Case Report: PD-L1-negative advanced bladder cancer effectively treated with anlotinib and tislelizumab: A report of two cases

Second-line treatment for metastatic or locally advanced urothelial cancer (UC) is limited. Immunotherapy is approved as a second-line treatment for metastatic UC. Its use as a first-line agent is limited to patients who are ineligible for cisplatin-based treatments. The fibroblast growth factor receptor (FGFR) inhibitor, erdafitinib, can be applied as a third-line approach after the failure of these prior treatments in eligible patients. Therefore, it is especially important to combine limited drugs for second-line treatment of advanced or metastatic UC. Anlotinib is a multiple tyrosine kinase inhibitor agent with both anti-angiogenic and FGFR inhibitory effects. For two patients with advanced and metastatic UC, we combined anlotinib and tislelizumab therapy even though there is no indication of its use. We describe two patients with programmed death ligand-1 (PD-L1)-negative advanced bladder cancer, one with FGFR3 mutation and another with FGFR3 wild type. Both patients had progressed after first-line chemotherapy with gemcitabine and cisplatin. We selected anlotinib in combination with tislelizumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, for second-line treatment. Responses were evaluated as partial remission in both cases, who achieved up to 12 months of progression-free survival with no significant adverse events. Two patients with PD-L1-negative UC underwent second-line therapy using tislelizumab in combination with anlotinib, and the efficacy was better than that of tislelizumab alone. These results suggest that anlotinib may act synergistically with tislelizumab in the treatment of UC

Serine 62 is a phosphorylation site in folliculin, the Birt–Hogg–Dubé gene product

AbstractRecently, it was reported that the product of Birt–Hogg–Dubé syndrome gene (folliculin, FLCN) is directly phosphorylated by 5′-AMP-activated protein kinase (AMPK). In this study, we identified serine 62 (Ser62) as a phosphorylation site in FLCN and generated an anti-phospho-Ser62-FLCN antibody. Our analysis suggests that Ser62 phosphorylation is indirectly up-regulated by AMPK and that another residue is directly phosphorylated by AMPK. By binding with FLCN-interacting proteins (FNIP1 and FNIP2/FNIPL), Ser62 phosphorylation is increased. A phospho-mimic mutation at Ser62 enhanced the formation of the FLCN–AMPK complex. These results suggest that function(s) of FLCN–AMPK–FNIP complex is regulated by Ser62 phosphorylation.Structured summaryMINT-7298145, MINT-7298166: Flcn (uniprotkb:Q76JQ2) physically interacts (MI:0915) with AMPK alpha 1 (uniprotkb:P54645) by anti tag coimmunoprecipitation (MI:0007)MINT-7298267: AMPK alpha 1 (uniprotkb:Q13131) phosphorylates (MI:0217) tsc2 (uniprotkb:P49816) by protein kinase assay (MI:0424)MINT-7298182: FNIP1 (uniprotkb:Q8TF40) physically interacts (MI:0915) with Flcn (uniprotkb:Q76JQ2) by anti tag coimmunoprecipitation (MI:0007)MINT-7298132: AMPK alpha 1 (uniprotkb:Q13131) phosphorylates (MI:0217) Flcn (uniprotkb:Q76JQ2) by protein kinase assay (MI:0424)MINT-7298229: FNIPL (uniprotkb:Q9P278) physically interacts (MI:0915) with Flcn (uniprotkb:Q76JQ2) by anti tag coimmunoprecipitation (MI:0007

Robust sensitive-information de-identification framework based on relative-position estimation of objects in closed-circuit television videos

Closed-circuit television (CCTV) videos provide important data for intelligent control systems; however, sensitive information such as human faces and vehicle license plates must be de-identified by a de-identification framework before such videos are used. Previous research has mainly focused on enhancing the performance of de-identification methods, and only a few are devoted to detecting sensitive information. To address this issue, this study proposes an artificial intelligence-based sensitive information de-identification framework. The framework detects objects and utilizes their structural information to estimate the relative position of sensitive data, followed by the de-identification process. To enhance the recall of the detection module, this study analyzes difficult-to-detect faces and license plates in CCTV videos and proposes relative position estimation methods. These methods minimize the possibility of sensitive information leakage while reducing the number of locations of sensitive information that need to be annotated. When evaluated using actual urban CCTV videos, the recall of the framework was 84.63%, which is 33.01% higher than that of the conventional algorithm

CCR4-NOT Deadenylates mRNA Associated with RNA-Induced Silencing Complexes in Human Cells▿

MicroRNAs (miRNAs) repress gene expression posttranscriptionally by inhibiting translation and by expediting deadenylation so as to trigger rapid mRNA decay. Their regulatory influence is mediated by the protein components of the RNA-induced silencing complex (RISC), which deliver miRNAs and siRNAs to their mRNA targets. Here, we present evidence that CCR4-NOT is the deadenylase that removes poly(A) from messages destabilized by miRNAs in human cells. Overproducing a mutationally inactivated form of either of the catalytic subunits of this deadenylase (CCR4 or CAF1/POP2) significantly impedes the deadenylation and decay of mRNA targeted by a partially complementary miRNA. The same deadenylase initiates the degradation of “off-target” mRNAs that are bound by an imperfectly complementary siRNA introduced by transfection. The greater inhibitory effect of inactive CAF1 or POP2 (versus inactive CCR4) suggests a predominant role for this catalytic subunit of CCR4-NOT in miRNA- or small interfering RNA (siRNA)-mediated deadenylation. These effects of mi/siRNAs and CCR4-NOT can be fully reproduced by directly tethering RISC to mRNA without the guidance of a small RNA, indicating that the ability of RISC to accelerate deadenylation is independent of RNA base pairing. Despite its importance for mi/siRNA-mediated deadenylation, CCR4-NOT appears not to associate significantly with RISC, as judged by the failure of CAF1 and POP2 to coimmunoprecipitate detectably with either the Ago or TNRC6 subunit of RISC, a finding at odds with deadenylase recruitment as the mechanism by which RISC accelerates poly(A) removal

Correction: Zhao, J., et al. Podophyllotoxin-Loaded Nanostructured Lipid Carriers for Skin Targeting: In Vitro and In Vivo Studies. Molecules 2016, 21, 1549

The authors wish to make the following correction to their paper [1]

Podophyllotoxin-Loaded Nanostructured Lipid Carriers for Skin Targeting: In Vitro and In Vivo Studies

Nanostructured lipid carriers (NLC) exhibit high skin targeting efficiency and good safety. They are promising vehicles for topical drug delivery. This study aims to increase the skin distribution of podophyllotoxin (POD) by incorporating it into NLCs. Two kinds of POD-loaded NLCs (POD-NLCs)—POD-NLCformulation 1 and POD-NLCformulation 2—were prepared and characterized. Their skin targeting efficiencies were compared by conducting in vitro and in vivo experiments. Obviously smaller mean particle size was observed for POD-NLCformulation 1 (106 nm) than POD-NLCformulation 2 (219 nm), whereas relatively low POD loadings (less than 0.5%) were observed for both POD-NLCformulation 1 (0.33%) and POD-NLCformulation 2 (0.49%). Significantly higher in vitro and in vivo rat skin deposit amounts of POD (p ˂ 0.01) were detected after the topical application of POD-NLCformulation 1 compared to POD-NLCformulation 2. To visualize the skin distribution behavior of hydrophobic active pharmaceutical ingredients (APIs) when NLCs were used as carriers, POD was replaced with Nile red (NR—a hydrophobic fluorescent probe), and the distribution behavior of NR-NLCformulation 1 and NR-NLCformulation 2 in rat skin in vivo was observed using confocal laser scanning microscopy (CLSM). Higher fluorescent intensity was observed in rat skin after the topical application of NR-NLCformulation 1 than NR-NLCformulation 2, suggesting that higher skin targeting efficiency might be obtained when NLCs with smaller mean particle size were used as carriers for hydrophobic APIs. This result was in accordance with those of skin distribution evaluation experiments of POD-NLCs. Skin irritation property of POD-NLCformulation 1 was investigated and no irritation was observed in intact or damaged rabbit skin, suggesting it is safe for topical use. Our results validated the safety of NLCs when applied topically. More importantly, mean particle size might be an important parameter for formulation optimization when NLCs are used as carriers for hydrophobic APIs for topical application, considering that their loading is relatively low

Forecasting Agricultural Commodity Prices Using Dual Input Attention LSTM

Fluctuations in agricultural commodity prices affect the supply and demand of agricultural commodities and have a significant impact on consumers. Accurate prediction of agricultural commodity prices would facilitate the reduction of risk caused by price fluctuations. This paper proposes a model called the dual input attention long short-term memory (DIA-LSTM) for the efficient prediction of agricultural commodity prices. DIA-LSTM is trained using various variables that affect the price of agricultural commodities, such as meteorological data, and trading volume data, and can identify the feature correlation and temporal relationships of multivariate time series input data. Further, whereas conventional models predominantly focus on the static main production area (which is selected for each agricultural commodity beforehand based on statistical data), DIA-LSTM utilizes the dynamic main production area (which is selected based on the production of agricultural commodities in each region). To evaluate DIA-LSTM, it was applied to the monthly price prediction of cabbage and radish in the South Korean market. Using meteorological information for the dynamic main production area, it achieved 2.8% to 5.5% lower mean absolute percentage error (MAPE) than that of the conventional model that uses meteorological information for the static main production area. Furthermore, it achieved 1.41% to 4.26% lower MAPE than that of benchmark models. Thus, it provides a new idea for agricultural commodity price forecasting and has the potential to stabilize the supply and demand of agricultural products