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1
Suzuki, Haruka, Junzo Hamanishi, Meng Qin, Masayo Ukita, Akihiko Ueda, Shunsuke Kawahara, Koji Yamanoi, et al. "Abstract 6109: Clonal relationship of B cells between tertiary lymphoid structures (TLSs) and tumor infiltrating lymphocytes (TILs) in advanced endometrial cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6109. http://dx.doi.org/10.1158/1538-7445.am2022-6109.
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Abstract Objective: Tertiary lymphoid structures (TLSs) are known to be a marker of peripheral inflammation. While high densities of TLSs were reported to be associated with longer patient survival in several cancer types, there is no direct evidence where B cells in TLSs(TLBs) are derived from and whether these clones are consistent with tumor infiltrating B cells (TIBs), in endometrial cancer. Methods: We analyzed the pathological distribution of TLSs and TIBs in human endometrial cancer samples using immunohistochemistry of a series of B cell markers and evaluated the relationship with patients’ clinical outcomes. Additionally, we micro-dissected six pairs of tumor nests and their neighbor TLSs and analyzed the clonal consistency between TLBs and TIBs using the sequencing of complementarity-determining region (CDR) of B cell receptor (BCR). Results: In 104 patients with endometrial cancer, TLSs were detected in 81 patients (78%), and the absence of TLS was related to worse progression-free survival (PFS) (HR, 0.15, P <0.01). Among TLS-detected cases, the high number of TIBs was significantly associated with better PFS (P<0.05). BCR analyses in the six patients found that three patients with advanced stage had a unique B cell clones in common between TLBs and TIBs, while the other three patients with early stage did not have any common B cell clones. The frequency of common B cell clones in the former three patients were 10.3% (5250/51146 reads), 9.7% (1873/19369 reads) and 3.0% (1034/34618 reads). Conclusion: TLSs and TIBs are associated with better prognosis in endometrial cancer. Common B cell clones were found in the advanced stage cases, suggesting that B cells may have gradually acquired immunospecificity in TLSs. Citation Format: Haruka Suzuki, Junzo Hamanishi, Meng Qin, Masayo Ukita, Akihiko Ueda, Shunsuke Kawahara, Koji Yamanoi, Taito Miyamoto, Shiro Takamatsu, Mana Taki, Yoko Hosoe, Takashi Kobayashi, Ken Yamaguchi, Masaki Mandai. Clonal relationship of B cells between tertiary lymphoid structures (TLSs) and tumor infiltrating lymphocytes (TILs) in advanced endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6109.
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Masuda, Tsukasa, Nobuyuki Tanaka, Kimiharu Takamatsu, Kyohei Hakozaki, Ryohei Takahashi, Tadatsugu Anno, Ryohei Kufukihara, et al. "Unique characteristics of tertiary lymphoid structures in kidney clear cell carcinoma: prognostic outcome and comparison with bladder cancer." Journal for ImmunoTherapy of Cancer 10, no. 3 (March 2022): e003883. http://dx.doi.org/10.1136/jitc-2021-003883.
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BackgroundThe aims of this study were (1) to clarify the impact of tertiary lymphoid structure (TLS) status on the outcome and immunogenomic profile of human clear cell renal cell carcinoma (ccRCC) and (2) to determine phenotypic differences in TLSs between different types of genitourinary cancer, that is, urinary ccRCC and bladder cancer.MethodsWe performed a quantitative immunohistological analysis of ccRCC tissue microarrays and conducted integrated genome mutation analysis by next-generation sequencing and methylation array analysis. Since the tumor immune microenvironment of ccRCC often differs from that of other cancer types, we analyzed the phenotypic differences in TLSs between ccRCC and in-house bladder cancer specimens.ResultsVarying distribution patterns of TLSs were observed throughout ccRCC tumors, revealing that the presence of TLSs was related to poor prognosis. An analysis of genomic alterations based on TLS status in ccRCC revealed that alterations in the PI3K-mTOR pathway were highly prevalent in TLS-positive tumors. DNA methylation profiling also revealed distinct differences in methylation signatures among ccRCC samples with different TLS statuses. However, the TLS characteristics of ccRCC and bladder cancer markedly differed: TLSs had the exact opposite prognostic impact on bladder cancer as on ccRCC. The maturity and spatial distribution of TLSs were significantly different between the two cancer types; TLSs were more mature with follicle-like germinal center organization and likely to be observed inside the tumor in bladder cancer. Labeling for CD8, FOXP3, PD-1, and PD-L1 showed marked differences in the diversity of the immune microenvironment surrounding TLSs. The proportions of CD8-, FOXP3-, and PD-L1-positive cells were significantly higher in TLSs in bladder cancer than in TLSs in ccRCC; rather the proportion of PD-1-positive cells was significantly higher in TLSs in ccRCC than in TLSs in bladder cancer.ConclusionThe immunobiology of ccRCC is unique, and various cancerous phenomena conflict with that seen in other cancer types; therefore, comparing the TLS characteristics between ccRCC and bladder cancer may help reveal differences in the prognostic impact, maturity and spatial distribution of TLSs and in the immune environment surrounding TLSs between the two cancers.
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Li, Zhe, Yuming Jiang, Bailiang Li, Zhen Han, Jeanne Shen, Yong Xia, and Ruijiang Li. "Development and Validation of a Machine Learning Model for Detection and Classification of Tertiary Lymphoid Structures in Gastrointestinal Cancers." JAMA Network Open 6, no. 1 (January 24, 2023): e2252553. http://dx.doi.org/10.1001/jamanetworkopen.2022.52553.
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ImportanceTertiary lymphoid structures (TLSs) are associated with a favorable prognosis and improved response to cancer immunotherapy. The current approach for evaluation of TLSs is limited by interobserver variability and high complexity and cost of specialized imaging techniques.ObjectiveTo develop a machine learning model for automated and quantitative evaluation of TLSs based on routine histopathology images.Design, Setting, and ParticipantsIn this multicenter, international diagnostic/prognostic study, an interpretable machine learning model was developed and validated for automated detection, enumeration, and classification of TLSs in hematoxylin-eosin–stained images. A quantitative scoring system for TLSs was proposed, and its association with survival was investigated in patients with 1 of 6 types of gastrointestinal cancers. Data analysis was performed between June 2021 and March 2022.Main Outcomes and MeasuresThe diagnostic accuracy for classification of TLSs into 3 maturation states and the association of TLS score with survival were investigated.ResultsA total of 1924 patients with gastrointestinal cancer from 7 independent cohorts (median [IQR] age ranging from 57 [49-64] years to 68 [58-77] years; proportion by sex ranging from 214 of 409 patients who were male [52.3%] to 134 of 155 patients who were male [86.5%]). The machine learning model achieved high accuracies for detecting and classifying TLSs into 3 states (TLS1: 97.7%; 95% CI, 96.4%-99.0%; TLS2: 96.3%; 95% CI, 94.6%-98.0%; TLS3: 95.7%; 95% CI, 93.9%-97.5%). TLSs were detected in 62 of 155 esophageal cancers (40.0%) and up to 267 of 353 gastric cancers (75.6%). Across 6 cancer types, patients were stratified into 3 risk groups (higher and lower TLS score and no TLS) and survival outcomes compared between groups: higher vs lower TLS score (hazard ratio [HR]; 0.27; 95% CI, 0.18-0.41; P &lt; .001) and lower TLS score vs no TLSs (HR, 0.65; 95% CI, 0.56-0.76; P &lt; .001). TLS score remained an independent prognostic factor associated with survival after adjusting for clinicopathologic variables and tumor-infiltrating lymphocytes (eg, for colon cancer: HR, 0.11; 95% CI, 0.02-0.47; P = .003).Conclusions and RelevanceIn this study, an interpretable machine learning model was developed that may allow automated and accurate detection of TLSs on routine tissue slide. This model is complementary to the cancer staging system for risk stratification in gastrointestinal cancers.
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Baneh, Hasan, Javad Ahmadpanah, and Yahya Mohammadi. "Genetic analysis of reproductive characteristics in Iran-Black sheep." Acta Scientiarum. Animal Sciences 42 (January 30, 2020): e47380. http://dx.doi.org/10.4025/actascianimsci.v42i1.47380.
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This study was conducted to estimate genetic parameters and trends for reproduction traits using data collected at the breeding station of Iran-Black sheep during 1980 to 2004. The traits included in the analyses were litter size at birth (LSB) and weaning (LSW) and litter mean weight per lamb born (LMWLB) and weaned (LMWLW) as basic traits, and total litter weight at birth (TLWB) and weaning (TLWW) as composite traits. Direct heritability estimates for LSB, TLWB, LMWLB, LSW, TLWW and LMWLW were 0.11, 0.07, 0.33, 0.08, 0.09 and 0.11, respectively. The permanent environmental effects had significant impact on all traits and ranged from 0.05 to 0.16. Effect of service sire was highly significant (p < 0.01) for all traits except LMWLW. Estimates of genetic correlations ranged from -0.76 (LSB-LMWLB) to 0.98 (LSB-LSW). Phenotypic and environmental correlations were generally lower than those of genetic correlations. Environmental correlations ranged from -0.55 (LSW-LMWLW) to 0.99 (LSB-LSW). Also, the estimated correlation for the effect of service sire ranged from -0.77 (LMWLB-TLWW) to 0.96 (LSB-LSW and LSB-TLWW). The results suggest that selection based on TLWB could be more effective than the other traits to enhance reproductive performance in Iran-Black ewes.
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Zou, Ji’an, Yingzhe Zhang, Yue Zeng, Yurong Peng, Junqi Liu, Chaoyue Xiao, and Fang Wu. "Tertiary Lymphoid Structures: A Potential Biomarker for Anti-Cancer Therapy." Cancers 14, no. 23 (December 2, 2022): 5968. http://dx.doi.org/10.3390/cancers14235968.
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A tertiary lymphoid structure (TLS) is a special component in the immune microenvironment that is mainly composed of tumor-infiltrating lymphocytes (TILs), including T cells, B cells, DC cells, and high endothelial venules (HEVs). For cancer patients, evaluation of the immune microenvironment has a predictive effect on tumor biological behavior, treatment methods, and prognosis. As a result, TLSs have begun to attract the attention of researchers as a new potential biomarker. However, the composition and mechanisms of TLSs are still unclear, and clinical detection methods are still being explored. Although some meaningful results have been obtained in clinical trials, there is still a long way to go before such methods can be applied in clinical practice. However, we believe that with the continuous progress of basic research and clinical trials, TLS detection and related treatment can benefit more and more patients. In this review, we generalize the definition and composition of TLSs, summarize clinical trials involving TLSs according to treatment methods, and describe possible methods of inducing TLS formation.
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Eteqadi, Bahareh, Navid Ghavi Hossein-Zadeh, and Abdol Ahad Shadparvar. "Genetic Analysis of Basic and Composite Reproduction Traits in Guilan Sheep." Annals of Animal Science 17, no. 1 (January 1, 2017): 105–16. http://dx.doi.org/10.1515/aoas-2016-0016.
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Abstract The objective of the present study was to estimate genetic parameters for reproductive traits in Guilan sheep. Data were comprised of 14,534 records of lambs from 136 sires and 2,021 dams which were collected during 1994 to 2011 by the Agriculture Organization of Guilan Province in the north of Iran. The basic reproductive traits were litter size at birth (LSB), litter size at weaning (LSW), litter mean weight per lamb born (LMWLB), and litter mean weight per lamb weaned (LMWLW). The composite reproductive traits were total litter weight at birth per ewe lambing (TLWB) and total litter weight at weaning per ewe lambing (TLWW). The general linear model procedure of SAS was used for determining the fixed effects which had significant effect on the traits under study. The flock-year-season of lambing had significant effect on studied traits (P<0.01). The genetic parameters were estimated with repeatability animal model using restricted maximum likelihood (REML) procedure of the Wombat program. Direct heritability estimates were 0.00, 0.00, 0.01, 0.01, and 0.03 for LSB, LSW, LMWLW, TLWB, and TLWW, respectively, and corresponding repeatabilities were 0.2, 0.00006, 0.01, 0.972 and 0.034, respectively. Genetic correlation estimates between traits ranged from -0.99 for LSB-LSW to 0.99 for LMWLW-TLWW. Phenotypic correlations ranged from -0.09 for LSB-TLWB to 0.98 for LMWLW-TLWW and environmental correlations ranged from -0.03 for LSW-TLWW to 0.98 for LMWLW-TLWW. The results showed that strong positive genetic correlations of LMWLB and LMWLW with other traits may improve meat production efficiency in Guilan sheep. The low estimates of heritability and repeatability obtained for ewe productivity traits indicate that selection based on the ewe’s own performance may result in slow genetic improvement.
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Li, Jianhui, Ye Nie, Weili Jia, Wenlong Wu, Wenjie Song, and Yongxiang Li. "Effect of Tertiary Lymphoid Structures on Prognosis of Patients with Hepatocellular Carcinoma and Preliminary Exploration of Its Formation Mechanism." Cancers 14, no. 20 (October 21, 2022): 5157. http://dx.doi.org/10.3390/cancers14205157.
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Background: Tertiary lymphoid structures (TLSs) are formed by the aggregation of tumour-infiltrating lymphocytes (TILs), which is driven by chemokines or cytokines in the tumour microenvironment. Studies have shown that TLSs are associated with good prognosis in patients with various solid tumours and can improve patient responses to immunotherapy. However, the role of TLSs in hepatocellular carcinoma (HCC) remains controversial, and the underlying molecular mechanism is unclear. Methods: According to haematoxylin-eosin (HE) staining results, HCC patients in Xijing Hospital data and TCGA data were divided into TLS+ and TLS- groups, and Kaplan–Meier (KM) analysis was performed to assess overall survival (OS) and recurrence-free survival (RFS). Immunofluorescence (IF) and immunohistochemistry (IHC) were used to identify TILs in the TLS+ group. Lymphocyte-specific protein tyrosine kinase (LCK), a molecule involved in TLS formation, was explored in LinkedOmics. TILs were divided into two groups by drawing receiver operating characteristic (ROC) curves to calculate cut-off values. Spearman correlation analysis was used to calculate the correlation between LCK and TILs, and the molecular pathways by which LCK regulates immunotherapy were clarified through enrichment analysis. The half-maximal inhibitory concentration (IC50) distribution of sorafenib was observed in groups that varied in LCK expression. Results: According to the HE results, 61 cases in the Xijing Hospital cohort and 195 cases in the TCGA cohort had TLSs, while 89 cases and 136 cases did not. The KM results showed that TLSs had no effect on the OS of HCC patients but significantly affected RFS. The IF/IHC results showed that higher TIL numbers in TLSs were correlated with better prognosis in HCC patients. Spearman correlation analysis showed that LCK expression was positively correlated with TIL numbers. Enrichment analysis showed that upregulation of LCK expression mainly regulated the cytokine signalling pathway, the chemokine signalling pathway and T-cell activation. The IC50 scores of sorafenib in HCC patients with high LCK expression were lower, and the sensitivity was higher. Conclusion: TLSs mainly affected the early RFS of HCC patients but had no effect on OS. The high expression of the TLS formation-related gene LCK can increase the sensitivity of HCC patients to ICIs.
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Pikarsky, Eli. "Abstract IA02: The good and the bad sides of tertiary lymphoid structures in liver cancer." Clinical Cancer Research 28, no. 17_Supplement (September 1, 2022): IA02. http://dx.doi.org/10.1158/1557-3265.liverca22-ia02.
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Abstract Tertiary lymphoid structures (TLSs) are formed in chronically inflamed tissues in response to stress. They form an in situ source for adaptive immune responses, and are considered the frontal command posts of the adaptive immune system. In cancer, they were first recognized to be associated with a good prognosis (e.g. in colorectal cancer and melanoma). Later on, we and others noted that in some cancers their presence can be associated with worse prognosis. In particular, we showed that they can form microniches in which tumor cells can proliferate, depending on cues that are derived from TLS residing cells. Recently, several studies showed that TLSs are important in responding to immune checkpoint inhibitors, indicating that T cell exhaustion could play a role in TLS dysfunction. We hypothesized, that similar to single cells, TLSs can also become dysfunctional, explaining why in particular cases they can be associated with a bad outcome in cancer. Using a mouse model of TLS dependent liver cancer we find that T cell exhaustion is prevalent in pro-tumorigenic TLSs in the liver, and dissect the cell types that are responsible for this immunopathologic state. Our studies of human tissues are in line with the notion that TLS dysfunction correlates with T cell exhaustion in TLSs. Citation Format: Eli Pikarsky. The good and the bad sides of tertiary lymphoid structures in liver cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA02.
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Zhang, Fa-Peng, Ke Zhu, Tai-Feng Zhu, Chao-Qun Liu, Hong-Hua Zhang, Lei-Bo Xu, Gang Xiao, and Chao Liu. "Intra-Tumoral Secondary Follicle-like Tertiary Lymphoid Structures Are Associated with a Superior Prognosis of Overall Survival of Perihilar Cholangiocarcinoma." Cancers 14, no. 24 (December 12, 2022): 6107. http://dx.doi.org/10.3390/cancers14246107.
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Ectopic lymphoid structures termed tertiary lymphoid structures (TLSs) have an immunomodulatory function and positively affect prognosis in certain cancers. However, their clinical relevance and prognostic utility in perihilar cholangiocarcinoma (pCCA) are unknown. Therefore, determining the involvement and prognostic utility of TLSs in pCCA is the aim of this study. Ninety-three patients with surgically resected pCCA were included retrospectively. Hematoxylin and eosin and immunohistochemical staining identified and classified the TLSs, and multiplex immunofluorescence determined the TLS composition in the pCCA sample. The correlations between clinical features and TLSs were analyzed using either Fisher’s exact test or the Chi-squared test. Recurrence-free survival (RFS) and overall survival (OS) correlations with TLSs were analyzed using Cox regression and Kaplan–Meier analyses. We identified TLSs in 86% of patients with pCCA, including lymphoid aggregates (6.45%), primary (13.98%) and secondary follicles (65.59%). Patients with intra-tumoral secondary follicle-like TLSs (S-TLSs) had better OS (p = 0.003) and RFS (p = 0.0313). The multivariate analysis identified the presence of S-TLSs as a good independent prognostic indicator for OS but not for RFS. Interestingly, the presence of S-TLS only indicated better 5-year OS in 54 patients without lymph node metastasis (LNM−, p = 0.0232) but not in the 39 patients with lymph node metastasis (LNM+, p = 0.1244). Intra-tumoral S-TLSs predicted longer OS in patients with surgically resected pCCA, suggesting intra-tumoral S-TLSs’ contribution to effective antitumor immunity and that S-TLSs hold promise for diagnostic and therapeutic development in pCCA.
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Nundel, Kerstin (Kiefer), Stephanie Moses, Jillian M. Richmond, Carla V. Rothlin, and Ann Marshak-Rothstein. "TLR9 dependent regulation of AXL expression impacts migration of autoreactive B cells." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 218.15. http://dx.doi.org/10.4049/jimmunol.204.supp.218.15.
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Abstract Migration of autoreactive B cells to target tissues and the formation of tertiary lymphoid structures (TLS) is an important step in end-organ damage in autoimmune disease. TLSs are thought to be the main site of autoantibody production by autoreactive B cells, leading to immune complex formation and deposition in the affected organ. The formation of TLS was reported to be dependent on B cells as well as chemokines like CXCL13. Hence it is of importance to understand the migratory behavior of autoreactive B cells to these sites and how it is regulated. The receptor tyrosine kinase AXL was shown to play a role in the migration of cancer cells and expression of AXL in cancer cells is usually associated with worse prognoses. We found that AXL expression on B cells is highly induced by crosslinking of the B cell receptor (BCR) and not by TLR ligation as in dendritic cells and macrophages. Intriguingly, co-engagement of TLR9 together with the BCR inhibits AXL upregulation. This is unique to TLR9 and does not occur following co-engagement with other TLRs. Furthermore, we have found that AXL deficient B cells have a diminished potential to migrate in response to the B cell chemokine CXCL13. Also, in the pristane induced model of SLE, mice with AXL deficient B cells have lower numbers of TLS in the peritoneum compared to mice with AXL sufficient B cells, further supporting a role of AXL in the migration of B cells. Our data suggests that TLR9 plays an important role in suppressing AXL expression and the concurrent inhibition of B cell migration to TLS. Our studies have the potential to identify a novel and pharmacologically tractable mechanism for restricting the migration of autoreactive B cells and ensuing tissue damage.
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Bružaitė, I., V. Janickis, I. Ancutienė, and Valentinas Snitka. "Formation of Thallium Sulphide Layers on Polyethylene (PE) Sulphurised in a Solution of Higher Polythionic Acid." Solid State Phenomena 106 (September 2005): 133–40. http://dx.doi.org/10.4028/www.scientific.net/ssp.106.133.
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Thallium sulphide layers of different composition were obtained on the surface of polyethylene when it was sulphurised in a solution of higher polythionic acid, H2S33O6, and then treated with an alkaline solution of thallium(I) sulphate. The stoichiometric composition of the thallium sulphide layers varied between Tl0.3S and Tl2.6S depending on the formation conditions of the layers of TlxSy. A phase composition of the layers obtained was confirmed by X-ray photoelectron spectroscopy. The spectra of Tl 4f7/2, O 1s and S 2p showed the bond of thallium with sulphur in TlS and Tl2S , but Tl2SO4, Tl(OH)3, S8 and Tl2O3 were also found on the surface of the layers. Five thallium sulphide phases TlS, Tl2S, Tl2S2, Tl4S3 and Tl2S5 have also been identified in the layers by X-ray diffraction. The peaks of the TlS phase predominate in the diffractograms.
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Mahmoudi, P., A. Rashidi, and M. Razmkabir. "Inbreeding effects on some reproductive traits in Markhoz goats." Animal Production Science 58, no. 12 (2018): 2178. http://dx.doi.org/10.1071/an17043.
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The objective of this study was to estimate the inbreeding coefficient and its effects on reproductive traits in Markhoz goats. The pedigree file included 5351 kids produced by 234 bucks and 1470 does. Average inbreeding coefficient for the whole population was 2.68%, and the minimum and maximum inbreeding coefficients were 0.05% and 31.25%, respectively. Average coefficient of inbreeding for inbred population was 5.17% and the number of inbred animals in the population was 2777. For investigating effects of inbreeding coefficient on reproductive traits, 3443 records were available for litter size at birth (LSB), litter size at weaning (LSW), total litter weight at birth (TLWB) and mean of litter weight at birth (MLWB). Furthermore, available records for total litter weight at weaning (TLWW) and mean of litter weight at weaning (MLWW) were 2918. Inbreeding depression was estimated as the linear regression of performance on the individual inbreeding coefficient of kids and dams using the most appropriate animal model based on Akaike’s information criterion. Furthermore, inbreeding depressions for LSB and LSW were estimated using threshold and Poisson models. Regression coefficients of LSB, LSW, TLWB, TLWW, MLWB and MLWW on inbreeding coefficient of kids were –0.035, –0.019, –0.077 kg, –0.782 kg, –0.009 kg and –0.332 kg, respectively. Furthermore, regression coefficients of LSB, LSW, TLWB, TLWW, MLWB and MLWW on inbreeding coefficient of dams were 0.064, –0.013, 0.241 kg, 0.638 kg, 0.028 kg and –1.783 kg, respectively. The obtained results from this study showed that inbreeding depression is controlled by an appropriate mating system policy.
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Javed, Shazia, and Noor Atinah Ahmad. "A Stochastic Total Least Squares Solution of Adaptive Filtering Problem." Scientific World Journal 2014 (2014): 1–6. http://dx.doi.org/10.1155/2014/625280.
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An efficient and computationally linear algorithm is derived for total least squares solution of adaptive filtering problem, when both input and output signals are contaminated by noise. The proposed total least mean squares (TLMS) algorithm is designed by recursively computing an optimal solution of adaptive TLS problem by minimizing instantaneous value of weighted cost function. Convergence analysis of the algorithm is given to show the global convergence of the proposed algorithm, provided that the stepsize parameter is appropriately chosen. The TLMS algorithm is computationally simpler than the other TLS algorithms and demonstrates a better performance as compared with the least mean square (LMS) and normalized least mean square (NLMS) algorithms. It provides minimum mean square deviation by exhibiting better convergence in misalignment for unknown system identification under noisy inputs.
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Tang, Jun, Daniel Ramis-Cabrer, Víctor Curull, Xuejie Wang, Mercé Mateu-Jiménez, Lara Pijuan, Xavier Duran, et al. "B Cells and Tertiary Lymphoid Structures Influence Survival in Lung Cancer Patients with Resectable Tumors." Cancers 12, no. 9 (September 16, 2020): 2644. http://dx.doi.org/10.3390/cancers12092644.
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Immune profile of B and T cells and tertiary lymphoid structures (TLSs) may differ in tumors of lung cancer (LC) patients with/without chronic obstructive pulmonary disease (COPD), and may also influence patient survival. We sought to analyze: (1) TLSs, germinal centers (GCs), B and T cells, and (2) associations of the immune biomarkers with the patients’ 10-year overall survival (OS). TLSs (numbers and area), B [cluster of differentiation (CD) 20], and T (CD3), and GCs cells were identified in both tumor and non-tumor specimens (thoracotomy) from 90 LC-COPD patients and 43 LC-only patients. Ten-year OS was analyzed in the patients. Immune profile in tumors of LC-COPD versus LC: TLS numbers and areas significantly decreased in tumors of LC-COPD compared to LC patients. No significant differences were observed in tumors between LC-COPD and LC patients for B or T cells. Immune profile in tumors versus non-tumor specimens: TLS areas and B cells significantly increased, T cells significantly decreased in tumors of both LC and LC-COPD patients. Survival: in LC-COPD patients: greater area of TLSs and proportion of B cells were associated with longer survival rates. The immune tumor microenvironment differs in patients with underlying COPD and these different phenotypes may eventually impact the response to immunotherapy in patients with LC.
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Mori, Takuya, Hiroaki Tanaka, Sota Deguchi, Yoshihito Yamakoshi, Yuichiro Miki, Mami Yoshii, Tatsuro Tamura, et al. "Clinical efficacy of nivolumab is associated with tertiary lymphoid structures in surgically resected primary tumors of recurrent gastric cancer." PLOS ONE 17, no. 1 (January 7, 2022): e0262455. http://dx.doi.org/10.1371/journal.pone.0262455.
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Nivolumab, an immune checkpoint blocker, has been approved for advanced gastric cancer (GC), but predictive factors of nivolumab’s efficacy in patients with GC, especially immune cells such as tissue-resident memory T cells or those forming tertiary lymphoid structures (TLS), remain unclear. Tissue samples were obtained from surgically resected specimens of patients with GC who were treated with nivolumab as third-line or later treatment. Immunohistochemical staining was performed to detect the presence of TLS and CD103+ T cells and assess the association between TLSs and response to nivolumab treatment. A total of 19 patients were analyzed. In patients with partial response (PR) to nivolumab, numerous TLS were observed, and CD103+ T cells were found in and around TLS. Patients with many TLS experienced immune-related adverse events more often than those with few TLS (p = 0.018). The prognosis of patients with TLS high was better than those with TLS low. Patients with a combination of TLS high and CD103 high tended to have a better prognosis than other groups. Our results suggested that TLS status might be a predictor of nivolumab effectiveness.
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Chen, Miaoxin, Yuanyuan Wu, Xin Huang, Wentao Li, Chunyan Sun, Zhenzhen Meng, Ai Ai, et al. "Embryo incubation by time-lapse systems versus conventional incubators in Chinese women with diminished ovarian reserve undergoing IVF/ICSI: a study protocol for a randomised controlled trial." BMJ Open 10, no. 11 (November 2020): e038657. http://dx.doi.org/10.1136/bmjopen-2020-038657.
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IntroductionThe time-lapse imaging system (TLS) is a newly developed non-invasive embryo assessment system. Compared with conventional incubators, a TLS provides stable culture conditions and consistent observations of embryo development, thereby potentially improving embryo quality and selection of the best quality embryo. Although TLSs have been routinely used in many in vitro fertilisation (IVF) centres globally, there is insufficient evidence to indicate that TLSs result in higher cumulative live birth rates over conventional incubators. The purpose of this study is to compare the cumulative live birth rates and safety including miscarriage in infertile patients with diminished ovarian reserve (DOR) from both TLSs and conventional incubators.Methods and analysisThis study is a double-blind randomised controlled clinical trial (1:1 treatment ratio of TLSs vs conventional incubator). A total of 730 patients with DOR undergoing the first or second cycle of IVF or intracytoplasmic sperm injection (ICSI) will be enrolled and randomised into two parallel groups. Participants will undergo embryo culture in the TLSs (group A) or the conventional incubators (group B), respectively. Embryos are selected for transfer in both groups by the morphological characteristics. The embryo selection algorithm software is not used in the TLSs. The primary outcome is the cumulative live birth rate of the trial IVF/ICSI cycle within 12 months after randomisation. This study is powered to detect an absolute difference of 10% (35% vs 25%) at the significance level of 0.05% and 80% statistical power based on a two-sided test.Ethics and disseminationThis trial has been approved by the Institutional Ethical Committee of Shanghai First Maternity and Infant Hospital (KS1958). All participants in the trial will provide written informed consent. The study will be conducted according to the principles outlined in the Declaration of Helsinki and its amendments. Results of this study will be disseminated in peer-reviewed scientific journals.Trial registration numberChinese Clinical Trial Registry (ChiCTR1900027746).
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Fridman, Wolf H. "Abstract IA007: B cell immunity generation in tertiary lymphoid structures, a major determinant of sarcoma immune response to immunotherapy." Clinical Cancer Research 28, no. 18_Supplement (September 15, 2022): IA007. http://dx.doi.org/10.1158/1557-3265.sarcomas22-ia007.
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Abstract The presence of tertiary lymphoid structures (TLSs) and a high intratumoral density of B lymphocytes have been associated with improved survival in several tumor types. We investigated the impact of TLS on responses to immunotherapy and, analyzing a large-scale retrospective analysis of three independent cohorts of patients with cancer, including sarcomas, who were treated with anti-PD-1 or anti-PD-L1 antibodies, we showed that the presence of mature TLSs was associated with improved objective response rates, progression-free survival and overall survival, independent of PD-L1 expression status and CD8+T cell density. To decipher the role of B cells in such responses, we performed spatial transcriptomics and examined the nature of B cell responses within TLS structure. B cells were enriched in TLS, and therein we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS and the presence of full mature clonotypes at distance. In TLS+ tumors, IgG producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptic malignant cells, suggestive of anti-tumor effector activity. We validated these findings in a prospective trial in metastatic Soft Tissue Sarcoma (STS) bearing patients. PEMBROSARC is a multi-cohort phase II study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced STS. The 6-months non-progressive rate (NPR) and the objective response rates previously reported in cohorts including all comers were 4.9% and 2.4%, respectively. In the cohort enrolling patients selected based on the presence of TLS, the 6-month NPR was 40% and the objective response rate was 30%. Exploratory analyses reveled that infiltration by IgG antibody-producing plasma cells was associated with improved clinical outcome as well as the presence of IgG antibodies on tumor cells. Altogether, these results establish that maturation, selection and amplification of B cells in intratumoral TLSs results in Plasma Cells generation which may produce anti-tumor antibodies. The latter may amplify in situ antitumor immune responses leading to better therapeutic responses to immunotherapy. Citation Format: Wolf H. Fridman. B cell immunity generation in tertiary lymphoid structures, a major determinant of sarcoma immune response to immunotherapy [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA007.
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Zhao, Hua, Hao Wang, Qiuru Zhou, and Xiubao Ren. "Insights into tertiary lymphoid structures in the solid tumor microenvironment: anti-tumor mechanism, functional regulation, and immunotherapeutic strategies." Cancer Biology & Medicine 18, no. 4 (September 24, 2021): 981–91. http://dx.doi.org/10.20892/j.issn.2095-3941.2021.0029.
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Tertiary lymphoid structures (TLSs) are ectopic immune cell aggregations that develop in peripheral tissues in response to a wide range of chronic inflammatory conditions, including infection, autoimmune disease, and cancer. In the tumor microenvironment (TME), the structures of TLSs, including B-cell- and T-cell-enriched areas indicate that the TLSs might be the local site during the initiation and maintenance of humoral and cellular immune responses against cancers. Numerous studies have evaluated the expression of TLSs in different cancer patients and their association with prognoses of cancer patients. It was shown that welldeveloped TLSs characterized by mature B cells synthesized tumor specific antibodies, which were considered as specific markers for a good prognosis. However, there are still some immunosuppressive factors existing in the TLSs that may affect anti-tumor responses. These factors include dysfunctional B cells, regulatory T cells, and T follicular regulatory cells. The complexity and heterogeneity of the TLS composition may affect the function and activity of TLSs; it is therefore essential to fully understand the function and influencing factors in TLSs. It has been reported that checkpoint inhibitors and vaccines are currently being developed to reprogram the TME by establishing mature TLSs to improve cancer immunotherapies. In this review, we focused on recent advances in TLSs in human solid tumors, including structural characteristics and classes, antitumor mechanisms, immunosuppressive factors, and TLSbased therapeutic approaches.
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Tortelli Guarrezi, Silvane, Marcelo Paes de Barros, and Dulce Ferreira da Silva. "Sequências de ensino-aprendizagem: uma abordagem baseada nas demandas de aprendizagem para o ensino de Física." Pesquisa e Ensino 1 (June 3, 2020): e202017. http://dx.doi.org/10.37853/pqe.e202017.
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Este artigo descreve o efeito de uma Sequência de Ensino Aprendizagem (Teaching-Learning Sequence – TLS), baseada nas demandas de aprendizagem, na promoção do aprendizado dos alunos em conteúdos de Física. A pesquisa investiga os argumentos escritos e orais produzidos por alunos do 1º ano do Ensino Médio, em Sorriso, MT, durante uma TLS completa desenvolvida em agosto de 2019. Os dados usados nesta análise foram derivados de respostas escritas, gravações de áudio e vídeo e notas de campo. Os resultados mostraram que esta TLS pode ser útil para promover a argumentação e melhorar o aprendizado dos alunos sobre conceitos de Física, com destaque para algumas estratégias que se mostraram com potencial para serem utilizadas em TLSs sobre diferentes temáticas.
Palavras-chave: Aprendizagem significativa. Sequência de ensino-aprendizagem. TLS. Ensino de física.
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Ichii, Osamu, Marina Hosotani, Md Abdul Masum, Taro Horino, Yuki Otani, Takashi Namba, Teppei Nakamura, Elewa Yaser Hosny Ali, and Yasuhiro Kon. "Close Association between Altered Urine–Urothelium Barrier and Tertiary Lymphoid Structure Formation in the Renal Pelvis during Nephritis." Journal of the American Society of Nephrology 33, no. 1 (October 22, 2021): 88–107. http://dx.doi.org/10.1681/asn.2021040575.
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BackgroundKidneys with chronic inflammation develop tertiary lymphoid structures (TLSs). Infectious pyelonephritis is characterized by renal pelvis (RP) inflammation. However, the pathologic features of TLSs, including their formation and association with non-infectious nephritis, are unclear.MethodsRPs from humans and mice that were healthy or had non-infectious chronic nephritis were analyzed for TLS development, and the mechanism of TLS formation investigated using urothelium or lymphoid structure cultures.ResultsRegardless of infection, TLSs in the RP, termed urinary tract–associated lymphoid structures (UTALSs), formed in humans and mice with chronic nephritis. Moreover, urine played a unique role in UTALS formation. Specifically, we identified urinary IFN-γ as a candidate factor affecting urothelial barrier integrity because it alters occludin expression. In a nephritis mouse model, urine leaked from the lumen of the RP into the parenchyma. In addition, urine immunologically stimulated UTALS-forming cells via cytokine (IFN-γ, TNF-α) and chemokine (CXCL9, CXCL13) production. CXCL9 and CXCL13 were expressed in UTALS stromal cells and urine stimulation specifically induced CXCL13 in cultured fibroblasts. Characteristically, type XVII collagen (BP180), a candidate autoantigen of bullous pemphigoid, was ectopically localized in the urothelium covering UTALSs and associated with UTALS development by stimulating CXCL9 or IL-22 induction via the TNF-α/FOS/JUN pathway. Notably, UTALS development indices were positively correlated with chronic nephritis development.ConclusionsTLS formation in the RP is possible and altered urine–urothelium barrier–based UTALS formation may represent a novel mechanism underlying the pathogenesis of chronic nephritis, regardless of urinary tract infection.
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Montecinos, Alicia Muriel. "TLS aimed to stimulate the attainment of a metacognitive strategy on kinematics models, within a cooperative learning approach." Revista Brasileira de Ensino de Física 37, no. 2 (June 2015): 2503–1. http://dx.doi.org/10.1590/s1806-11173721682.
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<p>This manuscript proposes a teaching-learning sequence (or TLS) for undergraduate students with prior calculus background about kinematics models, based on metacognition and cooperative learning. It aims to help them to acquire a well-structured, simple and short strategy to check their graphs of position, velocity and acceleration, in which the method is based on derivatives. It may be used in courses addressed with traditional methods, but it is designed for active learning approaches. This TLS was twice piloted, mainly with sophomore engineering students, having positive results, and it is offered as a contribution for the growing international repository of physics TLSs.</p>
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Tan, Kai, Jin Chen, Weiwei Qian, Weiguo Zhang, Fang Shen, and Xiaojun Cheng. "Intensity Data Correction for Long-Range Terrestrial Laser Scanners: A Case Study of Target Differentiation in an Intertidal Zone." Remote Sensing 11, no. 3 (February 8, 2019): 331. http://dx.doi.org/10.3390/rs11030331.
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The intensity data recorded by a terrestrial laser scanner (TLS) contain spectral characteristics of a scanned target and are mainly influenced by incidence angle and distance. In this study, an improved implementable method is proposed to empirically correct the intensity data of long-distance TLSs. Similar to existing methods, the incidence angle–intensity relationship is estimated using some reference targets scanned in the laboratory. By contrast, due to the length limit of indoor environments and the laborious data processing, the distance–intensity relationship is derived by selecting some natural homogeneous targets with distances covering the entire distance scale of the adopted long-distance TLS. A case study of intensity correction and point cloud classification in an intertidal zone in Chongming Island, Shanghai, China, is conducted to validate the feasibility of the improved method by using the intensity data of a long-distance TLS (Riegl VZ-4000). Results indicate that the improved method can accurately eliminate the effects of incidence angle and distance on the intensity data of long-distance TLSs; the coefficient of variation of the intensity data for the targets in the study intertidal zone can be reduced by approximately 54%. The classification results of the study intertidal zone show that the improved method can effectively eliminate the variations caused by the incidence angle and distance in the original intensity data of the same target to obtain a corrected intensity that merely depends on target characteristics for improving classification accuracy by 49%.
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Wang, Zhe, Liang Cao, Filippo Ubertini, and Simon Laflamme. "Numerical Investigation and Design of Reinforced Concrete Shear Wall Equipped with Tuned Liquid Multiple Columns Dampers." Shock and Vibration 2021 (February 28, 2021): 1–19. http://dx.doi.org/10.1155/2021/6610811.
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The tuned liquid multiple column damper (TLMCD) is a variation of the tuned liquid column damper (TLCD) that includes multiple vertical columns. A new damping system that embeds TLMCDs within reinforced concrete shear wall systems, termed tuned liquid wall damper (TLWD), is proposed, augmenting the traditional structural component with energy dissipation capabilities. The objective of this study is to assess energy mitigation and strength trade-offs in designing TLWDs and demonstrating the promise of TLWD systems in tall buildings through vertically distributed applications. This is done by investigating the performance of the proposed TLWD through the finite element model (FEM) of a simplified representation of a 42-story building equipped with the multifunctional component. A strength model for the TLWD is developed to empower faster performance evaluation on more complex models. Results from the FEM are used to validate the strength model and show that the model could be used conservatively in assessing strength performance. Design considerations are discussed based on the simplified representation. In particular, to improve mitigation performance while maintaining strength, it is found that a single-layer arrangement of the vertical columns is preferred, while distributing the inertia among a higher number of smaller columns. The proposed TLWD is numerically evaluated on a more realistic system consisting of a multi-degrees-of-freedom representation of the 42-story building under stochastic wind excitation. Simulation results demonstrate that the TLWD, used in a vertically distributed configuration through the building, could be used to mitigate vibrations, outperforming a traditional TLCD system with geometric constraints under 20 design wind realization. Results from the numerical simulations also confirmed the design considerations established through the simplified representation.
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Brooker, P. "Consistent and up-to-date aviation safety targets." Aeronautical Journal 108, no. 1085 (July 2004): 345–56. http://dx.doi.org/10.1017/s0001924000005169.
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AbstractThere is a need for consistency between aviation safety targets – target levels of safety (TLS). Consistent ‘risk philosophy’ ensures that resources can be allocated in areas where they will be most beneficial in reducing the number of potential accidents and fatalities. Many existing aviation targets were devised decades ago, have not been brought up to date to take account of the considerable improvement in the sector’s safety performance, and are not targeted at some specific future year. It appears feasible to construct consistent and up-to-date sets of TLSs covering the full range of aviation needs, in particular for air traffic management. However, this requires significant, more demanding, changes to some TLS values. One caveat to note is that the safety of ‘loosely coupled’ aviation systems may be better described and managed by the Health and Safety Executive version of risk assessment rather than by a TLS approach.
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Anghel, Dragoş-Victor, and Dmitry V. Churochkin. "The Anisotropic Glassy Properties of Decagonal Quasicrystals." Advances in Condensed Matter Physics 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/419202.
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We use an extended version of the standard tunneling model to explain the anisotropic sound absorption in decagonal quasicrystals. The glassy properties are determined by an ensemble of two level systems (TLSs), arbitrarily oriented. The TLS is characterized by a 3 × 3 symmetric tensor, [T], which couples to the strain field, [S], through a 3 × 3 × 3 × 3 tensor of coupling constants, [R]. The structure of [R] reflects the symmetry of the quasicrystal. We also analyze the probability distributions of the elements of [T] in this particular model for a better understanding of the characteristics of “isotropic” and “anisotropic” distributions of the ensemble of TLSs. We observe that the distribution of the elements is neither simple nor intuitive and therefore it is difficult to guess ita priory, using qualitative arguments based on the symmetry properties.
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Lynch, Kevin T., Samuel J. Young, Max O. Meneveau, Nolan A. Wages, Victor H. Engelhard, Craig L. Slingluff Jr, and Ileana S. Mauldin. "Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma." Journal for ImmunoTherapy of Cancer 9, no. 6 (June 2021): e002273. http://dx.doi.org/10.1136/jitc-2020-002273.
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BackgroundTertiary lymphoid structures (TLSs) are immune aggregates in peripheral tissues that may support adaptive immune responses. Their presence has been associated with clinical response to checkpoint blockade therapy (CBT), but it is unknown whether TLS have prognostic significance independent of CBT in melanoma. We hypothesized that TLS in melanoma metastases would be associated with increased intratumoral lymphocyte infiltration, but that the intra-TLS immunological milieu would be distinct from the intratumoral immunological milieu. We also hypothesized that the presence of TLS would be associated with improved survival, and that TLS maturation or intra-TLS lymphocyte activity would also correlate with survival.MethodsCutaneous melanoma metastases (CMM) from 64 patients were evaluated by multiplex immunofluorescence for the presence and maturation status of TLS. Intra-TLS lymphocyte density, proliferation and B-cell Ig somatic hypermutation (AID+) were analyzed, as were markers of T-cell exhaustion and Th1/Tc1 differentiation. Associations between TLS maturation and intra-TLS immunologic activity were assessed, as well as associations with intratumoral immune cell infiltration. Independent associations with overall survival (OS) were assessed using log-rank tests and Cox proportional hazards models.ResultsTLS were identified in 30 (47%) of 64 CMM (TLS+) and were associated with increased intratumoral lymphocyte infiltration. However, proliferation of intra-TLS lymphocytes did not correlate with intratumoral lymphocyte proliferation. Most were early TLS; however, subsets of primary or secondary follicle-like TLS were also present. TLS+ lesions were associated with lower risk of tumor recurrence after metastasectomy and with improved OS in multivariate analyses (HR 0.51, p=0.04). OS was longer for TLS with low fractions of CD21+ B-cells (HR 0.29, p=0.02) and shorter for those with low AID+ fraction of B-cells (HR 2.74, p=0.03).ConclusionsThe presence of TLS in CMMs is associated with improved OS in patients treated with surgery before CBT, but TLS vary widely in maturation state, in proportions of proliferating T and B cells, and in markers of B cell function, including AID and CD21. Importantly, these features have additional prognostic significance, which suggest that some TLS may have regulatory function, while others functioning to support antigen-driven immune responses, depending on the cellular composition and activation status.
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Li, Jiang-Ping, Chang-You Wu, Ming-Yuan Chen, Shang-Xin Liu, Shu-Mei Yan, Yin-Feng Kang, Cong Sun, Jennifer R. Grandis, Mu-Sheng Zeng, and Qian Zhong. "PD-1+CXCR5−CD4+ Th-CXCL13 cell subset drives B cells into tertiary lymphoid structures of nasopharyngeal carcinoma." Journal for ImmunoTherapy of Cancer 9, no. 7 (July 2021): e002101. http://dx.doi.org/10.1136/jitc-2020-002101.
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BackgroundA major current challenge is to exploit tertiary lymphoid structures (TLSs) to promote the lymphocyte infiltration, activation and differentiation by tumor antigens to increase antitumor immune responses. The mechanisms that underlie the role of TLS formation in the adaptive immune responses against nasopharyngeal carcinoma (NPC) remain largely unknown.MethodsCell populations and the corresponding markers were identified by single-cell RNA sequencing and fluorescence-activated cell sorting analysis. In vitro differentiation experiments were used to simulate the generation, regulation and function of the Th-CXCL13 cell subset in the tumor microenvironment of NPC. These were followed by histological evaluation of the colocalization of tumor-associated B cells (TABs) and Th-CXCL13 cells within TLSs, and statistical analysis of the relationship between the cells in TLSs and overall survival.ResultsA PD-1+CXCR5−CD4+ Th-CXCL13 cell subset was identified in NPC. This subset was a major source of CXCL13, representing the majority of the CD4+ T cells at levels comparable with Th1 and Tfh cells present in the TLSs. Monocytes activated by toll-like receptor 4 agonists served as the antigen-presenting cells that most efficiently triggered the expansion of Th-CXCL13 cells. Transforming growth factor beta 1 (TGF-β1) stimulation and activation of Sox4 were critical for the induction and polarization of Th-CXCL13 cells in this process. The potential functional contributions of TABs recruited by Th-CXCL13 cells which induced plasma cell differentiation and immunoglobulin production via interleukin-21 and CD84 interactions in the TLSs demonstrated improved survival.ConclusionsInduction of Th-CXCL13 cells links innate inflammation to immune privilege in tumor-associated TLSs and might predict better survival.
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Kretzer, Ryan M., Christopher Chaput, Daniel M. Sciubba, Ira M. Garonzik, George I. Jallo, Paul C. McAfee, Bryan W. Cunningham, and P. Justin Tortolani. "A computed tomography–based feasibility study of translaminar screw fixation in the upper thoracic spine." Journal of Neurosurgery: Spine 12, no. 3 (March 2010): 286–92. http://dx.doi.org/10.3171/2009.10.spine09546.
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Object Translaminar screws (TLSs) offer an alternative to pedicle screw (PS) fixation in the upper thoracic spine. Although cadaveric studies have described the anatomy of the laminae and pedicles at T1–2, CT imaging is the modality of choice for presurgical planning. In this study, the goal was to determine the diameter, maximal screw length, and optimal screw trajectory for TLS placement at T1–2, and to compare this information to PS placement in the upper thoracic spine as determined by CT evaluation. Methods One hundred patients (50 men and 50 women), whose average age was 41.7 ± 19.6 years, were selected by retrospective review of a trauma registry database over a 6-month period. Patients were included in the study if they were over the age of 18, had standardized axial bone-window CT imaging at T1–2, and had no evidence of spinal trauma. For each lamina and pedicle, width (outer cortical and cancellous), maximal screw length, and optimal screw trajectory were measured using eFilm Lite software. Statistical analysis was performed using the Student t-test. Results The T-1 lamina was estimated to accommodate, on average, a 5.8-mm longer screw than the T-2 lamina (p < 0.001). At T-1, the maximal TLS length was similar to PS length (TLS: 33.4 ± 3.6 mm, PS: 33.9 ± 3.3 mm [p = 0.148]), whereas at T-2, the maximal PS length was significantly greater than the TLS length (TLS: 27.6 ± 3.1 mm, PS: 35.3 ± 3.5 mm [p < 0.001]). When the lamina outer cortical and cancellous width was compared between T-1 and T-2, the lamina at T-2 was, on average, 0.3 mm wider than at T-1 (p = 0.007 and p = 0.003, respectively). In comparison with the corresponding pedicle, the mean outer cortical pedicle width at T-1 was wider than the lamina by an average of 1.0 mm (lamina: 6.6 ± 1.1 mm, pedicle: 7.6 ± 1.3 mm [p < 0.001]). At T-2, however, outer cortical lamina width was wider than the corresponding pedicle by an average of 0.6 mm (lamina: 6.9 ± 1.1 mm, pedicle: 6.3 ± 1.2 mm [p < 0.001]). At T-1, 97.5% of laminae measured could accept a 4.0-mm screw with 1.0 mm of clearance, compared with 99.5% of T-1 pedicles; whereas at T-2, 99% of laminae met this requirement, compared with 94.5% of pedicles. The ideal screw trajectory was also measured (T-1: 49.2 ± 3.7° for TLS and 32.8 ± 3.8° for PS; T-2: 51.1 ± 3.5° for TLS and 20.5 ± 4.4° for PS). Conclusions Based on CT evaluation, there are no anatomical limitations to the placement of TLSs compared with PSs at T1–2. Differences were noted, however, in lamina length and width between T-1 and T-2 that must be considered when placing TLS at these levels.
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Zemp, Logan, Anders E. Berglund, Jasreman Dhillon, Ryan Putney, Youngchul Kim, Rohit K. Jain, George Daniel Grass, et al. "The prognostic and predictive implications of the 12-chemokine score in muscle invasive bladder cancer." Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021): 466. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.466.
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466 Background: Adaptive anti-tumor immunity can be orchestrated by lymph node-like immune cell aggregates within the tumor microenvironment (TME) called tertiary lymphoid structures (TLSs). TLSs are postulated to be the gateway of lymphocyte infiltration into the TME, and are privileged sites for coordinated tumor antigen presentation and lymphocyte priming, differentiation, and proliferation, leading to a robust tumor-specific immune response. A 12-chemokine metagene grouping (12-CK score) has previously been described that correlates with the presence of TLSs in other solid tumor types. In this study, we explored the prognostic implication of the 12-CK score in bladder cancer and its correlation with the presence of TLSs. Methods: Cystectomy specimens from 132 patients with bladder cancer were arrayed on Affymetrix microarrays. 12-CK scores were normalized with > 1 denoting high scores (12-CKHi). Immunohistochemistry (IHC) antibody staining was performed for DC-LAMP, CD20, CD4, and CD8. A GU pathologist scored TLSs into Types I-III, with type III representing fully developed TLSs. The Fisher’s exact test was used to test the associations between the 12-CK scores and the type of lymphoid aggregate. Overall survival was estimated using the Kaplan Meier method. Findings were validated using 12-CK scores extracted from TCGA transcriptome sequencing data and the IMvigor210CoreBiologies package. Results: Twenty-five (n = 25) patients had 12CK scores > 1 and were classified as 12CK-High. Pathologic review of 43 bladder tumor specimens confirmed higher levels of Type III TLS patients (33% vs. 9%, p = 0.03), B cells (p = 0.002), CD8 T cells (p = 0.01), and activated DC (p = 0.01) in 12-CKHi compared to 12-CKLo. 12-CKHi was found to have a progression-free survival (PFS, HR 0.29, p = 0.003, Fig1a), disease specific survival (DSS, HR 0.29, p = 0.004, Fig1b), and overall survival (OS, HR 0.55, p = 0.03, fig1c) advantage compared to 12-CKLo in the Moffitt patient cohort. These results were validated using the publically available RNA expression data from TCGA. TCGA patients with 12-CKHi (18%,n = 72) had improved PFS ( HR 0.55, p = 0.007, fig1d), DSS (HR = 0.40, p = 0.002, fig1e), and 0S (HR = 0.59, p = 0.01, fig1f). From the IMVIGOR-210 patient who were 12-CKHi were more likely to have a complete response (p < 0.05, fig1g) and have a 11.2mo OS benefit (fig1h) after treatment using atezolizumab. Conclusions: Three important findings emerged from the current study: 12CK-High scores corresponded with formation of TLS in the TME; favorable prognosis in surgically treated MIBC patients; and CR in atezolizumab-treated patients. The findings herein suggest the 12CK gene signature to be a clinically actable biomarker for predicting response to immune checkpoint blockade. We believe the 12CK signature may serve as an important tool to refine patient selection for immune checkpoint blockade treatment.
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Seiler, Patrick, Bernhard Klein, and Dirk Plettemeier. "Analytical and Experimental Investigation of Substrate Permittivity and Loss up to 67 GHz." ECTI Transactions on Electrical Engineering, Electronics, and Communications 13, no. 1 (February 17, 2015): 26–34. http://dx.doi.org/10.37936/ecti-eec.2015131.170977.
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In this paper, we characterize the substrate permittivity and overall loss of different planar transmission lines (TL) such as microstrip (MS), coplanar waveguide (CPW) and grounded CPW (GCPW) using on-wafer probes and a thru-reflect-line (TRL) calibration technique. The theory for calculation of the related effective permittivity from S-Parameter measurements is given and numerical simulations are being used for a fast and precise mapping of the effective permittivity to the physical value of the TL's substrate. The method presented can be used for higher frequencies, as long as single mode operation of the TLs is ensured. Thus, an overview on higher order modes in TLs and design rules to suppress them is given. The results up to 67 GHz for the aforementioned TL on a conventional RF substrate are presented and used to evaluate approximate models known from publications.
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Júnior, Roberto S. S., Sergei G. F. R. Caldas, Lídia P. Martins, and Renato P. Martins. "Effects of stress relaxation in beta-titanium orthodontic loops: Part II." Angle Orthodontist 86, no. 3 (August 11, 2015): 386–90. http://dx.doi.org/10.2319/112614-846.1.
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ABSTRACT Objective: To determine which regions of beta-titanium T-loop springs (TLSs) are more affected by the stress relaxation over a 12-week period. Materials and Methods: Fifty TLS were previously activated by concentrated bends and divided into five groups of 10 each according to their evaluation periods: immediate assessment (G0), 24 hours (G1), 48 hours (G2), 1 week (G3), and 12 weeks (G4). Groups 1 to 4 were mounted into a structure simulating a clinical situation. After the experimental periods, the springs were scanned for measurement of their angles and numbered from 1 to 9. A two-way analysis of variance was used to detect differences among the angles measured and differences caused by time and also to detect interactions between those two factors. Tukey’s test was used to find differences among the groups. Results: Time influenced the angulations of the TLSs (P < .001). Tukey post hoc test showed that G0 (84.1°) presented a different profile, whereas G1 (90.2°), G2 (90.7°), and G3 (91.1°) had similar profiles among each other, with G4 (92.6°) showing a mean value different from all other groups. A significant interaction was detected between activation time and angular deformation in the TLSs (P < .01). Conclusion: Stress relaxation was observed in the TLSs. It was greatest within 24 hours and gradually increased up to 12 weeks. Two regions were identified as responsible for the relaxation of the TLSs: one at the bend between the vertical extensions of the springs and the base arch and the other at the preactivation bends made in the base arch.
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Chelvanambi, Manoj, Jennifer Taylor, and Walter Storkus. "STINGing the tumor microenvironment to promote therapeutic tertiary lymphoid organogenesis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 89.5. http://dx.doi.org/10.4049/jimmunol.204.supp.89.5.
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Abstract Classical tertiary lymphoid structures (TLS) are non-encapsulated aggregates of B cells, T cells and dendritic cells (DCs) that form around high endothelial venules (HEVs) in tissue sites affected by chronic inflammation. Homeostatic chemokines/cytokines CCL19, CCL21, lymphotoxin α, lymphotoxin β, IL-36γ, type I interferons, CXCL9 and CXCL10 have collectively been implicated in secondary lymphoid organogenesis as well as in formation of TLSs. As these factors can be produced by appropriately activated dendritic cells (DC), we posit that conditioning of intratumoral DCs/stromal cells can lead to TLS formation, improved immune cell infiltration and slowed tumor growth. We report that STING activation in bone marrow derived CD11c+ DCs leads to the production of various TLS forming factors through a STING-TBK1-IRF3 signaling cascade. In vivo, B16.F10 bearing mice treated intratumorally with a human/murine STING agonist, ML-RR-S2-CDA, showed slowed tumor growth dependent on CD8+ T cells. Immunofluorescent imaging of treated tumors showed increased aggregation of CD11c+ DCs with CD3+ T cells around PNAd+/MAdCAM1+ HEVs as early as 5 days post-treatment. These changes occurred in association with evidence for normalization of the tumor vasculature based on enhanced PDGFRβ+ pericyte coverage of CD31+ VECs. Future studies will analyze how the presence of TLS shapes the evolving local (tumor) vs. systemic therapeutic anti-tumor T cell repertoire.
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Molina, Camilo, Daniel M. Sciubba, Christopher Chaput, P. Justin Tortolani, George I. Jallo, and Ryan M. Kretzer. "A computed tomography–based feasibility study of translaminar screw placement in the pediatric thoracic spine." Journal of Neurosurgery: Pediatrics 9, no. 1 (January 2012): 27–34. http://dx.doi.org/10.3171/2011.10.peds11121.
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Object Translaminar screws (TLSs) were originally described as a safer alternative to pedicle and transarticular screw placement at C-2 in adult patients. More recently, TLSs have been used in both the cervical and thoracic spine of pediatric patients as a primary fixation technique and as a bailout procedure when dysplastic pedicle morphology prohibits safe pedicle screw placement. Although authors have reported the anatomical characteristics of the cervical and thoracic lamina in adults as well as those of the cervical lamina in pediatric patients, no such data exist to guide safe TLS placement in the thoracic spine of the pediatric population. The goal of this study was to report the anatomical feasibility of TLS placement in the thoracic spine of pediatric patients. Methods Fifty-two patients (26 males and 26 females), with an average age of 9.5 ± 4.8 years, were selected by retrospective review of a trauma registry database after institutional review board approval. Study inclusion criteria were an age from 2 to 16 years, standardized axial bone-window CT images of the thoracic spine, and the absence of spinal trauma. For each thoracic lamina the following anatomical features were measured using eFilm Lite software: laminar width (outer cortical and cancellous), laminar height (LH), maximal screw length, and optimal screw trajectory. Patients were stratified by age (an age < 8 versus ≥ 8 years) and sex. Results Collected data demonstrate the following general trends as one descends the thoracic spine from T-1 to T-12: 1) increasing laminar width to T-4 followed by a steady decrease to T-12, 2) increasing LH, 3) decreasing maximal screw length, and 4) increasing ideal screw trajectory angle. When stratified by age and sex, male patients older than 8 years of age had significantly larger laminae in terms of both width and height and allowed significantly longer screw placement at all thoracic levels compared with their female counterparts. Importantly, it was found that 78% of individual thoracic laminae, regardless of age or sex, could accept a 4.0-mm screw with 1.0 mm of clearance. As expected, when stratifying by age and sex, it was found that older male patients had the highest acceptance rates. Conclusions Data in the present study provide information regarding optimal TLS length, diameter, and trajectory for each thoracic spinal level in pediatric patients. Importantly, the data collected demonstrate no anatomical limitations within the pediatric thoracic spine to TLS instrumentation, although acceptance rates are lower for younger (< 8 years old) and/or female patients. Lastly, given the anatomical variation found in this study, CT scanning can be useful in the preoperative setting when planning TLS use in the thoracic spine of pediatric patients.
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Medić, Tomislav, Heiner Kuhlmann, and Christoph Holst. "Designing and Evaluating a User-Oriented Calibration Field for the Target-Based Self-Calibration of Panoramic Terrestrial Laser Scanners." Remote Sensing 12, no. 1 (December 18, 2019): 15. http://dx.doi.org/10.3390/rs12010015.
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Calibration of terrestrial laser scanners (TLSs) is one of the fundamental tasks for assuring the high measurement accuracy required by an increasing number of end-users. Nevertheless, the development of user-oriented calibration approaches is still an active topic of research. The calibration fields for the target-based self-calibration of TLSs described in the literature are based on the quasi-random distribution of a high number of targets, and they rely on heavy redundancy. This redundancy assures highly accurate calibration results, however, with the price of reduced efficiency. In contrast, this work follows the design, implementation, and validation of a user-oriented, cost-efficient calibration field intended for TLS calibration prior to measurement campaigns. Multiple goals and constraints are placed upon the design of the calibration field, such as comprehensive calibration for high-end panoramic TLSs considering all relevant mechanical misalignments, delivering stable and reusable calibration parameters, increasing calibration efficiency by minimizing calibration-field assembly, measurement acquisition and processing time through reducing the number of targets and scanner stations, as well as estimating calibration parameters with predefined quality criteria. The calibration field design was derived through a series of simulation experiments and it was compared with the current state of the art. The simulations indicate comparable calibration results, with eight times smaller number of targets (14 instead of 120). The implemented calibration field was tested on a range of instruments, successfully improving the measurement quality, both in situ and in the subsequent applications.
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Sánchez-Azofeifa, Gerardo Arturo, J. Antonio Guzmán-Quesada, Mauricio Vega-Araya, Carlos Campos-Vargas, Sandra Milena Durán, Nikhil D'Souza, Thomas Gianoli, Carlos Portillo-Quintero, and Iain Sharp. "Can terrestrial laser scanners (TLSs) and hemispherical photographs predict tropical dry forest succession with liana abundance?" Biogeosciences 14, no. 4 (March 2, 2017): 977–88. http://dx.doi.org/10.5194/bg-14-977-2017.
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Abstract. Tropical dry forests (TDFs) are ecosystems with long drought periods, a mean temperature of 25 °C, a mean annual precipitation that ranges from 900 to 2000 mm, and that possess a high abundance of deciduous species (trees and lianas). What remains of the original extent of TDFs in the Americas remains highly fragmented and at different levels of ecological succession. It is estimated that one of the main fingerprints left by global environmental and climate change in tropical environments is an increase in liana coverage. Lianas are non-structural elements of the forest canopy that eventually kill their host trees. In this paper we evaluate the use of a terrestrial laser scanner (TLS) in combination with hemispherical photographs (HPs) to characterize changes in forest structure as a function of ecological succession and liana abundance. We deployed a TLS and HP system in 28 plots throughout secondary forests of different ages and with different levels of liana abundance. Using a canonical correlation analysis (CCA), we addressed how the VEGNET, a terrestrial laser scanner, and HPs could predict TDF structure. Likewise, using univariate analyses of correlations, we show how the liana abundance could affect the prediction of the forest structure. Our results suggest that TLSs and HPs can predict the differences in the forest structure at different successional stages but that these differences disappear as liana abundance increases. Therefore, in well known ecosystems such as the tropical dry forest of Costa Rica, these biases of prediction could be considered as structural effects of liana presence. This research contributes to the understanding of the potential effects of lianas in secondary dry forests and highlights the role of TLSs combined with HPs in monitoring structural changes in secondary TDFs.
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Barends, Sharief, Joëlle Rudinger-Thirion, Catherine Florentz, Richard Giegé, Cornelis W. A. Pleij, and Barend Kraal. "tRNA-Like Structure Regulates Translation of Brome Mosaic Virus RNA." Journal of Virology 78, no. 8 (April 15, 2004): 4003–10. http://dx.doi.org/10.1128/jvi.78.8.4003-4010.2004.
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ABSTRACT For various groups of plant viruses, the genomic RNAs end with a tRNA-like structure (TLS) instead of the 3′ poly(A) tail of common mRNAs. The actual function of these TLSs has long been enigmatic. Recently, however, it became clear that for turnip yellow mosaic virus, a tymovirus, the valylated TLSTYMV of the single genomic RNA functions as a bait for host ribosomes and directs them to the internal initiation site of translation (with N-terminal valine) of the second open reading frame for the polyprotein. This discovery prompted us to investigate whether the much larger TLSs of a different genus of viruses have a comparable function in translation. Brome mosaic virus (BMV), a bromovirus, has a tripartite RNA genome with a subgenomic RNA4 for coat protein expression. All four RNAs carry a highly conserved and bulky 3′ TLSBMV (about 200 nucleotides) with determinants for tyrosylation. We discovered TLSBMV-catalyzed self-tyrosylation of the tyrosyl-tRNA synthetase but could not clearly detect tyrosine incorporation into any virus-encoded protein. We established that BMV proteins do not need TLSBMV tyrosylation for their initiation. However, disruption of the TLSs strongly reduced the translation of genomic RNA1, RNA2, and less strongly, RNA3, whereas coat protein expression from RNA4 remained unaffected. This aberrant translation could be partially restored by providing the TLSBMV in trans. Intriguingly, a subdomain of the TLSBMV could even almost fully restore translation to the original pattern. We discuss here a model with a central and dominant role for the TLSBMV during the BMV infection cycle.
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Oh, E. H., Y. A-Ran, K. Ye-Jee, K. Jeongseok, N. Namseok, P. Sang Hyoung, Y. Dong-Hoon, et al. "P337 Usefulness of drug-level monitoring in therapeutic guidance in patients with ulcerative colitis on anti-TNF-α maintenance therapy." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S324—S325. http://dx.doi.org/10.1093/ecco-jcc/jjz203.466.
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Abstract Background While treatment optimisation using therapeutic drug monitoring (TDM) of anti-TNF-α agents has become more common in clinical practices, studies comparing its correlation with clinical remission (CR), biochemical remission (BR) and mucosal healing (MH) in patients with ulcerative colitis (UC) are still lacking Methods Trough levels of infliximab/adalimumab (TLIs/TLAs) and levels of antibody to infliximab/adalimumab (ATI/ATA levels) were measured using serum samples collected between August 2017 and September 2019 from patients with UC on anti-TNF-α maintenance therapy. CR, BR and MH were defined as partial Mayo score of 0–1, within normal range of both ESR and serum C-reactive protein (CRP) level, and Mayo endoscopic subscore of 0–1, respectively. Results This study included 115 patients (72.8%, 91 [76.5%] on infliximab and 24 [61.5%] on adalimumab) in CR and 43 patients (27.2%) in non-CR. ATI/ATA were positive in 31 (26.1%) and 2 (5.1%) patients on infliximab/adalimumab therapy, respectively. TLI showed significant differences according to stats of CR (2.146 [0.273–4.296] vs. 0.405 [0.001–2.962], p = 0.019), BR (2.843 [0.282–4.835] vs. 0.987 [0.022–2.914], p = 0.007) and MH (2.411 [0.282–4.439] vs. 0.240 [0.001–1.674], p = 0.001), however, TLA didn’t (p = 0.783, 0.893 and 0.853, respectively) (Table 1 and Figure 1). In receiver operating characteristics (ROC) curve analysis, TLI of 2.314 μg/ml was identified as cut-off value discriminating MH (area under ROC 0.705, p = 0.001, sensitivity 0.527, specificity 0.885, negative predictive value [NPV] 0.343, positive predictive value [PPV] 0.942). After excluding 36 patients with MH even though their TLI < 1ug/ml, AUROC increased to 0.931 (p < 0.001, sensitivity 0.860, specificity 0.885, NPV 0.742, PPV 0.942) while cut-off TLI remained same. In incremental graph by ranges of TLI, MH rates showed plateau over 4 μg/ml of TLI. In multivariate logistic regression analysis, extensive colitis (hazard ratio [HR] 0.289, 95% confidence interval [CI] 0.079–1.060, p = 0.061) and TLI (HR 1.282, 95% CI 0.974–1.687, p = 0.076) were marginally associated with MH (Table 2). Conclusion In this study, TLIs correlated with CR, BR and MH, while TLAs did not. TLI should be targeted to be above 2.3 μg/ml.
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Caldas, Sergei Godeiro Fernandes Rabelo, Renato Parsekian Martins, Marcela Emílio de Araújo, Marília Regalado Galvão, Roberto Soares da Silva Júnior, and Lídia Parsekian Martins. "Stability of beta-titanium T-loop springs preactivated by gradual curvature." Dental Press Journal of Orthodontics 22, no. 6 (November 2017): 61–67. http://dx.doi.org/10.1590/2177-6709.22.6.061-067.oar.
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ABSTRACT Objective: Evaluate changes in the force system of T-Loop Springs (TLS) preactivated by curvature, due to stress relaxation. Methods: Ninety TLSs measuring 6 x 10 mm, produced out with 0.017 x 0.025-in TMA® wire and preactived by gradual curvature, were randomly distributed into nine groups according to time point of evaluation. Group 1 was tested immediately after spring preactivation and stress relief, by trial activation. The other eight groups were tested after 24, 48 and 72 hours, 1, 2, 4, 8 and 12 weeks, respectively. Using a moment transducer coupled to a digital extensometer indicator adapted to a universal testing machine, the amount of horizontal force, moment and moment-to-force ratios were recorded at every 0.5 mm of deactivation from 5 mm of the initial activation, in an interbracket distance of 23 mm. Results: The horizontal forces decreased gradually among the groups (p< 0.001) and the moments showed a significant and slow decrease over time among the groups (p< 0.001). All groups produced similar M/F ratios (p= 0.532), with no influence of time. Conclusions: The TLSs preactivated by curvature suffered a gradual deformation over time, which affected the force system, specifically the moments, which affected the horizontal forces produced.
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Jiao, Qisong, Hongbo Jiang, and Qiang Li. "Building Earthquake Damage Analysis Using Terrestrial Laser Scanning Data." Advances in Civil Engineering 2019 (May 23, 2019): 1–12. http://dx.doi.org/10.1155/2019/8308104.
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Terrestrial laser scanners (TLSs) can acquire high-precision three-dimensional point cloud data for earthquake-damaged buildings. In this study, we collected TLS data in the Wenchuan earthquake zone and developed the TLS-BSAM (terrestrial laser scanning-based building shape analysis model) to carry out a building earthquake damage analysis. This model involves equidistance polygon array extraction, shape dispersion parameter calculations, irregular building clustering segmentation, and damage analysis. We chose 21 buildings as samples for the experiments. The results show that when using an equidistance polygon array to depict a three-dimensional building, 0.5 m is a reasonable sampling interval for building earthquake damage analysis. Using certain characteristic parameters to carry out K-means clustering, one can efficiently divide irregular buildings into regular blocks. Then, by weighted averages, the shape dispersion parameters can be calculated to express the damage extent to buildings. Among the shape dispersion parameters, at least the weighted average standard deviations of the tilt direction, rectangularity, compactness, and center point are suitable to reflect the damage extent. Higher values reflect more serious damage. On the basis of existing data, the weighted average standard deviations of the tilt direction and center point can be used to establish discriminant functions that can effectively distinguish the damage extent.
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Zhan, Weihua, Jihong Guan, and Zhongzhi Zhang. "A New Method for Extracting the Hierarchical Organization of Networks." International Journal of Information Technology & Decision Making 16, no. 05 (September 2017): 1359–85. http://dx.doi.org/10.1142/s021962201450028x.
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Extracting the hierarchical organization of networks is currently a pressing task for understanding complex networked systems. The hierarchy of a network is essentially defined by the heterogeneity of link densities of communities at different scales. Here, we define a top-level partition (TLP) as a bipartition of the network (or a sub-network) such that no top-level community (TLC) runs across the two parts. It has been found that a TLP generally has a higher modularity than a non-top-level (TLP) partition when their TLCs have similar sizes and when the link densities of neighboring levels are well separated from each other. A spectral TLP procedure is proposed here to search for TLPs of a network (or sub-network). To extract the hierarchical organization of large complex networks, an algorithm called TLPA has been developed based on the TLP. Experiments have shown that the method developed in this research extract hierarchy accurately from network data.
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Bowell, E. L. G. "Too many TLAs." Astronomy & Geophysics 38, no. 6 (December 1, 1997): 9. http://dx.doi.org/10.1093/astrog/38.6.9-c.
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Piazza, Ornella. "TLRs genetic expression." Shock 33, no. 2 (February 2010): 225. http://dx.doi.org/10.1097/shk.0b013e3181b0fdbe.
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Foley, J. F. "MHCs and TLRs." Science Signaling 4, no. 170 (April 26, 2011): ec118-ec118. http://dx.doi.org/10.1126/scisignal.4170ec118.
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Tobias, Peter S. "TLRs in disease." Seminars in Immunopathology 30, no. 1 (January 17, 2008): 1–2. http://dx.doi.org/10.1007/s00281-007-0104-1.
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Bird, Lucy. "Remodelling by TLRs." Nature Reviews Immunology 4, no. 10 (October 2004): 748. http://dx.doi.org/10.1038/nri1474.
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Bordon, Yvonne. "TLRs get rhythm." Nature Reviews Immunology 13, no. 6 (May 17, 2013): 392. http://dx.doi.org/10.1038/nri3472.
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Bell, Jennifer. "Untangling the TLRs." Nature Reviews Immunology 2, no. 12 (December 2002): 904. http://dx.doi.org/10.1038/nri975.
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Muir, David C. F. "TLVs—what now?" American Journal of Industrial Medicine 13, no. 5 (1988): 605–6. http://dx.doi.org/10.1002/ajim.4700130509.
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Cook, Warren A. "TLVs for asbestos." American Journal of Industrial Medicine 21, no. 5 (1992): 765–66. http://dx.doi.org/10.1002/ajim.4700210515.
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Kania, Tomasz, Piotr Koszmider, and Niels Jakob Laustsen. "A weak∗-topological dichotomy with applications in operator theory." Transactions of the London Mathematical Society 1, no. 1 (2014): 1–28. http://dx.doi.org/10.1112/tlms/tlu001.
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