Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell transcriptome profiling ...of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions.
We compared weekly positivity rates of 8 respiratory viruses in South Korea during 2010-2019 and 2020. The overall mean positivity rate for these viruses decreased from 54.7% in 2010-2019 to 39.1% in ...2020. Pandemic control measures might have reduced the incidence of many, but not all, viral respiratory infections.
A new theranostic strategy is described. It is based on the use of an “all in one” prodrug, namely the biotinylated piperazine‐rhodol conjugate 4 a. This conjugate, which incorporates the anticancer ...drug SN‐38, undergoes self‐immolative cleavage when exposed to biological thiols. This leads to the tumor‐targeted release of the active SN‐38 payload along with fluorophore 1 a. This release is made selective as the result of the biotin functionality. Fluorophore 1 a is 32‐fold more fluorescent than prodrug 4 a. It permits the delivery and release of the SN‐38 payload to be monitored easily in vitro and in vivo, as inferred from cell studies and ex vivo analyses of mice xenografts derived from HeLa cells, respectively. Prodrug 4 a also displays anticancer activity in the HeLa cell murine xenograft tumor model. On the basis of these findings we suggest that the present strategy, which combines within a single agent the key functions of targeting, release, imaging, and treatment, may have a role to play in cancer diagnosis and therapy.
All in one: A new theranostic prodrug was developed containing a biotinylated piperazine‐rhodol conjugate linked to the drug SN‐38 through a self‐immolative disulfide spacer. When exposed to cellular thiols in cancer cells, it is able to release the active chemotherapeutic, SN38, along with a diagnostic fluorophore. This theranostic framework permits the targeted delivery, release of an active agent (SN‐38), and its facile monitoring in vitro and in vivo.
This paper presents an area-efficient and low-power 12-b successive approximation register/single-slope analog-todigital converter (SAR/SS ADC) for CMOS image sensor (CIS) applications. The number of ...unit capacitors of the proposed SAR/SS ADC is reduced to 1/64th of that of a conventional 12-b SAR ADC using only a 6-b capacitor digital-to-analog converter (DAC) and the power consumption is reduced by sharing analog circuits between the SAR ADC and the SS ADC. In addition, the proposed ADC properly operates without using any calibration method as it is designed to be robust to inaccuracies in analog circuits by connecting the ramp signal to the bottom plate of the unit capacitor in the capacitor DAC. A 1936 × 840 pixel 60 frames/s CIS with the proposed SAR/SS ADCs was fabricated using a 90-nm CMOS process, and each readout channel with the proposed SAR/SS ADC occupies an area of 2.24 μm × 998 μm and consumes a power of 30 μW. The measurement results show that the SAR/SS ADC has a differential nonlinearity of -0.45/+0.84 LSB and an integral nonlinearity of -1.5/+0.74 LSB. In addition, the developed CIS has a temporal noise of 2.7 LSB rms and a column fixed pattern noise of 0.07 LSB.
Background and Aims
Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly ...4‐1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor‐infiltrating CD8+ T cells (CD8+ tumor‐infiltrating lymphocytes TILs) and its association with distinct T‐cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC).
Approach and Results
Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA‐sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4‐1BB was most prominently expressed on CD8+ TILs. 4‐1BB expression was almost exclusively detected on CD8+ T cells in the tumor—especially on programmed death 1 (PD‐1)high cells and not PD‐1int and PD‐1neg cells. Compared to PD‐1int and 4‐1BBnegPD‐1high CD8+ TILs, 4‐1BBposPD‐1high CD8+ TILs exhibited higher levels of tumor reactivity and T‐cell activation markers and significant enrichment for T‐cell activation gene signatures. Per‐patient analysis revealed positive correlations between percentages of 4‐1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T‐cell activation. Among highly exhausted PD‐1high CD8+ TILs, 4‐1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4‐1BB–related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4‐1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti‐PD‐1–mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T‐cell activation.
Conclusion
4‐1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4‐1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T‐cell activation.
Background We sought to determine whether quantitative analysis of lung adenocarcinoma manifesting as a ground-glass opacity (GGO) nodule (GGN) on initial CT scans can predict further CT scanning ...change or rate of growth. Methods This retrospective study included patients with lung adenocarcinoma manifesting as pure GGN on initial CT scans who were followed up with interval CT scanning until resection. All pure GGNs were classified based on CT scanning interval change in three subgroups as follows: group A (development of solid component), group B (growth of GGO component), and group C (no change in size). Nodule size, volume, density, mass, and CT scanning attenuation values were assessed from initial CT data sets. Results Fifty-four pure GGNs were enrolled and classified into group A (n = 9), group B (n = 25), and group C (n = 20). Nodule size, volume, mass, and density of the GGNs in each subgroup were not significantly different. The 97.5th percentile CT scanning attenuation value and slope of CT scanning attenuation values from the 2.5th to the 97.5th percentile were significantly different among the three subgroups ( P = .02, P < .00). Three of nine (33%) pure GGNs showing a new solid component developed a solid component within 6 months. Conclusions The 97.5th percentile CT scanning attenuation value and slope of CT scanning attenuation values from the 2.5th to the 97.5th percentile could be helpful in predicting future CT scanning change and growth rate of pure GGNs. Pure GGNs showing higher 97.5th percentile CT scanning attenuation values and steeper slopes of CT scanning attenuation values may require more frequent follow-up than the usual interval of 6 months.
Background We aimed to characterize ground-glass opacity (GGO) nodules and evaluate the prognosis of clinical stage IA lung adenocarcinoma with GGO nodules after wedge resection. Methods Patients who ...underwent wedge resection for early stage lung cancer and proven adenocarcinoma on postoperative pathologic report were enrolled in the study between 2004 and 2010. Radiologic findings of the main tumor were evaluated for ground-glass opacities with chest computed tomography (CT). We divided patients into two groups based on the consolidation-to-tumor ratio (C/T ratio ≤0.25, pure GGO group; C/T ratio >0.25, mixed GGO group). Overall survival and recurrence-free survival were analyzed for all patients. Results A total of 97 patients were included in our study. Among these, 71 patients were categorized into the pure GGO group and 26 patients into the mixed GGO group. The 5-year overall survival rate was 98.6% in the pure GGO group and 95.5% in the mixed GGO group ( p = 0.663). Five patients (5.1%) experienced recurrences; only 1 patient (1/71, 1.4%) in the pure GGO group and 4 patients (4/26, 15.3%) in the mixed GGO group had recurrence. Conclusions GGO-dominant clinical stage IA lung adenocarcinoma (pure GGO group) showed an excellent prognosis. Wedge resection should be carefully considered for patients with mixed GGO nodules (C/T ratio >0.25) because of the high recurrence rate. Radiologic noninvasiveness (C/T ratio ≤0.25) might be a good indicator for candidates for sublobar resection in cases of early stage lung adenocarcinoma.
Background. Treatment outcomes of patients with Mycobacterium abscessus subspecies abscessus lung disease are poor, and the microbial characteristics associated with treatment outcomes have not been ...studied systematically. The purpose of this study was to identify associations between microbial characteristics and treatment outcomes in patients with M. abscessus lung disease. Methods. Sixty-seven consecutive patients with M. abscessus lung disease undergoing antibiotic treatment for ≥12 months between January 2002 and December 2012 were included. Morphotypic and genetic analyses were performed on isolates from 44 patients. Results. Final sputum conversion to culture negative occurred in 34 (51%) patients. Compared to isolates from 24 patients with persistently positive cultures, pretreatment isolates from 20 patients with final negative conversion were more likely to exhibit smooth colonies (9/20, 45% vs 2/24, 8%; P = .020), susceptibility to clarithromycin (7/20, 35% vs 1/24, 4%; P = .015), and be of the C28 sequevar with regard to the erm(41) gene (6/20, 30% vs 1/24, 4%; P = .035). Mycobacterium abscessus lung disease recurred in 5 (15%) patients after successful completion of antibiotic therapy. Genotypic analysis revealed that most episodes (22/24, 92%) of persistently positive cultures during antibiotic treatment and all cases of microbiologic recurrence after treatment completion were caused by different M. abscessus genotypes within a patient. Conclusions. Precise identification to the subspecies level and analysis of mycobacterial characteristics could help predict treatment outcomes in patients with M. abscessus lung disease. Treatment failures and recurrences are frequently associated with multiple genotypes, suggesting reinfection. Clinical Trials Registration. NCT00970801.
This paper deals with a 44pole-48slot fractional slot concentrated winding permanent magnet synchronous machine (FSCW PMSM) for a low-speed direct drive. Two different rotor topologies, a surface ...permanent magnet (SPM) rotor and a consequent pole (CP) rotor, are optimized and compared both analytically and experimentally. The experimental results confirmed that an FSCW PMSM with a CP rotor can achieve almost equivalent performance at the rated state when compared to an FSCW PMSM with an SPM rotor with 33% less permanent magnet material.
Coronavirus disease (COVID-19) has been spreading all over the world; however, its incidence and case-fatality ratio differ greatly between countries and between continents. We investigated factors ...associated with international variation in COVID-19 incidence and case-fatality ratio (CFR) across 107 northern hemisphere countries, using publicly available COVID-19 outcome data as of 14 September 2020. We included country-specific geographic, demographic, socio-economic features, global health security index (GHSI), healthcare capacity, and major health behavior indexes in multivariate models to explain this variation. Multiple linear regression highlighted that incidence was associated with ethnic region (p < 0.05), global health security index 4 (GHSI4) (beta coefficient β 0.50, 95% Confidence Interval CI 0.14-0.87), population density (β 0.35, 95% CI 0.10-0.60), and water safety level (β 0.51, 95% CI 0.19-0.84). The CFR was associated with ethnic region (p < 0.05), GHSI4 (β 0.53, 95% CI 0.14-0.92), proportion of population over 65 (β 0.71, 95% CI 0.19-1.24), international tourism receipt level (β - 0.23, 95% CI - 0.43 to - 0.03), and the number of physicians (β - 0.37, 95% CI - 0.69 to - 0.06). Ethnic region was the most influential factor for both COVID-19 incidence (partial Formula: see text = 0.545) and CFR (partial Formula: see text = 0.372), even after adjusting for various confounding factors.
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