Please cite this paper as: Lee C, Lin S, Lin C, Shih J, Lin T, Su Y. Clinical utility of array comparative genomic hybridisation for prenatal diagnosis: a cohort study of 3171 pregnancies. BJOG ...2012;119:614–625.
Objective To evaluate the clinical value of prenatal array comparative genomic hybridisation (CGH) in screening for submicroscopic genomic imbalances.
Design Cross‐sectional study.
Setting Tertiary referral centre.
Population From June 2008 to February 2011, 3171 fetuses underwent prenatal array CGH testing and karyotyping at the National Taiwan University Hospital. Indications for invasive prenatal diagnosis included abnormal karyotype, abnormal ultrasound, advanced maternal age and parental anxiety.
Methods In all, 2497 fetuses were screened with 1‐Mb resolution bacterial artificial chromosome array‐based CGH, and 674 fetuses with 60‐K oligonucleotide array‐based CGH. Multiplex ligation‐dependent probe amplification, fluorescence in situ hybridization, or 105‐K oligonucleotide array CGH provided further confirmation.
Main outcome measure Copy number variations identified by array CGH.
Results Array CGH detected numerical chromosome anomalies in 37 (1.2%) fetuses, microdeletion/duplication in 34 (1.1%) fetuses, large deletion/duplication in 13 (0.4%) fetuses, benign copy number changes in 13 (0.4%) fetuses and variation of unknown clinical significance in five (0.2%) fetuses. Array CGH was effective in identifying submicroscopic genomic imbalance in fetuses with de novo balance translocations (2/17, 1.8%), supernumerary marker chromosomes (3/6, 50%), and abnormal prenatal ultrasound findings (33/194, 17.0%). Array CGH detected microdeletions/duplications in 12 fetuses with normal karyotype.
Conclusion Prenatal array CGH is effective in screening for submicroscopic genomic imbalance. Array CGH may add 8.2% to the diagnostic field, compared with conventional karyotyping, for fetuses with abnormal ultrasound results, and is particularly useful in fetuses with karyotypic balanced translocation or marker chromosomes. There is a 0.52% baseline risk of submicroscopic genomic imbalance, even in women with an uneventful prenatal examination.
Talins are adaptor proteins that regulate focal adhesion signaling by conjugating integrins to the cytoskeleton. Talins directly bind integrins and are essential for integrin activation. We ...previously showed that β1 integrins are activated in metastatic prostate cancer (PCa) cells, increasing PCa metastasis to lymph nodes and bone. However, how β1 integrins are activated in PCa cells is unknown. In this study, we identified a novel mechanism of β1 integrin activation. Using knockdown experiments, we first demonstrated that talin1, but not talin2, is important in β1 integrin activation. We next showed that talin1 S425 phosphorylation, but not total talin1 expression, correlates with metastatic potential of PCa cells. Expressing a non-phosphorylatable mutant, talin1(S425A), in talin1-silenced PC3-MM2 and C4-2B4 PCa cells, decreased activation of β1 integrins, integrin-mediated adhesion, motility and increased the sensitivity of the cells to anoikis. In contrast, reexpression of the phosphorylation-mimicking mutant talin1(S425D) led to increased β1 integrin activation and generated biologic effects opposite to talin1(S425A) expression. In the highly metastatic PC3-MM2 cells, expression of a non-phosphorylatable mutant, talin1(S425A), in talin1-silenced PC3-MM2 cells, abolished their ability to colonize in the bone following intracardiac injection, while reexpression of phosphorylation-mimicking mutant talin1(S425D) restored their ability to metastasize to bone. Immunohistochemical staining demonstrated that talin S425 phosphorylation is significantly increased in human bone metastases when compared with normal tissues, primary tumors or lymph node metastases. We further showed that p35 expression, an activator of Cdk5, and Cdk5 activity were increased in metastatic tumor cells, and that Cdk5 kinase activity is responsible for talin1 phosphorylation and subsequent β1 integrin activation. Together, our study reveals Cdk5-mediated phosphorylation of talin1 leading to β1 integrin activation is a novel mechanism that increases metastatic potential of PCa cells.
Summary
Background
Peptic ulcer bleeding remains a major healthcare problem despite decreasing prevalence of peptic ulcer disease. The role of chronic obstructive pulmonary disease (COPD) in the risk ...of peptic ulcer bleeding has not yet been established.
Aim
To determine if COPD patients have a higher risk of peptic ulcer bleeding than the general population and to identify the risk factors of peptic ulcer bleeding in COPD patients.
Methods
From Taiwan's National Health Insurance research database, 62 876 patients, including 32 682 COPD and 30 194 age‐gender‐matched non‐COPD controls, were recruited. Cox proportional hazard regression was performed to evaluate independent risk factors for ulcer bleeding in all patients and to identify risk factors in COPD patients.
Results
During the 8‐year follow‐up, COPD patients had a significant higher rate of peptic ulcer bleeding than the control group (P < 0.001, by log‐rank test). By Cox proportional hazard regression analysis, COPD hazard ratio (HR) 1.93, 95% CI 1.73–2.17 was an independent risk factor after adjusting for age, gender, underlying comorbidities and ulcerogenic medication. Age > 65 years, male, comorbidities of hypertension, diabetes, heart failure, history of peptic ulcer disease, and chronic renal disease and use of nonsteroidal anti‐inflammatory drugs were risk factors of ulcer bleeding in COPD patients.
Conclusion
Patients with chronic obstructive pulmonary disease have a higher risk of peptic ulcer bleeding after adjustments for possible confounding factors like underlying comorbidities and ulcerogenic medication.
FLAG Review 2019 Aoki, S.; Aoki, Y.; Bečirević, D. ...
The European physical journal. C, Particles and fields,
02/2020, Letnik:
80, Številka:
2
Journal Article
Recenzirano
Odprti dostop
We review lattice results related to pion, kaon,
D
-meson,
B
-meson, and nucleon physics with the aim of making them easily accessible to the nuclear and particle physics communities. More ...specifically, we report on the determination of the light-quark masses, the form factor
f
+
(
0
)
arising in the semileptonic
K
→
π
transition at zero momentum transfer, as well as the decay constant ratio
f
K
/
f
π
and its consequences for the CKM matrix elements
V
us
and
V
ud
. Furthermore, we describe the results obtained on the lattice for some of the low-energy constants of
S
U
(
2
)
L
×
S
U
(
2
)
R
and
S
U
(
3
)
L
×
S
U
(
3
)
R
Chiral Perturbation Theory. We review the determination of the
B
K
parameter of neutral kaon mixing as well as the additional four
B
parameters that arise in theories of physics beyond the Standard Model. For the heavy-quark sector, we provide results for
m
c
and
m
b
as well as those for
D
- and
B
-meson decay constants, form factors, and mixing parameters. These are the heavy-quark quantities most relevant for the determination of CKM matrix elements and the global CKM unitarity-triangle fit. We review the status of lattice determinations of the strong coupling constant
α
s
. Finally, in this review we have added a new section reviewing results for nucleon matrix elements of the axial, scalar and tensor bilinears, both isovector and flavor diagonal.
Summary
Aims
To better inform medical practitioners on the role of antiseptics in oropharyngeal health and disease, this article focuses on povidone‐iodine (PVP‐I), an established and ...widely‐available antiseptic agent.
Methodology
Review of the anti‐infective profile, efficacy and safety of PVP‐I in managing common upper respiratory tract infections such as the common cold, influenza and tonsillo‐pharyngitis, as well as oral complications resulting from cancer treatment (oral mucositis), and dental conditions (periodontitis, caries).
Results
Antiseptics with broad‐spectrum anti‐infective activity and low resistance potential offer an attractive option in both infection control and prevention. While there is some evidence of benefit of antiseptics in a variety of clinical settings that include dental and oral hygiene, dermatology, oncology, and pulmonology, there appears to be discordance between the evidence‐base and practice. This is especially apparent in the management and prevention of oropharyngeal infections, for which the use of antiseptics varies considerably between clinical practices, and is in marked contrast to their dermal application, where they are extensively used as both a prophylaxis and a treatment of skin and wound infections, thus minimising the use of antibiotics.
Conclusion
The link between oral and oropharyngeal health status and susceptibility to infection has long been recognised. The high rates of antibiotic misuse and subsequent development of bacterial resistance (e.g. increasing vancomycin‐resistant enterococci (VRE) and methicillin‐resistant Staphylococcus aureus (MRSA)) in large parts of the world, especially across Asia Pacific, highlight the need for identifying alternative antimicrobials that would minimise the use of these medications. This, together with recent large‐scale outbreaks of, for example, avian and swine influenza virus, further underline the importance of an increasing armamentarium for infection prevention and control.
Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for ...predicting pCR and risk of metastatic recurrence.
Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years.
At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5).
Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.
•Lack of ctDNA clearance early during NAC portends poor response.•Detectable ctDNA during NAC is associated with poor outcomes.•Failure to clear ctDNA after NAC is associated with inferior distant disease-free recurrence survival.•Clearance of ctDNA is associated with improved survival even in patients who did not achieve pCR.
Intercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart. Mutations in genes ...encoding ICD components are linked to cardiovascular diseases. Here, we show that loss of Xinβ, a newly-identified component of ICDs, results in cardiomyocyte proliferation defects and cardiomyopathy. We uncovered a role for Xinβ in signaling via the Hippo-YAP pathway by recruiting NF2 to the ICD to modulate cardiac function. In Xinβ mutant hearts levels of phosphorylated NF2 are substantially reduced, suggesting an impairment of Hippo-YAP signaling. Cardiac-specific overexpression of YAP rescues cardiac defects in Xinβ knock-out mice-indicating a functional and genetic interaction between Xinβ and YAP. Our study reveals a molecular mechanism by which cardiac-expressed intercalated disc protein Xinβ modulates Hippo-YAP signaling to control heart development and cardiac function in a tissue specific manner. Consequently, this pathway may represent a therapeutic target for the treatment of cardiovascular diseases.
In this paper, we test whether time periods with hot proton temperature anisotropy are associated with electromagnetic ion cyclotron (EMIC) waves and whether the plasma conditions during the observed ...waves satisfy the linear theory threshold condition. We identify 865 events observed by the Composition Distribution Function instrument onboard Cluster spacecraft 4 during 1 January 2001 to 1 January 2011 that exhibit a positive temperature anisotropy (Ahp = T⊥ h/T∥ h − 1) in the 10–40 keV protons. The events occur over an L range from 4 to 10 in all magnetic local times and at magnetic latitudes (MLATs) within ±50°. Of these hot proton temperature anisotropy (HPTA) events, only 68 events have electromagnetic ion cyclotron (EMIC) waves. In these 68 HPTA events, for those at 3.8<L ≤ 5 and |MLAT| ≤ 10°, the EMIC waves with powers >1.0 nT2/Hz mainly appear in the region with fEMIC/fH,eq < 0.8. Two stop bands are present, one near the region with fEMIC/fH,eq ≈ 0.33, the other in the region with 0.8 < fEMIC/fH,eq < 0.9. Most of the EMIC waves in the He, H, and >H bands satisfy Ahp/(Ahp + 1) > fEMIC/fH,lo, Ahp/(Ahp + 1) > 0.45 × fEMIC/fH,lo, and Ahp/(Ahp + 1) < 0.45 × fEMIC/fH,lo. fEMIC, fH,eq, and fH,lo are the EMIC wave frequency, the magnetic equatorial, and the local proton gyrofrequencies. We also find that the EMIC waves predominantly occur with Ahp > 0.25. By testing a threshold equation for the EMIC instability based on linear theory, we find that for EMIC waves with |MLAT| ≤ 10° in the He, H, and >H bands, the percentages that satisfy the predicted conditions for wave growth by the threshold equation are 15.2%, 24.6%, and 25.6%. For the EMIC waves with |MLAT| > 10° the percentages that satisfy the wave growth predicted conditions are only 2.8%, 2.6%, and 0.0%. Finally, possible reasons for the low forecast accuracies of EMIC waves are suggested.
Key Points
We do the statistical analysis of EMIC waves from a 10 year Cluster observation
We test the A_hp versus EMIC wave frequency formula of Kennel and Petschek (1966)
We test the linear theory derived by Blum et al. (2009)
SARS-CoV-2 infection has emerged as a serious global pandemic. Because of the high transmissibility of the virus and the high rate of morbidity and mortality associated with COVID-19, developing ...effective and safe vaccines is a top research priority. Here, we provide a detailed evaluation of the immunogenicity of lipid nanoparticle-encapsulated, nucleoside-modified mRNA (mRNA-LNP) vaccines encoding the full-length SARS-CoV-2 spike protein or the spike receptor binding domain in mice. We demonstrate that a single dose of these vaccines induces strong type 1 CD4+ and CD8+ T cell responses, as well as long-lived plasma and memory B cell responses. Additionally, we detect robust and sustained neutralizing antibody responses and the antibodies elicited by nucleoside-modified mRNA vaccines do not show antibody-dependent enhancement of infection in vitro. Our findings suggest that the nucleoside-modified mRNA-LNP vaccine platform can induce robust immune responses and is a promising candidate to combat COVID-19.
Display omitted
•mRNA vaccines induce robust type 1 CD4+ and CD8+ T cells in the spleen and lung•Vaccine-induced T cells readily exit the vasculature and enter the lung parenchyma•mRNA vaccines elicit strong long-lived plasma cell and memory B cell responses•mRNA vaccines induce antibodies with potent anti-SARS-CoV-2 neutralization activity
SARS-CoV-2 mRNA-based vaccines are among the most promising vaccine candidates against COVID-19. Laczkó et al. evaluate two nucleoside-modified mRNA vaccine candidates in mice and demonstrate that they induce potent T and B cell immune responses and high levels of neutralizing antibodies after administration of a single vaccine dose.
PDF
