•CF patients homozygous for F508del mutation show differences in disease progression.•FIS assay in intestinal organoids can be used to precisely quantitate CFTR function.•FIS of intestinal organoids ...varied between subjects with identical mutations.•FIS correlates with individual disease severity in homozygous F508del patients.•Small changes in CFTR residual function may impact on long-term disease expression.
CFTR function measurements in intestinal organoids may help to better characterise individual disease expression in F508del homozygous people. Our objective was to study correlations between CFTR function as measured with forskolin-induced swelling in rectal organoids with clinical parameters in adult patients with homozygous F508del mutations.
Multicentre observational study. Thirty-four adults underwent rectal biopsy, pulmonary function tests (FEV1 and FVC), chest X-ray and chest CT. Body-mass index (BMI) was assessed at study visit and exacerbation rate was determined during five years prior to study visit. Organoids were cultured and measured after stimulation with 5 µm forskolin for three hours to quantitate CFTR residual function.
FIS was positively correlated with FEV1 (r = 0.36, 95% CI 0.02–0.62, p = 0.04) and BMI (r = 0.42, 95% CI 0.09–0.66, p = 0.015). FIS was negatively correlated with PRAGMA-CF CT score for% of disease (r = −0.37, 95% CI -0.62- -0.03, p = 0.049). We found no significant correlation between FIS and chest radiography score for CF (r = −0.16, 95% CI -0.48–0.20, p = 0.44). We observed a trend between higher FIS and a lower mean number of exacerbations over the last 5 years of observation, but this was not statistically significant (Poisson regression, p = 0.089).
FIS of intestinal organoids varied between subjects with homozygous F508del and correlated with pulmonary and nutritional parameters. These findings suggest that differences at low CFTR residual function may contribute to clinical heterogeneity in F508del homozygous patients and small changes in CFTR residual function might impact long-term disease expression.
Abstract
The High Energy Stereoscopic System has revealed many TeV (1012 eV) gamma-ray sources along the Galactic plane, and around 30 per cent of these sources remain unidentified. The morphology ...and dynamics of dense gas coincident and surrounding the gamma-ray emission can provide clues about the nature of the TeV emission. The H2O Southern Galactic Plane Survey (HOPS) undertaken with the Mopra radio telescope includes several dense gas tracers, such as NH3 (n,n) transitions and HC3N (3–2), star formation tracers including H2O masers and radio recombination lines that trace ionized gas. A search for dense gas, traced by NH3 (1,1) emission seen in HOPS and additional observations, towards Galactic TeV sources has been undertaken. Of the 49 Galactic TeV sources covered by 12 mm observations, NH3 (1,1) is detected towards or adjacent to 38 of them. Dense gas counterparts have been detected near several unidentified Galactic TeV sources that display morphology pointing to a hadronic origin to the TeV gamma-rays. The dense gas detected towards some TeV sources displays unusual emission characteristics, including very broad linewidths and enhanced ortho-to-para NH3 abundance ratios towards HESS J1745−303 and HESS J1801−233, which reflects previous shock activity within the gas.
In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses ...in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolin-induced swelling and studied the correlation with in vivo effects. The in vitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-to-excellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an in vitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner.
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•Organoids of CF patients were used to quantitate individual drug response in vitro•Organoid responses correlate with two clinical response parameters ppFEV1 and SCC•In vivo (non)responders were identified with a PPV of 100% and a NPV of 80%•Organoids may be used for personalized medicine in cystic fibrosis
Berkers et al. demonstrate that stem cell cultures (organoids) can be a tool for personalized medicine. They show a high correlation between in vitro and in vivo effects of drugs and demonstrate good-to-excellent predictive values of the organoid test for preclinical identification of responders to CFTR modulators.
AIM To evaluate a step up approach: Taking macrobiopsies and performing excision biopsies in patients with suspected rectal cancer in which biopsies taken though the flexible endoscope showed benign ...histology. METHODS Patients with a rectal neoplasm who underwent flexible endoscopy and biopsies were included. In case of benign biopsies rigid rectoscopy and macrobiopsies were employed. If this failed to prove malignancy, transanalendoscopic microsurgery(TEM) was used in a final effort to establish a certain preoperative diagnosis. The preoperative results were compared with the findings after surgical excision and follow up to calculate the reliability of this algorithm.RESULTS One hundred and thirty-two patients were included. One hundred and ten patients with a carcinoma and 22 with an adenoma. Seventy-five of 110 carcinomas were proven malignant after flexible endoscopy. With the addition of rigid endoscopy and taking of macrobiopsies, this number increased to 89. Performing TEM excision biopsies further enlarged the number of proven malignancies to 100.CONCLUSION The step-up approach includes taking macrobiopsies through the rigid rectoscope and performing excision biopsies using transanal endoscopic microsurgery in addition to flexible endoscopy. This approach, reduced the number of missed preoperative malignant diagnoses from 32% to 9%.
The production of positron-electron pairs in collisions of {sup 238}U+{sup 232}Th at 5.95 MeV/nucleon, and of {sup 238}U+{sup 181}Ta at 5.95, 6.1, and 6.3 MeV/nucleon, has been studied with the APEX ...spectrometer at Argonne National Laboratory. Several analyses have been performed to search for sharp structures in sum-energy spectra for positron-electron pairs. Such features have been reported in previous experiments. No statistically convincing evidence for such behavior is observed in the present data. (c) 1999 The American Physical Society.
The High Energy Stereoscopic System (H.E.S.S.) has revealed many TeV (10 12 eV) gamma-ray sources along the Galactic Plane and around 30 percent of these sources remain unidentified. The morphology ...and dynamics of dense gas coincident and surrounding the gamma-ray emission can provide clues about the nature of the TeV emission. The H2O Southern Galactic Plane Survey (HOPS) undertaken with the Mopra radio telescope, includes several dense gas tracers, such as NH3 (n,n) transitions and HC3N (3-2), star formation tracers including H2O masers, and radio recombination lines which trace ionised gas. A search for dense gas, traced by NH3 (1,1) emission seen in HOPS and additional observations, towards Galactic TeV sources has been undertaken. Of the 49 Galactic TeV sources covered by 12 mm observations, NH3 (1,1) is detected towards or adjacent to 38 of them. Dense gas counterparts have been detected near several unidentified Galactic TeV sources which display morphology pointing to a hadronic origin to the TeV gamma-rays. The dense gas detected towards some TeV sources displays unusual emission characteristics, including very broad linewidths and enhanced ortho-to-para NH3 abundance ratios towards HESS J1745-303 and HESS J1801-233, which reflects previous shock activity within the gas.
We present observations of fifty square degrees of the Mopra carbon monoxide (CO) survey of the Southern Galactic Plane, covering Galactic longitudes \(l = 300\)-\(350^\circ\) and latitudes \(|b| \le ...0.5^\circ\). These data have been taken at 0.6 arcminute spatial resolution and 0.1 km/s spectral resolution, providing an unprecedented view of the molecular clouds and gas of the Southern Galactic Plane in the 109-115 GHz \(J = 1\)-0 transitions of \(^{12}\)CO, \(^{13}\)CO, C\(^{18}\)O and C\(^{17}\)O. We present a series of velocity-integrated maps, spectra and position-velocity plots that illustrate Galactic arm structures and trace masses on the order of \(\sim\)10\(^{6}\) M\(_{\odot}\) per square degree; and include a preliminary catalogue of C\(^{18}\)O clumps located between \(l=330\)-\(340^\circ\). Together with information about the noise statistics of the survey these data can be retrieved from the Mopra CO website, the PASA data store and the Harvard Dataverse (doi:10.7910/DVN/LH3BDN ).
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