High Level Immunoglobulin Gene Expression and Reduced Intra-tumoral Bacteria Associated With the Transition from Initial to Progressive Diffuse Intrinsic Pontine Glioma.

BACKGROUND/AIM: In the past decade, diffuse intrinsic pontine glioma (DIPG), the most common childhood brainstem glioma, has benefitted from an increase in tissue-based research because of improved biopsy collection techniques. However, the adaptive immune receptor (IR) features represented by tumor material and tumor infiltrating lymphocytes have remained poorly understood. MATERIALS AND METHODS: Herein, we characterized the adaptive immune parameters of DIPG through the recovery of IR recombination reads from RNAseq files representing initial and progressive DIPG samples. RESULTS: An elevated level of immunoglobulin gene expression in the progressive DIPG sample files and a reduced number of bacterial sequencing read recoveries in comparison to RNAseq files representing the initial form of DIPG, was found. Furthermore, the RNAseq files representing both initial and progressive DIPG samples had significant numbers of reads representing Cutibacterium acnes, a bacterium previously linked to prostate cancer development. Results also indicated an opportunity to distinguish overall survival probabilities based on IGL complementarity determining region-3 amino acid sequence physicochemical parameters. CONCLUSION: Genomics analyses allow for a better understanding of adaptive IR features and bacterial infections in the DIPG setting.

How can research on modern and fossil bones help us build more resistant columns?

Bone is an economical material. Indeed, as moving a heavy skeleton is energetically costly, the vertebrate skeleton is adapted to maximise resistance to the stresses imposed with a minimum amount of material, so that bone tissue is deposited where it is needed. Using bone as a source of inspiration should therefore reduce the manufacturing cost (both financial and ecological) and increase the strength (and lifespan) of bioinspired (BI) structures. This study proposes to investigate which adaptive features of the outer shape and inner structure of bone, related to compressive strength, could be used to build BI support structures. To do so, we explain the choice of the bones to be analysed and present the results of the biomechanical analyses (finite element analysis) carried out on virtual models built from the structures of the different bone models and of the mechanical tests carried out on 3D-printed versions of these models. The compressive strength of these direct bone BI columns was compared with each other, and with those of a conventional filled cylindrical column, and of a cylindrical column whose internal structure is BI from the radius of the white rhinoceros. The results of our comparative analyses highlight that the shape of long bones is less effective than a cylinder in resisting compression but underline the relevance in designing BI cylindrical columns with heterogeneous structures inspired by the radius of the white rhinoceros and the tibia of the Asian elephant, and raise the interest in studying the fossil record using the radius of the giant rhinocerotoidParaceratherium.

Rigid PN cages as 3-dimensional building blocks for crystalline or amorphous networked materials.

Three-dimensional covalent connectors are valuable synthons for accessing crystalline or amorphous networks. Currently, fused polycyclic alkanes are employed as connectors in this context. We debut phosphorus-nitrogen (PN) cages as new 3-dimensional (3-D) inorganic connectors that yield crystalline and amorphous networks, including examples with gas porosity. We show that the high tunability of PN cages accelerates network diversification and the presence of a responsive 31P NMR spectroscopic handle provides structural insight. Collectively, this work unlocks a new and convenient 3-D synthon for reticular chemistry.

IGL CDR3 Hydropathy and Antigen Chemical Complementarity Associated with Greater Disease-Free Survival in Lung Adenocarcinoma: Implications for Gender Disparities.

With lung cancer remaining a challenging disease, new approaches to biomarker discovery and therapy development are needed. Recent immunogenomics, adaptive immune receptor approaches have indicated that it is very likely that B cells play an important role in mediating better overall outcomes. As such, we assessed physicochemical features of lung adenocarcinoma resident IGL complementarity determining region-3 (CDR3) amino acid (AA) sequences and determined that hydrophobic CDR3 AA sequences were associated with a better disease-free survival (DFS) probability. Further, using a recently developed chemical complementarity scoring algorithm particularly suitable for the evaluation of large patient datasets, we determined that IGL CDR3 chemical complementarity with certain cancer testis antigens was associated with better DFS. Chemical complementarity scores for IGL CDR3-MAGEC1 represented a gender bias, with an overrepresentation of males among the higher IGL-CDR3-CTA complementarity scores that were in turn associated with better DFS (logrank p < 0.065). Overall, this study pointed towards potential biomarkers for prognoses that, in some cases are likely gender-specific; and towards biomarkers for guiding therapy, e.g., IGL-based opportunities for antigen targeting in the lung cancer setting.

The specific NQO2 inhibitor, S29434, only marginally improves the survival of dopamine neurons in MPTP-intoxicated mice.

Over the years, evidence has accumulated on a possible contributive role of the cytosolic quinone reductase NQO2 in models of dopamine neuron degeneration induced by parkinsonian toxin, but most of the data have been obtained in vitro. For this reason, we asked the question whether NQO2 is involved in the in vivo toxicity of MPTP, a neurotoxin classically used to model Parkinson disease-induced neurodegeneration. First, we show that NQO2 is expressed in mouse substantia nigra dopaminergic cell bodies and in human dopaminergic SH-SY5Y cells as well. A highly specific NQO2 inhibitor, S29434, was able to reduce MPTP-induced cell death in a co-culture system of SH-SY5Y cells with astrocytoma U373 cells but was inactive in SH-SY5Y monocultures. We found that S29434 only marginally prevents substantia nigra tyrosine hydroxylase+ cell loss after MPTP intoxication in vivo. The compound produced a slight increase of dopaminergic cell survival at day 7 and 21 following MPTP treatment, especially with 1.5 and 3 mg/kg dosage regimen. The rescue effect did not reach statistical significance (except for one experiment at day 7) and tended to decrease with the 4.5 mg/kg dose, at the latest time point. Despite the lack of robust protective activity of the inhibitor of NQO2 in the mouse MPTP model, we cannot rule out a possible role of the enzyme in parkinsonian degeneration, particularly because it is substantially expressed in dopaminergic neurons.

Neuroblastoma and Glioblastoma Cases With Amplified Oncogenes Have Reduced Numbers of Tumor-Resident Adaptive Immune Receptor Recombinations.

PURPOSE: In certain cancers, oncogene amplification is correlated with an immunologically cold or noninflamed, tumor immune microenvironment (TIME) and a worse prognosis, for example, in the case of MYCN-amplified neuroblastoma (NBL). However, for other cancer types, the relationship between oncogene amplification and immune response is more complicated or unresolved. One such cancer is glioblastoma multiforme (GBM), in which the epidermal growth factor receptor (EGFR) oncogene is commonly amplified. Unlike MYCN-amplified NBL, EGFR-amplified GBM has not been shown to correlate with a distinct survival probability. METHODS: Given this contrasting state for NBL and GBM, we sought to apply a genomics approach to evaluating the immune response for cases with gene amplification. RESULTS: Our results confirmed and added further specificity to the cold TIME of MYCN-amplified NBL. Moreover, we demonstrated a novel state of immunologically cold EGFR-amplified GBM tumors. CONCLUSION: This approach to using copy number variation and immune receptor recombination read recovery levels to assess gene amplification and TIME, respectively, may be particularly efficient for the rapid evaluation of many other cancer types.

Blood-based T cell receptor anti-viral CDR3s are associated with worse overall survival for neuroblastoma.

With the advent of large collections of adaptive immune receptor recombination reads representing cancer, there is the opportunity to further investigate the adaptive immune response to viruses in the cancer setting. This is a particularly important goal due to longstanding but still not well-resolved questions about viral etiologies in cancer and viral infections as comorbidities. In this report, we assessed the T cell receptor complementarity determining region-3 (CDR3) amino acid (AA) sequences, for blood-sourced TCRs from neuroblastoma (NBL) cases, for exact AA sequence matches to previously identified anti-viral TCR CDR3 AA sequences. Results indicated the presence of anti-viral TCR CDR3 AA sequences in the NBL blood samples highly significantly correlated with worse overall survival. Furthermore, the TCR CDR3 AA sequences demonstrating chemical complementarity to many cytomegalovirus antigens represented cases with a worse outcome, including cases where such CDR3s were obtained from tumor samples. Overall, these results indicate a significant need for, and provide a novel strategy for assessing viral infection complications in NBL patients.

Measuring the Effectiveness of Food Policy Councils in Major Cities in the United States.

The United States food system is comprised of a diversity of stakeholders representing a range of sectors including agriculture, health, hospitality, and other sectors of the economy. Coordinating these wide-ranging aspects of the food system is a challenging responsibility of the United States Department of Agriculture (USDA) and its counterparts at the state and county level. While the USDA acknowledges the institutional importance of diversity, it has only recently begun to meaningfully consider the agricultural needs of urban environments, the unique experiences from communities of color, and opportunities for urban agriculture in its purview. This study provides a framework for food systems leaders, specifically in food policy councils (FPCs) in large urban communities, to assess the visibility and effectiveness of their diversity and inclusion initiatives represented across three key domains: (1) leadership and governance structures, (2) key stakeholder engagement strategies, and (3) advance food justice. A cluster analysis of the study results for FPCs in 19 U.S. cities and metropolitan areas across these three domains revealed four distinct groups of food policy councils. Results from the assessment of the urban FPCs reveal that they succeed in embedding diversity and inclusion in all three diversity measures, with key stakeholder engagement receiving the highest score at 73%. On average, FPCs received a score of 54% when assessing diversity and inclusion in their leadership and governance and a score of 49% in their activities to advance food justice. Results of the analysis also highlights opportunities to improve individual, thematic, and cumulative scores. Participation from food systems leadership groups such as food policy councils will be vital in advocating for equitable food systems through urban producer and consumer programs in the upcoming reauthorization of the U.S. farm bill in 2024.

The presence of intratumoral Porphyromonas gingivalis correlates with a previously defined pancreatic adenocarcinoma, immune cell expression phenotype and with tumor resident, adaptive immune receptor features.

The association between pancreatic adenocarcinoma (PAAD) and the pancreatic microbiome is not fully understood, although bacteria may decrease the effectiveness of chemotherapy and lead to anti-apoptotic, pro-inflammatory microenvironments. To better understand the relationship between the PAAD microbiome and the microenvironment, we identified Porphyromonas gingivalis-positive PAAD samples and found a strong association between intratumoral P. gingivalis and: (i) an immune cell gene expression phenotype previously defined by others as gene program 7; and (ii) recovery of immunoglobulin recombination, sequencing reads. We applied a novel chemical complementarity scoring algorithm, suitable for a big data setting, and determined that the previously established P. gingivalis antigen, rpgB had a reduced chemical complementarity with T-cell receptor (TCR) complementarity-determining region-3 amino acid sequences recovered from PAAD samples with P. gingivalis in comparison to TCR-rpgB chemical complementarity represented by the PAAD samples that lacked P. gingivalis. This finding strengthens the existing body of evidence correlating P. gingivalis with PAAD, which may have implications for the treatment and prognosis of patients. Furthermore, demonstrating the correlation of P. gingivalis and gene program 7 raises the question of whether P. gingivalis infection is responsible for the gene program 7 subdivision of PAAD?

A Bioinformatics Assessment Indicating Better Outcomes With Breast Cancer Resident, Immunoglobulin CDR3-MMP2 Binding.

BACKGROUND/AIM: The recombination of V, D, and J immunoglobulin (IG) gene segments leads to many variations in the amino acids (AAs) encoded at that site, the complementarity determining region-3 (CDR3). Thus, cancer patients may have varying degrees of CDR3 AA binding specificity for cancer proteases, for example, matrix metalloproteinase 2 (MMP2). MMP2 in breast cancer has been found to contribute to metastasis and is used as a marker for tumor staging. Thus, this report evaluated the tumor resident, patient specific IG CDR3 binding affinities to cancer proteases to test the hypothesis that greater binding affinities would be associated with a better outcome. MATERIALS AND METHODS: Using two independent bioinformatics tools, we evaluated the IG CDR3-MMP2 binding affinities throughout the cancer genome atlas breast cancer (TCGA-BRCA) dataset. RESULTS: Results indicated that the better the CDR3-MMP2 binding, the better the survival probability. An analogous evaluation for four other proteases, including calpain-1 and thermolysin, displayed no such associations with survival probabilities. CONCLUSION: This study is consistent with the possibility that patient IG-cancer protease interactions could impact outcomes and raises the question of whether therapeutic antibody targeting of MMP2 would reduce breast cancer mediated tissue destruction and breast cancer mortality rates.

Genes critical for development and differentiation of dopaminergic neurons are downregulated in Parkinson's disease.

We performed transcriptome analysis using RNA sequencing on substantia nigra pars compacta (SNpc) from mice after acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment and from Parkinson's disease (PD) patients. Acute and chronic exposure to MPTP resulted in decreased expression of genes involved in sodium channel regulation. However, upregulation of pro-inflammatory pathways was seen after single dose but not after chronic MPTP treatment. Dopamine biosynthesis and synaptic vesicle recycling pathways were downregulated in PD patients and after chronic MPTP treatment in mice. Genes essential for midbrain development and determination of dopaminergic phenotype such as, LMX1B, FOXA1, RSPO2, KLHL1, EBF3, PITX3, RGS4, ALDH1A1, RET, FOXA2, EN1, DLK1, GFRA1, LMX1A, NR4A2, GAP43, SNCA, PBX1, and GRB10 were downregulated in human PD and overexpression of GFP tagged LMX1B rescued MPP+ induced death in SH-SY5Y neurons. Downregulation of gene ensemble involved in development and differentiation of dopaminergic neurons indicate their potential involvement in pathogenesis and progression of human PD.

Delineation of a T-cell receptor CDR3-cancer mutanome aromaticity factor, assessable via blood samples, that facilitates the establishment of survival distinctions in bladder cancer.

PURPOSE: A very large and still expanding collection of adaptive immune receptor (IR) recombination reads, representing many diseases, is becoming available for downstream analyses. Among the most productive approaches has been to establish risk stratification parameters via the chemical features of the IR complementarity determining region-3 (CDR3) amino acid (AA) sequences, particularly for large datasets where clinical information is available. Because the IR CDR3 AA sequences often play a large role in antigen binding, the chemistry of these AAs has the likelihood of representing a disease-related fingerprint as well as providing pre-screening information for candidate antigens. To approach this issue in a novel manner, we developed a bladder cancer, case evaluation approach based on CDR3 aromaticity. METHODS: We developed and applied a simple and efficient algorithm for assessing aromatic, chemical complementarity between T-cell receptor (TCR) CDR3 AA sequences and the cancer specimen mutanome. RESULTS: Results indicated a survival distinction for aromatic CDR3-aromatic mutanome complementary, versus non-complementary, bladder cancer case sets. This result applied to both tumor resident and blood TCR CDR3 AA sequences and was supported by CDR3 AA sequences represented by both exome and RNAseq files. CONCLUSION: The described aromaticity factor algorithm has the potential of assisting in prognostic assessments and guiding immunotherapies for bladder cancer.

Immune receptor CDR3 chemical features that preserve sequence information are highly efficient in reflecting survival distinctions: A pan-cancer analysis.

Adaptive immune receptor (IR) chemical features have been used as signatures of an immune response for numerous medical conditions, raising the question of whether certain approaches to assessing the IR chemical features are more robust than others? In the cancer setting, a very large dataset of IR complementarity determining region-3 (CDR3) amino acid (AA) sequences has become available via the mining of cancer specimen and blood genomics files for IR recombination reads. The IR CDR3 AA sequences have been evaluated for chemical features, and survival rates have been correlated with distinct chemical features. Two common approaches have been i) to assign a single value to the CDR3, representing a chemical attribute, such as aromaticity; or ii) to reduce the actual CDR3 AA sequence to a chemical sequence motif, which merges similar CDR3 chemistries represented by distinct AA sequences but preserves potential functional aspects of the order of the AAs in the sequence. While a controlled comparison of the two approaches is not possible, the application of the two approaches to the same clinical datasets offers the opportunity to appreciate a trend with regard to the overall potential in distinguishing survival probabilities. We demonstrate that application of the chemical sequence motif approach is more likely to identify survival distinctions within cancer datasets, for both tumor specimen and blood sourced, adaptive IR CDR3 AA sequences.

Tumor Resident, B-Cell Receptor Chemical Characteristics Associated with Better Overall Survival for Neuroblastoma.

Pediatric neuroblastoma (NBL) is one of the most common pediatric cancers, and it can often be aggressive. Genetic and demographic factors can correlate with the severity of NBL, but the variations in the B-cell receptors (BCRs) or immunoglobulin proteins present in the NBL tumors, and their relationships to survival, are not well understood. BCRs contain variations in their complementary determining region-3 (CDR3s) amino acid sequences, due to variable recombinations of the V- and J-gene segments. Accordingly, these variations in CDR3s may represent different antigen interactions and thereby different survival probabilities. Thus, we mined the TARGET project, NBL tumor RNAseq files for BCR recombination reads. Evaluations of the physicochemical properties of IGK, IGL, and IGH CDR3s from these tumors pointed to properties of IGK and IGL in particular as associated with survival distinctions, based on several independent bioinformatics approaches, including a novel homology grouping approach facilitated by a recently developed web tool, adaptivematch.com. In conclusion, tumor resident BCR chemical features are likely useful for better risk stratification and for guiding therapy, and the availability of a user-friendly web tool will likely facilitate using BCR chemical features to meet those goals.

Expression of Staphylococcus aureus Virulence Factors in Atopic Dermatitis.

Atopic dermatitis (AD) is a skin inflammatory disease in which the opportunistic pathogen Staphylococcus aureus is prevalent and abundant. S. aureus harbors several secreted virulence factors that have well-studied functions in infection models, but it is unclear whether these extracellular microbial factors are relevant in the context of AD. To address this question, we designed a culture-independent method to detect and quantify S. aureus virulence factors expressed at the skin sites. We utilized RNase-H‒dependent multiplex PCR for preamplification of reverse-transcribed RNA extracted from tape strips of patients with AD sampled at skin sites with differing severity and assessed the expression of a panel of S. aureus virulence factors using qPCR. We observed an increase in viable S. aureus abundance on sites with increased severity of disease, and many virulence factors were expressed at the AD skin sites. Surprisingly, we did not observe any significant upregulation of the virulence factors at the lesional sites compared with those at the nonlesional control. Overall, we utilized a robust assay to directly detect and quantify viable S. aureus and its associated virulence factors at the site of AD skin lesions. This method can be extended to study the expression of skin microbial genes at the sites of various dermatological conditions.

Immunogenomics Parameters for Patient Stratification in Alzheimer's Disease.

BACKGROUND: Despite the fact that only modest adaptive immune system related approaches to treating Alzheimer's disease (AD) are available, an immunogenomics approach to the study of AD has not yet substantially advanced. OBJECTIVE: Thus, we sought to better understand adaptive immune receptor chemical features in the AD setting. METHODS: We characterized T-cell receptor alpha (TRA) complementarity determining region-3 (CDR3) physicochemical features and identified TRA CDR3 homology groups, represented by TRA recombination reads extracted from 2,665 AD-related, blood- and brain-derived exome files. RESULTS: We found that a higher isoelectric value for the brain TRA CDR3s was associated with a higher (clinically worse) Braak stage and that a number of TRA CDR3 chemical homology groups, in particular representing bloodborne TRA CDR3s, were associated with higher or lower Braak stages. Lastly, greater chemical complementarity of both blood- and brain-derived TRA CDR3s and tau, based on a recently described CDR3-candidate antigen chemical complementarity scoring process (https://adaptivematch.com), was associated with higher Braak stages. CONCLUSION: Overall, the data reported here raise the questions of (a) whether progression of AD is facilitated by the adaptive immune response to tau; and (b) whether assessment of such an anti-tau immune response could potentially serve as a basis for adaptive immune receptor related, AD risk stratification?