The objective of this series of studies was to investigate the effects of inflammatory diseases occurring before breeding on the developmental biology and reproductive responses in dairy cows. Data ...from 5 studies were used to investigate different questions associating health status before breeding and reproductive responses. Health information for all studies was composed of the incidence of retained fetal membranes, metritis, mastitis, lameness, and respiratory and digestive problems from parturition until the day of breeding. Retained placenta and metritis were grouped as uterine disease (UTD). Mastitis, lameness, digestive and respiratory problems were grouped as nonuterine diseases (NUTD). Study 1 evaluated the effect of disease before artificial insemination (AI), anovulation before synchronization of the estrous cycle, and low body condition score at AI on pregnancy per AI, as well as their potential interactions or additive effects. Study 2 investigated the effect of site of inflammation (UTD vs. NUTD) and time of occurrence relative to preantral or antral stages of ovulatory follicle development, and the effect of UTD and NUTD on fertility responses of cows bred by AI or by embryo transfer. Study 3 evaluated the effect of disease on fertilization and embryonic development to the morula stage. Study 4 evaluated the effect of disease on preimplantation conceptus development as well as secretion of IFN-τ and transcriptome. Study 5 investigated the effect of diseases before AI on the transcript expression of interferon-stimulated genes in peripheral blood leukocytes during peri-implantation stages of conceptus development after first AI postpartum. Altogether, these studies demonstrated that inflammatory disease before breeding reduced fertilization of oocytes and development to morula, and impaired early conceptus development to elongation stages and secretion of IFN-τ in the uterine lumen. Diseases caused inflammation-like changes in transcriptome of conceptus cells, increased risk of pregnancy loss, and reduced pregnancy or calving per breeding. Moreover, the effects on reproduction were independent of cyclic status before synchronization of the estrous cycle and body condition score at breeding, which all had additive negative effects on fertility of dairy cows. Occurrence of disease at preantral or at antral stages of ovulatory follicle development had similar detrimental effects on pregnancy results. The carryover effects of diseases on developmental biology might last longer than 4 mo. Reduced oocyte competence is a likely reason for carryover effects of diseases on developmental biology, but impaired uterine environment was also shown to be involved.
FOXM1 has been implicated in taxane resistance, but the molecular mechanism involved remains elusive. In here, we show that FOXM1 depletion can sensitize breast cancer cells and mouse embryonic ...fibroblasts into entering paclitaxel-induced senescence, with the loss of clonogenic ability, and the induction of senescence-associated β-galactosidase activity and flat cell morphology. We also demonstrate that FOXM1 regulates the expression of the microtubulin-associated kinesin KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Similar to FOXM1, KIF20A expression is downregulated by paclitaxel in the sensitive MCF-7 breast cancer cells and deregulated in the paclitaxel-resistant MCF-7Tax(R) cells. KIF20A depletion also renders MCF-7 and MCF-7Tax(R) cells more sensitive to paclitaxel-induced cellular senescence. Crucially, resembling paclitaxel treatment, silencing of FOXM1 and KIF20A similarly promotes abnormal mitotic spindle morphology and chromosome alignment, which have been shown to induce mitotic catastrophe-dependent senescence. The physiological relevance of the regulation of KIF20A by FOXM1 is further highlighted by the strong and significant correlations between FOXM1 and KIF20A expression in breast cancer patient samples. Statistical analysis reveals that both FOXM1 and KIF20A protein and mRNA expression significantly associates with poor survival, consistent with a role of FOXM1 and KIF20A in paclitaxel action and resistance. Collectively, our findings suggest that paclitaxel targets the FOXM1-KIF20A axis to drive abnormal mitotic spindle formation and mitotic catastrophe and that deregulated FOXM1 and KIF20A expression may confer paclitaxel resistance. These findings provide insights into the underlying mechanisms of paclitaxel resistance and have implications for the development of predictive biomarkers and novel chemotherapeutic strategies for paclitaxel resistance.
The objectives were to characterize the prevalence of periparturient diseases and their effects on reproductive performance of dairy cows in seasonal grazing farms. A total of 957 multiparous cows in ...2 farms (555 in farm A and 402 in farm B) were evaluated and diseases characterized. At calving, dystocia, twin birth, stillbirth, and retained fetal membranes were recorded and grouped as calving problems. On d 7±3 and 14±3 postpartum, cows were evaluated for metritis and on d 28±3 for clinical endometritis based on scoring of the vaginal discharge. From parturition to 30d after artificial insemination (AI), prevalence of mastitis, lameness, and digestive and respiratory problems were recorded. For subclinical diseases, diagnosis was based on blood samples collected from 771 cows and analyzed for concentrations of Ca, nonesterified fatty acids (NEFA), and β-hydroxybutyrate. Cows were considered as having elevated NEFA concentration if the concentration was ≥0.70mM, subclinical ketosis if the β-hydroxybutyrate concentration was ≥0.96mM, and subclinical hypocalcemia if the Ca concentration was ≤2.14mM. Ovaries were scanned on d 35±3 and 49±3 postpartum for determination of estrous cyclicity. All cows were enrolled in a timed AI program and inseminated on the first day of the breeding season: on average, 86d postpartum. Overall, 37.5% (359/957) of the cows presented at least 1 clinical disease and 59.0% (455/771) had at least 1 subclinical health problem. Prevalence of individual diseases was 8.5% for calving problems, 5.3% for metritis, 15.0% for clinical endometritis, 13.4% for subclinical endometritis, 15.3% for mastitis, 2.5% for respiratory problems, 4.0% for digestive problems, 3.2% for lameness, 20.0% for elevated NEFA concentration, 35.4% for subclinical ketosis, and 43.3% for subclinical hypocalcemia. Clinical and subclinical diseases had additive negative effects on reproduction, delaying resumption of estrous cyclicity and reducing pregnancy per AI (P/AI). Occurrence of multiple diseases further reduced reproductive efficiency compared with a single disease. Individually, subclinical hypocalcemia, elevated NEFA concentration, metritis, and respiratory and digestive problems reduced estrous cyclicity by d 49 postpartum. Elevated NEFA concentration, calving problem, metritis, clinical and subclinical endometritis, and digestive problems reduced P/AI on d 65 after AI. Moreover, calving problems and clinical endometritis increased the risk of pregnancy loss between gestation d 30 and 65. Serum concentrations of Ca and NEFA were negatively correlated, and both were associated with prevalence of uterine diseases. In conclusion, periparturient diseases were highly prevalent in seasonally calving grazing dairies and affected cows had delayed resumption of estrous cyclicity, reduced P/AI, and increased risk of pregnancy loss.
Loss of pregnancy can occur at many different stages of gestation and for a variety of causes but clearly produces a negative impact for reproductive and economic performances of dairy herds. This ...review describes four pivotal periods for pregnancy loss during the first trimester of gestation and discusses possible causes for pregnancy failure during these periods. The first period occurs during the first week after breeding with lack of fertilization and death of the early embryo producing major losses in pregnancy, particularly under specific environmental and hormonal conditions. In general, 20%–50% of high-producing lactating dairy cows have already experienced pregnancy loss during the first week of gestation with methods to decrease pregnancy loss during this period targeting improved oocyte quality by alleviating heat stress, inflammatory diseases, and body condition loss, and by increasing progesterone concentrations during preovulatory follicle development. The second pivotal period, from Days 8 to 27, encompasses embryo elongation and the classical “maternal recognition of pregnancy” period with losses averaging ∼30% but with surprising variation between farms (25%–41%). Maintenance of the CL of pregnancy is produced by the embryonic signal interferon-tau and alteration in uterine secretory patterns of prostaglandins F2α, E1, and E2. Failures or delays in trophoblast elongation and/or embryonic development result in loss of pregnancy during the second pivotal period possibly due to suboptimal histotroph. The third pivotal period is during the second month of pregnancy, Days 28 to 60, with losses of ∼12% based on a summary of published results from more than 20,000 pregnancies in high-producing dairy cows. Delays or defects in development of the chorioallantoic placentomes or embryo result in CL regression or embryo death during this pivotal period. Finally, a fourth period during the third month of pregnancy has reduced pregnancy losses (∼2%), compared with the first three periods but can be elevated in some cows, particularly in those carrying twins in the same uterine horn. Thus, there are varied causes for pregnancy losses during each pivotal period that correspond to key physiological changes in the embryo, uterine environment, and ovary. Similarly, strategies to reduce these losses are likely to require a multifaceted approach using rational methods that target the critical physiology in each pivotal period.
FOXM1 is implicated in genotoxic drug resistance but its mechanism of action remains elusive. We show here that FOXM1-depletion can sensitize breast cancer cells and mouse embryonic fibroblasts ...(MEFs) into entering epirubicin-induced senescence, with the loss of long-term cell proliferation ability, the accumulation of γH2AX foci, and the induction of senescence-associated β-galactosidase activity and cell morphology. Conversely, reconstitution of FOXM1 in FOXM1-deficient MEFs alleviates the accumulation of senescence-associated γH2AX foci. We also demonstrate that FOXM1 regulates NBS1 at the transcriptional level through an forkhead response element on its promoter. Like FOXM1, NBS1 is overexpressed in the epirubicin-resistant MCF-7Epi(R) cells and its expression level is low but inducible by epirubicin in MCF-7 cells. Consistently, overexpression of FOXM1 augmented and FOXM1 depletion reduced NBS1 expression and epirubicin-induced ataxia-telangiectasia mutated (ATM)phosphorylation in breast cancer cells. Together these findings suggest that FOXM1 increases NBS1 expression and ATM phosphorylation, possibly through increasing the levels of the MRN(MRE11/RAD50/NBS1) complex. Consistent with this idea, the loss of P-ATM induction by epirubicin in the NBS1-deficient NBS1-LBI fibroblasts can be rescued by NBS1 reconstitution. Resembling FOXM1, NBS1 depletion also rendered MCF-7 and MCF-7Epi(R) cells more sensitive to epirubicin-induced cellular senescence. In agreement, the DNA repair-defective and senescence phenotypes in FOXM1-deficent cells can be effectively rescued by overexpression of NBS1. Moreover, overexpression of NBS1 and FOXM1 similarly enhanced and their depletion downregulated homologous recombination (HR) DNA repair activity. Crucially, overexpression of FOXM1 failed to augment HR activity in the background of NBS1 depletion, demonstrating that NBS1 is indispensable for the HR function of FOXM1. The physiological relevance of the regulation of NBS1 expression by FOXM1 is further underscored by the strong and significant correlation between nuclear FOXM1 and total NBS1 expression in breast cancer patient samples, further suggesting that NBS1 as a key FOXM1 target gene involved in DNA damage response, genotoxic drug resistance and DNA damage-induced senescence.
Recommendations
To identify a person with diabetes at risk for foot ulceration, examine the feet annually to seek evidence for signs or symptoms of peripheral neuropathy and peripheral artery ...disease. (GRADE strength of recommendation: strong; Quality of evidence: low)
In a person with diabetes who has peripheral neuropathy, screen for a history of foot ulceration or lower‐extremity amputation, peripheral artery disease, foot deformity, pre‐ulcerative signs on the foot, poor foot hygiene and ill‐fitting or inadequate footwear. (Strong; Low)
Treat any pre‐ulcerative sign on the foot of a patient with diabetes. This includes removing callus, protecting blisters and draining when necessary, treating ingrown or thickened toe nails, treating haemorrhage when necessary and prescribing antifungal treatment for fungal infections. (Strong; Low)
To protect their feet, instruct an at‐risk patient with diabetes not to walk barefoot, in socks only, or in thin‐soled standard slippers, whether at home or when outside. (Strong; Low)
Instruct an at‐risk patient with diabetes to daily inspect their feet and the inside of their shoes, daily wash their feet (with careful drying particularly between the toes), avoid using chemical agents or plasters to remove callus or corns, use emollients to lubricate dry skin and cut toe nails straight across. (Weak; Low)
Instruct an at‐risk patient with diabetes to wear properly fitting footwear to prevent a first foot ulcer, either plantar or non‐plantar, or a recurrent non‐plantar foot ulcer. When a foot deformity or a pre‐ulcerative sign is present, consider prescribing therapeutic shoes, custom‐made insoles or toe orthosis. (Strong; Low)
To prevent a recurrent plantar foot ulcer in an at‐risk patient with diabetes, prescribe therapeutic footwear that has a demonstrated plantar pressure‐relieving effect during walking (i.e. 30% relief compared with plantar pressure in standard of care therapeutic footwear) and encourage the patient to wear this footwear. (Strong; Moderate)
To prevent a first foot ulcer in an at‐risk patient with diabetes, provide education aimed at improving foot care knowledge and behaviour, as well as encouraging the patient to adhere to this foot care advice. (Weak; Low)
To prevent a recurrent foot ulcer in an at‐risk patient with diabetes, provide integrated foot care, which includes professional foot treatment, adequate footwear and education. This should be repeated or re‐evaluated once every 1 to 3 months as necessary. (Strong; Low)
Instruct a high‐risk patient with diabetes to monitor foot skin temperature at home to prevent a first or recurrent plantar foot ulcer. This aims at identifying the early signs of inflammation, followed by action taken by the patient and care provider to resolve the cause of inflammation. (Weak; Moderate)
Consider digital flexor tenotomy to prevent a toe ulcer when conservative treatment fails in a high‐risk patient with diabetes, hammertoes and either a pre‐ulcerative sign or an ulcer on the distal toe. (Weak; Low)
Consider Achilles tendon lengthening, joint arthroplasty, single or pan metatarsal head resection, or osteotomy to prevent a recurrent foot ulcer when conservative treatment fails in a high‐risk patient with diabetes and a plantar forefoot ulcer. (Weak; Low)
Do not use a nerve decompression procedure in an effort to prevent a foot ulcer in an at‐risk patient with diabetes, in preference to accepted standards of good quality care. (Weak; Low)
Background
Prevention of foot ulcers in patients with diabetes is extremely important to help reduce the enormous burden of foot ulceration on both patient and health resources. A comprehensive ...analysis of reported interventions is not currently available, but is needed to better inform caregivers about effective prevention. The aim of this systematic review is to investigate the effectiveness of interventions to prevent first and recurrent foot ulcers in persons with diabetes who are at risk for ulceration.
Methods
The available medical scientific literature in PubMed, EMBASE, CINAHL and the Cochrane database was searched for original research studies on preventative interventions. Both controlled and non‐controlled studies were selected. Data from controlled studies were assessed for methodological quality by two independent reviewers.
Results
From the identified records, a total of 30 controlled studies (of which 19 RCTs) and another 44 non‐controlled studies were assessed and described. Few controlled studies, of generally low to moderate quality, were identified on the prevention of a first foot ulcer. For the prevention of recurrent plantar foot ulcers, multiple RCTs with low risk of bias show the benefit for the use of daily foot skin temperature measurements and consequent preventative actions, as well as for therapeutic footwear that demonstrates to relieve plantar pressure and that is worn by the patient. To prevent recurrence, some evidence exists for integrated foot care when it includes a combination of professional foot treatment, therapeutic footwear and patient education; for just a single session of patient education, no evidence exists. Surgical interventions can be effective in selected patients, but the evidence base is small.
Conclusion
The evidence base to support the use of specific self‐management and footwear interventions for the prevention of recurrent plantar foot ulcers is quite strong, but is small for the use of other, sometimes widely applied, interventions and is practically nonexistent for the prevention of a first foot ulcer and non‐plantar foot ulcer.
Large gaps in reef distribution may hinder the dispersal of marine organisms, interrupting processes vital to the maintenance of biodiversity. Here we show the presence and location of extensive reef ...habitats on the continental shelf between the Amazon Reef System (ARS) and the Eastern Brazilian Reef System (ERS), two reef complexes off eastern South America. Formations located 20-50 m deep include both biogenic and geogenic structures. The presence of diverse reef assemblages suggests the widespread occurrence of rocky substrates below 50 m. These habitats represent an expansion of both the ARS and ERS and the closure of the only remaining large-scale gap (~ 1000 km) among West Atlantic reef environments. This indicates that the SW Atlantic harbors a single, yet heterogeneous, reef system that stretches for about 4000 km, and thus, represents one of the largest semi-continuous tropical marine ecosystems in the world.
Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) and ERBB2 non-amplified. Somatic mutations in ERBB2/3 are ...emerging as a tractable mechanism underlying enhanced human epidermal growth factor 2 (HER2) activity. We tested the hypothesis that therapeutically targetable ERBB2/3 mutations in primary ILC of the breast associate with poor survival outcome in large public datasets.
We performed in silico comparison of ERBB2 non-amplified cases of ER+ stage I-III primary ILC (N = 279) and invasive ductal carcinoma (IDC, N = 1301) using METABRIC, TCGA, and MSK-IMPACT information. Activating mutations amenable to HER2-directed therapy with neratinib were identified using existing functional data from in vitro cell line and xenograft experiments. Multivariate analysis of 10-year overall survival (OS) with tumor size, grade, and lymph node status was performed using a Cox regression model. Differential gene expression analyses by ERBB2 mutation and amplification status was performed using weighted average differences and an in silico model of response to neratinib derived from breast cancer cell lines.
ILC tumors comprised 17.7% of all cases in the dataset but accounted for 47.1% of ERBB2-mutated cases. Mutations in ERBB2 were enriched in ILC vs. IDC cases (5.7%, N = 16 vs. 1.4%, N = 18, p < 0.0001) and clustered in the tyrosine kinase domain of HER2. ERBB3 mutations were not enriched in ILC (1.1%, N = 3 vs. 1.8%, N = 23; p = 0.604). Median OS for patients with ERBB2-mutant ILC tumors was 66 months vs. 211 months for ERBB2 wild-type (p = 0.0001), and 159 vs. 166 months (p = 0.733) for IDC tumors. Targetable ERBB2 mutational status was an independent prognostic marker of 10-year OS-but only in ILC (hazard ratio, HR = 3.7, 95% CI 1.2-11.0; p = 0.021). Findings were validated using a novel ERBB2 mutation gene enrichment score (HR for 10-year OS in ILC = 2.3, 95% CI 1.04-5.05; p = 0.040).
Targetable ERBB2 mutations are enriched in primary ILC and their detection represents an actionable strategy with the potential to improve patient outcomes. Biomarker-led clinical trials of adjuvant HER-targeted therapy are warranted for patients with ERBB2-mutated primary ILC.
Background Lactobacillus species produce biosurfactants that can contribute to the bacteria’s ability to prevent microbial infections associated with urogenital and gastrointestinal tracts and the ...skin. Here, we described the biological and physicochemical properties of biosurfactants produced by Lactobacillus jensenii P6A and Lactobacillus gasseri P65. Results The biosurfactants produced by L. jensenii P6A and L. gasseri P65 reduced the water surface tension from 72 to 43.2 mN m−1 and 42.5 mN m−1 as their concentration increased up to the critical micelle concentration (CMC) values of 7.1 and 8.58 mg mL−1, respectively. Maximum emulsifying activity was obtained at concentrations of 1 and 5 mg mL−1 for the P6A and P65 strains, respectively. The Fourier transform infrared spectroscopy data revealed that the biomolecules consist of a mixture of carbohydrates, lipids and proteins. The gas chromatography-mass spectrum analysis of L. jensenii P6A biosurfactant showed a major peak for 14-methypentadecanoic acid, which was the main fatty acid present in the biomolecule; conversely, eicosanoic acid dominated the biosurfactant produced by L. gasseri P65. Although both biosurfactants contain different percentages of the sugars galactose, glucose and ribose; rhamnose was only detected in the biomolecule produced by L. jensenii P6A. Emulsifying activities were stable after a 60-min incubation at 100 °C, at pH 2-10, and after the addition of potassium chloride and sodium bicarbonate, but not in the presence of sodium chloride. The biomolecules showed antimicrobial activity against clinical isolates of Escherichia coli and Candida albicans, with MIC values of 16 µg mL−1, and against Staphylococcus saprophyticus, Enterobacter aerogenes and Klebsiella pneumoniae at 128 µg mL−1. The biosurfactants also disrupted preformed biofilms of microorganisms at varying concentrations, being more efficient against E. aerogenes (64%) (P6A biosurfactant), and E. coli (46.4%) and S. saprophyticus (39%) (P65 biosurfactant). Both strains of lactobacilli could also co-aggregate pathogens. Conclusions This report presents the first characterization of biosurfactants produced by L. jensenii P6A and L. gasseri P65. The antimicrobial properties and stability of these biomolecules indicate their potential use as alternative antimicrobial agents in the medical field for applications against pathogens that are responsible for infections in the gastrointestinal and urogenital tracts and the skin.
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