The association between fatty acids and prostate cancer remains poorly explored in African-descent populations. Here, we analyze 24 circulating fatty acids in 2934 men, including 1431 prostate cancer ...cases and 1503 population controls from Ghana and the United States, using CLIA-certified mass spectrometry-based assays. We investigate their associations with population groups (Ghanaian, African American, European American men), lifestyle factors, the fatty acid desaturase (FADS) genetic locus, and prostate cancer. Blood levels of circulating fatty acids vary significantly between the three population groups, particularly trans, omega-3 and omega-6 fatty acids. FADS1/2 germline genetic variants and lifestyle factors explain some of the variation in fatty acid levels, with the FADS1/2 locus showing population-specific associations, suggesting differences in their control by germline genetic factors. All trans fatty acids, namely elaidic, palmitelaidic, and linoelaidic acids, associated with an increase in the odds of developing prostate cancer, independent of ancestry, geographic location, or potential confounders.
We examined associations between two forms of testosterone therapy (TT) and risks of seven cancers among men.
SEER-Medicare combines cancer registry data from the Surveillance, Epidemiology, and End ...Results programme with Medicare claims. Our population-based case-control study included incident cancer cases diagnosed between 1992-2015: prostate (n = 130,713), lung (n = 105,466), colorectal (n = 56,433), bladder (n = 38,873), non-Hodgkin lymphoma (n = 17,854), melanoma (n = 14,241), and oesophageal (n = 9116). We selected 100,000 controls from a 5% random sample of Medicare beneficiaries and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI).
TT was associated with lower risk of distant-stage prostate cancer (injection/implantation OR = 0.72, 95% CI: 0.60-0.86; topical OR = 0.50, 95% CI: 0.24-1.03). We also observed inverse associations for distant-stage colorectal cancer (injection/implantation OR = 0.75, 95% CI: 0.62-0.90; topical OR = 0.11, 95% CI: 0.05-0.24). Risks of distant-stage colorectal and prostate cancers decreased with time after initiating TT by injection/implantation. By contrast, TT was positively associated with distant-stage melanoma (injection/implantation OR = 1.70, 95% CI: 1.37-2.11). TT was not associated with bladder cancer, oesophageal cancer, lung cancer or non-Hodgkin lymphoma.
TT was inversely associated with distant-stage prostate and colorectal cancers but was positively associated with distant-stage melanoma. These observations may suggest an aetiologic role for TT or the presence of residual confounding.
There is evidence that tumor immunobiology and immunotherapy response may differ between African American and European American prostate cancer patients. Here, we determine if men of African descent ...harbor a unique systemic immune-oncological signature and measure 82 circulating proteins in almost 3000 Ghanaian, African American, and European American men. Protein signatures for suppression of tumor immunity and chemotaxis are elevated in men of West African ancestry. Importantly, the suppression of tumor immunity protein signature associates with metastatic and lethal prostate cancer, pointing to clinical importance. Moreover, two markers, pleiotrophin and TNFRSF9, predict poor disease survival specifically among African American men. These findings indicate that immune-oncology marker profiles differ between men of African and European descent. These differences may contribute to the disproportionate burden of lethal prostate cancer in men of African ancestry. The elevated peripheral suppression of tumor immunity may have important implication for guidance of cancer therapy which could particularly benefit African American patients.
This paper constructs a two‐country core–periphery New Keynesian model of a currency union to address the interaction between the objectives of regionally directed fiscal policy constrained by a ...single currency and the aggregate use of fiscal policy in face of the zero lower bound (ZLB) on policy interest rates. We identify an optimal path of aggregate and relative fiscal policy responses to a negative region‐specific demand shock. Our results show that (i) in a monetary union, the optimal policy response to an asymmetric reduction in demand concentrated in the periphery always entails a relative shift of fiscal expenditure toward the worse‐affected regions, (ii) though no aggregate fiscal response is required outside the ZLB, and (iii) optimal union‐wide fiscal policy is expansionary at the ZLB. Therefore, optimal policy always entails an expansion in the periphery at the ZLB, but the optimal fiscal response in the core regions can be either expansionary or contractionary depending on the parameters of the model. However, (iv) fiscal expansion in the core is warranted if the periphery cannot implement an expansion due to constraints on public spending.
The use of total area protected as the predominant indicator of progress in building protected area (PA) networks is receiving growing criticism. Documenting the full dynamics of PA networks, both in ...terms of the gains and losses in protection, provides a much more informative approach to tracking progress. To this end, documentation of PA downgrading, downsizing, and degazettement (PADDD) has increased. Studies of PADDD events generally fail to place these losses in the context of gains in protection; therefore, they omit important elements of PA network dynamics. To address this limitation, we used a spatially explicit approach to identify every parcel of land added to and excised from the Australian terrestrial PA network and PAs that had their level of protection changed over 17 years (1997-2014). By quantifying changes in the spatial configuration of the PA network with time-series data (spatial layers for nine separate time steps), ours is the first assessment of the dynamics (increases and decreases in area and level of protection) of a PA network and the first comprehensive assessment of PADDD in a developed country. We found that the Australian network was highly dynamic; there were 5233 changes in area or level of protection over 17 years. Against a background of enormous increases in area protected, we identified over 1500 PADDD events, which affected over one-third of the network, which were largely the result of widespread downgrading of protection. We believe our approach provides a mechanism for robust tracking of trends in the world's PAs through the use of data from the World Database on Protected Areas. However, this will require greater transparency and improved data standards in reporting changes to PAs. El uso del área total protegida como indicador predominante del progreso en la construcción de redes de áreas protegidas (AP) cada vez recibe más críticas. La documentación de las dinámicas completas de las redes de AP, tanto en términos de ganancia y pérdida de protección, proporciona una estrategia mucho más informativa al seguimiento del progreso. Para este fin, la documentación de la degradación, reducción y pérdida de protección legal (PADDD, en inglés) de las áreas protegidas ha incrementado. Los estudios de eventos de PADDD generalmente fallan en ubicar estas pérdidas en el contexto de la ganancia de protección, por lo que omiten elementos importantes de dinámicas de redes de AP. Para enfocarnos en esta limitación utilizamos una estrategia espacialmente explícita para identificar cada lote de suelo añadido y extirpado de la red australiana de AP terrestres y las AP que sufrieron un cambio en su nivel de protección durante 17 años (1997 - 2014). Con la cuantificación de los cambios en la configuración espacial de la red de AP con datos de series de tiempo (capas espaciales para nueve pasos temporales separados), realizamos la primera valoración de las dinámicas (incrementos y decrementos en el área y en el nivel de protección) de una red de AP y la primera valoración comprensiva del PADDD en un país desarrollado. Encontramos que la red australiana era altamente dinámica: hubo 5, 233 cambios en el área o en el nivel de protección durante 17 años. Frente a un fondo de incrementos enormes en el área protegida, identificamos más de 1, 500 eventos de PADDD, los cuales afectaron más de un tercio de la red y que eran en general el resultado de una degradación extensiva de la protección. Creemos que nuestra estrategia proporciona un mecanismo para el seguimiento convincente de las tendencias de las AP mundiales con el uso de datos de la Base de Datos Mundial de Áreas Protegidas. Sin embargo, esto requerirá de mayor transparencia y estándares de datos mejorados en el reporte de los cambios en las AP.
Acute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of ...pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression.
The study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis.
This study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes.
EudraCT no. 2021-000069-34.
gov NCT04966559. Registered on July 8, 2021.
A series of studies have been conducted by experimental and theoretical methods on the synthesis, structures, and reactions of Cp*Rh boryl complexes that are likely intermediates in the ...rhodium-catalyzed regioselective, terminal functionalization of alkanes. The photochemical reaction of Cp*Rh(η6-C6Me6) with pinacolborane (HBpin) generates the bisboryl complex Cp*Rh(H)2(Bpin)2 (2), which reacts with neat HBpin to generate Cp*Rh(H)(Bpin)3 (3). X-ray diffraction, density functional theory (DFT) calculations, and NMR spectroscopy suggest a weak, but measurable, B−H bonding interaction. Both 2 and 3 dissociate HBpin and coordinate PEt3 or P(p-Tol)3 to generate the conventional rhodium(III) species Cp*Rh(PEt3)(H)(Bpin) (4) and Cp*RhP(p-tol)3(Bpin)2 (5). Compounds 2 and 3 also react with alkanes and arenes to form alkyl- and arylboronate esters at temperatures similar to or below those of the catalytic borylation of alkanes and arenes. Further, these compounds were observed directly in catalytic reactions. The enthalpies and free energies for generation of the 16-electron intermediate and for the C−H bond cleavage and B−C bond formation have been calculated with DFT. These results strongly suggest that the C−H bond cleavage process occurs by a metal-assisted σ-bond metathesis mechanism to generate a borane complex that isomerizes if necessary to place the alkyl group cis to the boryl group. This complex with cis boryl and alkyl groups then undergoes B−C bond formation by a second σ-bond metathesis to generate the final functionalized product.
Immune-related adverse events (irAEs) often require treatment with high-dose systemic steroids (SS) and other immunosuppressive agents (ISAs). NCCN Guidelines recommend prophylactic antibiotics for ...Pneumocystis jirovecii pneumonia (PJP) for patients receiving prolonged SS/ISAs. However, there is a paucity of evidence regarding the incidence of opportunistic infections (OIs) and non-OIs and the role of prophylactic antibiotics in patients on SS/ISAs for irAEs.
A retrospective analysis was conducted of patients treated using immune checkpoint inhibitor (ICI) therapy at 5 MedStar Health hospitals from January 2011 to April 2018. OIs were defined per the Infectious Diseases Society of America guidelines for the prevention and treatment of OIs in patients with HIV. The study cohort included patients who received ≥20 mg daily of a prednisone equivalent for ≥4 weeks to manage irAEs.
The study cohort identified 112 (15%) of 758 total patients treated using ICIs. Baseline characteristics included the following: median age was 64 years, 74% (n=82) of patients were White, 89% (n=100) had an ECOG performance status ≤1, 61% (n=68) had melanoma, 19% (n=21) had non-small cell lung cancer, 45% (n=50) were treated using an anti-PD-(L)1 ICI, and 33% (n=37) were treated using an anti-PD-1/anti-CTLA-4 combination. The median starting SS dose was 100 mg of a prednisone equivalent, and 25% of patients required additional ISAs, with infliximab (n=15) and mycophenolate mofetil (n=9) being the most common. We found that 20% (n=22) of patients developed any infection, including 7% (n=8) with OIs (oral candidiasis n=4, nondisseminated varicella zoster infection n=2, PJP n=1, and Listeria monocytogenes endophthalmitis n=1) and 13% (n=14) with non-OIs (most common: Clostridium difficile and pneumonia n=5 each). PJP prophylaxis with sulfamethoxazole/trimethoprim was given to 13% (n=14) patients, of whom 43% (n=6) developed OIs/non-OIs.
Our study highlights the fundamental issues for patients on ICI therapy who require SS/ISAs for irAEs: the degree of immunosuppression and the relative risk of OI. We noted a low incidence of OIs overall and breakthrough infections despite PJP prophylaxis. We question whether PJP prophylaxis is efficacious or necessary. Prospective trials are required to answer these questions.
Trauma causes inflammation by releasing mitochondria that act as Danger-Associated Molecular Patterns (DAMPs). Trauma also increases susceptibility to infection. Human mitochondria contain 13 ...N-formyl peptides (mtFPs). We studied whether mtFPs released into plasma by clinical injury induce neutrophil (PMN) inflammatory responses, whether their potency reflects their similarity to bacterial FPs and how their presence at clinically relevant concentration affects PMN function.
N-terminal sequences of the 13 mtFPs were synthesized. Changes in human PMN cytosolic Ca concentration (Cai) and chemotactic responses to mtFPs were studied. Sequence similarity of mtFPs to the canonical bacterial peptide f-Met-Leu-Phe (fMLF/fMLP) was studied using the BLOcks SUbstitution Matrix 62 (BLOSUM 62) system. The presence of mtFPs in plasma of trauma patients was assayed by Enzyme-linked immunosorbent assay (ELISA). The effects of the most potent mtFP (ND6) on PMN signaling and function were then studied at ambient clinical concentrations by serial exposure of native PMN to ND6, chemokines and leukotrienes.
Five mtFPs (ND6, ND3, ND4, ND5, and Cox 1) induced Cai flux and chemotaxis in descending order of potency. Evolutionary similarity to fMLF predicted Cai flux and chemotactic potency linearly (R = 0.97, R = 0.95). Chemoattractant potency was also linearly related to Cai flux induction (R = 0.92). Active mtFPs appear to circulate in significant amounts immediately after trauma and persist through the first week. The most active mtFP, ND6, suppresses responses to physiologic alveolar chemoattractants (CXCL-1, leukotriene B4) as well as to fMLF where CXCL-1 and leukotriene B4 do not suppress N-formyl peptide receptor (FPR)-1 responses to mtFPs. Prior FPR-1 inhibition rescues PMN from heterologous suppression of CXCR-1 and BLT-1 by mtFPs.
The data suggest mtFPs released by injured tissue may attract PMN to trauma sites while suppressing PMN responses to other chemoattractants. Inhibition of mtFP-FPR1 interactions might increase PMN recruitment to lung bacterial inoculation after trauma. These findings suggest new paradigms for preventing infections after trauma.
Therapeutic, Level IV.
Racial and ethnic disparities in the incidence of esophageal cancer have not been thoroughly characterized with quantitative health-disparity measures. Using data from 1992-2013 from 13 US cancer ...registries in the Surveillance, Epidemiology, and End Results database, we assessed such disparities according to histological type, based on a variety of disparity metrics. The age-standardized incidence rate of squamous cell carcinoma (SCC) was highest among black persons, while adenocarcinoma mainly affected white men. The rate of SCC decreased over time in all racial/ethnic groups, and this was most pronounced in black persons (by 5.7% per year among men and 5.0% among women). The adenocarcinoma rate rose among non-Hispanic whites and among black men. Racial/ethnic disparities in the incidence of total esophageal cancer decreased over time, which was due mainly to reduced disparities in SCC. The 2 absolute disparity measures-range difference and between-group variance-for adenocarcinoma rose by 3.2% and 6.8% per year, respectively, in men and by 1.8% and 5.3% per year, respectively, in women. This study demonstrates decreased racial/ethnic disparities in the incidence of esophageal SCC over time in the United States, while disparities increased in adenocarcinoma incidence as measured on the absolute scale.
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