BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism.

Altered branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of chimeric antigen receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and decreasing BCAA transporter decreased cancer cell lysis efficacy. We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential. In an in vivo experiment, BCKDK-OE CAR-T cell treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and an increasing proportion of CAR-T cells in the peripheral circulation. BCKDK-KO CAR-T cell treatment resulted in shorter survival and a decreasing percentage of CAR-T cells in the peripheral circulation. In conclusion, BCKDK-engineered CAR-T cells exert a distinct phenotype for superior anticancer efficiency.

Analysis of Ionomic Profiles of Spinal Cords in a Rat Model with Bone Cancer Pain.

Background: Ionomics is used to study levels of ionome in different states of organisms and their correlations. Bone cancer pain (BCP) severely reduces quality of life of patients or their lifespan. However, the relationship between BCP and ionome remains unclear. Methods: The BCP rat model was constructed through inoculation of Walker 256 cells into the left tibia. Von Frey test, whole-cell patch-clamp recording and inductively coupled plasma mass spectrometry (ICP-MS) technologies were conducted for measuring tactile hypersensitivity, the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) of neurons of spinal slices, and ionome of spinal cord samples, respectively. Principal component analysis (PCA) was used to explore ionomic patterns of the spinal cord. Results: The BCP rat model was successfully constructed through implantation of Walker 256 cells into the left tibia. The frequency and amplitude of mEPSCs of neurons in the spinal cord slices from the BCP model rats were notably greater than those in the sham control. In terms of ionomics, the spinal cord levels of two macroelements (Ca and S), four microelements (Fe, Mn, Li and Sr) and the toxic element Ti in the BCP group of rats were significantly increased by inoculation of Walker 256 cancer cells, compared to the sham control. In addition, the correlation patterns between the elements were greatly changed between the sham control and BCP groups. PCA showed that inoculation of Walker 256 cells into the tibia altered the overall ionomic profiles of the spinal cord. There was a significant separation trend between the two groups. Conclusion: Taken together, inoculation of Walker 256 cells into the left tibia contributes to BCP, which could be closely correlated by some elements. The findings provided novel information on the relationship between the ionome and BCP.

Identification and functional characterization of chemosensory genes in olfactory and taste organs of Spodoptera litura (Lepidoptera: Noctuidae).

The tobacco cutworm Spodoptera litura is one of the most destructive polyphagous crop pests. Olfaction and taste play a crucial role in its host plant selection and sexual communication, but the expression profile of chemosensory genes remains unclear. In this study, we identified 185 chemosensory genes from 7 organs in S. litura by transcriptome sequencing, of which 72 genes were published for the first time, including 27 odorant receptors (ORs), 26 gustatory receptors (GRs), 1 ionotropic receptor (IR), 16 odorant-binding proteins (OBPs), and 2 chemosensory proteins (CSPs). Phylogenetic analyses revealed that ORs, IRs, OBPs, and sensory neuron membrane proteins (SNMPs) were mainly expressed in antennae and sequence-conserved among Noctuidae species. The most differentially expressed genes (DEGs) between sexes were ORs and OBPs, and no DEGs were found in GRs. GR transcripts were enriched in proboscis, and the expression of sugar receptors was the highest. Carbon dioxide receptors, sugar receptor-SliuGR6, and bitter GRs-SlituGR43 and SlituGR66 had higher sequence identities between Noctuidae species. CSPs were broadly expressed in various organs, and SlituCSP13 was a DEG in adult antennae. The functional analysis in the Drosophila OR67d expression system found that SlituOR50, a receptor highly expressed in female antennae, is selectively tuned to farnesyl acetate. The results provide a solid foundation for understanding the molecular mechanisms by which chemosensory genes operate to elicit behavioral responses in polyphagous insects.

pGM-CSF as an adjuvant in DNA vaccination against SARS-CoV-2.

The emergence of SARS-CoV-2 presents a significant global public health dilemma. Vaccination has long been recognized as the most effective means of preventing the spread of infectious diseases. DNA vaccines have attracted attention due to their safety profile, cost-effectiveness, and ease of production. This study aims to assess the efficacy of plasmid-encoding GM-CSF (pGM-CSF) as an adjuvant to augment the specific humoral and cellular immune response elicited by DNA vaccines based on the receptor-binding domain (RBD) antigen. Compared to the use of plasmid-encoded RBD (pRBD) alone, mice that were immunized with a combination of pRBD and pGM-CSF exhibited significantly elevated levels of RBD-specific antibody titers in serum, BALF, and nasal wash. Furthermore, these mice generated more potent neutralization antibodies against both the wild-type and Omicron pseudovirus, as well as the ancestral virus. In addition, pGM-CSF enhanced pRBD-induced CD4+ and CD8+ T cell responses and promoted central memory T cells storage in the spleen. At the same time, tissue-resident memory T (Trm) cells in the lung also increased significantly, and higher levels of specific responses were maintained 60 days post the final immunization. pGM-CSF may play an adjuvant role by promoting antigen expression, immune cells recruitment and GC B cell responses. In conclusion, pGM-CSF may be an effective adjuvant candidate for the DNA vaccines against SARS-CoV-2.

Validation of the IMPEDE VTE score for prediction of venous thromboembolism in Chinese patients with multiple myeloma: A single-center retrospective cohort study.

Multiple myeloma (MM) significantly increases the risk of venous thromboembolism (VTE) within 6 months of treatment initiation. The IMPEDE VTE score is a VTE risk prediction model which is recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, but it lacks validation among Asians, including Chinese MM patients. We performed a retrospective chart review of 405 Chinese with newly diagnosed MM who started therapy at Beijing Jishuitan Hospital between April 2013 to October 2022. The 6-month cumulative incidence of VTE was 3.8 % (95 % CI:1.6-7.6), 8.6 % (95 % CI: 5.3-21.9) and 40.5 % (95 % CI: 24.9-55.7) in the low-, intermediate- and high-risk groups (P < 0.001), respectively. The C-statistic of the IMPEDE VTE scores for predicting VTE within 6 months of treatment initiation was 0.74 (95 % CI: 0.65-0.83). Of note, in this single-center cohort study, we propose that the anticoagulant LMWH may be more effective than the antiplatelet aspirin in potentially preventing VTE in newly diagnosed MM patients. Our findings suggest that the IMPEDE VTE score is a valid evidence-based risk stratification tool in Chinese patients with newly diagnosed MM.

Investigating the epidemiological relevance of secretory otitis media and neighboring organ diseases through an Internet search.

Background: This study examined the epidemiological correlations between secretory otitis media (SOM) and diseases of neighboring organs. We measured changes in disease incidences during the 2020 COVID-19 pandemic using Internet big data spanning from 2011 to 2021. Methods: This study used the Baidu Index (BI) to determine the search volume for the terms "secretory otitis media (SOM)", "tonsillitis", "pharyngolaryngitis", "adenoid hypertrophy (AH)", "nasopharyngeal carcinoma (NPC)", "nasal septum deviation (NSD)", "rhinosinusitis", "allergic rhinitis (AR)", and "gastroesophageal reflux disease (GERD)" in Mandarin from January 2011 to December 2021. The correlations between these terms were analyzed using Spearman's correlation coefficients. The results were compared search data from 2019 and 2021 to assess the effects of isolation on SOM in 2020. Results: The seasonal variations trends of SOM and other diseases coincided well (P < 0.05), except for AR. During the 11-year timeframe, the monthly searches for rhinosinusitis, NSD, tonsillitis, pharyngolaryngitis, and NPC were statistically correlated with SOM (R = 0.825, 0.594, 0.650, 0.636, 0.664, respectively; P < 0.05). No correlation was found between SOM and AR, SOM and AH, or SOM and GERD (R =  - 0.028, R = 0.259, R = 0.014, respectively, P > 0.05). The total search volumes for SOM, rhinosinusitis, NPC, and AH decreased in 2020 compared to 2019. Discussion: SOM exhibited a discernible epidemiological connection with rhinosinusitis, nasal septal deviation (NSD), tonsillitis, pharyngolaryngitis, and nasopharyngeal carcinoma (NPC). A decrease in public gatherings was observed to effectively reduce the incidences of SOM. This underscores the pivotal role of social measures in influencing the prevalence of SOM and emphasizes the intricate interplay between SOM and various associated health factors, with implications for public health strategies.

Analysis of Breast Cancer Screening Results and Influencing Factors of Breast Cancer in Guangdong Province from 2017 to 2021.

BACKGROUNDS: Breast cancer screening plays an important role in the early detection, diagnosis and treatment of breast cancer. The aim of this study was to evaluate the screening results and explore the influencing factors of breast cancer detection rate in Guangdong. METHODS: This cross-sectional study was conducted among 2,024,960 women aged 35-64 in Guangdong Province during 2017-2021. The data about breast cancer screening information were collected from the Guangdong maternal and child health information system. Descriptive statistical analysis was used to explain demographic characteristics and results of breast cancer screening. The generalized linear regression model was applied to analyze the related influencing factors of breast cancer detection rate. RESULTS: The estimated detection rate of breast cancer in Guangdong Province is 70.32/105, with an early diagnosis rate of 82.06%. After adjusting covariates, those women with older age (45-55 [OR (95% CI) 2.174 (1.872, 2.526)], 55-65 [OR (95% CI) 2.162 (1.760, 2.657)]), education for high school ([OR (95% CI) 1.491 (1.254, 1.773)]) and older age at first birth ([OR (95% CI) 1.632 (1.445, 1.844)]) were more likely to have higher detection rate of breast cancer. No history of surgery or biopsy ([OR (95% CI) 0.527 (0.387, 0.718)]), no history of breast cancer check ([OR (95% CI) 0.873 (0.774, 0.985)]) and no family history of breast cancer ([OR (95% CI) 0.255 (0.151, 0.432)]) women were more likely to screen negative for breast cancer (P < 0.05). CONCLUSION: The detection rate of breast cancer in screening showed an increasing trend year by year in Guangdong Province. Older age, education for high school and older age at first birth were risk factors for breast cancer detection rate, while no surgery or biopsy history, no family history of breast cancer and no history of breast cancer check were protective factors.

Electrochemical immuno-biosensors for the detection of the tumor marker alpha-fetoprotein: A review.

Alpha-fetoprotein (AFP) is a glycoprotein that has many important physiological functions, including transportation, immunosuppression, and induction of apoptosis by T lymphocytes. AFP is closely related to the development of hepatocellular carcinoma and many kinds of tumors, all of which can show high concentrations, so it is used as a positive test indicator for many kinds of tumors. This paper reviews recent advances in the detection of the tumor marker AFP based on three immuno-biosensors: electrochemical (EC), photoelectrochemical (PEC), and electrochemical luminescence (ECL). The electrodes are modified by different materials or homemade composites, different signaling molecules are selected as single probes or dual probes for the detection of AFP. The detection limit was as low as 3 fg/mL, which indicated that the AFP immunosensor had achieved highly sensitive detection. In addition, we also reviewed and summarized the current development status and application prospect of AFP immunoelectrochemical sensors. There are not too many researches on immunosensors based on dual-signal ratios, and the commonly used probes are methylene blue (MB) and ferrocene (Fc). It would be more innovative to have more novel signaling molecules as probes to prepare dual-signal ratio sensors.

A novel lactate dehydrogenase-based risk score model to predict the prognosis of primary central nervous system germ cell tumor treated with chemoradiotherapy.

BACKGROUND: The prognostic role of lactate dehydrogenase (LDH) has been confirmed in many malignant tumors, but the role of serum LDH in primary central nervous system germ cell tumor (GCT) remains unknown. This study aimed to assess the prognostic value of LDH in GCT patients and develop a nomogram to predict prognosis in patients undergoing chemoradiotherapy. METHODS: A total of 161 patients with GCT were included in this study. Using a restricted cubic spline (RCS) model, the optimal cutoff point for LDH was determined to be 217 U/L. The survival of GCT patients was evaluated using the Kaplan-Meier method and log-rank test to analyze the effects of LDH levels. Univariate Cox regression, multivariate Cox regression, and LASSO Cox regression were conducted to identify prognostic factors, which were incorporated into a nomogram for predicting overall survival (OS). The predictive accuracy of the nomogram was assessed using the C-index, calibration curve, area under the time-dependent receiver operating characteristic curve (time-dependent AUC), and risk group stratification. The net benefits of the nomogram at different threshold probabilities were quantified using decision curve analysis (DCA). RESULTS: The high-LDH group had significantly shorter OS compared to the low-LDH group (P = 0.016). Based on the SYSUCC cohort, three variables were shown to be significant factors for OS and were incorporated in the nomogram: LDH, histopathology, and dissemination. It showed good discrimination ability, with C-index of 0.789 (95% CI, 0.671-0.907). Additionally, the clinical usefulness of the nomogram was confirmed by calibration curves and time-dependent AUC. DCA further highlighted the potential of the nomogram to guide clinical treatment strategies for patients. Moreover, there was a significant difference in OS among patients categorized into different risk groups (P < 0.001). CONCLUSION: LDH levels may serve as a reliable predictor for assessing the therapeutic effect of chemoradiotherapy in GCT. The developed nomogram exhibits high accuracy in predicting survival outcomes, aiding in the classification of prognostic groups, and supporting informed clinical decision-making.

Corydalis saxicolaBunting total alkaloid eliminates Porphyromonas gingivalis strain 33277 internalized into macrophages by inhibition of TLR2.

OBJECTIVE: This study aimed to investigate the impact of Corydalis Saxicola Bunting Total Alkaloid (CSBTA) on Porphyromonas gingivalis internalization within macrophages and explore the potential role of Toll-Like Receptor 2 (TLR2) in this process. METHODS: We established a P. gingivalis internalization model in macrophages by treating P. gingivalis-infected macrophages (MOI=100:1) with 200 µg/mL metronidazole and 300 µg/mL gentamicin for 1 h. Subsequently, the model was exposed to CSBTA at concentrations of 0.02 g/L or 1 µg/mL Pam3CSK4. After a 6 h treatment, cell lysis was performed with sterile water to quantify bacterial colonies. The mRNA expressions of TLR2 and interleukin-8 (IL-8) in macrophages were analyzed using RT-qPCR, while their protein levels were assessed via Western blot and ELISA respectively. RESULTS: P. gingivalis could internalize into macrophages and enhance the expression of TLR2 and IL-8. Activation of TLR2 by Pam3CSK4 contributed to P. gingivalis survival within macrophages and increased TLR2 and IL-8 expression. Conversely, 0.02 g/L CSBTA effectively cleared intracellular P. gingivalis, achieving a 90 % clearance rate after 6 h. Moreover, it downregulated the expression of TLR2 and IL-8 induced by P. gingivalis. However, the inhibitory effect of CSBTA on the internalized P. gingivalis model was attenuated by Pam3CSK4. CONCLUSION: CSBTA exhibited the ability to reduce the presence of live intracellular P. gingivalis and lower IL-8 expression in macrophages, possibly by modulating TLR2 activity.

Targeting of the CD161 inhibitory receptor enhances T-cell-mediated immunity against hematological malignancies.

ABSTRACT: The CD161 inhibitory receptor is highly upregulated by tumor-infiltrating T cells in multiple human solid tumor types, and its ligand, CLEC2D, is expressed by both tumor cells and infiltrating myeloid cells. Here, we assessed the role of the CD161 receptor in hematological malignancies. Systematic analysis of CLEC2D expression using the Cancer Cell Line Encyclopedia revealed that CLEC2D messenger RNA was most abundant in hematological malignancies, including B-cell and T-cell lymphomas as well as lymphocytic and myelogenous leukemias. CLEC2D protein was detected by flow cytometry on a panel of cell lines representing a diverse set of hematological malignancies. We, therefore, used yeast display to generate a panel of high-affinity, fully human CD161 monoclonal antibodies (mAbs) that blocked CLEC2D binding. These mAbs were specific for CD161 and had a similar affinity for human and nonhuman primate CD161, a property relevant for clinical translation. A high-affinity CD161 mAb enhanced key aspects of T-cell function, including cytotoxicity, cytokine production, and proliferation, against B-cell lines originating from patients with acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and Burkitt lymphoma. In humanized mouse models, this CD161 mAb enhanced T-cell-mediated immunity, resulting in a significant survival benefit. Single cell RNA-seq data demonstrated that CD161 mAb treatment enhanced expression of cytotoxicity genes by CD4 T cells as well as a tissue-residency program by CD4 and CD8 T cells that is associated with favorable survival outcomes in multiple human cancer types. These fully human mAbs, thus, represent potential immunotherapy agents for hematological malignancies.

Determination of dimethylated nucleosides in serum from colorectal cancer patients by hydrophilic interaction liquid chromatography-tandem mass spectrometry.

RNA modifications play a crucial regulatory role in a variety of biological processes and are closely related to numerous diseases, including cancer. The diversity of metabolites in serum makes it a favored biofluid for biomarkers discovery. In this work, a robust and accurate hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) approach was established for simultaneous determination of dimethylated nucleosides in human serum. Using the established method, we were able to accurately quantify the concentrations of N6-2'-O-dimethyladenosine (m6Am), N2,N2-dimethylguanosine (m2,2G), and 5,2'-O-dimethyluridine (m5Um) in serum samples from 53 healthy controls, 57 advanced colorectal adenoma patients, and 39 colorectal cancer (CRC) patients. The results showed that, compared with healthy controls and advanced colorectal adenoma patients, the concentrations of m6Am and m2,2G were increased in CRC patients, while the concentration of m5Um was decreased in CRC patients. These results indicate that these three dimethylated nucleosides could be potential biomarkers for early detection of colorectal cancer. Interestingly, the level of m5Um was gradually decreased from healthy controls to advanced colorectal adenoma patients to CRC patients, indicating m5Um could also be used to evaluate the level of malignancy of colorectal tumor. In addition, this study will contribute to the investigation on the regulatory mechanisms of RNA dimethylation in the onset and development of colorectal cancer.

Conditional survival probability of distant-metastatic hepatocellular carcinoma: A population-based study.

BACKGROUND: The prognosis of many patients with distant metastatic hepatocellular carcinoma (HCC) improved after they survived for several months. Compared with traditional survival analysis, conditional survival (CS) which takes into account changes in survival risk could be used to describe dynamic survival probabilities. AIM: To evaluate CS of distant metastatic HCC patients. METHODS: Patients diagnosed with distant metastatic HCC between 2010 and 2015 were extracted from the Surveillance, Epidemiology and End Results database. Univariate and multivariate Cox regression analysis were used to identify risk factors for overall survival (OS), while competing risk model was used to identify risk factors for cancer-specific survival (CSS). Six-month CS was used to calculate the probability of survival for an additional 6 mo at a specific time after initial diagnosis, and standardized difference (d) was used to evaluate the survival differences between subgroups. Nomograms were constructed to predict CS. RESULTS: Positive α-fetoprotein expression, higher T stage (T3 and T4), N1 stage, non-primary site surgery, non-chemotherapy, non-radiotherapy, and lung metastasis were independent risk factors for actual OS and CSS through univariate and multivariate analysis. Actual survival rates decreased over time, while CS rates gradually increased. As for the 6-month CS, the survival difference caused by chemotherapy and radiotherapy gradually disappeared over time, and the survival difference caused by lung metastasis reversed. Moreover, the influence of age and gender on survival gradually appeared. Nomograms were fitted for patients who have lived for 2, 4 and 6 mo to predict 6-month conditional OS and CSS, respectively. The area under the curve (AUC) of nomograms for conditional OS decreased as time passed, and the AUC for conditional CSS gradually increased. CONCLUSION: CS for distant metastatic HCC patients substantially increased over time. With dynamic risk factors, nomograms constructed at a specific time could predict more accurate survival rates.

Fabrication of Dimples by Jet-ECM of Zr-Based Bulk Metallic Glasses with NaCl-Ethylene Glycol Electrolyte.

Zr-based bulk metallic glasses (BMGs) possess unique mechanical and biochemical properties, which have been widely noticed. Jet electrochemical machining (jet-ECM), characterized by a high-speed jet, is a non-contact subtractive method with a high resolution and a high material removal rate (MRR). Past work on the electropolishing of Zr-based BMGs has indicated the feasibility of the NaCl-Ethylene Glycol (EG) electrolyte. In this research, the jet-ECM of Zr-based BMGs in the NaCl-EG electrolyte was studied to explore the dissolving mechanisms and surface integrity according to the voltage, pulse-on time and effective voltage time. The diameter, depth and surface morphologies of dimples were evaluated. The results showed that using this alcohol-based electrolyte led to a desirable surface morphology. The diameter and depth of the dimples varied with the voltage and the effective voltage time in a significantly positive proportional manner. Additionally, cases based on multiple parameter sets exhibited different stray corrosion severity. Afterward, machining performance can be enhanced in the next stage by tuning machining parameters to obtain microscale dimples with better quality.

Bckdk-Mediated Branch Chain Amino Acid Metabolism Reprogramming Contributes to Muscle Atrophy during Cancer Cachexia.

SCOPE: Branched chain amino acids (BCAAs) are essential amino acids and important nutrient signals for energy and protein supplementation. The study uses muscle-specific branched-chain α-keto acid dehydrogenase kinase (Bckdk) conditional knockout (cKO) mice to reveal the contribution of BCAA metabolic dysfunction to muscle wasting. METHOD AND RESULTS: Muscle-specific Bckdk-cKO mice are generated through crossbreeding of Bckdkf/f mice with Myf5Cre mice. Lewis lung cancer (LLC) tumor transplantation is used to establish the cancer cachexia model. The occurrence of cancer cachexia is accelerated in the muscle-specific Bckdk-cKO mice after bearing LLC tumor. Wasting skeletal muscle is characterized by increased protein ubiquitination degradation and impaired protein synthesis. The wasting muscle gastrocnemius is mechanized as a distinct BCAA metabolic dysfunction. Based on the atrophy phenotype resulting from BCAA metabolism dysfunction, the optimized BCAA supplementation improves the survival of cancer cachexia in muscle-specific Bckdk-cKO mice bearing LLC tumors, and improves the occurrence of cancer cachexia. The mechanism of BCAA supplementation on muscle mass preservation is based on the promotion of protein synthesis and the inhibition of protein ubiquitination degradation. CONCLUSIONS: Dysfunctional BCAA metabolism contributes to the inhibition of protein synthesis and increases protein degradation in the cancer cachexia model of muscle-specific Bckdk-cKO mice bearing LLC tumors. The reprogramming of BCAA catabolism exerts therapeutic effects by stimulating protein synthesis and inhibiting protein degradation in skeletal muscle.

Identifying quantitatively differential chromosomal compartmentalization changes and their biological significance from Hi-C data using DARIC.

BACKGROUND: Chromosomal compartmentalization plays a critical role in maintaining proper transcriptional programs in cell differentiation and oncogenesis. However, currently the prevalent method for comparative analysis of compartmentalization landscapes between different cell types is limited to the qualitative switched compartments. RESULTS: To identify genomic regions with quantitatively differential compartmentalization changes from genome-wide chromatin conformation data like Hi-C, we developed a computational framework named DARIC. DARIC includes three modules: compartmentalization quantification, normalization, and differential analysis. Comparing DARIC with the conventional compartment switching analysis reveals substantial regions characterized by quantitatively significant compartmentalization changes without switching. These changes are accompanied by changes in gene expression, chromatin accessibility, H3K27ac intensity, as well as the interactions with nuclear lamina proteins and nuclear positioning, highlighting the functional importance of such quantitative changes in gene regulation. We applied DARIC to dissect the quantitative compartmentalization changes during human cardiomyocyte differentiation and identified two distinct mechanisms for gene activation based on the association with compartmentalization changes. Using the quantitative compartmentalization measurement module from DARIC, we further dissected the compartment variability landscape in the human genome by analyzing a compendium of 32 Hi-C datasets from 4DN. We discovered an interesting correlation between compartmentalization variability and sub-compartments. CONCLUSIONS: DARIC is a useful tool for analyzing quantitative compartmentalization changes and mining novel biological insights from increasing Hi-C data. Our results demonstrate the functional significance of quantitative compartmentalization changes in gene regulation, and provide new insights into the relationship between compartmentalization variability and sub-compartments in the human genome.

Oncometabolite D-2-hydroxyglutarate-dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia.

Cancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, here we showed genetic mutation-mediated metabolic reprogramming in the progression of cancer cachexia by screening for metabolites and investigating their direct effect on muscle atrophy. Treatment with 93 µM D-2-hydroxyglutarate (D2HG) resulted in reduced myotube width and increased expression of E3 ubiquitin ligases. Isocitrate Dehydrogenase 1 (IDH1) mutant patients had higher D2HG than non-mutant patients. In the in vivo murine cancer cachexia model, mutant IDH1 in CT26 cancer cells accelerated cachexia progression and worsened overall survival. Transcriptomics and metabolomics revealed a distinct D2HG-induced metabolic imbalance. Treatment with the IDH1 inhibitor ivosidenib delayed the progression of cancer cachexia in murine GL261 glioma model and CT26 colorectal carcinoma models. These data demonstrate the contribution of IDH1 mutation mediated D2HG accumulation to the progression of cancer cachexia and highlight the individualized treatment of IDH1 mutation associated cancer cachexia.

An MRI-based machine learning radiomics can predict short-term response to neoadjuvant chemotherapy in patients with cervical squamous cell carcinoma: A multicenter study.

BACKGROUND AND PURPOSE: Neoadjuvant chemotherapy (NACT) has become an essential component of the comprehensive treatment of cervical squamous cell carcinoma (CSCC). However, not all patients respond to chemotherapy due to individual differences in sensitivity and tolerance to chemotherapy drugs. Therefore, accurately predicting the sensitivity of CSCC patients to NACT was vital for individual chemotherapy. This study aims to construct a machine learning radiomics model based on magnetic resonance imaging (MRI) to assess its efficacy in predicting NACT susceptibility among CSCC patients. METHODS: This study included 234 patients with CSCC from two hospitals, who were divided into a training set (n = 180), a testing set (n = 20), and an external validation set (n = 34). Manual radiomic features were extracted from transverse section MRI images, and feature selection was performed using the recursive feature elimination (RFE) method. A prediction model was then generated using three machine learning algorithms, namely logistic regression, random forest, and support vector machines (SVM), for predicting NACT susceptibility. The model's performance was assessed based on the area under the receiver operating characteristic curve (AUC), accuracy, and sensitivity. RESULTS: The SVM approach achieves the highest scores on both the testing set and the external validation set. In the testing set and external validation set, the AUC of the model was 0.88 and 0.764, and the accuracy was 0.90 and 0.853, the sensitivity was 0.93 and 0.962, respectively. CONCLUSIONS: Machine learning radiomics models based on MRI images have achieved satisfactory performance in predicting the sensitivity of NACT in CSCC patients with high accuracy and robustness, which has great significance for the treatment and personalized medicine of CSCC patients.