Comparison of veterinary drugs and veterinary homeopathy: part 1

For many years after its invention around 1796, homeopathy was widely used in people and later in animals. Over the intervening period (1796-2016) pharmacology emerged as a science from Materia Medica (medicinal materials) to become the mainstay of veterinary therapeutics. There remains today a much smaller, but significant, use of homeopathy by veterinary surgeons. Homeopathic products are sometimes administered when conventional drug therapies have not succeeded, but are also used as alternatives to scientifically based therapies and licensed products. The principles underlying the veterinary use of drug-based and homeopathic products are polar opposites; this provides the basis for comparison between them. This two-part review compares and contrasts the two treatment forms in respect of history, constituents, methods of preparation, known or postulated mechanisms underlying responses, the legal basis for use and scientific credibility in the 21st century. Part 1 begins with a consideration of why therapeutic products actually work or appear to do so

Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology

BackgroundTREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid -peptide (A) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD.MethodsA cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of A(1-42) (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score.ResultsCSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal A pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.ConclusionsA pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, A pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2

Spatio-temporal divergence in the responses of Finland's boreal forests to climate variables

Spring greening in boreal forest ecosystems has been widely linked to increasing temperature, but few studies have attempted to unravel the relative effects of climate variables such as maximum temperature (TMX), minimum temperature (TMN), mean temperature (TMP), precipitation (PRE) and radiation (RAD) on vegetation growth at different stages of growing season. However, clarifying these effects is fundamental to better understand the relationship between vegetation and climate change. This study investigated spatio-temporal divergence in the responses of Finland's boreal forests to climate variables using the plant phenology index (PPI) calculated based on the latest Collection V006 MODIS BRDF-corrected surface reflectance products (MCD43C4) from 2002 to 2018, and identified the dominant climate variables controlling vegetation change during the growing season (May-September) on a monthly basis. Partial least squares (PLS) regression was used to quantify the response of PPI to climate variables and distinguish the separate impacts of different variables. The study results show the dominant effects of temperature on the PPI in May and June, with TMX, TMN and TMP being the most important explanatory variables for the variation of PPI depending on the location, respectively. Meanwhile, drought had an unexpectedly positive impact on vegetation in few areas. More than 50 % of the variation of PPI could be explained by climate variables for 68.5 % of the entire forest area in May and 87.7 % in June, respectively. During July to September, the PPI variance explained by climate and corresponding spatial extent rapidly decreased. Nevertheless, the RAD was found be the most important explanatory variable to July PPI in some areas. In contrast, the PPI in August and September was insensitive to climate in almost all of the regions studied. Our study gives useful insights on quantifying and identifying the relative importance of climate variables to boreal forest, which can be used to predict the possible response of forest under future warming.Peer reviewe

A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer

Funding Information: D.B. has consulted for NanoString, reports honoraria from AstraZeneca and has a patent (PCT/GB2020/050221) issued on methods for cancer prognostication. J.R. and M.A.B. have consulted for Achilles Therapeutics. N.M. has stock options in and has consulted for Achilles Therapeutics. N.M. holds European patents relating to targeting neoantigens (PCT/EP2016/059401), identifying patient response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA loss of heterozygosity (PCT/GB2018/052004) and predicting survival rates of patients with cancer (PCT/GB2020/050221). A.H. attended one advisory board for Abbvie, Roche and GRAIL, and reports personal fees from Abbvie, Boehringer Ingelheim, Takeda, AstraZeneca, Daiichi Sankyo, Merck Serono, Merck/MSD, UCB and Roche for delivering general education/training in clinical trials. A.H. owned shares in Illumina and Thermo Fisher Scientific (sold in 2020) and receives fees for membership of Independent Data Monitoring Committees for Roche-sponsored clinical trials. S.A.Q. is co-founder and Chief Scientific Officer of Achilles Therapeutics. A.C.H. is a board member and equity holder in ImmunoQure, AG and Gamma Delta Therapeutics, and is an equity holder in Adaptate Biotherapeutics and chair of the scientific advisory board. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer Ingelheim, Archer Dx Inc (collaboration in minimal residual disease-sequencing technologies) and Ono Pharmaceuticals, is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial. C.S has consulted for Amgen, AstraZeneca, Bicycle Therapeutics, Bristol Myers Squibb, Celgene, Genentech, GlaxoSmithKline, GRAIL, Illumina, Medixci, Metabomed, MSD, Novartis, Pfizer, Roche-Ventana and Sarah Cannon Research Institute. C.S. has stock options in Apogen Biotechnologies, Epic Biosciences and GRAIL, and has stock options and is co-founder of Achilles Therapeutics. C.S. holds patents relating: to assay technology to detect tumor recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA loss of heterozygosity (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221); to treating cancer by targeting Insertion/deletion (indel) mutations (PCT/GB2018/051893); to identifying indel mutation targets (PCT/GB2018/051892); to methods for lung cancer detection (PCT/US2017/028013); and to identifying responders to cancer treatment (PCT/GB2018/051912). The remaining authors declare no competing interests. Funding Information: We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant no. 203141/Z/16/Z) for the generation and initial processing of the RNA-seq data from sorted TILs. We thank S. Bola for technical support and S. Vanloo for administrative support. The GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Y.W. was supported by a Wellcome Trust Clinical Research Career Development Fellowship (no. 220589/Z/20/Z), an Academy of Medical Sciences Starter Grant for Clinical Lecturers, a National Institute for Health Research (NIHR) Academic Clinical Lectureship and the NIHR University College London Hospitals Biomedical Research Centre. D.B. was supported by funding from the NIHR University College London Hospitals Biomedical Research Centre, the ideas 2 innovation translation scheme at the Francis Crick Institute, the Breast Cancer Research Foundation (BCRF) and a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award. M.J.H. is a CRUK Fellow and has received funding from CRUK, NIHR, Rosetrees Trust, UKI NETs and the NIHR University College London Hospitals Biomedical Research Centre. C.S. is Royal Society Napier Research Professor. This work was supported by the Francis Crick Institute which receives its core funding from CRUK (no. FC001169), the UK Medical Research Council (no. FC001169) and the Wellcome Trust (no. FC001169). This research was funded in whole, or in part, by the Wellcome Trust (no. FC001169). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. C.S. is funded by CRUK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), CRUK Lung Cancer Centre of Excellence (no. C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Professorship Enhancement Award (no. RP/EA/180007), the NIHR Biomedical Research Centre at University College London Hospitals, the CRUK–University College London Centre, Experimental Cancer Medicine Centre and the BCRF. This work was supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant no. SU2C-AACR-DT23-17 to S. M. Dubinett and A. E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. receives funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (no. FP7/2007-2013) Consolidator Grant (no. FP7-THESEUS-617844), European Commission ITN (no. FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the ERC under the European Union’s Horizon 2020 research and innovation program (grant no. 835297), and Chromavision from the European Union’s Horizon 2020 research and innovation program (grant no. 665233). Publisher Copyright: © 2022, The Author(s).Peer reviewedPublisher PD

Myeloid Heme Oxygenase-1 Haploinsufficiency Reduces High Fat Diet-Induced Insulin Resistance by Affecting Adipose Macrophage Infiltration in Mice

Increased adipose tissue macrophages contribute to obesity-induced metabolic syndrome. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with potent anti-inflammatory and proangiogenic activities in macrophages. However, the role of macrophage HO-1 on obesity-induced adipose inflammation and metabolic syndrome remains unclear. Here we show that high-fat diet (HFD) feeding in C57BL/6J mice induced HO-1 expression in the visceral adipose tissue, particularly the stromal vascular fraction. When the irradiated C57BL/6J mice reconstituted with wild-type or HO-1+/− bone marrow were fed with HFD for over 24 weeks, the HO-1+/− chimeras were protected from HFD-induced insulin resistance and this was associated with reduced adipose macrophage infiltration and angiogenesis, suggesting that HO-1 affects myeloid cell migration toward adipose tissue during obesity. In vivo and in vitro migration assays revealed that HO-1+/− macrophages exhibited an impaired migration response. Chemoattractant-induced phosphorylation of p38 and focal adhesion kinase (FAK) declined faster in HO-1+/− macrophages. Further experiments demonstrated that carbon monoxide and bilirubin, the byproducts derived from heme degradation by HO-1, enhanced macrophage migration by increasing phosphorylation of p38 and FAK, respectively. These data disclose a novel role of hematopoietic cell HO-1 in promoting adipose macrophage infiltration and the development of insulin resistance during obesity

Tracking genomic cancer evolution for precision medicine: The Lung TRACERx Study

The importance of intratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx]), a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multiregion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types

Quantifying soil moisture impacts on light use efficiency across biomes.

Terrestrial primary productivity and carbon cycle impacts of droughts are commonly quantified using vapour pressure deficit (VPD) data and remotely sensed greenness, without accounting for soil moisture. However, soil moisture limitation is known to strongly affect plant physiology. Here, we investigate light use efficiency, the ratio of gross primary productivity (GPP) to absorbed light. We derive its fractional reduction due to soil moisture (fLUE), separated from VPD and greenness changes, using artificial neural networks trained on eddy covariance data, multiple soil moisture datasets and remotely sensed greenness. This reveals substantial impacts of soil moisture alone that reduce GPP by up to 40% at sites located in sub-humid, semi-arid or arid regions. For sites in relatively moist climates, we find, paradoxically, a muted fLUE response to drying soil, but reduced fLUE under wet conditions. fLUE identifies substantial drought impacts that are not captured when relying solely on VPD and greenness changes and, when seasonally recurring, are missed by traditional, anomaly-based drought indices. Counter to common assumptions, fLUE reductions are largest in drought-deciduous vegetation, including grasslands. Our results highlight the necessity to account for soil moisture limitation in terrestrial primary productivity data products, especially for drought-related assessments

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches