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Innovative Phase I Trials
Published in Susan Halabi, Stefan Michiels, Textbook of Clinical Trials in Oncology, 2019
Cody Chiuzan, Nathaniel O'Connell
Overall, the two-stage adaptive design demonstrates good operating characteristics, even for relatively small sample sizes (N = 25). The main conclusion is that by using an efficacy-driven randomization with safety constraints, the allocation distribution is skewed toward doses that are more promising. For example, when the first three doses have low toxicity (≤0.12 as in Tox3), the adaptive design assigns most of the patients to the dose with the highest T-cell percent persistence, i.e., dose 3 for efficacy scenarios Eff1-Eff3, and dose 1 and 3 for the plateau trend Eff4 (see Figure 3.3). Also, at doses with higher efficacy, there is an improvement in estimation of outcomes (less bias, greater precision).
Relationship of digit ratio with sexual steroid hormone receptor related genes - single nucleotide polymorphisms in a sample from Northern China
Published in Annals of Human Biology, 2023
Jie Dang, Chengfeng Ma, Fan Li, Jing Zhang, Yuan Wang, Liang Peng, Zhenghao Huo, Hong Lu, Zhanbing Ma
As it is difficult to replicate the mouse experiment in humans, researchers have focussed on investigating the single-nucleotide polymorphisms (SNPs) located in sex hormone-regulating genes. Medland and colleagues (Medland et al. 2010) first found that the SNP (rs314277) in LIN28B was associated with an increased 2D:4D, while Lawrance-Owen et al. (Lawrance-Owen et al. 2013) found that rs4902759 of gene SMOC1 was associated with a decreased 2D:4D. However, their results have not been consistently replicated in other studies, possibly because the contribution of a single SNP to the digit ratio is small (Liguo 2013). Recently, Warrington et al. replicated the association between rs2332175 in SMOC1 and 2D:4D using the largest genome-wide association meta-analysis. Besides, they also found 10 non-X-linked loci (GLIS1, rs4927012; EFNA1, rs11581730; LDAH, rs340600; OLA1, rs12474669; FLI1, rs10790969; HOXD11/12, rs847158; GLI3, rs77640775; SALL1, rs6499762; TOX3, rs1080014; and SALL3, rs4799176) that were associated with 2D:4D (Warrington et al. 2018). However, even with these 10 loci associated with 2D:4D, they only explain 3.8% of the digit ratio variability.
Emerging molecular therapeutic targets for spinal cord injury
Published in Expert Opinion on Therapeutic Targets, 2019
Shuo Wang, George M Smith, Michael E. Selzer, Shuxin Li
Blocking the major cytokines generated by M1 macrophages is also neuroprotective after SCI. Because TNFα contributes to neuronal and glial loss after SCI, its antagonists enhance recovery after SCI. Etanercept, a recombinant dimer of TNFα receptor, functions as a TNFα antagonist and promotes functional recovery after SCI in both preclinical [21] and clinical [22] studies although there is no such an effect if treatment is delayed for 14 d after SCI [23]. Epigallocatechin gallate, an abundant catechin in green tea, prevents tissue damage after CNS injury by altering the levels of TNFα and other cytokines [24]. Suppressing several ILs also reduces inflammation and tissue damage and promotes neural tissue repair after CNS injury. An antibody against IL-6, a product of M1 macrophages, increased the number of M2 macrophages around the lesion, spared myelin and improved recovery of locomotor functions [25]. Microglia generate IL-1α several hours after SCI, thus recruiting leukocytes, producing IL-1β and amplifying post-injury inflammation. Intrathecal anakinra, a recombinant IL-1-R1 antagonist, promotes functional recovery in SCI rodents. IL-1α inhibition also protects OLs after SCI by upregulating transcriptional factor Tox3. IL-33, another member of the IL-1 family, and its associated chemokines are also therapeutic targets in SCI. IL-33 treatment promotes an M2 macrophage response, prevents demyelination, reduces lesion size and improves locomotor function in SCI rodents. Injured OLs could secrete IL-33 in SCI animals, which upregulates chemotactic proteins (such as CCL2, CCL5, CXCL1, CXCL2, and CXCL10) in astrocytes and microglia.
CD4+ T cells in classical Hodgkin lymphoma express exhaustion associated transcription factors TOX and TOX2
Published in OncoImmunology, 2022
Johanna Veldman, Jessica Rodrigues Plaça, Lauren Chong, Miente Martijn Terpstra, Mirjam Mastik, Léon C. van Kempen, Klaas Kok, Tomohiro Aoki, Christian Steidl, Anke van den Berg, Lydia Visser, Arjan Diepstra
Besides the already known characteristic feature of being CD26-, we identified two additional proteins enriched in CD4+ T cells in the TME. These proteins, i.e. TOX and TOX2, were also frequently expressed by rosetting T cells in cHL. The TOX protein family consists of four members that all function as transcription factors: TOX (also known as TOX1), TOX2, TOX3 and TOX4.32 TOX and/or TOX2 are involved in many early lymphoid developmental processes, including positive selection in thymocytes, early development of CD4+ T and NK cells, development of innate lymphoid cells and lymph node organogenesis.33–35 More important in the setting of our study, they are essential for the development of Tfh cells and the induction of exhaustion in both CD4+ and CD8+ T cells.36–41 Corresponding with our DEG, TOX can induce the expression of the Tfh defining chemokine CXCL13, and immune checkpoint molecule PD-1, which is a well-established marker of exhaustion.42,43 Of note, in our immunohistochemistry analysis, T cells expressing TOX and/or TOX2 outnumbered cells expressing CXCL13 and PD-1, confirming a previous report that the exhaustion phenotype is a dominant feature in the cHL TME.3 In line with this induction of exhaustion by TOX and TOX2, is the inability of CD4+ CD26- T cells to upregulate production of several cytokines upon in vitro stimulation.20 It is well known that TOX and TOX2 are both induced by chronic antigen stimulation of the TCR.37,40 It would be interesting to study if this is also the case in HL, given the importance of HLA class II-TCR interactions in HL rosetting.10