Fluid Distribution Patterns in Early-Stage Upper Extremity Lymphedema.

INTRODUCTION: Magnetic resonance imaging (MRI) stage 1 (early stage) upper extremity lymphedema is characterized by fluid infiltration in the subcutaneous tissues that does not exceed 50% of the extremity circumference at any level. The spatial fluid distribution in these cases has not been detailed and may be important to help determine the presence and location of compensatory lymphatic channels. The aim of this study is to determine whether there was a pattern of distribution of fluid infiltration in patients with early-stage lymphedema that could correspond to known lymphatic pathways in the upper extremity. METHODS: A retrospective review identified all patients with MRI stage 1 upper extremity lymphedema who were evaluated at a single lymphatic center. Using a standardized scoring system, a radiologist graded the severity of fluid infiltration at 18 anatomical locations. A cumulative spatial histogram was then created to map out regions where fluid accumulation occurred most and least frequently. RESULTS: Eleven patients with MRI stage 1 upper extremity lymphedema were identified between January 2017 and January 2022. The mean age was 58 years and the mean BMI was 30 m/kg2. One patient had primary lymphedema and the remaining 10 had secondary lymphedema. The forearm was affected in nine cases, and fluid infiltration was predominantly concentrated along the ulnar aspect, followed by the volar aspect, while the radial aspect was completely spared. Within the upper arm, fluid was primarily concentrated distally and posteriorly, and occasionally medially. CONCLUSIONS: In patients with early-stage lymphedema, fluid infiltration is concentrated along the ulnar forearm and the posterior distal upper arm, which aligns with the tricipital lymphatic pathway. There is also sparing of fluid accumulation along the radial forearm in these patients, suggesting a more robust lymphatic drainage along this region, possibly due to a connection to the lateral upper arm pathway.

Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9.

Toll-like receptors (TLRs) activate the innate immune system in response to pathogens. Here we show that TLR9 proteolytic cleavage is a prerequisite for TLR9 signaling. Inhibition of lysosomal proteolysis rendered TLR9 inactive. The carboxy-terminal fragment of TLR9 thus generated included a portion of the TLR9 ectodomain, as well as the transmembrane and cytoplasmic domains. This cleavage fragment bound to the TLR9 ligand CpG DNA and, when expressed in Tlr9(-/-) dendritic cells, restored CpG DNA-induced cytokine production. Although cathepsin L generated the requisite TLR9 cleavage products in a cell-free in vitro system, several proteases influenced TLR9 cleavage in intact cells. Lysosomal proteolysis thus contributes to innate immunity by facilitating specific cleavage of TLR9.

Nuclear science and technology in the Malaysian context: Three phases of technoscientific knowledge transfer (ETTLG).

This essay considers the development of the nuclear science programme in Malaysia from a transnational perspective by examining the interactions between state agents and other external nuclear-knowledge/technology related actors and agents. Going beyond the model of knowledge diffusion that brings together concerns articulated in Harris's (2011) geographies of long distance knowledge and Reinhardt's (2011) role of the expert in knowledge transfer, the proposed three-phase model of knowledge transfer theorises the pathways undertaken by a late-blooming participant of modern science and technology as the latter moves from epistemic dependency to increasing independence despite the hurdles encountered, and the underdevelopment of many areas of its technoscientific economy. The model considers tensions stemming from the pressures of expediency for meeting national developmental goals on the one side, and the call to support the objectives of basic science on the other. The three phases of the model are epistemic transition, epistemic transplantation and localisation, and epistemic generation (ETTLG). As additional support for the proposed model, three arguments are proffered as deeper explanations of the epistemic goal by using Malaysia as a case study: knowledge transfer for political legitimization, knowledge transfer for countering agnotology, and knowledge transfer for social engineering and science diplomacy.

The protein synthesis inhibitor blasticidin s enters mammalian cells via leucine-rich repeat-containing protein 8D.

Leucine-rich repeat-containing 8 (LRRC8) proteins have been identified as putative receptors involved in lymphocyte development and adipocyte differentiation. They remain poorly characterized, and no specific function has been assigned to them. There is no consensus on how this family of proteins might function because homology searches suggest that members of the LRRC8 family act not as plasma membrane receptors, but rather as channels that mediate cell-cell signaling. Here we provide experimental evidence that supports a role for LRRC8s in the transport of small molecules. We show that LRRC8D is a mammalian protein required for the import of the antibiotic blasticidin S. We characterize localization and topology of LRRC8A and LRRC8D and demonstrate that LRRC8D interacts with LRRC8A, LRRC8B, and LRRC8C. Given the suggested involvement in solute transport, our results support a model in which LRRC8s form one or more complexes that may mediate cell-cell communication by transporting small solutes.

required to maintain repression2 is a novel protein that facilitates locus-specific paramutation in maize.

Meiotically heritable epigenetic changes in gene regulation known as paramutations are facilitated by poorly understood trans-homolog interactions. Mutations affecting paramutations in maize (Zea mays) identify components required for the accumulation of 24-nucleotide RNAs. Some of these components have Arabidopsis thaliana orthologs that are part of an RNA-directed DNA methylation (RdDM) pathway. It remains unclear if small RNAs actually mediate paramutations and whether the maize-specific molecules identified to date define a mechanism distinct from RdDM. Here, we identify a novel protein required for paramutation at the maize purple plant1 locus. This required to maintain repression2 (RMR2) protein represents the founding member of a plant-specific clade of predicted proteins. We show that RMR2 is required for transcriptional repression at the Pl1-Rhoades haplotype, for accumulation of 24-nucleotide RNA species, and for maintenance of a 5-methylcytosine pattern distinct from that maintained by RNA polymerase IV. Genetic tests indicate that RMR2 is not required for paramutation occurring at the red1 locus. These results distinguish the paramutation-type mechanisms operating at specific haplotypes. The RMR2 clade of proteins provides a new entry point for understanding the diversity of epigenomic control operating in higher plants.

23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function.

Immune checkpoint inhibition (ICI) has revolutionized cancer treatment; however, only a subset of patients benefit long term. Therefore, methods for identification of novel checkpoint targets and development of therapeutic interventions against them remain a critical challenge. Analysis of human genetics has the potential to inform more successful drug target discovery. We used genome-wide association studies of the 23andMe genetic and health survey database to identify an immuno-oncology signature in which genetic variants are associated with opposing effects on risk for cancer and immune diseases. This signature identified multiple pathway genes mapping to the immune checkpoint comprising CD200, its receptor CD200R1, and the downstream adapter protein DOK2. We confirmed that CD200R1 is elevated on tumor-infiltrating immune cells isolated from cancer patients compared to the matching peripheral blood mononuclear cells. We developed a humanized, effectorless IgG1 antibody (23ME-00610) that bound human CD200R1 with high affinity (KD <0.1 nM), blocked CD200 binding, and inhibited recruitment of DOK2. 23ME-00610 induced T-cell cytokine production and enhanced T cell-mediated tumor cell killing in vitro. Blockade of the CD200:CD200R1 immune checkpoint inhibited tumor growth and engaged immune activation pathways in an S91 tumor cell model of melanoma in mice.

Discovery of a Series of Potent, Selective, and Orally Bioavailable Nucleoside Inhibitors of CD73 That Demonstrates In Vivo Antitumor Activity.

CD73 (ecto-5'-nucleotidase) has emerged as an attractive target for cancer immunotherapy of many cancers. CD73 catalyzes the hydrolysis of adenosine monophosphate (AMP) into highly immunosuppressive adenosine that plays a critical role in tumor progression. Herein, we report our efforts in developing orally bioavailable and highly potent small-molecule CD73 inhibitors from the reported hit molecule 2 to lead molecule 20 and then finally to compound 49. Compound 49 was able to reverse AMP-mediated suppression of CD8+ T cells and completely inhibited CD73 activity in serum samples from various cancer patients. In preclinical in vivo studies, orally administered 49 showed a robust dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship that correlated with efficacy. Compound 49 also demonstrated the expected immune-mediated antitumor mechanism of action and was efficacious upon oral administration not only as a single agent but also in combination with either chemotherapeutics or checkpoint inhibitor in the mouse tumor model.

Medicinal cannabis law in the USA: history, movements, trends, and countertrends / Legislação sobre cannabis medicinal nos Estados Unidos: histórico, movimentos, tendências e contra-tendências

ABSTRACT BACKGROUND AND OBJECTIVES: In recent decades, the United States (USA), after banning the use, possession, and commerce of the CS plant for medicinal and social purposes for nearly a century, has embarked on law reform processes and movements at the state level to legalize the plant, forging regulated markets to support these changes. The present study's objective was to describe the history of prohibition and eventual legalization, observing the social, political, and economic components that contributed to this paradigm shift. CONTENTS: Qualitative research, using observation, literature review, and analysis of practical experience in advocacy processes, law reform, and building regulated markets to replace prohibition. The historical, social, and economic processes that made up the end of the prohibition of CS and its later regulation as a substance for medicinal and social use were described. CONCLUSION: CS during the last century has been labeled as a drug with no medicinal potential for purely political and non-scientific reasons. A number of civil society movements in the US led to the legalization of CS due to its therapeutic properties. These movements have succeeded in redefining the plant as a medicine rather than a drug, while also taking into account the high social and economic costs of criminalizing it.

RESUMO JUSTIFICATIVA E OBJETIVOS: Nas últimas décadas, os Estados Unidos (EUA), depois de proibir o uso, a posse e a comercialização da planta Cannabis sativa para fins medicinais e sociais por quase um século, embarcou em processos e movimentos de reforma de lei em nível estadual para legalizar a planta, forjando mercados regulamentados para amparar essas mudanças. O objetivo deste estudo foi descrever o histórico da proibição e da eventual legalização, observando os componentes sociais, políticos e econômicos que contribuíram para essa mudança de paradigma. CONTEÚDO: Utilizou-se de revisão de literatura, amparada por análise de experiência prática em processos de "advocacy" e construção de mercados regulamentados em substituição a proibição. Foram descritos os processos históricos, sociais e econômicos que compuseram o fim da proibição da Cannabis sativa e sua eventual regulamentação como substância para uso medicinal e social nos EUA. CONCLUSÃO: Durante o último século, a Cannabis sativa foi rotulada como droga sem potencial medicinal por motivos puramente políticos e não científicos. Uma série de movimentos da sociedade civil nos EUA levou à legalização da Cannabis sativa devido a suas propriedades terapêuticas. Esses movimentos tiveram êxito ao redefinirem a planta como um remédio ao invés de uma droga, levando em conta também o alto custo social e econômico de sua criminalização.

Gene expression profiles of normal human fibroblasts after exposure to ionizing radiation: a comparative study of low and high doses.

Several types of cellular responses to ionizing radiation, such as the adaptive response or the bystander effect, suggest that low-dose radiation may possess characteristics that distinguish it from its high-dose counterpart. Accumulated evidence also implies that the biological effects of low-dose and high-dose ionizing radiation are not linearly distributed. We have investigated, for the first time, global gene expression changes induced by ionizing radiation at doses as low as 2 cGy and have compared this to expression changes at 4 Gy. We applied cDNA microarray analyses to G1-arrested normal human skin fibroblasts subjected to X irradiation. Our data suggest that both qualitative and quantitative differences exist between gene expression profiles induced by 2 cGy and 4 Gy. The predominant functional groups responding to low-dose radiation are those involved in cell-cell signaling, signal transduction, development and DNA damage responses. At high dose, the responding genes are involved in apoptosis and cell proliferation. Interestingly, several genes, such as cytoskeleton components ANLN and KRT15 and cell-cell signaling genes GRAP2 and GPR51, were found to respond to low-dose radiation but not to high-dose radiation. Pathways that are specifically activated by low-dose radiation were also evident. These quantitative and qualitative differences in gene expression changes may help explain the non-linear correlation of biological effects of ionizing radiation from low dose to high dose.

A reporter screen in a human haploid cell line identifies CYLD as a constitutive inhibitor of NF-κB.

The development of forward genetic screens in human haploid cells has the potential to transform our understanding of the genetic basis of cellular processes unique to man. So far, this approach has been limited mostly to the identification of genes that mediate cell death in response to a lethal agent, likely due to the ease with which this phenotype can be observed. Here, we perform the first reporter screen in the near-haploid KBM7 cell line to identify constitutive inhibitors of NF-κB. CYLD was the only currently known negative regulator of NF-κB to be identified, thus uniquely distinguishing this gene. Also identified were three genes with no previous known connection to NF-κB. Our results demonstrate that reporter screens in haploid human cells can be applied to investigate the many complex signaling pathways that converge upon transcription factors.

Accessory molecules for Toll-like receptors and their function.

Toll-like receptors (TLRs) are essential components of the innate immune system. Accessory proteins are required for the biosynthesis and activation of TLRs. Here, we summarize recent findings on TLR accessory proteins that are required for cell-surface and endosomal TLR function, and we classify these proteins based on their function as ligand-recognition and delivery cofactors, chaperones and trafficking proteins. Because of their essential roles in TLR function, targeting of such accessory proteins may benefit strategies aimed at manipulating TLR activation for therapeutic applications.