The association of the intrinsic optical and biophysical properties of cells to homeostasis and pathogenesis has long been acknowledged. Defining these label-free cellular features obviates the need ...for costly and time-consuming labelling protocols that perturb the living cells. However, wide-ranging applicability of such label-free cell-based assays requires sufficient throughput, statistical power and sensitivity that are unattainable with current technologies. To close this gap, we present a large-scale, integrative imaging flow cytometry platform and strategy that allows hierarchical analysis of intrinsic morphological descriptors of single-cell optical and mass density within a population of millions of cells. The optofluidic cytometry system also enables the synchronous single-cell acquisition of and correlation with fluorescently labeled biochemical markers. Combined with deep neural network and transfer learning, this massive single-cell profiling strategy demonstrates the label-free power to delineate the biophysical signatures of the cancer subtypes, to detect rare populations of cells in the heterogeneous samples (10-5), and to assess the efficacy of targeted therapeutics. This technique could spearhead the development of optofluidic imaging cell-based assays that stratify the underlying physiological and pathological processes based on the information-rich biophysical cellular phenotypes.
An optofluidic imaging cytometry strategy that hierarchically analyzes single-cell biophysical morphology beyond millions of cells at high sensitivity and specificity.
Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common and preventable event in patients with chronic obstructive pulmonary disease (COPD). Data regarding the impact of ...AECOPD on short- and long-term renal outcomes are lacking.
We included all COPD patients who were followed at Queen Mary Hospital (QMH) in year 2015 and reviewed their clinical/renal outcomes in subsequent five years. Relationships between AECOPD and adverse renal outcomes were evaluated.
371 COPD patients were included. 169 patients had hospitalized AECOPD in past one year (HAE group) while 202 patients did not (non-HAE group). 285 patients (76.8%) had renal progression/death and 102 (27.5%) patients developed acute kidney injury (AKI). HAE group showed a more rapid eGFR decline than non-HAE group (-4.64 mL/min/1.73m
/year vs. -2.40 mL/min/1.73m
/year, p = 0.025). HAE group had significantly higher risk for renal progression/death at 5 years adjusted OR (aOR) 2.380 (95% CI = 1.144-4.954), p = 0.020. The frequency of hospitalized AECOPD in past 3 years, any AECOPD in past 3 years, hospitalized AECOPD in past 3 years were also predictive of renal progression/death at 5 years aOR were 1.176 (95% CI = 1.038- 1.331), 2.998 (95% CI = 1.438-6.250) and 2.887 (95% CI = 1.409-5.917) respectively; p = 0.011, 0.003 and 0.004. HAE group also showed significantly higher risk of AKI adjusted HR (aHR) 2.430; 95% CI = 1.306-4.519, p = 0.005.
AECOPD, in particular HAE, was associated with increased risk of renal progression/death and AKI. Prevention of AECOPD, especially HAE, may potentially improve short- and long-term renal outcomes in COPD patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Retinitis pigmentosa (RP) is a group of inherited retinal degenerations leading to blindness due to photoreceptor loss. Retinitis pigmentosa is a rare disease, affecting only approximately 100 000 ...people in the United States. There is no cure and no approved medical therapy to slow or reverse RP. The purpose of this clinical trial was to evaluate the safety, reliability, and benefit of the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) in restoring some visual function to subjects completely blind from RP. We report clinical trial results at 1 and 3 years after implantation.
The study is a multicenter, single-arm, prospective clinical trial.
There were 30 subjects in 10 centers in the United States and Europe. Subjects served as their own controls, that is, implanted eye versus fellow eye, and system on versus system off (native residual vision).
The Argus II System was implanted on and in a single eye (typically the worse-seeing eye) of blind subjects. Subjects wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina.
The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests.
A total of 29 of 30 subjects had functioning Argus II Systems implants 3 years after implantation. Eleven subjects experienced a total of 23 serious device- or surgery-related adverse events. All were treated with standard ophthalmic care. As a group, subjects performed significantly better with the system on than off on all visual function tests and functional vision assessments.
The 3-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind from RP. Earlier results from this trial were used to gain approval of the Argus II by the Food and Drug Administration and a CE mark in Europe. The Argus II System is the first and only retinal implant to have both approvals.
Health authorities worldwide, especially in the Asia Pacific region, are seeking effective public-health interventions in the continuing epidemic of severe acute respiratory syndrome (SARS). We ...assessed the epidemiology of SARS in Hong Kong.
We included 1425 cases reported up to April 28, 2003. An integrated database was constructed from several sources containing information on epidemiological, demographic, and clinical variables. We estimated the key epidemiological distributions: infection to onset, onset to admission, admission to death, and admission to discharge. We measured associations between the estimated case fatality rate and patients’age and the time from onset to admission.
After the initial phase of exponential growth, the rate of confirmed cases fell to less than 20 per day by April 28. Public-health interventions included encouragement to report to hospital rapidly after the onset of clinical symptoms, contact tracing for confirmed and suspected cases, and quarantining, monitoring, and restricting the travel of contacts. The mean incubation period of the disease is estimated to be 6.4 days (95% Cl 5.2–7.7). The mean time from onset of clinical symptoms to admission to hospital varied between 3 and 5 days, with longer times earlier in the epidemic. The estimated case fatality rate was 13.2% (9.8–16.8) for patients younger than 60 years and 43.3% (35.2–52.4) for patients aged 60 years or older assuming a parametric γ distribution. A non-parametric method yielded estimates of 6.8% (4.0–9.6) and 55.0% (45.3–64.7), respectively. Case clusters have played an important part in the course of the epidemic.
Patients’age was strongly associated with outcome. The time between onset of symptoms and admission to hospital did not alter outcome, but shorter intervals will be important to the wider population by restricting the infectious period before patients are placed in quarantine.
Published online May 7, 2003 http://image.thelancet.com/extras/03art4453web.pdf
The phase III randomized PROFILE 1014 study demonstrated superiority of crizotinib to first-line chemotherapy in prolonging progression-free survival (PFS) in previously untreated patients with ALK ...receptor tyrosine kinase gene (ALK)-positive advanced nonsquamous NSCLC. This result was consistent with that in the smaller subset of East Asian patients in PROFILE 1014. The subsequent study reported here prospectively evaluated crizotinib in a larger East Asian patient population.
In this open-label phase III study (PROFILE 1029), patients were randomized 1:1 to receive orally administered crizotinib 250 mg twice daily continuously (3-week cycles) or intravenously administered chemotherapy (pemetrexed 500 mg/m2, plus cisplatin 75 mg/m2, or carboplatin at a dose to produce area under the concentration–time curve of 5–6 mg·min/mL) every 3 weeks for a maximum of six cycles. PFS confirmed by independent radiology review was the primary end point.
Crizotinib significantly prolonged PFS (hazard ratio, 0.402; 95% confidence interval CI: 0.286–0.565; p < 0.001). The median PFS was 11.1 months with crizotinib and 6.8 months with chemotherapy. The objective response rate was 87.5% (95% CI: 79.6–93.2%) with crizotinib versus 45.6% (95% CI: 35.8–55.7%) with chemotherapy (p < 0.001). The most common adverse events were increased transaminase levels, diarrhea, and vision disorders with crizotinib and leukopenia, neutropenia, and anemia with chemotherapy. Significantly greater improvements from baseline in patient-reported outcomes were seen in crizotinib-treated versus chemotherapy-treated patients.
First-line crizotinib significantly improved PFS, objective response rate, and patient-reported outcomes compared with standard platinum-based chemotherapy in East Asian patients with ALK-positive advanced NSCLC, which is similar to the results from PROFILE 1014. The safety profiles of crizotinib and chemotherapy were consistent with those previously published.
Epstein-Barr virus (EBV or HHV4), a member of the human herpesvirus (HHV) family, has recently been shown to encode microRNAs (miRNAs). In contrast to most eukaryotic miRNAs, these viral miRNAs do ...not have close homologs in other viral genomes or in the genome of the human host. To identify other miRNA genes in pathogenic viruses, we combined a new miRNA gene prediction method with small-RNA cloning from several virus-infected cell types. We cloned ten miRNAs in the Kaposi sarcoma-associated virus (KSHV or HHV8), nine miRNAs in the mouse gammaherpesvirus 68 (MHV68) and nine miRNAs in the human cytomegalovirus (HCMV or HHV5). These miRNA genes are expressed individually or in clusters from either polymerase (pol) II or pol III promoters, and share no substantial sequence homology with one another or with the known human miRNAs. Generally, we predicted miRNAs in several large DNA viruses, and we could neither predict nor experimentally identify miRNAs in the genomes of small RNA viruses or retroviruses.
Abstract We report on the discovery of two low-luminosity, broad-line active galactic nuclei (AGNs) at z > 5 identified using JWST NIRSpec spectroscopy from the Cosmic Evolution Early Release Science ...(CEERS) survey. We detect broad H α emission in the spectra of both sources, with FWHM of 2060 ± 290 km s −1 and 1800 ± 200 km s −1 , resulting in virial black hole (BH) masses that are 1–2 dex below those of existing samples of luminous quasars at z > 5. The first source, CEERS 2782 at z = 5.242, is 2–3 dex fainter than known quasars at similar redshifts and was previously identified as a candidate low-luminosity AGN based on its morphology and rest-frame optical spectral energy distribution (SED). We measure a BH mass of M BH = (1.3 ± 0.4) × 10 7 M ⊙ , confirming that this AGN is powered by the least massive BH known in the Universe at the end of cosmic reionization. The second source, CEERS 746 at z = 5.624, is inferred to be a heavily obscured, broad-line AGN caught in a transition phase between a dust-obscured starburst and an unobscured quasar. We estimate its BH mass to be in the range of M BH ≃ (0.9–4.7) × 10 7 M ⊙ , depending on the level of dust obscuration assumed. We perform SED fitting to derive host stellar masses, M ⋆ , allowing us to place constraints on the BH–galaxy mass relationship in the lowest mass range yet probed in the early Universe. The M BH / M ⋆ ratio for CEERS 2782, in particular, is consistent with or higher than the empirical relationship seen in massive galaxies at z = 0. We examine the narrow emission line ratios of both sources and find that their location on the BPT and OHNO diagrams is consistent with model predictions for moderately low metallicity AGNs with Z / Z ⊙ ≃ 0.2–0.4. The spectroscopic identification of low-luminosity, broad-line AGNs at z > 5 with M BH ≃ 10 7 M ⊙ demonstrates the capability of JWST to push BH masses closer to the range predicted for the BH seed population and provides a unique opportunity to study the early stages of BH–galaxy assembly.
Guidelines of care for the management of primary cutaneous melanoma Bichakjian, Christopher K., MD; Halpern, Allan C., MD (Co-chair); Johnson, Timothy M., MD (Co-chair) ...
Journal of the American Academy of Dermatology,
11/2011, Letnik:
65, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The incidence of primary cutaneous melanoma has been increasing dramatically for several decades. Melanoma accounts for the majority of skin cancer–related deaths, but treatment is nearly always ...curative with early detection of disease. In this update of the guidelines of care, we will discuss the treatment of patients with primary cutaneous melanoma. We will discuss biopsy techniques of a lesion clinically suspicious for melanoma and offer recommendations for the histopathologic interpretation of cutaneous melanoma. We will offer recommendations for the use of laboratory and imaging tests in the initial workup of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, we will provide recommendations for surgical margins and briefly discuss nonsurgical treatments. Finally, we will discuss the value and limitations of sentinel lymph node biopsy and offer recommendations for its use in patients with primary cutaneous melanoma.
Cilium and flagellum beating are important in reproduction and defects in their motion are associated with ectopic pregnancy and infertility. Adrenomedullin (ADM) is a polypeptide present in the ...reproductive system. This report demonstrates a novel action of ADM in enhancing the flagellar/ciliary beating of human spermatozoa and rat oviductal ciliated cells. At the concentration found in the seminal plasma, it increases the progressive motility of spermatozoa. ADM binds to its classical receptor, calcitonin receptor-like receptor/receptor activity-modifying protein complex on spermatozoa. ADM treatment increases the protein kinase A activities, the cyclic adenosine monophosphate, and nitric oxide levels of spermatozoa and oviductal cells. Pharmacological activators and inhibitors confirmed that the ADM-induced flagella/ciliary beating was protein kinase A dependent. Whereas nitric oxide donors had no effect on sperm motility, they potentiated the motility-inducing action of protein kinase A activators, demonstrating for the first time the synergistic action of nitric oxide and protein kinase A signaling in flagellar/ciliary beating. The ADM-induced motility enhancement effect in spermatozoa also depended on the up-regulation of intracellular calcium, a known key regulator of sperm motility and ciliary beating. In conclusion, ADM is a common activator of flagellar/ciliary beating. The study provides a physiological basis on possible use of ADM as a fertility regulation drug.
Adrenomedullin modulates the beating of flagella and cilia through a synergistic action of nitric oxide and protein kinase-A signaling.
Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from ...these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10−94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10−30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10−16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.
•PRS, based on the known CLL loci, predicts CLL risk with high discrimination.•This PRS predicts risk of monoclonal B-cell lymphocytosis, a precursor to CLL and a condition that has clinical impact beyond risk for CLL.
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