Impact of response patterns for patients with advanced acral melanoma treated with anti-programmed death-1 monotherapy.

BACKGROUND: Acral melanoma (AM) is less responsive to immunotherapy than nonacral cutaneous melanoma. Variable responses are seen during immunotherapy, including pseudoprogression, hyperprogressive disease (HPD) and heterogeneous responses. There are currently no studies on the response patterns of patients with AM treated with immunotherapy and the impact on the outcome. OBJECTIVES: To evaluate the response patterns and prognosis of patients with AM treated with anti-programmed death (PD)-1 antibodies. METHODS: Patients with advanced AM treated prospectively in five clinical trials of anti-PD-1 monotherapy at Peking University Cancer Hospital were included. Responses of individual metastases and heterogeneous responses were evaluated during immunotherapy. Cox proportional hazards regression analysis was conducted to identify the possible predictive factors and generate a nomogram to predict the risk of 1-year and 2-year mortality. RESULTS: The overall response rate was 18·0%, the disease control rate was 36·1%, median progression-free survival was 3·5 months [95% confidence interval (CI) 1·7-5·3] and median overall survival was 17·5 months (95% CI 15·1-19·9) for anti-PD-1 monotherapy. Overall, 9·8% of patients met the criteria of HPD, and displayed a dramatically worse outcome than patients without HPD. In total, 369 metastatic lesions were assessed, with the highest response rate in lymph nodes (20·4%) and the lowest in the liver (5·6%). Homogeneous response, heterogeneous response and heterogeneous or homogeneous progression had different prognoses from the best to the worst. A predictive model was constructed and achieved good accuracy with a C-index of 0·73 (95% CI 0·63-0·84) in the training set and 0·74 (95% CI 0·61-0·86) in the validation set. CONCLUSIONS: HPD during immunotherapy serves as an essential biomarker of poor prognosis in advanced AM. Metastases in different sites respond distinctively to immunotherapy. Clinically heterogeneous responses to immunotherapy affect the outcome of patients. A predictive model was built to distinguish the prognosis of acral melanoma under immunotherapy.

Analysis of enhanced CT imaging signs and clinicopathological prognostic factors in hepatoid adenocarcinoma of stomach patients with radical surgery: a retrospective study.

BACKGROUND: To investigate the association between CT signs and clinicopathological features and disease recurrence in patients with hepatoid adenocarcinoma of stomach (HAS). METHODS: Forty nine HAS patients undergoing radical surgery were retrospectively collected. Association between CT and clinicopathological features and disease recurrence was analyzed. Multivariate logistic model was constructed and evaluated for predicting recurrence by using receiver operating characteristic (ROC) curve. Survival curves between model-defined risk groups was compared using Kaplan-Meier method. RESULTS: 24(49.0%) patients developed disease recurrence. Multivariate logistic analysis results showed elevated serum CEA level, peritumoral fatty space invasion and positive pathological vascular tumor thrombus were independent factors for disease recurrence. Odds ratios were 10.87 (95%CI, 1.14-103.66), 6.83 (95%CI, 1.08-43.08) and 42.67 (95%CI, 3.66-496.85), respectively. The constructed model showed an area under ROC of 0.912 (95%CI,0.825-0.999). The model-defined high-risk group showed poorer overall survival and recurrence-free survival than the low-risk group (both P < 0.001). CONCLUSIONS: Preoperative CT appearance of peritumoral fatty space invasion, elevated serum CEA level, and pathological vascular tumor thrombus indicated poor prognosis of HAS patients.

Utility of CT in differentiating liver metastases of well-differentiated gastroenteropancreatic neuroendocrine neoplasms from poorly-differentiated neuroendocrine neoplasms.

OBJECTIVE: To determine the capability of dynamic enhanced computed tomography (CT) to differentiate liver metastases (LMs) of well-differentiated from poorly-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). METHODS: Patients with LMs of GEP-NENs who underwent dynamic enhanced CT examination in Peking University Cancer Hospital from January 2009 to October 2015 were included and data were retrospectively analyzed. We assessed the qualitative and quantitative CT features to identify the significant differentiating CT features of LMs of poorly-differentiated GEP-NENs from those of well-differentiated GEP-NENs using univariate analysis and a multivariate logistic regression model. RESULTS: The study included 22 patients with LMs of well-differentiated GEP-NENs and 32 patients with LMs of poorly-differentiated GEP-NENs. Univariate analysis revealed statistically significant differences between the LMs of well- and poorly-differentiated GEP-NENs in terms of feeding arteries (36.4% vs. 75.0%, χ2=8.061, P=0.005), intratumoral neovascularity (18.2% vs. 59.4%, χ2=9.047, P=0.003), lymphadenopathy (27.3% vs. 81.2%, χ2=15.733, P<0.001), tumor-to-aortic ratio in the hepatic arterial and portal venous phase (T-A/AP: 0.297±0.080vs. 0.251±0.059, t=2.437, P=0.018; T-A/PVP: 0.639±0.138 vs. 0.529±0.117, t=3.163, P=0.003) and tumor-to-liver ratio in the hepatic arterial phase (T-L/AP: 1.108±0.267 vs. 0.907±0.240, t=2.882, P=0.006). The LMs of poorly-differentiated GEP-NENs showed more feeding arteries, more intratumoral neovascularity, more lymphadenopathy and a lower tumor-to-aortic ratio. Multivariate analysis suggested that intratumoral neovascularity [P=0.015, OR=0.108, 95% confidence interval (95% CI), 0.018-0.646], lymphadenopathy (P=0.001, OR=0.055, 95% CI, 0.009-0.323) and T-A/PVP (P=0.004, OR=5.3E-5, 95% CI, 0.000-0.044) were independent factors for differentiating LMs of poorly-differentiated from well-differentiated GEP-NENs. CONCLUSIONS: Dynamic enhanced CT features (intratumoral neovascularity, lymphadenopathy and T-A/PVP) are useful in the pathological classification of LMs of GEP-NENs.

Molecular characterization of neuropeptide Y (NPY) receptors (Y1, Y4 and Y6) and investigation of the tissue expression of their ligands (NPY, PYY and PP) in chickens.

Neuropeptide Y (NPY) receptors and its ligands, NPY, peptide YY (PYY) and pancreatic polypeptide (PP), are suggested to regulate many physiological processes including food intake in birds. However, our knowledge regarding this avian NPY system remains rather limited. Here, we examined the tissue expression of NPY, PYY and PP and the gene structure, expression and signaling of three NPY receptors (cY1, cY4 and cY6) in chickens. The results showed that 1) NPY is widely expressed in chicken tissues with abundance noted in the hypothalamus via quantitative real-time PCR, whereas PYY is highly expressed in the pancreas, gastrointestinal tract and various brain regions, and PP is expressed almost exclusively in the pancreas; 2) cY1, cY4 and cY6 contain novel non-coding exon(s) at their 5'-UTR; 3) The wide tissue distribution of cY1 and cY4 and cY6 were detected in chickens by quantitative real-time PCR and their expression is controlled by the promoter near exon 1, which displays strong promoter activity in DF-1 cells as demonstrated by Dual-luciferase reporter assay; 4) Monitored by luciferase reporter assays, activation of cY1 and cY4 expressed in HEK293 cells by chicken NPY1-36, PYY1-37, and PP1-36 treatment inhibits cAMP/PKA and activates MAPK/ERK signaling pathways, while cY6-expressing cells show little response to peptide treatment, indicating that cY1 and cY4, and not cY6, can transmit signals in vitro. Taken together, our study offers novel information about the expression and functionality of cY1, cY4, cY6 and their ligands in birds, and helps to decipher their conserved roles in vertebrates.

Molecular characterization of three NPY receptors (Y2, Y5 and Y7) in chickens: Gene structure, tissue expression, promoter identification, and functional analysis.

Six neuropeptide Y (NPY) receptors are suggested to mediate the biological actions of NPY, peptide YY (PYY), and pancreatic polypeptide (PP), such as food intake in birds, however, information regarding the structure and signaling of avian NPY receptors are rather limited. In this study, we investigated the gene structure, tissue expression and signaling property of three NPY receptors (cY2, cY5 and cY7) in chickens. The results showed that 1) cY2, cY5 and cY7 contain novel non-coding exons upstream of their start codon and alternative mRNA splicing in their 5'-UTR results in the formation of multiple transcript variants; 2) cY2, cY5 and cY7 transcripts were detected to be widely expressed in adult chicken tissues including various brain regions by RT-PCR, and their expression is controlled by a promoter(s) near exon 1, which display promoter activity in DF-1 cells as demonstrated by Dual-luciferase reporter assay; 3) cY2, cY5 and cY7 expressed in HEK293 cells were preferentially (or potently) activated by cNPY1-36 and cPYY1-37, but not by cPP1-36, and their activation led to the inhibition of cAMP/PKA signaling pathway and activation of MAPK/ERK signaling pathway, monitored by the cell-based luciferase reporter systems or western blots, indicating that the three NPY receptors are functional and capable of transmitting signals effectively. On the whole, our data establishes a molecular basis to elucidate the actions of three functional NPY receptors (cY2, cY5 and cY7) and their ligands in birds, which helps to uncover the conserved roles of these ligand-receptor pairs in vertebrates.

Diffusion-tensor imaging as an adjunct to dynamic contrast-enhanced MRI for improved accuracy of differential diagnosis between breast ductal carcinoma in situ and invasive breast carcinoma.

OBJECTIVE: To determine the value of diffusion-tensor imaging (DTI) as an adjunct to dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for improved accuracy of differential diagnosis between breast ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC). METHODS: The MRI data of 63 patients pathologically confirmed as breast cancer were analyzed. The conventional MRI analysis metrics included enhancement style, initial enhancement characteristic, maximum slope of increase, time to peak, time signal intensity curve (TIC) pattern, and signal intensity on FS-T2WI. The values of apparent diffusion coefficient (ADC), directionally-averaged mean diffusivity (Davg), exponential attenuation (EA), fractional anisotropy (FA), volume ratio (VR) and relative anisotropy (RA) were calculated and compared between DCIS and IBC. Multivariate logistic regression was used to identify independent factors for distinguishing IBC and DCIS. The diagnostic performance of the diagnosis equation was evaluated using the receiver operating characteristic (ROC) curve. The diagnostic efficacies of DCE-MRI, DWI and DTI were compared independently or combined. RESULTS: EA value, lesion enhancement style and TIC pattern were identified as independent factor for differential diagnosis of IBC and DCIS. The combination diagnosis showed higher diagnostic efficacy than a single use of DCE-MRI (P=0.02), and the area of the curve was improved from 0.84 (95% CI, 0.67-0.99) to 0.94 (95% CI, 0.85-1.00). CONCLUSIONS: Quantitative DTI measurement as an adjunct to DCE-MRI could improve the diagnostic performance of differential diagnosis between DCIS and IBC compared to a single use of DCE-MRI.

Fused monochromatic imaging acquired by single source dual energy CT in hepatocellular carcinoma during arterial phase: an initial experience.

OBJECTIVE: To explore whether single and fused monochromatic images can improve liver tumor detection and delineation by single source dual energy CT (ssDECT) in patients with hepatocellular carcinoma (HCC) during arterial phase. METHODS: Fifty-seven patients with HCC who underwent ssDECT scanning at Beijing Cancer Hospital were enrolled retrospectively. Twenty-one sets of monochromatic images from 40 to 140 keV were reconstructed at 5 keV intervals in arterial phase. The optimal contrast-noise ratio (CNR) monochromatic images of the liver tumor and the lowest-noise monochromatic images were selected for image fusion. We evaluated the image quality of the optimal-CNR monochromatic images, the lowest-noise monochromatic images and the fused monochromatic images, respectively. The evaluation indicators included the spatial resolution of the anatomical structure, the noise level, the contrast and CNR of the tumor. RESULTS: In arterial phase, the anatomical structure of the liver can be displayed most clearly in the 65-keV monochromatic images, with the lowest image noise. The optimal-CNR monochromatic images of HCC tumor were 50-keV monochromatic images in which the internal structural features of the liver tumors were displayed most clearly and meticulously. For tumor detection, the fused monochromatic images and the 50-keV monochromatic images had similar performances, and were more sensitive than 65-keV monochromatic images. CONCLUSIONS: We achieved good arterial phase images by fusing the optimal-CNR monochromatic images of the HCC tumor and the lowest-noise monochromatic images. The fused images displayed liver tumors and anatomical structures more clearly, which is potentially helpful for identifying more and smaller HCC tumors.

Identification of Fusarium oxysporum Causing Leaf Blight on Dendrobium chrysotoxum in Yunnan Province, China.

Leaf-blight disease caused by the Fusarium oxysporum is an emerging problem in Dendrobium chrysotoxum production in China. Symptoms of leaf blight were observed on seedlings of D. chrysotoxum cultivated in a nursery in Ruili City, Yunnan Province, China. In this study, we isolated the Fusarium sp. associated with leaf-blight disease of D. chrysotoxum from the diseased seedlings. A pathogenicity test was performed to fulfill Koch's postulates to confirm the pathogenicity of isolated strains and identified using morphological and molecular techniques. The results revealed that all four isolated Fusarium sp. isolates (DHRL-01~04) produced typical blight symptoms followed by marginal necrosis of leaves on the D. chrysotoxum plants. On the PDA medium, the fungal colony appeared as a white to purplish color with cottony mycelium growth. Microconidia are oval-shaped, whereas macroconidia are sickle-shaped, tapering at both ends with 2-4 septations. The phylogenetic trees were construed based on internal transcribed spacer (ITS), translation elongation factor (EF-1α), and RNA polymerase subunit genes RPB1 and RPB2 genes, respectively, and blasted against the NCBI database for species confirmation. Based on the NCBI database's blast results, the isolates showed that more than 99% identify with Fusarium oxysporum. To our knowledge, this is the first comprehensive report on the identification of Fusarium oxysporum as the causal agent of Dendrobium chrysotoxum leaf blight in Yunnan Province, China, based on morphological and molecular characteristics.

Spectral CT in the demonstration of the gastrocolic ligament: a comparison study.

PURPOSE: To investigate the performance of spectral CT in the depiction of the gastrocolic ligament (GCL) compared to conventional polychromatic CT. METHODS: Gemstone spectral CT and conventionally polychromatic CT examinations were randomly allocated to be performed on 62 consecutive patients. A total of 11 groups of monochromatic images were generated on energy levels ranging from 40 to 140 keV at an interval of 10 keV. A five-score classification system was used to evaluate the performances of CT images in the demonstration of GCL. The inter-observer agreement between two radiologists in their evaluation of the GCL by each method was evaluated using kappa statistics. RESULTS: There were statistically significant differences between the spectral CT and polychromatic CT in their abilities to highlight the GCL (observer 1: χ(2) = 18.310, P < 0.001; observer 2: χ(2) = 19.780, P < 0.001). The distinct display (score ≥ 3) rates of the GCL by integrated monochromatic images were higher than that of polychromatic images (P < 0.001). The best energy level for displaying the GCL by spectral CT was 50-70 keV. The kappa value for the image scores on the integrated keV images between the two radiologists was higher than that for polychromatic CT images (P < 0.01). CONCLUSIONS: Spectral CT can improve the visualisation of the GCL compared to polychromatic CT.

Efficacy evaluation of different measurement methods for target lesions after neoadjuvant chemotherapy and radical radiotherapy in locally advanced hypopharyngeal carcinoma.

AIM: To assess the diagnostic efficacy in response evaluation of hypopharyngeal carcinoma (HPC) using different CT measurement methods. METHODS AND MATERIALS: One hundred and three patients with locally advanced HPC receiving neoadjuvant chemotherapy (NACT) and radical radiotherapy (RT) were retrospectively enrolled. The long diameter, short diameter and largest axial area of the tumors and the largest metastatic cervical lymph node (LN) were measured before and after NACT, at the end of RT and 1 month after RT. Tumor regression ratios of the sum of the tumor's long diameter and LN's short diameter (LDTSDL), the sum of tumor and LN's short diameter (TTSDL), the sum of tumor and LN's largest axial area (AATML) were calculated. Analysis was conducted for overall survival (OS), metastasis-free survival, regional recurrence-free survival (RRFS), and local recurrence-free survival (LRFS). RESULTS: Note that 35, 28, 23, and 16 patients suffered death, local recurrence, regional recurrence and distant metastasis, respectively. TTSDL-defined effective group demonstrated better LRFS (p = .039) and RRFS (p = .047) after NACT and better OS since the end of RT (p = .037); AATML-defined effective groups demonstrated better OS, LRFS, and RRFS since the end of RT (p = .015, .008, and .005). While LDTSDL-defined groups showed differences in OS and LRFS until 1 month after RT (p = .013 and .014). CONCLUSIONS: The regression rate of TTSDL and AATML can distinguish prognosis at an earlier time and demonstrated better reliability compared with LDTSDL. They were recommended for response evaluation in HPC.

Hepatocyte proliferation during liver regeneration is impaired in mice with methionine diet-induced hyperhomocysteinemia.

Elevated homocysteine levels are defined as hyperhomocysteinemia (HHcy), a disorder that is associated with cardiovascular and neurodegenerative diseases as well as with hepatic fibrosis. Recent studies have shown that HHcy promotes hepatic injury by increasing oxidative stress. Although homocysteine induces cell cycle arrest in a variety of different cell types, it is not known whether HHcy has a definitive role in hepatocyte proliferation during liver regeneration. In this report, we investigated the effect of homocysteine on liver regeneration. Our results demonstrated that mice with HHcy exhibited an impairment in liver regeneration after partial hepatectomy, as measured by immunohistochemical staining of proliferation cell nuclear antigen and bromodeoxyuridine incorporation. Impaired proliferation was also correlated with reduced cyclin D1 induction and elevated expression levels of both p53 and p21Cip1. In addition, the phosphorylation of Akt, which plays an essential role in normal regeneration responses, was attenuated during the early phases of liver regeneration in HHcy mice. Our results also indicated that the cAMP/protein kinase A pathway mediated the inhibitory effect of homocysteine on liver regeneration. These findings provide evidence that impairment of liver regeneration by HHcy may result in delayed recovery from liver injury induced by homocysteine itself.

Enhancement of green-light photoluminescence of Ta2O5 nanoblock stacks.

In this study we have explored the structural, electronic, and photoluminescence (PL) properties of Ta(2)O(5) nanoblock stacks. The Ta(2)O(5) nanoblocks were synthesized by the hot filament metal-oxide vapor deposition (HFMOVD) technique and randomly arranged in large-area stacks. Field-emission scanning electron microscopy (FESEM) showed most of the stacking Ta(2)O(5) nanoblocks to be 21 nm wide. Energy dispersive spectroscopy (EDS) analysis verified the presence of only the elements Ta and O. X-Ray photoemission spectroscopy (XPS) not only revealed the electronic structures and chemical properties of the stacking Ta(2)O(5) nanoblocks but also their stoichiometric Ta/O ratio of ∼0.416 (i.e. Ta:O = 2.08 : 5). Photoluminescence (PL) spectroscopy showed very strong green-light emissions, which emerged from the trap-levels of the oxygen vacancies within the Ta(2)O(5) bandgap. The PL intensities were linearly enhanced by increasing the laser power and the excitation time. The PL results suggest that the nanoblocks are excellent visible-light emitters.

Scanning photoemission spectromicroscopic study of 4-nm ultrathin SiO(3.4) protrusions probe-induced on the native SiO(2) layer.

Atomic force microscopy probe-induced large-area ultrathin SiO(x) (x ≡ O/Si content ratio and x > 2) protrusions only a few nanometers high on a SiO(2) layer were characterized by scanning photoemission microscopy (SPEM) and X-ray photoemission spectroscopy (XPS). SPEM images of the large-area ultrathin SiO(x) protrusions directly showed the surface chemical distribution and chemical state specifications. The peak intensity ratios of the XPS spectra of the large-area ultrathin SiO(x) protrusions provided the elemental quantification of the Si 2p core levels and Si oxidation states (such as the Si(4+), Si(3+), Si(2+), and Si(1+) species). The O/Si content ratio (x) was evidently determined by the height of the large-area ultrathin SiO(x) protrusions.

Homocysteine enhances cell proliferation in hepatic myofibroblastic stellate cells.

Homocysteine is an intermediate in sulfur amino acid metabolism, which takes place mainly in the liver. Recent studies have shown that hyperhomocysteinemia in patients and murine models develop hepatic fibrosis. To define mechanisms underlying homocysteine-induced hepatic fibrosis, the effect of homocysteine on hepatic stellate cell (HSC) proliferation was examined. In the present study, homocysteine promoted proliferation in myofibroblastic HSCs. Homocysteine elicited a transient formation of reactive oxygen species (ROS). The initial ROS activated extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, which were involved in the activation of NAD(P)H oxidases and the generation of more ROS. The activation of NAD(P)H oxidases resulted from upregulation of the expression of p22(phox) and the phosphorylation of p47(phox). The ROS derived from NAD(P)H oxidases activated the PI3K/Akt pathway, thus promoting cellular proliferation in HSCs. These findings provide a mechanistic explanation for the development and progression of hepatic fibrosis in hyperhomocysteinemia.

Creation and manipulation of surface magnetic domains in an alternating up-and-down pattern.

According to Lenz's law, the magnetic field from the oscillating magnetic probe will induce out-of-plane surface magnetic domains (SMDs) from the in-plane magnetization at the locally tapped points on a ferromagnetic La(0.7)Sr(0.3)MnO3 (LSMO) thin film. It was possible to control and manipulate the out-of-plane SMDs by varying the tapping intervals and changing the scanning direction. We also found that the anisotropic stresses from the out-of-plane SMDs caused the appearance of large-area straight striped domain structures on the order of several micrometers. Smaller oscillating magnetic probe tapping intervals produced larger periods (or widths) of the straight striped domain structure.

Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC.

INTRODUCTION: Programmed death receptor-1 (PD-1) inhibitors have shown efficacy in first-line treatment of NSCLC; however, evidence of PD-1 inhibitor as neoadjuvant treatment is limited. This is a phase 1b study to evaluate the safety and outcome of PD-1 inhibitor in neoadjuvant setting. METHODS: Treatment-naive patients with resectable NSCLC (stage IA-IIIB) received two cycles of sintilimab (200 mg, intravenously, day 1 out of 22). Operation was performed between day 29 and 43. Positron emission tomography-computed tomography scans were obtained at baseline and before the operation. The primary end point was safety. Efficacy end points included rate of major pathologic response (MPR) and objective response rate. Expression of programmed cell death ligand 1 was also evaluated (registration number: ChiCTR-OIC-17013726). RESULTS: A total of 40 patients enrolled, all of whom received two doses of sintilimab and 37 underwent radical resection. A total of 21 patients (52.5%) experienced neoadjuvant treatment-related adverse events (TRAEs). Four patients (10.0%) experienced grade 3 or higher neoadjuvant TRAEs, and one patient had grade 5 TRAE. Eight patients achieved radiological partial response, resulting in an objective response rate of 20.0%. Among 37 patients, 15 (40.5%) achieved MPR, including six (16.2%) with a pathologic complete response in primary tumor and three (8.1%) in lymph nodes as well. Squamous cell NSCLC exhibited superior response compared with adenocarcinoma (MPR: 48.4% versus 0%). Decrease of maximum standardized uptake values after sintilimab treatment correlated with pathologic remission (p < 0.00001). Baseline programmed cell death ligand 1 expression of stromal cells instead of tumor cells was correlated with pathologic regression (p = 0.0471). CONCLUSIONS: Neoadjuvant sintilimab was tolerable for patients with NSCLC, and 40.5% MPR rate is encouraging. The decrease of maximum standardized uptake values after sintilimab might predict pathologic response.

The molecular mechanism of endoplasmic reticulum stress-induced apoptosis in PC-12 neuronal cells: the protective effect of insulin-like growth factor I.

Endoplasmic reticulum (ER) stress has been implicated in several neurodegenerative diseases. Although CCAAT/enhancer-binding protein homologous protein (CHOP) has been shown to play a critical role in ER stress, the precise apoptosis cascade downstream of CHOP is unknown. In this report, we investigated the mechanism of ER stress-mediated apoptosis as well as the action of IGF-I in PC-12 neuronal cells. Our results demonstrated that tribbles-related protein 3 (TRB3), which is a target gene of CHOP, was responsible for tunicamycin (an ER stress inducer)-induced apoptosis. TRB3 could promote dephosphorylation of Akt in PC-12 cells. IGF-I inhibited ER stress-induced apoptosis by restoring the phosphorylation level of Akt. Both wortmannin (a phosphatidylinositide 3-kinase inhibitor) and SB 212090 (a p38 MAPK inhibitor) suppressed the protective effect of IGF-I on ER stress-induced apoptosis. Interestingly, IGF-I attenuated ER stress-mediated expression of TRB3 but not CHOP. This action of IGF-I was abolished by SB 212090 but not by wortmannin. Immunoprecipitation analysis revealed that IGF-I promoted the phosphorylation of CHOP by activating p38 MAPK, probably leading to a decrease in the transcriptional activity of CHOP. The dephosphorylation of Akt resulted in increased expression of a proapoptotic protein, p53 up-regulated modulator of apoptosis (PUMA), in a forkhead box O3a-dependent manner. Knockdown of PUMA by short hairpin RNA attenuated ER stress-mediated apoptosis. Thus, our current study indicates that both TRB3 and PUMA are critical molecules in ER stress-induced apoptosis. IGF-I effectively protects PC-12 neuronal cells against ER stress-induced apoptosis through the phosphatidylinositide 3-kinase/Akt and p38 MAPK pathways.

A safe and potent anti-CD19 CAR T cell therapy.

Anti-CD19 chimeric antigen receptor (CAR) T cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application. Here we generated a new anti-CD19 CAR molecule (CD19-BBz(86)) derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains. We found that CD19-BBz(86) CAR T cells produced lower levels of cytokines, expressed higher levels of antiapoptotic molecules and proliferated more slowly than the prototype CD19-BBz CAR T cells, although they retained potent cytolytic activity. We performed a phase 1 trial of CD19-BBz(86) CAR T cell therapy in patients with B cell lymphoma (ClinicalTrials.gov identifier NCT02842138 ). Complete remission occurred in 6 of 11 patients (54.5%) who each received a dose of 2 × 108-4 × 108 CD19-BBz(86) CAR T cells. Notably, no neurological toxicity or CRS (greater than grade 1) occurred in any of the 25 patients treated. No significant elevation in serum cytokine levels after CAR T cell infusion was detected in the patients treated, including in those who achieved complete remission. CD19-BBz(86) CAR T cells persistently proliferated and differentiated into memory cells in vivo. Thus, therapy with the new CD19-BBz(86) CAR T cells produces a potent and durable antilymphoma response without causing neurotoxicity or severe CRS, representing a safe and potent anti-CD19 CAR T cell therapy.

[CT in differentiation of cT3 and cT4a Siewert type II esophagogastric junction adenocarcinoma: A comparison study based on UICC/AJCC 8th edition and IGCA 4th edition].

OBJECTIVE: To investigate the accuracy of CT in preoperative discrimination of cT3 from cT4 in patients with Siewert II esophagogastric junction (EGJ) adenocarcinoma according to UICC/AJCC 8th edition and IGCA 4th edition. METHODS: CT imaging data of 43 consecutive patients with Siewert II EGJ adenocarcinoma who underwent preoperative CT and were diagnosed as pT3 or pT4 by postoperative pathology were retrospectively analyzed. Inclusion criteria were as follows:(1)no previous history of gastric operation, radiochemotherapy, targeted treatment; no contraindications of CT enhanced scanning; (2) good filling of gastric cavity by CT, clear image without artifacts, all axial-coronal-sagittal 3-plane reconstruction images obtained by abdominal stage 3 enhanced scan; (3) operation within 1 week after CT examination; (4) Siewert II EGJ adenocarcinoma confirmed by operation, pT3 and pT4 by postoperative pathology. Transverse and multiplanar reconstruction images were reviewed by two radiologists in double-blind method. Distance between cancer epicenter and esophagogastric junction line, and the contour of the serosa were retrospectively measured on CT scans. The cT staging judgment was performed according to the UICC/AJCC 8th edition (Siewert II EGJ adenocarcinoma should be staged as esophageal cancer) and IGCA 4th edition (Siewert II EGJ adenocarcinoma should be staged as gastric cancer) respectively. Consistency of cT staging and pathological pT staging was compared between UICC/AJCC and IGCA. RESULTS: Preoperative CT revealed that the mean length between tumor epicenter and esophagogastric junction line was(1.5±0.4) cm (0.7-2.5 cm), and such length was ≤2 cm in 41 cases, whose concordance with surgical judgment was 95.3%(41/43). IGCA staging: 18 cases were preoperatively assessed as cT3 and 25 cases as cT4a. UICC/AJCC staging: 41 cases with cancer epicenter locating within 2 cm below esophagogastric junction line were staged as cT3 according to esophageal cancer staging; 2 cases with cancer epicenter locating > 2 cm below esophagogastric junction line were staged according to gastric cancer staging, of whom one was staged as cT3 due to regular serosa and the other was staged as cT4a due to irregular serosa. Postoperative pathology: 33 cases were pT3 and 10 cases were pT4a. The accuracy of preoperative CT in discrimination of T3 from T4a was 74.4%(32/43) with UICC/AJCC criteria and 65.1%(28/43) with IGCA criteria, whose difference was significant(P<0.01). CONCLUSIONS: Preoperative CT can accurately localize the 2 cm threshold line of Siewert II esophagogastric junction adenocarcinoma, which is beneficial to the discrimination of cT3 from cT4a EGJ adenocarcinoma. Application of the UICC/AJCC 8th edition criteria to above discrimination has higher accuracy as compared to IGCA 4th edition in cT-staging by CT.

Dynamic enhanced CT: is there a difference between liver metastases of gastroenteropancreatic neuroendocrine tumor and adenocarcinoma.

This study proposed to evaluate the feasibility of dynamic enhanced CT in differentiation of liver metastases of gastroenteropancreatic well-differentiated neuroendocrine tumors (GEP NETs) from GEP adenocarcinomas based on their characteristic features. CT images of 23 well-differentiated (G1 or G2) GEP NETs and 23 GEP adenocarcinomas patients with liver metastases were retrospectively reviewed. The distribution type, shape, intra-tumoral neovascularity, enhancement on hepatic artery phase, dynamic enhancement pattern and lymphadenopathy were subjective analyzed. Meanwhile, the size, number, CT value of tumor and adjacent normal liver parenchyma were measured and the metastasis-to-liver ratios were calculated objectively. Compared with GEP adenocarcinomas, the liver metastases of GEP NETs more frequently demonstrated a hyper enhancement on hepatic artery phase, washout dynamic enhancement pattern, absence of lymphadenopathy and higher metastasis-to-liver ratios on both hepatic artery phase and portal venous phase (P=0.017, P<0.001, P =0.038, P <0.001 and P =0.008, respectively). Logistic regression analysis showed that the dynamic enhancement pattern (P=0.012), and the metastasis-to-liver ratios on hepatic artery phase (P=0.009) were independent CT predictors for liver metastases of GEP NETs. The sensitivity and specificity of combing the two predictors in differentiation of liver metastases of GEP adenocarcinomas from GEP NET were 82.6% (19 of 23) and 91.3% (21 of 23), respectively. CT features are helpful in differentiating liver metastases of well-differentiated GEP NETs from that of GEP adenocarcinomas.