Is the CRAFITY score a superior predictor of prognosis and adverse events in hepatocellular carcinoma patients treated with locoregional-immunotherapy?

BACKGROUND: The level of C­reactive protein (CRP) and alpha­fetoprotein (AFP) in immunotherapy (CRAFITY) score was associated with the prognosis of hepatocellular carcinoma (HCC) patients treated with immunotherapy. Based on the CRAFITY score, this study aimed to investigate the efficacy and safety of locoregional-immunotherapy for treating HCC patients. METHODS: HCC patients who received locoregional-immunotherapy were consecutively recruited at Sun Yat-sen University Cancer Center in 2019. CRAFITY 0 score was defined as the AFP level below 100 ng/ml and a CRP level of less than 1 mg/dl, CRAFITY 1 score was defined as the AFP level of at least 100 ng/ml or the CRP level of at least 1 mg/dl, and CRAFITY 2 score was defined as both the AFP level over 100 ng/ml and the CRP level of more than 1 mg/dl. The primary outcomes were progression-free survival (PFS) and overall survival (OS). The second outcomes were tumor response rate and treatment-related adverse events (AEs). RESULTS: The median PFS for HCC patients with the CRAFITY 0 score was not estimable. The PFS was 11.0 months [95% confidence interval (CI) 7.2-14.9] and 6.0 months (95% CI 4.2-7.8) for patients with CRAFITY 1 and 2 scores, respectively, with a significant difference between the two groups (p < 0.001). HCC patients with CRAFITY 0, 1, and 2 scores had 3 years OS rates of 63.8%, 60.8%, and 32.1%, respectively, with statistical differences among the three groups (p < 0.001). Patients with the CRAFITY 2 score were more likely to experience fever than those with other scores (p < 0.05). A greater CRAFITY score was correlated with a higher incidence of grade 3 and above liver injury (p < 0.01). CONCLUSIONS: The CRAFITY score is a superior predictor of prognosis and treatment-related AEs in HCC patients treated with locoregional-immunotherapy.

On High-Dimensional Covariate Adjustment for Estimating Causal Effects in Randomized Trials with Survival Outcomes.

The purpose of this work is to improve the efficiency in estimating the average causal effect (ACE) on the survival scale where right-censoring exists and high-dimensional covariate information is available. We propose new estimators using regularized survival regression and survival Random Forest (RF) to adjust for the high-dimensional covariate to improve efficiency. We study the behavior of the adjusted estimators under mild assumptions and show theoretical guarantees that the proposed estimators are more efficient than the unadjusted ones asymptotically when using RF for the adjustment. In addition, these adjusted estimators are n - consistent and asymptotically normally distributed. The finite sample behavior of our methods is studied by simulation. The simulation results are in agreement with the theoretical results. We also illustrate our methods by analyzing the real data from transplant research to identify the relative effectiveness of identical sibling donors compared to unrelated donors with the adjustment of cytogenetic abnormalities.

GBP5 Identifies Immuno-Hot Tumors and Predicts the Therapeutic Response to Immunotherapy in NSCLC.

Background: Immunotherapy drugs, immune checkpoint inhibitors (ICIs), have been approved for first- and second-line treatment of non-small cell lung cancer (NSCLC), but only a portion of patients respond to ICIs. It is crucial to screen the beneficiaries of immunotherapy through biomarkers accurately. Methods: Several datasets were used to explore the predictive value for immunotherapy and immune relevance of guanylate binding protein 5 (GBP5) in NSCLC, including the GSE126044 dataset, The Cancer Genome Atlas (TCGA) dataset, Clinical Proteomic Tumor Analysis Consortium (CPTAC) dataset, the Kaplan-Meier plotter dataset, the HLuA150CS02 cohort, and the HLugS120CS01 cohort. Results: GBP5 was upregulated in tumor tissues but associated with a good prognosis in NSCLC. Moreover, our findings demonstrated that GBP5 was strongly correlated with the expression of many immune-related genes, TIIC levels, and PD-L1 expression based on RNA-seq data onto online databases and validation of the NSCLC tissue microarray using IHC staining. Moreover, pan-cancer analysis has shown that GBP5 was a factor in identifying immuno-hot tumors, except for a few tumor types. Conclusion: In summary, our current research suggests that GBP5 expression is a potential biomarker for predicting the outcome of NSCLC patients treated with ICIs. More research with large-scale samples is needed to determine their value as biomarkers of ICIs benefit.

Factors influencing USgHIFU ablation for adenomyosis with NPVR ≥ 50.

OBJECTIVE: To investigate the influencing factors of ultrasound-guided HIFU (USgHIFU) ablation for adenomyosis with a non-perfused volume ratio (NPVR)≥50%. METHODS: A total of 299 patients with adenomyosis who underwent USgHIFU ablation were enrolled. Quantitative signal intensity (SI) analysis was performed on T2WI and dynamic enhancement type. The energy efficiency factor (EEF) was defined as the ultrasound energy delivered for ablating 1 mm3 of tissue. NPVR ≥ 50% was used as the criterion for technical success. Adverse effects and complications were recorded. Logistic regression analyses of variables were conducted to identify the factors affecting NPVR ≥ 50%. RESULTS: The median NPVR was 53.5% (34.7%). There were 159 cases in the NPVR ≥ 50% group and 140 cases in the NPVR < 50% group. The EEF in NPVR < 50.0% group was significantly higher than that in NPVR ≥ 50% group (p < 0.05). The incidence of intraoperative adverse effects and postoperative adverse events in the NPVR < 50% group were higher than those in the NPVR ≥ 50% group (p < 0.05 for both). Logistic regression analysis showed that abdominal wall thickness, SI difference on T2WI between adenomyosis and rectus abdominis, and enhancement type on T1WI were protective factors for NPVR ≥ 50% (p < 0.05), while the history of childbirth was an independent risk factor (p < 0.001). CONCLUSIONS: Compared with NPVR < 50%, NPVR ≥ 50% did not increase the intraprocedural and postprocedural adverse reactions. The possibility of NPVR ≥ 50% was higher in patients with thinner abdominal walls, showed slight enhancement of adenomyosis on T1WI, with a history of childbirth, or in whom the SI difference on T2WI between adenomyosis and rectus abdominis was more minor.

Preventive effect and mechanism of Tibetan tea extract on thrombosis in arachidonic acid-induced zebrafish determined via RNA-seq transcriptome profiles.

Thrombosis is a key pathological event in cardiovascular diseases and is also the most important targeting process for their clinical management. In this study, arachidonic acid (AA) was used to induce thrombus formation in zebrafish larvae. Blood flow, red blood cell (RBCs) aggregation and cellular oxidative stress were measured to evaluate the antithrombotic effect of Tibetan tea (TT). Meanwhile, the potential molecular mechanism was further explored by transcriptome sequencing (RNA-seq). The results indicated that TT could significantly restore heart RBCs intensity of thrombotic zebrafish, whilst decreasing RBCs accumulation in the caudal vein. The transcriptome analysis revealed that the preventive effect of TT on thrombosis could be mostly attributed to changes in lipid metabolism related signaling pathways, such as fatty acid metabolism, glycerollipid metabolism, ECM-receptor interaction and steroid biosynthesis signaling pathway. This study demonstrated that Tibetan tea could alleviate thrombosis by reducing oxidative stress levels and regulating lipid metabolism.

Application of Computing as a High-Practicability and -Efficiency Auxiliary Tool in Nanodrugs Discovery.

Research and development (R&D) of nanodrugs is a long, complex and uncertain process. Since the 1960s, computing has been used as an auxiliary tool in the field of drug discovery. Many cases have proven the practicability and efficiency of computing in drug discovery. Over the past decade, computing, especially model prediction and molecular simulation, has been gradually applied to nanodrug R&D, providing substantive solutions to many problems. Computing has made important contributions to promoting data-driven decision-making and reducing failure rates and time costs in discovery and development of nanodrugs. However, there are still a few articles to examine, and it is necessary to summarize the development of the research direction. In the review, we summarize application of computing in various stages of nanodrug R&D, including physicochemical properties and biological activities prediction, pharmacokinetics analysis, toxicological assessment and other related applications. Moreover, current challenges and future perspectives of the computing methods are also discussed, with a view to help computing become a high-practicability and -efficiency auxiliary tool in nanodrugs discovery and development.

A High-Temperature Accelerometer with Excellent Performance Based on the Improved Graphene Aerogel.

A high-temperature accelerometer plays an important role for ensuring normal operation of equipment in aerospace, such as monitoring and identifying abnormal vibrations of aircraft engines. Phase transitions of piezoelectric crystals, mechanical failure and current leakage of piezoresistive/capacitive materials are the prominent inherent limitations of present high-temperature accelerometers working continuously above 973 K. With the rapid development of aerospace, it is a great challenge to develop a new type of vibration sensor to meet the crucial demands at high temperature. Here we report a high-temperature accelerometer working with a contact resistance mechanism. Based on the improved graphene aerogel (GA) prepared by a modulated treatment process, the accelerometer can operate continuously and stably at 1073 K and intermittently at 1273 K. The developed sensor is lightweight (sensitive element <5 mg) and has high sensitivity (an order of magnitude higher than MEMS accelerometers) and wide frequency response range (up to 5 kHz at 1073 K) with marked stability, repeatability and low nonlinearity error (<1%). These merits are attributed to the excellent and stable mechanical properties of the improved GA in the range of 299-1073 K. The accelerometer could be a promising candidate for high-temperature vibration sensing in space stations, planetary rovers and others.

Genome Sequence Resource of a Colletotrichum graminicola Field Strain from China.

The maize anthracnose stalk rot and leaf blight diseases caused by the fungal pathogen Colletotrichum graminicola is emerging as an important threat to corn production worldwide. In this work, we provide an improved genome assembly of a C. graminicola strain (TZ-3) by using the PacBio Sequel II and Illumina high-throughput sequencing technologies. The genome of TZ-3 consisting of 36 contigs with a length of 59.3 Mb. By correcting and evaluating with the Illumina sequencing data and BUSCO, this genome showed a high assembly quality and integrity. Gene annotation of this genome predicted 11,911 protein-coding genes, among which 983 secreted protein-coding genes and 332 effector genes were predicted. Comparing with previous genomes of C. graminicola strains, TZ-3 genome is more superior in nearly all parameters. The genome assembly and annotation will enhance our knowledge of the pathogen's genetic makeup and molecular mechanisms underlying its pathogenicity, as well as provide valuable insights into the genome variation across different regions.

The role of lipid metabolic reprogramming in tumor microenvironment.

Metabolic reprogramming is one of the most important hallmarks of malignant tumors. Specifically, lipid metabolic reprogramming has marked impacts on cancer progression and therapeutic response by remodeling the tumor microenvironment (TME). In the past few decades, immunotherapy has revolutionized the treatment landscape for advanced cancers. Lipid metabolic reprogramming plays pivotal role in regulating the immune microenvironment and response to cancer immunotherapy. Here, we systematically reviewed the characteristics, mechanism, and role of lipid metabolic reprogramming in tumor and immune cells in the TME, appraised the effects of various cell death modes (specifically ferroptosis) on lipid metabolism, and summarized the antitumor therapies targeting lipid metabolism. Overall, lipid metabolic reprogramming has profound effects on cancer immunotherapy by regulating the immune microenvironment; therefore, targeting lipid metabolic reprogramming may lead to the development of innovative clinical applications including sensitizing immunotherapy.

Protocol to identify novel immunotherapy biomarkers based on transcriptomic data in human cancers.

Immune checkpoint inhibitors have transformed the management of advanced cancers, but biomarkers for the prediction of therapeutic responses have not been fully uncovered. Here, we provide a step-by-step approach for the identification of novel biomarkers from public transcriptomic datasets. We comprehensively summarize the available transcriptomic datasets containing immunotherapy information and describe the necessary procedures to evaluate the effectiveness of a novel immunotherapy biomarker, which may accelerate the identification of novel immunotherapy biomarkers. For complete details on the use and execution of this protocol, please refer to Mei et al.1.

[Inhibition of glutaminolysis alleviates myocardial fibrosis induced by angiotensin II].

The present study was aimed to investigate the role and mechanism of glutaminolysis of cardiac fibroblasts (CFs) in hypertension-induced myocardial fibrosis. C57BL/6J mice were administered with a chronic infusion of angiotensin II (Ang II, 1.6 mg/kg per d) with a micro-osmotic pump to induce myocardial fibrosis. Masson staining was used to evaluate myocardial fibrosis. The mice were intraperitoneally injected with BPTES (12.5 mg/kg), a glutaminase 1 (GLS1)-specific inhibitor, to inhibit glutaminolysis simultaneously. Immunohistochemistry and Western blot were used to detect protein expression levels of GLS1, Collagen I and Collagen III in cardiac tissue. Neonatal Sprague-Dawley (SD) rat CFs were treated with 4 mmol/L glutamine (Gln) or BPTES (5 µmol/L) with or without Ang II (0.4 µmol/L) stimulation. The CFs were also treated with 2 mmol/L α-ketoglutarate (α-KG) under the stimulation of Ang II and BPTES. Wound healing test and CCK-8 were used to detect CFs migration and proliferation respectively. RT-qPCR and Western blot were used to detect mRNA and protein expression levels of GLS1, Collagen I and Collagen III. The results showed that blood pressure, heart weight and myocardial fibrosis were increased in Ang II-treated mice, and GLS1 expression in cardiac tissue was also significantly up-regulated. Gln significantly promoted the proliferation, migration, mRNA and protein expression of GLS1, Collagen I and Collagen III in the CFs with or without Ang II stimulation, whereas BPTES significantly decreased the above indices in the CFs. α-KG supplementation reversed the inhibitory effect of BPTES on the CFs under Ang II stimulation. Furthermore, in vivo intraperitoneal injection of BPTES alleviated cardiac fibrosis of Ang II-treated mice. In conclusion, glutaminolysis plays an important role in the process of cardiac fibrosis induced by Ang II. Targeted inhibition of glutaminolysis may be a new strategy for the treatment of myocardial fibrosis.

Pre-Induced ICD Membrane-Coated Carrier-Free Nanoparticles for the Personalized Lung Cancer Immunotherapy.

Immunotherapy is a required adjuvant method in lung cancer therapy clinically. The single immune adjuvant failed to show the expected clinical therapeutic efficacy due to its rapid drug metabolism and inability to accumulate in the tumor site efficiently. Immunogenic cell death (ICD) is a new anti-tumor strategy combined with immune adjuvants. It can provide tumor-associated antigens, activate dendritic cells, and attract lymphoid T cells into the tumor microenvironment. Here doxorubicin-induced tumor membrane-coated iron (II)-cytosine-phosphate-guanine nanoparticles (DM@NPs) are shown for efficient co-delivery of tumor-associated antigens and adjuvant. Higher expression of ICD-related membrane proteins on the surface of the DM@NPs leads to the enhanced uptake of DM@NPs by dendritic cells (DCs), thereby promoting the DCs maturation and pro-inflammatory cytokines release. DM@NPs can remarkably increase the T cell infiltrations, remodel the tumor immune microenvironment and inhibit tumor progression in vivo. These findings reveal that pre-induced ICD tumor cell membrane-encapsulated nanoparticles can enhance immunotherapy responses and provide an effective biomimetic nanomaterial-based therapeutic strategy for lung cancer.

Real-World Data Showing Trends and Outcomes by Race and Ethnicity in Allogeneic Hematopoietic Cell Transplantation: A Report from the Center for International Blood and Marrow Transplant Research.

The use of HLA-mismatched donors could enable more patients with ethnically diverse backgrounds to receive allogeneic hematopoietic cell transplantation (HCT) in the United States. However, real-world trends and outcomes following mismatched donor HCT for diverse patients remain largely undefined. We conducted this study to determine whether the use of mismatched donor platforms have increased the access to allogeneic HCT for ethnically diverse patients, particularly through the application of novel graft-versus-host disease (GVHD) prophylaxis regimens, and whether outcomes for diverse patients are comparable to those of non-Hispanic White patients. This observational cross-sectional study used real-world data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. All patients receiving their first allogeneic HCT in the United States between 2009 and 2020 were included, with a focus on transplantations performed in 2020. Data from patients undergoing allogeneic HCT using bone marrow, peripheral blood, or cord blood from HLA-matched or mismatched related and unrelated donors were analyzed. Specifically, relative proportion of allogeneic HCT was generated as percentage of total for donor type and for patient age, disease indication, GVHD prophylaxis, and race and ethnicity. Causes of death were summarized using frequencies, and the Kaplan-Meier estimator was used for estimating overall survival. Compared to matched related donor and matched unrelated donor HCT, more ethnically diverse patients received mismatched unrelated donor, haploidentical donor, and cord blood HCT. Although matched unrelated donor remains the most common donor type, the use of haploidentical donors has increased significantly over the last 5 years. Paralleling this increase in haploidentical HCT is the increased use of post-transplantation cyclophosphamide (PTCy) as GVHD prophylaxis. Relative to previous transplantation eras, the most contemporary era is associated with the highest survival rates following allogeneic HCT irrespective of patient race and ethnicity. Nonetheless, disease relapse remains the primary cause of death for both adult and pediatric allogeneic HCT recipients by donor type and across all patient racial/ethnic groups. Ethnically diverse patients are undergoing allogeneic HCT at higher rates, largely through the use of alternative donor platforms incorporating PTCy. Maintaining access to potential life-saving allogeneic HCT using alternative donors and novel GVHD prophylaxis strategies and improving HCT outcomes, particularly disease relapse, remain urgent clinical needs.

JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens.

Janus kinase/signal transduction and transcription activation (JAK/STAT) pathways were originally thought to be intracellular signaling pathways that mediate cytokine signals in mammals. Existing studies show that the JAK/STAT pathway regulates the downstream signaling of numerous membrane proteins such as such as G-protein-associated receptors, integrins and so on. Mounting evidence shows that the JAK/STAT pathways play an important role in human disease pathology and pharmacological mechanism. The JAK/STAT pathways are related to aspects of all aspects of the immune system function, such as fighting infection, maintaining immune tolerance, strengthening barrier function, and cancer prevention, which are all important factors involved in immune response. In addition, the JAK/STAT pathways play an important role in extracellular mechanistic signaling and might be an important mediator of mechanistic signals that influence disease progression, immune environment. Therefore, it is important to understand the mechanism of the JAK/STAT pathways, which provides ideas for us to design more drugs targeting diseases based on the JAK/STAT pathway. In this review, we discuss the role of the JAK/STAT pathway in mechanistic signaling, disease progression, immune environment, and therapeutic targets.

Periodontal repair for advanced bone loss caused by orthodontic elastic bands: A case report with 7-year follow-up and literature review.

A 16-year-old girl developed severe acute periodontitis involving the maxillary central incisor and lateral incisor caused by elastic bands. Periodontal surgical interventions and orthodontic adjustment achieved good outcomes which were maintained for 7 years. This report demonstrates the criticality of correct diagnosis, early periodontal surgery, and interdisciplinary approach.

RNA binding proteins are potential novel biomarkers of egg quality in yellow catfish.

BACKGROUND: Egg quality is a major concern in fish reproduction and development. An effective evaluation of egg quality prior to fertilization is helpful in improving the fertilization rate and survival rate of the larva. In this study, we aim to identify quality instructors from the combination study of fertilization rate, hatching rate, embryo malformation rate and gene expression profile. RESULTS: Eggs from 25 female fish were fertilized with sperm from the same fish. The egg quality was determined by the fertilization rates, hatching rate and embryo malformation rate and divided into three categories, low-quality (< 35%), medium-quality (35 to 75%), and high-quality (> 75%). Due to the distinct difference in fertilization, hatching and embryo malformation rate between low-quality eggs and high-quality eggs, these two groups were considered for the identification of quality markers. Then RNA-seq was performed for the originally preserved eggs from the low-quality group and high-quality group. We profiled the differentially expressed genes and identified a group of RNA-binding proteins (RBPs) as potential regulators. Gene function analysis indicated that most of these genes were enriched in RNA-regulated pathways including RNA processing. The RBPs were more related to egg quality from the PLS-DA analysis. Finally, gene expression was validated by qRT-PCR. CONCLUSIONS: We found a cluster of RBP genes including igf2bp3, zar1, elavl1, rbm25b and related regulatory factors including yy1, sirt1, anp32e, btg4 as novel biomarkers of egg quality.

Hormone replacement therapy alone or in combination with tamoxifen in women with thin endometrium undergoing frozen-thawed embryo transfer: A retrospective study.

Research question: To investigate the effects of two protocols (hormone replacement therapy (HRT) alone or in combination with tamoxifen) on the endometrium and pregnancy outcome of patients with thin endometrium in frozen-thawed embryo transfer (FET) cycles. Design: A total of 465 infertile patients with thin endometrium who underwent FET between January 2020 to June 2021 at the Drum Tower Hospital affiliated with Nanjing University Medical School were retrospectively analyzed. A total of 187 patients were given tamoxifen in addition to HRT (TMXF-HRT group), whereas 278 patients were given only HRT (HRT group). Clinical data were compared between the two groups, including general characteristics, endometrial thickness, and clinical pregnancy outcomes. Results: There were no significant differences in baseline characteristics of all enrolled patients between two groups. Serum progesterone (P) was higher in HRT group than in the TMXF-HRT group (0.28 ± 0.53 ng/mL vs. 0.15 ± 0.25 ng/mL, P = 0.002). There was a significant increase in endometrial thickness in the TMXF-HRT group compared with the HRT group (OR: 1.54, 95% CI: 1.32-1.75, P < 0.001). There were no significant differences in the clinical pregnancy rate, embryo implantation rate, early miscarriage rate, or live birth rate between these two groups. Conclusion: Although tamoxifen when used in combination with hormone replacement therapy can significantly increase endometrial thickness, it may not have a role in improving the pregnancy outcomes of patients with thin endometrium undergoing FET cycles.

Cell Membranes from Tumor-Tropic MSCs Screened by a Microfluidic Chip for Drug Nanoparticles Encapsulation and Cancer Targeted Therapy.

Nanoparticles (NPs)-based drug carriers are effective in reducing systemic toxicity and drug resistance for chemotherapy, and an emerging trend focuses on integrating cell membranes with nanomedicines for tumor targeting. Mesenchymal stem cells (MSCs) are promising candidates due to their unique tropism toward cancer cells, yet the tumor-tropic abilities can differ for MSCs sourced from different tissues. Here, a multichannel microfluidic chip to screen different sourced MSCs with the greatest tropism toward cervical cancer cells is developed. Based on this, the cell membranes from the chorionic plate-derived MSC are isolated and membrane-camouflaged platinum prodrug composite NPs for cervical cancer treatment are prepared. Results demonstrate that the composite NPs can effectively target tumor sites and have a therapeutic effect both in vitro and in vivo. It is believed that the present microfluidic platform is a powerful tool for cell screening and tumor-on-a-chip studies, and the derived nanodelivery system represents the great value of cell membrane-camouflaged nanomedicine for targeted cancer therapy.

Hypoxia-mediated chemotaxis and residence of macrophage in decidua by secreting VEGFA and CCL2 during normal pregnancy.

In brief: Hypoxia is vital for the establishment of the maternal-fetal interface during early pregnancy. This study shows that decidual macrophages (dMφ) could be recruited and reside in decidua under the regulation of hypoxia/VEGFA-CCL2 axis. Abstract: Infiltration and residence of decidual macrophages (dMφ) are of great significance to pregnancy maintenance for their role in angiogenesis, placental development, and inducing immune tolerance. Besides, hypoxia has now been acknowledged as an important biological event at maternal-fetal interface in the first trimester. However, whether and how hypoxia regulates biofunctions of dMφ remain elusive. Herein, we observed increased expression of C-C motif chemokine ligand 2 (CCL2) and residence of macrophages in decidua compared to secretory-phase endometrium. Moreover, hypoxia treatment on stromal cells improved the migration and adhesion of dMφ. Mechanistically, these effects might be mediated by upregulated CCL2 and adhesion molecules (especially ICAM2 and ICAM5) on stromal cells in the presence of endogenous vascular endothelial growth factor-A (VEGFA) in hypoxia. These findings were also verified by recombinant VEGFA and indirect coculture, indicating that the interaction between stromal cells and dMφ in hypoxia condition may facilitate dMφ recruitment and residence. In conclusion, VEGFA derived from a hypoxic environment may manipulate CCL2/CCR2 and adhesion molecules to enhance the interactions between dMφ and stromal cells and thus contribute to the enrichment of macrophages in decidua early during normal pregnancy.