Why are we failing to implement imaging studies with radiolabelled new molecular entities in early oncology drug development?

In early drug development advanced imaging techniques can help with progressing new molecular entities (NME) to subsequent phases of drug development and thus reduce attrition. However, several organizational, operational, and regulatory hurdles pose a significant barrier, potentially limiting the impact these techniques can have on modern drug development. Positron emission tomography (PET) of radiolabelled NME is arguably the best example of a complex technique with a potential to deliver unique decision-making data in small cohorts of subjects. However, to realise this potential the impediments to timely inclusion of PET into the drug development process must be overcome. In the present paper, we discuss the value of PET imaging with radiolabelled NME during early anticancer drug development, as exemplified with one such NME. We outline the multiple hurdles and propose options on how to streamline the organizational steps for future studies

Practice Considerations for Adapting In-Person Groups to Telerehabilitation

The Coronavirus-2019 (COVID-19) pandemic has shifted research and healthcare system priorities, stimulating literature on implementation and evaluation of telerehabilitation for a variety of patient populations. While there is substantial literature on individual telerehabilitation, evidence about group telerehabilitation remains limited despite its increasing use by rehabilitation providers. Therefore, the purpose of this manuscript is to describe our expert team’s consensus on practice considerations for adapting in-person group rehabilitation to group telerehabilitation to provide rapid guidance during a pandemic and create a foundation for sustainability of group telerehabilitation beyond the pandemic’s end. &nbsp

ZNF280BY and ZNF280AY: autosome derived Y-chromosome gene families in Bovidae

<p>Abstract</p> <p>Background</p> <p>Recent progress in exploring the Y-chromosome gene content in humans, mice and cats have suggested that "autosome-to-Y" transposition of the male fertility genes is a recurrent theme during the mammalian Y-chromosome evolution. These transpositions are lineage-dependent. The purpose of this study is to investigate the lineage-specific Y-chromosome genes in bovid.</p> <p>Results</p> <p>We took a direct testis cDNA selection strategy and discovered two novel gene families, <it>ZNF280BY </it>and <it>ZNF280AY</it>, on the bovine (<it>Bos taurus</it>) Y-chromosome (BTAY), which originated from the transposition of a gene block on the bovine chromosome 17 (BTA17) and subsequently amplified. Approximately 130 active <it>ZNF280BY </it>loci (and ~240 pseudogenes) and ~130 pseudogenized <it>ZNF280AY </it>copies are present over the majority of the male-specific region (MSY). Phylogenetic analysis indicated that both gene families fit with the "birth-and-death" model of evolution. The active <it>ZNF280BY </it>loci share high sequence similarity and comprise three major genomic structures, resulted from insertions/deletions (indels). Assembly of a 1.2 Mb BTAY sequence in the MSY ampliconic region demonstrated that <it>ZNF280BY </it>and <it>ZNF280AY</it>, together with <it>HSFY </it>and <it>TSPY </it>families, constitute the major elements within the repeat units. The <it>ZNF280BY </it>gene family was found to express in different developmental stages of testis with sense RNA detected in all cell types of the seminiferous tubules while the antisense RNA detected only in the spermatids. Deep sequencing of the selected cDNAs revealed that different loci of <it>ZNF280BY </it>were differentially expressed up to 60-fold. Interestingly, different copies of the <it>ZNF280AY </it>pseudogenes were also found to differentially express up to 10-fold. However, expression level of the <it>ZNF280AY </it>pseudogenes was almost 6-fold lower than that of the <it>ZNF280BY </it>genes. <it>ZNF280BY </it>and <it>ZNF280AY </it>gene families are present in bovid, but absent in other mammalian lineages.</p> <p>Conclusions</p> <p><it>ZNF280BY </it>and <it>ZNF280AY </it>are lineage-specific, multi-copy Y-gene families specific to <it>Bovidae</it>, and are derived from the transposition of an autosomal gene block. The temporal and spatial expression patterns of <it>ZNF280BY</it>s in testis suggest a role in spermatogenesis. This study offers insights into the genomic organization of the bovine MSY and gene regulation in spermatogenesis, and provides a model for studying evolution of multi-copy gene families in mammals.</p

The future of targeting cytotoxic T-lymphocyte-associated protein-4: Is there a role?

The 2022 yearly Think Tank Meeting in Siena, Tuscany (Italy), organized by the Italian Network for Tumor Biotherapy (NIBIT) Foundation, the Parker Institute for Cancer Immunotherapy and the World Immunotherapy Council, included a focus on the future of integrating and expanding the use of targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The conference members exchanged their views on the lessons from targeting CTLA-4 and compared the effect to the impact of blocking Programmed cell death protein 1 (PD1) or its ligand (PDL1). The increasing experience with both therapeutic approaches and their combination suggests that targeting CTLA-4 may lead to more durable responses for a sizeable proportion of patients, though the specific mechanism is not entirely understood. Overcoming toxicity of blocking CTLA-4 is currently being addressed with different doses and dose regimens, especially when combined with PD1/PDL1 blocking antibodies. Novel therapeutics targeting CTLA-4 hold the promise to reduce toxicities and thus allow different combination strategies in the future. On the whole, the consent was that targeting CTLA-4 remains an important strategy to improve the efficacy of cancer immunotherapies

Genomic Responses to Abnormal Gene Dosage: The X Chromosome Improved on a Common Strategy

This new primer, which discusses a study by Zhang et al., provides an overview of the process by which chromosomes achieve dose compensation and the mechanisms underlying this phenomenon in Drosophila S2 cells

A highly polymorphic insertion in the Y-chromosome amelogenin gene can be used for evolutionary biology, population genetics and sexing in Cetacea and Artiodactyla

<p>Abstract</p> <p>Background</p> <p>The early radiation of the <it>Cetartiodactyla </it>is complex, and unambiguous molecular characters are needed to clarify the positions of hippotamuses, camels and pigs relative to the remaining taxa (<it>Cetacea </it>and <it>Ruminantia</it>). There is also a need for informative genealogic markers for Y-chromosome population genetics as well as a sexing method applicable to all species from this group. We therefore studied the sequence variation of a partial sequence of the evolutionary conserved amelogenin gene to assess its potential use in each of these fields.</p> <p>Results and discussion</p> <p>We report a large interstitial insertion in the Y amelogenin locus in most of the <it>Cetartiodactyla </it>lineages (cetaceans and ruminants). This sex-linked size polymorphism is the result of a 460–465 bp inserted element in intron 4 of the amelogenin gene of Ruminants and Cetaceans. Therefore, this polymorphism can easily be used in a sexing assay for these species.</p> <p>When taking into account this shared character in addition to nucleotide sequence, gene genealogy follows sex-chromosome divergence in <it>Cetartiodactyla </it>whereas it is more congruent with zoological history when ignoring these characters. This could be related to a loss of homology between chromosomal copies given the old age of the insertion.</p> <p>The 1 kbp <it>Amel-Y </it>amplified fragment is also characterized by high nucleotide diversity (64 polymorphic sites spanning over 1 kbp in seven haplotypes) which is greater than for other Y-chromosome sequence markers studied so far but less than the mitochondrial control region.</p> <p>Conclusion</p> <p>The gender-dependent polymorphism we have identified is relevant not only for phylogenic inference within the <it>Cetartiodactyla </it>but also for Y-chromosome based population genetics and gender determination in cetaceans and ruminants. One single protocol can therefore be used for studies in population and evolutionary genetics, reproductive biotechnologies, and forensic science.</p

Can Intra-Y Gene Conversion Oppose the Degeneration of the Human Y Chromosome? A Simulation Study

The human Y is a genetically degenerate chromosome, which has lost about 97% of the genes originally present. Most of the remaining human Y genes are in large duplicated segments (ampliconic regions) undergoing intense Y–Y gene conversion. It has been suggested that Y–Y gene conversion may help these genes getting rid of deleterious mutations that would inactivate them otherwise. Here, we tested this idea by simulating the evolution of degenerating Y chromosomes with or without gene conversion using the most up-to-date population genetics parameters for humans. We followed the fate of a variant with Y–Y gene conversion in a population of Y chromosomes where Y–Y gene conversion is originally absent. We found that this variant gets fixed more frequently than the neutral expectation, which supports the idea that gene conversion is beneficial for a degenerating Y chromosome. Interestingly, a very high rate of gene conversion is needed for an effect of gene conversion to be observed. This suggests that high levels of Y-Y gene conversion observed in humans may have been selected to oppose the Y degeneration. We also studied with a similar approach the evolution of ampliconic regions on the Y chromosomes and found that the fixation of many copies at once is unlikely, which suggest these regions probably evolved gradually unless selection for increased dosage favored large-scale duplication events. Exploring the parameter space showed that Y–Y gene conversion may be beneficial in most mammalian species, which is consistent with recent data in chimpanzees and mice

Characterisation of Inactivation Domains and Evolutionary Strata in Human X Chromosome through Markov Segmentation

Markov segmentation is a method of identifying compositionally different subsequences in a given symbolic sequence. We have applied this technique to the DNA sequence of the human X chromosome to analyze its compositional structure. The human X chromosome is known to have acquired DNA through distinct evolutionary events and is believed to be composed of five evolutionary strata. In addition, in female mammals all copies of X chromosome in excess of one are transcriptionally inactivated. The location of a gene is correlated with its ability to undergo inactivation, but correlations between evolutionary strata and inactivation domains are less clear. Our analysis provides an accurate estimate of the location of stratum boundaries and gives a high–resolution map of compositionally different regions on the X chromosome. This leads to the identification of a novel stratum, as well as segments wherein a group of genes either undergo inactivation or escape inactivation in toto. We identify oligomers that appear to be unique to inactivation domains alone