NAC056 transcription factor confers freezing tolerance by positively regulating the expression of CBFs and NIA1 in Arabidopsis.

It is well known that freezing stress can seriously affect the growth and development of plants. However, the mechanisms of these effects and plant response to freezing stress need to be further explored. Here, we identified a NAC family transcription factor (TF) NAC056 that can promote freezing tolerance. The NAC056 mRNA level was obviously induced by freezing stress in roots. We showed that the nac056 mutant compromised freezing tolerance. NAC056 acts positively in response to freezing by directly promoting the key CBF pathway genes. Interestingly, we found that the CBF1 regulates nitrate assimilation by regulating the nitrate reductase gene, NIA1, in plants, therefore, NAC056-CBF1-NIA1 form a regulatory module for the assimilation of nitrate and the growth of roots under freezing stress. In addition, 35S::NAC056 transgenic plants promoted freezing tolerance. The cbfs triple mutant could partly reverse the 35S::NAC056-induced freezing tolerance. Thus, NAC056 confers freezing tolerance through the CBF pathway. Therefore, NAC056 mediates the response of plants to balance plant growth and freezing stress tolerance.

Clinical efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapy for relapsed/refractory multiple myeloma: a systematic review and meta-analysis.

Background: The low rates of durable response against relapsed/refractory multiple myeloma (RRMM) in recent studies prompt that chimeric antigen receptor (CAR)-T cell therapies are yet to be optimized. The combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high clinical efficacy in several clinical trials for RRMM. We here conducted a meta-analysis to confirm its efficacy and safety. Methods: We collected data from Embase, Web of Science, PubMed, CNKI, Wanfang and Cochrane databases up to April 2023. We extracted and evaluated data related to the efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapies in RRMM patients. The data was then analyzed using RevMan5.4 and StataSE-64 software. PROSPERO number was CRD42023455002. Results: Our meta-analysis included 12 relevant clinical trials involving 347 RRMM patients who were treated with combined anti-BCMA and anti-CD19 CAR-T cell therapies. For efficacy assessment, the pooled overall response rate (ORR) was 94% (95% CI: 91%-98%), the complete response rate (CRR) was 50% (95% CI: 29%-71%), and the minimal residual disease (MRD) negativity rate within responders was 73% (95% CI: 66%-80%). In terms of safety, the pooled all-grade cytokine release syndrome (CRS) rate was 98% (95% CI: 97%-100%), grade≥3 CRS rate was 9% (95% CI: 4%-14%), and the incidence of neurotoxicity was 8% (95% CI: 4%-11%). Of hematologic toxicity, neutropenia was 82% (95% CI: 75%-89%), anemia was 71% (95% CI: 53%-90%), thrombocytopenia was 67% (95% CI: 40%-93%) and infection was 42% (95% CI: 9%-76%). The median progression-free survival (PFS) was 12.97 months (95% CI: 6.02-19.91), and the median overall survival (OS) was 26.63 months (95% CI: 8.14-45.11). Conclusions: As a novel immunotherapy strategy with great potential, the combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high efficacy in RRMM, but its safety needs further improvement. This meta-analysis suggests possible optimization of combined CAR-T therapy. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023455002.

Construction and validation of an 18F-FDG-PET/CT-based prognostic model to predict progression-free survival in newly diagnosed multiple myeloma patients.

OBJECTIVE: To investigate the relationship between 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) related parameters and the prognosis of multiple myeloma and to establish and validate a prediction model regarding the progression-free survival (PFS) of multiple myeloma. METHODS: A retrospective analysis of 126 newly diagnosed multiple myeloma patients who attended Nanjing Drum Tower Hospital from 2014-2021. All patients underwent PET/CT before treatment and were divided into a training cohort (n = 75) and a validation cohort (n = 51). Multivariate Cox proportional hazard regression analysis incorporated PET/CT-related parameters and clinical indicators. A nomogram was established to individually predict PFS in MM patients. The model was evaluated by calculating the C-index and calibration curve. RESULTS: Here, 4.2 was used as the cut-off value of SUVmax to divide patients into high and low groups. PFS significantly differed between patients in the high-SUVmax group and low-SUVmax group, and SUVmax was an independent predictor of PFS in newly diagnosed multiple myeloma (NDMM) patients. Univariate and multivariate cox regression analysis suggested that lactate dehydrogenase (LDH), bone marrow plasma cell (BMPC), and SUVmax affected PFS. These factors were incorporated to construct a nomogram model for predicting PFS at 1 and 2 years in NDMM patients. The C-index and calibration curves of the nomogram exhibited good accuracy and consistency, and the DCA curves suggested that the model had good clinical utility. CONCLUSION: The PET/CT parameter SUVmax is closely related to the prognosis of myeloma patients. The nomogram constructed in this study based on PET/CT-related parameters and clinical indicators individually predicts the PFS rate of NDMM patients and enables further risk stratification of NDMM patients.

Bifunctional iRGD-Exo-DOX crosses the blood-brain barrier to target central nervous system lymphoma.

Central nervous system lymphoma (CNSL) is a type of hematological tumor. Treatment of CNSL is difficult due to the existence of the blood-brain barrier (BBB). Here, we used exosomes (Exos), a type of extracellular vesicle, and iRGD to construct a new drug carrier system and use it to load doxorubicin (DOX). The results of in vitro and in vivo experiments showed that the iRGD-Exo-DOX system can efficiently and securely transport DOX through the BBB and target tumor cells. The results suggest that iRGD-Exo-DOX may cross the BBB through brain microvascular endothelial cell-mediated endocytosis. Together, our study indicates an impactful treatment of central nervous system tumors.

Preparation of cellulose-based flexible SERS and its application for rapid and ultra-sensitive detection of thiram on fruits and vegetables.

In response to the prevalent issue of thiram as a common pesticide residue on the surface of fruits and vegetables, our research team employed an acidic hydrated metal salt low co-fusion solvent to dissolve cellulose lysis slurry. Subsequently, a regenerated cellulose membrane (RCM) was successfully prepared via sol-gel method. Uniformly sized Ag nanoparticles (NPs) were deposited on RCM utilizing the continuous ion layer adsorption and reaction (SILAR) technique. The resulting Ag NPs/RCM flexible surface-enhanced Raman spectroscopy (SERS) substrates exhibited a minimum detection limit of 5 × 10-9 M for Rhodamine 6G (R6G), demonstrating good uniformity (RSD = 4.86 %) and reproducibility (RSD = 3.07 %). Moreover, the substrate displayed a remarkable sensitivity of 10-10 M toward thiram standard solution. Given its inherent flexibility, the substrate proves advantageous for the detection of three-dimensional environments such as fruit and vegetable surfaces, and its practicality has been confirmed in the detection of thiram residue on apples, tomatoes, pears, and other fruits and vegetables.

Identification of a novel fusion gene, RARA::ANKRD34C, in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia that is distinguished by the chromosomal translocation t(15;17)(q24;q21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA). Recently, we identified a novel fusion gene in APL, RARA::ankyrin repeat domain 34C (ANKRD34C), identified its functions by morphological, cytogenetic, molecular biological and multiplex fluorescence in situ hybridization analyses, and demonstrated the potential therapeutic effect clinically and experimentally of all-trans retinoic acid (ATRA); the findings have important implications for the diagnosis and treatment of atypical APL.

Prevalence of Vitamin A Deficiency in Children Aged 6 to 17 Years - Western and Central Rural Areas, China, 2012-2021.

What is already known about this topic?: Vitamin A deficiency (VAD) is a leading global nutritional concern, ranking among the top four major nutritional deficiencies worldwide. The prevalence of VAD is unevenly distributed across various regions, both within China and globally. What is added by this report?: The report adds valuable insights into the vitamin A nutritional status of rural students aged 6-17 years who participated in the Nutrition Improvement Programme for Rural Compulsory Education Students (NIPRCES). Over the decade from 2012 to 2021, there was a modest improvement in vitamin A status. The prevalence of VAD and sub-clinical VAD (SVAD) declined as the students aged. Throughout the majority of the survey years, the incidence of VAD was higher among males and western regions compared to females and central regions, respectively. What are the implications for public health practice?: A comprehensive approach, incorporating dietary diversification, nutrition education, and food fortification, should be implemented to prevent VAD and SVAD especially in males, younger children and children in western areas.

Electrophysiological assessment of radial shock wave therapy for carpal tunnel syndrome.

This study presents an electrophysiological assessment of radial extracorporeal shock wave therapy on patients with carpal tunnel syndrome (CTS). Sixteen CTS subjects received radial extracorporeal shock wave therapy once a week for five consecutive weeks. Outcome performance was assessed using the Boston Carpal Tunnel Questionnaire (BCTQ) and electrodiagnostic measurements including a nerve conduction study of the median nerve and a compound muscle action potential (CMAP) scan of the abductor pollicis brevis muscle. The BCTQ and the sensory conduction test measurements were all statistically improved after the treatment. However, the motor conduction test measurements were not significantly different before and after the treatment. The CMAP scan examination revealed MScanFit motor unit number estimation (MUNE) was significantly higher after the treatment, while no significant change was found in StairFit MUNE and step index. These results confirmed the effectiveness of shock wave therapy for treating CTS symptoms and the associated sensory property changes. The reasons for the inconsistencies from different CMAP scan processing methods are worthwhile targets for further investigation.

Clinical characteristics and proposed mechanism of pediatric spinal cord injury resulting from backbend practice.

Objective: Pediatric spinal cord injury without radiographic abnormality (SCIWORA) caused by backbend practice is increasing. This study proposed an underlying 'combined injury mechanism' related to the spinal cord and femoral nerve overstretching. Methods: Pediatric patients diagnosed with backbend-associated SCIWORA at the China Rehabilitation Research Center during 2017-2021 were recruited. Clinical and imaging data were collected, and each patient's clinical course and prognosis were determined. Healthy dancers were recruited to simulate the backbend, obtain images, and estimate the spinal cord and femoral nerve stretch ratio. A model for the 'combined injury mechanism' was established using 4-week-old SD rats. Results: Forty-two SCIWORA female patients with an average age of 6 (SD 1) years and an average hospitalization time of 91 (SD 43) days were assessed. The primary initial symptom was pain in the back and/or lower extremities (33, 79%). The average time from injury onset to severe paralysis was 2.0 (SD 0.6) hours. Most patients had complete paraplegia (32, 76%), and neurological levels were distributed mainly in thoracic segments (38, 91%). Patients with elicited tendon reflexes on admission tended to have an incomplete spinal cord injury (p = 0.001) and improved motor recovery (p = 0.018). After one year, the most common complications were scoliosis (31, 74%) and abnormal hips (14, 33%). Injury of the caudal spinal cord torn by nerve roots was confirmed by surgical exploration in a case. The thoracic spinal cord and femoral nerves were overstretched by 148.8 ± 3.6% and111.7 ± 4.0%, respectively, in a full backbend posture. The 'combined injury mechanism' was partially replicated in the animal model. Conclusion: Spinal overstretch and transient dislocation are considered the primary mechanisms by which SCIWORA occurs in children. Overstretching the femoral nerve aggravates spinal cord injuries caused by backbend practice.

Current Advances and Future Strategies for BCL-2 Inhibitors: Potent Weapons against Cancers.

Targeting the intrinsic apoptotic pathway regulated by B-cell lymphoma-2 (BCL-2) antiapoptotic proteins can overcome the evasion of apoptosis in cancer cells. BCL-2 inhibitors have evolved into an important means of treating cancers by inducing tumor cell apoptosis. As the most extensively investigated BCL-2 inhibitor, venetoclax is highly selective for BCL-2 and can effectively inhibit tumor survival. Its emergence and development have significantly influenced the therapeutic landscape of hematological malignancies, especially in chronic lymphocytic leukemia and acute myeloid leukemia, in which it has been clearly incorporated into the recommended treatment regimens. In addition, the considerable efficacy of venetoclax in combination with other agents has been demonstrated in relapsed and refractory multiple myeloma and certain lymphomas. Although venetoclax plays a prominent antitumor role in preclinical experiments and clinical trials, large individual differences in treatment outcomes have been characterized in real-world patient populations, and reduced drug sensitivity will lead to disease recurrence or progression. The therapeutic efficacy may vary widely in patients with different molecular characteristics, and key genetic mutations potentially result in differential sensitivities to venetoclax. The identification and validation of more novel biomarkers are required to accurately predict the effectiveness of BCL-2 inhibition therapy. Furthermore, we summarize the recent research progress relating to the use of BCL-2 inhibitors in solid tumor treatment and demonstrate that a wealth of preclinical models have shown promising results through combination therapies. The applications of venetoclax in solid tumors warrant further clinical investigation to define its prospects.

A novel polyhedral oligomeric silsesquioxane nanohybrid fluorescent sensor designed based on an osmotic mechanism for specific detection and intelligent scavenging of magnesium ions.

BACKGROUND: Mg2+ has long been recognized as one of the most vital cations due to its diverse physiological and pathological roles, making it indispensable in both biomedical and biological research. Organic fluorescent sensors are commonly employed for Mg2+ detection, but they often lack high selectivity and exhibit poor hydrophilicity, limiting their biomedical applications. RESULTS: Herein, we introduced a novel organic-inorganic hybrid fluorescence sensor, PFHBS, constructed on the POSS nanoplatforms. The efficient connection between PEGylated POSS and the small molecule sensor FHBS through Click chemistry enhances the selectivity and reduces interference, making this chemical sensor ideal for the accurate detection of Mg2+. Furthermore, the incorporation of POSS amplifies the ligand field effect of FHBS, making it more conducive to Mg2+ capture. The modification of PEG chains enhances the sensor's amphiphilicity, facilitating efficient cell penetration and effective Mg2+ detection at the biological level. SIGNIFICANCE: Finally, relying on spontaneous permeation, coupled with its strong ligand field effect and excellent cell permeability, the chemosensor demonstrates the capability to intelligently remove excess Mg2+ from the body. It has been successfully applied to mitigate renal overload resulting from acute Mg2+ poisoning.

Semi-supervised enhanced discriminative local constraint preserving projection for dimensionality reduction of medical hyperspectral images.

Microscopic hyperspectral images has the advantage of containing rich spatial and spectral information. However, the large number of spectral bands provides a significant amount of spectral features, but also leads to data redundancy and noise, which seriously affect the recognition and classification performance of the images, as well as increasing the requirements for computation and storage. To address this issue, we propose a dimensionality reduction algorithm named enhanced discriminant local constraint preserving projection (EDLCPP). Specifically, the global spectral attention mechanism focuses on important bands, the high discriminability sample selection module measures the discriminability of samples using a modified average neighborhood margin, the graph construction module preserves the local geometric relationship and discriminant information, and the graph embedding module embeds the constructed graphs into a low-dimensional space to obtain the projection matrices. Experimental results on eight cholangiocarcinoma (CCA) hyperspectral images, Bloodcell1-3, and Bloodcell2-2 datasets have demonstrated the effectiveness of the proposed method.

Establishing a Mouse Model of Chlorpromazine-Induced Corneal Trigeminal Denervation.

Purpose: This study aimed to establish a mouse model of chlorpromazine-induced corneal trigeminal denervation (CCTD). Methods: Retrobulbar chlorpromazine injections were administered to 6- to 8-week-old C57BL/6j mice to induce corneal denervation. Additionally, apoptosis was assessed in isolated primary trigeminal ganglion cells after culturing in a conditioned medium containing chlorpromazine. Finally, the success rate of model generation, mortality and complication rates, and model-preparation learning curves were compared between the CCTD model and the electrocoagulation and axotomy models. Results: Chlorpromazine retrobulbar injections resulted in trigeminal denervation, leading to a reduced blink reflex, corneal nerve density, and corneal epithelium thickness. Furthermore, 90% (9/10) of the mice developed epithelial defects, accompanied by increased apoptosis and inhibited proliferation of corneal epithelial cells. In vitro, trigeminal ganglion cell apoptosis increased after culturing in a conditioned medium containing chlorpromazine. Moreover, the CCTD model exhibited a higher success rate, longer survival rate, and lower complication rate compared to the electrocoagulation and axotomy models. Crucially, the learning curve demonstrated that the method used to generate the CCTD model was easy to learn. Conclusions: The CCTD model is a user-friendly mouse model for studying corneal trigeminal denervation that offers a less invasive alternative to existing models. Translational Relevance: The CCTD model serves as a valuable tool for investigating the functional mechanisms of corneal trigeminal nerves and their interactions with corneal cells.

Survival of 48866 cancer patients: results from Nantong area, China.

Objective: This study aimed to provide a realistic observation of survival by major site for 48,866 cancer patients treated at a tertiary cancer hospital in a rural area of China. Methods: Patients with cancer registered between 2007 and 2017 in the Nantong rural area were followed up. The starting date for survival calculation was the date of the first diagnosis of cancer at the Nantong Tumor Hospital, and the closing date was December 31, 2020. Observed survival (OS) was analyzed according to ICD-10 site, sex, age, region, and hospitalization period using the life table method and compared using the Wilcoxon (Gehan) statistic. Results: The overall 5-year OS rate was 40.48% for all 48,866 patients, 30.19% for males, and 51.90% for females. The top five cancer sites, accounting for 60.51% of the total cases, were the esophagus, lung, stomach, liver, and cervix, with 5-year OS rates of 33.72%, 18.64%, 32.10%, 19.04%, and 71.51%, respectively. The highest 5-year OS was observed in the thyroid (87.52%) and the lowest was in the pancreas (6.37%). Survival was significantly higher in younger patients than in older patients, with 5-year OSs of 69.26% and 19.84% in those aged 20-29 and 90-99 years, respectively. Five-year OSs improved significantly from 39.35% in 2007-2011 to 41.26% in 2012-2017. Conclusion: Overall survival improved over the years, although the improvement at some sites was not significant. The observed survival varies from region to region, reflecting differences in the patterns of major sites, disparities in proportions of hospitalization, and demographic characteristics.

Two-dimensional substrate assisted SERS immunosensor for accurate detection of carcinoembryonic antigen.

Accurate and sensitive detection of carcinoembryonic antigen (CEA) is essential for the detection of various diseases in healthcare and the medical field. Currently, due to the high false negative rate of CEA assay in clinical setting and its use as a common indicator for early cancer screening, a novel CEA detection method with high sensitivity, increased specificity and the lower cost has become a clinical challenge. Here, a facile sandwich type immunosensor based on surface-enhanced Raman scattering (SERS) was presented including 4-mercaptobenzonitrile (4MBN) labeled gold core-silver shell nanoparticles (Au@4MBN@Ag NPs) as SERS tag and 4-mercaptophenylboronic acid (4-MPBA) functionalized two-dimensional (2D) silver nanoparticle film (Ag FM) as SERS capture substrate for CEA detection. A linearity of 10-9-10-14M was observed with high sensitivity and excellent selectivity for the detection of CEA. Additionally, the spiking experiment yielded 105.33-127.00% recovery with variation coefficients below 10% demonstrating high assay accuracy and precision. The immunosensor we proposed here is a promising approach to quantify CEA in liquid biopsy samples with high sensitivity, which could be further developed for early cancer screening.

A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy.

Currently the main treatment of acute myeloid leukemia (AML) is chemotherapy combining hematopoietic stem cell transplantation. However, the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice. Thus, there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects. Here, we revealed that umbilical cord-derived mesenchymal stem cells (UC-MSC) efficiently induced AML cell differentiation by shuttling the neutrophil elastase (NE)-packaged extracellular vesicles (EVs) into AML cells. Interestingly, the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor (VDR) activation in UC-MSC. Chemical activation of VDR by using its agonist 1α,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model. Based on these discoveries, to evade the risk of hypercalcemia, we synthetized and identified sw-22, a novel non-steroidal VDR agonist, which exerted a synergistic pro-differentiation function with UC-MSC on mitigating the progress of AML. Collectively, our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.

Unsupervised dimensionality reduction of medical hyperspectral imagery in tensor space.

BACKGROUND AND OBJECTIVES: Compared with traditional RGB images, medical hyperspectral imagery (HSI) has numerous continuous narrow spectral bands, which can provide rich information for cancer diagnosis. However, the abundant spectral bands also contain a large amount of redundancy information and increase computational complexity. Thus, dimensionality reduction (DR) is essential in HSI analysis. All vector-based DR methods ignore the cubic nature of HSI resulting from vectorization. To overcome the disadvantage of vector-based DR methods, tensor-based techniques have been developed by employing multi-linear algebra. METHODS: To fully exploit the structure features of medical HSI and enhance computational efficiency, a novel method called unsupervised dimensionality reduction via tensor-based low-rank collaborative graph embedding (TLCGE) is proposed. TLCGE introduces entropy rate superpixel (ERS) segmentation algorithm to generate superpixels. Then, a low-rank collaborative graph weight matrix is constructed on each superpixel, greatly improving the efficiency and robustness of the proposed method. After that, TLCGE reduces dimensions in tensor space to well preserve intrinsic structure of HSI. RESULTS: The proposed TLCGE is tested on cholangiocarcinoma microscopic hyperspectral data sets. To further demonstrate the effectiveness of the proposed algorithm, other machine learning DR methods are used for comparison. Experimental results on cholangiocarcinoma microscopic hyperspectral data sets validate the effectiveness of the proposed TLCGE. CONCLUSIONS: The proposed TLCGE is a tensor-based DR method, which can maintain the intrinsic 3-D data structure of medical HSI. By imposing the low-rank and sparse constraints on the objective function, the proposed TLCGE can fully explore the local and global structures within each superpixel. The computational efficiency of the proposed TLCGE is better than other tensor-based DR methods, which can be used as a preprocessing step in real medical HSI classification or segmentation.

Variations in Rope Skipping Counts Among Rural Primary and Secondary School Students - China, 2013-2021.

What is already known about this topic?: Physical fitness is closely associated with children's development. Limited research has been published on the changes in physical fitness among Chinese children during the implementation of the Nutrition Improvement Program for Rural Compulsory Education Students (NIPRCES). What is added by this report?: This research utilized data from the NIPRCES between 2013 and 2021 to examine alterations in children's physical fitness levels. Over this period, there was a significant increase in the number of rope skipping counts among children. In 2021, variations in these counts were observed, which depended on factors such as age, gender, geographic location, and region. What are the implications for public health practice?: Physical fitness has been linked to a multitude of non-communicable diseases. Enhanced nutritional measures for children lead to significant improvements in their overall physical fitness, as evidenced by NIPRCES findings. It is crucial for policymakers to implement comprehensive interventions aimed at promoting and advancing children's physical fitness.