dye platform with C-aromatic substituents and N-lipophilic/hydrophilic modification was constructed. Based on these, we developed the renal-clearable, water-soluble, and kidney injury biomarker leucine aminopeptidase (LAP) activated ratiometric fluorescent probe DPP-S-L. In the mouse model of cisplatin-induced acute kidney injury and during the development of type 2 diabetes to diabetic kidney disease, we visualized for the first time the upregulation of LAP in the kidney and urine by dual-channel ratiometric fluorescence signal and diagnosed the kidney injury earlier and more sensitively than blood/urine enzyme detection and tissue analysis. This study showcases an excellent asymmetric DPP dye platform and renal-clearable ratiometric fluorescent probe design strategy that is extended to determination and visualization of other biomarkers for early disease diagnosis.

Lysosome-targeted Aza-BODIPY photosensitizers for anti-cancer photodynamic therapy.

Developing effective near-infrared (NIR) photosensitizers (PSs) has been an attractive goal of photodynamic therapy (PDT) for cancer treatment. In this study, we synthesized N, N-diethylaminomethylphenyl-containing Aza-BODIPY photosensitizers and comprehensively investigated their photophysical/photochemical properties, as well as cell-based and animal-based anti-tumor studies. Among them, BDP 1 has strong NIR absorption at 680 nm and higher singlet oxygen yield in PBS which showed favorable pH-activatable and lysosome-targeting ability. BDP 1 could be easily taken up by tumor cells and showed negligible dark activity (IC50 > 50 µM), however strong phototoxicity upon exposure to light irradiation. The acceptable fluorescence emission from BDP 1 allowed convenient in vivo fluorescence imaging for organ distribution studies in mice. After PDT treatment with upon single time PDT treatment at the beginning using relatively low light dose (54 J/ cm2), BDP 1 (2 mg/kg, 0.1 mL) was found to have strong efficacy to inhibit tumor growth and even to ablate off tumor without causing body weight loss. Therefore, pH-activatable and lysosome-targeted PS may become an effective way to develop potent PDT agent.

Improving stroke prognosis by TLR4 KO to enhance N2 neutrophil infiltration and reduce M1 macrophage polarization.

Cerebral ischemic stroke remains a leading cause of mortality and morbidity worldwide. Toll-like receptor 4 (TLR4) has been implicated in neuroinflammatory responses poststroke, particularly in the infiltration of immune cells and polarization of macrophages. This study aimed to elucidate the impact of TLR4 deficiency on neutrophil infiltration and subsequent macrophage polarization after middle cerebral artery occlusion (MCAO), exploring its role in stroke prognosis. The objective was to investigate how TLR4 deficiency influences neutrophil behavior poststroke, its role in macrophage polarization, and its impact on stroke prognosis using murine models. Wild-type and TLR4-deficient adult male mice underwent MCAO induction, followed by various analyses, including flow cytometry to assess immune cell populations, bone marrow transplantation experiments to evaluate TLR4-deficient neutrophil behaviors, and enzyme-linked immunosorbent assay and Western blot analysis for cytokine and protein expression profiling. Neurobehavioral tests and infarct volume analysis were performed to assess the functional and anatomical prognosis poststroke. TLR4-deficient mice exhibited reduced infarct volumes, increased neutrophil infiltration, and reduced M1-type macrophage polarization post-MCAO compared to wild-type mice. Moreover, the depletion of neutrophils reversed the neuroprotective effects observed in TLR4-deficient mice, suggesting the involvement of neutrophils in mediating TLR4's protective role. Additionally, N1-type neutrophils were found to promote M1 macrophage polarization via neutrophil gelatinase-associated lipocalin (NGAL) secretion, a process blocked by TLR4 deficiency. The study underscores the protective role of TLR4 deficiency in ischemic stroke, delineating its association with increased N2-type neutrophil infiltration, diminished M1 macrophage polarization, and reduced neuroinflammatory responses. Understanding the interplay between TLR4, neutrophils, and macrophages sheds light on potential therapeutic targets for stroke management, highlighting TLR4 as a promising avenue for intervention in stroke-associated neuroinflammation and tissue damage.

Hematologic health services and practical characteristics: report of a nationwide survey among Chinese hematologists.

BACKGROUND: In the past 40 years, China has experienced tremendous economic development, but the current situation of hematologists has rarely been reported. A landscape survey of human resources is essential for healthcare development and policy formulation in the future. METHODS: The Chinese Society of Hematology initiated a survey of Chinese hematologists in mainland China for evaluating demographic and practice characteristics. Respondents were anonymous, and there were no limitations regarding their age, sex, etc. RESULTS: Totally 2032 hematologists responded, with a median age bracket of 36-45 years. Respondents were well engaged into subspecialties, and 28.1% acquired doctorates of philosophy. Hematopoietic cell transplantation (HCT) centers have been established all over China. Higher-GDP regions reported more advantages, including bigger scale of transplant centers (P < 0.001), younger age structure (P = 0.039), better education qualifications (P = 0.001) and less turnover intentions (P = 0.004), despite of increased risk of medical disputes (P = 0.028). Although females accounted for 65.5% of hematologists, males were older (P < 0.001), and had more senior professional titles (P < 0.001), academic positions (P < 0.001), opportunities for continuing education (P < 0.001), and paper publishing in the recent two years (P = 0.001). For turnover intention, the higher GDP regions led to an independently reduced risk (HR = 0.673, 95%CI [0.482-0.940], P = 0.020), whereas medical disputes resulted in an increased the risk (HR = 2.037, 95%CI [1.513-2.743], P < 0.001). Considering the impact of the COVID-19 pandemic, majority of respondents believed that the decline in patient visits and delay in treatment was within 30%. 67.9% of respondents reported a decrease of the use of bone marrow as grafts but 18.8% reported an increase of cord blood units. 35.0% of the respondents switched their daily work to support the anti-epidemic medical activities. CONCLUSIONS: We concluded the discipline of hematology in China has flourished in recent years with a young workforce, while regional economic and gender disparities warrant further continuous optimization. Joint efforts against the impact of COVID-19 are needed in the post-pandemic era.

Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial).

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

Quasi-LD-Targeted and ONOO--Responsive Fluorescent Probe for Investigating the Interaction of Nonalcoholic Fatty Liver with Drug-Induced Liver Injury.

Hepatic lipid droplets (LDs) and peroxynitrite (ONOO-) levels are closely related to nonalcoholic fatty liver disease (NAFLD). Additionally, some drug-induced liver injury (DILI) is often associated with ONOO-. Here, we constructed and screened the quasi-LDs-targeted and ONOO--responsive fluorescent probe MBDP-Py+ to investigate the interaction of NAFLD with DILI. By monitoring the upregulation of the ONOO- levels and the accumulation of LDs, MBDP-Py+ was more sensitive and efficient than tissue staining and serum markers detection in evaluating the early toxicity of NAFLD and diagnosing the anticancer-DILI. More importantly, the sensitive enhancement of fluorescence signals demonstrated that in different stages of NAFLD, the dominant element of liver injury was different in the NAFLD combined with DILI mice models. As the degree of NAFLD deepens, the synergistic effect of the two will lead to more serious liver damage.

Elevated serum IL-13 level is associated with increased Treg cells in tumor microenvironment and disease progression of diffuse large B-cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common aggressive lymphoid malignancy, with an immunosuppressive microenvironment affecting clinical outcome. Interleukin (IL)-13 overexpression is observed in multiple solid tumors and contributes to tumor progression. This study aims to investigate pretreatment serum IL-13 levels and their relationship with the prognosis of DLBCL patients. One hundred and sixty-six patients with newly diagnosed DLBCL from June 2015 to July 2017 were included. Patients with elevated pretreatment serum IL-13 levels (IL-13≥1.63 pg/ml) were classified into the high IL-13 group and they had significantly lower complete remission rate (60% vs. 74%, p = 0.0059), higher progression rate (43% vs. 23%, p = 0.0051), and poor progression-free survival (2-year PFS, 63% vs. 78%, p = 0.0078) and overall survival (2-year OS, 75% vs. 92%, p = 0.0027), when compared to those in the low IL-13 group (IL-13<1.63 pg/ml). Meanwhile, increased Treg cell ratio in peripheral blood (p = 0.0147) and elevated serum IL-2 levels (p = 0.0272) were observed in the high IL-13 group. Moreover, RNA sequencing data showed that patients in the high IL-13 group had significantly elevated expression of chemokines and chemokine receptors (CCR4, CCL19, CCL21, CXCL2) related to Treg activation and recruitment. Consistent with the chemokine profile, tumor immunophenotyping analysis revealed that higher Treg cells recruitment in the high IL-13 group than the low IL-13 group (p = 0.0116). In vitro, when lymphoma cells co-cultured with peripheral blood monocytes of healthy controls, metformin down-regulated both IL-13 level and Treg cell ratio, in consistent with the decreased serum IL-13 levels of patients after 6 months of metformin maintenance therapy in the high IL-13 group. Taken together, pretreatment serum IL-13 level is related to the immunosuppressive microenvironment and poor clinical outcome of DLBCL patients and could be targeted by metformin, thus providing a new therapeutic strategy in treating DLBCL with high serum IL-13 levels.

Assessment of Hidden Blood Loss in Spinal Metastasis Surgery: A Comprehensive Approach with MRI-Based Radiomics Models.

BACKGROUND: Patients undergoing surgery for spinal metastasis are predisposed to hidden blood loss (HBL), which is associated with poor surgical outcomes but unpredictable. PURPOSE: To evaluate the role of MRI-based radiomics models for assess the risk of HBL in patients undergoing spinal metastasis surgery. STUDY TYPE: Retrospective. SUBJECTS: 202 patients (42.6% female) operated on for spinal metastasis with a mean age of 58 ± 11 years were divided into a training (n = 162) and a validation cohort (n = 40). FIELD STRENGTH/SEQUENCE: 1.5T or 3.0T scanners. Sagittal T1-weighted and fat-suppressed T2-weighted imaging sequences. ASSESSMENT: HBL was calculated using the Gross formula. Patients were classified as low and high HBL group, with 1000 mL as the threshold. Radiomics models were constructed with radiomics features. The radiomics score (Radscore) was obtained from the optimal radiomics model. Clinical variables were accessed using univariate and multivariate logistic regression analyses. Independent risk variables were used to build a clinical model. Clinical variables combined with Radscore were used to establish a combined model. STATISTICAL TESTS: Predictive performance was evaluated using area under the curve (AUC), accuracy, sensitivity, specificity, and F1 score. Calibration curves and decision curves analyses were produced to evaluate the accuracy and clinical utility. RESULTS: Among the radiomics models, the fusion (T1WI + FS-T2WI) model demonstrated the highest predictive efficacy (AUC: 0.744, 95% confidence interval [CI]: 0.576-0.914). The Radscore model (AUC: 0.809, 95% CI: 0.664-0.954) performs slightly better than the clinical model (AUC: 0.721, 95% CI: 0.524-0.918; P = 0.418) and the combined model (AUC: 0.752, 95% CI: 0.593-0.911; P = 0.178). DATA CONCLUSION: A radiomics model may serve as a promising assessment tool for the risk of HBL in patients undergoing spinal metastasis surgery, and guide perioperative planning to improve surgical outcomes. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Multimodal deep learning model on interim [18F]FDG PET/CT for predicting primary treatment failure in diffuse large B-cell lymphoma.

OBJECTIVES: The prediction of primary treatment failure (PTF) is necessary for patients with diffuse large B-cell lymphoma (DLBCL) since it serves as a prominent means for improving front-line outcomes. Using interim 18F-fluoro-2-deoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) imaging data, we aimed to construct multimodal deep learning (MDL) models to predict possible PTF in low-risk DLBCL. METHODS: Initially, 205 DLBCL patients undergoing interim [18F]FDG PET/CT scans and the front-line standard of care were included in the primary dataset for model development. Then, 44 other patients were included in the external dataset for generalization evaluation. Based on the powerful backbone of the Conv-LSTM network, we incorporated five different multimodal fusion strategies (pixel intermixing, separate channel, separate branch, quantitative weighting, and hybrid learning) to make full use of PET/CT features and built five corresponding MDL models. Moreover, we found the best model, that is, the hybrid learning model, and optimized it by integrating the contrastive training objective to further improve its prediction performance. RESULTS: The final model with contrastive objective optimization, named the contrastive hybrid learning model, performed best, with an accuracy of 91.22% and an area under the receiver operating characteristic curve (AUC) of 0.926, in the primary dataset. In the external dataset, its accuracy and AUC remained at 88.64% and 0.925, respectively, indicating its good generalization ability. CONCLUSIONS: The proposed model achieved good performance, validated the predictive value of interim PET/CT, and holds promise for directing individualized clinical treatment. KEY POINTS: • The proposed multimodal models achieved accurate prediction of primary treatment failure in DLBCL patients. • Using an appropriate feature-level fusion strategy can make the same class close to each other regardless of the modal heterogeneity of the data source domain and positively impact the prediction performance. • Deep learning validated the predictive value of interim PET/CT in a way that exceeded human capabilities.

Predictive model based on DCE-MRI and clinical features for the evaluation of pain response after stereotactic body radiotherapy in patients with spinal metastases.

OBJECTIVE: To investigate the correlation of conventional MRI, DCE-MRI and clinical features with pain response after stereotactic body radiotherapy (SBRT) in patients with spinal metastases and establish a pain response prediction model. METHODS: Patients with spinal metastases who received SBRT in our hospital from July 2018 to April 2022 consecutively were enrolled. All patients underwent conventional MRI and DCE-MRI before treatment. Pain was assessed before treatment and in the third month after treatment, and the patients were divided into pain-response and no-pain-response groups. A multivariate logistic regression model was constructed to obtain the odds ratio and 95% confidence interval (CI) for each variable. C-index was used to evaluate the model's discrimination performance. RESULTS: Overall, 112 independent spinal lesions in 89 patients were included. There were 73 (65.2%) and 39 (34.8%) lesions in the pain-response and no-pain-response groups, respectively. Multivariate analysis showed that the number of treated lesions, pretreatment pain score, Karnofsky performance status score, Bilsky grade, and the DCE-MRI quantitative parameter Ktrans were independent predictors of post-SBRT pain response in patients with spinal metastases. The discrimination performance of the prediction model was good; the C index was 0.806 (95% CI: 0.721-0.891), and the corrected C-index was 0.754. CONCLUSION: Some imaging and clinical features correlated with post-SBRT pain response in patients with spinal metastases. The model based on these characteristics has a good predictive value and can provide valuable information for clinical decision-making. KEY POINTS: • SBRT can accurately irradiate spinal metastases with ablative doses. • Predicting the post-SBRT pain response has important clinical implications. • The prediction models established based on clinical and MRI features have good performance.

Feasibility of AI-assisted compressed sensing protocols in knee MR imaging: a prospective multi-reader study.

OBJECTIVES: To evaluate the image quality and diagnostic performance of AI-assisted compressed sensing (ACS) accelerated two-dimensional fast spin-echo MRI compared with standard parallel imaging (PI) in clinical 3.0T rapid knee scans. METHODS: This prospective study enrolled 130 consecutive participants between March and September 2022. The MRI scan procedure included one 8.0-min PI protocol and two ACS protocols (3.5 min and 2.0 min). Quantitative image quality assessments were performed by evaluating edge rise distance (ERD) and signal-to-noise ratio (SNR). Shapiro-Wilk tests were performed and investigated by the Friedman test and post hoc analyses. Three radiologists independently evaluated structural disorders for each participant. Fleiss κ analysis was used to compare inter-reader and inter-protocol agreements. The diagnostic performance of each protocol was investigated and compared by DeLong's test. The threshold for statistical significance was set at p  < 0.05. RESULTS: A total of 150 knee MRI examinations constituted the study cohort. For the quantitative assessment of four conventional sequences with ACS protocols, SNR improved significantly (p < 0.001), and ERD was significantly reduced or equivalent to the PI protocol. For the abnormality evaluated, the intraclass correlation coefficient ranged from moderate to substantial between readers (κ = 0.75-0.98) and between protocols (κ = 0.73-0.98). For meniscal tears, cruciate ligament tears, and cartilage defects, the diagnostic performance of ACS protocols was considered equivalent to PI protocol (Delong test, p > 0.05). CONCLUSIONS: Compared with the conventional PI acquisition, the novel ACS protocol demonstrated superior image quality and was feasible for achieving equivalent detection of structural abnormalities while reducing acquisition time by half. CLINICAL RELEVANCE STATEMENT: Artificial intelligence-assisted compressed sensing (ACS) providing excellent quality and a 75% reduction in scanning time presents significant clinical advantages in improving the efficiency and accessibility of knee MRI for more patients. KEY POINTS: • The prospective multi-reader study showed no difference in diagnostic performance between parallel imaging and AI-assisted compression sensing (ACS) was found. • Reduced scan time, sharper delineation, and less noise with ACS reconstruction. • Improved efficiency of the clinical knee MRI examination by the ACS acceleration.

Hydrogen peroxide enhanced photoinactivation of Candida albicans by a novel boron-dipyrromethene (BODIPY) derivative.

Photodynamic inactivation (PDI) has received increasing attention as a promising approach to combat Candida albicans infections. This study aimed to evaluate the synergistic effect of a new BODIPY (4,4-difluoro-boradiazaindacene) derivative and hydrogen peroxide on C. albicans. BDP-4L in combination with H2O2 demonstrated enhanced photokilling efficacy. In suspended cultures of C. albicans, the maximum decrease was 6.20 log and 2.56 log for PDI using BDP-4L (2.5 µM) with or without H2O2, respectively. For mature C. albicans biofilms, 20 µM BDP-4L plus H2O2 eradicated C. albicans, causing an over 6.7 log count reduction in biofilm-associated cells, while only a reduction of ~ 1 log count was observed when H2O2 was omitted. Scanning electron microscopy analysis and LIVE/DEAD assays suggested that PDI using BDP-4L plus H2O2 induced more damage to the cell membrane. Correspondingly, amplification of nucleic acids release was observed in biofilms treated with the combined PDI. Additionally, we also discovered that the addition of hydrogen peroxide potentiated the generation of 1O2 in PDI using the singlet oxygen sensor green probe. Collectively, BDP-4L combined with H2O2 presents a promising approach in the treatment of C. albicans infections.

Use of venous-venous extracorporeal membrane oxygenation in the treatment of postpartum pulmonary hypertension crisis.

The incidence of heart disease in pregnancy ranges from 0.5% to 3.0% and is regarded as one of the top three causes of maternal death. The mortality rate of patients with pulmonary hypertension and Eisenmenger syndrome is as high as 16.7%-50%. Changes in haemodynamics during pregnancy and childbirth increase the burden on the heart, and induced pulmonary hypertension crisis is one of the main causes of maternal death. Extracorporeal Membrane Oxygenation (ECMO) is the last-resort treatment strategy to treat patients with pulmonary hypertension crisis. We report a ventricular septal defect in a pregnant woman with pulmonary hypertension and Eisenmenger's syndrome, which is a postpartum pulmonary hypertension crisis that leads to respiratory and circulatory disorders. The patient was successfully treated with venous-venous extracorporeal membrane oxygenation.

Access to Pyridinyl or Pyridinium Aza-BODIPYs with Tunable Near-Infrared Fluorescence through ICT from 4-Pyridinyl Pyrroles.

Aza-dipyrromethene boron difluoride (Aza-BODIPY) dyes have attracted much interest in recent decades. In this manuscript, we provide a facile way to access pyridine-substituted pyrroles. A series of 1/7-pyridinyl and pyridinium near-infrared (NIR) Aza-BODIPYs with/without rigidity were constructed and their spectroscopic properties were extensively investigated. These pyridinyl Aza-BOIDIPYs displayed slight bathochromic shifts and maintained bright NIR emission. Pyridinium Aza-BODIPYs showed increased bathochromic shift, however, the molar extinction coefficients and fluorescence quantum yields were decreased owing to ICT effect. The impacts followed the order of pyridin-4-ium>pyridin-2-ium>pyridin-3-ium, which was in consistence with their ICT strength. MO calculation was performed to provide possible explanation to the red-shifted absorption/emission, and apparent charge separation in pyridin-4-ium Aza-BODIPYs. The pyridinium Aza-BODIPY localized in lysosome and potentially avoided harmful ''alkalinizing effects'' of traditional lysosome-targeting fluorescent dyes containing amine moiety. We are working on construction of pyridinyl and pyridinium Aza-BODIPY photosensitizers against microbials or tumors.

A genomic-augmented multivariate prognostic model for the survival of natural-killer/T-cell lymphoma patients from an international cohort.

With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural-killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next-generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk-features in International Prognostic Index (IPI), Prognostic Index for Natural-Killer cell lymphoma (PINK), and PINK-Epstein-Barr virus (PINK-E). Cox-proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression-free survival (PFS, HR: 3.73, 95% CI 2.07-6.73; p < .001) and overall survival (OS, HR: 5.23, 95% CI 2.57-10.65; p = .001) with known risk-features of these indices. When we assign an additional risk-score to samples, which are mutant for the GPM, the Harrell's C-indices of GPM-augmented IPI, PINK, and PINK-E improved significantly (p < .001, χ2 test) for both PFS and OS. Thus, we report on how genomic mutational information could steer toward better prognostication of NKTCL patients.

Water-soluble near-infrared fluorescent heptamethine dye for lymphatic mapping applications.

The identification of sentinel lymph node (SLN) is an important method for prognostic evaluation and minimally invasive staging of metastatic tumors. Here, we report a series of near-infrared fluorescent heptamethylamine dyes (series A, B and C) with central cycloalkene ring modified by tyrosine or N-Boc tyrosine via ether linkage. N-Boc tyrosine/tyrosine modification provided enhanced absorption coefficient and fluorescence quantum yield in DMSO, however with slight hypsochromic shift compared to the mother dyes in DMSO. In PBS, series A and B were found to be more fluorescent than ICG and showed brighter images. Compound A1 was found to exhibit the most favorable imaging performance among all the dyes investigated and was selected for in vivo sentinel lymph node mapping experiments in mice. A1 showed faster response and stronger fluorescence emission than FDA-approved ICG. The lymph node tracing with A1 could be assisted by MB staining. Ex vivo imaging of harvested organs indicated that similar metabolic characteristics of A1 and ICG. Overall, A1 is advantageous over ICG and is very promising for non-invasive lymph node imaging.

CytoTree: an R/Bioconductor package for analysis and visualization of flow and mass cytometry data.

BACKGROUND: The rapidly increasing dimensionality and throughput of flow and mass cytometry data necessitate new bioinformatics tools for analysis and interpretation, and the recently emerging single-cell-based algorithms provide a powerful strategy to meet this challenge. RESULTS: Here, we present CytoTree, an R/Bioconductor package designed to analyze and interpret multidimensional flow and mass cytometry data. CytoTree provides multiple computational functionalities that integrate most of the commonly used techniques in unsupervised clustering and dimensionality reduction and, more importantly, support the construction of a tree-shaped trajectory based on the minimum spanning tree algorithm. A graph-based algorithm is also implemented to estimate the pseudotime and infer intermediate-state cells. We apply CytoTree to several examples of mass cytometry and time-course flow cytometry data on heterogeneity-based cytology and differentiation/reprogramming experiments to illustrate the practical utility achieved in a fast and convenient manner. CONCLUSIONS: CytoTree represents a versatile tool for analyzing multidimensional flow and mass cytometry data and to producing heuristic results for trajectory construction and pseudotime estimation in an integrated workflow.

CircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/ß-catenin axis.

BACKGROUND: Epstein-Barr virus (EBV) represents an important pathogenic factor of lymphoma and is significantly associated with poor clinical outcome of diffuse large B-cell lymphoma (DLBCL). Circular RNAs (circRNAs) play an essential role in lymphoma progression. However, the underlying mechanism of circRNA on DLBCL progression related to EBV remains largely unknown. METHODS: CircRNA was screened by high-throughput sequencing in tumor samples of 12 patients with DLBCL according to EBV infection status. Expression of circEAF2, as well as the relationship with clinical characteristics and prognosis, were further analyzed in tumor samples of 100 DLBCL patients using quantitative real-time PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of circEAF2 both in vitro and in vivo. The underlying mechanism of circRNA on DLBCL progression were further determined by RNA sequencing, RNA pull down assay, dual-luciferase reporter assay, rescue experiments and western blotting. RESULTS: We identified a novel circRNA circEAF2, which was downregulated in EBV + DLBCL and negatively correlated with EBV infection and DLBCL progression. In EBV-positive B lymphoma cells, circEAF2 overexpression induced lymphoma cell apoptosis and sensitized lymphoma cells to epirubicin. As mechanism of action, circEAF2 specifically targeted EBV-encoded miR-BART19-3p, upregulated APC, and suppressed downstream ß-catenin expression, resulting in inactivation of Wnt signaling pathway and inhibition of EBV + DLBCL cell proliferation. In EBV-positive B-lymphoma murine models, xenografted tumors with circEAF2 overexpression presented decreased Ki-67 positivity, increased cell apoptosis and retarded tumor growth. CONCLUSIONS: CircEAF2 counteracted EBV + DLBCL progression via miR-BART19-3p/APC/ß-catenin axis, referring circEAF2 as a potential prognostic biomarker. Therapeutic targeting EBV-encoded miRNA may be a promising strategy in treating EBV-associated lymphoid malignancies.