Phase separation is required for PML nuclear body biogenesis and function.

PML nuclear body (NB) malfunction often leads to acute leukemia outbreaks and other severe diseases. PML NB rescue is the molecular basis of arsenic success in acute promyelocytic leukemia (APL) treatment. However, it is unclear how PML NBs are assembled. Here, we observed the presence of liquid-liquid phase separation (LLPS) in NB formation by fluorescence recovery after photobleaching (FRAP) experiment. Compared with the wild-type (WT) NBs, PML A216V derived from arsenic-resistant leukemia patients markedly crippled LLPS, but not altered the overall structure and PML RBCC oligomerization. In parallel, we also reported several Leu to Pro mutations that were critical to PML coiled-coil domain. FRAP characterization and comparison between L268P and A216V revealed markedly different LLPS activities in these mutant NBs. Transmission electron microscopy (TEM) inspections of LLPS-crippled and uncrippled NBs showed aggregation- and ring-like PML packing in A216V and WT/L268P NBs, respectively. More importantly, the correct LLPS-driven NB formation was the prerequisite for partner recruitment, post-translational modifications (PTMs), and PML-driven cellular regulations, such as ROS stress control, mitochondria production, and PML-p53-mediated senescence and apoptosis. Altogether, our results helped to define a critical LLPS step in PML NB biogenesis.

Assessing the option water-saving willingness of irrigation areas considering farmers' risk tolerance.

Water option trading could facilitate water conservation in irrigation areas to achieve optimal allocation of agricultural water resources. However, the risk associated with water-saving decisions increases due to the uncertainties of tradeable water and water-saving benefits, which makes farmers in the irrigation area with heterogeneous risk tolerances exhibit varied option water-saving willingness (OWSW) in response to the water option contract. Thus, this article provides a novel framework for prior assessing the OWSW in the irrigated area that considers farmers' heterogeneous risk tolerance and proposes the optimal contractual water demand to stimulate the OWSW. First, a multiobjective optimal allocation model for cropping water is constructed to predict tradeable water, and then risk trust, risk-return perception and reference are integrated into water-saving return analysis for proposing a willingness calculation model involving forecast information. Finally, the influence of heterogeneous risk tolerance on farmers' water-saving path choices and the irrigation area's OWSW is analyzed with three sets of comparative data from 2014 to 2021. Results indicate that the intensity and stability of OWSW in water-scarce irrigation areas increase as farmers' risk tolerance rises, but the enhancement utility exhibits a diminishing marginal trend. When both prediction accuracy and farmers' risk tolerance are low, contracts with relatively adventurous and differentiated water demands are more likely to stimulate OWSW. This study provides insights into activating water options trading and stimulating water conservation in agriculture from a risk management perspective.

Combination of midostaurin and ATRA exerts dose-dependent dual effects on acute myeloid leukemia cells with wild type FLT3.

BACKGROUND: Midostaurin combined with chemotherapy is currently used to treat newly diagnosed acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3 (FLT3)-mutations. However, midostaurin acts as an antagonist to some chemotherapeutic agents in leukemia cell lines without FLT3 mutations. All-trans retinoic acid (ATRA) induces apoptosis when used in combination with midostaurin in FLT3-mutated AML cells. This combination has been shown to be safe in AML patients. However, the effect of this combination has not been investigated in AML without FLT3 mutations. METHODS: Cell proliferation was assessed by a cell counting assay. Cell death was evaluated by cell viability and Annexin-V assays. Cell differentiation was assessed by CD11b expression profiling and morphological analysis. To explore the underlying mechanisms, we studied the role of caspase3/7, Lyn, Fgr, Hck, RAF, MEK, ERK, AKT, PU.1, CCAAT/enhancer binding protein ß (C/EBPß) and C/EBPε by Western blot analysis and immunoprecipitation assays. Antitumor activity was also confirmed in mouse xenograft models established with AML cells. RESULTS: In this study, 0.1 - 0.25 µM midostaurin (mido(L)) combined with ATRA induced differentiation while 0.25 - 0.5 µM midostaurin (mido(H)) combined with ATRA triggered apoptosis in some AML cell lines without FLT3-mutations. Midostaurin combined with ATRA (mido-ATRA) also exhibited antitumor activity in mouse xenograft models established with AML cells. Mechanistically, mido(H)-ATRA-induced apoptosis was dependent on caspase-3/7. Mido(L)-ATRA inhibited Akt activation which was associated with decreased activity of Lyn/Fgr/Hck, resulted in dephosphorylation of RAF S259, activated RAF/MEK/ERK, along with upregulating the protein levels of C/EBPß, C/EBPε and PU.1. A MEK specific inhibitor was observed to suppress mido(L)-ATRA-induced increases in the protein levels of C/EBPs and PU.1 and mido(L)-ATRA-induced differentiation. Furthermore, inhibition of Akt activity promoted mido(L)-ATRA-induced downregulation of RAF S259 phosphorylation and mido(L)-ATRA-induced differentiation. Therefore, Lyn/Fgr/Hck-associated Akt inhibition activated RAF/MEK/ERK and controlled mido(L)-ATRA-induced differentiation by upregulation of C/EBPs and PU.1. Mido(L)-ATRA also promoted assembly of the signalosome, which may facilitate RAF activation. CONCLUSIONS: Midostaurin combined with ATRA exerts antitumor activity against AML with wild-type FLT3 mutations in vitro and in vivo. These findings may provide novel therapeutic strategies for some AML patients without FLT3 mutations and imply a new target of midostaurin.

Clinical significance of circulating tumour cells and tumour marker detection in the chemotherapeutic evaluation of advanced colorectal cancer.

AIM: Systemic chemotherapy combining biological targeted therapies is the standard therapy for patients with metastatic colorectal cancer (mCRC), but effective markers are needed to identify clinical responders. Circulating tumour cells (CTCs) have been associated with prognosis in patients with mCRC. This study aimed to explore the relationship between CTC number and the clinical response of patients with advanced CRC. METHOD: Epithelial cell adhesion molecule-independent enrichment and CD45- fluorescence in situ hybridization immunofluorescence were used to detect peripheral blood CTCs in 79 patients with advanced CRC. Fisher's exact test and Spearman's rank correlation coefficient were used to analyse the correlation between CTC number and efficacy of chemotherapy. Kaplan-Meier and Cox regression analyses were used to evaluate progression-free survival (PFS). RESULTS: Among the evaluable patients, CTCs were significantly correlated with clinical response (r =4.891, p = 0.031). High CTC numbers were associated with a poor treatment response (r = -0.250, p = 0.027). Dynamic decrease in CTC number was associated with clinical response (p = 0.046). High baseline CTC number and carcinoembryonic antigen levels were prognostic factors for unfavourable PFS in multivariable analysis [hazard ratio (HR) = 3.30, p = 0.011 and HR = 2.04, p = 0.044, respectively]. Compared with the CTC-positive group, the CTC-negative group showed superior PFS (median PFS 15.53 vs. 9.43 months, p = 0.041) among CRC patients receiving first-line treatment. CONCLUSION: CTC number is a feasible biomarker for predicting outcomes in mCRC patients receiving systemic chemotherapy.

Clinicopathological features, prognostic significance, and associated tumor cell functions of family with sequence similarity 111 member B in pancreatic adenocarcinoma.

BACKGROUD: Among digestive tract tumors, pancreatic adenocarcinoma (PAAD) has a high degree of malignancy. Therefore, it is important to search for pancreatic adenocarcinoma-related differential genes and new oncogene therapeutic targets for early diagnosis, treatment, and prognosis of pancreatic adenocarcinoma. AIMS: This study aims to investigate the expression and clinical significance of Family with sequence similarity 111 member B (FAM111B) in PAAD. MATERIALS & METHODS: Bioinformatics was used to analyze the relationship between FAM111B expression and pancreatic adenocarcinoma and to predict its role in related pathways. Tissue microarrays were used to assess the levels of FAM111B in pancreatic cancer tissues by immunohistochemical staining, and the effects of FAM111B expression levels on apoptosis, proliferation, invasion and migration of tumor cells were observed and verified by in vitro cellular assays. RESULTS: FAM111B expression was higher in PAAD tissue than in matched normal tissues (p < 0.05). The expression level of FAM111B, the metastatic status of lymph nodes was an independent prognostic factor for PAAD survival (p < 0.05). Meanwhile, overexpression of FAM111B promoted PAAD cell proliferation, migration, invasion and inhibited PAAD cell apoptosis (p < 0.05). In contrast, knockdown of FAM111B triggered the opposite result (p < 0.05). In the results of GSEA, it was shown that FAM111B may be involved in PAAD progression through p53 signaling pathway, cell cycle, and other signaling pathways (p < 0.05 and FDR q-val <0.25). FAM111B is highly expressed in PAAD tissues and is closely associated with poor prognosis of PAAD. CONCLUSION: FAM111B significantly promotes the proliferation, invasion, and migration of pancreatic adenocarcinoma cells while it inhibits their apoptosis. FAM111B may be a new biomarker for PAAD. It may provide a new direction for the treatment and diagnosis of PAAD.

Multiplexed sensing interrogation technique based on a flexibly switchable multi-passband RF filter by using a Solc-Sagnac loop.

In this paper, we have proposed and experimentally demonstrated a multiplexed sensing interrogation technique based on a flexibly switchable multi-passband RF filter with a polarization maintaining fiber (PMF) Solc-Sagnac loop. A high-order Solc-Sagnac loop can be used as a spectrum slicer as well as sensing heads, and a multi-passband microwave photonic filter (MPF) can be achieved together with a dispersive medium. Environmental parameter variations will cause a frequency shift of the corresponding passband of the MPF, so by employing only one Sagnac loop, it is possible to monitor several environmental parameters simultaneously. In this article, we have demonstrated and analyzed the performance of the flexibly switchable multi-passband MPF by using a second-order Solc-Sagnac loop. To demonstrate the temperature sensing capabilities of our interrogation system, we have applied temperature changes individually to Sensor Head 1 (L P M F 1 ≈0.97m) only, Sensor Head 2 (L P M F 2 ≈2.97m) only, and both Sensor Head 1 and 2 in the experiment. By monitoring frequency shift of the MPF's passbands, the sensitivities for Sensor Head 1 and Sensor Head 2 have been estimated to be -0.275 ± 0.011 MHz/℃ and -0.811 ± 0.013 MHz/℃ respectively, which show a good sensing linearity and stability. By utilizing the longer length of the sensing PMF, higher sensitivity can be achieved. By using Solc-Sagnac loop with higher order, more sensors can be multiplexed.

Antiferromagnetism Induced by Bond Su-Schrieffer-Heeger Electron-Phonon Coupling: A Quantum Monte Carlo Study.

Antiferromagnetism (AFM) such as Néel ordering is often closely related to Coulomb interactions such as Hubbard repulsion in two-dimensional (2D) systems. Whether Néel AFM ordering in two dimensions can be dominantly induced by electron-phonon couplings (EPC) has not been completely understood. Here, by employing numerically exact sign-problem-free quantum Monte Carlo (QMC) simulations, we show that bond Su-Schrieffer-Heeger (SSH) phonons with frequency ω and EPC constant λ can induce AFM ordering for a wide range of phonon frequency ω>ω_{c}. For ω<ω_{c}, a valence-bond-solid (VBS) order appears and there is a direct quantum phase transition between VBS and AFM phases at ω_{c}. The phonon mechanism of the AFM ordering is related to the fact that SSH phonons directly couple to electron hopping whose second-order process can induce an effective AFM spin exchange. Our results shall shed new light on understanding AFM ordering in correlated quantum materials.

Electrochemical Insights, Developing Strategies, and Perspectives toward Advanced Potassium-Sulfur Batteries.

The boosting demand for high-capacity energy storage systems requires innovative battery technologies with low-cost and sustainability. The advancement of potassium-sulfur (K-S) batteries have been triggered recently due to abundant resource and cost effectiveness. However, the functional performance of K-S batteries is fundamentally restricted by the vague understanding of K-S electrochemistry and the imperfect cell components or architectures, facing the issues of low cathode conductivity, intermediate shuttle loss, poor anode stability, electrode volume fluctuation, etc. Inspired by considerable research efforts on rechargeable metal-sulfur batteries, the holistic K-S system can be stabilized and promoted through various strategies on rational physical regulation and chemical engineering. In this review, first an attempt is made to address the electrochemical kinetic concept of K-S system on the basis of the emerging studies. Then, the classification of performance-improving strategies is thoroughly discussed in terms of specific battery component and prospective outlooks in materials optimization, structure innovations, as well as relevant electrochemistry are provided. Finally, the critical perspectives and challenges are discussed to demonstrate the forward-looking developmental directions of K-S batteries. This review not only endeavors to provide a deep understanding of the electrochemistry mechanism and rational designs for high-energy K-S batteries, but also encourages more efforts in their large-scale practical realization.

Temperature measurement using a multi-wavelength fiber ring laser based on a hybrid gain medium and Sagnac interferometer.

In this paper, a multi-wavelength fiber ring laser (MWFRL) based on a hybrid gain medium and Sagnac interferometer (SI) used for temperature measurement has been proposed and experimentally demonstrated. Experiments have been carried out with polarization maintaining fibers (PMF) of different lengths, which are incorporated in the SI as sensing elements. Stable multi-wavelength oscillation at 1560 nm band is successfully achieved with the wavelength instability of ±0.08 nm and the signal-to-noise of 42 dB. The experimental results show that the wavelength change of the MWFRL with temperature variation has a good linear response and the temperature sensitivity of 1.8063 ± 0.00933 nm/°C is obtained when the length of the PMF is 1.7 m. As the length of PMF increases, the sensitivity can be improved.

The success and the challenge of all-trans retinoic acid in the treatment of cancer.

All-trans retinoic acid (ATRA), an active metabolite of vitamin A, plays important roles in cell proliferation, cell differentiation, apoptosis, and embryonic development. The effects of ATRA are mediated by nuclear retinoid receptors as well as non-genomic signal pathway, such as MAPK and PKA. The great success of differentiation therapy with ATRA in acute promyelocytic leukemia (APL) not only improved the prognosis of APL but also spurred the studies of ATRA in the treatment of other tumors. Since the genetic and physiopathological simplicity of APL is not common in human malignancies, the combination of ATRA with other agents (chemotherapy, epigenetic modifiers, and arsenic trioxide, etc) had been extensively investigated in a variety of tumors. In this review, we will discuss in details about ATRA and its role in cancer treatment.

Down-regulation of FN1 inhibits colorectal carcinogenesis by suppressing proliferation, migration, and invasion.

Fibronectin 1 (FN1) is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, metastasis, and implicated in various biochemical processes. However, its effects on the development and progression of human cancer, especially colorectal cancer (CRC), are unclear. To evaluate the relationship between the expression of FN1 and the histopathologic parameters of patients with CRC or the proliferation, migration, and invasion of colorectal cancer cell lines, we screened FN1 as a new candidate gene which promotes development of CRC, in an independent dataset (The Human Protein Atlas website). Here, we reported that FN1 was elevated in CRC tissues compared with normal colon tissues. Further, FN1 expression level was correlated with age, lymph vascular invasion, and survival rate. Knockdown of FN1 in two CRC cell lines, LOVO, and SW1116, significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis. Western blot analysis showed that down-regulation of FN1 significantly decreased the expression of Bcl-2, MMP-9, Twist, and increased the expression of Bax, Caspase-3, and E-cadherin in LOVO and SW1116 cells. Then, we found that the protein ITGA5 was identified as a binding partner of FN1 and ITGA5 overexpression reversed FN1-induced tumorigenesis of CRC in vitro. Taken together, FN1 suppressed apoptosis and promoted viability, invasion, and migration in CRC through interacting with ITGA5. FN1 may be a prognostic factor and potential target for CRC treatment.

Mechanical Properties and Porosity of Acrylic Cement Bone Loaded with Alendronate Powder.

Aseptic loosening is the most common complication of joint replacement. Previous studies showed that acrylic bone cement loaded with a commercially-available alendronate powder (APAC) had good promise against wear debris-mediated osteolysis for prevention of aseptic loosening. The purpose of the present study was to investigate the effect of adding alendronate powder to an acrylic bone cement on quasi-static mechanical properties (namely, compressive strength, compressive modulus, tensile strength, and flexural strength), fatigue life, porosity, and microstructure of the cement. The results showed that adding up to 1 wt./wt.% alendronate powder exerted no detrimental effect on any of the quasi-static mechanical properties. However, the fatigue life of APAC decreased by between ~17% and ~27 % and its porosity increased by between ~ 5-7 times compared with corresponding values for the control cement (no alendronate powder added). Fatigue life was negatively and significantly correlated with porosity. Considering that fatigue life of the cement plays a significant role in joint replacement survival, clinical use of APAC cannot be recommended.

MicroRNA-19a and CD22 Comprise a Feedback Loop for B Cell Response in Sepsis.

BACKGROUND: MicroRNA-19a (miR-19a), an oncogenic microRNA, has been recently reported to target CD22 in B cell lymphoma cell lines, but its role in inflammatory response is unclear. CD22 is a negative regulator for BCR signaling, and we hypothesize that miR-19a regulates B cell response by targeting CD22 in sepsis. MATERIAL AND METHODS: In order to determine whether miR-19a-CD22 pathway was involved in sepsis, and what role it played in the regulatory mechanisms, we detected the levels of miR-19a in B cells obtained from patients with sepsis, and measured the levels of miR-19a and CD22 expression in B cells activated by LPS in vitro. Additionally, we investigated the correlation between miR-19a and CD22, as well as the influence of this pathway on BCR signaling, in transfected B cells. RESULTS: We found that septic patients displayed up-regulated miR-19a in B cells. In vitro, miR-19a was increased in activated B cells, with CD22 expression initially enhanced but subsequently decreased. Moreover, overexpression of miR-19a resulted in an amplified BCR signaling, while overexpression of CD22 attenuated the effect of miR-19a and increased its expression. CONCLUSIONS: Our study demonstrated that miR-19a and CD22 comprised a feedback loop for B cell response in sepsis, providing a potential therapeutic target to recover the immune homeostasis.

Diagnostic and prognostic roles of soluble CD22 in patients with Gram-negative bacterial sepsis.

BACKGROUND: Soluble CD22 (sCD22) is a fragment of CD22, a B cell-specific membrane protein that negatively regulates B-cell receptor signaling. To date, sCD22 has only been regarded as a tumor marker of B-cell malignancies. Its expression in infectious diseases has not yet been assessed. METHODS: Serum concentrations of sCD22, procalcitonin (PCT) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assays in patients with intra-abdominal Gram-negative bacterial infection. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic accuracy of these biomarkers in this type of infection. The correlations between biomarkers and the Acute Physiology and Chronic Health Evaluation (APACHE) II scores were also analyzed. RESULTS: Concentrations of sCD22 were significantly elevated in patients with sepsis and the elevation is correlated with the severity of sepsis. sCD22 was also slightly elevated in patients with non-infected systemic inflammatory response syndrome or local infection. The diagnostic accuracy of sCD22 for sepsis was equivalent to that of PCT or IL-6. In addition, the correlation of sCD22 with APACHE II scores was stronger than that of PCT or IL-6. CONCLUSIONS: Serum sCD22 is a novel inflammatory mediator released during infection. This soluble biomarker plays a potential role in the diagnosis of Gram-negative bacterial sepsis, with a diagnostic accuracy as efficient as that of PCT or IL-6. Furthermore, sCD22 is more valuable to predict the outcomes in patients with sepsis than PCT or IL-6. The present study suggested that sCD22 might be potentially useful in supplementing current criteria for sepsis.

Comparison of Periarticular Multimodal Drug Injection and Femoral Nerve Block for Postoperative Pain Management in Total Knee Arthroplasty: A Systematic Review and Meta-Analysis.

The analgesic efficacy and safety of periarticular multimodal drug injection (PMDI) compared with femoral nerve block (FNB) for postoperative pain management in total knee arthroplasty (TKA) still remains controversial. We therefore conducted a meta-analysis to quantitatively compare PMDI to FNB in TKA. 10 randomized controlled trials (RCTs) with 744 TKAs in 728 patients were included in this study. The meta-analysis showed that single shot FNB may have better pain relief in the early postoperative period compared with single shot PMDI, and continuous PMDI provided postoperative analgesia comparable to that of continuous FNB. No significant difference was seen in regard to the complications between the two groups. However, due to the variation of the included studies, no firm conclusions can be drawn.

Krüppel-like factor 5 promotes lung tumorigenesis through upregulation of Sox4.

BACKGROUND: Krüppel-like factor 5 (KLF5), a member of zinc finger class of DNA-binding transcriptional regulators, has attracted attention because of its important regulatory activities linked to diverse functions such as cell growth, proliferation, differentiation, apoptosis and tumorigenesis in a number of systems. However, its biological functions in the initiation and progression of lung tumorigenesis remain largely unexplored. METHODS: Quantitative realtime PCR and Western Blot were used to detect the expression of KLF5 in lung cancer tissues and cell lines. Retro-viruses were used to generate KLF5 stable expression lung cancer cell line. Small interfering RNA was used to silence the expression of KLF5 and Sox4. BrdU assay was used to determine the proliferation of cells. Luciferase and Chromatin immunoprecipitation assays were used to detect the regulation of Sox4 by KLF5. RESULTS: KLF5 was up-regulated in lung cancer tissues and cell lines. Overexpression of KLF5 promotes while knockdown of its expression inhibits cell proliferation in two cell lines derived from lung carcinoma. At the molecular level, our results revealed that KLF5 positively regulates Sox4 expression through a transcriptional mechanism. Sox4 deficiency blocked the proliferative roles of KLF5 in lung cancer cells. CONCLUSION: our data identified the KLF5/Sox4 regulatory signaling play an important role in lung tumorigenesis, which might represent novel therapeutic targets to manage lung carcinoma.

miR-144 suppresses the proliferation and metastasis of hepatocellular carcinoma by targeting E2F3.

MicroRNAs (miRNAs) play essential roles in the progression of hepatocellular carcinoma (HCC). miR-144 acts as a tumor suppressor in some malignancies, while its role in HCC is unclear. Here, we found that miR-144 was significantly decreased in HCC tissues and cell lines. Forced overexpression of miR-144 remarkably reduced cell proliferation, increased apoptosis, and suppressed migration and invasion of HCC cells. E2F transcription factor 3 (E2F3) was identified as a target of miR-144 in HCC cells. Moreover, E2F3 overexpression partially attenuated the tumor suppressive effects of miR-144, and the expression of E2F3 was negatively correlated with miR-144 level in HCC tissues. Our data suggest that miR-144 might suppress the growth and motility of HCC cells partially by targeting E2F3.

Combination of Ethacrynic Acid and ATRA Triggers Differentiation and/or Apoptosis of Acute Myeloid Leukemia Cells through ROS.

BACKGROUND AND OBJECTIVE: All-trans retinoic acid (ATRA), an effective differentiation inducer, has been applied clinically to treat acute promyelocytic leukemia (APL). Unfortunately, it is not as potent in other kinds of acute myeloid leukemia (AML). Ethacrynic acid (EA), a classical powerful diuretic, can increase reactive oxygen species (ROS) contents, which can assist ATRA in inducing differentiation in AML cells. Here, we investigated the effect of EA combined with ATRA (EA+RA) on some AML cells except APL. METHODS: Apoptosis and differentiation were determined by morphology, cell viability, Annexin-V assay and CD11c expression. Western blot analysis and the detection of ROS and mitochondrial transmembrane potentials (MMP) were used to investigate the mechanisms. RESULTS: AML cells exhibited differentiation and/or apoptosis after EA+RA treatment. EA+RA increased the intracellular ROS contents. EA+RA-induced apoptosis was accompanied by MMP attenuation and caspase-3/7 activation. EA+RA-induced differentiation was along with MEK/ERK and Akt activation and increased expression of PU.1, CCAAT/enhancer-binding protein ß (C/EBPß) and C/EBPε. N-acetyl-L-cysteine (NAC), an antioxidant, thoroughly reduced EA+RA-increased ROS, and also inhibited MMP attenuation, the activation of caspase- 3/7, MEK/ERK and Akt pathways, the elevation of PU.1 and C/EBPs, and apoptosis and differentiation. However, MEK or PI3K specific inhibitors only suppressed EA+RA-triggered differentiation and the elevation of PU.1 and C/EBPs, but not ROS levels. CONCLUSION: EA+RA induced cell apoptosis through ROS dependent MMP attenuation and caspase 3/7 activation while inducing differentiation by ROS-MEK/ERK-PU.1/C/EBPs and ROS-Akt-PU.1/C/EBPs pathways. In summary, it may provide innovative ATRA-based combination therapy strategies for AML patients via ROS.

Urban vs. rural: colorectal cancer survival and prognostic disparities from 2000 to 2019.

This study aimed to analyze the differences in colorectal cancer (CRC) survival between urban and rural areas over the past 20 years, as well as investigate potential prognostic factors for CRC survival in both populations. Using registry data from Surveillance, Epidemiology, and End Results (SEER) from 2000 to 2019, 463,827 CRC cases were identified, with 85.8% in urban and 14.2% in rural areas. The mortality of CRC surpassed its survival rate by the sixth year after diagnosis in urban areas and the fifth year in rural areas. Furthermore, the 5-year overall survival (OS) of CRC increased by 2.9-4.3 percentage points in urban and 0.6-1.5 percentage points in rural areas over the past two decades. Multivariable Cox regression models identified independent prognostic factors for OS and disease-specific survival (DSS) of CRC in urban and rural areas, including age over 40, Black ethnicity, and tumor size greater than 5 cm. In addition, household income below $75,000 was found to be an independent prognostic factor for OS and DSS of CRC in urban areas, while income below $55,000 was a significant factor for rural areas. In conclusion, this study found a notable difference in CRC survival between rural and urban areas. Independent prognostic factors shared among both rural and urban areas include age, tumor size, and race, while household income seem to be area-specific predictive variables. Collaboration between healthcare providers, patients, and communities to improve awareness and early detection of CRC may help to further advance survival rates.

ARHGAP4 Inhibits Proliferation and Growth of SW620 Colon Cancer Cells by Cell Cycle and Differentiation Pathways.

The aim of this study is to explore the mechanism by which ARHGAP4 regulates the proliferation and growth of colon cancer cells, and it relates to the metastasis of colorectal cancer (CRC). Various techniques including western blot, CCK8, qRT-PCR, RNA seq assay, plate cloning, subcutaneous tumorigenesis assays, and bioinformatics tools were employed to identify genes that were upregulated or downregulated upon ARHGAP4 knockdown and their involvement in tumor cell proliferation and growth. The expression of ARHGAP4 in T and M stages of CRC uses immunohistochemistry. The expression levels of ARHGAP4 were found to be high in SW620, SW480, and HCT116 cell lines, while they were being low in HT29, LoVo, and NCM460 cell lines. Depletion of ARHGAP4 resulted in inhibited proliferation and growth in SW620 cells and inhibited subcutaneous tumorigenesis in nude mice, whereas overexpression of ARHGAP4 promoted proliferation and growth in HT29 cells and promoted subcutaneous tumorigenesis in nude mice. A total of 318 upregulated genes and 637 downregulated genes were identified in SW620 cells upon ARHGAP4 knockdown. The downregulated genes were primarily associated with cell cycle pathways, while the upregulated genes were enriched in differentiation-related pathways. Notable upregulated genes involved in cell differentiation included KRT10, KRT13, KRT16, IVL, and CD24, while significant downregulation was observed in genes related to the cell cycle such as CCNA2, CDKN2C, CDKN3, CENPA, and CENPF. ARHGAP4 expression is markedly elevated in the M1 stage of CRC compared to the M0 stage, suggesting ARHGAP4 linked to the metastatic in CRC. ARHGAP4 regulates the proliferation and growth of colon cancer cells by up- and downregulated cell cycle and differentiation-related molecules, which may be related to the metastasis of CRC.