Influence of dietary dacitic tuff breccia on laying hen performance and egg quality parameters and bone structure at 85 weeks of age after a non-anorexic molt program at 73 to 77 weeks.

The objective of the study was to assess the efficacy of AZOMITE (AZM), a dacitic tuff breccia, in laying hens through egg quality and production parameters. A total of ninety six 73-wk-old Hy-Line W-36 commercial laying hens were randomly assigned to 2 dietary treatments, a control diet and the same diet containing 0.25% AZM, with 24 replicates of 2 hens/replication. From 73 to 77 wk, hens went through nonanorexic molt, and, from 77 to 85 wk, the hens were evaluated for egg production, eggshell quality, and bone health. At wk 85, tibiotarsi were collected for ash and mineral composition, ileal contents were collected for calcium, phosphorus, apparent metabolizable energy corrected for N (AMEn), and apparent nitrogen retention (ANR) evaluation. AZM-fed hens tended to have higher body weight (P = 0.07) from 82 to 83 and 84 to 85 wk, and higher hen day egg production than control (90.54 vs. 79.51%, P = 0.005) from 84 to 85 wk. In general, no differences were reported in feed intake, eggshell color, egg weight, albumen height, Haugh units, or eggshell thickness (P > 0.05). However, shell strength and elasticity were improved (P < 0.02) and yolk color was decreased (P = 0.03) in AZM-fed hens than control. Moreover, the digestibility of Ca, AMEn, and ANR was increased with 0.25% AZM compared to control (P < 0.01). Tibiotarsi P and Ca percentage were lower in AZM-fed birds than control (P < 0.01), without affecting bone strength and mineral density (P > 0.36). Therefore, the use of 0.25% AZM showed a potential in improving egg production and eggshell strength, while maintaining bone quality in post-molt laying hens.

An exploration of healthcare providers' experiences and perspectives of Traditional and complementary medicine usage and disclosure by Indigenous cancer patients.

BACKGROUND: Traditional and complementary medicines (T&CM) are any form of medicine, practice, treatment, product, technology, knowledge system or ceremony outside of conventional medical practice that aims to prevent and/or treat illness and/or promote well-being. Alongside conventional cancer treatments, T&CM usage is increasing; with 19% of indigenous Australians with cancer reporting using T&CM. There is limited evidence surrounding T&CM use and disclosure by indigenous patients. Our aim was to explore healthcare providers' views about usage, disclosure/non-disclosure of T&CM by Indigenous cancer patients. METHODS: Semi-structured, in-depth interviews with 18 healthcare providers, including three indigenous providers, at a large urban hospital providing care to Indigenous cancer patients were conducted to explore providers' experiences and attitudes towards T&CM use by Indigenous cancer patients. An interpretive phenomenological approach was used to thematically analyse the data. RESULTS: Analysis revealed six themes: concern about risk; no 'real' benefits; perception of T&CM and conventional medicine as antithetical; barriers to disclosure; 'patients' choice' a double-edged sword; and providers' lack of knowledge about T&CM. Healthcare providers perceived discord between T&CM and conventional medicine. Most lacked knowledge of T&CM, and had concerns around negative-interactions with conventional treatments. They considered T&CM outside their role, citing this as reasoning for their lack of knowledge. Indigenous healthcare providers had greater understanding and openness towards T&CM. CONCLUSIONS: Given the potential usage of T&CM by Indigenous cancer patients, providers need a more comprehensive understanding of T&CM in order to inform discussion and facilitate effective disclosure on this topic. If indigenous Australians with cancer feel that cancer care providers are unreceptive to discussing T&CM, patient care risks being compromised; particularly given the potential for negative interactions between T&CM and conventional cancer treatments. Fostering health care interactions where indigenous patients feel comfortable to discuss T&CM usage should be a priority for all cancer care services.

Exploring traditional and complementary medicine use by Indigenous Australian women undergoing gynaecological cancer investigations.

BACKGROUND: Indigenous Australian women experience worse gynaecological cancer outcomes than non-Indigenous women. While traditional and complementary medicine (T&CM) is increasingly used by cancer patients alongside conventional treatments, little is known about T&CM use by Indigenous women. This study aimed to explore the beliefs, attitudes and experiences related to T&CM use and disclosure among Indigenous women undergoing gynaecological cancer investigations. METHODS: A mixed-methods design explored T&CM use among Indigenous women who presented for gynaecological cancer investigation at an urban Queensland hospital (September 2016 and January 2018). RESULTS: Fourteen women participated. The reported use (86%) and perceived value of T&CM was high among the participants, however, women reported major challenges in communicating with healthcare providers about T&CM, commonly associated with trust and rapport. CONCLUSIONS: These findings highlight the need for strategies to facilitate culturally-appropriate doctor-patient communication around T&CM to foster trust and transparency in gynaecological cancer care for Indigenous women.

Short communication: Effect of 3 phytoceutical products on elimination of bacteria in experimentally induced Streptococcus uberis clinical mastitis.

Our objective was to assess the ability of 3 herbal products to eliminate experimentally induced Streptococcus uberis mastitis. These herbal products, also known as phytoceuticals, are used in organically managed dairy cattle to maintain or promote udder health. The products tested were an intramammary product, a topical product, and a product applied to the vulvar area. These products are not approved by the US Food and Drug Administration for treatment of mastitis but they are sold to enhance milk quality or for maintenance or improvement of udder health. Each of the products contains at least one component shown to have antibacterial activity. In this study, we successfully challenge-inoculated 25 lactating dairy cows maintained under organic conditions with an isolate of S. uberis. All challenged cows were positive for S. uberis by milk culture after challenge. When cows met predefined criteria indicating the presence of clinical mastitis, treatment with 1 of the 3 products was initiated based upon a predetermined random allocation. Culture of aseptically collected quarter milk samples was performed before, during, and following challenge with S. uberis. Eight, 8, and 9 cows received the intravulvar, intramammary, and topical treatments, respectively. Milk from all cows that were treated with phytoceuticals were culture-positive for S. uberis at every time point following treatment through 168 h following the last phytoceutical treatment. Based upon the presence of clinical signs and for humane reasons, 2 intravulvar-treated cows, 1 topical-treated, and 4 intramammary-treated cows received intramammary antibiotic therapy. We concluded that the phytoceuticals tested, as dosed and used in this trial, did not produce bacterial cures in S. uberis-induced mastitis.

Antitrypanosomal activity and evaluation of the mechanism of action of diterpenes from aerial parts of Baccharis retusa (Asteraceae).

Baccharis retusa, a medicinal Brazilian plant from Asteraceae, has been used in Brazilian folk medicine to treatment of several illnesses, including parasitic diseases. Bioactivity-guided fractionation of the n-hexane extract from the aerial parts of B. retusa resulted in the isolation and characterization of three active related diterpenes: ent-15ß-senecioyl-oxy-kaur-16-en-19-oic acid (1), ent-kaur-16-en-19-oic (2) and ent-16-oxo-17-nor-kauran-19-oic (3) acids. The structures of isolated compounds were defined by spectroscopic analysis, including NMR and HRESIMS. Antitrypanosomal activity of 1-3 was performed against cell-derived trypomastigotes using the colorimetric resazurin assay. The obtained results demonstrated that isolated compounds displayed a reduced toxicity against NCTC cells and were effective against the trypomastigote forms of T. cruzi with IC50 values of 3.8µM (1), 75.3µM (2) and 44.2µM (3). Additionally, compound 3 displayed activity against amastigote forms of T. cruzi with IC50 of 83.2µM. Compound 1 displayed the highest selectivity index (SI) when considered the trypomastigote forms, and its effect in the plasma membrane of parasite was evaluated using the fluorescent probe SYTOX Green. A considerable permeabilization (57%) in the membrane of the parasite was observed when compared to the untreated trypomastigotes. These data demonstrate, for the first time, the antitrypanosomal activity and mechanism of action of 1 and related compounds 2 and 3, obtained from aerial parts of B. retusa.

Brain regions implicated in inhibitory control and appetite regulation are activated in response to food portion size and energy density in children.

OBJECTIVE: Large portions of energy-dense foods drive energy intake but the brain mechanisms underlying this effect are not clear. Our main objective was to investigate brain function in response to food images varied by portion size (PS) and energy density (ED) in children using functional magnetic resonance imaging (fMRI). METHODS AND DESIGN: Blood-oxygen-level-dependent (BOLD) fMRI was completed in 36 children (ages 7-10 years) after a 2-h fast while viewing food images at two levels of PS (Large PS, Small PS) and two levels of ED (High ED, Low ED). Children rated perceived fullness pre- and post-fMRI, as well as liking of images on visual analog scales post-fMRI. Anthropometrics were completed 4 weeks before the fMRI. Large PS vs Small PS and High ED vs Low ED were compared with region-of-interest analyses using Brain Voyager v 2.8. RESULTS: Region-of-interest analyses revealed that activation in the right inferior frontal gyrus (P=0.03) was greater for Large PS vs Small PS. Activation was reduced for High ED vs Low ED in the left hypothalamus (P=0.03). Main effects were no longer significant after adjustment for pre-fMRI fullness and liking ratings (PS, P=0.92; ED, P=0.58). CONCLUSION: This is the first fMRI study to report increased activation to large portions in a brain region that is involved in inhibitory control. These findings may contribute to understanding why some children overeat when presented with large portions of palatable food.

Parasaccharibacter apium, gen. nov., sp. nov., Improves Honey Bee (Hymenoptera: Apidae) Resistance to Nosema.

The honey bee, Apis mellifera L., is host to a variety of microorganisms. The bacterial community that occupies the adult worker gut contains a core group of approximately seven taxa, while the hive environment contains its own distribution of bacteria that is in many ways distinct from the gut. Parasaccharibacter apium, gen. nov., sp. nov., is a hive bacterium found in food stores and in larvae, worker jelly, worker hypopharyngeal glands, and queens. Parasaccharibacter apium increases larval survival under laboratory conditions. To determine if this benefit is extended to colonies in the field, we tested if P. apium 1) survives and reproduces in supplemental pollen patty, 2) is distributed throughout the hive when added to pollen patty, 3) benefits colony health, and 4) increases the ability of bees to resist Nosema. Parasaccharibacter apium survived in supplemental diet and was readily consumed by bees. It was distributed throughout the hive under field conditions, moving from the pollen patty to hive larvae. While P. apium did not significantly increase colony brood production, food stores, or foraging rates, it did increase resistance to Nosema infection. Our data suggest that P. apium may positively impact honey bee health.

The oxytocin-CD38-vitamin A axis in pregnant women involves both hypothalamic and placental regulation.

OBJECTIVE: Oxytocin, a hypothalamic hormone secreted upon release of ectoenzyme CD38, plays a vital role in interpersonal bonding behaviors. Reduced plasma oxytocin characterizes autistic individuals. CD38 levels, which were found to be low in LBCs derived from autistic patients, is upregulated upon the addition of a vitamin A derivative. During pregnancy, oxytocin is also secreted by placenta. Recent controversial studies have suggested an increased risk for autism when oxytocin is used during induction and augmentation of labor. We aimed to examine the tripartite relationship between oxytocin, CD38 and vitamin A in pregnant women and their newborns. METHODS: Thirty-one healthy expectant mothers were enlisted for this study. Levels of oxytocin, CD38 and ATRA were measured in both maternal peripheral and newborn cord blood, and the tripartite relationship between these parameters examined. Estrogen and progesterone levels of the mothers were also recorded. Several clinical measures were also noted. RESULTS: Mean maternal oxytocin and vitamin A levels were approximately 8- and 4-fold higher, respectively, than neonatal levels. CD38 expression, however, was 9 times higher in neonates than in the maternal group. Positive correlation was found between maternal and cord blood for both oxytocin and CD38. CONCLUSIONS: This establishment of normative values for oxytocin, CD38 and vitamin A in healthy pregnant women and newborns may serve as a reference in the investigation of developing pathologies of disorders such as autism.

Subchondral and epiphyseal bone remodeling following surgical transection and noninvasive rupture of the anterior cruciate ligament as models of post-traumatic osteoarthritis.

OBJECTIVE: Animal models are frequently used to study post-traumatic osteoarthritis (PTOA). A common anterior cruciate ligament (ACL) injury model is surgical transection, which may introduce confounding factors from surgery. Noninvasive models could model human injury more closely. The purpose of this study was to compare subchondral and epiphyseal trabecular bone remodeling after surgical transection and noninvasive rupture of the ACL. METHODS: Thirty-six rats were randomized to an uninjured control, surgical transection (Transection), or noninvasive rupture (Rupture). Animals were randomized to 4 or 10 week time points (n = 6 per group). Micro computed tomography (µCT) imaging was performed with an isotropic voxel size of 12 µm. Subchondral and epiphyseal bone was segmented semi-automatically, and morphometric analysis was performed. RESULTS: Transection caused a greater decrease in subchondral bone volume fraction (BV/TV) than Rupture in the femur and tibia. Rupture had greater subchondral bone tissue mineral density (TMD) at 4 and 10 weeks in the femur and tibia. Subchondral bone thickness (SCB.Th) was decreased in the femur in Transection only. Epiphyseal BV/TV was decreased in Transection only, and Rupture exhibited increased femoral epiphyseal TMD compared to both Control and Transection. Rupture exhibited greater femoral epiphyseal trabecular thickness (Tb.Th.) compared to Control and Transection at 4 weeks, and both Rupture and Transection had increased femoral epiphyseal Tb.Th. at 10 weeks. Epiphyseal trabecular number (Tb.N) was decreased in both injury groups at both time points. Femoral and tibial epiphyseal structure model index (SMI) increased in both groups. CONCLUSIONS: The two injury models cause differences in post-injury bone morphometry, and surgical transection may be introducing confounding factors that affect downstream bony remodeling.

Vitamin D and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case-Control Consortium.

BACKGROUND: The potential role of vitamin D in the aetiology of pancreatic cancer is unclear, with recent studies suggesting both positive and negative associations. PATIENTS AND METHODS: We used data from nine case-control studies from the International Pancreatic Cancer Case-Control Consortium (PanC4) to examine associations between pancreatic cancer risk and dietary vitamin D intake. Study-specific odds ratios (ORs) were estimated using multivariable logistic regression, and ORs were then pooled using a random-effects model. From a subset of four studies, we also calculated pooled estimates of association for supplementary and total vitamin D intake. RESULTS: Risk of pancreatic cancer increased with dietary intake of vitamin D [per 100 international units (IU)/day: OR = 1.13, 95% confidence interval (CI) 1.07-1.19, P = 7.4 × 10(-6), P-heterogeneity = 0.52; ≥230 versus <110 IU/day: OR = 1.31, 95% CI 1.10-1.55, P = 2.4 × 10(-3), P-heterogeneity = 0.81], with the association possibly stronger in people with low retinol/vitamin A intake. CONCLUSION: Increased risk of pancreatic cancer was observed with higher levels of dietary vitamin D intake. Additional studies are required to determine whether or not our finding has a causal basis.

Short communication: an in vitro assessment of the antibacterial activity of plant-derived oils.

Nonantibiotic treatments for mastitis are needed in organic dairy herds. Plant-derived oils may be useful but efficacy and potential mechanisms of action of such oils in mastitis therapy have not been well documented. The objective of the current study was to evaluate the antibacterial activity of the plant-derived oil components of Phyto-Mast (Bovinity Health LLC, Narvon, PA), an herbal intramammary product, against 3 mastitis-causing pathogens: Staphylococcus aureus, Staphylococcus chromogenes, and Streptococcus uberis. Plant-derived oils evaluated were Thymus vulgaris (thyme), Gaultheria procumbens (wintergreen), Glycyrrhiza uralensis (Chinese licorice), Angelica sinensis, and Angelica dahurica. Broth dilution testing according to standard protocol was performed using ultrapasteurized whole milk instead of broth. Controls included milk only (negative control), milk + bacteria (positive control), and milk + bacteria + penicillin-streptomycin (antibiotic control, at 1 and 5% concentrations). Essential oil of thyme was tested by itself and not in combination with other oils because of its known antibacterial activity. The other plant-derived oils were tested alone and in combination for a total of 15 treatments, each replicated 3 times and tested at 0.5, 1, 2, and 4% to simulate concentrations potentially achievable in the milk within the pre-dry-off udder quarter. Thyme oil at concentrations ≥2% completely inhibited bacterial growth in all replications. Other plant-derived oils tested alone or in various combinations were not consistently antibacterial and did not show typical dose-response effects. Only thyme essential oil had consistent antibacterial activity against the 3 mastitis-causing organisms tested in vitro. Further evaluation of physiological effects of thyme oil in various preparations on mammary tissue is recommended to determine potential suitability for mastitis therapy.

Effect of 2 herbal intramammary products on milk quantity and quality compared with conventional and no dry cow therapy.

Dry cow therapy, administered at the end of lactation, is aimed at eliminating current and preventing future intramammary (IMM) bacterial infections and typically involves intramammary administration of antibiotics. Certified organic dairies in the United States are restricted from using antibiotics and must consider an alternative therapy or no dry cow therapy. The current study compared 2 herbal products to conventional dry cow therapy and no treatment for a total of 5 treatments over 2 trials. Trial 1 was conducted over 3 yr on 1 research farm and trial 2 included 4 commercial farms plus the research herd over 2 yr. Treatments included (1) a conventional IMM antibiotic and internal teat sealant (penicillin-dihydrostreptomycin and bismuth subnitrate; CON); (2) an herbal IMM product purported to act as a teat sealant (Cinnatube, New AgriTech Enterprises, Locke, NY; CIN); (3) an herbal IMM product (Phyto-Mast, Bovinity Health LLC, Narvon, PA; P-M); (4) Phyto-Mast and Cinnatube (PC); or (5) no dry cow therapy (NT). Each treatment group was balanced by breed, lactation number, due date, herd, and year. However, the CON treatment was used only in the research herd because of the intent to avoid antibiotic usage on the other 4 farms. Comparisons among treatments included the difference between pre- and posttreatment 305-d mature equivalent milk production (trial 1), somatic cell score change from dry-off to freshening at the cow and quarter levels (trials 1 and 2), and milk microbiology change over the dry period (trial 2). We detected no significant differences among treatments for milk yield differences between the lactation following treatment and the lactation preceding treatment. Changes in somatic cell score from one lactation to the next also did not differ significantly among treatments in either trial. Cure rates were not significantly different among treatments; only 19.6% of all quarters were infected at dry off. The proportion of quarters with new infections at 3 to 5d postcalving did not significantly differ among treatments, except between CIN and NT. Percentages (least squares means ± standard error) of quarters with new infections were 24 ± 21% for CON, 15 ± 7% for CIN, 30 ± 10% for P-M, 32 ± 11% for PC, and 35 ± 11% for NT. The efficacy of the herbal products was similar to that of conventional therapy, and the herbal products had no apparent adverse effects.

Intake of coffee, caffeine and other methylxanthines and risk of Type I vs Type II endometrial cancer.

BACKGROUND: Coffee and other sources of methylxanthines and risk of Type I vs Type II endometrial cancer (EC) have not been evaluated previously. METHODS: Prospective cohort of 23,356 postmenopausal women with 471 Type I and 71 Type II EC cases. RESULTS: Type I EC was statistically significantly associated with caffeinated (relative risk (RR)=0.65 for 4+ cups per day vs ≤1 cup per month: 95% confidence interval (CI): 0.47-0.89) but not decaffeinated (RR=0.76; 95% CI: 0.50-1.15) coffee intake; there were no associations with tea, cola or chocolate, or for Type II EC. The inverse association with caffeinated coffee intake was specific to women with a body mass index 30+ kg m(-2) (RR=0.56; 95% CI: 0.36-0.89). CONCLUSION: Coffee may protect against Type I EC in obese postmenopausal women.

Molecular epidemiology of Staphylococcus aureus mastitis in dairy heifers.

The specific purpose was to investigate the possible interrelationships of genotypes of Staphylococcus aureus found in mammary glands, horn flies, and extramammary sites on 3 southeastern US dairies. A total of 1,228 samples were obtained from various sources on the 3 dairy herds, each of which had a history of Staph. aureus mastitis. Dairy herds studied had access to pasture, and samples were collected during the summer when horn flies (Haematobia irritans) were active. Samples collected included milk samples from all lactating herd cows, colostrum samples from heifers calving during the study period, heifer body sites (mouth, nostrils, and teats), the heifer environment (water, feed, and soil/vegetation/pasture), horn flies, and humans (hands and nostrils). Isolation of Staph. aureus was attempted from all samples, with isolates subjected to genotypic analysis using pulsed-field gel electrophoresis. A total of 244/1228 (or 19.9%) of all samples were positive for Staph. aureus. For milk samples, 52/383 (or 13.6%) of samples were Staph. aureus positive, and 70/411 (or 17.0%) of heifer quarter colostrum samples were positive. Horn fly samples were frequently positive, with over one-half (29/52, or 55.8%) of samples positive for Staph. aureus. Staphylococcus aureus obtained during the study comprised isolates from 12 different genotype groups as defined in this study. Identical genotypes were obtained from horn flies, heifer colostrum samples, and cow milk samples. Group B genotypes were shared among flies, heifer colostrum samples, body sites, and cow milk samples, whereas group A genotypes were common to the same sample locations and body sites but rarely (once) found in horn flies. We conclude, based upon the finding of identical pulsed-field gel electrophoresis genotypes in flies, heifer body sites, and heifer colostrum samples, that flies and heifer body sites could be important sources of Staph. aureus for heifer intramammary infections.

Emerging therapies targeting tumor vasculature in multiple myeloma and other hematologic and solid malignancies.

Research on the formation of new blood vessels (angiogenesis) in general and vascular endothelial growth factor (VEGF) in particular is a major focus in biomedicine and has led to the clinical approval of the monoclonal anti- VEGF antibody bevazicumab; and the second-generation multitargeted receptor kinase inhibitors (RTKIs) sorafenib, sunitinib, and pazopanib. Although these agents show significant preclinical and clinical anti-cancer activity, they prolong overall survival of cancer patients for only months, followed by a restoration of tumor growth and progression. Therefore, there is a clear need to increase our understanding of tumor angiogenesis and the development of resistance. In this review we discuss up-to-date knowledge on mechanisms of tumor angiogenesis, and summarize preclinical and clinical data on existing and potential future anti-angiogenic agents and treatment strategies for Multiple Myeloma (MM) and other hematologic and solid malignancies.

Milk and plasma disposition of thymol following intramammary administration of a phytoceutical mastitis treatment.

Despite the recent growth of the organic dairy industry, organic producers and veterinarians have limited information when choosing mastitis treatments for animals in organic dairy production. Organic producers commonly administer homeopathic or other plant-based products without having research evaluating the efficacy of these products and using estimated or no withholding times to treat mastitis and other health problems in their herds. In this pilot study, we attempted to identify several active ingredients of Phyto-Mast (Penn Dutch Cow Care, Narvon, PA), a plant-based mastitis treatment used on organic dairy farms, and to quantify the product residue in milk and plasma after intramammary administration. We developed an assay to quantify thymol (one of the active ingredients in Phyto-Mast) in milk and plasma using gas chromatography and mass spectrometry (GC-MS). Thymol is a volatile aromatic compound with antiinflammatory properties. As a model for dairy cows, 5 healthy, lactating alpine dairy goats were given 5 mL of Phyto-Mast per udder half. For 10 d following treatment, we analyzed blood and milk samples for thymol residues using GC-MS. The GC-MS assay was very sensitive for thymol detection, to a concentration of 0.01 µg/mL in plasma. Using thymol as a marker, Phyto-Mast was detectable and quantifiable in plasma beginning with the 15-min posttreatment sample, but was no longer detectable in the 4-h posttreatment sample. Thymol residues were only detected in the 12-h posttreatment milk sample. An inflammatory response was not evident in the udder following phytoceutical administration. Although this study provides information about the elimination of thymol, the product contains several other active chemicals, which may have different pharmacokinetic behaviors. Further analysis and additional study animals will help to determine a milk withholding time for Phyto-Mast. Given the recent growth of the organic dairy industry, understanding the pharmacokinetics of therapeutics used in organic production and developing accurate withholding recommendations will help to ensure milk safety.

Dietary and supplemental intake of one-carbon nutrients and the risk of type I and type II endometrial cancer: a prospective cohort study.

BACKGROUND: Type I and II endometrial cancer are biologically and clinically distinct, with type II cancers having a high frequency of p53 mutations and an association with chromosomal instability. This raises the hypothesis that one-carbon nutrients (folate, methionine, and the enzymic cofactors vitamins B2, B6, and B12), which mediate chromosomal stability and DNA methylation, may be protective for type II but not type I endometrial cancer. METHODS: Using a prospective cohort of 23 356 postmenopausal women followed 20 years, we estimated the relative risks (RRs) of type I (N = 471) and II (N = 71) endometrial cancers according to intake of one-carbon nutrients, adjusting for confounders. RESULTS: No associations were observed between dietary or supplemental intake of any one-carbon nutrient and risk of type I cancer. For type II cancer, positive associations were due to supplemental, rather than dietary, intake of these nutrients: supplemental folate (RR = 1.80 for >228.6 versus 0 µg/day; P trend = 0.027) and vitamins B2 (RR = 1.94 for >1.70 versus 0 mg/day; P trend = 0.011), B6 (RR = 2.08 for >2.00 versus 0 mg/day; P trend = 0.012), and B12 (RR = 2.10 for >3.43 versus 0 µg/day; P trend = 0.0060). CONCLUSION: Contrary to our hypothesis, use of supplements containing folate and vitamins B2, B6, and B12 was associated with an increased risk of type II endometrial cancer.

Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials.

The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique ß-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.

Elevation of serum epidermal growth factor and interleukin 1 receptor antagonist in active psoriasis vulgaris.

BACKGROUND: Psoriatic plaques present a complex expression profile, including high levels of cytokines, chemokines and growth factors. Circulating cytokines have been suggested to reflect the activation status of the inflammatory process. OBJECTIVES: To analyse 20 cytokines, chemokines and growth factors in 14 patients with psoriasis vulgaris at the start and during the course of ultraviolet B treatment. METHODS: A multiplex cytokine assay was used. RESULTS: We identified increased serum levels of epidermal growth factor (EGF) (mean 323 vs. 36·6 pg mL⁻¹, P = 0·0001), interleukin (IL)-1 receptor antagonist (mean 39·1 vs. 14·6 pg mL⁻¹, P = 0·02) and tumour necrosis factor-α (mean 7·5 vs. 4·5 pg mL⁻¹, P = 0·04) at baseline in patients with psoriasis compared with matched controls. None of these cytokines was correlated to the severity of the disease (Psoriasis Area and Severity Index) or decreased with phototherapy, suggesting that sources other than lesional skin contribute to the production of these cytokines. Using cluster analysis, we observed coordinate upregulation of EGF, IL-6, macrophage inflammatory protein-1ß and vascular endothelial growth factor. CONCLUSIONS: The sustained high expression of inflammatory circulating cytokines is a potential mechanism linking psoriasis with its extracutaneous comorbidities.

Ascorbic acid inhibits antitumor activity of bortezomib in vivo.

Earlier studies have shown that ascorbic acid (vitamin C) inhibits bortezomib-induced cytotoxicity against cancer cells in vitro. However, the clinical significance of vitamin C on bortezomib treatment is unclear. In this study, we examined whether daily oral intake of vitamin C inhibits antimultiple myeloma (MM) activities of bortezomib. Vitamin C, at orally achievable concentrations, inhibited in vitro MM cell cytotoxicity of bortezomib and blocked its inhibitory effect on 20S proteasome activity. Specifically, plasma collected from healthy volunteers taking 1 g/day vitamin C reduced bortezomib-induced MM cell death in vitro. This antagonistic effect of vitamin C against proteasome inhibitors is limited to the boronate class of inhibitors (bortezomib and MG262). In vivo activity of this combination treatment was then evaluated using our xenograft model of human MM in SCID (severe combined immune-deficient) mice. Bortezomib (0.1 mg/kg twice a week for 4 weeks) significantly inhibits in vivo MM cell growth, which was blocked by oral vitamin C (40 mg/kg/day). Therefore, our results for the first time show that vitamin C can significantly reduce the activity of bortezomib treatment in vivo; and importantly, suggest that patients receiving treatment with bortezomib should avoid taking vitamin C dietary supplements.