Malignant melanoma is an aggressive, therapy-resistant malignancy of melanocytes. The incidence of melanoma has been steadily increasing worldwide, resulting in an increasing public health problem. ...Exposure to solar UV radiation, fair skin, dysplastic nevi syndrome, and a family history of melanoma are major risk factors for melanoma development. The interactions between genetic and environmental risk factors that promote melanomagenesis are currently the subject of ongoing research. Avoidance of UV radiation and surveillance of high-risk patients have the potential to reduce the population burden of melanoma. Biopsies of the primary tumor and sampling of draining lymph nodes are required for optimal diagnosis and staging. Several clinically relevant pathologic subtypes have been identified and need to be recognized. Therapy for early disease is predominantly surgical, with a minor benefit noted with the use of adjuvant therapy. Management of systemic melanoma is a challenge because of a paucity of active treatment modalities. In the first part of this 2-part review, we discuss epidemiology, risk factors, screening, prevention, and diagnosis of malignant melanoma. Part 2 (which will appear in the April 2007 issue) will review melanoma staging, prognosis, and treatment.
Dietary micronutrients have the ability to strongly influence animal physiology and ecology. For songbirds, dietary polyunsaturated fatty acids (PUFAs) and antioxidants are hypothesized to be ...particularly important micronutrients because of their influence on an individual's capacity for aerobic metabolism and recovery from extended bouts of exercise. However, the influence of specific fatty acids and hydrophilic antioxidants on whole‐animal performance remains largely untested. We used diet manipulations to directly test the effects of dietary PUFA, specifically linoleic acid (18:2n6), and anthocyanins, a hydrophilic antioxidant, on basal metabolic rate (BMR), peak metabolic rate (PMR), and rates of fat catabolism, lean catabolism, and energy expenditure during sustained flight in a wind tunnel in European starlings (Sturnus vulgaris). BMR, PMR, energy expenditure, and fat metabolism decreased and lean catabolism increased over the course of the experiment in birds fed a high (32%) 18:2n6 diet, while birds fed a low (13%) 18:2n6 diet exhibited the reverse pattern. Additionally, energy expenditure, fat catabolism, and flight duration were all subject to diet‐specific effects of whole‐body fat content. Dietary antioxidants and diet‐related differences in tissue fatty acid composition were not directly related to any measure of whole‐animal performance. Together, these results suggest that the effect of dietary 18:2n6 on performance was most likely the result of the signaling properties of 18:2n6. This implies that dietary PUFA influence the energetic capabilities of songbirds and could strongly influence songbird ecology, given their availability in terrestrial systems.
Metabolic capacity contributes to the ability of songbirds to engage in endurance flight and may be influenced by dietary micronutrients such as fatty acids and antioxidants. We tested the effects of linoleic acid and anthocyanins on songbird metabolism with a diet manipulation experiment. The variable influence of linoleic acid on basal, peak, and sustained metabolism over the experiment suggests that these effects are mediated via linoleic acid's signaling properties and demonstrates the potential impact of diet selection on songbird performance.
During migration, birds substantially increase their metabolic rate and burn fats as fuel and yet somehow avoid succumbing to overwhelming oxidative damage. The physiological means by which ...vertebrates such as migrating birds can counteract an increased production of reactive species (RS) are rather limited: they can upregulate their endogenous antioxidant system and/or consume dietary antioxidants (prophylactically or therapeutically). Thus, birds can alter different components of their antioxidant system to respond to the demands of long-duration flights, but much remains to be discovered about the complexities of RS production and antioxidant protection throughout migration. Here, we use bird migration as an example to discuss how RS are produced during endurance exercise and how the complex antioxidant system can protect against cellular damage caused by RS. Understanding how a bird's antioxidant system responds during migration can lend insights into how antioxidants protect birds during other life-history stages when metabolic rate may be high, and how antioxidants protect other vertebrates from oxidative damage during endurance exercise.
Laser-driven shock compression experiments reveal the presence of a phase transition in MgSiO(3) over the pressure-temperature range 300-400 GPa and 10 000-16 000 K, with a positive Clapeyron slope ...and a volume change of ∼6.3 (±2.0) percent. The observations are most readily interpreted as an abrupt liquid-liquid transition in a silicate composition representative of terrestrial planetary mantles, implying potentially significant consequences for the thermal-chemical evolution of extrasolar planetary interiors. In addition, the present results extend the Hugoniot equation of state of MgSiO(3) single crystal and glass to 950 GPa.
Malignant melanoma is an aggressive, therapy-resistant malignancy of melanocytes. The incidence of melanoma has been steadily increasing worldwide, resulting in an increasing public health problem. ...Exposure to solar UV radiation, fair skin, dysplastic nevi syndrome, and a family history of melanoma are major risk factors for melanoma development. The interactions between genetic and environmental risk factors that promote melanomagenesis are currently the subject of ongoing research. Avoidance of UV radiation and surveillance of high-risk patients have the potential to reduce the population burden of melanoma. Biopsies of the primary tumor and sampling of draining lymph nodes are required for optimal diagnosis and staging. Several clinically relevant pathologic subtypes have been identified and need to be recognized. Therapy for early disease is predominantly surgical, with a minor benefit noted with the use of adjuvant therapy. Management of systemic melanoma is a challenge because of a paucity of active treatment modalities. In the first part of this 2-part review, we discuss epidemiology, risk factors, screening, prevention, and diagnosis of malignant melanoma. Part 2 (which will appear in the April 2007 issue) will review melanoma staging, prognosis, and treatment.
To assess the safety and effectiveness of percutaneous cryoablation to treat limited metastases to the musculoskeletal system, with the goal of complete disease remission.
In a single-institution ...retrospective study of data from December 2003 to October 2011, 43 consecutive patients underwent initial cryoablation of limited (five or fewer) musculoskeletal metastases with the goal of complete disease remission (ie, no clinical or radiographic evidence of disease). Three patients were lost to follow-up. As a result, the present report describes 40 patients who underwent 40 cryoablation procedures to treat 52 tumors.
Local control was achieved in 45 of 52 tumors (87%; 95% confidence interval CI, 75%-93%) at a median follow-up of 21 months (range, 4-62 mo). Thirteen of 19 treated bone metastases (68%) and 32 of 33 soft-tissue metastases (97%) showed local control (P = .007). One- and 2-year overall survival rates were 91% (95% CI, 75%-97%) and 84% (95% CI, 65%-93%), respectively. Median overall survival was 47 months (95% CI, 26-62 mo). One- and 2-year disease-free survival rates were 22% (95% CI, 11%-37%) and 7% (95% CI,<1% to 26%), respectively. Median disease-free survival was 7 months (95% CI, 5-10 mo). Two of 40 procedures (5%) were associated with major complications.
Percutaneous cryoablation is a safe and effective treatment to achieve local tumor control and short-term complete disease remission in patients with limited metastatic disease to the musculoskeletal system.
In 2011, Lake Erie experienced the largest harmful algal bloom in its recorded history, with a peak intensity over three times greater than any previously observed bloom. Here we show that long-term ...trends in agricultural practices are consistent with increasing phosphorus loading to the western basin of the lake, and that these trends, coupled with meteorological conditions in spring 2011, produced record-breaking nutrient loads. An extended period of weak lake circulation then led to abnormally long residence times that incubated the bloom, and warm and quiescent conditions after bloom onset allowed algae to remain near the top of the water column and prevented flushing of nutrients from the system. We further find that all of these factors are consistent with expected future conditions. If a scientifically guided management plan to mitigate these impacts is not implemented, we can therefore expect this bloom to be a harbinger of future blooms in Lake Erie.
BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO ...pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.
Endurance flight impose substantial oxidative costs on the avian oxygen delivery system. In particular, the accumulation of irreversible damage in red blood cells can reduce the capacity of blood to ...transport oxygen and limit aerobic performance. Many songbirds consume large amounts of anthocyanin-rich fruit, which is hypothesized to reduce oxidative costs, enhance post-flight regeneration, and enable greater aerobic capacity. While their antioxidant benefits appear most straightforward, the effects of anthocyanins on blood composition remain so far unknown. We fed thirty hand-raised European starlings (Sturnus vulgaris) two semisynthetic diets (with or without anthocyanin supplement) and manipulated the extent of flight activity in a wind tunnel (daily flying or non-flying for over two weeks) to test for their interactive effects on functionally important haematological variables.
Supplemented birds had on average 15% more and 4% smaller red blood cells compared to non-supplemented individuals and these diet effects were independent of flight manipulation. Haemoglobin content was 7% higher in non-supplemented flying birds compared to non-flying birds, while similar haemoglobin content was observed among supplemented birds that were flown or not. Neither diet nor flight activity influenced haematocrit.
The concerted adjustments suggest that supplementation generally improved antioxidant protection in blood, which could prevent the excess removal of cells from the bloodstream and may have several implications on the oxygen delivery system, including improved gas exchange and blood flow. The flexible haematological response to dietary anthocyanins may also suggest that free-ranging species preferentially consume anthocyanin-rich fruits for their natural blood doping, oxygen delivery-enhancement effects.
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