Target Therapy for Kidney Cancer

Renal cell carcinoma (RCC) is considered a chemotherapy-resistant tumor; the landscape of metastatic RCC (mRCC) is rapidly changing due to the development of target therapy. By now, 10 novel agents have dramatically improved the prognosis of mRCC. The purpose of this chapter is to provide an updated overview of the clinical data, which support the use of these agents. We conducted a systematic review using PubMed and ClinicalTrials.gov about target therapy in RCC according to the existing guidelines, made analysis of the clinic trials, and discussed their mechanism, impact on quality of life (QoL), and patient selection algorithms. A total of 11 completed phase III trials were included in our research data. Agreement was correlated with the availability of data in seven trials, contributing to the category 1 option of first-line therapy for patients with mRCC. Three completed phase III trials contributed for the subsequent therapy as the evidence. Target therapy shows promise in clinical practice. Guidelines and algorithms should be revised and adapted to the new target drugs. However, more research is needed in parallel to discover biomarkers that enable the prediction of a treatment response and therefore lead to better patient selection

ISAC-Enabled Beam Alignment for Terahertz Networks: Scheme Design and Coverage Analysis

As a key pillar technology for the future 6G networks, terahertz (THz) communication can provide high-capacity transmissions, but suffers from severe propagation loss and line-of-sight (LoS) blockage that limits the network coverage. Narrow beams are required to compensate for the loss, but they in turn bring in beam misalignment challenge that degrades the THz network performance. The high sensing accuracy of THz signals enables integrated sensing and communication (ISAC) technology to assist the LoS blockage and user mobility-induced beam misalignment, enhancing THz network coverage. In line with the 5G beam management, we propose a joint synchronization signal block (SSB) and reference signal (RS)-based sensing (JSRS) scheme to predict the need for beam switches, and thus prevent beam misalignment. We further design an optimal sensing signal pattern that minimizes beam misalignment with fixed sensing resources, which reveals design insights into the time-to-frequency allocation. We derive expressions for the coverage probability and spatial throughput, which provide instructions on the ISAC-THz network deployment and further enable evaluations for the sensing benefit in THz networks. Numerical results show that the JSRS scheme is effective and highly compatible with the 5G air interface. Averaged in tested urban use cases, JSRS achieves near-ideal performance and reduces around 80% of beam misalignment, and enhances the coverage probability by about 75%, compared to the network with 5G-required positioning ability

NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance

Lack of proper innate sensing inside tumor microenvironment (TME) limits T cell-targeted immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly enriched in multiple tumor types and has emerged as a promising target for direct tumor-killing. Here, we demonstrate that NQO1-targeting prodrug β-lapachone triggers tumor-selective innate sensing leading to T cell-dependent tumor control. β-Lapachone is catalyzed and bioactivated by NQO1 to generate ROS in NQO1high tumor cells triggering oxidative stress and release of the damage signals for innate sensing. β-Lapachone-induced high mobility group box 1 (HMGB1) release activates the host TLR4/MyD88/type I interferon pathway and Batf3 dendritic cell-dependent cross-priming to bridge innate and adaptive immune responses against the tumor. Furthermore, targeting NQO1 is very potent to trigger innate sensing for T cell re-activation to overcome checkpoint blockade resistance in well-established tumors. Our study reveals that targeting NQO1 potently triggers innate sensing within TME that synergizes with immunotherapy to overcome adaptive resistance

Second Primary Lung Cancer After Breast Cancer: A Population-Based Study of 6,269 Women

Purpose: Breast cancer (BC) and lung cancer are the most two common cancers with highest morbidity and mortality for women. With prolonged survival, there comes the possibility that BC patients will develop second primary cancers. We evaluate the characteristics, incidence and survival of second primary non-small cell lung cancer (BC-NSCLC) and small cell lung cancer (BC-SCLC) after breast cancer.Patients and methods: Second primary lung cancer risks using standardized incidence ratios (SIRs) [95% confidence intervals (95% CIs)] were calculated among breast cancer patients in SEER-18 (2000–2014). Survival outcomes were also analyzed for both BC-NSCLC and BC-SCLC.Results: A total of 6,269 second lung cancer patients after a localized or regional BC were identified. The incidence rate was modestly higher compared to the general population (SIR = 1.03; 95%CI: 1.00–1.06). For ER-, PR- and HER2- groups, SIRs were 1.26, 1.16, 1.13, respectively (all p < 0.05). Triple negative breast cancer (TNBC) patients have an even higher incidence rate of lung cancer (SIR = 1.59, 95%CI: 1.29–1.94). Elevated SIRs were also observed among the following groups: within 1 year after BC diagnosed, a young age at BC diagnosed, black people, poorly or undifferentiated histological grade of breast cancer. Median survival (MST) after localized, regional and distant BC-NSCLC was 68.0, 26.0, and 6.0m. Five-year survival rates for BC-NSCLC were 53.9, 29.8 and 5.7% in each stage, which were significantly higher compared to first primary NSCLC (all p < 0.001). ER-/PR- or TNBC were unfavorable prognostic factors for BC-NSCLC. The survival rates of BC-SCLC were no significant different compared to first primary SCLC.Conclusion: BC patients, especially for TNBC, are at a high risk of developing second primary lung cancers. BC history may be a favorable prognostic factor for NSCLC (but not SCLC) patients. Clinicians should closely follow up BC patients with high-risk factors

Construction of a one-step multiplex real-time PCR assay for the detection of serogroups A, B, and E of Pasteurella multocida associated with bovine pasteurellosis

Bovine pasteurellosis, caused by serogroups A, B, and E of Pasteurella multocida (Pm), is mainly manifested as bovine respiratory disease (BRD) and hemorrhagic septicemia (HS). The disease has caused a great economic loss for the cattle industry globally. Therefore, identifying the Pm serogroups is critical for optimal diagnosis and subsequent clinical treatment and even epidemiological studies. In this study, a one-step multiplex real-time PCR assay was established. Three pairs of specific primers were prepared to detect the highly conserved genomic regions of serogroups A (HyaD), B (bcbD), and E (ecbJ) of Pm, respectively. The results depicted that the method had no cross-reaction with other bovine pathogens (Mannheimia hemolytica, Escherichia coli, Listeria monocytogenes, Staphylococcus aureus, Salmonella Dublin, Mycobacterium paratuberculosis, infectious bovine rhinotracheitis virus, and Mycoplasma bovis). The linear range (107 to 102 copies/μL) showed the R2 values for serogroups A, B, and E of Pm as 0.9975, 0.9964, and 0.996, respectively. The multiplex real-time PCR efficiency was 90.30%, 90.72%, and 90.57% for CartA, CartB, and CartE, respectively. The sensitivity result showed that the serogroups A, B, and E of Pm could be detected to be as low as 10 copies/μL. The repeatability result clarified that an intra-assay and an inter-assay coefficient of variation of serogroups A, B, and E of Pm was < 2%. For the clinical samples, the detection rate was higher than the OIE-recommended ordinary PCR. Overall, the established one-step multiplex real-time PCR assay may be a valuable tool for the rapid and early detection of the serogroups A, B, and E of Pm with high specificity and sensitivity

Insights Into Forensic Features and Genetic Structures of Guangdong Maoming Han Based on 27 Y-STRs

Maoming is located in the southwest region of Guangdong Province and is the cradle of Gaoliang culture, which is the representative branch of Lingnan cultures. Historical records showed that the amalgamations between Gaoliang aborigines and distinct ethnic minorities had some influences on the shaping of Gaoliang culture, especially for the local Tai-kadai language-speaking Baiyue and Han Chinese from Central China. However, there is still no exact genetic evidence for the influences on the genetic pool of Maoming Han, and the genetic relationships between Maoming Han and other Chinese populations are still unclear. Hence, in order to get a better understanding of the paternal genetic structures and characterize the forensic features of 27 Y-chromosomal short tandem repeats (Y-STRs) in Han Chinese from Guangdong Maoming, we firstly applied the AmpFLSTR® Yfiler® Plus PCR Amplification Kit (Thermo Fisher Scientific, Waltham, MA, United States) to genotype the haplotypes in 431 Han males residing in Maoming. A total of 263 different alleles were determined across all 27 Y-STRs with the corresponding allelic frequencies from 0.0004 to 0.7401, and the range of genetic diversity (GD) was 0.4027 (DYS391) to 0.9596 (DYS385a/b). In the first batch of 27 Yfiler data in Maoming Han, 417 distinct haplotypes were discovered, and nine off-ladder alleles were identified at six Y-STRs; in addition, no copy number variant or null allele was detected. The overall haplotype diversity (HD) and discrimination capacity (DC) of 27 Yfiler were 0.9997 and 0.9675, respectively, which demonstrated that the 6-dye and 27-plex system has sufficient system effectiveness for forensic applications in Maoming Han. What is more, the phylogenetic analyses indicated that Maoming Han, which is a Southern Han Chinese population, has a close relationship with Meizhou Kejia, which uncovered that the role of the gene flows from surrounding Han populations in shaping the genetic pool of Maoming Han cannot be ignored. From the perspectives of genetics, linguistics, and geographies, the genetic structures of Han populations correspond to the patterns of the geographical-scale spatial distributions and the relationships of language families. Nevertheless, no exact genetic evidence supports the intimate relationships between Maoming Han and Tai-Kadai language-speaking populations and Han populations of Central Plains in the present study

The Role of FGFR1 Gene Amplification as a Poor Prognostic Factor in Squamous Cell Lung Cancer: A Meta-Analysis of Published Data

Objectives. The prognostic factors of the fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) remain controversial. Methods. We conducted a meta-analysis of published studies from 1974 to February 2015. In absence of quality difference between studies of reporting significant and nonsignificant results, the relationship between FGFR1 amplification and clinicopathological parameters in NSCLC was analyzed. And also the combined hazard ratio (HR) and their corresponding 95% confidence interval (CI) were calculated in terms of overall survival. Results. 3178 patients (12 studies) were included in the analysis. It was shown that FGFR1 amplification was significantly more prevalent among male patients (RR 2.03, 95% CI 1.57-2.63) with squamous cell lung cancer (SQCC) (RR 3.49, 95% CI 2.62-4.64) and current smokers (RR 2.63, 95% CI 1.92-3.60). The pooled data also showed that the FGFR1 amplification was a poor prognostic factor in SQCC (HR 1.38, 95% CI 1.07-1.78), Asian patients (HR 1.78, 95% CI 1.22-2.60), and fluorescence in situ hybridization (FISH) method (HR 1.30, 95% CI 1.06-1.58). Conclusions. This meta-analysis strongly suggests that FGFR1 amplification occurs more frequently in male, SQCC and smokers, and it is a risk factor for poor prognosis among Asian patients with SQCC

Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma.

Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study GBM\u27s natural evolutionary trajectory by using rare multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES transition potentially via activation of the HIF1A-FOSL2 axis. High-NES tumor cells could recruit and polarize bone marrow-derived macrophages through activation of the FOSL2-ANXA1-FPR1/3 axis. These polarized macrophages can efficiently suppress T-cell activity and accelerate NES transition in tumor cells. Moreover, the polarized macrophages could upregulate CCL2 to induce tumor cell migration. SIGNIFICANCE: GBM progression could be induced by hypoxia via the HIF1A-FOSL2 axis. Tumor-derived ANXA1 is associated with recruitment and polarization of bone marrow-derived macrophages to suppress the immunoenvironment. The polarized macrophages promote tumor cell NES transition and migration. This article is highlighted in the In This Issue feature, p. 2711

Off-line evaluation of indoor positioning systems in different scenarios: the experiences from IPIN 2020 competition

Every year, for ten years now, the IPIN competition has aimed at evaluating real-world indoor localisation systems by testing them in a realistic environment, with realistic movement, using the EvAAL framework. The competition provided a unique overview of the state-of-the-art of systems, technologies, and methods for indoor positioning and navigation purposes. Through fair comparison of the performance achieved by each system, the competition was able to identify the most promising approaches and to pinpoint the most critical working conditions. In 2020, the competition included 5 diverse off-site off-site Tracks, each resembling real use cases and challenges for indoor positioning. The results in terms of participation and accuracy of the proposed systems have been encouraging. The best performing competitors obtained a third quartile of error of 1 m for the Smartphone Track and 0.5 m for the Foot-mounted IMU Track. While not running on physical systems, but only as algorithms, these results represent impressive achievements.Track 3 organizers were supported by the European Union’s Horizon 2020 Research and Innovation programme under the Marie Skłodowska Curie Grant 813278 (A-WEAR: A network for dynamic WEarable Applications with pRivacy constraints), MICROCEBUS (MICINN, ref. RTI2018-095168-B-C55, MCIU/AEI/FEDER UE), INSIGNIA (MICINN ref. PTQ2018-009981), and REPNIN+ (MICINN, ref. TEC2017-90808-REDT). We would like to thanks the UJI’s Library managers and employees for their support while collecting the required datasets for Track 3. Track 5 organizers were supported by JST-OPERA Program, Japan, under Grant JPMJOP1612. Track 7 organizers were supported by the Bavarian Ministry for Economic Affairs, Infrastructure, Transport and Technology through the Center for Analytics-Data-Applications (ADA-Center) within the framework of “BAYERN DIGITAL II. ” Team UMinho (Track 3) was supported by FCT—Fundação para a Ciência e Tecnologia within the R&D Units Project Scope under Grant UIDB/00319/2020, and the Ph.D. Fellowship under Grant PD/BD/137401/2018. Team YAI (Track 3) was supported by the Ministry of Science and Technology (MOST) of Taiwan under Grant MOST 109-2221-E-197-026. Team Indora (Track 3) was supported in part by the Slovak Grant Agency, Ministry of Education and Academy of Science, Slovakia, under Grant 1/0177/21, and in part by the Slovak Research and Development Agency under Contract APVV-15-0091. Team TJU (Track 3) was supported in part by the National Natural Science Foundation of China under Grant 61771338 and in part by the Tianjin Research Funding under Grant 18ZXRHSY00190. Team Next-Newbie Reckoners (Track 3) were supported by the Singapore Government through the Industry Alignment Fund—Industry Collaboration Projects Grant. This research was conducted at Singtel Cognitive and Artificial Intelligence Lab for Enterprises (SCALE@NTU), which is a collaboration between Singapore Telecommunications Limited (Singtel) and Nanyang Technological University (NTU). Team KawaguchiLab (Track 5) was supported by JSPS KAKENHI under Grant JP17H01762. Team WHU&AutoNavi (Track 6) was supported by the National Key Research and Development Program of China under Grant 2016YFB0502202. Team YAI (Tracks 6 and 7) was supported by the Ministry of Science and Technology (MOST) of Taiwan under Grant MOST 110-2634-F-155-001