Notes

A new perception-based nanosensor program to identify most cancers biomarkers.
The value of vitamin D supplementation in the treatment or prevention of various conditions is often viewed with scepticism as a result of contradictory results of randomised trials. It is now becoming apparent that there is a pattern to these inconsistencies. A recent large trial has shown that high-dose intermittent bolus vitamin D therapy is ineffective at preventing rickets - the condition that is most unequivocally caused by vitamin D deficiency. There is a plausible biological explanation since high-dose bolus replacement induces long-term expression of the catabolic enzyme 24-hydroxylase and fibroblast growth factor 23, both of which have vitamin D inactivating effects. Meta-analyses of vitamin D supplementation in prevention of acute respiratory infection and trials in tuberculosis and other conditions also support efficacy of low dose daily maintenance rather than intermittent bolus dosing. This is particularly relevant during the current COVID-19 pandemic given the well-documented associations between COVID-19 risk and vitamin D deficiency. Selleck Escin We would urge that clinicians take note of these findings and give strong support to widespread use of daily vitamin D supplementation.
The activation of tumor-associated macrophages (TAMs) facilitates the progression of gastric cancer (GC). link2 Cell metabolism reprogramming has been shown to play a vital role in the polarization of TAMs. However, the role of methionine metabolism in function of TAMs remains to be explored.

Monocytes/macrophages were isolated from peripheral blood, tumor tissues or normal tissues from healthy donors or patients with GC. The role of methionine metabolism in the activation of TAMs was evaluated with both in vivo analyses and in vitro experiments. Pharmacological inhibition of the methionine cycle and modulation of key metabolic genes was employed, where molecular and biological analyses were performed.

TAMs have increased methionine cycle activity that are mainly attributed to elevated methionine adenosyltransferase II alpha (MAT2A) levels. MAT2A modulates the activation and maintenance of the phenotype of TAMs and mediates the upregulation of RIP1 by increasing the histone H3K4 methylation (H3K4me3) at its promoter regions.

Our data cast light on a novel mechanism by which methionine metabolism regulates the anti-inflammatory functions of monocytes in GC. MAT2A might be a potential therapeutic target for cancer cells as well as TAMs in GC.
Our data cast light on a novel mechanism by which methionine metabolism regulates the anti-inflammatory functions of monocytes in GC. MAT2A might be a potential therapeutic target for cancer cells as well as TAMs in GC.
The predictive power of novel biological markers for treatment response to immune checkpoint inhibitors (ICI) is still not satisfactory for the majority of patients with cancer. One should identify valid predictive markers in the peripheral blood, as this is easily available before and during treatment. The current interim analysis of patients of the ST-ICI cohort therefore focuses on the development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with metastatic cancer to ICI targeting the programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis.

A total of 104 patients were prospectively enrolled. 54 immune cell subsets were prospectively analyzed in patients' peripheral blood by multicolor flow cytometry before treatment with ICI (pre-ICI; n=89), and after the first application of ICI (n=65). Pre-ICI, patients were randomly allocated to a training (n=56) and a validation cohort (n=33). Univariate Cox proportional hazards regress exception of brain metastases. NKT cells and neutrophils of the LIPS can be used as dynamic predictive biomarkers for OS and PFS after first administration of the ICI.

Our study identified a predictive LIPS for survival of patients with cancer treated with PD-1/PD-L1 ICI, which is based on immune cell subsets in the peripheral whole blood.

NCT03453892.
NCT03453892.
In ambulatory patients with cancer with asymptomatic or pauci-symptomatic SARS-CoV-2 infection, the safety of targeted therapies (TTs), chemotherapy (CT) or immune checkpoint inhibitors (ICIs) therapy is still unknown.

From the start of the first epidemic wave of SARS-CoV-2 in Bergamo, Italy, we have prospectively screened all consecutive outpatients who presented for treatment to the Oncology Division of the Papa Giovanni XXIII Hospital, Bergamo for SARS-CoV-2 antigen expression. We identified patients treated with ICIs and compared these to patients with the same cancer subtypes treated with TTs or CT.

Between March 5 and May 18, 293 consecutive patients (49% melanoma, 34% non-small cell lung cancer, 9% renal cell carcinoma, 8% other) were included in this study 159 (54%), 50 (17%) and 84 (29%) received ICIs, CT or TTs, respectively. Overall 89 patients (30.0%) were SARS-CoV-2 positive. Mortality of SARS-CoV-2-positive patients was statistically significantly higher compared with SARS-CoV-2 negative ppositive patients treated with ICIs and CT, mostly in advanced disease. No SAEs were observed in patients treated with TTs. SAEs were COVID-19 related rather than treatment related. Treatment with ICIs does not appear to significantly increase risk of SAEs compared with CT. This information should be considered when determining treatment options for patients.
Despite the numerous applications of monoclonal antibodies (mAbs) in cancer therapeutics, animal models available to test the therapeutic efficacy of new mAbs are limited. NOD.Cg-
Il2rg
/SzJ (NSG) mice are one of the most highly immunodeficient strains and are universally used as a model for testing cancer-targeting mAbs. However, this strain lacks several factors necessary to fully support antibody-mediated effector functions-including antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity (CDC)-due to the absence of immune cells as well as a mutation in the
gene, which is needed for a functional complement system.

We have developed a humanized mouse model using a novel NSG strain, NOD.Cg

Il2rgtm1Wjl/SzJ (NSG
), which contains the corrected mutation in the
gene to support CDC in addition to other mechanisms endowed by humanization. With this model, we reevaluated the anticancer efficacies of nanoencapsulated rituximab after xenograft of the human Burkitt lymphoma cell line 2F7-BR44.

As expected, xenografted humanized NSG
mice supported superior lymphoma clearance of native rituximab compared with the parental NSG strain. Nanoencapsulated rituximab with CXCL13 conjugation as a targeting ligand for lymphomas further enhanced antilymphoma activity in NSG
mice and, more importantly, mediated antilymphoma cellular responses.

These results indicate that NSG
mice can serve as a feasible model for both studying antitumor treatment using cancer targeting as well as understanding induction mechanisms of antitumor cellular immune response.
These results indicate that NSG-Hc1 mice can serve as a feasible model for both studying antitumor treatment using cancer targeting as well as understanding induction mechanisms of antitumor cellular immune response.Programmed cell death 1 (PD-1)-based immunotherapy has revolutionized the treatment of various cancers. However, only a certain group of patients benefit from PD-1 blockade therapy and many patients succumb to hyperprogressive disease. Although, CD8 T cells and conventional T cells are generally considered to be the primary source of PD-1 in cancer, accumulating evidence suggests that other distinct cell types, including B cells, regulatory T cells, natural killer cells, dendritic cells, tumor-associated macrophages and cancer cells, also express PD-1. Hence, the response of patients with cancer to PD-1 blockade therapy is a cumulative effect of anti-PD-1 antibodies acting on a myriad of cell types. Although, the contribution of CD8 T cells to PD-1 blockade therapy has been well-established, recent studies also suggest the involvement of non-canonical PD-1 signaling in blockade therapy. This review discusses the role of non-canonical PD-1 signaling in distinct cell types and explores how the available knowledge can improve PD-1 blockade immunotherapy, particularly in identifying novel biomarkers and combination treatment strategies.
Galactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy, the most common primary GN worldwide. Although serum levels of galactose-deficient IgA1 have a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly established.

To identify novel loci associated with galactose-deficient IgA1, we performed a quantitative genome-wide association study for serum galactose-deficient IgA1 levels, on the basis of two different genome-wide association study panels conducted in 1127 patients with IgA nephropathy. To test genetic associations with susceptibility to IgA nephropathy, we also enrolled 2352 patients with biopsy-diagnosed IgA nephropathy and 2632 healthy controls. Peripheral blood samples from 59 patients and 27 healthy controls were also collected for gene expression analysis.

We discovered two loci, in
and
that achieved genome-wide significance, explaining about 3.7% and 3.4% of variance in serum galactose-deficient IgA1 le-deficient IgA1 in the development of IgA nephropathy.
Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease.

Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome.
and
studies determined the functional significance of the mutations identified.

Three biallelic variants of the transcriptional regulator
were detected in six families with proteinuric kidney disease. Four families with a variant in the protein's zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. link3 All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in
embryos disrupted pronephric development. Human wild-type
RNA rescued the disruption, but the three
variants did not. Finally, CRISPR-mediated knockout of
in human podocytes led to dysregulation of several renal developmental genes.

Variants in
can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.
Variants in PRDM15 can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.
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