Breast milk is the most effective strategy to protect infants against necrotizing enterocolitis (NEC), a devastating disease that is characterized by severe intestinal necrosis. Previous studies have ...demonstrated that the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) plays a critical role in NEC development via deleterious effects on mucosal injury and repair. We now hypothesize that breast milk protects against NEC by inhibiting TLR4 within the intestinal epithelium, and sought to determine the mechanisms involved. Breast milk protected against NEC and reduced TLR4 signaling in wild-type neonatal mice, but not in mice lacking the epidermal growth factor receptor (EGFR), whereas selective removal of EGF from breast milk reduced its protective properties, indicating that breast milk inhibits NEC and attenuates TLR4 signaling via EGF/EGFR activation. Overexpression of TLR4 in the intestinal epithelium reversed the protective effects of breast milk. The protective effects of breast milk occurred via inhibition of enterocyte apoptosis and restoration of enterocyte proliferation. Importantly, in IEC-6 enterocytes, breast milk inhibited TLR4 signaling via inhibition of glycogen synthase kinase-3β (GSK3β). Taken together, these findings offer mechanistic insights into the protective role for breast milk in NEC, and support a link between growth factor and innate immune receptors in NEC pathogenesis.
Extramedullary relapse (EMR) represents a poor prognostic marker in the course of multiple myeloma (MM). We reviewed data from 329 patients, diagnosed between 2000 and 2010, without extramedullary ...disease at onset to explore possible risk factors for EMR. The median overall survival of our study cohort was 6.4 years. The risk of EMR was 28 % with a median time from diagnosis to first EMR of 2.2 years (0.2–9.1 years). Patients with soft tissue masses located in extra-osseous organs (EMR-S) showed the worst outcome, compared to those with tumor masses arising from adjacent bone (EMR-B) (median OS 1.6 vs 2.4 years,
p
= 0.006). In addition, patients with EMR-S showed a significant trend for further development of extramedullary masses in a very short time (3.7 vs 5.7 months for EMR-B,
p
= 0.043). Multivariate analysis failed to identify any clinically presenting features predictive for EMR. The occurrence of EMR was higher in patients with more complex treatment history, defined on the basis of longer treatment duration (≥6 vs <6 months) and on elevated number of treatment lines administered (>2 vs ≤2 lines) (HR = 4.5,
p
< 0.001 and HR = 9.0,
p
< 0.001, respectively, when one or both factors are present).In conclusion, increasing burden of treatment might be a possible risk factor for EMR. MM patients with multiple relapses should be comprehensively investigated including, when possible, a whole-body-targeted radiologic technique to accurately detect EMR. Treatment choice should take into account the very poor outcome for patients with soft tissue involvement.
Recent reports identify the ratio between absolute neutrophil count (ANC) and absolute lymphocyte count (ALC), called neutrophil to lymphocyte ratio (NLR), as a predictor of progression-free survival ...(PFS) and overall survival (OS) in various malignancies. We retrospectively examined the NLR in a cohort of 309 newly diagnosed multiple myeloma (MM) patients treated upfront with novel agents. NLR was calculated using data obtained from the complete blood count (CBC) at diagnosis and subsequently correlated with PFS and OS. The median NLR was 1.9 (range 0.4–15.9). Higher NLR was independent of international staging system (ISS) stage, plasma cell infiltration or cytogenetics. The 5-year PFS and OS estimates were, respectively, 18.2 and 36.4 % for patients with NLR ≥ 2 versus 25.5 and 66.6 % in patients with NLR < 2. Among younger patients (age <65 years,
N
= 179), NLR ≥ 2 had a negative prognostic impact on both PFS and OS, in all ISS stages. By combining ISS stage and NLR in a model limited to young patients, we found that 19 % of the patients were classified as very low risk, 70 % standard risk and 11 % very high risk. The 5-year estimates were 39.3, 19.4 and 10.9 % for PFS and 95.8, 50.9 and 23.6 % for OS for very low, standard-risk and very high-risk groups. We found NLR to be a predictor of PFS and OS in MM patients treated upfront with novel agents. NLR can be combined with ISS staging system to identify patients with dismal outcome. However, larger cohorts and prospective studies are needed to use NLR as additional parameter to personalise MM therapy in the era of novel agents.
Rain forest regeneration and management Gomez-Pompa, A. (ed.); Whitmore, T.C. (ed.); Hadley, M. (ed.)
Man and the Biosphere Series (UNESCO),
1991, Letnik:
6
Book
The Notch pathway is a crucial cell-fate regulator in the developing heart. Attention in the past centered on Notch function in cardiomyocytes. However, recent advances demonstrate that ...region-specific endocardial Notch activity orchestrates the patterning and morphogenesis of cardiac chambers and valves through regulatory interaction with multiple myocardial and neural crest signals. Notch also regulates cardiomyocyte proliferation and differentiation during ventricular chamber development and is required for coronary vessel specification. Here, we review these data and highlight disease connections, including evidence that Notch-Hey-Bmp2 interplay impacts adult heart valve disease and that Notch contributes to cardiac arrhythmia and pre-excitation syndromes.
In country, non‐target arthropod (NTA) field evaluations are required to comply with the regulatory process for cultivation of genetically modified (GM) maize in Mexico. Two sets of field trials, ...Experimental Phase and Pilot Phase, were conducted to identify any potential harm of insect‐protected and glyphosate‐tolerant maize (MON‐89Ø34‐3 × MON‐88Ø17‐3 and MON‐89Ø34‐3 × MON‐ØØ6Ø3‐6) and glyphosate‐tolerant maize (MON‐ØØ6Ø3‐6) to local NTAs compared to conventional maize. NTA abundance data were collected at 32 sites, providing high geographic and environmental diversity within maize production areas from four ecological regions (ecoregions) in northern Mexico. The most abundant herbivorous taxa collected included field crickets, corn flea beetles, rootworm beetles, cornsilk flies, aphids, leafhoppers, plant bugs and thrips while the most abundant beneficial taxa captured were soil mites, spiders, predatory ground beetles, rove beetles, springtails (Collembola), predatory earwigs, ladybird beetles, syrphid flies, tachinid flies, minute pirate bugs, parasitic wasps and lacewings. Across the taxa analysed, no statistically significant differences in abundance were detected between GM maize and the conventional maize control for 69 of the 74 comparisons (93.2%) indicating that the single or stacked insect‐protected and herbicide‐tolerant GM traits generally exert no marked adverse effects on the arthropod populations compared with conventional maize. The distribution of taxa observed in this study provides evidence that irrespective of variations in overall biodiversity of a given ecoregion, important herbivore, predatory and parasitic arthropod taxa within the commercial maize agroecosystem are highly similar indicating that relevant data generated in one ecoregion can be transportable for the risk assessment of the same or similar GM crop in another ecoregion.
Surgery is the only chance for cure in pancreatic ductal adenocarcinoma. In unresectable, locally advanced pancreatic cancer (LAPC), the National Comprehensive Cancer Network (NCCN) suggests ...chemotherapy and consideration for radiation in cases of unresectable LAPC. Here we present a rare case of unresectable LAPC with a complete histopathological response after chemoradiation followed by surgical resection. A 54-year-old female presented to our clinic in December 2013 with complaints of abdominal pain and 30-pound weight loss. An MRI demonstrated a mass in the pancreatic body measuring 6.2×3.2 cm; biopsy revealed proven ductal adenocarcinoma. Due to splenic vein/artery and contiguous celiac artery encasement, she was deemed surgically unresectable. She was started on FOLFIRINOX therapy (three cycles), intensity modulated radiation to a dose of 54 Gy in 30 fractions concurrent with capecitabine, followed by FOLFIRI, and finally XELIRI. After 8 cycles of ongoing XELIRI completed in March 2015, restaging showed a remarkable decrease in tumor size, along with PET-CT revealing no FDG-avid uptake. She was reevaluated by surgery and taken for definitive resection. Histopathological evaluation demonstrated a complete R0 resection and no residual tumor. Based on this patient and literature review, this strategy demonstrates potential efficacy of neoadjuvant chemoradiation with prolonged chemotherapy, followed by surgery, which may improve outcomes in patients deemed previously unresectable.
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