PET/CT deep learning prognosis for treatment decision support in esophageal squamous cell carcinoma.

OBJECTIVES: The clinical decision-making regarding choosing surgery alone (SA) or surgery followed by postoperative adjuvant chemotherapy (SPOCT) in esophageal squamous cell carcinoma (ESCC) remains controversial. We aim to propose a pre-therapy PET/CT image-based deep learning approach to improve the survival benefit and clinical management of ESCC patients. METHODS: This retrospective multicenter study included 837 ESCC patients from three institutions. Prognostic biomarkers integrating six networks were developed to build an ESCC prognosis (ESCCPro) model and predict the survival probability of ESCC patients treated with SA and SPOCT. Patients who did not undergo surgical resection were in a control group. Overall survival (OS) was the primary end-point event. The expected improvement in survival prognosis with the application of ESCCPro to assign treatment protocols was estimated by comparing the survival of patients in each subgroup. Seven clinicians with varying experience evaluated how ESCCPro performed in assisting clinical decision-making. RESULTS: In this retrospective multicenter study, patients receiving SA had a median OS 9.2 months longer than controls. No significant differences in survival were found between SA patients with predicted poor outcomes and the controls (p > 0.05). It was estimated that if ESCCPro was used to determine SA and SPOCT eligibility, the median OS in the ESCCPro-recommended SA group and SPOCT group would have been 15.3 months and 24.9 months longer, respectively. In addition, ESCCPro also significantly improved prognosis accuracy, certainty, and the efficiency of clinical experts. CONCLUSION: ESCCPro assistance improved the survival benefit of ESCC patients and the clinical decision-making among the two treatment approaches. CRITICAL RELEVANCE STATEMENT: The ESCCPro model for treatment decision-making is promising to improve overall survival in ESCC patients undergoing surgical resection and patients undergoing surgery followed by postoperative adjuvant chemotherapy. KEY POINTS: ESCC is associated with a poor prognosis and unclear ideal treatments. ESCCPro predicts the survival of patients with ESCC and the expected benefit from SA. ESCCPro improves clinicians' stratification of patients' prognoses.

Effect of electroacupuncture stimulation of "Sibai"(ST2) and "Quanliao"(SI18) on excitatory neurons of sensorimotor cortex in mice. / 电针"四白"和"颧髎"æ¿€æ´»å°é¼ èº¯ä½“æ„Ÿè§‰è¿åŠ¨çš®å±‚çš„å ´å¥‹æ€§ç¥žç»å ƒ.

OBJECTIVES: To observe the activation state and neuronal types of somatosensory cortex and the primary motor cortex induced by electroacupuncture (EA) stimulation of "Sibai" (ST2) and "Quanliao" (SI18) acupoints in mice. METHODS: Male C57BL/6J mice were randomly divided into blank control and EA groups, with 6 mice in each group. Rats of the EA group received EA stimulation (2 Hz, 0.6 mA) at ST2 and SI18 for 30 minutes. Samples were collected after EA intervention, and immunofluorescence staining was performed to quantify the expression of the c-Fos gene (proportion of c-Fos positive cells) in the somatosensory cortex and primary motor cortex. The co-labelled cells of calcium/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) and gamma-aminobutyric acid (GABA) in the somatosensory cortex and primary motor cortex were observed and counted by using microscope after immunofluorescence staining. Another 10 mice were used to detect the calcium activity of excitatory neurons in the somatosensory cortex and primary motor cortex by fiber photometry. RESULTS: In comparison with the blank control group, the number of c-Fos positive cells, and the proportion of c-Fos and CaMKⅡ co-labelled cells in both the somatosensory cortex and primary motor cortex were significantly increased after EA stimulation (P<0.05). No significant changes were found in the proportion of c-Fos and GABA co-labeled cells in both the somatosensory cortex and primary motor cortex after EA. Results of fiber optic calcium imaging technology showed that the spontaneous calcium activity of excitatory neurons in both somatosensory cortex and primary motor cortex were obviously increased during EA compared with that before EA (P<0.01), and strikingly reduced after cessation of EA compared with that during EA (P<0.05). CONCLUSIONS: Under physiological conditions, EA of ST2 and SI18 can effectively activate excitatory neurons in the somatosensory cortex and primary motor cortex.

COL19A1 is a predictive biomarker for the responsiveness of esophageal squamous cell carcinoma patients to immune checkpoint therapy.

BACKGROUND: The use of neoadjuvant immunotherapy plus chemotherapy has revolutionized the management of esophageal squamous cell carcinoma (ESCC) patients. Nevertheless, patients who would maximally benefit from these therapies have not been identified. METHODS: We collected postoperative specimens from 103 ESCC patients, of which 66 patients comprised a retrospective cohort and 37 comprised a prospective cohort. Patient specimens were subjected to applied multi-omics analysis to uncover the mechanistic basis for patient responsiveness to cancer immunotherapy. The tumor microenvironment characteristics of these patient specimens was explored and identified by multiplex immunofluorescence and immunohistochemistry. RESULTS: Results demonstrated high COL19A1 expression to be a novel biomarker for successful immunotherapy (COL19A1high , odds ratio [95% confidence interval]: 0.31 [0.10-0.97], p = 0.044). Compared with COL19A1low patients, COL19A1high patients benefited more from neoadjuvant immunotherapy (p < 0.01), obtained better major pathological remissions (63.3%, p < 0.01), with a trend toward better recurrence-free survival (p = 0.013), and overall survival (p = 0.056). Moreover, analysis of an immune-activation subtype of patients demonstrated increased B cell infiltration to be associated with favorable patient survival and a better response to neoadjuvant immunotherapy plus chemotherapy. CONCLUSIONS: The findings of this study provide insight into the optimal design of individual treatments for ESCC patients.

Artificial intelligence-based computer-aided diagnosis system supports diagnosis of lymph node metastasis in esophageal squamous cell carcinoma: A multicenter study.

Background: This study aimed to develop an artificial intelligence-based computer-aided diagnosis system (AI-CAD) emulating the diagnostic logic of radiologists for lymph node metastasis (LNM) in esophageal squamous cell carcinoma (ESCC) patients, which contributed to clinical treatment decision-making. Methods: A total of 689 ESCC patients with PET/CT images were enrolled from three hospitals and divided into a training cohort and two external validation cohorts. 452 CT images from three publicly available datasets were also included for pretraining the model. Anatomic information from CT images was first obtained automatically using a U-Net-based multi-organ segmentation model, and metabolic information from PET images was subsequently extracted using a gradient-based approach. AI-CAD was developed in the training cohort and externally validated in two validation cohorts. Results: The AI-CAD achieved an accuracy of 0.744 for predicting pathological LNM in the external cohort and a good agreement with a human expert in two external validation cohorts (kappa = 0.674 and 0.587, p < 0.001). With the aid of AI-CAD, the human expert's diagnostic performance for LNM was significantly improved (accuracy [95% confidence interval]: 0.712 [0.669-0.758] vs. 0.833 [0.797-0.865], specificity [95% confidence interval]: 0.697 [0.636-0.753] vs. 0.891 [0.851-0.928]; p < 0.001) among patients underwent lymphadenectomy in the external validation cohorts. Conclusions: The AI-CAD could aid in preoperative diagnosis of LNM in ESCC patients and thereby support clinical treatment decision-making.

Decreased cyclic-AMP caused by ATP contributes to fosfomycin heteroresistance in avian Escherichia coli.

BACKGROUND: Fosfomycin is an important broad-spectrum bactericidal antibiotic to treat multidrug-resistant bacteria infections. It is generally accepted that heteroresistant bacteria are an intermediate stage in the formation of drug resistance, but there are few studies on the formation mechanism underlying fosfomycin heteroresistance (FHR). OBJECTIVES: To reveal the characteristics and formation mechanisms of FHR in Escherichia coli isolates obtained from chickens. METHODS: We identified the FHR according to the population analysis profile (PAP) test and in vitro time-kill assay. Growth curves for FHR E. coli and their subpopulations were measured. Also, the subpopulations were repeatedly cultured in fosfomycin-free medium for 5-20 overnight incubation periods. The formation mechanisms of FHR in E. coli isolates were identified through accumulation assay, carbohydrate utilization testing, real-time relative quantitative PCR analysis, DNA sequencing, transcriptomic analysis, intracellular ATP and cAMP-level assessment. RESULTS: Four of six E. coli strains were confirmed to show FHR, with a total of six subpopulations. The subpopulations restored phenotypic susceptibilities to fosfomycin within 5-20 overnight incubation sessions, but four of six subpopulations still maintained FHR characteristics. Differing from their parental isolates, the uptake of fosfomycin in the subpopulations through GlpT was reduced remarkably. Further studies identified that the low expression of glpT was due to the decrease of intracellular cAMP levels in the subpopulations, which was caused by the decreased ATP levels in cells. CONCLUSIONS: Our findings revealed the formation mechanism of E. coli isolates showing FHR obtained from chicken in China and characterized the dynamic change traits in vitro of the subpopulations.

Portal vein thrombosis in a noncirrhotic patient after hemihepatectomy: A case report and review of literature.

BACKGROUND: Portal vein thrombosis (PVT) is a condition caused by hemodynamic disorders. It may be noted in the portal vein system when there is an inflammatory stimulus in the abdominal cavity. However, PVT is rarely reported after hepatectomy. At present, related guidelines and major expert opinions tend to consider vitamin K antagonists or low-molecular weight heparin (LMWH) as the standard treatment. But based on research, direct oral anticoagulants may be more effective and safe for noncirrhotic PVT and are also beneficial by reducing the recurrence rate of PVT. CASE SUMMARY: A 51-year-old woman without any history of disease felt discomfort in her right upper abdomen for 20 d, with worsening for 7 d. Contrast-enhanced computed tomography (CECT) of the upper abdomen showed right liver intrahepatic cholangiocarcinoma with multiple intrahepatic metastases but not to the left liver. Therefore, she underwent right hepatic and caudate lobectomy. One week after surgery, the patient underwent a CECT scan, due to nausea, vomiting, and abdominal distension. Thrombosis in the left branch and main trunk of the portal vein and near the confluence of the splenic vein was found. After using LMWH for 22 d, CECT showed no filling defect in the portal vein system. CONCLUSION: Although PVT after hepatectomy is rare, it needs to be prevented during the perioperative period.

[Clinical and gene mutation features of cystic fibrosis: an analysis of 8 cases]. / 8ä¾‹å›Šæ€§çº¤ç»´åŒ–æ‚£å„¿ä¸´åºŠåŠåŸºå› çªå˜åˆ†æž.

OBJECTIVES: To study the clinical features and gene mutation sites of children with cystic fibrosis (CF), in order to improve the understanding of CF to reduce misdiagnosis and missed diagnosis. METHODS: A retrospective analysis was performed on the medical records of 8 children with CF who were diagnosed in Hebei Children's Hospital from 2018 to 2021. RESULTS: Among the 8 children with CF, there were 5 boys and 3 girls, with an age of 3-48 months (median 8 months) at diagnosis, and the age of onset ranged from 0 to 24 months (median 2.5 months). Clinical manifestations included recurrent respiratory infection in 7 children, sinusitis in 3 children, bronchiectasis in 4 children, diarrhea in 8 children, fatty diarrhea in 3 children, suspected pancreatic insufficiency in 6 children, pancreatic cystic fibrosis in 1 child, malnutrition in 5 children, and pseudo-Bartter syndrome in 4 children. The most common respiratory pathogens were Pseudomonas aeruginosa (4 children). A total of 16 mutation sites were identified by high-throughput sequencing, multiplex ligation-dependent probe amplification, and Sanger sequencing, including 5 frameshift mutations, 4 nonsense mutations, 4 missense mutations, 2 exon deletions, and 1 splice mutation. CFTR mutations were found in all 8 children. p.G970D was the most common mutation (3 children), and F508del mutation was observed in one child. Four novel mutations were noted: deletion exon15, c.3796_3797dupGA(p.I1267Kfs*12), c.2328dupA(p.V777Sfs*2), and c.2950G>A(p.D984N). CONCLUSIONS: p.G970D is the most common mutation type in children with CF. CF should be considered for children who have recurrent respiratory infection or test positive for Pseudomonas aeruginosa, with or without digestive manifestations or pseudo-Bartter syndrome.

Cucurbitacin B regulates lung cancer cell proliferation and apoptosis via inhibiting the IL-6/STAT3 pathway through the lncRNA XIST/miR-let-7c axis.

CONTEXT: Lung cancer, the most common type of cancer, has a high mortality rate. Cucurbitacin B (CuB), a natural compound extracted from Cucurbitaceae plants, has antitumor effects. OBJECTIVE: We investigated the role of CuB on lung cancer and its potential mechanisms. MATERIALS AND METHODS: A549 cells were treated with 0.1, 0.3, 0.6, and 0.9 µM CuB for 12, 24, and 48 h or untreated. Gene and protein levels were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Enzyme-linked immunosorbent assay (ELISA) detected inflammatory factors levels (TNF-α and IL-10). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and colony formation assays measured cell viability, apoptosis, and proliferation. The interaction between miR-let-7c and long non-coding RNA X inactive-specific transcript (XIST) or interleukin-6 (IL-6) was verified by dual-luciferase reporter assays. RESULTS: CuB treatment inhibited the proliferation of lung cancer cells and promoted cell apoptosis, and increased the expression of Bax and cleaved caspase3, decreased cyclin B1 and Bcl-2 expression. CuB suppressed XIST and IL-6 expression, and enhanced miR-let-7c expression. XIST silencing enhanced the inhibitory effect of CuB on cell proliferation and the promotion effect on apoptosis via upregulating miR-let-7c. Moreover, XIST targeted miR-let-7c to activate the IL-6/STAT axis. MiR-let-7c overexpression enhanced the regulatory effect of CuB on proliferation and apoptosis via suppressing the IL-6/STAT3 pathway. DISCUSSION AND CONCLUSION: CuB regulated cell proliferation and apoptosis by inhibiting the XIST/miR-let-7c/IL-6/STAT3 axis in lung cancer. These findings indicate CuB may have the possibility of clinical application in lung cancer treatment.

Exosomal miR-132-3p from mesenchymal stem cells alleviated LPS-induced acute lung injury by repressing TRAF6.

Exosomes isolated from mesenchymal stem cells (MSC) had shown beneficial effect on acute lung injury (ALI). However, the effective components in MSC-derived exosomes need further investigation. ALI mice model was established by lipopolysaccharide (LPS) injection. In vitro inflammatory model was established by LPS stimulation of MLE-12 cells. The cell proliferation was evaluated by EdU assay. TUNEL and Annexin V/PI were applied to evaluate the apoptosis of tissue and cell respectively. HE staining was performed to evaluate the lung injury. Transmission electronic microscope was used to observe isolated exosomes. Level of cytokines, MDA, KGF were determined by ELISA kit. Direct interaction of miR-132-3p and TRAF6 were verified by dual luciferase assay. The level of mRNA or proteins were determined by qRT-PCR or western blots respectively. TRAF6 was upregulated while miR-132-3p was downregulated in LPS-stimulated ALI model. MiR-132-3p negatively regulated TRAF6 by direct binding. MiR-132-3p potentiated proliferation and suppressed apoptosis of LPS-induced MLE-12 cells at least partly dependent on targeting TRAF6. Treatment of exosome alleviated the LPS-induced ALI in mice and LPS-induced inflammatory response in MLE-12 cells. Moreover, overexpression of miR-132-3p promoted the protective effect of exosomes in LPS-induced MLE-12 cells injury and LPS-induced ALI. Mechanically, it was suggested that miR-132-3p inactivated PI3K/Akt signalling via targeting TRAF6. In the present study, our results indicated that miR-132-3p mediated protective effect of MSC-derived exosomes on LPS-induced ALI. Exosomal miR-132-3p ameliorated LPS-induced ALI via targeting TRAF6 and inactivating PI3K/Akt signalling.

LncRNA XIST knockdown alleviates LPS-induced acute lung injury by inactivation of XIST/miR-132-3p/MAPK14 pathway : XIST promotes ALI via miR-132-3p/MAPK14 axis.

Acute lung injury (ALI) is a fatal inflammatory response syndrome. LncRNA XIST (XIST) is a lung cancer-related gene and participates in pneumonia. However, whether XIST participates in lipopolysaccharides (LPS)-induced ALI remains unclear. LPS-induced inflammation model was constructed in vitro, then cell viability, cytokines, cell apoptosis, protein, and mRNA expressions were individually detected by cell counting kit-8, enzyme-linked immunosorbent assay and flow cytometry, Western blot, and qRT-PCR. A dual-luciferase reporter assay confirmed the relationships among XIST, miR-132-3p, and MAPK14. Furthermore, inflammation and conditions after knockdown of XIST were assessed by hematoxylin and eosin staining, lung wet-to-dry weight ratio, PaO2/FiO2 ratio, and malondialdehyde (MDA) contents using LPS-induced in vivo model. Our findings indicated that the LPS challenge decreased cell viability, increased cell apoptosis, and caused secretions of pro-inflammatory cytokines. Noticeably, LPS significantly upregulated XIST, MAPK14, and downregulated miR-132-3p. Mechanistically, XIST acted as a molecular sponge to suppress miR-132-3p, and MAPK14 was identified as a target of miR-132-3p. Functional analyses demonstrated that XIST silencing remarkably increased cell survival and alleviated cell death and lung injury through decreasing TNF-α, IL-1ß, IL-6, accumulation of inflammatory cells, alveolar hemorrhage, MDA release, and increased PaO2/FiO2 ratio, as well as upregulating Bcl-2, and downregulating Bax, MAPK14, and p-extracellular signal-regulated kinases ½. In contrast, inhibition of the miR-132-3p antagonized the effects of XIST silencing. In conclusion, inhibition of XIST exhibited a protective role in LPS-induced ALI through modulating the miR-132-3p/MAPK14 axis.

The effect of gemcitabine combined with AMD3100 applying to cholangiocarcinoma RBE cell lines to CXCR4/CXCL12 axis.

PURPOSE: To evaluate the effect of AMD3100 treatment to cholangiocarcinoma by analyzing the relationship between them, and provide experimental evidence for whether AMD3100 can become a clinical treatment drug for cholangiocarcinoma. MATERIALS AND METHODS: Cholangiocarcinoma RBE cell lines were used in this study. MTT cell proliferation test was used for evaluating the effect of gemcitabine and AMD3100 to cell. CXCR4, N-cadherin, VEGF-C and MMP-9 were detect by RT-PCR and western. Transwell was used for evaluating the invasion effect. RESULTS: We demonstrated that as the concentration of gemcitabine increasing from 0.33, 3.33 to 33.33 uM, the cell survival rate was 76.65%, 71.40%, 52.25%, respectively. RT-PCR and Western blot that gemcitabine could affect the expression of CXCR4 protein and the level of mRNA transcription in a dose-dependent manner. N-cadherin VEGF-C, MMP-9 mRNA transcription level showed a significant upward trend in gemcitabine group. In Transwell test, the number of cells in the gemcitabine group was significantly higher than that in the no-medication group (p < .05), the AMD3100 group and the combination group of gemcitabine and AMD3100, the difference between the no-medication group and the AMD3100 monotherapy group was not significant, and the combination group was between them. CONCLUSIONS: This study showed that gemcitabine significantly inhibited the growth of cholangiocarcinoma RBE cells in a dose-dependent manner, and gemcitabine can affect the expression of CXCR4, N-cadherin, VEGF-C, MMP-9 protein and mRNA. Cell invasion and metastasis-related factors decreased after AMD3100 combined with gemcitabine.

Circular RNA AFF4 modulates osteogenic differentiation in BM-MSCs by activating SMAD1/5 pathway through miR-135a-5p/FNDC5/Irisin axis.

Bone marrow-derived mesenchymal stem cells (BM-MSCs), the common progenitor cells of adipocytes and osteoblasts, have been recognized as the key mediator during bone formation. Herein, our study aim to investigate molecular mechanisms underlying circular RNA (circRNA) AFF4 (circ_AFF4)-regulated BM-MSCs osteogenesis. BM-MSCs were characterized by FACS, ARS, and ALP staining. Expression patterns of circ_AFF4, miR-135a-5p, FNDC5/Irisin, SMAD1/5, and osteogenesis markers, including ALP, BMP4, RUNX2, Spp1, and Colla1 were detected by qRT-PCR, western blot, or immunofluorescence staining, respectively. Interactions between circ_AFF4 and miR-135a-5p, FNDC5, and miR-135a-5p were analyzed using web tools including TargetScan, miRanda, and miRDB, and further confirmed by luciferase reporter assay and RNA pull-down. Complex formation between Irisin and Integrin αV was verified by Co-immunoprecipitation. To further verify the functional role of circ_AFF4 in vivo during bone formation, we conducted animal experiments harboring circ_AFF4 knockdown, and born samples were evaluated by immunohistochemistry, hematoxylin and eosin, and Masson staining. Circ_AFF4 was upregulated upon osteogenic differentiation induction in BM-MSCs, and miR-135a-5p expression declined as differentiation proceeds. Circ_AFF4 knockdown significantly inhibited osteogenesis potential in BM-MSCs. Circ_AFF4 stimulated FNDC5/Irisin expression through complementary binding to its downstream target molecule miR-135a-5p. Irisin formed an intermolecular complex with Integrin αV and activated the SMAD1/5 pathway during osteogenic differentiation. Our work revealed that circ_AFF4, acting as a sponge of miR-135a-5p, triggers the promotion of FNDC5/Irisin via activating the SMAD1/5 pathway to induce osteogenic differentiation in BM-MSCs. These findings gained a deeper insight into the circRNA-miRNA regulatory system in the bone marrow microenvironment and may improve our understanding of bone formation-related diseases at physiological and pathological levels.

PET/CT and contrast-enhanced CT imaging findings in benign solitary schwannomas.

OBJECTIVES: Imaging features of positron emission tomography (PET)/computed tomography (CT) and contrast-enhanced CT and pathological changes in benign solitary schwannoma were retrospectively analyzed, and the factors associated with high uptake of fluorodeoxyglucose (FDG) were examined. METHODS: The PET/CT, contrast-enhanced CT, and pathological results of 58 cases of benign solitary schwannomas confirmed by surgery or biopsy were retrospectively analyzed. The association of each variable with the maximum standardized uptake value (SUVmax) was evaluated. RESULTS: The SUVmax of the 58 benign schwannoma cases was 4.1 ± 2.1 (1.5-11.1). When the locations of schwannomas were divided into gastrointestinal system/heart/abdominal and pelvic cavities/thoracic wall (type-1 locations) and other sites (type-2 locations), the schwannoma location was significantly correlated with the SUVmax (r = 0.538, p = 0.000). The SUVmax values were 5.8 ± 2.4 and 3.3 ± 1.5, respectively (p = 0.000). Peritumoral lymphoid cuffs were observed in 7 cases, 4 of which were tumors of gastrointestinal origin, accounting for 80 % of the gastrointestinal schwannomas (4/5). The presence of peritumoral lymphoid cuffs was significantly correlated with the SUVmax (r = 0.456, p = 0.000). The location of the schwannoma was significantly correlated with the presence of peritumoral lymphoid cuffs (r = 0.640, p = 0.000). We found that a peritumoral lymphoid cuff is strongly correlated with the presence of regional lymphadenopathy. Among the 7 cases showing peritumoral lymphoid cuffs, 5 cases had the presence of peritumoral enlarged lymph nodes. The degree of enhancement was significantly correlated with the SUVmax (r = 0.556, p = 0.000). CONCLUSIONS: Benign schwannomas originating from the gastrointestinal system/heart/abdominal location and showing the presence of peritumoral lymphoid cuffs or moderate and significant enhancement on contrast-enhanced CT were significantly associated with high FDG uptake. An accurate understanding of the factors associated with high FDG uptake can help reduce the misdiagnosis rate.

Response of human epidermal growth factor receptor 2-positive colorectal cancer to lapatinib monotherapy: A case report.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) amplification is a molecular driver for a subset of colorectal cancers (CRCs) and one of the major causes of anti-epidermal growth factor receptor (EGFR) treatment failure. Compared to dual anti-HER2 treatments, which have been shown to be effective in HER2-positive metastatic CRC patients, single-agent anti-HER2 therapy is rarely used to treat CRC. CASE SUMMARY: Herein, we report a case of RAS/BRAF-wild-type metastatic CRC that was identified as HER2-positive through circulating tumor DNA (ctDNA) testing by next-generation sequencing following the failure of two lines of therapy. Subsequently, the patient was given lapatinib monotherapy that led to a partial response with a progression-free survival of 7.9 mo. Moreover, serial ctDNA detection was used to monitor the efficacy of lapatinib. The aberration of HER2 copy number disappeared when radiographic assessment revealed a partial response. However, a high level of HER2 amplification was detected again at the time of disease progression. Finally, a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutation was identified at the time of tumor progression, which may explain the acquired resistance to lapatinib. CONCLUSION: This is the first case report of HER2-positive RAS/BRAF wild-type metastatic CRC patient responding to lapatinib monotherapy. It highlights that ctDNA testing is an effective and feasible approach to evaluate the efficacy of anti-HER2 therapy.

Dihydroquercetin attenuates lipopolysaccharide-induced acute lung injury through modulating FOXO3-mediated NF-κB signaling via miR-132-3p.

BACKGROUND: Dihydroquercetin (DHQ) is a potent flavonoid which has been demonstrated to have multiple biological activities including anti-inflammation activity, antioxidant activity as well as anti-cancer activity etc. Recently, many studies have focused on the antioxidant activity of DHQ. However, the use of the anti-inflammation activity of DHQ in acute lung injury (ALI) has not been reported. METHODS: Cell viability was examined by CCK-8 assay. The relative expression of miR-132-3p, FOXO3 were detected by qPCR. The levels of TNF-α, IL-6 and IL-1ß were detected using enzyme-linked immunosorbent assay. The amount of apoptosis cells was detected by flow cytometry. The protein levels of Bcl-2, Bax, p-p65 and p-IκBα were measured by western blot. RESULTS: We found that DHQ-induced the expression of miR-132-3p in LPS-induced ALI. Overexpression of miR-132-3p resulted in the inhibition of FOXO3 expression and then suppressed FOXO3-activated NF-κB pathway, attenuating LPS-induced inflammatory response and apoptosis. CONCLUSION: We demonstrated FOXO3 to be a target of miR-132-3p, and DHQ could induce the expression of miR-132-3p, relieving LPS-induced ALI via miR-132-3p/FOXO3/NF-κB axis, providing a promising therapeutic target for ALI.

The MyD88 inhibitor TJ-M2010-2 suppresses proliferation, migration and invasion of breast cancer cells by regulating MyD88/GSK-3ß and MyD88/NF-κB signalling pathways.

MyD88 has been implicated in the tumourigenesis, metastasis and recurrence of breast cancer (BC). Here we utilized TJ-M2010-2 (TJ), an inhibitor of MyD88 homodimerimerization, and siMyD88 to suppress the function of MyD88 in MCF-7 and MDA-MB-231 cells. BC cells were treated in vitro and xenografted into nude mice to generate a model in vivo. TJ inhibited BC cell growth by impeding proliferation rather than by promoting apoptosis in vitro. Additionally, TJ and siMyD88 significantly attenuated cell migration and invasion, inhibited EMT-like progression and reduced cytokine (IL-6, IL-8, TGF-ß1 and TNF-α) secretion induced by LPS. In vivo, TJ significantly hindered tumour growth in mice. Notably, TJ also decreased the secretion of IL-6, IL-8, TGF-ß1, and TNF-α and M2 macrophage infiltration in the tumour microenvironment. The expression of MyD88, TRAF6, NF-κB p65, Snail, MMP-2, MMP-9, p-GSK-3ß and p-Akt was significantly downregulated by TJ in BC cells and tumour tissues. Collectively, these results suggest that a MyD88 inhibitor (TJ) may be a promising therapeutic modality for treating BC patients.

Intraductal Therapy in Breast Cancer: Current Status and Future Prospective.

With our improved understanding of the biological behavior of breast cancer, minimally invasive intervention is urgently needed for personalized treatment of early disease. Intraductal therapy is one such minimally invasive approach. With the help of appropriate tools, technologies using the intraductal means of entering the ducts may be used both to diagnose and treat lesions in the mammary duct system with less trauma and at the same time avoid systemic toxicity. Traditional agents such as those targeting pathways, endocrine therapy, immunotherapy, or gene therapy can be used alone or combined with other new technologies, such as nanomaterials, through the intraductal route. Additionally, relevant mammary tumor models in rodents which reflect changes in the tumor microenvironment will help deepen our understanding of their biological behavior and heterogeneity. This article reviews the current status and future prospects of intraductal therapy in breast cancer, with emphasis on ductal carcinoma in situ.

Clinical outcome of open surgery versus laparoscopic surgery for cirrhotic hepatocellular carcinoma patients: a meta-analysis.

BACKGROUND AND AIM: Open surgery remains the major approach to treat hepatocellular carcinoma, and laparoscopy-assisted liver resection has been recommended as a superior treatment. However, the efficacy of laparoscopic surgery versus open surgery for cirrhotic patients is under debate. Therefore, the aim of this meta-analysis was to compare the clinical outcomes of laparoscopic and open resection of hepatocellular carcinoma in patients with cirrhosis. METHODS: Electronic databases were searched for eligible literature updated on November 2018. After rigorous review of quality, the data were extracted from eligible trials. All the data were pooled with the corresponding 95% confidence interval using RevMan software. Sensitivity analyses and heterogeneity were quantitatively evaluated. RESULTS: Fourteen trials met the inclusion criteria. According to the pooled result of surgery duration, laparoscopic surgery was associated with significantly shorter hospital stay [STD mean difference (SMD) = -0.61, 95% confidence interval -0.89 to -0.32; P < 0.0001], lower intraoperative blood loss (SMD = -0.56, 95% confidence interval -0.99 to -0.12; P = 0.01), fewer complications (odds ratio = 0.38, 95% confidence interval 0.28 to 0.52; P < 0.00001) and lower transfusion rate (odds ratio = 0.58, 95% confidence interval 0.36-0.93; P = 0.02). Nevertheless, there was no remarkable difference in operative time (SMD = 0.17, 95% confidence interval -0.25 to -0.59; P = 0.42) between the two groups. The pooled analysis of overall survival showed that laparoscopic surgery did not achieve benefit compared with open surgery (P = 0.02). Moreover, the pooled results of three subgroups indicated that laparoscopic surgery was associated with significantly better disease-free survival (P < 0.05). CONCLUSION: The current analysis indicates that laparoscopic liver resection for hepatocellular carcinoma improved intraoperative and disease-free survival, with similar overall survival compared to the open procedure. Laparoscopic surgery may serve as a safe and feasible alternative for selected hepatocellular carcinoma patients with cirrhosis.

LncRNA-CASC7 enhances corticosteroid sensitivity via inhibiting the PI3K/AKT signaling pathway by targeting miR-21 in severe asthma.

BACKGROUND: Asthma, a common chronic inflammatory disease, is treated with corticosteroid in most cases, but corticosteroid resistance in severe asthma patients seriously impairs the therapeutic effects. LncRNA-CASC7 inhibits cell proliferation and enhances drug sensitivity, but the molecular mechanisms of corticosteroid resistance in severe asthma are still unknown. METHODS: Airway smooth muscle cells (ASMCs) from healthy and severe asthmatic subjects were used in this study. The expression of CASC7 and miR-21 were modified by transfection with the pcDNA3.1-CASC7, miR-21 mimics and inhibitor. MTT assay was conducted to measure cell proliferation. ELISA assay was used to determine the secretion of CCL5, CCL11 and IL-6. The phosphorylation of glucocorticoid receptor (GR) and the PI3K/AKT signaling were assessed by western blotting assays. qRT-PCR was used to analyze the expression of CASC7, miR-21 and PTEN. Dual-luciferase reporter assay was used to assess the interaction among CASC7, miR-21 and PTEN. RESULTS: Compared with AMSCs from severe asthma patients, dexamethasone inhibited cytokines (CCL5, CCL11 and IL-6) and promoted the phosphorylation of GR more significantly in normal AMSCs. CASC7 expression was suppressed while miR-21 expression and AKT activity were promoted in ASMCs from severe asthma patients. CASC7 promoted PTEN expression via directly inhibiting miR-21 expression. Overexpression of CASC7 suppressed the PI3K/AKT signaling pathway and promoted the inhibition effects of dexamethasone on cell proliferation and cytokines secretion via targeting miR-21. CONCLUSION: CASC7 increased corticosteroid sensitivity by inhibiting the PI3K/AKT signaling pathway via targeting miR-21, which provided a promising potential target for designing novel therapeutic strategy for severe asthma.

Modulation of anti-malaria immunity by vitamin A in C57BL/6J mice infected with heterogenic plasmodium.

Vitamin A (VA) is an anti-inflammatory agent that is important in modulating and balancing the immune system. The present study aimed to investigate the immunoregulatory effects of vitamin A supplement (VAS) in C57BL/6J mice infected with Plasmodium yoelii 17XL (P.y17XL) or Plasmodium berghei ANKA (P.bANKA). Following VA treatment, parasitaemia decreased, but survival rate did not significantly change during P.y17XL infection. However, in P.bANKA infected C57BL/6J mice, VA pretreatment decreased parasitaemia, and a lag in cerebral malaria (CM) was observed during the early stages of infection. Furthermore, VA pretreatment was also demonstrated to upregulate MHCII expression in dendritic cells (DCs), downregulate Th1 and Tregs, and downregulate TNF-α and IFN-γ production. The results of the current study indicated that VAS downregulated the inflammation response in CM, but did not exhibit an immunoregulatory effect against P.y17XL infection. VAS protected the onset of CM by reducing inflammation, and was also correlated with the downregulation of Th1 by modifying the function of DCs and Tregs. However, no significant effect was observed during P.y17XL infection.