Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins.

T cell infiltration into tumors is a favorable prognostic feature, but most solid tumors lack productive T cell responses. Mechanisms that coordinate T cell exclusion are incompletely understood. Here we identify hepatocyte activation via interleukin-6/STAT3 and secretion of serum amyloid A (SAA) proteins 1 and 2 as important regulators of T cell surveillance of extrahepatic tumors. Loss of STAT3 in hepatocytes or SAA remodeled the tumor microenvironment with infiltration by CD8+ T cells, while interleukin-6 overexpression in hepatocytes and SAA signaling via Toll-like receptor 2 reduced the number of intratumoral dendritic cells and, in doing so, inhibited T cell tumor infiltration. Genetic ablation of SAA enhanced survival after tumor resection in a T cell-dependent manner. Likewise, in individuals with pancreatic ductal adenocarcinoma, long-term survivors after surgery demonstrated lower serum SAA levels than short-term survivors. Taken together, these data define a fundamental link between liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer.

Discovery of photosynthesis genes through whole-genome sequencing of acetate-requiring mutants of Chlamydomonas reinhardtii.

Large-scale mutant libraries have been indispensable for genetic studies, and the development of next-generation genome sequencing technologies has greatly advanced efforts to analyze mutants. In this work, we sequenced the genomes of 660 Chlamydomonas reinhardtii acetate-requiring mutants, part of a larger photosynthesis mutant collection previously generated by insertional mutagenesis with a linearized plasmid. We identified 554 insertion events from 509 mutants by mapping the plasmid insertion sites through paired-end sequences, in which one end aligned to the plasmid and the other to a chromosomal location. Nearly all (96%) of the events were associated with deletions, duplications, or more complex rearrangements of genomic DNA at the sites of plasmid insertion, and together with deletions that were unassociated with a plasmid insertion, 1470 genes were identified to be affected. Functional annotations of these genes were enriched in those related to photosynthesis, signaling, and tetrapyrrole synthesis as would be expected from a library enriched for photosynthesis mutants. Systematic manual analysis of the disrupted genes for each mutant generated a list of 253 higher-confidence candidate photosynthesis genes, and we experimentally validated two genes that are essential for photoautotrophic growth, CrLPA3 and CrPSBP4. The inventory of candidate genes includes 53 genes from a phylogenomically defined set of conserved genes in green algae and plants. Altogether, 70 candidate genes encode proteins with previously characterized functions in photosynthesis in Chlamydomonas, land plants, and/or cyanobacteria; 14 genes encode proteins previously shown to have functions unrelated to photosynthesis. Among the remaining 169 uncharacterized genes, 38 genes encode proteins without any functional annotation, signifying that our results connect a function related to photosynthesis to these previously unknown proteins. This mutant library, with genome sequences that reveal the molecular extent of the chromosomal lesions and resulting higher-confidence candidate genes, will aid in advancing gene discovery and protein functional analysis in photosynthesis.

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.

Outcomes and predictors of clinical T1 renal mass (cT1) upstaged to pathological T3a (pT3a) after partial nephrectomy: A single-center experience.

OBJECTIVES: Clinical T1 (cT1) renal mass treated surgically has a good prognosis, but there is an upstaging risk that potentially threatens oncological outcomes after partial nephrectomy (PN). We aim to analyze and study the incidence, predictors, perioperative morbidity, and oncological outcomes of pT3a upstaging. METHODOLOGY: A retrospective study of 313 patients who underwent PN for cT1 renal mass at a single center from a single tertiary referral center between 2000 and 2021 was done. Demographic, perioperative, pathological, and outcome variables were reviewed. We compared these parameters between upstaged and non-upstaged groups. Multivariate logistic regression analysis was used to study preoperative variables associated with upstaging. RESULTS: Nineteen patients were upstaged to pT3a. Making an incidence of 6.1%. Upstaged tumors were bigger (5.02 cm vs. 4.08 cm, p = 0.004), had higher clinical stage T1b (84.2 vs. 40.5%, p < 0.001), had more tumors which were central location (21 vs. 3.4%, p < 0.001), had more endophytic and mesophytic tumors (15.8 vs. 5.8% and 52.6 vs. 9.5%, p < 0.001), and had higher R.E.N.A.L Nephrometry score (8.05 vs. 6, p < 0.001). Upstaged tumors had more operative times (227 vs. 203 min, p = 0.01), more postoperative complications (68.4 vs. 13.1%, p < 0.001), more major complications of Clavien Dindo Grade 3 and above (15.8 vs. 4.4%, p < 0.001). Age (OR 1.035, p = 0.034), Radiological tumor dimension (OR 1.578, p = 0.003), Radiological or Clinical stage (T1b) (9.19, p = 0.008), Higher Nephrometry score (Intermediate and High) (OR 6.184, p = 0.004) were preoperative predictors of upstaging. Oncological outcomes were comparable. CONCLUSION: Tumor upstaging was uncommon with more perioperative morbidity. Higher age, larger tumor size, higher tumor stage, and higher nephrometry scores were preoperative predictors of upstaging.

Effect of pharmacist interventions on the management of overweight and obesity: A systematic review.

BACKGROUND: Pharmacists are underused healthcare professionals who are well positioned to provide weight management interventions; however, a systematic review of the literature supporting the role of pharmacists in weight management is lacking. OBJECTIVES: To conduct a systematic review to assess the body of evidence supporting the role of pharmacists in the management of obesity. METHODS: A literature search of OVID MEDLINE, Embase, Web of Science, and CINAHL was conducted from inception through February 23, 2023, to identify studies involving pharmacist interventions for weight management. Included studies were retrospective or prospective studies reporting a change in body weight, body mass index (BMI), or waist circumference as a primary endpoint; and a weight management intervention involving a pharmacist. Studies were excluded if they did not report the desired outcomes, involved pediatric populations, or lacked a pharmacist in the intervention. RESULTS: Twenty-nine studies met the eligibility criteria. A total of 6,423 study participants were enrolled with a mean BMI of 27 to 46 kg/m2. The included studies were conducted across 8 different countries with 15 from the United States. The primary approach was a prepost/quasi-experimental study design, typically conducted in community pharmacies. The pharmacists' role varied widely but mainly involved educational counseling as the pharmacist made medication recommendations in only 5 studies. Multidisciplinary collaboration was infrequent. All but 3 studies reported a significant improvement in the weight loss outcome of interest, although most study durations were less than 6 months. A critical appraisal of the 29 studies found the overall quality of the available studies to be relatively poor. CONCLUSION: Pharmacist interventions for weight management were mostly effective in reducing body weight; however, more robust clinical trials with a comparator group and for longer duration are warranted. The pharmacist's role in managing weight loss medications also requires further study.

Tumor resident, TRA anti-viral CDR3 chemical sequence motifs are associated with a better breast cancer outcome.

While for certain cancers, such as cervical cancer, the link to viral infections is very strong and very clear, other cancers represent a history of links to viral infections that are either co-morbidities or drive the cancer in ways that are not yet fully understood, for example the "hit and run" possibility. To further understand the connection of viral infections and the progress of breast cancer, we identified the chemical features of known anti-viral, T-cell receptor alpha chain (TRA) complementarity determining region-3 (CDR3) amino acid sequences among the CDR3s of breast cancer patient TRA recombinations and assessed the association of those features with patient outcomes. The application of this novel paradigm indicated consistent associations of tumor-derived, anti-CMV CDR3 chemical sequence motifs with better breast cancer patient outcomes but did not indicate an opportunity to establish risk stratifications for other cancer types. Interestingly, breast cancer samples with no detectable TRA recombinations represented a better outcome than samples with the non-anti-CMV CDR3s, further adding to a rapidly developing series of results allowing a distinction between positive and possibly harmful cancer immune responses.

Outcomes of primary Latarjet vs. revision Latarjet after prior surgery for anterior shoulder instability: a systematic review and meta-analysis.

BACKGROUND: Latarjet has become an increasingly popular treatment option for recurrent anterior shoulder instability. With the reported complication rates for primary Latarjet surgery, there are concerns about the complications of Latarjet as a revision surgery. It remains unclear if poor results after previous surgical management can be improved with revision Latarjet as well as with primary Latarjet. The aim of this systematic review and meta-analysis is to compare the outcomes of primary Latarjet and revision Latarjet for the treatment of anterior shoulder instability. METHODS: A systematic search was performed on 3 databases for studies that compared primary Latarjet with revision Latarjet used after failed arthroscopic stabilization or failed free bone block procedures. From the included studies, demographic data, clinical outcome scores, range of motion measurements, and postoperative complications were obtained. RESULTS: A total of 11 studies were included for data analysis. Compared with the primary Latarjet cohort, revision Latarjet cohorts had a higher infection rate (1.2% vs. 2.6%; RR 0.46, P = .039). The primary Latarjet group showed a greater rate of return to sport (89.7% vs. 80.5%; RR 1.12, P = .41) and less subjective feeling of instability (12.6% vs. 20.9%; RR 0.60, P = .085) compared with the revision Latarjet group; however, this was not statistically significant. There were no significant differences in complication rates, reoperation, recurrence, and range of motion between primary Latarjet and revision Latarjet groups. Clinical outcome scores such as visual analog scale and Rowe scores were not significantly different between the cohorts. CONCLUSION: Based on the current evidence, primary Latarjet presents reduced infection rates but similar clinical outcome measures, overall complication, and range of motion measurements than revision Latarjet performed after failed prior operative treatment.

Outcomes of acute vs. delayed reverse shoulder arthroplasty for proximal humerus fractures in the elderly: a systematic review and meta-analysis.

HYPOTHESIS: Reverse shoulder arthroplasty (RSA) has become an increasingly popular treatment option for proximal humerus fractures in the elderly. There is however contradictory evidence on the impact of timing of RSA on patient outcomes. It remains unclear if poor results after initial nonsurgical or surgical management can be improved with delayed RSA. The aim of this systematic review and meta-analysis is to compare the outcomes of acute RSA and delayed RSA for the treatment of proximal humerus fractures in the elderly. MATERIALS AND METHODS: A systematic search was performed on 4 databases for studies that compared acute RSA with RSA used after prior nonoperative or operative treatment. Studies with a mean cohort age of <65 years were excluded. Demographical data, clinical outcome scores, range of motion measurements, and postoperative complications were collected from the included studies. RESULTS: Sixteen studies were included for data analysis. Compared with delayed RSA cohorts, acute RSA cohorts had higher forward flexion (124.3° vs. 114.9°; P = .019), external rotation (24.7° vs. 20.2°; P = .041), and abduction (113.2° vs. 99.8°; P = .03). Compared with RSA after conservative management, acute RSA had greater external rotation (29.9° vs. 21.4°; P = .043). The acute RSA cohort had significantly higher American Shoulder and Elbow Surgeons (76.4 vs. 68.2; P = .025) and Constant-Murley scores (65.6 vs. 57.3; P = .002) compared with the delayed RSA cohort. Subgroup analyses showed significantly greater Constant-Murley (64.9 vs. 56.9; P = .020) and Simple Shoulder Test scores (8.8 vs. 6.8; P = .031) with acute RSA compared with RSA after conservative treatment. The American Shoulder and Elbow Surgeons score was higher in the acute RSA cohort compared with RSA after open reduction internal fixation (77.9 vs. 63.5; P = .008). The overall complication rate per 100 patient-years was 11.7 for the acute RSA cohort and 18.5 for the delayed RSA cohort (risk ratio: 0.55; P = .015). CONCLUSION: Based on the current evidence, acute RSA presents better clinical outcome measures and range of motion measurements, with decreased complication rates than RSA performed after prior nonoperative or operative treatment.

Bone Graft Substitutes and Enhancement in Craniomaxillofacial Surgery.

Critical-sized bone defects are a reconstructive challenge, particularly in the craniomaxillofacial (CMF) skeleton. The "gold standard" of autologous bone grafting has been the work horse of reconstruction in both congenital and acquired defects of CMF skeleton. Autologous bone has the proper balance of the protein (or organic) matrix and mineral components with no immune response. Organic and mineral adjuncts exist that offer varying degrees of osteogenic, osteoconductive, osteoinductive, and osteostimulative properties needed for treatment of critical-sized defects. In this review, we discuss the various mostly organic and mostly mineral bone graft substitutes available for autologous bone grafting. Primarily organic bone graft substitutes/enhancers, including bone morphogenic protein, platelet-rich plasma, and other growth factors, have been utilized to support de novo bone growth in setting of critical-sized bone defects. Primarily mineral options, including various calcium salt formulation (calcium sulfate/phosphate/apatite) and bioactive glasses have been long utilized for their similar composition to bone. Yet, a bone graft substitute that can supplant autologous bone grafting is still elusive. However, case-specific utilization of bone graft substitutes offers a wider array of reconstructive options.

Gemfibrozil Protects Dopaminergic Neurons in a Mouse Model of Parkinson's Disease via PPARα-Dependent Astrocytic GDNF Pathway.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder in humans. Despite intense investigations, effective therapies are not yet available to halt the progression of PD. Gemfibrozil, a Food and Drug Administration-approved lipid-lowering drug, is known to decrease the risk of coronary heart disease by increasing the level of high-density lipoprotein cholesterol and decreasing the level of low-density lipoprotein cholesterol. This study underlines the importance of gemfibrozil in protecting dopaminergic neurons in an animal model of PD. Oral administration of the human equivalent dose of gemfibrozil protected tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra pars compacta and TH fibers in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-insulted mice of both sexes. Accordingly, gemfibrozil also normalized striatal neurotransmitters and improved locomotor activities in MPTP-intoxicated mice. Gemfibrozil-mediated protection of the nigrostriatal and locomotor activities in WT but not PPARα-/- mice from MPTP intoxication suggests that gemfibrozil needs the involvement of peroxisome proliferator-activated receptor α (PPARα) in protecting dopaminergic neurons. While investigating further mechanisms, we found that gemfibrozil stimulated the transcription of glial-derived neurotrophic factor (GDNF) gene in astrocytes via PPARα and that gemfibrozil protected nigral neurons, normalized striatal fibers and neurotransmitters, and improved locomotor activities in MPTP-intoxicated Gfafcre mice, but not GdnfΔastro mice lacking GDNF in astrocytes. These findings highlight the importance of the PPARα-dependent astroglial GDNF pathway in gemfibrozil-mediated protection of dopaminergic neurons in an animal model of PD and suggest the possible therapeutic use of gemfibrozil in PD patients.SIGNIFICANCE STATEMENT Increasing the level of glial cell-derived neurotrophic factor (GDNF) in the brain is important for the protection of dopamine neurons in Parkinson's disease (PD). Although gene manipulation and GDNF protein infusion into the brain are available options, it seems from the therapeutic angle that the best option would be to stimulate/induce the production of GDNF in vivo in the brain of PD patients. Here, we delineate that gemfibrozil, a lipid-lowering drug, stimulates GDNF in astrocytes via peroxisome proliferator-activated receptor α (PPARα). Moreover, gemfibrozil protected nigral neurons, normalized striatal fibers and neurotransmitters, and improved locomotor activities from MPTP toxicity via the PPARα-dependent astroglial GDNF pathway. These studies highlight a new property of gemfibrozil and suggest its possible therapeutic use in PD patients.

Candida auris Pan-Drug-Resistant to Four Classes of Antifungal Agents.

Candida auris is an urgent antimicrobial resistance threat due to its global emergence, high mortality, and persistent transmissions. Nearly half of C. auris clinical and surveillance cases in the United States are from the New York and New Jersey Metropolitan area. We performed genome, and drug-resistance analysis of C. auris isolates from a patient who underwent multi-visceral transplantation. Whole-genome comparisons of 19 isolates, collected over 72 days, revealed closed similarity (Average Nucleotide Identity > 0.9996; Aligned Percentage > 0.9764) and a distinct subcluster of NY C. auris South Asia Clade I. All isolates had azole-linked resistance in ERG11(K143R) and CDR1(V704L). Echinocandin resistance first appeared with FKS1(S639Y) mutation and then a unique FKS1(F635C) mutation. Flucytosine-resistant isolates had mutations in FCY1, FUR1, and ADE17. Two pan-drug-resistant C. auris isolates had uracil phosphoribosyltransferase deletion (FUR1[1Δ33]) and the elimination of FUR1 expression, confirmed by a qPCR test developed in this study. Besides ERG11 mutations, four amphotericin B-resistant isolates showed no distinct nonsynonymous variants suggesting unknown genetic elements driving the resistance. Pan-drug-resistant C. auris isolates were not susceptible to two-drug antifungal combinations tested by checkerboard, Etest, and time-kill methods. The fungal population pattern, discerned from SNP phylogenetic analysis, was consistent with in-hospital or inpatient evolution of C. auris isolates circulating locally and not indicative of a recent introduction from elsewhere. The emergence of pan-drug-resistance to four major classes of antifungals in C. auris is alarming. Patients at high risk for drug-resistant C. auris might require novel therapeutic strategies and targeted pre-and/or posttransplant surveillance.

Transcriptomic analysis of field-droughted sorghum from seedling to maturity reveals biotic and metabolic responses.

Drought is the most important environmental stress limiting crop yields. The C4 cereal sorghum [Sorghum bicolor (L.) Moench] is a critical food, forage, and emerging bioenergy crop that is notably drought-tolerant. We conducted a large-scale field experiment, imposing preflowering and postflowering drought stress on 2 genotypes of sorghum across a tightly resolved time series, from plant emergence to postanthesis, resulting in a dataset of nearly 400 transcriptomes. We observed a fast and global transcriptomic response in leaf and root tissues with clear temporal patterns, including modulation of well-known drought pathways. We also identified genotypic differences in core photosynthesis and reactive oxygen species scavenging pathways, highlighting possible mechanisms of drought tolerance and of the delayed senescence, characteristic of the stay-green phenotype. Finally, we discovered a large-scale depletion in the expression of genes critical to arbuscular mycorrhizal (AM) symbiosis, with a corresponding drop in AM fungal mass in the plants' roots.

Temporal study of physicochemical parameters of leachates and assessment of solid waste and ground water quality of Pirana dumping site, Ahmedabad, India.

The characterisation of solid waste (SW), leachate, is essential for developing an appropriate management strategy or treatment method. However, due to a range of contributing factors, such as waste type and dumping site locations, forecasting leachate quality is often challenging. This research article discusses leachate quality indicators and the temporal variations of leachate quality collected throughout various seasons and after 1-2 years of storage. In addition to that, the article also provides the data of different physicochemical parameters of SW and ground water (GW) quality collected from of Pirana solid waste dumping area (Pirana SWD), Ahmedabad, India, and surrounding areas throughout various seasons. The parameters like pH, COD, TDS, sulphates, nitrates, ammonia nitrogen, hardness, and heavy metals were all monitored to see whether there any temporal variations. When leachates were obtained 'fresh,' all parameters evaluated showed significantly higher values. As time passed, the values of the parameters (COD, ammonia nitrogen) stabilised. Heavy metals such as Hg, As, Pb, and Cr were detected in both fresh and old samples. Similarly in SW, the presence of heavy metals Hg (0.39 ppb), Pb (1.12 ppb), and Cr (16.86 ppb) were also detected. In case of GW, some samples also show the high TDS but the presence of metals like Cr, Ni, and Zn is less than permissible limit.

P065 A One-Time Education for Gastroenterologists Regarding Osteoporosis Screening for IBD Patients Improves Provider Knowledge But Not Screening Rates.

BACKGROUND: Inflammatory Bowel Disease (IBD) is a chronic gastrointestinal inflammatory condition and has been increasing in prevalence in the United States, with a 30-40% increase over the past few decades. Osteoporosis can be seen in up to 40% of IBD patients. Screening for osteoporosis in IBD patients involves the use of DEXA scans and is recommended by the IBD Cornerstone Committee for select patients, including steroid use > 3 months consecutively or a total of 1 year in the past 2 years, family history of osteoporosis, malnutrition, amenorrheic or post-menopausal. Our quality improvement study looked to improve osteoporosis screening among gastroenterologists. METHODS: We conducted a retrospective chart review on all IBD patients within the St. Luke's Network and extrapolated data on age (>50 in male and >65 in female), sex, chronic glucocorticoid use (3 month consecutively or cumulative), osteoporosis/osteopenia diagnosis, vitamin D (vit-D) levels, and DEXA scan between 2019 to 2021. We gave a 5-minute presentation on current DEXA screen recommendations for patients with IBD on 5/27/2021 to all the network's gastroenterologists, which totaled 12. We performed a pre and post education survey consisting of 5 questions on provider knowledge and comfortability with osteoporosis screening. We assessed provider knowledge, as well as rates of osteoporosis screening. All statistical analyses were conducted in IBM SPSS for Windows Version 26. Chi Square tests were used to compare two groups in categorical variables while Mann-Whitney tests were done to compare continuous variables like age and vit-D levels. RESULTS: There were a total of 5442 patients; 3927 patients before the educational intervention on 5/27/2021 and 1515 patients after the intervention. Both pre and post intervention groups were balanced in terms of age, gender, smoking status, and alcohol risk. Percent of DEXA scans were similar between both groups (13.0% vs 12.3%, p=0.5). DEXA screening rates among patients with chronic steroid use pre-intervention vs post-intervention was 44.45 vs 42.4% respectively. Vit-D levels compared between both groups was not statistically significant (30.5 vs 31.8, p=0.1). Surveys conducted before and after the intervention showed an overall increase in percentage of agreement responses about knowledge and confidence in DEXA screening (88.5% vs 97.5%). CONCLUSION: DEXA scanning can help detect premature decrease in bone mineral density and provide physicians with the opportunity to prevent further morbidity. Our study showed no difference in DEXA screening rates before and after intervention. However, there was an increase in provider knowledge based on post-intervention surveys. A similar study showed that it took three interventions, including educational presentation, flyers, and on screen EMR reminders for there to be a sustainable improvement in the rate of DEXA screening. Our project may have required additional interventions to produce an effect and thus reinforces the need for further efforts to improve osteoporosis screening in IBD patients.

SARS-CoV-2 pandemic: a review of molecular diagnostic tools including sample collection and commercial response with associated advantages and limitations.

The unprecedented global pandemic known as SARS-CoV-2 has exercised to its limits nearly all aspects of modern viral diagnostics. In doing so, it has illuminated both the advantages and limitations of current technologies. Tremendous effort has been put forth to expand our capacity to diagnose this deadly virus. In this work, we put forth key observations in the functionality of current methods for SARS-CoV-2 diagnostic testing. These methods include nucleic acid amplification-, CRISPR-, sequencing-, antigen-, and antibody-based detection methods. Additionally, we include analysis of equally critical aspects of COVID-19 diagnostics, including sample collection and preparation, testing models, and commercial response. We emphasize the integrated nature of assays, wherein issues in sample collection and preparation could impact the overall performance in a clinical setting.

A comparison of immune receptor recombination databases sourced from tumour exome or RNAseq files: Verifications of immunological distinctions between primary and metastatic melanoma.

It became apparent several years ago that RNAseq and exome files prepared from tissue could be mined for adaptive immune receptor (IR) recombinations, which has given extra value to datasets originally intended for gene expression or mutation studies. For example, recovery of IR recombination reads from tumour specimen genomics files can correlate with survival rates. In particular, many benchmarking processes have been applied to the two sets of the IR recombination reads obtained from the cancer genome atlas files, but these two sets have never been directly compared. Here we show that both sets largely agree regarding several parameters. For example, recovery of TRB recombination reads from both WXS and RNAseq files representing metastatic melanoma was associated with a better outcome (p < .0004 in both cases); and T-cell receptor recombination read recovery, for both genomics file types, associated very strongly with T-cell gene expression markers. However, the use of CDR3 chemical features for survival distinctions was not consistent. This topic, and the surprising result that both datasets indicated that primary melanoma with recovery of IR recombination reads, in stark contrast to metastatic melanoma, represents a worse outcome, are discussed.

Aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory.

Despite its long history, until now, no receptor has been identified for aspirin, one of the most widely used medicines worldwide. Here we report that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor involved in fatty acid metabolism, serves as a receptor of aspirin. Detailed proteomic analyses including cheminformatics, thermal shift assays, and TR-FRET revealed that aspirin, but not other structural homologs, acts as a PPARα ligand through direct binding at the Tyr314 residue of the PPARα ligand-binding domain. On binding to PPARα, aspirin stimulated hippocampal plasticity via transcriptional activation of cAMP response element-binding protein (CREB). Finally, hippocampus-dependent behavioral analyses, calcium influx assays in hippocampal slices and quantification of dendritic spines demonstrated that low-dose aspirin treatment improved hippocampal plasticity and memory in FAD5X mice, but not in FAD5X/Ppara-null mice. These findings highlight a property of aspirin: stimulating hippocampal plasticity via direct interaction with PPARα.

Electrostatic Complementarity of T-Cell Receptor-Alpha CDR3 Domains and Mutant Amino Acids Is Associated with Better Survival Rates for Sarcomas.

While sarcoma immunology has advanced with regard to basic, and even some applied topics, this disease has not been subject to more recent immunogenomics approaches. Thus, we assessed the immune receptor recombinations available from the cancer genome atlas (TCGA) sarcoma database via tumor sample exome and RNASeq files. Results indicated that recovery of T-cell receptor-alpha recombination reads (TRA) correlated with a better survival rate, with the expression of T-cell biomarkers, and with tumor sample apoptosis signatures consistent with the longer patient survival times. Furthermore, samples representing TRA complementarity determining region-3 (CDR3) net charge per residue (NCPR) based complementarity with the corresponding sarcoma mutanome had a better survival rate, and more granzyme expression, than samples lacking such complementarity. By specifically using RNASeq-recovered TRA CDR3s and related NCPR assessments, three genes, TP53, ATRX, and RB1, were identified as being key components of the mutanome-based complementarity. Thus, these genes may represent key immune system targets for soft tissue sarcomas. Also, several key results from above were reproduced with a pediatric osteosarcoma dataset, work that led to identification of MUC6 mutations as potentially linked to a strong immune response. In sum, TRA CDR3s are likely to be important prognostic indicators, and possibly a beginning tool for immunotherapy development strategies, for adult and pediatric sarcomas.

PPARα serves as a new receptor of aspirin for neuroprotection.

Acetyl salicylic acid, commonly known as aspirin, has been being widely used as an anti-inflammatory drug for almost 100 years. However, there was no receptor known for this popular drug. Recently, we have established that peroxisome proliferator-activated receptor alpha (PPARα) acts as a novel receptor of aspirin. Activation of PPARα by aspirin stimulated a series of downstream signaling pathways that could potentially ameliorate different Alzheimer's disease (AD)-related pathologies. In this mini-review, we have discussed how aspirin-PPARα interaction plays a pivotal role in the amelioration of AD pathology via the stimulation of neurotrophic factors, upregulation of plasticity-associated genes, and removal of plaque burden in hippocampal neurons.

CT Myelography: Clinical Indications and Imaging Findings.

CT myelography is an important imaging modality that combines the advantages of myelography and the high resolution of CT. It provides a detailed delineation of pathologic spine conditions, especially those involving the thecal sac and its contents. However, the role of CT myelography has dramatically and appropriately decreased with the advent of MRI, which provides a noninvasive method to demonstrate pathologic spine conditions with high signal intensity in soft tissues. At the present time, CT myelography is often performed in patients who require evaluation of the thecal sac but have a contraindication to undergoing MRI. However, there remain many situations in which CT myelography is indicated and plays a critical role in patient treatment. The authors review common and uncommon indications for CT myelography and demonstrate various pathologic conditions in which CT myelography plays a vital role in patient treatment in this modern era of MRI.©RSNA, 2020.