Fibrolamellar carcinoma (FLC) is a rare liver tumor driven by the DNAJ-PKAc fusion protein that affects healthy young patients. Little is known about the immune response to FLC, limiting rational ...design of immunotherapy. Multiplex immunohistochemistry and gene expression profiling were performed to characterize the FLC tumor immune microenvironment and adjacent non-tumor liver (NTL). Flow cytometry and T cell receptor (TCR) sequencing were performed to determine the phenotype of tumor-infiltrating immune cells and the extent of T cell clonal expansion. Fresh human FLC tumor slice cultures (TSCs) were treated with antibodies blocking programmed cell death protein-1 (PD-1) and interleukin-10 (IL-10), with results measured by cleaved caspase-3 immunohistochemistry. Immune cells were concentrated in fibrous stromal bands, rather than in the carcinoma cell compartment. In FLC, T cells demonstrated decreased activation and regulatory T cells in FLC had more frequent expression of PD-1 and CTLA-4 than in NTL. Furthermore, T cells had relatively low levels of clonal expansion despite high TCR conservation across individuals. Combination PD-1 and IL-10 blockade signficantly increased cell death in human FLC TSCs. Immunosuppresion in the FLC tumor microenvironment is characterized by T cell exclusion and exhaustion, which may be reversible with combination immunotherapy.
Artificial van der Waals heterostructures with two-dimensional (2D) atomic crystals are promising as an active channel or as a buffer contact layer for next-generation devices. However, genuine 2D ...heterostructure devices remain limited because of impurity-involved transfer process and metastable and inhomogeneous heterostructure formation. We used laser-induced phase patterning, a polymorph engineering, to fabricate an ohmic heterophase homojunction between semiconducting hexagonal (2H) and metallic monoclinic (1T') molybdenum ditelluride (MoTe2) that is stable up to 300°C and increases the carrier mobility of the MoTe2 transistor by a factor of about 50, while retaining a high on/off current ratio of 106. In situ scanning transmission electron microscopy results combined with theoretical calculations reveal that the Te vacancy triggers the local phase transition in MoTe2, achieving a true 2D device with an ohmic contact.
In an early-phase study involving patients with advanced non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly ...among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC.
In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more.
Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval CI, 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P = 0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy.
First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.).
Summary
Background Giant congenital melanocytic naevi (GCMN) are known risk factors for the development of melanoma. However, melanoma risk among Asians is rarely evaluated.
Objectives To evaluate ...the clinical characteristics and risk of melanoma development from GCMN in Koreans, we performed a nationwide retrospective cohort study in Korea. GCMN were defined as those comprising ≥ 5% body surface area in children or measuring ≥ 20 cm in adults.
Methods In total, 131 patients with GCMN were enrolled, with a mean age of 10·3 years (range: birth–70 years).
Results The posterior trunk was the most common site (67, 51·1%), followed by lateral trunk, anterior trunk, legs, both anterior and posterior trunk, buttocks, and arms. Satellite naevi were present in 69 cases (52·7%), and axial areas were more commonly involved in patients with satellite naevi than in those without satellite lesions. Atypical features such as rete ridge elongation and bridges were seen, and, among these, pagetoid spread and ballooning cell changes were more common in patients < 4 years old. Proliferative nodules were found in three cases. Melanomas had developed in three of 131 patients (2·3%; a 6‐year‐old girl, a 14‐year‐old girl and a 70‐year‐old man), and the incidence rate was 990 per 100 000 person‐years. Melanomas in these three patients consisted of two cutaneous melanomas and one extracutaneous meningeal melanoma.
Conclusions We should be aware of melanoma development from GCMN, and lifelong follow‐up is required due to the risk of melanoma arising in GCMN.
Aim
To investigate the molecular mechanisms of nitric oxide (NO)‐induced cytotoxic effect in human gingival fibroblast (HGF) cells.
Methodology
After sodium nitroprusside (SNP), as NO donor, was ...treated to HGF, viability was measured by MTT assay and apoptosis was determined by TUNEL and DNA fragmentation assay. Mitochondrial membrane potential was detected using confocal microscopy, and caspase activity assay was measured by spectrophotometer. Mitogen‐activated protein kinases (MAPK) activation, Bax/Bcl‐2 ratio and cytochrome c release were analysed by Western blot analyses. Cells were exposed to MAPK inhibitors (U0126, SB203580 and SP600125) before SNP treatment to investigate the effects of MAPK kinases on the NO‐induced apoptosis in HGF. Statistical analysis was performed using one‐way analysis of variance with the Student–Newman–Keuls post hoc test for multiple group comparison.
Results
Apoptosis was significantly increased (P = 0.011 and 0.0004, respectively) in the presence of SNP (1 and 3 mmol L−1) after 12 h in HGF. However, 1H‐1,2,4 oxadiatolo 4, 3‐a cluinoxaline‐1‐one (ODQ), a soluble guanylate cyclase inhibitor, did not block the decrement of cell viability by NO. SNP treatment induced the loss of mitochondrial membrane potential, release of cytochrome c, increased Bax/Bcl‐2 ratio and activation of caspases in HGF. Also, SNP treatment increased phosphorylation of MAPKinases and c‐Jun N‐terminal kinase (JNK) inhibitor (5 and 10 μmol L−1) rescued cell viability decreased by SNP in HGF (P = 0.024 and 0.0149, respectively).
Conclusion
Nitric oxide induced apoptosis in human gingival fibroblast through the mitochondria‐mediated pathway by regulation of Bcl‐2 family and JNK activation.
We present the first measurements of the absolute branching fractions of Ξc+ decays into Ξ−π+π+ and pK−π+ final states. Our analysis is based on a data set of (772±11)×106 BB¯ pairs collected at the ...ϒ(4S) resonance with the Belle detector at the KEKB e+e− collider. We measure the absolute branching fraction of B¯0→Λ¯c−Ξc+ with the Ξc+ recoiling against Λ¯c− in B¯0 decays resulting in B(B¯0→Λ¯c−Ξc+)=1.16±0.42(stat.)±0.15(syst.)×10−3. We then measure the product branching fractions B(B¯0→Λ¯c−Ξc+)B(Ξc+→Ξ−π+π+) and B(B¯0→Λ¯c−Ξc+)B(Ξc+→pK−π+). Dividing these product branching fractions by B¯0→Λ¯c−Ξc+ yields B(Ξc+→Ξ−π+π+)=2.86±1.21(stat.)±0.38(syst.)% and B(Ξc+→pK−π+)=0.45±0.21(stat.)±0.07(syst.)%. Our result for B(Ξc+→Ξ−π+π+) can be combined with Ξc+ branching fractions measured relative to Ξc+→Ξ−π+π+ to set the absolute scale for many Ξc+ branching fractions.
Critical factors that determine the percolation threshold of carbon nanotube (CNT)‐reinforced polymer nanocomposites are studied. An improved analytical model is developed based on an interparticle ...distance concept. Two dispersion parameters are introduced in the model to correctly reflect the different dispersion states of CNTs in the matrix—entangled bundles and well‐dispersed individual CNTs. CNT–epoxy nanocomposites with different dispersion states are fabricated from the same constituent materials by employing different processing conditions. The corresponding percolation thresholds of the nanocomposites vary over a wide range, from 0.1 to greater than 1.0 wt %, and these variations are explained in terms of dispersion parameters and aspect ratios of CNTs. Important factors that control the percolation threshold of nanocomposites are identified based on the comparison between modeling data and experimental results.
Experiments and modeling are used to study the effect of carbon nanotube (CNT) dispersions and aspect ratios on the percolation threshold of CNT–polymer nanocomposites. Four different processing conditions are used to achieve mixtures of individual CNTs and entangled bundles (see figure), and their electrical properties are characterized.
A transparent heater is produced from single‐walled carbon nanotubes (SWCNTs) with a high thermal conductivity. A transparent conducting SWCNT film is fabricated on glass or polymer substrates by ...using a vacuum infiltration method. SWCNT films with a transparency of 65–97 % and a sheet resistance of 230–3500 Ω square–1 are demonstated. These films are good candidates for many applications that require transparent film heaters.
With the full data sample of 772×106 BB¯ pairs recorded by the Belle detector at the KEKB electron-positron collider, the decay B¯→D*τ−ν¯τ is studied with the hadronic τ decays τ−→π−ντ and τ−→ρ−ντ. ...The τ polarization Pτ(D*) in two-body hadronic τ decays is measured, as well as the ratio of the branching fractions R(D*)=B(B¯→D*τ−ν¯τ)/B(B¯→D*ℓ−ν¯ℓ), where ℓ− denotes an electron or a muon. Our results, Pτ(D*)=−0.38±0.51(stat)−0.16+0.21(syst) and R(D*)=0.270±0.035(stat)−0.025+0.028(syst), are consistent with the theoretical predictions of the standard model. The polarization values of Pτ(D*)>+0.5 are excluded at the 90% confidence level.
Ubiquitin C-terminal hydrolase-L1 (UCH-L1) catalyses the hydrolysis of ubiquitin ester and amide mainly in neuronal cells. Recently it was proposed as a marker with a potential role in ...carcinogenesis. However, the molecular mechanism underlying the biological function of UCH-L1 in tumor cells is poorly understood. We found that UCH-L1 is highly expressed in non-small lung cancer cell line H157, having high invasive potential, and that the expression of UCH-L1 in tumor cells enhances their invasive potential in vitro and in vivo. UCH-L1 changes cell morphology by regulating cell adhesion through Akt-mediated pathway. Suppressing UCH-L1 expression by RNAi significantly suppressed the invasion in vitro and in vivo, and the activation of Akt and downstream mitogen activated protein kinases c-Jun N-terminal kinases and p38, but not ERK. In Akt-negative mutants, overexpression of UCH-L1 does not affect the invasion and migration capability of H157 cells. These results suggest that UCH-L1 is a key molecule to regulate tumor-cell invasion by upstream activation of Akt.
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