Different surgical interventions for unstable intertrochanteric fracture of the femur: Network meta-analysis.

OBJECTIVE: Although a large body of evidence has reported on surgical approaches for the treatment of unstable intertrochanteric femoral fractures, studies that comprehensively evaluate treatment outcomes are limited. The purpose of this study was to compare the effectiveness of extramedullary fixation (i.e., dynamic hip screw [DHS]), intramedullary fixation (i.e., the proximal femoral nailing [PFN]), and hemiarthroplasty (HA) for the treatment of unstable intertrochanteric femoral fractures using network meta-analysis. METHODS: This study meets the preferred reporting items for systematic reviews and meta-analyses criteria. The Patient, Intervention, Comparison and Outcome search protocol framework was used to search the Google Scholar, PubMed, Embase, and Cochrane Library databases were searched from inception until June 2023. RESULTS: A total of 15 randomized controlled trials, including 1282 patients were analyzed. The Harris hip score (HHS) after DHS fixation was the lowest compared with that of PFN fixation and HA. DHS fixation had a significantly longer operation time than that of PFN fixation. Compared with HA, a lower incidence of superficial wound infection was observed with PFN and DHS fixations. PFN was significantly more likely to be implant cut out compared with HA. Compared with DHS, PFN and HA showed a lower incidence of fracture healing malunion. CONCLUSION: HA and PFN have good efficacy in improving the HHS and preventing joint deformities. However, HA showed a higher incidence of superficial infection than that observed with PFN, whereas a higher risk of screw cutout is observed with PFN than with HA.

Tumor microenvironment RNA test to predict immunotherapy outcomes in advanced gastric cancer: The TIMES001 trial.

BACKGROUND: Clinical trials support the efficacy of immune checkpoint blockades (ICBs) plus chemotherapy in a subset of patients with metastatic gastric cancer (mGC). To identify the determinants of response, we developed a TMEscore model to assess tumor microenvironment (TME), which was previously proven to be a biomarker for ICBs. METHODS: A reference database of TMEscore assays was established using PCR assay kits containing 30 TME genes. This multi-center prospective clinical trial (NCT#04850716) included patients with mGC who were administered ICB combined with chemotherapy as a first-line regimen. Eighty-six tumor samples extracted from five medical centers before treatment were used to estimate the TMEscore, PD-L1 (CPS), and mismatch repair deficiency. FINDINGS: The objective response rate (ORR) and median PFS of the cohort were 31.4% and six months. Enhanced ORR was observed in TMEscore-high mGC patients (ORR = 59%). The survival analysis demonstrated that high TMEscore was significantly associated with a more favorable PFS and OS. Moreover, TMEscore was found to be a predictive biomarker that surpassed MSI and CPS (AUC = 0.873, 0.511, and 0.524, respectively). By integrating the TMEscore and clinical variables, the fused model further enhances the predictive efficiency and translational application in a clinical setting. CONCLUSIONS: This prospective clinical study indicates that the TMEscore assay is a robust biomarker for screening patients with mGC who may derive survival benefits from ICB plus chemotherapy. FUNDING: Guangdong Basic and Applied Basic Research Foundation (2023A1515011214), Science and Technology Program of Guangzhou (202206080011), and Guangzhou Science and Technology Project (2023A03J0722 and 2023A04J2357).

[Analysis of clinical features of 193 Chinese patients with McCune-Albright syndrome through a literature review].

OBJECTIVE: To retrospectively analyze the clinical characteristics of 193 Chinese patients with McCune-Albright syndrome (MAS). METHODS: By using keywords "McCune-Albright syndrome", "Albright syndrome", or " fibrous dysplasia " as the search terms, 193 cases of MAS reported in China from January 1990 to November 2022 from the Wanfang data, CNKI, VIP, PubMed, and Embase databases were obtained, and their clinical data was retrospectively analyzed. Intergroup comparisons were carried out by using t test, Mann-Whitney U test, and X2 test. RESULTS: The 193 MAS patients had included 42 males and 151 females, with the median first-visit age of females being younger than males. The typical triad group had accounted for 46.1% of patients, and the middle first-visit and diagnosis age was younger than the atypical group. The primary reason for first-visit in males of MAS was fibrous dysplasia (FD), whilst that in females of MAS was peripheral precocious puberty (PPP). FD has occurred in 84.5% of the patients, with an average age of onset age being 6.1 years old, and 90% was ≤ 16 years of age. Endocrine hyperfunction was found in 79.3% of the patients, with a higher proportion in females compared with males (P < 0.05). Pituitary involvement was seen in 21.8% of the patients, and the incidence of craniofacial FD and cranial nerve compression was significantly higher in those with elevated growth hormone (GH) than without (P < 0.05). Café-au-Lait Spots were noted in 86.5% of the patients, and 28.3% (28/99) had located on the different side of FD. CONCLUSION: Most MAS patients had atypical manifestations and multi-systemic involvement. It is more common and occurs earlier in females. The most common reasons for initial diagnosis in male and female patients were FD and PPP, respectively. Patients with elevated GH should be examined for cranial nerve compression.

UM171 suppresses breast cancer progression by inducing KLF2.

PURPOSE: Breast cancer is the most frequent cancer in women with significant death rate. Morbidity is associated with drug resistance and metastasis. Development of novel drugs is unmet need. The aim of this study is to show potent anti-neoplastic activity of the UM171 compound on breast cancer cells and its mechanism of action. METHODS: The inhibitory effect of UM171 on several breast cancer (BC) cell lines was examined using MTT and colony-forming assays. Cell cycle and apoptosis assays were utilized to determine the effect of UM171 on BC cell proliferation and survival. Wound healing scratch and transwell migration assays were used to examine the migration of BC cell lines in culture. Xenograft of mouse model with 4T1 cells was used to determine inhibitory effect of UM171 in vivo. Q-RT-PCR and western blotting were used to determine the expression level of genes effected by UM171. Lentivirus-mediated shRNAs were used to knockdown the expression of KLF2 in BC cells. RESULTS: UM171 was previously identified as a potent agonist of human hematopoietic stem cell renewal and inhibitor of leukemia. In this study, UM171 was shown to inhibit the growth of multiple breast cancer cell lines in culture. UM171-mediated growth inhibition was associated with the induction of apoptosis, G2/M cell cycle arrest, lower colony-forming capacity, and reduced motility. In a xenotransplantation model of mouse triple-negative breast cancer 4T1 cells injected into syngeneic BALB/c mice, UM171 strongly inhibited tumor growth at a level comparable to control paclitaxel. UM171 increased the expression of the three PIM genes (PIM1-3) in breast cancer cells. Moreover, UM171 strongly induced the expression of the tumor suppressor gene KLF2 and cell cycle inhibitor P21CIP1. Accordingly, knockdown of KLF2 using lentivirus-mediated shRNA significantly attenuated the growth suppressor activity of UM171. As PIM1-3 act as oncogenes and are involved in breast cancer progression, induction of these kinases likely impedes the inhibitory effect of KLF2 induction by UM171. Accordingly, combination of UM171 with a PAN-PIM inhibitor LGH447 significantly reduced tumor growth in culture. CONCLUSION: These results suggested that UM171 inhibited breast cancer progression in part through activation of KLF2 and P21. Combination of UM171 with a PAN-PIM inhibitor offer a novel therapy for aggressive forms of breast cancer.

An intricate regulatory circuit between FLI1 and GATA1/GATA2/LDB1/ERG dictates erythroid vs. megakaryocytic differentiation.

During hematopoiesis, megakaryocytic erythroid progenitors (MEPs) differentiate into megakaryocytic or erythroid lineages in response to specific transcriptional factors, yet the regulatory mechanism remains to be elucidated. Using the MEP­like cell line HEL western blotting, RT­qPCR, lentivirus­mediated downregulation, flow cytometry as well as chromatin immunoprecipitation (ChIp) assay demonstrated that the E26 transformation­specific (ETS) transcription factor friend leukemia integration factor 1 (Fli­1) inhibits erythroid differentiation. The present study using these methods showed that while FLI1­mediated downregulation of GATA binding protein 1 (GATA1) suppresses erythropoiesis, its direct transcriptional induction of GATA2 promotes megakaryocytic differentiation. GATA1 is also involved in megakaryocytic differentiation through regulation of GATA2. By contrast to FLI1, the ETS member erythroblast transformation­specific­related gene (ERG) negatively controls GATA2 and its overexpression through exogenous transfection blocks megakaryocytic differentiation. In addition, FLI1 regulates expression of LIM Domain Binding 1 (LDB1) during erythroid and megakaryocytic commitment, whereas shRNA­mediated depletion of LDB1 downregulates FLI1 and GATA2 but increases GATA1 expression. In agreement, LDB1 ablation using shRNA lentivirus expression blocks megakaryocytic differentiation and modestly suppresses erythroid maturation. These results suggested that a certain threshold level of LDB1 expression enables FLI1 to block erythroid differentiation. Overall, FLI1 controlled the commitment of MEP to either erythroid or megakaryocytic lineage through an intricate regulation of GATA1/GATA2, LDB1 and ERG, exposing multiple targets for cell fate commitment and therapeutic intervention.

Design, Synthesis, and Anti-Leukemic Evaluation of a Series of Dianilinopyrimidines by Regulating the Ras/Raf/MEK/ERK and STAT3/c-Myc Pathways.

Although the long-term survival rate for leukemia has made significant progress over the years with the development of chemotherapeutics, patients still suffer from relapse, leading to an unsatisfactory outcome. To discover the new effective anti-leukemia compounds, we synthesized a series of dianilinopyrimidines and evaluated the anti-leukemia activities of those compounds by using leukemia cell lines (HEL, Jurkat, and K562). The results showed that the dianilinopyrimidine analog H-120 predominantly displayed the highest cytotoxic potential in HEL cells. It remarkably induced apoptosis of HEL cells by activating the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9 and cleaved poly ADP-ribose polymerase (PARP)), increasing apoptosis protein Bad expression, and decreasing the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL). Furthermore, it induced cell cycle arrest in G2/M; concomitantly, we observed the activation of p53 and a reduction in phosphorylated cell division cycle 25C (p-CDC25C) / Cyclin B1 levels in treated cells. Additionally, the mechanism study revealed that H-120 decreased these phosphorylated signal transducers and activators of transcription 3, rat sarcoma, phosphorylated cellular RAF proto-oncogene serine / threonine kinase, phosphorylated mitogen-activated protein kinase kinase, phosphorylated extracellular signal-regulated kinase, and cellular myelocytomatosis oncogene (p-STAT3, Ras, p-C-Raf, p-MEK, p-MRK, and c-Myc) protein levels in HEL cells. Using the cytoplasmic and nuclear proteins isolation assay, we found for the first time that H-120 can inhibit the activation of STAT3 and c-Myc and block STAT3 phosphorylation and dimerization. Moreover, H-120 treatment effectively inhibited the disease progression of erythroleukemia mice by promoting erythroid differentiation into the maturation of erythrocytes and activating the immune cells. Significantly, H-120 also improved liver function in erythroleukemia mice. Therefore, H-120 may be a potential chemotherapeutic drug for leukemia patients.

Integrating transcriptomics and machine learning for immunotherapy assessment in colorectal cancer.

Colorectal cancer (CRC) is a highly prevalent and lethal malignancy worldwide. Although immunotherapy has substantially improved CRC outcomes, intolerance remains a major concern among most patients. Considering the pivotal role of the tumor microenvironment (TME) in tumor progression and treatment outcomes, profiling the TME at the transcriptomic level can provide novel insights for developing CRC treatment strategies. Seventy-seven TME-associated signatures were acquired from previous studies. To elucidate variations in prognosis, clinical features, genomic alterations, and responses to immunotherapy in CRC, we employed a non-negative matrix factorization algorithm to categorize 2595 CRC samples of 27 microarrays from the Gene Expression Omnibus database. Three machine learning techniques were employed to identify a signature specific to immunotherapy. Subsequently, the mechanisms by which this signature interacts with TME subtypes and immunotherapy were investigated. Our findings revealed five distinct TME subtypes (TMESs; TMES1-TMES5) in CRC, each exhibiting a unique pattern of immunotherapy response. TMES1, TMES4, and TMES5 had relatively inferior outcomes, TMES2 was associated with the poorest prognosis, and TMES3 had a superior outcome. Subsequent investigations revealed that activated dendritic cells could enhance the immunotherapy response rate, with their augmentation effect closely associated with the activation of CD8+T cells. We successfully classified CRC into five TMESs, each demonstrating varying response rates to immunotherapy. Notably, the application of machine learning to identify activated dendritic cells helped elucidate the underlying mechanisms contributing to these differences. We posit that these TMESs hold promising clinical implications for prognostic evaluation and guidance of immunotherapy strategies, thereby providing valuable insights to inform clinical decision-making.

FLI1 induces erythroleukemia through opposing effects on UBASH3A and UBASH3B expression.

BACKGROUND: FLI1 is an oncogenic transcription factor that promotes diverse malignancies through mechanisms that are not fully understood. Herein, FLI1 is shown to regulate the expression of Ubiquitin Associated and SH3 Domain Containing A/B (UBASH3A/B) genes. UBASH3B and UBASH3A are found to act as an oncogene and tumor suppressor, respectively, and their combined effect determines erythroleukemia progression downstream of FLI1. METHODS: Promoter analysis combined with luciferase assays and chromatin immunoprecipitation (ChIP) analysis were applied on the UBASH3A/B promoters. RNAseq analysis combined with bioinformatic was used to determine the effect of knocking-down UBASH3A and UBASH3B in leukemic cells. Downstream targets of UBASH3A/B were inhibited in leukemic cells either via lentivirus-shRNAs or small molecule inhibitors. Western blotting and RT-qPCR were used to determine transcription levels, MTT assays to assess proliferation rate, and flow cytometry to examine apoptotic index. RESULTS: Knockdown of FLI1 in erythroleukemic cells identified the UBASH3A/B genes as potential downstream targets. Herein, we show that FLI1 directly binds to the UBASH3B promoter, leading to its activation and leukemic cell proliferation. In contrast, FLI1 indirectly inhibits UBASH3A transcription via GATA2, thereby antagonizing leukemic growth. These results suggest oncogenic and tumor suppressor roles for UBASH3B and UBASH3A in erythroleukemia, respectively. Mechanistically, we show that UBASH3B indirectly inhibits AP1 (FOS and JUN) expression, and that its loss leads to inhibition of apoptosis and acceleration of proliferation. UBASH3B also positively regulates the SYK gene expression and its inhibition suppresses leukemia progression. High expression of UBASH3B in diverse tumors was associated with worse prognosis. In contrast, UBASH3A knockdown in erythroleukemic cells increased proliferation; and this was associated with a dramatic induction of the HSP70 gene, HSPA1B. Accordingly, knockdown of HSPA1B in erythroleukemia cells significantly accelerated leukemic cell proliferation. Accordingly, overexpression of UBASH3A in different cancers was predominantly associated with good prognosis. These results suggest for the first time that UBASH3A plays a tumor suppressor role in part through activation of HSPA1B. CONCLUSIONS: FLI1 promotes erythroleukemia progression in part by modulating expression of the oncogenic UBASH3B and tumor suppressor UBASH3A.

Gene variants and clinical characteristics of children with sitosterolemia.

OBJECTIVE: To enhance the detection, management and monitoring of Chinese children afflicted with sitosterolemia by examining the physical characteristics and genetic makeup of pediatric patients. METHODS: In this group, 26 children were diagnosed with sitosterolemia, 24 of whom underwent genetic analysis. Patient family medical history, physical symptoms, tests for liver function, lipid levels, standard blood tests, phytosterol levels, cardiac/carotid artery ultrasounds, fundus examinations, and treatment were collected. RESULTS: The majority (19, 73.1%) of the 26 patients exhibited xanthomas as the most prevalent manifestation. The second most common symptoms were joint pain (7, 26.9%) and stunted growth (4, 15.4%). Among the 24 (92.3%) patients whose genetics were analyzed, 16 (66.7%) harbored ABCG5 variants (type 2 sitosterolemia), and nearly one-third (8, 33.3%) harbored ABCG8 variants (type 1 sitosterolemia). Additionally, the most common pathogenic ABCG5 variant was c.1166G > A (p.Arg389His), which was found in 10 patients (66.7%). Further analysis did not indicate any significant differences in pathological traits among those carrying ABCG5 and ABCG8 variations (P > 0.05). Interestingly, there was a greater abundance of nonsense variations in ABCG5 than in ABCG8 (P = 0.09), and a greater frequency of splicing variations in ABCG8 than ABCG5 (P = 0.01). Following a change in diet or a combination of ezetimibe, the levels of cholesterol and low-density lipoprotein were markedly decreased compared to the levels reported before treatment. CONCLUSION: Sitosterolemia should be considered for individuals presenting with xanthomas and increased cholesterol levels. Phytosterol testing and genetic analysis are important for early detection. Managing one's diet and taking ezetimibe can well control blood lipids.

Fatty acid-balanced oil improved nutrient digestibility, altered milk composition in lactating sows and fecal microbial composition in piglets.

OBJECTIVE: This study aimed to investigate the effects of dietary supplementation of a fatty acid-balanced oil, instead of soybean oil, on reproductive performance, nutrient digestibility, blood indexes, milk composition in lactating sows, and fecal microbial composition in piglets. METHODS: Twenty-four sows (Landrace×Yorkshire, mean parity 4.96) were randomly allotted to two treatments with twelve pens per treatment and one sow per pen based on their backfat thickness and parity. The experiment began on day 107 of gestation and continued until weaning on day 21 of lactation, lasting for 28 days. The control group (CG) was fed a basal diet supplemented with 2% soybean oil and the experimental group (EG) was fed the basal diet supplemented with 2% fatty acid-balanced oil. RESULTS: The fatty acid-balanced oil supplementation increased (p<0.05) the apparent total tract digestibility of dry matter, crude protein, and gross energy in sows. The lower (p<0.05) serum high-density lipoprotein cholesterol and albumin levels of sows were observed in the EG on day 21 of lactation. Dietary supplementation with the fatty acid-balanced oil decreased the fat content, increased the immunoglobulin G level, and changed (p<0.05) some fatty acid content in milk. Moreover, the fatty acid-balanced oil supplementation changed (p<0.05) the fecal microbial composition of piglets, where the average relative abundance of Spirochaetota was decreased (p<0.05) by 0.55% at the phylum level, and the average relative abundance of some potentially pathogenic fecal microorganism was decreased (p<0.05) at the species level. CONCLUSION: The fatty acid-balanced oil improved nutrient digestibility, changed the serum biochemical indices and milk composition of sows, and ameliorated the fecal microbial composition of piglets.

Comparison of short-term outcomes of robotic-assisted radical colon cancer surgery using the Kangduo Surgical Robotic System and the Da Vinci Si Robotic System: a prospective cohort study.

BACKGROUND: Robotic surgery has been a revolution for colon cancer (CC) patients, with the increasing availability of different competitive robotic systems, but evidence of relevant oncologic outcomes is indeed scarce. Our goal was to compare the surgical quality and short-term oncologic outcomes of the Kangduo Surgical Robotic System and the da Vinci Si Robotic System in patients with CC. METHODS: These are results from a subcohort of a multicenter randomized controlled noninferiority trial performed in three centers in China. Enrolled patients were randomly assigned to undergo surgery using either the KD-SR-01 system (KD group) or the da Vinci Si (DV) robotic system (DV group). Neither investigators nor patients were masked to treatment allocation, but assessment of pathological outcomes was masked to treatment allocation. The primary endpoint was surgical success rate. The secondary endpoints were surgical outcomes, pathologic outcomes, and postoperative outcomes. The study is registered at www.chictr.org.cn (ChiCTR2200063172). Although the long-term follow-up results were not a predefined endpoint for this study, late-stage work is in progress. RESULTS: A total of 58 CC patients were included in this study, 28 in the KD group and 30 in the DV group. All patients were successfully operated without any intermediate open/conventional laparoscopic surgery and the success rate of surgery was 100%. Assessment of equipment docking task load and intraoperative operating sensation score were similar between the two groups. Adverse events and Clavien-Dindo grade II or higher grade complication rates were comparable between the two groups. Device arm docking time, robotic arm operation time, and intraoperative bleeding were not significantly different between the two groups. Similar results were obtained from postoperative pathological outcomes and internal environment indexes. CONCLUSIONS: The efficacy and safety of the Kangduo Robotic Surgical System has been proved, operation of the Kangduo Robotic System by experienced surgeons for CC is not less effective than the da Vinci robotic System.

Optimizing Anesthetic Practices for Mud Crab: A Comparative Study of Clove Oil, MS-222, Ethanol, and Magnesium Chloride.

Anesthesia serves as an effective method to mitigate the stress response in aquatic animals during aquaculture and product transportation. In this study, we assessed the anesthetic efficacy of clove oil, tricaine methane-sulfonate (MS-222), ethanol, and magnesium chloride by anesthesia duration, recovery time, 24-hour survival rate, and the behavior of mud crabs (Scylla paramamosain). Additionally, the optimal anesthetic concentration for varying body weights of mud crabs was also investigated. The results revealed that clove oil emerged as the optimal anesthetic for mud crabs, with a 24-hour survival rate surpassing those observed in MS-222 and magnesium chloride treatments. Ethanol caused amputation and hyperactivity in mud crabs. Regression analyses between the optimal anesthetic concentration of clove oil and the weight categories of 0.03-27.50 g and 27.50-399.73 g for mud crabs yielded the following equations: y = 0.0036 x3 - 0.1629 x2 + 1.7314 x + 4.085 (R2 = 0.7115) and y = 0.0437 x + 2.9461 (R2 = 0.9549). Clove oil exhibited no significant impact on serum cortisol, glucose, lactate content, aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities, or superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) levels in mud crabs across different treatment groups. Anesthesia induced by clove oil in mud crabs resulted in an increase in inhibitory neurotransmitters such as glycine. However, the recovery from anesthesia was associated with elevated levels of the excitatory neurotransmitters L-aspartic acid and glutamate. In conclusion, clove oil proves to be a safe and optimal anesthetic agent for mud crabs, exerting no physiological stress on the species.

LAMP2A, LAMP2B and LAMP2C: similar structures, divergent roles.

LAMP2 (lysosomal associated membrane protein 2) is one of the major protein components of the lysosomal membrane. There currently exist three LAMP2 isoforms, LAMP2A, LAMP2B and LAMP2C, and they vary in distribution and function. LAMP2A serves as a receptor and channel for transporting cytosolic proteins in a process called chaperone-mediated autophagy (CMA). LAMP2B is required for autophagosome-lysosome fusion in cardiomyocytes and is one of the components of exosome membranes. LAMP2C is primarily implicated in a novel type of autophagy in which nucleic acids are taken up into lysosomes for degradation. In this review, the current evidence for the function of each LAMP2 isoform in various pathophysiological processes and human diseases, as well as their possible mechanisms, are comprehensively summarized. We discuss the evolutionary patterns of the three isoforms in vertebrates and provide technical guidance on investigating these isoforms. We are also concerned with the newly arising questions in this particular research area that remain unanswered. Advances in the functions of the three LAMP2 isoforms will uncover new links between lysosomal dysfunction, autophagy and human diseases.Abbreviation: ACSL4: acyl-CoA synthetase long-chain family member 4; AD: Alzheimer disease; Ag: antigens; APP: amyloid beta precursor protein; ATG14: autophagy related 14; AVSF: autophagic vacuoles with unique sarcolemmal features; BBC3/PUMA: BCL2 binding component 3; CCD: C-terminal coiled coil domain; CMA: chaperone-mediated autophagy; CVDs: cardiovascular diseases; DDIT4/REDD1: DNA damage inducible transcript 4; ECs: endothelial cells; ER: endoplasmic reticulum; ESCs: embryonic stem cells; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBA/ß-glucocerebrosidase: glucosylceramidase beta; GSCs: glioblastoma stem cells; HCC: hepatocellular carcinoma; HD: Huntington disease; HSCs: hematopoietic stem cells; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; IL3: interleukin 3; IR: ischemia-reperfusion; LAMP2: lysosomal associated membrane protein 2; LDs: lipid droplets; LRRK2: leucine rich repeat kinase 2; MA: macroautophagy; MHC: major histocompatibility complex; MST1: macrophage stimulating 1; NAFLD: nonalcoholic fatty liver disease; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NLRP3: NLR family pyrin domain containing 3; PARK7: Parkinsonism associated deglycase; PD: Parkinson disease; PEA15/PED: proliferation and apoptosis adaptor protein 15; PKM/PKM2: pyruvate kinase M1/2; RA: rheumatoid arthritis; RARA: retinoic acid receptor alpha; RCAN1: regulator of calcineurin 1; RCC: renal cell carcinoma; RDA: RNautophagy and DNautophagy; RNAi: RNA interference; RND3: Rho Family GTPase 3; SG-NOS3/eNOS: deleterious glutathionylated NOS3; SLE: systemic lupus erythematosus; TAMs: tumor-associated macrophages; TME: tumor microenvironment; UCHL1: ubiquitin C-terminal hydrolase L1; VAMP8: vesicle associated membrane protein 8.

Congenital hepatoblastoma presenting with hepatic arteriovenous fistulas: a case report.

Aim: Congenital hepatoblastoma, a rare malignant liver tumor in infancy, typically presents with abdominal distension or mass. Tumors detected antenatally or during the first three months of age are considered congenital hepatoblastoma. Hepatic arteriovenous fistulas (HAVF) are associated with high mortality in the neonatal period and can be caused by many secondary factors. This case report focuses on a patient with congenital hepatoblastoma accompanied by HAVF, highlighting the clinical and imaging characteristics and management strategies. Case presentation: A term infant presented with sudden tachypnea and heart failure on his first day of life. A cystic-solid mixed lesion in the fetus's liver was detected by an antenatal ultrasound scan. Postnatal digital subtraction angiography confirmed the presence of arteriovenous fistulas, which were treated with trans-arterial embolization. However, despite the intervention, the patient's heart failure did not improve. The patient underwent a left hepatectomy, and hepatoblastoma was discovered by histology of the resected hepatic lobe. Unfortunately, metastases were later discovered in the intracranial and ocular regions. Ultimately, the family decided to discontinue further treatment. Conclusion: Congenital hepatoblastoma presenting with hepatic arteriovenous fistulas has not been previously described. Hepatoblastoma should be considered when alpha-fetoprotein levels show a significant elevation in newborns. Prenatal diagnosis may improve pre- and postnatal management.

FLI1 Regulates Histamine Decarboxylase Expression to Control Inflammation Signaling and Leukemia Progression.

Aim: Histamine decarboxylase (HDC) catalyzes decarboxylation of histidine to generate histamine. This enzyme affects several biological processes including inflammation, allergy, asthma, and cancer, although the underlying mechanism is not fully understood. The present study provides a novel insight into the relationship between the transcription factor FLI1 and its downstream target HDC, and their effects on inflammation and leukemia progression. Methods: Promoter analysis combined with chromatin immunoprecipitation (ChIp) was used to demonstrate binding of FLI1 to the promoter of HDC in leukemic cells. Western blotting and RT-qPCR were used to determine expression of HDC and allergy response genes, and lentivirus shRNA was used to knock-down target genes. Proliferation, cell cycle, apoptosis assays and molecular docking were used to determine the effect of HDC inhibitors in culture. An animal model of leukemia was employed to test the effect of HDC inhibitory compounds in vivo. Results: Results presented herein demonstrate that FLI1 transcriptionally regulates HDC by direct binding to its promoter. Using genetic and pharmacological inhibition of HDC, or the addition of histamine, the enzymatic product of HDC, we show neither have a discernable effect on leukemic cell proliferation in culture. However, HDC controls several inflammatory genes including IL1B and CXCR2 that may influence leukemia progression in vivo through the tumor microenvironment. Indeed, diacerein, an IL1B inhibitor, strongly blocked Fli-1-induced leukemia in mice. In addition to allergy, FLI1 is shown to regulate genes associated with asthma such as IL1B, CPA3 and CXCR2. Toward treatment of these inflammatory conditions, epigallocatechin (EGC), a tea polyphenolic compound, is found strongly inhibit HDC independently of FLI1 and its downstream effector GATA2. Moreover, the HDC inhibitor, tetrandrine, suppressed HDC transcription by directly binding to and inhibiting the FLI1 DNA binding domain, and like other FLI1 inhibitors, tetrandrine strongly suppressed cell proliferation in culture and leukemia progression in vivo. Conclusion: These results suggest a role for the transcription factor FLI1 in inflammation signaling and leukemia progression through HDC and point to the HDC pathway as potential therapeutics for FLI1-driven leukemia.

Molecular subtyping in colorectal cancer: A bridge to personalized therapy (Review).

Colorectal cancer (CRC) is a malignant tumor and a major cause of morbidity and mortality globally. The classic Tumor-Node-Metastasis staging system, which currently underlies the diagnosis and treatment of CRC, is primarily a 'one drug fits all' model for patients exhibiting the same pathological features. However, a high degree of variability has been established in the long-term survival outcomes of patients with CRC with similar pathological types and stages, which can be partially attributed to tumor-specific molecular biology to some extent. Molecular classification of CRC can further assist with understanding the biological behavior of tumor genesis, development and prognosis, and assist clinicians in improving or customizing the treatment strategy of CRC. In the present study, clinical studies carried out to date are reviewed, and their clinical value is discussed. A multilevel overview of the major molecular types of CRC is provided, in the hope that investigators are encouraged to combine multiple omics studies for interrogating cancer.

Application of the Xi robotic platform for familial adenomatous polyposis with ultra-low rectal cancer: exploration of minimally invasive and refined therapies.

When a familial adenomatous polyposis (FAP) patient's rectal polyp undergoes malignant transformation, the surgeon needs to consider how to balance the quality of surgery with the patient's quality of life. Here, we present a case of robotic surgery in a patient with familial adenomatous polyposis and ultra-low rectal cancer. Fiberoptic colonoscopy found that hundreds of polyp-like bulges were diffusely distributed throughout the colon, and a malignant mass was found at the end of the rectum. The patient underwent total colectomy with abdominoperineal extended radical resection for rectal cancer using the Xi robotic platform. The patient recovered well in the postoperative period. The ileostomy was well used. And the patient was in good health and metastasis free at 9 months postoperatively. We identified total colectomy combined with extended radical rectal resection under the assistance of the da Vinci robot platform is of great benefit to the patient.

Lovastatin inhibits erythroleukemia progression through KLF2-mediated suppression of MAPK/ERK signaling.

BACKGROUND: Lovastatin, an HMG-CoA inhibitor and an effective cholesterol lowering drug, exhibits anti-neoplastic activity towards several types of cancer, although the underlying mechanism is still not fully understood. Herein, we investigated mechanism of growth inhibition of leukemic cells by lovastatin. METHODS: RNAseq analysis was used to explore the effect of lovastatin on gene expression in leukemic cells. An animal model of leukemia was used to test the effect of this statin in vivo. FAM83A and DDIT4 expression was knocked-downed in leukemia cells via lentivirus-shRNA. Western blotting, RT-qPCR, cell cycle analysis and apoptosis assays were used to determine the effect of lovastatin-induced growth suppression in leukemic cells in vitro. RESULTS: Lovastatin treatment strongly inhibited cancer progression in a mouse model of erythroleukemia induced by Friend virus. In tissue culture, lovastatin inhibited cell proliferation through induction of G1 phase cell cycle arrest and apoptosis. Interestingly, lovastatin induced most known genes associated with cholesterol biosynthesis in leukemic cells. Moreover, it suppressed ERK1/2 phosphorylation by downregulating FAM83A and DDIT4, two mediators of MAP-Kinase signaling. RNAseq analysis of lovastatin treated leukemic cells revealed a strong induction of the tumor suppressor gene KLF2. Accordingly, lentivirus-mediated knockdown of KLF2 antagonized leukemia cell suppression induced by lovastatin, associated with higher ERK1/2 phosphorylation compared to control. We further show that KLF2 induction by lovastatin is responsible for lower expression of the FAM83A and DDIT4 oncogenes, involved in the activation of ERK1/2. KLF2 activation by lovastatin also activated a subset of cholesterol biosynthesis genes that may further contribute to leukemia suppression. CONCLUSIONS: These results implicate KLF2-mediated FAM83A/DDIT4/MAPK suppression and activation of cholesterol biosynthesis as the mechanism of leukemia cell growth inhibition by lovastatin.

Rise and metabolic roles of Vibrio during the fermentation of crab paste.

Microbial community may systematically promote the development of fermentation process of foods. Traditional fermentation is a spontaneous natural process that determines a unique nutritional characteristic of crab paste of Portunus trituberculatus, However, rare information is available regarding the development pattern and metabolic role of bacterial community during the fermentation of crab paste. Here, using a 16S rRNA gene amplicon sequencing technology, we investigated dynamics of bacterial community and its relationship with metabolites during the fermentation of crab paste. The results showed that bacterial community changed dynamically with the fermentation of crab paste which highlighted by consistently decreased α-diversity and overwhelming dominance of Vibrio at the later days of fermentation. Vibrio had a positive correlation with trimethylamine, hypoxanthine, formate, and alanine while a negative correlation with inosine and adenosine diphosphate. In contrast, most of other bacterial indicators had a reverse correlation with these metabolites. Moreover, Vibrio presented an improved function potential in the formation of the significantly increased metabolites. These findings demonstrate that the inexorable rise of Vibrio not only drives the indicator OTUs turnover in the bacterial community but also has incriminated the quality of crab paste from fresh to perished.