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Electromagnetically induced transparency (EIT) in K39 and K41 was probed using electro-optic frequency combs generated by applying chirped waveforms to a phase modulator. The carrier tone of the frequency comb served as the pump beam and induced the necessary optical cycling. Comb tooth spacings as narrow as 20 kHz were used to probe potassium in both buffer gas and evacuated cells at elevated temperatures. Atomic absorption features as narrow as 33(5) kHz were observed, allowing for the K39 lower-state hyperfine splitting to be optically measured with a fit uncertainty of 2 kHz. Due to the ultranarrow width of the EIT features, long-lived optical free induction decays were also observed which allowed for background-free detection.
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We describe an ultra-sensitive cavity ring-down spectrometer which operates in the mid-infrared spectral region near 4.5 µm. With this instrument a noise-equivalent absorption coefficient of 2.6×10-11 cm-1 Hz-1/2 was demonstrated with less than 150 nW of optical power incident on the photodetector. Quantum noise was observed in the individual ring-down decay events, leading to quantum-noise-limited short-time performance. We believe that this spectrometer's combination of high sensitivity and robustness make it well suited for measurements of ultra-trace gas species as well as applications in optics and fundamental physics.
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This study was designed to evaluate whether subjects with amyloid beta (Aß) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than subjects without Aß pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer's disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aß+) or negative (Aß-), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aß+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aß+ MCI subjects demonstrated greater worsening compared with Aß- subjects on the ADAS-Cog over 36 months (5.66 ± 1.47 vs -0.71 ± 1.09, P = 0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test (P < 0.05). Similar to MCI subjects, Aß+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency (P<0.05), whereas Aß+ AD patients showed greater declines in verbal fluency and the MMSE (P < 0.05). Aß+ subjects in all diagnostic groups also showed greater decline on the CDR-SB (P<0.04), a global clinical assessment. Aß+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aß+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aß- subjects do.
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Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Compostos de Anilina , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Progressão da Doença , Etilenoglicóis , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Nootrópicos/uso terapêutico , Tomografia por Emissão de Pósitrons , Estudos Prospectivos , Compostos RadiofarmacêuticosRESUMO
Dual-drive Mach-Zehnder modulators were utilized to produce power-leveled optical frequency combs (OFCs) from a continuous-wave laser. The resulting OFCs contained up to 50 unique frequency components and spanned more than 200 GHz. Simple changes to the modulation frequency allowed for agile control of the comb spacing. These OFCs were then utilized for broadband, multiheterodyne measurements of CO2 using both a multipass cell and an optical cavity. This technique allows for robust measurements of trace gas species and alleviates much of the cost and complexity associated with the use of femtosecond OFCs produced with mode-locked pulsed lasers.
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We recently described a disorder termed Huntington disease-like 2 (HDL2) that completely segregates with an unidentified CAG/CTG expansion in a large pedigree (W). We now report the cloning of this expansion and its localization to a variably spliced exon of JPH3 (encoding junctophilin-3), a gene involved in the formation of junctional membrane structures.
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Doença de Huntington/genética , Proteínas de Membrana/genética , Repetições de Trinucleotídeos , Sequência de Bases , Clonagem Molecular , Feminino , Humanos , Masculino , Dados de Sequência Molecular , LinhagemRESUMO
We present high-reflectivity substrate-transferred single-crystal GaAs/AlGaAs interference coatings at a center wavelength of 4.54 µm with record-low excess optical loss below 10 parts per million. These high-performance mirrors are realized via a novel microfabrication process that differs significantly from the production of amorphous multilayers generated via physical vapor deposition processes. This new process enables reduced scatter loss due to the low surface and interfacial roughness, while low background doping in epitaxial growth ensures strongly reduced absorption. We report on a suite of optical measurements, including cavity ring-down, transmittance spectroscopy, and direct absorption tests to reveal the optical losses for a set of prototype mirrors. In the course of these measurements, we observe a unique polarization-orientation-dependent loss mechanism which we attribute to elastic anisotropy of these strained epitaxial multilayers. A future increase in layer count and a corresponding reduction of transmittance will enable optical resonators with a finesse in excess of 100 000 in the mid-infrared spectral region, allowing for advances in high resolution spectroscopy, narrow-linewidth laser stabilization, and ultrasensitive measurements of various light-matter interactions.
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BACKGROUND: Donanemab (LY3002813) is an IgG1 antibody directed at an Nterminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques. OBJECTIVES: To assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity. DESIGN: Phase 1b, investigator- and patient-blind, randomized, placebo-controlled study. SETTING: Patients recruited at clinical research sites in the United States and Japan. PARTICIPANTS: 61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer's disease and mild-to-moderate Alzheimer's disease dementia. INTERVENTION: Six cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15). MEASUREMENTS: Brain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity. RESULTS: Treatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: -16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and -49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; -50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and -58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-half-life following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients). CONCLUSIONS: Single and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.
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Doença de Alzheimer/tratamento farmacológico , Amiloide/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Tomografia por Emissão de Pósitrons , Idoso , Compostos de Anilina , Disfunção Cognitiva/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Etilenoglicóis , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Estados UnidosRESUMO
We report a quantitative measurement of the amount of charge that is transferred when the single ammonia complex of the photoacid beta-naphthol (2HNA) is excited by light. The measurement was made by comparing the permanent electric dipole moments of cis-2HNA in its ground (S(0)) and excited (S(1)) states, determined by Stark-effect studies of its fully resolved S(1)<--S(0) electronic spectrum. While the increase in electron transfer from the donor (NH(3)) to the acceptor (2HN) upon excitation is small ( approximately 0.05e), it is sufficient to redshift the electronic spectrum of the complex by approximately 600 cm(-1) ( approximately 0.1 eV). Thereby explored is the incipient motion of the acid-base complex along the excited state (electron-coupled) proton transfer coordinate.
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BACKGROUND: E (epithelial)-cadherin, the cell adhesion molecule also considered a potential invasion/metastasis suppressor, is mutationally inactivated in nearly half of all undifferentiated-scattered (diffuse-type) gastric carcinomas. In addition, silencing of E-cadherin by CpG methylation within its promoter region has been reported in several gastric carcinoma cell lines. We investigated the methylation status of the E-cadherin promoter region in 53 primary human gastric carcinomas. METHODS: Hypermethylation of the E-cadherin promoter was determined by utilizing methylation-specific polymerase chain reaction (PCR)-single-strand conformation polymorphism (MSP-SSCP) analysis followed by direct sequencing of PCR products. Expression of E-cadherin was studied by western blot analysis. All statistical tests were two-sided. RESULTS: Hypermethylation of the E-cadherin promoter was evident in 27 (51%) of 53 primary gastric carcinomas examined by MSP-SSCP. It occurred more frequently in carcinomas of the undifferentiated-scattered type (in 15 [83%] of 18) than in other histologic subtypes (in 12 [34%] of 35) (P =.0011, Fisher's exact test), and it was present at similar rates in early (in six [60%] of 10) versus advanced (in 21 [49%] of 43) carcinomas (P =.73, Fisher's exact test). Methylation occurring at all cytosine-guanosine sequences (CpGs) near the transcriptional start site was confirmed in six of six tumors examined by bisulfite-DNA sequencing, including two early gastric carcinomas. In addition, loss or diminished expression of E-cadherin was confirmed by western blotting in four of the six tumor tissues demonstrating hypermethylation. CONCLUSIONS: The E-cadherin promoter frequently undergoes hypermethylation in human gastric cancers, particularly those of the undifferentiated-scattered histologic subtype. E-cadherin promoter hypermethylation is associated with decreased expression and may occur early in gastric carcinogenesis.
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Caderinas/genética , Carcinoma/metabolismo , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/metabolismo , Western Blotting , Carcinoma/genética , Citosina/metabolismo , Primers do DNA , DNA de Neoplasias/química , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Guanosina/metabolismo , Humanos , Metilação , Reação em Cadeia da Polimerase/métodos , Polimorfismo Conformacional de Fita Simples , Análise de Sequência de DNA , Neoplasias Gástricas/genéticaRESUMO
BACKGROUND: The adenomatous polyposis coli (APC) locus on chromosome 5q21-22 shows frequent loss of heterozygosity (LOH) in esophageal carcinomas. However, the prevalence of truncating mutations in the APC gene in esophageal carcinomas is low. Because hypermethylation of promoter regions is known to affect several other tumor suppressor genes, we investigated whether the APC promoter region is hypermethylated in esophageal cancer patients and whether this abnormality could serve as a prognostic plasma biomarker. METHODS: We assayed DNA from tumor tissue and matched plasma from esophageal cancer patients for hypermethylation of the promoter region of the APC gene. We used the maximal chi-square statistic to identify a discriminatory cutoff value for hypermethylated APC DNA levels in plasma and used bootstrap-like simulations to determine the P: value to test for the strength of this association. This cutoff value was used to generate Kaplan-Meier survival curves. All P values were based on two-sided tests. RESULTS: Hypermethylation of the promoter region of the APC gene occurred in abnormal esophageal tissue in 48 (92%) of 52 patients with esophageal adenocarcinoma, in 16 (50%) of 32 patients with esophageal squamous cell carcinoma, and in 17 (39.5%) of 43 patients with Barrett's metaplasia but not in matching normal esophageal tissues. Hypermethylated APC DNA was observed in the plasma of 13 (25%) of 52 adenocarcinoma patients and in two (6.3%) of 32 squamous carcinoma patients. High plasma levels of methylated APC DNA were statistically significantly associated with reduced patient survival (P =.016). CONCLUSION: The APC promoter region was hypermethylated in tumors of the majority of patients with primary esophageal adenocarcinomas. Levels of hypermethylated APC gene DNA in the plasma may be a useful biomarker of biologically aggressive disease in esophageal adenocarcinoma patients and should be evaluated as a potential biomarker in additional tumor types.
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Adenocarcinoma/metabolismo , Polipose Adenomatosa do Colo/genética , Biomarcadores Tumorais/sangue , Cromossomos Humanos Par 5/genética , DNA de Neoplasias/sangue , Neoplasias Esofágicas/metabolismo , Adenocarcinoma/genética , Esôfago de Barrett/metabolismo , Biomarcadores Tumorais/isolamento & purificação , Carcinoma de Células Escamosas/metabolismo , Distribuição de Qui-Quadrado , DNA de Neoplasias/isolamento & purificação , Neoplasias Esofágicas/genética , Mucosa Gástrica/metabolismo , Humanos , Perda de Heterozigosidade , Metilação , Reação em Cadeia da Polimerase/métodos , Lesões Pré-Cancerosas/metabolismo , Prognóstico , Regiões Promotoras Genéticas , Análise de SobrevidaRESUMO
Insulin-like growth factor binding protein 3 (IGFBP-3) is an important regulator of normal and malignant cell growth. It modulates the mitogenic effects of insulin-like growth factors (IGFs) by inhibiting growth through mechanisms both dependent on and independent of IGF binding. IGF-I and IGF-II levels are regulated by binding to the IGF-II receptor, which is inactivated by mutation in human gastrointestinal (GI) tumors. We have previously demonstrated elevated IGF-II ligand expression in IGF-II receptor-mutant GI tumors, implicating the IGF signaling system in GI tumorigenesis. Therefore, to investigate the potential involvement of IGFBP-3 in human GI carcinogenesis, direct DNA sequencing of exons 1-4 and intron-exon boundaries of the IGFBP-3 gene was performed in 10 colorectal cancers, 10 gastric cancers, and 10 esophageal cancers. Four distinct sequence alterations were identified: (a) in one gastric and one esophageal tumor, an A to C transversion occurred at nucleotide 5795 (CAC-->CCC), leading to a His-->Pro substitution at codon 179; (b) a second esophageal tumor had a C to T transition at nucleotide 8291 (ACC-->ATC), leading to a Thr-->Ile substitution at codon 277 of IGFBP-3; (c) one alteration comprised a G to C transversion in exon 1 at nucleotide 2132 (GGG-->GCG), leading to a Gly-->Ala substitution at codon 32 in two gastric cancers, seven esophageal cancers, and nine colon cancers; and (d) a C to G transversion located 17 nucleotides from the 3' splice site in intron 1 was observed in three colon cancers and four esophageal cancers. All of these DNA sequence alterations were present in matched normal DNA from the same subjects, which suggests that some or all of them may represent polymorphisms. However, we cannot exclude the possibility that the germ-line nonconservative amino acid substitutions predicted to occur as a result of these alterations result in subtle changes to IGFBP-3 protein function and a predisposition to developing GI malignancy.
Assuntos
Sistema Digestório/química , Neoplasias Gastrointestinais/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/química , Mutação , Sequência de Aminoácidos , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Dados de Sequência MolecularRESUMO
Twelve to 15% of sporadic colorectal cancers display defective DNA mismatch repair (MMR), manifested as microsatellite instability (MSI). In this group of cancers, promoter hypermethylation of the MMR gene hMLH1 is strongly associated with, and believed to be the cause of, MSI. A subset of colorectal neoplastic lesions arising in inflammatory bowel disease (IBD) is also characterized by MSI. We wished to determine whether hMLH1 hypermethylation was associated with diminished hMLH1 protein expression and MSI in IBD neoplasms. We studied 148 patients with IBD neoplasms, defined as carcinoma or dysplasia occurring in patients with ulcerative colitis or Crohn's disease. MSI was evaluated using multiplex fluorescent PCR to amplify loci D2S123, BAT-25, BAT-26, D5S346, and D17S250 in all cases. Lesions were characterized as high-frequency MSI (MSI-H) if they manifested instability at two or more loci, low-frequency MSI (MSI-L) if unstable at only one locus, or MS-stable (MSS) if showing no instability at any loci. Methylation-specific PCR was performed to determine the methylation status of the hMLH1 promoter region. hMLH1 protein expression was also evaluated by immunohistochemistry. Thirteen (9%) of 148 neoplasms arising in IBD were MSI-H, comprising 11 carcinomas and 2 dysplastic lesions. Sixteen additional lesions (11%) were MSI-L, comprising 11 carcinomas and 5 dysplastic lesions. The remaining 118 neoplasms (80%) were MSS. Six (46%) of 13 MSI-H, 1 (6%) of 16 MSI-L, and 4 (15%) of 27 MSS lesions showed hMLH1 hypermethylation (P = 0.013). Diminished hMLH1 protein expression in neoplastic cell nuclei relative to surrounding normal cell nuclei was demonstrated immunohistochemically in four of four (100%) hypermethylated lesions tested. In IBD neoplasia, hMLH1 promoter hypermethylation occurs frequently in the setting of MSI, particularly MSI-H. Furthermore, hMLH1 hypermethylation and MSI are strongly associated with diminished hMLH1 protein expression in IBD neoplasms. These findings suggest that hMLH1 hypermethylation causes defective DNA MMR in at least a subset of IBD neoplasms.
Assuntos
Neoplasias Colorretais/genética , Metilação de DNA , Reparo do DNA/genética , Doenças Inflamatórias Intestinais/genética , Repetições de Microssatélites/genética , Proteínas de Neoplasias/genética , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Inativação Gênica , Humanos , Imuno-Histoquímica , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/metabolismo , Proteína 1 Homóloga a MutL , Proteínas de Neoplasias/biossíntese , Proteínas Nucleares , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas/genéticaRESUMO
Human gastric carcinoma shows a higher prevalence of microsatellite instability (MSI) than does any other type of sporadic human cancer. The reasons for this high frequency of MSI are not yet known. In contrast to endometrial and colorectal carcinoma, mutations of the DNA mismatch repair (MMR) genes hMLH1 or hMSH2 have not been described in gastric carcinoma. However, hypermethylation of the hMLH1 MMR gene promoter is quite common in MSI-positive endometrial and colorectal cancers. This hypermethylation has been associated with hMLH1 transcriptional blockade, which is reversible with demethylation, suggesting that an epigenetic mechanism underlies hMLH1 gene inactivation and MMR deficiency. Therefore, we studied the prevalence of hMLH1 promoter hypermethylation in a total of 65 gastric tumors: 18 with frequent MSI (MSI-H), 8 with infrequent MSI (MSI-L), and 39 that were MSI negative. We found a striking association between hMLH1 promoter hypermethylation and MSI; of 18 MSI-H tumors, 14 (77.8%) showed hypermethylation, whereas 6 of 8 MSI-L tumors (75%) were hypermethylated at hMLH1. In contrast, only 1 of 39 (2.6%) MSI-negative tumors demonstrated hMLH1 hypermethylation (P<0.0001 for MSI-H or MSI-L versus MSI-negative). Moreover, hypermethylated cancers demonstrated diminished expression of hMLH1 protein by both immunohistochemistry and Western blotting, whereas nonhypermethylated tumors expressed abundant hMLH1 protein. These data indicate that hypermethylation of hMLH1 is strongly associated with MSI in gastric cancers and suggest an epigenetic mechanism by which defective MMR occurs in this group of cancers.
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Adenocarcinoma/genética , Metilação de DNA , Reparo do DNA , Perda de Heterozigosidade , Repetições de Microssatélites , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas , Neoplasias Gástricas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma/patologia , Proteínas de Transporte , Humanos , Imuno-Histoquímica , Proteína 1 Homóloga a MutL , Proteínas Nucleares , Neoplasias Gástricas/patologia , Transcrição GênicaRESUMO
An optical frequency comb generated with an electro-optic phase modulator and a chirped radiofrequency waveform is used to perform pump-probe spectroscopy on the D1 and D2 transitions of atomic potassium at 770.1 nm and 766.7 nm, respectively. With a comb tooth spacing of 200 kHz and an optical bandwidth of 2 GHz the hyperfine transitions can be simultaneously observed. Interferograms are recorded in as little as 5 µs (a timescale corresponding to the inverse of the comb tooth spacing). Importantly, the sub-Doppler features can be measured as long as the laser carrier frequency lies within the Doppler profile, thus removing the need for slow scanning or a priori knowledge of the frequencies of the sub-Doppler features. Sub-Doppler optical frequency comb spectroscopy has the potential to dramatically reduce acquisition times and allow for rapid and accurate assignment of complex molecular and atomic spectra which are presently intractable.
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A germline sequence alteration at codon 1307 of the APC gene (I1307K) has been reported in 6-7% of the Ashkenazi Jewish population in the United States. This alteration is believed to predispose the APC gene to a secondary mutation at the same locus, resulting in an increased risk of colorectal carcinoma. There is an increased risk of colorectal carcinoma in patients with inflammatory bowel disease (IBD), a relatively large proportion of whom are Ashkenazi Jews. We therefore sought to determine whether the I1307K sequence variant occurred in the germline DNA of IBD patients. To our surprise, we found this sequence in only two of 267 patients with IBD (0.7%), occurring in only 1.5% of Jewish IBD patients. The I1307K sequence variant was not found in 67 patients with esophageal cancer, 53 patients with gastric carcinoma (13 MSI-H and 44 MSI-negative), or ten patients with sporadic MSI-H colon cancer. These findings suggest that the I1307K sequence is relatively rare in the germline of Jewish as well as non-Jewish IBD patients. It does not appear to contribute to the increased colorectal cancer risk present in these patients.
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Genes APC , Doenças Inflamatórias Intestinais/genética , Judeus/genética , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/genética , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Doenças Inflamatórias Intestinais/etnologia , RiscoRESUMO
A significant portion of gastric cancers exhibit defective DNA mismatch repair, manifested as microsatellite instability (MSI). High-frequency MSI (MSI-H) is associated with hypermethylation of the human mut-L homologue 1 (hMLH1) mismatch repair gene promoter and diminished hMLH1 expression in advanced gastric cancers. However, the relationship between MSI and hMLH1 hypermethylation has not been studied in early gastric neoplasms. We therefore investigated hMLH1 hypermethylation, hMLH1 expression and MSI in a group of early gastric cancers and gastric adenomas. Sixty-four early gastric neoplasms were evaluated, comprising 28 adenomas, 18 mucosal carcinomas, and 18 carcinomas with superficial submucosal invasion but clear margins. MSI was evaluated using multiplex fluorescent PCR to amplify loci D2S123, D5S346, D17S250, BAT 25 and BAT 26. Methylation-specific PCR was performed to determine the methylation status of hMLH1. In two hypermethylated MSI-H cancers, hMLH1 protein expression was also evaluated by immunohistochemistry. Six of sixty-four early gastric lesions were MSI-H, comprising 1 adenoma, 4 mucosal carcinomas, and 1 carcinoma with superficial submucosal invasion. Two lesions (one adenoma and one mucosal carcinoma) demonstrated low-frequency MSI (MSI-L). The remaining 56 neoplasms were MSI-stable (MSI-S). Six of six MSI-H, one of two MSI-L, and none of thirty MSI-S lesions showed hMLH1 hypermethylation (P<0.001). Diminished hMLH1 protein expression was demonstrated by immunohistochemistry in two of two MSI-H hypermethylated lesions. hMLH1 promoter hypermethylation is significantly associated with MSI and diminished hMLH1 expression in early gastric neoplasms. MSI and hypermethylation-associated inactivation of hMLH1 are more prevalent in early gastric cancers than in gastric adenomas. Thus, hypermethylation-associated inactivation of the hMLH1 gene can occur early in gastric carcinogenesis.
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Metilação de DNA , Repetições de Microssatélites , Proteínas de Neoplasias/genética , Neoplasias Gástricas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adenoma/genética , Adenoma/patologia , Pareamento Incorreto de Bases , Carcinoma/genética , Carcinoma/patologia , Proteínas de Transporte , Estudos de Casos e Controles , Mucosa Gástrica/patologia , Humanos , Proteína 1 Homóloga a MutL , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares , Reação em Cadeia da Polimerase/métodos , Regiões Promotoras Genéticas , Neoplasias Gástricas/patologiaRESUMO
The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal cancers. In addition, hypermethylation of CpG islands in the upstream portion of APC, a potential alternative mechanism of tumor suppressor gene inactivation, has been described in colorectal cancer. Because a subset of both gastric and colorectal cancers display the CpG island methylator phenotype, we hypothesized that epigenetic inactivation of APC was likely to occur in at least some gastric cancers. APC exhibits two forms of transcripts from exons 1A and 1B in the stomach. Therefore, we investigated CpG island methylation in the sequences upstream of exons 1A and 1B, i.e., promoters 1A and 1B, respectively. We evaluated DNAs from 10 gastric cancer cell lines, 40 primary gastric cancers, and 40 matching non-cancerous gastric mucosae. Methylated alleles of promoter 1A were present in 10 (100%) of 10 gastric cancer cell lines, 33 (82.5%) of 40 primary gastric cancers, and 39 (97.5%) of 40 noncancerous gastric mucosae. In contrast, promoter 1B was unmethylated in all of these same samples. APC transcripts from exon 1A were not expressed in nine of the 10 methylated gastric cancer cell lines, whereas APC transcripts were expressed from exon 1B. Thus, expression from a given promoter correlated well with its methylation status. We conclude that in contrast to the colon, methylation of promoter 1A is a normal event in the stomach; moreover, promoter 1B is protected from methylation in the stomach and thus probably does not participate in this form of epigenetic APC inactivation.
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Metilação de DNA , DNA de Neoplasias/metabolismo , Genes APC , Regiões Promotoras Genéticas , Neoplasias Gástricas/genética , Adolescente , Sequência de Bases , Feminino , Mucosa Gástrica/metabolismo , Expressão Gênica , Humanos , Dados de Sequência Molecular , RNA Mensageiro , RNA Neoplásico , Células Tumorais CultivadasRESUMO
Pulmonary artery perforation by flow-directed catheters is associated with high mortality, particularly in heparinized patients. We report a recent case and discuss recognition and management.
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Cateterismo de Swan-Ganz/efeitos adversos , Hemoptise/terapia , Artéria Pulmonar/lesões , Idoso , Ponte Cardiopulmonar , Hemoptise/etiologia , Humanos , Complicações Intraoperatórias , Intubação Intratraqueal , Masculino , Pneumonectomia , Respiração com Pressão Positiva , RupturaRESUMO
The traditional therapy for acute bacterial endocarditis of the mitral valve refractory to medical treatment is valve replacement. Successful valvuloplasty may be feasible in selected cases, in which the infection is limited to a small portion of the mitral valve anulus. The following report describes a case in which valvuloplasty with excision of the affected valve was performed successfully with no recurrence of infection over a 3-year follow-up period.
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Endocardite Bacteriana/cirurgia , Valva Mitral/cirurgia , Adulto , Endocardite Bacteriana/etiologia , Humanos , Masculino , Serratia marcescens , Transtornos Relacionados ao Uso de Substâncias/complicaçõesRESUMO
Partial pulmonary resection in early childhood is well tolerated. Although long-term outcome has been described in several follow-up studies, almost no information is available on postoperative lung perfusion. We studied 14 patients 3 to 20 years (mean, 11.6 years) after they underwent partial pulmonary resection at 1 week to 30 months of age (mean, 6.8 months). We examined development, pulmonary function, endurance, radiographs and ventilation-perfusion scans. We used predicted pulmonary function test values, which were corrected for the relative amount of lung removed and called predicted-corrected values. We hypothesized that the remaining lung would have altered ventilation-perfusion characteristics. We found no abnormalities in the patients' physical development. Most children had abnormal regional ventilation, but normal equilibration occurred; five patients had gas retention; all had decreased perfusion to the area of resection; nine patients showed ventilation-perfusion mismatch characterized by dead-space ventilation. Lung volumes were within the predicted range in 12 patients. Residual volume and functional residual capacity were larger than predicted-corrected values in most patients but residual volume in relation to total lung capacity was at or below normal in 6 of 11 and did not correlate with the amount of lung removed. Most patients had prolonged expiratory flows. We conclude that lung resection in early childhood leads to good functional recovery. However, decreased expiratory flows, regional ventilation abnormalities, and decreased perfusion suggest dysplastic parenchyma and vascular bed in the area of resection.