Multiple studies show that reactive oxygen species (ROS) play a major role in prostate cancer (PCa) development and progression. Previously, we reported an induction of Spermidine/Spermine N(1) ...-Acetyl Transferase (SSAT) by androgen-activated androgen receptor (AR)-JunD protein complex that leads to over-production of ROS in PCa cells. In our current research, we identify small molecules that specifically block AR-JunD in this ROS-generating metabolic pathway.
A high throughput assay based on Gaussia Luciferase reconstitution was used to identify inhibitors of the AR-JunD interaction. Selected hits were further screened using a fluorescence polarization competitor assay to eliminate those that bind to the AR Ligand Binding Domain (LBD), in order to identify molecules that specifically target events downstream to androgen activation of AR. Eleven molecules were selected for studies on their efficacy against ROS generation and growth of cultured human PCa cells by DCFH dye-oxidation assay and DNA fluorescence assay, respectively. In situ Proximity Ligation Assay (PLA), SSAT promoter-luciferase reporter assay, and western blotting of apoptosis and cell cycle markers were used to study mechanism of action of the lead compound.
Selected lead compound GWARJD10 with EC(50) 10 μM against ROS production was shown to block AR-JunD interaction in situ as well as block androgen-induced SSAT gene expression at IC(50) 5 μM. This compound had no effect on apoptosis markers, but reduced cyclin D1 protein level.
Inhibitor of AR-JunD interaction, GWARJD10 shows promise for prevention of progression of PCa at an early stage of the disease by blocking growth and ROS production.
Rodent pain models play an important role in understanding the mechanisms of nociception and have accelerated the search for new treatment approaches for pain. Creating an objective metric for ...orofacial nociception in these models presents significant technical obstacles. No animal assay accurately measures pain-induced orofacial dysfunction that is directly comparable to human orofacial dysfunction. We developed and validated a high throughput, objective, operant, nociceptive animal assay, and an instrument to perform the assay termed the dolognawmeter, for evaluation of conditions known to elicit orofacial pain in humans. Using the device our assay quantifies gnawing function in the mouse. We quantified a behavioral index of nociception and demonstrated blockade of nociception in three models of orofacial pain: (1) TMJ inflammation, (2) masticatory myositis, and (3) head and neck cancer. This assay will be useful in the study of nociceptive mediators involved in the development and progression of orofacial pain conditions and it will also provide a unique tool for development and assessment of new therapeutic approaches.
Aim
Macroecological studies that require habitat suitability data for many species often derive this information from expert opinion. However, expert‐based information is inherently subjective and ...thus prone to errors. The increasing availability of GPS tracking data offers opportunities to evaluate and supplement expert‐based information with detailed empirical evidence. Here, we compared expert‐based habitat suitability information from the International Union for Conservation of Nature (IUCN) with habitat suitability information derived from GPS‐tracking data of 1,498 individuals from 49 mammal species.
Location
Worldwide.
Time period
1998–2021.
Major taxa studied
Forty‐nine terrestrial mammal species.
Methods
Using GPS data, we estimated two measures of habitat suitability for each individual animal: proportional habitat use (proportion of GPS locations within a habitat type), and selection ratio (habitat use relative to its availability). For each individual we then evaluated whether the GPS‐based habitat suitability measures were in agreement with the IUCN data. To that end, we calculated the probability that the ranking of empirical habitat suitability measures was in agreement with IUCN's classification into suitable, marginal and unsuitable habitat types.
Results
IUCN habitat suitability data were in accordance with the GPS data (> 95% probability of agreement) for 33 out of 49 species based on proportional habitat use estimates and for 25 out of 49 species based on selection ratios. In addition, 37 and 34 species had a > 50% probability of agreement based on proportional habitat use and selection ratios, respectively.
Main conclusions
We show how GPS‐tracking data can be used to evaluate IUCN habitat suitability data. Our findings indicate that for the majority of species included in this study, it is appropriate to use IUCN habitat suitability data in macroecological studies. Furthermore, we show that GPS‐tracking data can be used to identify and prioritize species and habitat types for re‐evaluation of IUCN habitat suitability data.
Glycine transporter inhibitors have recently been reported to improve symptoms in patients with schizophrenia. Here we used acute ketamine in the nonhuman primate to test the effectiveness of the ...novel glycine transporter inhibitor, PF-3463275, in a model of cognitive dysfunction relevant to schizophrenia. PF-3463275 (0.01-0.17 mg/kg; subcutaneously) or a vehicle was given before the administration of ketamine (median dose of 1.0 mg/kg intramuscularly) or placebo (saline). Ketamine induced hallucinatory-like behaviors that were not reversed by PF-3463275. In contrast, all doses of PF-3463275 alleviated the deficit in spatial working memory induced by ketamine. Theses findings build upon those in patients by providing translational support for targeting glycine transporter in adjunctive treatment for cognitive dysfunction in schizophrenia.
Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may ...alter executive functioning.
To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function.
This retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022.
Accidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury.
Volume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning.
A total of 598 children and adolescents (mean SD age, 14.05 3.06 years; range, 5.45-19.70 years; 386 male participants 64.5%; 212 female participants 35.5%) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume (d = -0.37; 95% CI, -0.52 to -0.22; P < .001) and subregional cerebellum volumes (eg, corpus medullare; d = -0.43; 95% CI, -0.58 to -0.28; P < .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, >6 months postinjury) of injury (total cerebellar volume, d = -0.55; 95% CI, -0.75 to -0.35; P < .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (β = -208.9 mm3; 95% CI, -319.0 to -98.0 mm3; P = .008) and Metacognition Index score (β = -202.5 mm3; 95% CI, -319.0 to -85.0 mm3; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (β = 0.0052 mm3; 95% CI, 0.0013 to 0.0090 mm3; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (β=0.52 mm3; 95% CI, 0.19 to 0.84 mm3; P = .005).
In this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.
Purpose:
Clergy have influence on the health of congregations and communities yet struggle with health behaviors. Interventions tailored to their occupation-specific demands and unique needs may ...provide a solution. Qualitative methods were used to identify opportunities and resources for the development of an effective obesity-related program for clergy.
Approach:
Ninety-minute focus groups were held with clergy (3 groups) and spouses (3 separate groups). Discussion explored: Program target(s); Opportunities and barriers that influence diet, physical activity, and stress-reduction practices; Empowering and culturally relevant health promotion strategies.
Setting:
All study activities took place in Memphis, TN.
Participants:
Eighteen clergy and fourteen spouses participated. All clergy were male, all spouses were female.
Method:
Previous research with clergy informed the interview guide and the PEN-3 framework aided in organizing the coding of clergy and spouse focus groups. Focus groups were audio recorded and transcripts analyzed using NVivo® 12.
Results:
Themes included: 1) Intervention targets—clergy, spouses, congregations; 2) Opportunities and barriers—making time, establishing boundaries, church traditions, individuals who support and hinder behavior change; 3) Intervention strategies—tools for healthy eating, goal setting, camaraderie, combining face-to-face with eHealth modalities.
Conclusion:
The relationship between clergy, spouse, and congregation make it important for obesity-related programs to target the unique needs of both clergy and spouses. Strategies should focus on healthy eating and personal connections no matter the modality used.
Arbuscular mycorrhizal (AM) and dark-septate endophytic (DSE) fungi were quantified in plant roots from high-elevation sites in the Cordillera Vilcanota of the Andes (Perú) and the Front Range of the ...Colorado Rocky Mountains (U.S.A.). At the highest sites in the Andes (5391 m) AM fungi were absent in the two species of plants sampled (both Compositae) but roots of both were heavily colonized by DSE fungi. At slightly lower elevations (5240–5250 m) AM fungi were present in roots while DSE fungi were rare in plants outside of the composite family. At the highest sites sampled in Colorado (4300 m) AM fungi were present, but at very low levels and all plants sampled contained DSE fungi. Hyphae of coarse AM fungi decreased significantly in plant roots at higher altitude in Colorado, but no other structures showed significant decreases with altitude. These new findings indicate that the altitudinal distribution of mycorrhizal fungi observed for European mountains do not necessarily apply to higher and drier mountains that cover much of the Earth (e.g. the Himalaya, Hindu Kush, Andes, and Rockies) where plant growth is more limited by nutrients and water than in European mountains. This paper describes the highest altitudinal records for both AM and DSE fungi, surpassing previous reported altitudinal maxima by about 1500 meters.
To analyze the association of a surgeon's experience with postoperative outcomes of pancreatoduodenectomies (PDs) when stratified by Fistula Risk Score (FRS).
Centralization is now well-established ...for pancreatic surgery. Nevertheless, the benefits of individual surgeon's experience in high-volume settings remain undefined.
Pancreatoduodenectomies performed by 82 surgeons across 18 international specialty institutions (median: 140 PD/year) were analyzed. Surgeon cumulative PD volume was linked with postoperative outcomes through multivariable models, adjusted for patient/operative characteristics and the FRS. Then, surgeon experience was also stratified by the 10, previously defined, most clinically impactful scenarios for clinically relevant pancreatic fistula (CR-POPF) development.
Of 8189 PDs, 18.7% suffered severe complications (Accordion≥3), 4.8% were reoperated upon and 2.2% expired. Although the most experienced surgeons (top-quartile; >525 career PDs) more often operated on riskier cases, their experience was significantly associated with declines in CR-POPF ( P <0.001), severe complications ( P =0.008), reoperations ( P <0.001), and length of stay (LOS) ( P <0.001)-accentuated even more in the most impactful FRS scenarios (2830 patients). Risk-adjusted models indicate male sex, increasing age, ASA class, and FRS, but not surgeon experience, as being associated with severe complications, failure-to-rescue, and mortality. Instead, upper-echelon experience demonstrates significant reductions in CR-POPF (OR 0.66), reoperations (OR 0.64), and LOS (OR 0.65) in moderate-to-high fistula risk circumstances (FRS≥3, 68% of cases).
At specialty institutions, major morbidity, mortality, and failure-to-rescue are primarily associated with baseline patient characteristics, while cumulative surgical experience impacts pancreatic fistula occurrence and its attendant effects for most higher-risk pancreatoduodenectomies. These data also suggest an extended proficiency curve exists for this operation.
Numerous studies have documented reduced access to patient care due to the COVID-19 pandemic including access to a diagnostic or screening tests, prescription medications, and treatment for an ...ongoing condition. In the context of clinical management for venous thromboembolism, this could result in suboptimal therapy with warfarin. We aimed to determine the impact of the pandemic on utilization of International normalized ratio (INR) testing and the percentage of high and low results.
INR data from 11 institutions were extracted to compare testing volume and the percentage of INR results ≥3.5 and ≤1.5 between a pre-pandemic period (January-June 2019, period 1) and a portion of the COVID-19 pandemic period (January-June 2020, period 2). The analysis was performed for inpatient and outpatient cohorts.
Testing volumes showed relatively little change in January and February, followed by a significant decrease in March, April and May, and then returned to baseline in June. Outpatient testing showed a larger percentage decrease in testing volume compared to inpatient testing. At 10 of the 11 study sites we observed an increase in the percentage of abnormal high INR results as test volumes decreased, primarily among outpatients.
The COVID-19 pandemic impacted INR testing among outpatients which may be attributable to several factors. Increased supratherapeutic INR results during the pandemic period when there was reduced laboratory utilization and access to care is concerning because of the risk of adverse bleeding events in this group of patients. This could be mitigated in the future by offering drive through testing and/or widespread implementation of home INR monitoring.
Autoimmune mechanisms are thought to have a major role in the pathogenesis of multiple sclerosis. We aimed to identify coexisting autoimmune phenotypes in patients with multiple sclerosis from ...families with several members with the disease and in their first-degree relatives.
A total of 176 families (386 individuals and 1107 first-degree relatives) were characterised for a history of other autoimmune disorders. Family-based or case–control analyses were done to assess the association of cytotoxic T-lymphocyte-antigen 4 (
CTLA4) and protein tyrosine phosphatase (
PTPN22) variants with susceptibility to multiple sclerosis.
46 (26%) index cases reported at least one coexisting autoimmune disorder. The most common were Hashimoto thyroiditis (10%), psoriasis (6%), inflammatory bowel disease (3%), and rheumatoid arthritis (2%). 112 (64%) families with a history of multiple sclerosis reported autoimmune disorders (excluding multiple sclerosis) in one or more first-degree relatives, whereas 64 (36%) families reported no history of autoimmunity. Similar to index cases, Hashimoto thyroiditis, psoriasis, and inflammatory bowel disease were also the most common disorders occurring in family members. A common variant within
CTLA4 was strongly associated with multiple sclerosis in families who had other autoimmune diseases (p=0·009) but not in families without a history of other autoimmune disorders (p=0·90).
The presence of various immune disorders in families with several members with multiple sclerosis suggests that the disease might arise on a background of a generalised susceptibility to autoimmunity. This distinct multiple-sclerosis phenotype, defined by its association with other autoimmune diseases, segregates with specific genotypes that could underlie the common susceptibility.
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