The Effect of Temperature on the Sensitivity to and Preference for an Omega-3 and an Omega-6 Polyunsaturated Fatty Acid in Mice (Mus musculus)

Previous studies have shown that laboratory mice (Mus musculus) in the cold increase their preference for diets supplemented with natural oils rich in PUFAs, but it is not known whether this phenomenon is driven by a change in preference for specific PUFAs. Arnold and Ruf (2008) proposed that increasing the n-6 to n-3 PUFA ratio in cardiac myocyte membranes decreases the risk of arrhythmia hibernators face and this study tests the hypothesis that normothermic mice in the cold increase their PUFA preference specifically to receive a similar benefit from n-6 PUFAs. Solutions of single fatty acids were used in a two-bottle paradigm to test the sensitivity, or relative level of detection, to and preference for an n-3 and an n-6 PUFA at 5°C and 23°C. To examine sensitivity for the two PUFAs, mice were offered either PUFA solutions of increasing concentrations (0% - 1%) simultaneously with a vehicle solution. Data suggest that they were more sensitive to both PUFAs at 5°C (P \u3c 0.0001) compared with at 23°C but did not have a differential response to PUFA type (P = 0.48). When given both PUFAs simultaneously to determine preference, mice preferred n-6 to n-3 PUFAs (P \u3c 0.0001) with no difference in preference between temperatures (P = 0.08). Together, the results of this study suggest that the increased PUFA preference in the cold is driven by an increased sensitivity to the PUFAs tested in this study but not a change in the relative preference for these PUFAs

Effects Of Diets Rich In Saturated And Polyunsaturated Fatty Acids On Performance Of Mus Musculus In Warm And Cold Environments

The homeoviscous adaptation hypothesis predicts that cell membranes should incorporate higher proportions of unsaturated fatty acids at lower temperatures to counteract cold-induced increases in membrane viscosity and thus to maintain membrane function. In a previous experiment in our laboratory, the obligate homeotherm, Mus musculus, increased its preference for a diet rich in polyunsaturated fatty acids (PUFAs) when exposed to cold. However, cold-induced changes in diet preference over three weeks were not associated with improved performance in the cold, nor were there substantial differences in membrane composition after this three-week period. In the current experiment, mice in each of three treatment groups (N = 15 in each group) were fed a single diet [chow rich in n-3 PUFAs, in n-6 PUFAs, or saturated fatty acids (SFAs), respectively] for ten weeks at 23 C. Grip strength, memory, and nocioception were then tested in each diet group at 5 C and at 23 C; fatty acid composition of their membranes was also assayed. While some trends were consistent with the homeoviscous adaptation hypothesis, preliminary analysis showed no significant effects of diet or temperature on most measures of performance. Further studies are needed to determine the function of cold-enhanced preference for PUFAs in this species

Pushing Fluids: A Case for Liquid Biomarkers Before Imaging in Pre–Prostate Biopsy Decision-making

For patients with clinical suspicion of prostate cancer, liquid biomarkers are the next best test because of their accessibility, objectiveness, and noninvasive nature. A highly sensitive cutoff for these biomarkers should be used to triage patients before use of magnetic resonance imaging

Fatty acid metabolism reprogramming in ccRCC: mechanisms and potential targets

Lipid droplet formation is a defining histological feature in clear-cell renal cell carcinoma (ccRCC) but the underlying mechanisms and importance of this biological behaviour have remained enigmatic. De novo fatty acid (FA) synthesis, uptake and suppression of FA oxidation have all been shown to contribute to lipid storage, which is a necessary tumour adaptation rather than a bystander effect. Clinical studies and mechanistic investigations into the roles of different enzymes in FA metabolism pathways have revealed new metabolic vulnerabilities that hold promise for clinical effect. Several metabolic alterations are associated with worse clinical outcomes in patients with ccRCC, as lipogenic genes drive tumorigenesis. Enzymes involved in the intrinsic FA metabolism pathway include FA synthase, acetyl-CoA carboxylase, ATP citrate lyase, stearoyl-CoA desaturase 1, cluster of differentiation 36, carnitine palmitoyltransferase 1A and the perilipin family, and each might be potential therapeutic targets in ccRCC owing to the link between lipid deposition and ccRCC risk. Adipokines and lipid species are potential biomarkers for diagnosis and treatment monitoring in patients with ccRCC. FA metabolism could potentially be targeted for therapeutic intervention in ccRCC as small-molecule inhibitors targeting the pathway have shown promising results in preclinical models

Localized Amyloidosis of the Seminal Tract is not Associated With Subsequent Development of Systemic Amyloidosis

To investigate if localized amyloidosis of the seminal tract (LAST) is associated with subsequent development of systemic amyloidosis. Prior reports recorded no systemic amyloidosis at the time of LAST diagnosis. However, no follow-up studies exist to confirm that LAST is not a risk factor for subsequent development of systemic amyloidosis. Our study cohort included patients whose prostate biopsy (PB) or radical prostatectomy (RP) specimen demonstrated LAST between 2014–2021. Clinical variables including age, race/ethnicity, prostate specific antigen (PSA), and prostate weight were analyzed. Patients were assessed for clinical and laboratory evidence of systemic amyloidosis and lymphoproliferative conditions during the follow-up period. Thirty-six men (26 RPs, 9 PBs, and 1 cystoprostatectomy) had LAST. Our study cohort included 18 white Hispanic, 9 white non-Hispanic, 7 black, and 1 Asian men. Median age was 67 years, mean PSA was 9.8 ng/mL. Over a median follow-up period of 20 months (mean, 30) in 27 men, none developed systemic amyloidosis. Frequency of LAST in RP specimens was 1.2% (26/2,135) and corelated with age (67 vs 63 years, P-value = .004). Race/ethnicity, PSA, and prostate weight were not associated with the incidence of LAST. LAST is not a harbinger of systemic disease. The incidence of LAST in a contemporary RP cohort is significantly lower than in previously published studies. While patient age positively corelates with LAST, PSA and prostate weight are not associated with the condition. There is no difference in the frequency of LAST between white Hispanic, white non-Hispanic, and black men

Clinical and genomic factors associated with tumor mutational burden (TMB) in prostate cancer

240 Background: TMB is an emerging biomarker to predict clinical benefit from immune checkpoint inhibitors (ICI). Although high TMB in prostate cancer is rare, and we sought to evaluate independent associations of TMB by clinical factors, prior treatment, and genomics. Methods: This study used the US-based nationwide de-identified Flatiron Health-Foundation Medicine prostate cancer clinico-genomic database. The de-identified data originated from approximately 280 US cancer clinics (~800 sites) between January 2011-March 2022. Multivariable linear regression model was used to assess independent prediction of TMB levels, which were log2+1 transformed to better normalize distribution. Data are expressed as (estimate, [95% CI], p-value). Results: The study included 2,748 tissue specimens: 51.7% were from the prostate, 10.3% from bone, and 14.6% from lymph nodes. Specimens from white patients comprised 61.2% of samples, with another 7.5% from Black, 1.1% from Asian, and 30% from other or unknown race patients. Of our cohort, 58.5%, 15.5%, and 26.0% were from patients who received 0, 1-24 months, and >24 months of androgen deprivation therapy (ADT), respectively. Also 19.7%, 1.8%, 11.4%, and 0.4% had any exposure to novel hormonal therapies (NHT), Radium-223, taxanes, and ICI, respectively. Higher TMB was independently associated with ADT use >24 months (0.16, [0.05-0.27], p=0.005) and Asian race (0.36, [0.03-0.69], p=0.034). Prior treatment with NHT, taxanes, or radium was not associated with higher TMB. Compared to prostate, bladder (0.22, [0.03-0.41], p=0.023), liver (0.27, [0.13-0.42], p<0.001), and other (0.29, [0.15-0.43], p<0.001) biopsy sites were associated with high TMB, but lymph node biopsy was not. MSI-high (2.30, [1.96-2.64], p<0.001), MSI-intermediate (0.51, [0.14-0.88], p=0.007), and MSI-unknown (0.84, [0.60-1.09], p<0.001) were associated with increased TMB. Individually altered genes associated with increased TMB included MLH1 (0.77, [0.31-1.24], p=0.001), MSH2 (1.09, [0.74-1.45], p<0.001), MSH3 (0.64, [0.018-1.11], p=0.006), MSH6 (0.94, [0.61-1.26], p<0.001), BRCA2 (0.56, [0.43-0.69], p<0.001), CDK12 (0.38, [0.24-0.53], p<0.001), FANCA (0.42, [0.07-0.77], p=0.02), MRE11 (0.87, [0.11-1.62], p=0.025), and PALB2 (0.83, [0.48-1.18], p<0.001). No individual gene was independently associated with lower TMB. Conclusions: TMB associates with MSI status and MMR genes. However, aside from associating with long term ADT use, TMB does not have strong association with prior systemic treatment. Certain biopsy specimen sites including bladder and liver have increased TMB but overall, the association is relatively weak in comparison to MMR genes and MSI status. This study allows better understanding of how prior treatments, clinical and genomic factors affect TMB status, which may add value to MSI status in predicting treatment response in advanced prostate cancer