Phonon-Lithium Ion Interactions: A Case Study of LiM(SeO3)2 (M = Al, Ga, In, Sc, Y, and La).

Li ion diffusion is fundamentally a thermally activated ion hopping process. Recently, soft lattice, anharmonic phonon, and paddlewheel mechanism have been proposed to potentially benefit the ion transport, while the understanding of vibrational couplings of mobile ions and anions is still very limited but essential. Herein, we accessed the ionic conductivity, stability, and especially, lattice dynamics in LiM(SeO3)2 (M = Al, Ga, In, Sc, Y, and La) with two different types of oxygen anions within a LiO4 polyhedron, namely, edge-shared and corner-shared with MO6 polyhedra, the prototype of which, LiGa(SeO3)2, has been theoretically reported before with the similar structural features to NASICON and later experimentally synthesized with the room temperature conductivity ∼0.11 mS cm-1. It is interesting to note that LiM(SeO3)2 with a higher Li phonon band center shows higher Li conductivity, which is in contradiction to the conventional understanding of the importance for soft lattice to superionic conductors. The anharmonic and harmonic phonon interactions as well as the couplings between the vibration of the edge-bonded or corner-bonded anion in Li polyanions and the Li ion diffusion have been studied in detail. With transition metal M changing from La, Y, In, Ga, Al, and Sc, anharmonic phonons increase with reduced activation energy for Li diffusion. The phonon modes dominated by the edge-bonded oxygen anions contribute more to the migration of the Li ion than those dominated by the corner-bonded oxygen anions because of the greater atomic interaction between the Li ion and the edge-bonded anions. Thus, rather than the overall lattice softness, attention shall be given to reduce the frequency of the critical phonons contributing to Li ion diffusion as well as to increase the anharmonicity, i.e., through asymmetric Li polyhedra, for the design of Li ion superionic conductors for all-solid-state batteries.

m6A-driven NAT10 translation facilitates fatty acid metabolic rewiring to suppress ferroptosis and promote ovarian tumorigenesis through enhancing ACOT7 mRNA acetylation.

RNA epigenetic modifications have been implicated in cancer progression. However, the interplay between distinct RNA modifications and its role in cancer metabolism remain largely unexplored. Our study demonstrates that N-acetyltransferase 10 (NAT10) is notably upregulated in ovarian cancer (OC), correlating with poor patient prognosis. IGF2BP1 enhances the translation of NAT10 mRNA in an m6A-dependent manner in OC cells. NAT10 drives tumorigenesis by mediating N4-acetylcytidine (ac4C) modification of ACOT7 mRNA, thereby augmenting its stability and translation. This NAT10-ACOT7 axis modulates fatty acid metabolism in cancer cells and promotes tumor progression by suppressing ferroptosis. Additionally, our research identifies fludarabine as a small molecule inhibitor targeting NAT10, inhibits the ac4C modification and expression of ACOT7 mRNA. By using cell derived xenograft model and patient derived organoid model, we show that fludarabine effectively suppresses ovarian tumorigenesis. Overall, our study highlights the pivotal role of the NAT10-ACOT7 axis in the malignant cancer progression, underscoring the potential of targeting NAT10-mediated ac4C modification as a viable therapeutic strategy for this disease.

Multimodal apparent diffusion MRI model in noninvasive evaluation of breast cancer and Ki-67 expression.

BACKGROUND: To assess the capability of multimodal apparent diffusion (MAD) weighted magnetic resonance imaging (MRI) to distinguish between malignant and benign breast lesions, and to predict Ki-67 expression level in breast cancer. METHODS: This retrospective study was conducted with 93 patients who had postoperative pathology-confirmed breast cancer or benign breast lesions. MAD images were acquired using a 3.0 T MRI scanner with 16 b values. The MAD parameters, as flow (fF, DF), unimpeded (fluid) (fUI), hindered (fH, DH, and αH), and restricted (fR, DR), were calculated. The differences of the parameters were compared by Mann-Whitney U test between the benign/malignant lesions and high/low Ki-67 expression level. The diagnostic performance was assessed by the area under the receiver operating characteristic curve (AUC). RESULTS: The fR in the malignant lesions was significantly higher than in the benign lesions (P = 0.001), whereas the fUI and DH were found to be significantly lower (P = 0.007 and P < 0.001, respectively). Compared with individual parameter in differentiating malignant from benign breast lesions, the combination parameters of MAD (fR, DH, and fUI) provided the highest AUC (0.851). Of the 73 malignant lesions, 42 (57.5%) were assessed as Ki-67 low expression and 31 (42.5%) were Ki-67 high expression. The Ki-67 high status showed lower DH, higher DF and higher αH (P < 0.05). The combination parameters of DH, DF, and αH provided the highest AUC (0.691) for evaluating Ki-67 expression level. CONCLUSIONS: MAD weighted MRI is a useful method for the breast lesions diagnostics and the preoperative prediction of Ki-67 expression level.

Initial Experience of CT-Based Online Adaptive Radiotherapy for Nasopharyngeal Carcinoma With a Novel Integrated Platform: A Case Report.

Intensity-modulated radiation therapy (IMRT) improves tumor control and reduces long-term radiation-induced complications of patients with nasopharyngeal carcinoma (NPC), contingent upon accurate contouring and precise delivery of treatment plans. Online adaptive radiotherapy (ART) involves real-time treatment plan modification based on the variations in targets and organs at risk (OARs) to uphold treatment planning accuracy. This study describes the first reported case of fan beam computed tomography (FBCT)-guided online ART for NPC using a novel integrated platform. Online ART was performed at the 25th fraction in this case, as tumors and the patient's anatomy were observed to regress inter-fractionally, necessitating adjustments to the contours based on the anatomy of the day. Online ART plan optimized target volume coverage while reducing doses to OARs. Notably, online ART significantly improved radiotherapy efficiency. This patient achieved a clinical complete response 12 weeks post-treatment, with Epstein-Barr virus DNA levels reduced to 0 copies/ml. Currently, the patient is alive without evidence of high-grade toxicity or local recurrence at approximately 10 months post-treatment. This case confirms the feasibility and dosimetric benefit of online ART for NPC using a novel integrated platform. Further research is needed to confirm its clinical benefits.

Improving the sulfite-detection performance of a fluorescent probe via post-synthetic modification with a metal-organic framework.

In this work, a post-synthetic modification strategy was attempted to improve the performance of the probe for sulfite detection. The assembled platform UiO-66-NH-DQA, which was acquired by anchoring the sulfite-response fluorescent probe DQA onto the surface of UiO-66-NH2via amide covalent bonds, exhibited enhanced fluorescence intensity and practical intracellular imaging capability. In spite of the structural similarity, as verified by characterization tests, the conversion rate of post-synthetic modification was calculated as 35%, equaling an approximate assembly ratio of 1 : 2 between UiO-66-NH2 and DQA. Most significantly, conversion into UiO-66-NH-DQA led to a 5.6-fold enhancement in the reporting signal with a red shift of 20 nm. For sulfite detection, the linear range was 0-150 µM, with a limit of detection value of 0.025 µM. UiO-66-NH-DQA retained advantages including high stability (within pH 5.0-9.0), rapid response (within 15 min) and high selectivity. Based on low cytotoxicity and relatively rapid cellular uptake, UiO-66-NH-DQA achieved the imaging of both the exogenous and endogenous sulfite levels in living cells. In particular, its rapid cell-permeating capability was guaranteed during the modification. The post-synthetic modification strategy reported herein has potential for improving the practical properties of fluorescent monitoring materials.

Programmable intelligent DNA nanoreactors (iDNRs) for in vivo tumor diagnosis and therapy.

With the rapid advancement of DNA technology, intelligent DNA nanoreactors (iDNRs) have emerged as sophisticated tools that harness the structural versatility and programmability of DNA. Due to their structural and functional programmability, iDNRs play an important and unique role in in vivo tumor diagnosis and therapy. This review provides an overview of the structural design methods for iDNRs based on advanced DNA technology, including enzymatic reaction-mediated and enzyme-free strategies. This review also focuses on how iDNRs achieve intelligence through functional design, as well as the applications of iDNRs for in vivo tumor diagnosis and therapy. In summary, this review summarizes current advances in iDNRs technology, discusses existing challenges, and proposes future directions for expanding their applications, which are expected to provide insights into the development of the field of in vivo tumor diagnostics and targeted therapies.

Integrating UPLC-Q-Exactive Orbitrap/MS, Network pharmacology and experimental validation to reveal the potential mechanism of Kadsura cocicinea roots in Colon Cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Kadsura coccinea roots are a traditional folk medicine used to treat gastrointestinal diseases. In recent years, research on K. coccinea has predominantly focused on the analysis of chemical composition and screening for activity, but there is a scarcity of studies that employ mass spectrometry to analyze Kadsura coccinea roots. AIM OF THE STUDY: This study aimed to characterize the chemical composition of K. coccinea roots and explore the pharmacological mechanisms with network pharmacology. Cell assay and Western blot analysis were used to verify the pharmacological mechanism of the main compounds in K. coccinea roots. MATERIALS AND METHODS: UPLC-Q-Exactive Orbitrap/MS was used for chemical analysis of K. coccinea roots, and the compounds were identified by employing diagnostic product ions, fragmentation patterns, ChemSpider, and in-house databases. Network pharmacology was employed to estimate the pathways related to pharmacological mechanisms. In addition, MTT assay was conducted to determine the inhibitory activity of colon cancer cell lines, and their apoptotic abilities were evaluated by flow cytometry and Western blot. RESULTS: The UPLC-Q-Exactive Orbitrap/MS identified a total of 54 compounds in K. coccinea roots. The 54 compounds were subjected to network pharmacology analysis, exploring the pharmacological action of the main components of K. coccinea roots. The common targets between the compounds and colon cancer comprised 2009 GO biological process items and 186 KEGG signal pathways. Flow cytometry indicated that treatments with 20 µM of the above-named compounds resulted in an apoptosis rate of 16.6%, 79.7%, and 22.2% in HCT-116 cells, respectively. Meanwhile, Western blot analysis confirmed that the compounds promoted the expression of Bax and Caspase-3 level expression. CONCLUSION: The findings demonstrated that K. coccinea roots can treat colon cancer through multiple components, targets, and pathways. This study revealed the effective components and molecular mechanisms of K. coccinea, which were preliminarily verified using in vitro experiments.

α-Amino-ß-Carboxymuconate-ε-Semialdehyde Decarboxylase Catalyzes Enol/Keto Tautomerization of Oxaloacetate.

ACMSD (α-amino-ß-carboxymuconate-ε-semialdehyde decarboxylase) is a key metalloenzyme critical for regulating de novo endogenous NAD+/NADH biosynthesis through the tryptophan-kynurenine pathway. This decarboxylase is a recognized target implicated in mitochondrial diseases and neurodegenerative disorders. However, unraveling its enzyme-substrate complex has been challenging due to its high catalytic efficiency. Here, we present a combined biochemical and structural study wherein we determined the crystal structure of ACMSD in complex with malonate. Our analysis revealed significant rearrangements in the active site, particularly in residues crucial for ACMS decarboxylation, including Arg51, Arg239* (a residue from an adjacent subunit), His228, and Trp194. Docking modeling studies proposed a putative ACMS binding mode. Additionally, we found that ACMSD catalyzes oxaloacetic acid (OAA) tautomerization at a rate of 6.51 ± 0.42 s-1 but not decarboxylation. The isomerase activity of ACMSD on OAA warrants further investigation in future biological studies. Subsequent mutagenesis studies and crystallographic analysis of W194A variant shed light on the roles of specific second-coordination sphere residues. Our findings indicate that Arg51 and Arg239* are crucial for OAA tautomerization. Moreover, our comparative analysis with related isomerase superfamily members underscores a general strategy employing arginine residues to promote OAA isomerization. Given the observed isomerase activity of ACMSD on OAA and its structural similarity to ACMS, we propose that ACMSD may facilitate isomerization to ensure ACMS is in the optimal tautomeric form for subsequent decarboxylation initiated by the zinc-bound hydroxide ion. Overall, these findings deepen the understanding of the structure and function of ACMSD, offering insights into potential therapeutic interventions.

Health data science course for clinicians: Time to bridge the skills gap?

BACKGROUND: Data science skills are highly relevant for clinicians working in an era of big data in healthcare. However, these skills are not routinely taught, representing a growing unmet educational need. This education report presents a structured short course that was run to teach clinicians data science and the lessons learnt. METHODS: A 1-day introductory course was conducted within a tertiary hospital in London. It consisted of lectures followed by facilitated pair programming exercises in R, an object-oriented programming language. Feedback was collated and participant responses were graded using a Likert scale. RESULTS: The course was attended by 20 participants. The majority of participants (69%) were in higher speciality cardiology training. While more than half of the participants (56%) received prior training in statistics either through formal taught programmes (e.g., a Master's degree) or online courses, the participants reported several barriers to expanding their skills in data science due to limited programming skills, lack of dedicated time, training opportunities and awareness. After the short course, there was a significant increase in participants' self-rated confidence in using R for data analysis (mean response; before the course: 1.69 ± 1.0, after the course: 3.2 ± 0.9, p = .0005) and awareness of the capabilities of R (mean response; before the course: 2.1 ± 0.9, after the course: 3.6 ± 0.7, p = .0001, on a 5-point Likert scale). CONCLUSION: This proof-of-concept study demonstrates that a structured short course can effectively introduce data science skills to clinicians and supports future educational initiatives to integrate data science teaching into medical education.

Photodynamic therapy with intratumoral injection of photosensitizers combined with immunotherapy brings hope to patients with refractory cutaneous malignant ulcers.

Cutaneous squamous cell carcinoma (CSCC) is common among the elderly, typically treated with surgery. However, for surgery-ineligible patients or those with non-healing wounds progressing to malignant ulcers, non-surgical local treatments are viable. This case details an 80-year-old with recurrent back CSCC and intractable malignant ulcers post-radiotherapy and chemotherapy. Treatment involved Hematoporphyrin Derivative (HpD) Photodynamic Therapy (PDT) with low-dose cindilimab immunotherapy (intravenous and intralesional). Two cycles achieved lesion remission, altering peripheral immune cell counts. HpD-PDT combined with immunotherapy is promising for treating CSCC, particularly with malignant ulcers.

Systematic analysis based on bioinformatics and experimental validation identifies Alox5 as a novel therapeutic target of quercetin for sepsis.

PURPOSE: This study investigated the molecular mechanism of quercetin in the treatment of sepsis using network pharmacological prediction and experimentation. METHODS: Hub genes were identified by intersecting the differentially expressed genes (DEGs) of the GSE131761 and GSE9960 databases with genes from the hub modules of Weighted Gene Co-Expression Network Analysis (WGCNA), targets of quercetin, and ferroptosis. Subsequently, in order to determine the functional characteristics and molecular link of hub gene obtained above, we redetermined the hub-DEGs in GSE131761 according to high or low hub gene expression. Afterward, the main pathways of enrichment analysis were validated using these hub-DEGs. Finally, an experiment was conducted to validate the findings. RESULTS: By intersecting 1415 DEGs in GSE131761, 543 DEGs in GSE9960, 5784 key modular genes, 470 ferroptosis-related genes, and 154 quercetin-related genes, we obtained one quercetin-related gene, Alox5. Subsequently, 340 hub-DEGs were further validated according to high or low Alox5 expression. The results of the enrichment analysis revealed that hub-DEGs were mainly associated with inflammation and the immune response. Immune infiltration analysis showed that higher expression of Alox5 was related to macrophage infiltration and could be a predictor of diagnosis in patients with sepsis. The expression pattern of Alox5 was then depicted and the upregulation of Alox5 in the vital organs of septic mice was further demonstrated. In vitro and in vivo experiments showed that upregulation of Alox5 and inflammation-related cytokines induced by sepsis could be inhibited by quercetin (p < 0.05). CONCLUSIONS: Alox5 may be involved in the occurrence and development of multi-organ functional disturbances in sepsis and is a reliable target of quercetin against sepsis.

Bending-induced enhanced spatial separation of dopants and long-lived conventional nanoribbon p-n junctions.

The spatial separation of dopants is crucial in extending the lifetime of nanoribbon p-n junctions, which is traditionally realized via van der Waals heterostructures at a high cost. In this study, we employ atomistic quantum mechanical simulations to demonstrate that a simple in-plane bending deformation can lead to an enhanced doping preference in conventional nanoribbons. Dopants with larger atomic sizes than those of host atoms tend to reside on the tensile side close to the outermost edge of the bent nanoribbons, while dopants with smaller atomic sizes than those of host atoms tend to reside on the compressive side close to the innermost edge of the bent nanoribbons. We also show that this doping preference induces an enhanced spatial separation of n-type and p-type dopants with different atomic sizes. As conventional nanoribbons are easier to synthesize and cost-effective, our results provide a pathway for modulating dopant distribution and designing long-lived nanoribbon p-n junctions via inhomogeneous strain engineering.

Circadian variation pattern of sudden cardiac arrest occurred in Chinese community.

BACKGROUND: The circadian variation pattern of sudden cardiac arrest (SCA) occurred in Chinese community including both community healthcare centres and primary hospitals remains unknown. This study analysed the circadian variation of SCA in the Chinese community. METHODS: Data between 2018 and 2022 from the remote ECG diagnosis system of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine were analysed to examine the circadian rhythm of SCA, stratified by initial shockable (ventricular tachycardia or ventricular fibrillation) versus non-shockable (asystole or pulseless electrical activity) rhythm. RESULTS: Among 10 210 cases of SCA, major cases (8736, 85.6%) were non-shockable and 1474 (14.4%) cases were shockable. The circadian rhythm of SCA was as follows: peak time was from 08:00 to 11:59 (30.1%), while deep valley was from 00:00 to 03:59 (7.5%). The proportions of events by non-shockable and shockable events were similar and both reached their peak from 08:00 to 11:59, with a percentage of 29.0% and 36.4%, respectively. Multivariable analysis showed that the relative risk of shockable compared with non-shockable arrests was lower between 00:00 and 03:59 (adjusted OR (aOR): 0.72, 95% CI: 0.54 to 0.97, p=0.028) and 04:00 to 07:59 (aOR: 0.60, 95% CI: 0.46 to 0.79, p<0.001), but higher between 08:00 and 11:59 (aOR: 1.34, 95% CI: 1.09 to 1.64, p=0.005). CONCLUSIONS: In Chinese community, there is a distinct circadian rhythm of SCA, regardless of initial rhythms. Our findings may be helpful in decision-making, in that more attention and manpower should be placed on the morning hours of first-aid and resuscitation management in Chinese community.

Engineering microporous ethane-trapping metal-organic frameworks for boosting ethane/ethylene separation.

Realization of ethane-trapping materials for separating ethane (C2H6) from ethylene (C2H4) by adsorption, to potentially replace the energy-intensive cryogenic distillation technology, is of prime importance in the petrochemical industry. It is still very challenging to target C2H6-selective adsorbents with both high C2H6 capture capacity and gas selectivity. Herein, we report that a crystal engineering or reticular chemistry strategy enables the control of pore size and functionality in a family of isomorphic metal-organic frameworks (MOFs) for boosting the C2H6 uptake and selectivity simultaneously. By altering the carboxylic acid linker in Ni(bdc)(ted)0.5, we developed two novel isoreticular MOFs, Ni(ndc)(ted)0.5 and Ni(adc)(ted)0.5 (termed ZJU-120 and ZJU-121, respectively), in which the pore sizes and nonpolar aromatic rings can be finely engineered. We discover that activated ZJU-120a with the optimized pore size (4.4 Å) and aromatic rings exhibits both a very high C2H6 uptake (96 cm3 g-1 at 0.5 bar and 296 K) and C2H6/C2H4 selectivity (2.74), outperforming most of the C2H6-selective MOFs reported. Computational studies indicate that the suitable pore size and more nonpolar aromatic rings on the pore surfaces of ZJU-120a mainly contribute to its exceptional C2H6 uptake and selectivity. The breakthrough experiments demonstrate that ZJU-120a can efficiently separate C2H6 from 50/50 and 10/90C2H6/C2H4 mixtures under ambient conditions.

Elevated circulating regenerating islet-derived protein 4 levels in patients with metabolic syndrome and related to its key components.

PURPOSE: Regenerating islet-derived protein 4 (REG4) is a secretory protein that belongs to the C-type lectin superfamily. This study aims to explore the diagnostic value of REG4 as a potential biomarker for metabolic syndrome by analyzing the correlation between serum REG4 levels and metabolic syndrome. METHODS: Serum REG4 levels were measured using enzyme-linked immunosorbent assay (ELISA). Bioinformatics analysis was conducted to investigate REG4-related genes and metabolic signaling pathways. RESULTS: Serum REG4 levels were significantly elevated in MetS patients compared to healthy controls (439.7 vs. 422.6 ng/L, p < 0.01). In addition, circulating REG4 levels showed a positive correlation with AUGg, HbA1c, VAI, BMI, WHR, TG, TC, LDL-C, while being inversely correlated with HDL-C in the study population. Serum REG4 levels were positively correlated with MetS score. Multiple linear regression analysis identified HOMA-IR and LDL-C as independent factors affecting serum REG4 concentration. Interventional studies have shown that OGTT can significantly increase serum REG4 levels in healthy individuals, but significantly reduce REG4 levels in MetS patients. Bioinformatics analysis suggested that REG4 is linked to several metabolism-related genes and is enriched in various metabolism-related signaling pathways. CONCLUSION: REG4 may serve as a valuable biomarker and potential treatment target for insulin resistance (IR) and MetS. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR2000032878.

A Phase 3, Open-Label, Single-Arm Trial of the Efficacy and Safety of Triptorelin 6-Month Formulation in Chinese Children with Central Precocious Puberty.

INTRODUCTION: This phase 3 study assessed the efficacy, safety, and pharmacokinetics of the 6-month prolonged release (PR) formulation in Chinese children with central precocious puberty (CPP). METHODS: In this open-label study (NCT05029622), Chinese children (girls < 9 years, boys < 10 years) received two doses of triptorelin pamoate 22.5 mg (day 1 and month 6). Primary endpoint was the proportion at month 6 with luteinizing hormone (LH) suppression (stimulated peak LH ≤ 5 IU/L after gonadotropin-releasing hormone stimulation). Secondary endpoints included safety assessments, hormone level changes, and clinical parameters from baseline. RESULTS: Overall, 66 children completed the study (93.9% girls; median age 8.0 [range 5-9] years). At month 6, all patients had LH suppression; this was maintained at month 12 in 98.5% of patients. Mean basal and peak LH and follicle-stimulating hormone levels were suppressed throughout follow-up. All patients at months 3 to 12 had sex hormone suppression to prepubertal levels. Stable or reduced breast development was seen for 98.4% and 93.5% of girls at month 6 and 12, respectively; all boys had regression or stable genital development until month 12. Compared with baseline (9.82 cm/year), mean growth velocity was 5.88 cm/year at month 6 and 5.17 cm/year at month 12. Mean bone age/chronological age ratio decreased from 1.27 at baseline to 1.23 and 1.21 at month 6 and 12, respectively. In girls, 64.5% showed decreased uterine length at month 6 and 12 versus baseline, while 75.0% of boys showed stable testicular volume versus baseline. Thirteen patients (19.7%) had 22 drug-related treatment emergent adverse events (TEAEs); no grade ≥ 3 TEAEs were reported. CONCLUSION: The efficacy and safety profile of triptorelin 6-month PR in Chinese children with CPP was consistent with data previously reported in non-Chinese children with CPP, supporting this as a viable treatment option for Chinese children with CPP. TRIAL REGISTRATION: Trial registration: ClinicalTrials.gov identifier, NCT05029622.

WHAT IS CENTRAL PRECOCIOUS PUBERTY (CPP)?: CPP is a condition where reproductive organs and sexual characteristics develop too early, before the age of 8 years in girls or 9 years in boys. CPP can negatively affect the mental health of patients and their caregivers. It can also lead to long-term problems like obesity and diabetes. CPP is caused by high levels of a hormone called luteinizing hormone. HOW IS CPP TREATED?: Triptorelin is an injectable treatment that can lower luteinizing hormone levels. Triptorelin injections are available for use once every month, once every 3 months, or once every 6 months. The injection for use once every 6 months (the 6-monthly injection) is not currently approved for CPP treatment in China. WHAT DID THIS STUDY LOOK AT?: This study assessed how well the 6-monthly triptorelin injections worked in 66 Chinese children with CPP. One injection was given at the start of the study and one after 6 months. WHAT WERE THE RESULTS?: Six months after their first injection, all children had luteinizing hormone levels that were below those seen with CPP. The development of sexual characteristics had slowed, such as pubic hair growth, breast and uterine length for girls, and testicular volume for boys. In addition, the rate at which children were increasing in height had also slowed down. These treatment effects were also seen at 12 months (6 months after the second injection). No children stopped treatment because of side effects. The researchers concluded that 6-monthly triptorelin may be a good treatment option for Chinese children with CPP.

Deficiency of SLC26A3 promotes jejunal barrier damage in metabolic disease-susceptible transgenic pigs.

Intestinal disorders are common in metabolic syndrome. However, their pathogenesis is still not fully understood. Pig and human intestines are highly similar in terms of associated metabolic processes. Here, we successfully constructed a metabolic disease-susceptible transgenic (TG) Bama pig model by knocking in three humanized disease risk genes with the CRISPR/Cas9 technique to assess its potential as a model for human intestinal diseases and explore the possible pathological mechanisms involved. We found that jejunal barrier integrity was disrupted and that the infiltration of inflammatory cells increased in TG pigs after high-fat and high-sucrose diet (HFHSD) treatment. We revealed significant differences in the transcriptome, associated microbiome profiles and microbial metabolite short-chain fatty acid (SCFA) content of the jejunum of TG pigs. Notably, we found that SLC26A3 was significantly downregulated in TG pigs. Knockdown or overexpression of the SLC26A3 gene in IPEC-J2 cells significantly affected the expression of MUC2, MUC13 and occludin. Furthermore, in vitro experiments further verified that CDX2 directly regulated the expression of SLC26A3. Mechanistically, CDX2 mediated intestinal barrier function by enhancing the expression of SLC26A3 by binding to its promoter region between -1120 and - 1070 bp. TG pigs represent a promising model that provides new insights into preclinical research on human intestinal metabolic diseases associated with metabolic disorders and revealed that SLC26A3 may be a potential therapeutic target for intestinal metabolic diseases.

Toripalimab in combination with chemotherapy effectively suppresses local recurrence and metastatic sarcomatoid renal cell carcinoma: A case report.

BACKGROUND: Sarcomatoid renal cell carcinoma (SRCC) is a rare variant of renal cell carcinoma associated with an unfavorable prognosis. The efficacy of conventional chemotherapy and targeted therapies are limited, whereas the emergence of immune checkpoint inhibitor has introduced new avenues for managing advanced SRCC. CASE SUMMARY: A 77-year-old female patient was referred to our hospital following the incidental detection of a right kidney tumor without specific symptoms. The tumor was successfully resected, and subsequent pathological examination confirmed SRCC. She experienced both local recurrence and distant metastasis eight months after the initial laparoscopic resection. Following six cycles of toripalimab combined with pirarubicin chemotherapy, the patient achieved a partial response. Subsequently, the patient attained an almost-complete continuous response to toripalimab monotherapy maintenance for an additional six cycles. She has not experienced disease progression for 15 months, and her overall survival has reached 24 months thus far. CONCLUSION: Combination therapy with programmed death 1 antibodies and cytotoxic agents may be a recommended first-line treatment approach for SRCC.

Construction of self-driving anti-αFR CAR-engineered NK cells based on IFN-γ and TNF-α synergistically induced high expression of CXCL10.

INTRODUCTION: Ovarian cancer is the most malignant gynecological tumor. Previous studies have demonstrated that chimeric antigen receptor (CAR)-engineered NK-92 cells targeting folate receptor α (αFR) (NK-92-αFR-CAR) can specifically kill αFR-positive ovarian cancer cells. However, the migration barrier restricts antitumor effects of CAR-engineered cells. OBJECTIVES: To elucidate the mechanism by which NK-92-αFR-CAR cells induce the secretion of chemokine CXCL10 during killing ovarian cancer cells. It is speculated that NK-92-αFR-CAR-CXCR3A can target αFR and have chemotaxis of CXCL10, and they may have stronger killing effect of ovarian cancer. METHODS: Study the mechanism of CXCL10 expression strongly induced by TNF-α and IFN-γ combined stimulation in ovarian cancer cells. Construct the fourth generation of NK-92-αFR-CAR-CXCR3A cells, which were co-expressed CXCR3A and αFR-CAR. Evaluate the killing and migration effects of NK-92-αFR-CAR-CXCR3A in vitro and in vivo. RESULTS: RNA sequencing (RNA-seq) first revealed that the expression level of the chemokine CXCL10 was most significantly increased in ovarian cancer cells co-cultured with NK-92-αFR-CAR. Secondly, cytokine stimulation experiments confirmed that IFN-γ and TNF-α secreted by NK-92-αFR-CAR synergistically induced high CXCL10 expression in ovarian cancer cells. Further signaling pathway experiments showed that IFN-γ and TNF-α enhanced the activation level of the IFN-γ-IFNGR-JAK1/2-STAT1-CXCL10 signaling axis. Cytotoxicity experiments showed that NK-92-αFR-CAR-CXCR3A cells could not only efficiently kill αFR-positive ovarian cancer cells in vitro but also secrete IFN-γ and TNF-α. Higher migration than that of NK-92-αFR-CAR was detected in NK-92-αFR-CAR-CXCR3A using transwell assay. NK-92-αFR-CAR-CXCR3A effectively killed tumor cells in different mouse xenograft models of ovarian cancer and increased infiltration into tumor tissue. CONCLUSION: This study confirmed that IFN-γ and TNF-α secreted by αFR-CAR-engineered NK cells can synergistically induce high expression of CXCL10 in ovarian cancer cells and constructed self-driving αFR-CAR-engineered NK cells that can break through migration barriers based on CXCL10, which may provide a new therapeutic weapon for ovarian cancer.