SOX9 Modulates the Transformation of Gastric Stem Cells Through Biased Symmetric Cell Division.

BACKGROUND & AIMS: Transformation of stem/progenitor cells has been associated with tumorigenesis in multiple tissues, but stem cells in the stomach have been hard to localize. We therefore aimed to use a combination of several markers to better target oncogenes to gastric stem cells and understand their behavior in the initial stages of gastric tumorigenesis. METHODS: Mouse models of gastric metaplasia and cancer by targeting stem/progenitor cells were generated and analyzed with techniques including reanalysis of single-cell RNA sequencing and immunostaining. Gastric cancer cell organoids were genetically manipulated with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) for functional studies. Cell division was determined by bromodeoxyuridine-chasing assay and the assessment of the orientation of the mitotic spindles. Gastric tissues from patients were examined by histopathology and immunostaining. RESULTS: Oncogenic insults lead to expansion of SOX9+ progenitor cells in the mouse stomach. Genetic lineage tracing and organoid culture studies show that SOX9+ gastric epithelial cells overlap with SOX2+ progenitors and include stem cells that can self-renew and differentiate to generate all gastric epithelial cells. Moreover, oncogenic targeting of SOX9+SOX2+ cells leads to invasive gastric cancer in our novel mouse model (Sox2-CreERT;Sox9-loxp(66)-rtTA-T2A-Flpo-IRES-loxp(71);Kras(Frt-STOP-Frt-G12D);P53R172H), which combines Cre-loxp and Flippase-Frt genetic recombination systems. Sox9 deletion impedes the expansion of gastric progenitor cells and blocks neoplasia after Kras activation. Although Sox9 is not required for maintaining tissue homeostasis where asymmetric division predominates, loss of Sox9 in the setting of Kras activation leads to reduced symmetric cell division and effectively attenuates the Kras-dependent expansion of stem/progenitor cells. Similarly, Sox9 deletion in gastric cancer organoids reduces symmetric cell division, organoid number, and organoid size. In patients with gastric cancer, high levels of SOX9 are associated with recurrence and poor prognosis. CONCLUSION: SOX9 marks gastric stem cells and modulates biased symmetric cell division, which appears to be required for the malignant transformation of gastric stem cells.

Integrated profiling identifies DXS253E as a potential prognostic marker in colorectal cancer.

BACKGROUND: Increasing evidence suggests that DXS253E is critical for cancer development and progression, but the function and potential mechanism of DXS253E in colorectal cancer (CRC) remain largely unknown. In this study, we evaluated the clinical significance and explored the underlying mechanism of DXS253E in CRC. METHODS: DXS253E expression in cancer tissues was investigated using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The Kaplan-Meier plot was used to assess the prognosis of DXS253E. The cBioPortal, MethSurv, and Tumor Immune Estimation Resource (TIMER) databases were employed to analyze the mutation profile, methylation, and immune infiltration associated with DXS253E. The biological functions of DXS253E in CRC cells were determined by CCK-8 assay, plate cloning assay, Transwell assay, flow cytometry, lactate assay, western blot, and qRT-PCR. RESULTS: DXS253E was upregulated in CRC tissues and high DXS253E expression levels were correlated with poor survival in CRC patients. Our bioinformatics analyses showed that high DXS253E gene methylation levels were associated with the favorable prognosis of CRC patients. Furthermore, DXS253E levels were linked to the expression levels of several immunomodulatory genes and an abundance of immune cells. Mechanistically, the overexpression of DXS253E enhanced proliferation, migration, invasion, and the aerobic glycolysis of CRC cells through the AKT/mTOR pathway. CONCLUSIONS: We demonstrated that DXS253E functions as a potential role in CRC progression and may serve as an indicator of outcomes and a therapeutic target for regulating the AKT/mTOR pathway in CRC.

[Clinical features and prognosis of children with fungal bloodstream infection following chemotherapy for acute leukemia]. / å„¿ç«¥æ€¥æ€§ç™½è¡€ç— åŒ–ç–—åŽåˆå¹¶çœŸèŒè¡€æµæ„ŸæŸ“çš„ä¸´åºŠç‰¹å¾åŠé¢„åŽåˆ†æž.

OBJECTIVES: To investigate the clinical features and prognosis of children with fungal bloodstream infection (BSI) following chemotherapy for acute leukemia (AL). METHODS: A retrospective analysis was performed on 23 children with fungal BSI following chemotherapy for AL in three hospitals in Fujian Province, China, from January 2015 to December 2023. Their clinical features and prognosis were analyzed. RESULTS: Among all children following chemotherapy for AL, the incidence rate of fungal BSI was 1.38% (23/1 668). At the time of fungal BSI, 87% (20/23) of the children had neutrophil deficiency for more than one week, and all the children presented with fever, while 22% (5/23) of them experienced septic shock. All 23 children exhibited significant increases in C-reactive protein and procalcitonin levels. A total of 23 fungal isolates were detected in peripheral blood cultures, with Candida tropicalis being the most common isolate (52%, 12/23). Caspofungin or micafungin combined with liposomal amphotericin B had a relatively high response rate (75%, 12/16), and the median duration of antifungal therapy was 3.0 months. The overall mortality rate in the patients with fungal BSI was 35% (8/23), and the attributable death rate was 22% (5/23). CONCLUSIONS: Fungal BSI following chemotherapy in children with AL often occurs in children with persistent neutrophil deficiency and lacks specific clinical manifestations. The children with fungal BSI following chemotherapy for AL experience a prolonged course of antifungal therapy and have a high mortality rate, with Candida tropicalis being the most common pathogen.

TMT Labeling under Acidic pH Overcomes Detrimental Overlabeling and Improves Peptide Identification Rates.

Tandem mass tags (TMT) are one of the most widely used techniques in proteomics quantification due to their ability to accurately and precisely analyze up to 18 samples in a multiplexed manner. Moreover, TMT tags are introduced chemically by covalent coupling of the primary amines of digested proteins, making them universally applicable for any kind of sample. However, in addition to amine groups, the hydroxyl groups of serine, threonine, and tyrosine residues can also be labeled to some extent during TMT labeling, which compromises the analytical sensitivity and results in lower peptide identification rates compared to label-free methods. In this work, we investigated in-depth the chemical nature of TMT overlabeling and revealed that peptides simultaneously containing histidine and hydroxyl-containing residues were prone to overlabeling due to an intramolecular catalysis mediated by the histidyl imidazolyl group. Based on the understanding of the chemical mechanism, we developed a novel TMT labeling method under acidic pH that completely overcomes overlabeling. Compared to the standard labeling method provided by the TMT vendor, our method achieved comparable labeling efficiency on target groups but greatly reduced overlabeled peptides, resulting in the identification of 33.9% more unique peptides and 20.9% more proteins in proteomic analysis.

[Reducing the Incidence of Postoperative Hypothermia in Patients Undergoing Robotic-Assisted Mitral Valve Surgery].

BACKGROUND & PROBLEMS: Post-operation hypothermia tends to induce complications. Sixty percent of robotic-assisted mitral valve surgery patients experienced hypothermia while admitted to our intensive care unit (ICU), resulting in prolonged ICU stays and 57% (eight) of those patients with hypothermia also experiencing cardiac arrhythmia. The causes of hypothermia in our ICU included low temperature in the operating room, delayed initiation of blanket coverage after surgery, and lack of postoperative thermal blankets, insufficient cardiopulmonary bypass rewarming time, cold ICU beds, lack of in-service training for hypothermia, and lack of procedure auditing. PURPOSE: This intervention was designed to reduce the incidence of hypothermia in ICU patients undergoing robotic-assisted mitral valve surgery upon ICU admission from 60% to 36% and the one-hour hypothermia rate from 43.3% to 26%. RESOLUTIONS: We implemented several measures including increasing the room temperature, pre-heating the ICU bed, achieving team consensus regarding prolonging the rewarming time after cardiopulmonary bypass, establishing a blanket warming area for postoperative patient use, and holding in-service training to enhance the awareness of the nurses were implemented. RESULTS: The incidence of hypothermia in ICU patients receiving robotic-assisted mitral valve surgery upon ICU admission decreased from 60% to 19.4%, while the one-hour hypothermia rate decreased from 43.3% to 19.4%. CONCLUSIONS: Using systemic interprofessional collaboration, combined thermal care can be achieved to significantly reduce the incidence of postoperative hypothermia in patients undergoing robotic-assisted mitral valve surgeries resulting in higher patient care quality and shorter ICU stays. We recommend applying this combined method to improve the quality of perioperative care for long-duration and major surgical procedures that involve large postoperative wounds and for patients who may require wider exposure during their operation.

[Clinical features and prognosis of high hyperdiploid childhood acute lymphoblastic leukemia: a multicenter retrospective analysis in Fujian Province, China]. / é«˜è¶ äºŒå€ä½“æ ¸åž‹å„¿ç«¥æ€¥æ€§æ·‹å·´ç»†èƒžç™½è¡€ç— çš„ä¸´åºŠç‰¹å¾åŠé¢„åŽ.

OBJECTIVES: To study the clinical features and prognosis of high hyperdiploid (HHD) childhood acute lymphoblastic leukemia (ALL). METHODS: A retrospective analysis was performed on the medical data of 1 414 children who were newly diagnosed with ALL and were admitted to five hospitals in Fujian Province of China from April 2011 to December 2020. According to karyotype, they were divided into two groups: HHD (n=172) and non-HHD (n=1 242). The clinical features and treatment outcome were compared between the two groups, and the factors influencing the prognosis were further explored. RESULTS: Among the 1 414 children with ALL, 172 (12.16%) had HHD. Compared with the non-HHD group, the HHD group had significantly lower proportions of children with risk factors for poor prognosis at diagnosis (age of onset ≥10 years or <1 year, white blood cell count ≥50×109/L, and T-cell phenotype) or positive fusion genes (TEL-AML1, BCR-ABL1, E2A-PBX1, and MLL gene rearrangement) (P<0.05). The HHD group had a significantly higher proportion of children with minimal residual disease (MRD) <0.01% at the end of induction chemotherapy (P<0.05). The 10-year event-free survival (EFS) rate and overall survival (OS) rate in the HHD group were significantly higher than those in the non-HHD group (P<0.05). The univariate analysis showed that the number of chromosomes of 58-66, trisomy of chromosome 10, trisomy of chromosome 17, bone marrow MRD <1% on day 15 or 19 of induction chemotherapy, and bone marrow MRD <0.01% on day 33 or 46 of induction chemotherapy were associated with a higher EFS rate (P<0.05), and trisomy of chromosome 10 was associated with a higher OS rate (P<0.05). The multivariate Cox analysis showed that trisomy of chromosome 17 was closely associated with a high EFS rate (P<0.05). CONCLUSIONS: The ALL children with HHD have few risk factors for poor prognosis at diagnosis and often have good prognosis. The number of chromosomes and trisomy of specific chromosomes are associated with prognosis in these children.

Reduced Platelet miR-223 Induction in Kawasaki Disease Leads to Severe Coronary Artery Pathology Through a miR-223/PDGFRß Vascular Smooth Muscle Cell Axis.

RATIONALE: Kawasaki disease (KD) is an acute vasculitis of early childhood that can result in permanent coronary artery structural damage. The cause for this arterial vulnerability in up to 15% of patients with KD is unknown. Vascular smooth muscle cell dedifferentiation play a key role in the pathophysiology of medial damage and aneurysm formation, recognized arterial pathology in KD. Platelet hyperreactivity is also a hallmark of KD. We recently demonstrated that uptake of platelets and platelet-derived miRNAs influences vascular smooth muscle cell phenotype in vivo. OBJECTIVE: We set out to explore whether platelet/vascular smooth muscle cell (VSMC) interactions contribute to coronary pathology in KD. METHODS AND RESULTS: We prospectively recruited and studied 242 patients with KD, 75 of whom had documented coronary artery pathology. Genome-wide miRNA sequencing and droplet digital PCR demonstrated that patient with KD platelets have significant induction of miR-223 compared with healthy controls (HCs). Platelet-derived miR-223 has recently been shown to promote vascular smooth muscle quiescence and resolution of wound healing after vessel injury. Paradoxically, patients with KD with the most severe coronary pathology (giant coronary artery aneurysms) exhibited a lack of miR-223 induction. Hyperactive platelets isolated from patients with KD are readily taken up by VSMCs, delivering functional miR-223 into the VSMCs promoting VSMC differentiation via downregulation of PDGFRß (platelet-derived growth factor receptor ß). The lack of miR-223 induction in patients with severe coronary pathology leads to persistent VSMC dedifferentiation. In a mouse model of KD (Lactobacillus casei cell wall extract injection), miR-223 knockout mice exhibited increased medial thickening, loss of contractile VSMCs in the media, and fragmentation of medial elastic fibers compared with WT mice, which demonstrated significant miR-223 induction upon Lactobacillus casei cell wall extract challenge. The excessive arterial damage in the miR-223 knockout could be rescued by adoptive transfer of platelet, administration of miR-223 mimics, or the PDGFRß inhibitor imatinib mesylate. Interestingly, miR-223 levels progressively increase with age, with the lowest levels found in <5-year-old. This provides a basis for coronary pathology susceptibility in this very young cohort. CONCLUSIONS: Platelet-derived miR-223 (through PDGFRß inhibition) promotes VSMC differentiation and resolution of KD induced vascular injury. Lack of miR-223 induction leads to severe coronary pathology characterized by VSMC dedifferentiation and medial damage. Detection of platelet-derived miR-223 in patients with KD (at the time of diagnosis) may identify patients at greatest risk of coronary artery pathology. Moreover, targeting platelet miR-223 or VSMC PDGFRß represents potential therapeutic strategies to alleviate coronary pathology in KD. Graphic Abstract: A graphic abstract is available for this article.

Safety and feasibility of esophagectomy following combined neoadjuvant immunotherapy and chemotherapy for locally advanced esophageal cancer: a propensity score matching.

OBJECTIVES: This study aims to investigate the efficacy and feasibility of esophagectomy following combined neoadjuvant immunotherapy and chemotherapy for locally advanced esophageal cancer. METHODS: We retrospectively identified patients who were treated with neoadjuvant immunotherapy and chemotherapy (NICT, n = 27) or chemotherapy alone (NCT, n = 95) at our institution between January, 2017 and April, 2021. The primary end point was 30-day complications. Major complications were defined as Clavien-Dindo classification grade ≥ 3. Secondary end points were interval to surgery, operation time, postoperative thoracic drainage, thoracic drainage tube stay, 30-day readmission rate, and 30-day mortality. Propensity score matching (PSM) was used to reduce bias caused by potential confounding. RESULTS: All patients included successfully completed neoadjuvant therapy and underwent McKeown minimally invasive esophagectomy negative margins. Out of 122 eligible patients, 26 patients in NICT group and 52 patients in NCT group were identified by 1:2 PSM. After PSM, the clinical stage was matched and demographic characteristics of the two groups were well balanced, including age, gender, BMI, ASA status, age-adjusted Charlson index, smoking, drinking, chemotherapy regimens, neoadjuvant cycle, tumor location, lymphadenectomy, pathological stage, histologic sub-type, anastomotic position, route of gastric conduit, procedure type, and operative approach were comparable between groups after PSM. Although NICT group had a higher incidence of pneumonia and pleural effusion, however, the CCI index, other complication and major complications were comparable between the two groups. There were no significant differences in operation time, intraoperative blood loss, thoracic drainage tube stays, thoracic drainage volume, ICU stay, postoperative hospital stay and hospital cost. Furthermore, 30-day mortality, 30-day readmission, ICU readmission were similar in both groups. CONCLUSIONS: Based on our preliminary experience, esophagectomy is safe and feasible following combined neoadjuvant immunotherapy with chemotherapy for locally advanced esophageal cancer.

VvHDZ28 positively regulate salicylic acid biosynthesis during seed abortion in Thompson Seedless.

Seedlessness in grapes is one of the features most appreciated by consumers. However, the mechanisms underlying seedlessness in grapes remain obscure. Here, we observe small globular embryos and globular embryos in Pinot Noir and Thompson Seedless from 20 to 30 days after flowering (DAF). From 40 to 50 DAF, we observe torpedo embryos and cotyledon embryos in Pinot Noir but aborted embryos and endosperm in Thompson Seedless. Thus, RNA-Seq analyses of seeds at these stages from Thompson Seedless and Pinot Noir were performed. A total of 6442 differentially expressed genes were identified. Among these, genes involved in SA biosynthesis, VvEDS1 and VvSARD1, were more highly expressed in Thompson Seedless than in Pinot Noir. Moreover, the content of endogenous SA is at least five times higher in Thompson Seedless than in Pinot Noir. Increased trimethylation of H3K27 of VvEDS1 and VvSARD1 may be correlated with lower SA content in Pinot Noir. We also demonstrate that VvHDZ28 positively regulates the expression of VvEDS1. Moreover, over-expression of VvHDZ28 results in seedless fruit and increased SA contents in Solanum lycopersicum. Our results reveal the potential role of SA and feedback regulation of VvHDZ28 in seedless grapes.

TOE1 acts as a 3' exonuclease for telomerase RNA and regulates telomere maintenance.

In human cells, telomeres are elongated by the telomerase complex that contains the reverse transcriptase hTERT and RNA template TERC/hTR. Poly(A)-specific ribonuclease (PARN) is known to trim hTR precursors by removing poly(A) tails. However, the precise mechanism of hTR 3' maturation remains largely unknown. Target of Egr1 (TOE1) is an Asp-Glu-Asp-Asp (DEDD) domain containing deadenylase that is mutated in the human disease Pontocerebella Hypoplasia Type 7 (PCH7) and implicated in snRNA and hTR processing. We have previously found TOE1 to localize specifically in Cajal bodies, where telomerase RNP complex assembly takes place. In this study, we showed that TOE1 could interact with hTR and the telomerase complex. TOE1-deficient cells accumulated hTR precursors, including oligoadenylated and 3'-extended forms, which was accompanied by impaired telomerase activity and shortened telomeres. Telomerase activity in TOE1-deficient cells could be rescued by wild-type TOE1 but not the catalytically inactive mutant. Our results suggest that hTR 3' end processing likely involves multiple exonucleases that work in parallel and/or sequentially, where TOE1 may function non-redundantly as a 3'-to-5' exonuclease in conjunction with PARN. Our study highlights a mechanistic link between TOE1 mutation, improper hTR processing and telomere dysfunction in diseases such as PCH7.

Stress and other factors associated with colorectal cancer outpatients with temporary colostomies.

This study investigated stress and other factors associated with colorectal cancer (CRC) outpatients with temporary colostomies in Taiwan. Temporary colostomies have been incorporated as a defecation alternative to maintain physical function and are accompanied by chemotherapy/radiotherapy in CRC patients. A cross-sectional study was conducted, and a convenience sampling approach was adopted to recruit 110 discharged CRC patients with temporary colostomies from a medical centre in southern Taiwan. The mean score of the Stress of Colostomy Patients Scale was 66.49 (out of 120). Demographic attributes were found to have an impact on different stress types. Stress of changes in familial and social interaction was affected by age, employment status, educational level and colostomy assistant caregiver. The stress of colostomy care was impacted by the factor of employment status, and the stress of changes of self-concept was impacted by the factors of educational level and self-perception of disease. The results provide post-operative information regarding stress and stress types among CRC patients with temporary colostomies, serve as a reference for clinical assessment, practice and care, and generate up-to-date knowledge and comprehension of learning how to live with a temporary colostomy.

Fabrication of Waterborne Silicone-Modified Polyurethane Nanofibers for Nonfluorine Elastic Waterproof and Breathable Membranes.

Waterproof and breathable membranes have a huge market demand in areas, such as textiles and medical protection. However, existing fluorinated nanofibrous membranes, while possessing good waterproof and breathable properties, pose health and environmental hazards. Consequently, fabricating fluorine-free, eco-friendly waterborne membranes by integrating outstanding waterproofing, breathability, and robust mechanical performance remains a significant challenge. Herein, we successfully prepared waterborne silicone-modified polyurethane nanofibrous membranes with excellent elasticity, waterproofing, and breathability properties through waterborne electrospinning, using a small quantity of poly(ethylene oxide) as a template polymer and in situ doping of the poly(carbodiimide) crosslinking agent, followed by a simple hot-pressing treatment. The silicone imparted the nanofibrous membrane with high hydrophobicity, and the crosslinking agent enabled its stable porous structure. The hot-pressing treatment (120 °C) further reduced the pore size and improved the water resistance. This environmentally friendly nanofibrous membrane showed a high elongation at break of 428%, an ultra-high elasticity of 67.5% (160 cycles under 400% tensile strain), an air transmission of 13.2 mm s-1, a water vapor transmission rate of 5476 g m-2 d-1, a hydrostatic pressure of 51.5 kPa, and a static water contact angle of 137.9°. The successful fabrication of these environmentally friendly, highly elastic membranes provides an important reference for applications in healthcare, protective textiles, and water purification.

[Clinical Characteristics and Prognosis of Children with Hypodiploid B-cell Precursor Acute Lymphoblastic Leukemia].

OBJECTIVE: To analyze the clinical characteristics and prognosis of children with hypodiploid B-cell precursor acute lymphoblastic leukemia (BCP-ALL). METHODS: The clinical data of 1 287 children with BCP-ALL admitted to five hospital in Fujian province from April 2011 to December 2020 were retrospectively analyzed. According to the results of chromosome karyotype, all the patients were grouped into hypodiploid subgroup and non-hypodiploid subgroup. The clinical characteristics, early treatment response ï¼»minimal residual disease (MRD) on middle stage of induction chemotherapy and end of induction chemotherapyï¼½ and long-term efficacy ï¼»overall survival (OS) and event-free survival (EFS)ï¼½ were compared. The prognostic factors of hypodiploid BCP-ALL were further explored. RESULTS: Among 1 287 BCP-ALL patients， 28 patients (2.2%) were hypodiploid BCP-ALL. The proportion of patients with white blood cell count （WBC）≥50×109/L in the hypodiploid subgroup was significantly higher than that in the non-hypodiploid subgroup (P =0.004), while there was no statistically significant difference in gender ratio, age group at initial diagnosis, and early treatment response between the two groups (all P >0.05). The 5-year EFS and OS rate of the hypodiploid subgroup were 75.0%(95%CI ：66.8%-83.2%) and 77.8%(95%CI ：69.8%-85.8%), respectively, which were lower than those of non-hypodiploid subgroup ï¼»EFS: 79.6%(95%CI ：78.4%-80.8%); OS: 86.4%(95%CI ：85.4%-87.5%)ï¼½, but the difference was not statistically significant (all P >0.05). Further subgroup analysis by risk stratification showed that the 5-year EFS and OS rates of the hypodiploid subgroup were significantly lower than those in the low-risk (LR) group ï¼»LR group EFS: 91.4% (95%CI ：88.4%-93.6% ), P < 0.001; OS: 94.7% (95%CI ：92.1%-96.4%), P < 0.001ï¼½ ; it was similar to that of BCP-ALL children stratified into intermediate-risk (IR) excluding hypodiploid ï¼»IR group EFS: 79.4%(95%CI ：74.9%-83.2%), P =0.343; OS: 87.3%(95%CI ：83.6%-90.2%), P =0.111ï¼½; while was higher than that of EFS in HR group, but the difference was not statistically significant ï¼»HR group EFS: 58.7%(95%CI ：52.6%-64.8%), P =0.178. OS: 69.9%(95%CI ：63.5%-75.4%), P =0.417ï¼½. Univariate analysis showed that gender, age, white blood cell count, and MRD on middle stage of induction chemotherapy had no significant impact on OS and EFS; chromosome count< 40 was a risk factor for lower OS (P =0.026), but has no significant effect on EFS; MRD≥0.01% after induction therapy was a risk factor for lower OS and EFS (P =0.002, and 0.001, respectively). CONCLUSION: Children with hypodiploid BCP-ALL have an intermediate prognosis, and MRD ≥0.01% after induction chemotherapy may be a risk factors for poor prognosis.

Preparation of Waterborne Silicone-Modified Polyurethane Nanofibers and the Effect of Crosslinking Agents on Physical Properties.

Silicone-modified polyurethane (PUSX) refers to the introduction of a silicone short chain into the polyurethane chain to make it have the dual properties of silicone and polyurethane (PU). It can be used in many fields, such as coatings, films, molding products, adhesives, and so on. The use of organic solvents to achieve the fiberization of silicone-modified polyurethane has been reported. However, it is challenging to achieve the fiberization of silicone-modified polyurethane based on an environmentally friendly water solvent. Herein, we report a simple and powerful strategy to fabricate environmentally friendly waterborne silicone-modified polyurethane nanofiber membranes through the addition of polyethylene glycol (PEG) with different molecular weights using electrospinning technology and in situ doping with three crosslinking agents with different functional groups (a polyoxazoline crosslinking agent, a polycarbodiimide crosslinking agent, and a polyisocyanate crosslinking agent) combined with various heating treatment conditions. The influence of PEG molecular weight on fiber formation was explored. The morphology, structure, water resistance, and mechanical properties were analyzed regarding the effect of the introduction of silicone into PU. The effects of the type and content of crosslinking agent on the morphology and physical properties of PUSX nanofiber membranes are discussed. These results show that the introduction of silicone can improve the water resistance and high temperature resistance of waterborne PU, and the addition of a crosslinking agent can further improve the water resistance of the sample, so that the sample can maintain good morphology after immersion. Crosslinking agents with different functional groups had different effects on the mechanical properties of PUSX nanofiber membranes due to different reactions. Among them, the oxazoline crosslinking agent had a significant effect on improving tensile strength, while the isocyanate crosslinking agent had a significant effect on improving the elongation at break. The PUSX nanofiber membrane prepared in this work did not use organic solvents that were harmful to humans and the environment, and it can be used in outdoor textiles, oil-water separation, medical health, and other fields.

NUAK1 activates STAT5/GLI1/SOX2 signaling to enhance cancer cell expansion and drives chemoresistance in gastric cancer.

The gene encoding the NUAK family kinase 1 (NUAK1) is frequently amplified and its expression is upregulated, activating oncogenic signaling in various cancers. However, little is known about its role in gastric cancer (GC). We investigate the mechanistic links among NUAK1, Hedgehog signaling, and tumorigenesis in GC. NUAK1 overexpression is validated in local and public GC cohorts. Patient-derived xenograft and transgenic mouse models demonstrate that NUAK1 depletion or inhibition dramatically ameliorates gastric tumorigenesis. NUAK1 upregulates GLI1 expression by activating STAT5-mediated transcription and stabilizing GLI1 protein. NUAK1 depletion or inhibition impairs cancer cell expansion, tumor formation, and chemotherapy resistance in in vitro and in vivo models. Clinicopathological analysis confirms that upregulated NUAK1 expression correlates with poor prognosis and chemotherapy resistance in human GC. Our findings demonstrate that the signaling axis NUAK1/STAT5/GLI1 promotes cancer cell expansion and tumorigenesis and indicate that NUAK1 is an attractive therapeutic target and prognostic factor in GC.

Togaram1 is expressed in the neural tube and its absence causes neural tube closure defects.

Neural tube closure defect pathomechanisms in human embryonic development are poorly understood. Here we identified spina bifida patients expressing novel variants of the TOGARAM gene family. TOGARAM1 has been associated with the ciliopathy Joubert syndrome, but its connection to spina bifida and role in neural development is unknown. We show that Togaram1 is expressed in the neural tube and Togaram1 knockout mice have abnormal cilia, reduced sonic hedgehog (Shh) signaling, abnormal neural tube patterning, and display neural tube closure defects. Neural stem cells from Togaram1 knockout embryos showed reduced cilia and defects in Shh signaling. Overexpression in IMCD3 and HEK293 cells of TOGARAM1 carrying the variant found in the spina bifida patient resulted in cilia defect along with reduced pericentriolar material one (PCM1), a critical constituent of centriolar satellites involved in transporting proteins toward the centrosome and primary cilia. Our results demonstrate the role of TOGARAM1 in regulating Shh signaling during early neural development that is critical for neural tube closure and elucidates potential mechanisms whereby the ciliopathy-associated gene TOGARAM1 gives rise to spina bifida aperta in humans.

Copy number amplification-induced overexpression of lncRNA LOC101927668 facilitates colorectal cancer progression by recruiting hnRNPD to disrupt RBM47/p53/p21 signaling.

BACKGROUND: Somatic copy number alterations (SCNAs) are pivotal in cancer progression and patient prognosis. Dysregulated long non-coding RNAs (lncRNAs), modulated by SCNAs, significantly impact tumorigenesis, including colorectal cancer (CRC). Nonetheless, the functional significance of lncRNAs induced by SCNAs in CRC remains largely unexplored. METHODS: The dysregulated lncRNA LOC101927668, induced by copy number amplification, was identified through comprehensive bioinformatic analyses utilizing multidimensional data. Subsequent in situ hybridization was employed to ascertain the subcellular localization of LOC101927668, and gain- and loss-of-function experiments were conducted to elucidate its role in CRC progression. The downstream targets and signaling pathway influenced by LOC101927668 were identified and validated through a comprehensive approach, encompassing RNA sequencing, RT-qPCR, Western blot analysis, dual-luciferase reporter assay, evaluation of mRNA and protein degradation, and rescue experiments. Analysis of AU-rich elements (AREs) within the mRNA 3' untranslated region (UTR) of the downstream target, along with exploration of putative ARE-binding proteins, was conducted. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and dual-luciferase reporter assays were employed to elucidate potential interacting proteins of LOC101927668 and further delineate the regulatory mechanism between LOC101927668 and its downstream target. Moreover, subcutaneous xenograft and orthotopic liver xenograft tumor models were utilized to evaluate the in vivo impact of LOC101927668 on CRC cells and investigate its correlation with downstream targets. RESULTS: Significantly overexpressed LOC101927668, driven by chr7p22.3-p14.3 amplification, was markedly correlated with unfavorable clinical outcomes in our CRC patient cohort, as well as in TCGA and GEO datasets. Moreover, we demonstrated that enforced expression of LOC101927668 significantly enhanced cell proliferation, migration, and invasion, while its depletion impeded these processes in a p53-dependent manner. Mechanistically, nucleus-localized LOC101927668 recruited hnRNPD and translocated to the cytoplasm, accelerating the destabilization of RBM47 mRNA, a transcription factor of p53. As a nucleocytoplasmic shuttling protein, hnRNPD mediated RBM47 destabilization by binding to the ARE motif within RBM47 3'UTR, thereby suppressing the p53 signaling pathway and facilitating CRC progression. CONCLUSIONS: The overexpression of LOC101927668, driven by SCNAs, facilitates CRC proliferation and metastasis by recruiting hnRNPD, thus perturbing the RBM47/p53/p21 signaling pathway. These findings underscore the pivotal roles of LOC101927668 and highlight its therapeutic potential in anti-CRC interventions.

[Clinical Features and Prognosis of Acute T-cell Lymphoblastic Leukemia in Children--Multi-Center Data Analysis in Fujian].

OBJECTIVE: To evaluate the efficacy of acute T-cell lymphoblastic leukemia (T-ALL) in children and explore the prognostic risk factors. METHODS: The clinical data of 127 newly diagnosed children with T-ALL admitted to five hospitals in Fujian province from April 2011 to December 2020 were retrospectively analyzed, and compared with children with newly diagnosed acute precursor B-cell lymphoblastic leukemia (B-ALL) in the same period. Kaplan-Meier analysis was used to evaluate the overall survival (OS) and event-free survival (EFS), and COX proportional hazard regression model was used to evaluate the prognostic factors. Among 116 children with T-ALL who received standard treatment, 78 cases received the Chinese Childhood Leukemia Collaborative Group (CCLG)-ALL 2008 protocol (CCLG-ALL 2008 group), and 38 cases received the China Childhood Cancer Collaborative Group (CCCG)-ALL 2015 protocol (CCCG-ALL 2015 group). The efficacy and serious adverse event (SAE) incidence of the two groups were compared. RESULTS: Proportion of male, age≥10 years old, white blood cell count (WBC)≥50×109/L, central nervous system leukemia, minimal residual disease (MRD)≥1% during induction therapy, and MRD≥0.01% at the end of induction in T-ALL children were significantly higher than those in B-ALL children (P <0.05). The expected 10-year EFS and OS of T-ALL were 59.7% and 66.0%, respectively, which were significantly lower than those of B-ALL (P <0.001). COX analysis showed that WBC≥100×109/L at initial diagnosis and failure to achieve complete remission (CR) after induction were independent risk factors for poor prognosis. Compared with CCLG-ALL 2008 group, CCCG-ALL 2015 group had lower incidence of infection-related SAE (15.8% vs 34.6%, P =0.042), but higher EFS and OS (73.9% vs 57.2%, P EFS=0.090; 86.5% vs 62.3%, P OS=0.023). CONCLUSIONS: The prognosis of children with T-ALL is worse than children with B-ALL. WBC≥100×109 /L at initial diagnosis and non-CR after induction (especially mediastinal mass has not disappeared) are the risk factors for poor prognosis. CCCG-ALL 2015 regimen may reduce infection-related SAE and improve efficacy.

Increased ONECUT2 induced by Helicobacter pylori promotes gastric cancer cell stemness via an AKT-related pathway.

Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2's role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/ß-catenin phosphorylation. AKT/ß-catenin phosphorylation facilitates ß-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and ß-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/ß-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment.