FBXO3 stabilizes USP4 and Twist1 to promote PI3K-mediated breast cancer metastasis.

Tumor metastasis is the major cause of breast cancer morbidity and mortality. It has been reported that the F-box protein FBXO3 functions as an E3 ubiquitin ligase in regulating various biological processes, including host autoimmune, antiviral innate immunity, and inflammatory response. However, the role of FBXO3 in tumor metastasis remains elusive. We have previously shown that ΔNp63α is a common inhibitory target in oncogene-induced cell motility and tumor metastasis. In this study, we show that FBXO3 plays a vital role in PI3K-mediated breast cancer metastasis independent of its E3 ligase activity and ΔNp63α in breast cancer cells and in mouse. FBXO3 can bind to and stabilize USP4, leading to Twist1 protein stabilization and increased breast cancer cell migration and tumor metastasis. Mechanistically, FBXO3 disrupts the interaction between USP4 and aspartyl aminopeptidase (DNPEP), thereby protecting USP4 from DNPEP-mediated degradation. Furthermore, p110αH1047R facilitates the phosphorylation and stabilization of FBXO3 in an ERK1-dependent manner. Knockdown of either FBXO3 or USP4 leads to significant inhibition of PI3K-induced breast cancer metastasis. Clinically, elevated expression of p110α/FBXO3/USP4/Twist1 is associated with poor overall survival (OS) and recurrence-free survival (RFS) of breast cancer patients. Taken together, this study reveals that the FBXO3-USP4-Twist1 axis is pivotal in PI3K-mediated breast tumor metastasis and that FBXO3/USP4 may be potential therapeutic targets for breast cancer treatment.

ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes.

BACKGROUND: The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. METHODS: Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. RESULTS: Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth. CONCLUSION: ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.

Disruption of SLFN11 Deficiency-Induced CCL2 Signaling and Macrophage M2 Polarization Potentiates Anti-PD-1 Therapy Efficacy in Hepatocellular Carcinoma.

BACKGROUND & AIMS: The therapeutic effect of immune checkpoint inhibitors (ICIs) is poor in hepatocellular carcinoma (HCC) and varies greatly among individuals. Schlafen (SLFN) family members have important functions in immunity and oncology, but their roles in cancer immunobiology remain unclear. We aimed to investigate the role of the SLFN family in immune responses against HCC. METHODS: Transcriptome analysis was performed in human HCC tissues with or without response to ICIs. A humanized orthotopic HCC mouse model and a co-culture system were constructed, and cytometry by time-of-flight technology was used to explore the function and mechanism of SLFN11 in the immune context of HCC. RESULTS: SLFN11 was significantly up-regulated in tumors that responded to ICIs. Tumor-specific SLFN11 deficiency increased the infiltration of immunosuppressive macrophages and aggravated HCC progression. HCC cells with SLFN11 knockdown promoted macrophage migration and M2-like polarization in a C-C motif chemokine ligand 2-dependent manner, which in turn elevated their own PD-L1 expression by activating the nuclear factor-κB pathway. Mechanistically, SLFN11 suppressed the Notch pathway and C-C motif chemokine ligand 2 transcription by binding competitively with tripartite motif containing 21 to the RNA recognition motif 2 domain of RBM10, thereby inhibiting tripartite motif containing 21-mediated RBM10 degradation to stabilize RBM10 and promote NUMB exon 9 skipping. Pharmacologic antagonism of C-C motif chemokine receptor 2 potentiated the antitumor effect of anti-PD-1 in humanized mice bearing SLFN11 knockdown tumors. ICIs were more effective in patients with HCC with high serum SLFN11 levels. CONCLUSIONS: SLFN11 serves as a critical regulator of microenvironmental immune properties and an effective predictive biomarker of ICIs response in HCC. Blockade of C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 signaling sensitized SLFN11low HCC patients to ICI treatment.

Medicaid Expansion Increases Access for Rural and Impoverished Patients with Pancreatic Ductal Adenocarcinoma in Southern States.

INTRODUCTION: Medicaid expansion (ME) impacted patients when assessed at a national level. However, of the 32 states in which Medicaid expansion occurred, only 3 were Southern states. Whether results apply to Southern states that share similar geopolitical perspectives remains elusive. We aimed to assess the impact of ME on pancreatic ductal adenocarcinoma (PDAC) treatment in eight Southern states in the USA. PATIENTS AND METHODS: We identified uninsured or Medicaid patients (age 40-64 years) diagnosed with PDAC between 2011 and 2018 in Southern states from the North American Association of Central Cancer Registries-Cancer in North America (NAACCR-CiNA) research dataset. Medicaid-expanded states (MES; Louisiana, Kentucky, and Arkansas) were compared with non-MES (NMES; Tennessee, Alabama, Mississippi, Texas, and Oklahoma) using multivariate logistic regression. P < 0.05 was considered statistically significant. RESULTS: Among 3036 patients, MES significantly increased odds of Medicaid insurance by 36%, and increased proportions of insured Black patients by 3.7%, rural patients by 3.8%, and impoverished patients by 18.4%. After adjusting for age, race, rural-urban status, poverty status, and summary stage, the odds of receiving radiation therapy decreased by 26% for each year of expansion in expanded states (P = 0.01). Last, ME did not result in a significant difference between MES and NMES in diagnosing early stage disease (P = 0.98) nor in receipt of chemotherapy or surgery (P = 0.23 and P = 0.63, respectively). CONCLUSIONS: ME in Southern states increased insurance access to traditionally underserved groups. Interestingly, ME decreased the odds of receiving radiation therapy yearly and had no significant impact on receipt of chemotherapy or surgery.

Noncanonical TGF-ß signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis.

Transforming growth factor-ß (TGF-ß) signaling plays a critical role in promoting epithelial-to-mesenchymal transition (EMT), cell migration, invasion, and tumor metastasis. ΔNp63α, the major isoform of p63 protein expressed in epithelial cells, is a key transcriptional regulator of cell adhesion program and functions as a critical metastasis suppressor. It has been documented that the expression of ΔNp63α is tightly controlled by oncogenic signaling and is frequently reduced in advanced cancers. However, whether TGF-ß signaling regulates ΔNp63α expression in promoting metastasis is largely unclear. In this study, we demonstrate that activation of TGF-ß signaling leads to stabilization of E3 ubiquitin ligase FBXO3, which, in turn, targets ΔNp63α for proteasomal degradation in a Smad-independent but Erk-dependent manner. Knockdown of FBXO3 or restoration of ΔNp63α expression effectively rescues TGF-ß-induced EMT, cell motility, and tumor metastasis in vitro and in vivo. Furthermore, clinical analyses reveal a significant correlation among TGF-ß receptor I (TßRI), FBXO3, and p63 protein expression and that high expression of TßRI/FBXO3 and low expression of p63 are associated with poor recurrence-free survival (RFS). Together, these results demonstrate that FBXO3 facilitates ΔNp63α degradation to empower TGF-ß signaling in promoting tumor metastasis and that the TßRI-FBXO3-ΔNp63α axis is critically important in breast cancer development and clinical prognosis. This study suggests that FBXO3 may be a potential therapeutic target for advanced breast cancer treatment.

Trivalent Phosphine-Catalyzed [4+1] Spiro-annulation Reaction Using Allenyl Imide and Methylene Cyclocompounds.

The trivalent phosphine-catalyzed [4+1] spiro-annulation reaction of allenyl imide and activated methylene cyclocompounds has been developed for the construction of various spiro-2-cyclopenten-1-ones. Oxindoles, 3-isochromanones, and 2-indanones are selected as 1C synthons to capture the in situ-generated bis-electrophilic α,ß-unsaturated ketenyl phosphonium intermediate, affording the corresponding monospiro- and bispiro-cyclopentenones in good to excellent yields (≤91%) under mild conditions. The primary attempt at asymmetric catalysis using monophosphine (R)-SITCP provides promising enantioselectivity (45% ee). A plausible reaction mechanism is also proposed.

TGFß4 alleviates the phenotype of Charcot-Marie-Tooth disease type 1A.

The duplication of the peripheral myelin protein 22 (PMP22) gene causes a demyelinating type of neuropathy, commonly known as Charcot-Marie-Tooth disease type 1A (CMT1A). Development of effective drugs for CMT1A still remains as an unmet medical need. In the present study, we assessed the role of the transforming growth factor beta 4 (TGFß4)/Nodal axis in the pathogenesis of CMT1A. First, we identified PMP22 overexpression-induced Nodal expression in Schwann cells, which might be one of the downstream effectors in CMT1A. Administration of Nodal protein at the developmental stage of peripheral nerves induced the demyelinating phenotype in vivo. Second, we further isolated TGFß4 as an antagonist that could abolish Nodal-induced demyelination. Finally, we developed a recombinant TGFß4-fragment crystallizable (Fc) fusion protein, CX201, and demonstrated that its application had promyelinating efficacy in Schwann cells. CX201 administration improved the demyelinating phenotypes of CMT1A mouse models at both pre-symptomatic and post-symptomatic stages. These results suggest that the TGFß4/Nodal axis plays a crucial role in the pathogenesis of CMT1A and might be a potential therapeutic target for CMT1A.

Survival paradox between stage IIB/C and stage IIIA colon cancer: is it time to revise the American Joint Committee on Cancer TNM system?

INTRODUCTION: A survival paradox between T4N0 (Stage IIB/IIC) and Stage IIIA colon cancer exists, even after adjusting for adequate lymph node (LN) retrieval and receipt of adjuvant chemotherapy (C). We conducted a large hospital-based study to re-evaluate this survival paradox based on the newest 8th edition staging system. METHODS: The National Cancer Data Base was queried to evaluate 35,606 patients diagnosed with Stage IIB, IIC, and IIIA colon cancer between 2010 and 2017. The Kaplan-Meier method and log-rank test were used to compare unadjusted overall survival (OS). Multivariable Cox proportional hazards model was used to determine the association of stage with hazard ratios adjusted for relevant demographic and clinical variables including ≥ 12 LNs retrieved and receipt of adjuvant chemotherapy. P value < 0.05 was considered statistically significant. RESULTS: The 5-year OS for optimally treated stage IIIA colon cancer (receipt of C) was 84.3%, which was significantly higher than stage IIB/C (≥ 12 LNs retrieved + C) (72.8%; P < 0.0001). Stage was an independent predictor of OS. Among optimally treated Stage IIIA patients, T1N1 had the best survival (90.6%) while stage T4bN0 (stage IIC) had the worst (70.9%) (P < 0.0001). Compared to stage IIB, stage IIC had a 17% increased risk of overall death while stage IIIA had a 21% reduction in death (P < 0.0001). CONCLUSION: Stage IIB/C and Stage IIIA survival paradox persists even after accounting for receipt of adjuvant chemotherapy and adequate lymph node retrieval. Future iteration of the TNM system should take this paradox into consideration.

Confinement effects of mandrel degradation in ICF target fabrication.

Understanding and further regulating the degradation of mandrel materials is a key aspect of target fabrication in inertial confinement fusion (ICF). Here, a quasi-one-dimensional confinement model is developed using a series of single-walled carbon nanotubes with varying diameters (Dm), and the degradation of poly-α-methylstyrene (PAMS) as a typical mandrel material is investigated under such confined conditions by using the combined method of quantum mechanics and molecular mechanics. In comparison to the isolated system, the calculations show that confinement can decrease or increase the energy barriers of PAMS degradation, which directly depends on Dm. Following which a clear exponential relationship between the degradation rate of PAMS and its own density is derived, indicating that the density of PAMS can be used to regulate mandrel degradation. This work highlights the important effects of confinement on degradation and provides a valuable reference for further development of polymer degradation technologies in ICF target fabrication and other fields.

OSGIN1 is a novel TUBB3 regulator that promotes tumor progression and gefitinib resistance in non-small cell lung cancer.

BACKGROUND: Oxidative stress induced growth inhibitor 1 (OSGIN1) regulates cell death. The role and underlying molecular mechanism of OSGIN1 in non-small cell lung cancer (NSCLC) are uncharacterized. METHODS: OSGIN1 expression in NSCLC samples was detected using immunohistochemistry and Western blotting. Growth of NSCLC cells and gefitinib-resistant cells expressing OSGIN1 or TUBB3 knockdown was determined by MTT, soft agar, and foci formation assays. The effect of OSGIN1 knockdown on in vivo tumor growth was assessed using NSCLC patient-derived xenograft models and gefitinib-resistant patient-derived xenograft models. Potentially interacting protein partners of OSGIN1 were identified using IP-MS/MS, immunoprecipitation, PLA, and Western blotting assays. Microtubule dynamics were explored by tubulin polymerization assay and immunofluorescence. Differential expression of signaling molecules in OSGIN1 knockdown cells was investigated using phospho-proteomics, KEGG analysis, and Western blotting. RESULTS: We found that OSGIN1 is highly expressed in NSCLC tissues and is positively correlated with low survival rates and tumor size in lung cancer patients. OSGIN1 knockdown inhibited NSCLC cell growth and patient-derived NSCLC tumor growth in vivo. Knockdown of OSGIN1 strongly increased tubulin polymerization and re-established gefitinib sensitivity in vitro and in vivo. Additionally, knockdown of TUBB3 strongly inhibited NSCLC cell proliferation. Mechanistically, we found that OSGIN1 enhances DYRK1A-mediated TUBB3 phosphorylation, which is critical for inducing tubulin depolymerization. The results of phospho-proteomics and ontology analysis indicated that knockdown of OSGIN1 led to reduced propagation of the MKK3/6-p38 signaling axis. CONCLUSIONS: We propose that OSGIN1 modulates microtubule dynamics by enhancing DYRK1A-mediated phosphorylation of TUBB3 at serine 172. Moreover, elevated OSGIN1 expression promotes NSCLC tumor growth and gefitinib resistance through the MKK3/6-p38 signaling pathway. Our findings unveil a new mechanism of OSGIN1 and provide a promising therapeutic target for NSCLC treatment in the clinic.

MAIT cells confer resistance to Lenvatinib plus anti-PD1 antibodies in hepatocellular carcinoma through TNF-TNFRSF1B pathway.

The combination of antiangiogenic agents and immune checkpoint inhibitors is more efficient than monotherapy in the management of hepatocellular carcinoma (HCC). Lenvatinib plus anti-PD1 antibodies have become the mainstay in HCC treatment. However, more than half the patients with HCC are non-responsive, and the mechanisms underlying drug resistance are unknown. To address this issue, we performed single-cell sequencing on samples from six HCC patients, aiming to explore cellular signals and molecular pathways related to the effect of lenvatinib plus anti-PD1 antibody treatment. GSVA analysis revealed that treatment with lenvatinib plus anti-PD1 antibody led to an increase in the TNF-NFKB pathway across all immune cell types, as compared to the non-treatment group. Mucosal-associated invariant T (MAIT) cells were found to secrete TNF, which activates TNFRSF1B on regulatory T cells, thereby promoting immunosuppression. Additionally, TNFSF9 was highly expressed in anticancer immune cells, including CD8+ effector T cells, MAIT, and γδ T cells in the treatment group. We also detected CD3+ macrophages in both HCC and pan-cancer tissues. Overall, our findings shed light on the potential mechanisms behind the effectiveness of lenvatinib plus anti-PD1 antibody treatment in HCC patients. By understanding these mechanisms better, we may be able to develop more effective treatment strategies for patients who do not respond to current therapies.

Functional analysis of transgenic cry1Ah-1 maize.

Maize is an important food crop in the world, but the yield and quality of maize have been significantly reduced due to the impact of insect pests. In order to address this issue, the cry1Ah gene was subjected to error-prone PCR for mutagenesis, and subsequently, the mutant cry1Ah-1 gene was introduced into maize inbred line GSH9901 callus using the Agrobacterium-mediated method. The T2 generation transformed plants were obtained by subculture, and 9 transgenic positive plants were obtained by molecular detection which was carried out by PCR, qRT-PCR, Bt gold-labeled immunoassay test strips, Western blot and ELISA. It was found that the Cry1Ah-1 gene could be transcribed normally in maize leaves, of which OE1 and OE3 had higher relative expression levels and could successfully express proteins of 71.94 KD size. They were expressed in different tissues at the 6-leaf stage, heading stage and grain-filling stage, and could ensure the protection of maize from corn borer throughout the growth period. The biological activities of OE1 and OE3 were tested indoors and in the field, and the results showed that in indoors, the corn borer that fed on OE1 and OE3 corn leaves had a mortality rate of 100 % after 3 days; in the field, OE1 and OE3 had strong insecticidal activity against corn borer, reaching a high resistance level. In conclusion, the transgenic cry1Ah-1 maize has a strong insecticidal effect on corn borer, and has a good prospect of commercialization.

Multiple High-Risk Features for Stage II Colon Carcinoma Portends Worse Survival Than Stage III Disease.

BACKGROUND: High-risk features in stage II colon cancer worsen survival and serve as an impetus for adjuvant chemotherapy. Limited data exist on the effect of multiple high-risk features on survival. OBJECTIVE: The study aimed to compare the survival of 0, 1, or multiple high-risk features in stage II to stage III colon cancer. DESIGN: Patients with stage II and III colon cancer diagnosed between 2010 and 2016 were identified using the Survival, Epidemiology, and End Results database. Patients with stage II colon cancer were then classified according to the presence of 0, 1, or 2 or more of the following high-risk features: pathologic T4, perineural invasion, fewer than 12 lymph nodes assessed, or poor histologic differentiation. Overall survival and cause-specific survival were calculated. Each group was then stratified on the basis of whether chemotherapy was given. SETTINGS: This study used the Survival, Epidemiology, and End Results database (2010-2016). PATIENTS: Patients who had stage II or III colon cancer were included. MAIN OUTCOME MEASURES: The primary outcome measures were 5-year overall survival and cause-specific survival. RESULTS: A total of 65,831 patients were studied. Of these, 18,056 patients with stage II cancer had 0 high-risk features, 9426 had 1 high-risk feature, and 3503 had 2 or more high-risk features. There were 34,842 patients diagnosed with stage III disease. The 5-year overall survival and cause-specific survival for patients with stage II cancer with 2 or more high-risk features (49.2%, 59.5%) were lower than those without high-risk features (74.9%, 90.7%), with 1 high-risk feature (67.1%, 82.4%), or stage III disease (59.1%, 68.1%; p < 0.05). Although chemotherapy is associated with improved cause-specific survival in stage III disease, it is associated with worse cause-specific survival in patients with stage II disease. LIMITATIONS: This study being a retrospective database analysis is the main limitation. Also, lymphovascular invasion, margin status, and clinical obstruction or perforation were absent from the dataset. CONCLUSIONS: Multiple high-risk features in stage II colon cancer predict worse survival than lymph node metastasis. Chemotherapy is associated with adverse cause-specific survival in patients with stage II disease. Further study into this group should focus on the type and duration of adjuvant therapy and biological features of these tumors. See Video Abstract at http://links.lww.com/DCR/B929 . MLTIPLES CARACTERSTICAS DE ALTO RIESGO PARA EL CARCINOMA DE COLON EN ESTADIO II PRESAGIAN PEOR SUPERVIVENCIA QUE LA ENFERMEDAD EN ESTADIO III: ANTECEDENTES:Las características de alto riesgo en el cáncer de colon en estadio II empeoran la supervivencia y sirven como impulso para la quimioterapia adyuvante. Existen datos limitados sobre el efecto de múltiples características de alto riesgo en la supervivencia.OBJETIVO:Comparar la supervivencia de cero, una o múltiples características de alto riesgo en el cáncer de colon en estadio II con la enfermedad en estadio III.DISEÑO:Los pacientes con cáncer de colon en estadio II y III diagnosticados entre 2010 y 2016 se identificaron mediante la base de datos de supervivencia, epidemiología y resultados finales. Luego, los pacientes en etapa II se clasificaron según la presencia de cero, 1 o 2+ de las siguientes características de alto riesgo: T4 patológico, invasión perineural, menos de 12 ganglios linfáticos evaluados (< 12 ganglios linfáticos) o mala diferenciación histológica. Se calculó la supervivencia observada y específica de la causa. Luego, cada grupo se estratificó en función de si se administró quimioterapia.ESCENARIO:Este estudio utilizó la base de datos de supervivencia, epidemiología y resultados finales, 2010-2016.PACIENTES:Los pacientes tenían cáncer de colon en estadio II o III.PRINCIPALES MEDIDAS DE RESULTADO:La medida principal fue la supervivencia observada a 5 años y la supervivencia por causa específica.RESULTADOS:Se estudiaron un total de 65,831 pacientes. 18,056 pacientes estaban en estadio II sin características de alto riesgo, 9.426 con 1 característica de alto riesgo y 3.503 con 2+ características de alto riesgo. Hubo 34.842 pacientes a los que se les diagnosticó enfermedad en estadio III. La supervivencia observada a los 5 años y la supervivencia específica de la causa para los pacientes con cáncer en estadio II con 2+ características de alto riesgo (49.2 %, 59.5 %) fueron más bajas, en comparación con aquellos sin características de alto riesgo (74.9 %, 90.7 %), con 1 característica de alto riesgo (67.1 %, 82.4 %) o enfermedad en estadio III (59.1 %, 68.1 %) (p < 0.05). Si bien la quimioterapia se asocia con una mejor supervivencia por causa específica en la enfermedad en estadio III, se asocia con una peor supervivencia por causa específica en pacientes con enfermedad en estadio II.LIMITACIONES:Este es un análisis de base de datos retrospectivo. La invasión linfovascular, el estado de los márgenes y la obstrucción o perforación clínicas estaban ausentes en la base de datos.CONCLUSIONES:Múltiples características de alto riesgo en el cáncer de colon en estadio II predicen una peor supervivencia que la metástasis en los ganglios linfáticos. La quimioterapia se asocia con una supervivencia específica de causa adversa en pacientes con enfermedad en estadio II. El estudio adicional de este grupo deberá centrarse en el tipo y la duración de la terapia adyuvante y las características biológicas de estos tumores. Consulte Video Resumen en http://links.lww.com/DCR/B929 . (Traducción-Dr. Jorge Silva Velazco ).

How should preoperative examinations be chosen for infants with a ventricular septal defect: transthoracic echocardiography, cardiac CTA, or a combination of these two technologies?

OBJECTIVE: To evaluate the accuracy of transthoracic echocardiography (TTE) and cardiac computed tomography angiography (CTA) in detecting the size and location of ventricular septal defects (VSD) in infants. METHODS: Data from 258 infants diagnosed with VSD between January 2020 and December 2022 were retrospectively analyzed. All infants underwent both TTE and cardiac CTA. The accuracy of these imaging modalities was assessed by comparing their findings with intraoperative observations of VSD size and location. RESULTS: Intraoperatively, the average VSD size was 6.1 ± 2.5 mm. The defects were classified as committed VSD (Type 1) in 45 patients, noncommitted VSD (Type 2) in 198 patients, inlet VSD (Type 3) in 12 patients, and muscular VSD (Type 4) in 3 patients. Echocardiography estimated the average VSD size at 5.6 ± 2.7 mm, with 42 patients identified as Type 1, 203 as Type 2, 10 as Type 3, and 3 as Type 4. Cardiac CTA estimated the average size at 5.9 ± 3.2 mm, with 48 patients identified as Type 1, 196 as Type 2, 11 as Type 3, and 3 as Type 4. The accuracy rates of TTE and cardiac CTA in diagnosing VSD location were 98.1% and 98.8%, respectively. A survey of surgeons indicated that 80% believe both TTE and cardiac CTA are essential preoperative evaluations. CONCLUSIONS: TTE accurately diagnoses the size and location of VSD, while cardiac CTA serves as a valuable complementary method to TTE. Most surgeons advocate for the combined use of these examinations for preoperative assessment.

Rural versus urban commuting patients with stage III colon cancer: is there a difference in treatment and outcome?

BACKGROUND: To evaluate if there are differences in outcomes for patients with stage III colon cancer in those from urban vs. rural commuting areas. METHODS: Data were evaluated on patients diagnosed with stage III colon cancer between 2012 and2018 from the Louisiana Tumor Registry. Patients were classified into rural and urban groups. Data on overall survival, time from diagnosis to surgery and time from surgery to chemotherapy, and sociodemographic factors (including race, age, and poverty level) were recorded. RESULTS: Of 2652 patients identified, 2159 were urban (81.4%) and 493 rural (18.6%). No age difference between rural and urban patients (p = 0.56). Stage IIIB accounted for 66.7%, followed by IIIC (21.6%) and IIIA (11%), with a significant difference between rural and urban patients based on stage (p = 0.02). There was no difference in the extent of surgery (p = 0.34) or tumor size (p = 0.72) between urban and rural settings. No difference in undergoing chemotherapy (p = 0.12). There was a statistically significant difference in receiving timely treatment for hospital volume (p < 0.0001) and poverty level (p < 0.0001), but no difference in time from diagnosis to surgery (p = 0.48), and time from surgery to chemotherapy (p = 0.27). Non-Hispanic Blacks were less likely to receive timely treatment when compared with non-Hispanic Whites for both surgery and adjuvant chemotherapy, (aHR 0.91, 95% CI 0.83-0.99) and (aHR 0.86, 95% CI 0.77-0.97), respectively. There was no difference in Kaplan-Meier overall survival curves comparing rural vs. urban patients (p = 0.77). CONCLUSIONS: There was no statistical difference in overall survival, time to surgery, and time to adjuvant chemotherapy between rural and urban patients with Stage III colon cancer.

Predictors of Long-Term Rebleeding Risk in Cirrhotic Patients Undergoing Esophagogastric Devascularization and Splenectomy: Impact of Portal Vein Thrombosis and Hemoglobin Levels.

BACKGROUND Esophagogastric devascularization and splenectomy (EGDS) is widely used to treat patients with portal hypertension in China. This study aimed to determine risk factors that increase risk of rebleeding after EGDS and evaluate the effect of portal vein thrombosis (PVT) on rebleeding rates after EGDS. MATERIAL AND METHODS Clinical data of patients with cirrhosis (n=138) who underwent EGDS between December 2010 and January 2016 were retrospectively analyzed. Patients were assigned to rebleeding or non-rebleeding groups and followed up. Univariate and multivariate Cox regression analyses identified the independent predictors of 3-year and 5-year rebleeding. RESULTS A total of 138 consecutive patients who underwent EGDS and met the inclusion criteria were enrolled. Total bilirubin (HR: 2.392, 95% CI 1.032-5.545, P=0.042) and PVT (HR: 3.345, 95% CI 1.477-7.573, P=0.004) predicted 3-year rebleeding during univariate analysis. Multivariate analysis revealed that PVT (HR: 3.967, 95% CI 1.742-9.035, P=0.001) was an independent predictor. Hemoglobin >87.5 g/L (HR: 3.104, 95% CI 1.283-7.510, P=0.012) and PVT (HR: 2.349, 95% CI 1.231-4.483, P=0.010) were predictors of 5-year rebleeding during multivariate analysis. Albumin >37.5 g/L was an independent predictor of rebleeding in patients with PVT at 3 and 5 years (HR: 3.964, 95% CI 1.301-9.883, P=0.008; HR: 3.193, 95% CI 1.275-7.997, P=0.013, respectively). CONCLUSIONS PVT is associated with increased 3-year and 5-year rebleeding rates after EGDS but not at 10 years. Also, hemoglobin >87.5 g/L predicted rebleeding at 5 years. Albumin has huge prospects as a predictor of rebleeding at 3 and 5 years in patients with PVT.

Integrative analyses identify CD73 as a prognostic biomarker and immunotherapeutic target in intrahepatic cholangiocarcinoma.

BACKGROUND: CD73 promotes progression in several malignancies and is considered as a novel immune checkpoint. However, the function of CD73 in intrahepatic cholangiocarcinoma (ICC) remains uncertain. In this study, we aim to investigate the role of CD73 in ICC. METHODS: Multi-omics data of 262 ICC patients from the FU-iCCA cohort were analyzed. Two single-cell datasets were downloaded to examine the expression of CD73 at baseline and in response to immunotherapy. Functional experiments were performed to explore the biological functions of CD73 in ICC. The expression of CD73 and HHLA2 and infiltrations of CD8 + , Foxp3 + , CD68 + , and CD163 + immune cells were evaluated by immunohistochemistry in 259 resected ICC samples from Zhongshan Hospital. The prognostic value of CD73 was assessed by Cox regression analysis. RESULTS: CD73 correlated with poor prognosis in two ICC cohorts. Single-cell atlas of ICC indicated high expression of CD73 on malignant cells. TP53 and KRAS gene mutations were more frequent in patients with high CD73 expression. CD73 promoted ICC proliferation, migration, invasion, and epithelial-mesenchymal transition. High CD73 expression was associated with a higher ratio of Foxp3 + /CD8 + tumor-infiltrating lymphocytes (TILs) and CD163 + /CD68 + tumor-associated macrophages (TAMs). A positive correlation between CD73 and CD44 was observed, and patients with high CD73 expression showed elevated expression of HHLA2. CD73 expression in malignant cells was significantly upregulated in response to immunotherapy. CONCLUSIONS: High expression of CD73 is associated with poor prognosis and a suppressive tumor immune microenvironment in ICC. CD73 could potentially be a novel biomarker for prognosis and immunotherapy in ICC.

Transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation.

AMP-activated protein kinase (AMPK) functions as an energy sensor and is pivotal in maintaining cellular metabolic homeostasis. Numerous studies have shown that down-regulation of AMPK kinase activity or protein stability not only lead to abnormality of metabolism but also contribute to tumor development. However, whether transcription regulation of AMPK plays a critical role in cancer metastasis remains unknown. In this study, we demonstrate that AMPKα1 expression is down-regulated in advanced human breast cancer and is associated with poor clinical outcomes. Transcription of AMPKα1 is inhibited on activation of PI3K and HER2 through ΔNp63α. Ablation of AMPKα1 expression or inhibition of AMPK kinase activity leads to disruption of E-cadherin-mediated cell-cell adhesion in vitro and increased tumor metastasis in vivo. Furthermore, restoration of AMPKα1 expression significantly rescues PI3K/HER2-induced disruption of cell-cell adhesion, cell invasion, and cancer metastasis. Together, these results demonstrate that the transcription control is another layer of AMPK regulation and suggest a critical role for AMPK in regulating cell-cell adhesion and cancer metastasis.

Therapeutic Implications of the Drug Resistance Conferred by Extracellular Vesicles Derived from Triple-Negative Breast Cancer Cells.

Anticancer drug resistance is a significant impediment in current cancer treatment. Extracellular vesicles (EVs) derived from cancer cells were recently acknowledged as a critical mechanism of drug resistance, tumor progression, and metastasis. EVs are enveloped vesicles comprising a lipid bilayer that transfers various cargo, including proteins, nucleic acids, lipids, and metabolites, from an originating cell to a recipient cell. Investigating the mechanisms whereby EVs confer drug resistance is still in the early stages. In this review, I analyze the roles of EVs derived from triple-negative breast cancer cells (TNBC-EVs) in anticancer drug resistance and discuss strategies to overcome TNBC-EV-mediated drug resistance.

Correlation between microbial communities and key odourants in fermented capsicum inoculated with Pediococcus pentosaceus and Cyberlindnera rhodanensis.

BACKGROUND: Fermented capsicum (i.e. pickled pepper) is one of the most popular fermented vegetables. However, the effect of inoculated microbial fermentation on pickled pepper is not yet fully understood. RESULTS: Cyberlindnera rhodanensis J52 with a rich ester flavour and Pediococcus pentosaceus AL with a strong inhibitory effect on foodborne pathogenic bacteria were selected to prepare single- and double-strain fermented capsicum under low salt (< 10 g L-1 sodium chloride) conditions. The inhibition zone of P. pentosaceus AL against Escherichia coli was up to 44 mm in diameter. Biochemical indicator analyses found that co-fermentation of P. pentosaceus AL and C. rhodanensis J52 changed the contents of vitamin C and short-chain fatty acids. Analysis of microbial diversity and volatile metabolome showed that 125 microbial species and 72 volatile compounds were detected, and P. pentosaceus was the dominant bacterium that inhibited the growth of other bacteria, while C. rhodanensis was the fungus that contributed the most to flavour. Correlation analysis between microorganisms and flavour compounds showed 725 correlations, and 124 microbial species may have participated in the formation of 69 compounds. Furthermore, 10 and 29 correlations were detected between P. pentosaceus AL or C. rhodanensis J52 and flavour compounds, respectively. Among them, 3-methyl-1-butanol acetate is speculated to be the main substance affecting the flavour of fermented capsicum by inoculation with C. rhodanensis J52. CONCLUSION: The inoculation of P. pentosaceus and C. rhodanensis had a significant impact on the microbial community and volatile compounds of fermented capsicum and helped to improve its organoleptic qualities. © 2022 Society of Chemical Industry.