Dual-role transcription factors stabilize intermediate expression levels.

Precise control of gene expression levels is essential for normal cell functions, yet how they are defined and tightly maintained, particularly at intermediate levels, remains elusive. Here, using a series of newly developed sequencing, imaging, and functional assays, we uncover a class of transcription factors with dual roles as activators and repressors, referred to as condensate-forming level-regulating dual-action transcription factors (TFs). They reduce high expression but increase low expression to achieve stable intermediate levels. Dual-action TFs directly exert activating and repressing functions via condensate-forming domains that compartmentalize core transcriptional unit selectively. Clinically relevant mutations in these domains, which are linked to a range of developmental disorders, impair condensate selectivity and dual-action TF activity. These results collectively address a fundamental question in expression regulation and demonstrate the potential of level-regulating dual-action TFs as powerful effectors for engineering controlled expression levels.

Induction of mouse totipotent stem cells by a defined chemical cocktail.

In mice, only the zygotes and blastomeres from 2-cell embryos are authentic totipotent stem cells (TotiSCs) capable of producing all the differentiated cells in both embryonic and extraembryonic tissues and forming an entire organism1. However, it remains unknown whether and how totipotent stem cells can be established in vitro in the absence of germline cells. Here we demonstrate the induction and long-term maintenance of TotiSCs from mouse pluripotent stem cells using a combination of three small molecules: the retinoic acid analogue TTNPB, 1-azakenpaullone and the kinase blocker WS6. The resulting chemically induced totipotent stem cells (ciTotiSCs), resembled mouse totipotent 2-cell embryo cells at the transcriptome, epigenome and metabolome levels. In addition, ciTotiSCs exhibited bidirectional developmental potentials and were able to produce both embryonic and extraembryonic cells in vitro and in teratoma. Furthermore, following injection into 8-cell embryos, ciTotiSCs contributed to both embryonic and extraembryonic lineages with high efficiency. Our chemical approach to totipotent stem cell induction and maintenance provides a defined in vitro system for manipulating and developing understanding of the totipotent state and the development of multicellular organisms from non-germline cells.

NETosis: Sculpting tumor metastasis and immunotherapy.

The process of neutrophil extracellular traps (NETs) formation, called NETosis, is a peculiar death modality of neutrophils, which was first observed as an immune response against bacterial infection. However, recent work has revealed the unique biology of NETosis in facilitating tumor metastatic process. Neutrophil extracellular traps released by the tumor microenvironment (TME) shield tumor cells from cytotoxic immunity, leading to impaired tumor clearance. Besides, tumor cells tapped by NETs enable to travel through vessels and subsequently seed distant organs. Targeted ablation of NETosis has been proven to be beneficial in potentiating the efficacy of cancer immunotherapy in the metastatic settings. This review outlines the impact of NETosis at almost all stages of tumor metastasis. Furthermore, understanding the multifaceted interplay between NETosis and the TME components is crucial for supporting the rational development of highly effective combination immunotherapeutic strategies with anti-NETosis for patients with metastatic disease.

Copper-coordinated cellulose ion conductors for solid-state batteries.

Although solid-state lithium (Li)-metal batteries promise both high energy density and safety, existing solid ion conductors fail to satisfy the rigorous requirements of battery operations. Inorganic ion conductors allow fast ion transport, but their rigid and brittle nature prevents good interfacial contact with electrodes. Conversely, polymer ion conductors that are Li-metal-stable usually provide better interfacial compatibility and mechanical tolerance, but typically suffer from inferior ionic conductivity owing to the coupling of the ion transport with the motion of the polymer chains1-3. Here we report a general strategy for achieving high-performance solid polymer ion conductors by engineering of molecular channels. Through the coordination of copper ions (Cu2+) with one-dimensional cellulose nanofibrils, we show that the opening of molecular channels within the normally ion-insulating cellulose enables rapid transport of Li+ ions along the polymer chains. In addition to high Li+ conductivity (1.5 × 10-3 siemens per centimetre at room temperature along the molecular chain direction), the Cu2+-coordinated cellulose ion conductor also exhibits a high transference number (0.78, compared with 0.2-0.5 in other polymers2) and a wide window of electrochemical stability (0-4.5 volts) that can accommodate both the Li-metal anode and high-voltage cathodes. This one-dimensional ion conductor also allows ion percolation in thick LiFePO4 solid-state cathodes for application in batteries with a high energy density. Furthermore, we have verified the universality of this molecular-channel engineering approach with other polymers and cations, achieving similarly high conductivities, with implications that could go beyond safe, high-performance solid-state batteries.

SHP-1 Regulates CD8+ T Cell Effector Function but Plays a Subtle Role with SHP-2 in T Cell Exhaustion Due to a Stage-Specific Nonredundant Functional Relay.

SHP-1 (Src homology region 2 domain-containing phosphatase 1) is a well-known negative regulator of T cells, whereas its close homolog SHP-2 is the long-recognized main signaling mediator of the PD-1 inhibitory pathway. However, recent studies have challenged the requirement of SHP-2 in PD-1 signaling, and follow-up studies further questioned the alternative idea that SHP-1 may replace SHP-2 in its absence. In this study, we systematically investigate the role of SHP-1 alone or jointly with SHP-2 in CD8+ T cells in a series of gene knockout mice. We show that although SHP-1 negatively regulates CD8+ T cell effector function during acute lymphocytic choriomeningitis virus (LCMV) infection, it is dispensable for CD8+ T cell exhaustion during chronic LCMV infection. Moreover, in contrast to the mortality of PD-1 knockout mice upon chronic LCMV infection, mice double deficient for SHP-1 and SHP-2 in CD8+ T cells survived without immunopathology. Importantly, CD8+ T cells lacking both phosphatases still differentiate into exhausted cells and respond to PD-1 blockade. Finally, we found that SHP-1 and SHP-2 suppressed effector CD8+ T cell expansion at the early and late stages, respectively, during chronic LCMV infection.

Forced vital capacity and body mass index of Xinjiang children and adolescents: an analysis based on seven successive national surveys, 1985-2014.

BACKGROUND: Pulmonary function is very important for the healthy development of children and adolescents. However, fewer studies have been conducted on pulmonary function trends in children and adolescents in remote areas. The aim of this study was to estimate the forced vital capacity (FVC) trend and its relationship with body mass index (BMI) among young people in Xinjiang during 1985-2014 using data from seven successive national surveys. METHODS: A total of 19,449 Xinjiang children and adolescents aged 7-18 years were extracted from the Chinese National Survey on Students' Constitution and Health. Height, weight, and FVC were measured repeatedly in each survey. FVC comparisons between adjacent surveys by age and sex were conducted by nonparametric Kruskal-Wallis after Kolmogorov-Smirnov of normality. One-way ANOVA and least significant difference(LSD) method was used to compare differences in FVC levels of Xinjiang children and adolescents with different BMI. The relationship between BMI and FVC was investigated using a nonlinear regression model. RESULTS: The FVC levels of Xinjiang children and adolescents peaked in 2000, with overall FVC levels being 8.7% higher in 2000 than in 1985. Since then, a substantial decline occurred, contrasting to 2000, with FVC levels decreasing by 27% in 2014, which was still lower than that in 1985 by 20.73%. The proportion of overnutrition boys increased from 0.2% in 1985 to 22.1% in 2014, and girls from 0.5% in 1985 to 14.5% in 2014. An inverted U-shape association between FVC and BMI values was obtained for Xinjiang children and adolescents. CONCLUSIONS: Targeted measures should be carried out in schools to control BMI levels to ensure good lung function in children and adolescents in Xinjiang. Future studies should pay more attention to other factors affecting FVC, such as dietary behaviour, physical activity, and racial differences among children and adolescents.

Mental Wellness Self-Care in Singapore With mindline.sg: A Tutorial on the Development of a Digital Mental Health Platform for Behavior Change.

BACKGROUND: Singapore, like the rest of Asia, faces persistent challenges to mental health promotion, including stigma around unwellness and seeking treatment and a lack of trained mental health personnel. The COVID-19 pandemic, which created a surge in mental health care needs and simultaneously accelerated the adoption of digital health solutions, revealed a new opportunity to quickly scale innovative solutions in the region. OBJECTIVE: In June 2020, the Singaporean government launched mindline.sg, an anonymous digital mental health resource website that has grown to include >500 curated local mental health resources, a clinically validated self-assessment tool for depression and anxiety, an artificial intelligence (AI) chatbot from Wysa designed to deliver digital therapeutic exercises, and a tailored version of the website for working adults called mindline at work. The goal of the platform is to empower Singapore residents to take charge of their own mental health and to be able to offer basic support to those around them through the ease and convenience of a barrier-free digital solution. METHODS: Website use is measured through click-level data analytics captured via Google Analytics and custom application programming interfaces, which in turn drive a customized analytics infrastructure based on the open-source platforms Titanium Database and Metabase. Unique, nonbounced (users that do not immediately navigate away from the site), engaged, and return users are reported. RESULTS: In the 2 years following launch (July 1, 2020, through June 30, 2022), the website received >447,000 visitors (approximately 15% of the target population of 3 million), 62.02% (277,727/447,783) of whom explored the site or engaged with resources (referred to as nonbounced visitors); 10.54% (29,271/277,727) of those nonbounced visitors returned. The most popular features on the platform were the dialogue-based therapeutic exercises delivered by the chatbot and the self-assessment tool, which were used by 25.54% (67,626/264,758) and 11.69% (32,469/277,727) of nonbounced visitors. On mindline at work, the rates of nonbounced visitors who engaged extensively (ie, spent ≥40 seconds exploring resources) and who returned were 51.56% (22,474/43,588) and 13.43% (5,853/43,588) over a year, respectively, compared to 30.9% (42,829/138,626) and 9.97% (13,822/138,626), respectively, on the generic mindline.sg site in the same year. CONCLUSIONS: The site has achieved desired reach and has seen a strong growth rate in the number of visitors, which required substantial and sustained digital marketing campaigns and strategic outreach partnerships. The site was careful to preserve anonymity, limiting the detail of analytics. The good levels of overall adoption encourage us to believe that mild to moderate mental health conditions and the social factors that underly them are amenable to digital interventions. While mindline.sg was primarily used in Singapore, we believe that similar solutions with local customization are widely and globally applicable.

Superionic Conduction in K3SbS4 Enabled by Cl-Modified Anion Lattice.

All-solid-state potassium batteries emerge as promising alternatives to lithium batteries, leveraging their high natural abundance and cost-effectiveness. Developing potassium solid electrolytes (SEs) with high room-temperature ionic conductivity is critical for realizing efficient potassium batteries. In this study, we present the synthesis of K2.98Sb0.91S3.53Cl0.47, showcasing a room-temperature ionic conductivity of 0.32 mS/cm and a low activation energy of 0.26 eV. This represents an increase of over two orders of magnitude compared to the parent compound K3SbS4, marking the highest reported ionic conductivity for non-oxide potassium SEs. Solid-state 39K magic-angle-spinning nuclear magnetic resonance on K2.98Sb0.91S3.53Cl0.47 reveals an increased population of mobile K+ ions with fast dynamics. Ab initio molecular dynamics (AIMD) simulations further confirm a delocalized K+ density and significantly enhanced K+ diffusion. This work demonstrates diversification of the anion sublattice as an effective approach to enhance ion transport and highlights K2.98Sb0.91S3.53Cl0.47 as a promising SE for all-solid-state potassium batteries.

Combustion Synthesis and Polymer Doping of Metal Oxides for High-Performance Electronic Circuitry.

ConspectusTransparent conducting oxides (TCOs) are inorganic electrical conductors with optical band gaps greater than 3.3 eV. TCOs have been extensively explored in functional windows, touch screen applications, transparent displays, solar cells, and even electronic circuits. Amorphous metal oxide (a-MO) semiconductors are a TCO class that has made impressive progress since the first 2004 demonstration of their utility as the semiconducting layer in thin-film transistors (TFTs). Their excellent counterintuitive electron mobilities in the amorphous state fill the performance gap between amorphous silicon and polysilicon, widening TFT applicability to high-value products such as high-resolution flat panel displays and emerging flexible/wearable electronics. The possibility of solution processing MO "inks" from air-stable precursors, via roll-to-roll and high-throughput printing, further expands their appeal. However, most MO TFTs fabricated using solution-processing require postdeposition film annealing at elevated temperatures (>400 °C) to ensure high-quality films and stable charge transport. Thus, MO fabrication on and TFT integration with inexpensive and typically temperature-sensitive flexible polymer substrates remains challenging, as does reducing MO processing times to those acceptable for high-throughput semiconductor circuit manufacture. Consequently, new MO film processing methodologies are being developed to meet these requirements. Among them, science-based combustion synthesis (CS) and polymer doping are promising complementary approaches to optimize materials quality and manufacturing efficiency; they are the topic of this Account.This Account summarizes the progress in CS and MO polymer doping research, made largely at Northwestern University over the past decade, to create high-performance MO TFTs. Regarding CS, we begin with an overview of combustion precursor chemistry that strongly affects the resulting film quality and device performance. Then, single fuel and dual fuel combustion syntheses for diverse MO systems are discussed. Representative examples highlight recent advances, with a focus on the relationship between (co)fuel-oxidizer types/amounts, thermal behavior, film microstructure, and TFT performance. Next, the discussion focuses on polymer doping of several MO matrices as a new approach to achieve semiconducting MO compositions with excellent performance and mechanical flexibility. Thus, the effect of the polymer architecture and content in the MO precursor formulations on the MO film composition, microstructure, electronic structure, and charge transport are discussed. The concluding remarks highlight challenges and emerging opportunities.

Kv1.3 mediates ox-LDL-induced vascular smooth muscle cell proliferation through JAK2/STAT3 signaling pathway.

Kv1.3 channel has been shown to participate in regulating inflammatory activation, proliferation and apoptosis in several cell types. However, most of those existing studies focused on the ion-conducting properties of Kv1.3 in maintaining the resting potential and regulating Ca2+ influx. The aim of our study was to explore whether the Kv1.3-JAK2/STAT3 signaling pathway was involved in oxidized low density lipoprotein (ox-LDL) induced vascular smooth muscle cell (VSMC) proliferation. VSMCs from mouse aorta were cultured and treated with ox-LDL (25 µg/mL). The cell counting kit-8 was used to assess cell proliferation, and western blotting was performed to detect expression levels of Kv1.3, JAK2/STAT3, phosphorylated JAK2/STAT3, cyclin B1 and cyclin D1 in treated VSMCs. VSMCs were transfected with Kv1.3 small interfering RNA (Kv1.3-siRNA) or infected with a Kv1.3 lentiviral expression vector (Lv-Kv1.3) and treated with a JAK2 inhibitor LY2784544 to assess the role of Kv1.3 and JAK2/STAT3 signaling in mediating VSMC proliferation induced by ox-LDL. Ox-LDL induced cell proliferation and upregulated the expression of Kv1.3 in mouse VSMCs. In VSMCs transfected with Kv1.3-siRNA, ox-LDL was not efficient in inducing cell proliferation or the levels of proliferation associated proteins, cyclin B1 and cyclin D1. However, cell proliferation, cyclin B1 and cyclin D1 levels increased in VSMCs infected with Lv-Kv1.3. Levels of phosphorylated JAK2 and STAT3 were increased in ox-LDL-treated VSMCs, and this increase was prevented in VSMCs transfected with Kv1.3-siRNA. Treatment with the JAK2 inhibitor LY2784544 also prevented the increase in VSMCs proliferation treated with ox-LDL. Our findings demonstrated that Kv1.3 promoted proliferation of VSMCs treated with ox-LDL, and that this effect might be mediated through activation of the JAK2/STAT3 signaling pathway.

Relationship between body mass index and physical fitness index in Chinese college students: Results from a cross-sectional survey.

BACKGROUND: To explore the cross-sectional relationship between the body mass index (BMI) and physical fitness index (PFI) of Chinese college students. METHODS: In total, 30 497 (male 16 197, 55.5%) Chinese college students aged 19-22 were tested for height, weight and five physical fitness indicators (50-m sprint, sit and reach, standing long jump, 1000/800-m run, pull-up/bent-leg sit-up). Stratified according to age and gender, according to BMI percentile, divided into BMI < 10th Percentile (A), 10th ≤ BMI < 25th Percentile (B), 25th ≤ BMI < 75th Percentile (C), 75th ≤ BMI < 90th Percentile (D), BMI ≥ 90th Percentile (E), a total of 5 groups, and the PFI composed of 5 indicators of physical fitness was calculated according to age and gender. The comparison of PFI between different BMI groups was carried out using the effect size, and the non-linear relationship between BMI-Z and PFI was analyzed. RESULTS: The relationship between BMI-Z and PFI of male and female college students in China showed an inverted "U"-shaped curve. With comparable BMI, PFI change was greater in males than in females. CONCLUSION: The relationship between BMI and PFI of Chinese college students is nonlinear. The physical fitness level of college students who are underweight or overweight and those with obesity is lower than that of normal-weight students.

Experimental and theoretical evidence for hydrogen doping in polymer solution-processed indium gallium oxide.

The field-effect electron mobility of aqueous solution-processed indium gallium oxide (IGO) thin-film transistors (TFTs) is significantly enhanced by polyvinyl alcohol (PVA) addition to the precursor solution, a >70-fold increase to 7.9 cm2/Vs. To understand the origin of this remarkable phenomenon, microstructure, electronic structure, and charge transport of IGO:PVA film are investigated by a battery of experimental and theoretical techniques, including In K-edge and Ga K-edge extended X-ray absorption fine structure (EXAFS); resonant soft X-ray scattering (R-SoXS); ultraviolet photoelectron spectroscopy (UPS); Fourier transform-infrared (FT-IR) spectroscopy; time-of-flight secondary-ion mass spectrometry (ToF-SIMS); composition-/processing-dependent TFT properties; high-resolution solid-state 1H, 71Ga, and 115In NMR spectroscopy; and discrete Fourier transform (DFT) analysis with ab initio molecular dynamics (MD) liquid-quench simulations. The 71Ga{1H} rotational-echo double-resonance (REDOR) NMR and other data indicate that PVA achieves optimal H doping with a Ga···H distance of ∼3.4 Å and conversion from six- to four-coordinate Ga, which together suppress deep trap defect localization. This reduces metal-oxide polyhedral distortion, thereby increasing the electron mobility. Hydroxyl polymer doping thus offers a pathway for efficient H doping in green solvent-processed metal oxide films and the promise of high-performance, ultra-stable metal oxide semiconductor electronics with simple binary compositions.

The importance of temperature monitoring in predicting wound healing.

CONCLUSION: Upon wound formation, the wound temperature rises in the first 3-4 days until reaching its peak. It then falls at about one week after wound formation. In the second week after wound formation, the wound temperature decreases steadily to the baseline indicating a good wound condition and progression towards healing. While a continuous high temperature is often a sign of excessive inflammation or infection, which indicates urgent need of intervention and treatment.

[Genetic analysis of a family with BCL11A-related intellectual disability].

OBJECTIVE: To explore the genetic basis for two patients from a family with BCL11A-related intellectual disability (BCL11A-ID). METHODS: Clinical data of the proband and her family members was analyzed. Chromosomal karyotyping analysis, trio-whole exome sequencing (trio-WES) and copy number variation sequencing (CNV-seq) were carried out. For the suspected genetic variants, Sanger sequencing was used to verify, and pathogenicity assessment was conducted. RESULTS: The proband and her mother both had intellectual and language impairment, and their fetal hemoglobin (HbF) was significantly elevated. A heterozygous c.1327_c.1328delTC (p.Ser443Hisfs*128) variant was found in exon 4 of the BCL11A gene by WES, which has resulted in truncated expression of the encoded protein, and Sanger sequencing has verified that the variant was inherited from the mother. The variant was not found in related databases. The variant was predicted as pathogenic according to the guidelines from the American College of Medical Genetics and Genomics (ACMG) (PVS1+PM2+PP1). No karyotypic abnormality was found in the proband, her parents and brother, and no pathogenic CNVs was found in the proband and her parents. CONCLUSION: The c.1327_c.1328delTC (p.Ser443Hisfs*128) variant may underlay the BCL11A-ID in the proband and her mother. This de novo variant has expanded the mutational spectrum of the BCL11A gene.

[Clinical phenotype and genetic analysis of a child with 14q12q13 microdeletion syndrome manifesting as congenital hypothyroidism].

OBJECTIVE: To analyze the clinical phenotype and genetic etiology for a child featuring congenital hypothyroidism (CH). METHODS: Whole exome sequencing (WES), copy number variation (CNV) sequencing and chromosomal microarray analysis (CMA) were carried out for a newborn infant who had presented at Linyi People's Hospital for CH. Clinical data of the child was analyzed, in addition with a literature review. RESULTS: The main characteristics of the newborn infant had included peculiar face, vulvar edema, hypotonia, psychomotor retardation, recurrent respiratory tract infection with laryngeal wheezing and feeding difficulties. Laboratory test indicated hypothyroidism. WES suggested a CNV deletion on chromosome 14q12q13. CMA further confirmed a 4.12 Mb deletion at chromosome 14q12q13.3 (32649595_36769800), which has encompassed 22 genes including NKX2-1, the pathogenic gene for CH. The same deletion was found in neither of her parents. CONCLUSION: Through the analysis of clinical phenotype and genetic variant, the child was diagnosed with 14q12q13.3 microdeletion syndrome.

Phosphorus Regulates the Level of Signaling Molecules in Rice to Reduce Cadmium Toxicity.

Phosphorus treatment can reduce Cd accumulation and Cd toxicity in rice, but alterations in the internal regulatory network of rice during this process have rarely been reported. We have removed the effect of cadmium phosphate precipitation from the hydroponic system, treated a pair of different Cd-response rice varieties with different levels of phosphorus and cadmium and examined the changes in physiological indicators and regulatory networks. The results demonstrated that phosphorus treatment significantly reduced Cd accumulation in both types of rice, although the antioxidant systems within the two types of rice produced opposite responses. Overall, 3 mM phosphorus treatment to Cd-N decreased the expression of OsIAA17 and OsACO1 by 32% and 37%, respectively, while increasing the expression of OsNR2 by 83%; these three genes regulate the synthesis of auxin, ethylene, and nitric oxide in rice. IAA and NO levels in rice shoots increased by 24% and 96%, respectively, and these changes contribute to Cd detoxification. The cadmium transporter genes OsHMA2, OsIRT1, and OsABCC1 were significantly down-regulated in Cd-N roots after triple phosphorus treatment. These data suggest that phosphorus treatment can reduce Cd accumulation and enhance Cd resistance in rice by affecting the expression of signaling molecules.

Kv1.3 Channel Is Involved In Ox-LDL-induced Macrophage Inflammation Via ERK/NF-κB signaling pathway.

Macrophage inflammatory response is crucial for the initiation and progression of atherosclerosis. The voltage-gated potassium channel Kv1.3 plays an important role in the modulation of macrophage function. The aim of this study was to investigate the effect and possible mechanism of Kv1.3 on inflammation in oxidized low-density lipoprotein (ox-LDL)-induced RAW264.7 macrophages. Treatment with Kv1.3-siRNA attenuated the expression of IL-6 and TNF-α and reduced the phosphorylation of ERK1/2 and NF-κB in ox-LDL-induced macrophages. In contrast, overexpression of Kv1.3 with Lv-Kv1.3 promoted the expression of IL-6 and TNF-α, and increased ERK1/2 and NF-κB phosphorylation in macrophages. PD-98059, a specific inhibitor of ERK, reversed the expression of IL-6 and TNF-α in ox-LDL-treated macrophages. Kv1.3-siRNA did not inhibit inflammation any further when cells were treated with PD-98059. This suggests that ERK acts as a downstream regulator of the Kv1.3 channel. In conclusion, Kv1.3 may be an indispensable membrane protein in ox-LDL-induced RAW264.7 macrophage inflammation in atherosclerosis through the ERK/NF-κB pathway.

KIF18b-dependent hypomethylation of PARPBP gene promoter enhances oxaliplatin resistance in colorectal cancer.

As the new platinum drug oxaliplatin has been widely used in clinical treatment of colorectal cancer (CRC), oxaliplatin resistance has become a burning problem. In this study, higher expression of PARP-1 binding protein (PARPBP) was detected in oxaliplatin-resistant CRC (OR-CRC) cells than in non-resistant cells. Further research showed that kinesin family member 18 b (KIF18b) induced the overexpression of PARPBP, sustaining oxaliplatin resistance in OR-CRC cells. Through exploring the PARPBP gene promoter, we found that SP1-recruited DNMT3b methylated PARPBP promoter to suppress transcription in CRC cells, and increased KIF18b attenuated the recruitment of DNMT3b to PARPBP promoter by directly interacting with SP1 in OR-CRC cells. Clinical analysis suggested a positive relationship between KIF18b and PARPBP in CRC tissues and indicated poor prognosis in CRC patients with high level of KIF18b or PARPBP. In summary, KIF18b-induced PARPBP contributes to the resistant phenotype of OR-CRC.

E2F1 promotes cell cycle progression by stabilizing spindle fiber in colorectal cancer cells.

BACKGROUND: E2F1 is a transcription factor that regulates cell cycle progression. It is highly expressed in most cancer cells and activates transcription of cell cycle-related kinases. Stathmin1 and transforming acidic coiled-coil-containing protein 3 (TACC3) are factors that enhance the stability of spindle fiber. METHODS: The E2F1-mediated transcription of transforming acidic coiled-coil-containing protein 3 (TACC3) and stathmin1 was examined using the Cancer Genome Atlas (TCGA) analysis, quantitative polymerase chain reaction (qPCR), immunoblotting, chromatin immunoprecipitation (ChIP), and luciferase reporter. Protein-protein interaction was studied using co-IP. The spindle structure was shown by immunofluorescence. Phenotype experiments were performed through MTS assay, flow cytometry, and tumor xenografts. Clinical colorectal cancer (CRC) specimens were analyzed based on immunohistochemistry. RESULTS: The present study showed that E2F1 expression correlates positively with the expression levels of stathmin1 and TACC3 in colorectal cancer (CRC) tissues, and that E2F1 transactivates stathmin1 and TACC3 in CRC cells. Furthermore, protein kinase A (PKA)-mediated phosphorylation of stathmin1 at Ser16 is essential to the phosphorylation of TACC3 at Ser558, facilitating the assembly of TACC3/clathrin/α-tubulin complexes during spindle formation. Overexpression of Ser16-mutated stathmin1, as well as knockdown of stathmin1 or TACC3, lead to ectopic spindle poles including disorganized and multipolar spindles. Overexpression of wild-type but not Ser16-mutated stathmin1 promotes cell proliferation in vitro and tumor growth in vivo. Consistently, a high level of E2F1, stathmin1, or TACC3 not only associates with tumor size, lymph node metastasis, TNM stage, and distant metastasis, but predicts poor survival in CRC patients. CONCLUSIONS: E2F1 drives the cell cycle of CRC by promoting spindle assembly, in which E2F1-induced stathmin1 and TACC3 enhance the stability of spindle fiber.

Risk factors of chylous ascites and its relationship with long-term prognosis in laparoscopic D3 lymphadenectomy for right colon cancer.

BACKGROUND: Chylous ascites (CA) after laparoscopic D3 lymphadenectomy for right colon cancer is not rare. However, the risk factors for CA have not been fully explored. Few studies have investigated the effect of CA on long-term prognosis. METHODS: The clinical data of patients with right colon cancer who underwent laparoscopic D3 lymphadenectomy in five centers from January 2013 to December 2018 were retrospectively collected. Univariate and multivariate analyses were performed to determine the clinicopathological factors associated with CA. Then, the long-term prognosis of patients with and without CA was compared by propensity score matching and Kaplan-Meier survival analysis. RESULTS: The incidence of CA was 4.4% (48/1090). Pathological T stage (p = 0.025), dissection along the left side of the superior mesenteric artery (p < 0.001) and the number of retrieved lymph nodes (p < 0.001) were independent risk factors for CA. After propensity score matching, 48 patients in the CA group and 353 patients in the non-CA group were enrolled. Kaplan-Meier survival analysis indicated that CA was not associated with overall survival (p = 0.454) and disease-free survival (p = 0.163). In patients with stage III right colon cancer, there were no significant differences in overall survival (p = 0.501) and disease-free survival (p = 0.254). CONCLUSIONS: Pathological T stage, number of retrieved lymph nodes, and left side dissection along the superior mesenteric artery were independent risk factors for CA after laparoscopic D3 lymphadenectomy. CA does not impair the oncological outcomes of patients.