6,012 research outputs found
Successful pregnancy in a patient with short bowel syndrome after surgical rehabilitation and sGLP-2 treatment: novel report on endogenous GLP-2 levels at delivery and during breastfeeding
Pregnant patients with short bowel syndrome (SBS) and chronic intestinal failure (CIF) can successfully reach to term their pregnancies while on parenteral nutrition (PN) but with high rates of complications. The combination of rehabilitation surgery, combined with the use of novel treatment with enterohormones, especially semisynthetic glucagon-like peptide 2 (sGLP-2), has increased the chances to achieve intestinal sufficiency. Here, we report the case of a 33-year-old female with SBS/CIF (anatomy type 2), weaned off PN using sGLP-2 for 3.7 years, discontinued when she became pregnant. She was able to carry the pregnancy to term without any additional PN support. Considering that, we queried if the endogenous GLP-2 (eGLP-2) levels in this SBS patient, during the pregnancy and breastfeeding period, could be like those presented in healthy pregnant women and in non-pregnant SBS patients. Also, we inquired if there was any passage or increase in the plasmatic eGLP-2 from the fetus to the mother. Thus, we determined eGLP-2 levels in paired neonatal (cord blood) and maternal plasma samples from the SBS pregnant patient (n = 1), healthy pregnant women (controls, n = 2), and non-pregnant SBS patients (n = 12). The results indicated that the SBS pregnant patient showed higher eGLP-2 levels than non-SBS pregnant patients and healthy pregnant women along all the period studied. Furthermore, we found that the maternal sample had higher eGLP-2 levels than the neonatal sample, suggesting that fetal contribution to maternal eGLP2 levels would be minor. In conclusion, this study not only reports for the first time a case of a patient with SBS that was able to achieve intestinal adaptation after combining the use of autologous reconstructive surgery and sGLP-2, but also enlightens the possibility of carrying out an uneventful pregnancy and lactation without any nutritional support and remaining independent of sGLP-2.Fil: Gentilini, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Doeyo, M.. Fundación Favaloro; ArgentinaFil: Ortega, M.. Fundación Favaloro; ArgentinaFil: Illidge Perez, L.. Fundación Favaloro; ArgentinaFil: Rumbo, C.. Fundación Favaloro; ArgentinaFil: Arriola Benitez, Paula Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Crivelli, A.. Fundación Favaloro; ArgentinaFil: Rumbo, Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Solar, H.. Fundación Favaloro; ArgentinaFil: Gondolesi, Gabriel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentin
Clinical subgroups in bilateral meniere disease
Meniere disease (MD) is a heterogeneous clinical condition characterized by sensorineural hearing loss, episodic vestibular symptoms, and tinnitus associated with several comorbidities, such as migraine or autoimmune disorders (AD). The frequency of bilateral involvement may range from 5 to 50%, and it depends on the duration of the disease. We have performed a two-step cluster analysis in 398 patients with bilateral MD (BMD) to identify the best predictors to define clinical subgroups with a potential different etiology to improve the phenotyping of BMD and to develop new treatments. We have defined five clinical variants in BMD. Group 1 is the most frequently found, includes 46% of patients, and is defined by metachronic hearing loss without migraine and without AD. Group 2 is found in 17% of patients, and it is defined by synchronic hearing loss without migraine or AD. Group 3, with 13% of patients, is characterized by familial MD, while group 4, that includes 12% of patients, is associated by the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by AD. This approach can be helpful in selecting patients for genetic and clinical research. However, further studies will be required to improve the phenotyping in these clinical variants for a better understanding of the diverse etiological factors contributing to BMD
Effect of ABCB1 and ABCC3 Polymorphisms on Osteosarcoma Survival after Chemotherapy: A Pharmacogenetic Study
Standard treatment for osteosarcoma patients consists of a
combination of cisplatin, adriamycin, and methotrexate before surgical resection
of the primary tumour, followed by postoperative chemotherapy including
vincristine and cyclophosphamide. Unfortunately, many patients still relapse or
suffer adverse events. We examined whether common germline polymorphisms in
chemotherapeutic transporter and metabolic pathway genes of the drugs used in
standard osteosarcoma treatment may predict treatment response.
METHODOLOGY/PRINCIPAL FINDINGS: In this study we screened 102 osteosarcoma
patients for 346 Single Nucleotide Polymorphisms (SNPs) and 2 Copy Number
Variants (CNVs) in 24 genes involved in the metabolism or transport of cisplatin,
adriamycin, methotrexate, vincristine, and cyclophosphamide. We studied the
association of the genotypes with tumour response and overall survival. We found
that four SNPs in two ATP-binding cassette genes were significantly associated
with overall survival: rs4148416 in ABCC3 (per-allele HR = 8.14, 95%CI =
2.73-20.2, p-value = 5.1x10(-)(5)), and three SNPs in ABCB1, rs4148737
(per-allele HR = 3.66, 95%CI = 1.85-6.11, p-value = 6.9x10(-)(5)), rs1128503 and
rs10276036 (r(2) = 1, per-allele HR = 0.24, 95%CI = 0.11-0.47 p-value =
7.9x10(-)(5)). Associations with these SNPs remained statistically significant
after correction for multiple testing (all corrected p-values [permutation test]
</= 0.03). CONCLUSIONS: Our findings suggest that these polymorphisms may affect
osteosarcoma treatment efficacy. If these associations are independently
validated, these variants could be used as genetic predictors of clinical outcome
in the treatment of osteosarcoma, helping in the design of individualized
therapy
RNase H2, mutated in Aicardi-Goutières syndrome, promotes LINE-1 retrotransposition
Long INterspersed Element class 1 (LINE-1) elements are a type of
abundant retrotransposons active in mammalian genomes. An
average human genome contains ~100 retrotransposition-competent
LINE-1s, whose activity is influenced by the combined action
of cellular repressors and activators. TREX1, SAMHD1 and ADAR1
are known LINE-1 repressors and when mutated cause the autoinflammatory
disorder Aicardi-Goutières syndrome (AGS). Mutations
in RNase H2 are the most common cause of AGS, and its activity
was proposed to similarly control LINE-1 retrotransposition. It has
therefore been suggested that increased LINE-1 activity may be
the cause of aberrant innate immune activation in AGS. Here, we
establish that, contrary to expectations, RNase H2 is required for
efficient LINE-1 retrotransposition. As RNase H1 overexpression
partially rescues the defect in RNase H2 null cells, we propose a
model in which RNase H2 degrades the LINE-1 RNA after reverse
transcription, allowing retrotransposition to be completed. This
also explains how LINE-1 elements can retrotranspose efficiently
without their own RNase H activity. Our findings appear to be at
odds with LINE-1-derived nucleic acids driving autoinflammation
in AGS.M.B.-G. is funded by a “Formacion Profesorado
Universitario” (FPU) PhD fellowship from the Government of Spain (MINECO,
Ref FPU15/03294), and this paper is part of her thesis project (“Epigenetic
control of the mobility of a human retrotransposon”). R.V.-A. is funded by a
PFIS Fellowship from the Government of Spain (ISCiii, FI16/00413). O.M. is
funded by an EMBO Long-Term Fellowship (ALTF 7-2015), the European
Commission FP7 (Marie Curie Actions, LTFCOFUND2013, GA-2013-609409) and
the Swiss National Science Foundation (P2ZHP3_158709). S.R.H. is funded by
the Government of Spain (MINECO, RYC-2016-21395 and SAF2015-71589-P).
A.P.J’s laboratory is supported by the UK Medical Research Council (MRC University Unit grant U127527202). J.L.G.P’s laboratory is supported by CICEFEDER-
P12-CTS-2256, Plan Nacional de I+D+I 2008-2011 and 2013-2016 (FISFEDER-
PI14/02152), PCIN-2014-115-ERA-NET NEURON II, the European
Research Council (ERC-Consolidator ERC-STG-2012-233764), by an International
Early Career Scientist grant from the Howard Hughes Medical Institute
(IECS-55007420), by The Wellcome Trust-University of Edinburgh Institutional
Strategic Support Fund (ISFF2) and by a private donation from Ms Francisca
Serrano (Trading y Bolsa para Torpes, Granada, Spain)
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Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology
BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers
Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.
Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided.
Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed.
Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations
Measurement of Branching Fractions and Rate Asymmetries in the Rare Decays B -> K(*) l+ l-
In a sample of 471 million BB events collected with the BABAR detector at the
PEP-II e+e- collider we study the rare decays B -> K(*) l+ l-, where l+ l- is
either e+e- or mu+mu-. We report results on partial branching fractions and
isospin asymmetries in seven bins of di-lepton mass-squared. We further present
CP and lepton-flavor asymmetries for di-lepton masses below and above the J/psi
resonance. We find no evidence for CP or lepton-flavor violation. The partial
branching fractions and isospin asymmetries are consistent with the Standard
Model predictions and with results from other experiments.Comment: 16 pages, 14 figures, accepted by Phys. Rev.
Branching fraction and form-factor shape measurements of exclusive charmless semileptonic B decays, and determination of |V_{ub}|
We report the results of a study of the exclusive charmless semileptonic
decays, B^0 --> pi^- l^+ nu, B^+ --> pi^0 l^+ nu, B^+ --> omega l^+ nu, B^+ -->
eta l^+ nu and B^+ --> eta^' l^+ nu, (l = e or mu) undertaken with
approximately 462x10^6 B\bar{B} pairs collected at the Upsilon(4S) resonance
with the BABAR detector. The analysis uses events in which the signal B decays
are reconstructed with a loose neutrino reconstruction technique. We obtain
partial branching fractions in several bins of q^2, the square of the momentum
transferred to the lepton-neutrino pair, for B^0 --> pi^- l^+ nu, B^+ --> pi^0
l^+ nu, B^+ --> omega l^+ nu and B^+ --> eta l^+ nu. From these distributions,
we extract the form-factor shapes f_+(q^2) and the total branching fractions
BF(B^0 --> pi^- l^+ nu) = (1.45 +/- 0.04_{stat} +/- 0.06_{syst})x10^-4
(combined pi^- and pi^0 decay channels assuming isospin symmetry), BF(B^+ -->
omega l^+ nu) = (1.19 +/- 0.16_{stat} +/- 0.09_{syst})x10^-4 and BF(B^+ --> eta
l^+ nu) = (0.38 +/- 0.05_{stat} +/- 0.05_{syst})x10^-4. We also measure BF(B^+
--> eta^' l^+ nu) = (0.24 +/- 0.08_{stat} +/- 0.03_{syst})x10^-4. We obtain
values for the magnitude of the CKM matrix element V_{ub} by direct comparison
with three different QCD calculations in restricted q^2 ranges of B --> pi l^+
nu decays. From a simultaneous fit to the experimental data over the full q^2
range and the FNAL/MILC lattice QCD predictions, we obtain |V_{ub}| = (3.25 +/-
0.31)x10^-3, where the error is the combined experimental and theoretical
uncertainty.Comment: 35 pages, 14 figures, submitted to PR
Observation of time-reversal violation in the B0 meson system
The individually named authors work collectively as The BABAR Collaboration. Copyright @ 2012 American Physical Society.Although CP violation in the B meson system has been well established by the B factories, there has been no direct observation of time-reversal violation. The decays of entangled neutral B mesons into definite flavor states (B0 or B¯¯¯0), and J/ψK0L or cc¯K0S final states (referred to as B+ or B−), allow comparisons between the probabilities of four pairs of T-conjugated transitions, for example, B¯¯¯0→B− and B−→B¯¯¯0, as a function of the time difference between the two B decays. Using 468×106 BB¯¯¯ pairs produced in Υ(4S) decays collected by the BABAR detector at SLAC, we measure T-violating parameters in the time evolution of neutral B mesons, yielding ΔS+T=−1.37±0.14(stat)±0.06(syst) and ΔS−T=1.17±0.18(stat)±0.11(syst). These nonzero results represent the first direct observation of T violation through the exchange of initial and final states in transitions that can only be connected by a T-symmetry transformation.DOE and NSF (USA), NSERC (Canada), CEA and CNRS-IN2P3 (France), BMBF and
DFG(Germany), INFN (Italy), FOM (The Netherlands),
NFR (Norway), MES (Russia), MINECO (Spain), STFC
(United Kingdom). Individuals have received support from
the Marie Curie EIF (European Union), the A. P. Sloan
Foundation (USA) and the Binational Science Foundation
(USA-Israel)
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