Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as ...compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown.
In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival.
At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval CI, 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group.
Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.).
More than 2% of adults harbor a pancreatic cyst, a subset of which progresses to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we ...determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and solid pseudopapillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10 ± 4.6, 27 ± 12, 16 ± 7.6, and 2.9 ± 2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of the von Hippel–Lindau gene (VHL), a key component of the VHL ubiquitin ligase complex that has previously been associated with renal cell carcinomas, SCAs, and other neoplasms. Six of the eight IPMNs and three of the eight MCNs harbored mutations of RNF43, a gene coding for a protein with intrinsic E3 ubiquitin ligase activity that has not previously been found to be genetically altered in any human cancer. The preponderance of inactivating mutations in RNF43 unequivocally establish it as a suppressor of both IPMNs and MCNs. SPNs contained remarkably few genetic alterations but always contained mutations of CTNNB1, previously demonstrated to inhibit degradation of the encoded protein (β-catenin) by E3 ubiquitin ligases. These results highlight the essential role of ubiquitin ligases in these neoplasms and have important implications for the diagnosis and treatment of patients with cystic tumors.
Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the ...monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.
Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in ...mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer.
We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.
A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging,
F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.
Mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).
Advances in medicine and improvements in life quality has led to an increase in the life expectancy of the general population. An ageing world population have placed demands on the use of assistive ...technology and, in particular, towards novel healthcare devices and sensors. Besides the electromagnetic field immunity, polymer optical fiber (POF) sensors have additional advantages due to their material features such as high flexibility, lower Young's modulus (enabling high sensitivity for mechanical parameters), higher elastic limits, and impact resistance. Such advantages are well-aligned with the instrumentation requirements of many healthcare devices and in movement analysis. Aiming at these advantages, this review paper presents the state-of-the-art developments of POF sensors for healthcare applications. A plethora of healthcare applications are discussed, which include movement analysis, physiological parameters monitoring, instrumented insoles, as well as instrumentation of healthcare robotic devices such as exoskeletons, smart walkers, actuators, prostheses, and orthosis. This review paper shows the feasibility of using POF sensors in healthcare applications and, due to the aforementioned advantages, it is possible to envisage a further widespread use of such sensors in this research field in the next few years.
Recent studies have indicated that biosurfactants play a role both in maintaining channels between multicellular structures in biofilms and in dispersal of cells from biofilms. A combination of ...caprylic acid (0.01 %
v
/
v
) together with rhamnolipids (0.04 %
v
/
v
) was applied to biofilms of
Pseudomonas aeruginosa
ATCC 15442,
Staphylococcus aureus
ATCC 9144 and a mixed culture under BioFlux flowthrough conditions and caused disruption of the biofilms. The biofilms were also treated with a combination of rhamnolipids (0.04 %
v
/
v
) and sophorolipids (0.01 %). Control treatments with PBS 1× had no apparent effect on biofilm disruption. The Gram-positive bacterium (
S. aureus
ATCC 9144) was more sensitive than
P. aeruginosa
ATCC 15442 in terms of disruption and viability as shown by Live/Dead staining. Disruption of biofilms of
P. aeruginosa
ATCC 15442 was minimal. Oxygen consumption by biofilms, after different treatments with biosurfactants, confirms that sophorolipid on its own is unable to kill/inhibit cells of
P. aeruginosa
ATCC 15442, and even when used in combination with rhamnolipids, under static conditions, no decrease in the cell viability was observed. Cells in biofilms exposed to mono-rhamnolipids (0.04 %
v
/
v
) showed behaviour typical of exposure to bacteriostatic compounds, but when exposed to di-rhamnolipids (0.04 %
v
/
v
), they displayed a pattern characteristic of bactericidal compounds.
The Colorectal MicroRNAome Cummins, Jordan M.; He, Yiping; Leary, Rebecca J. ...
Proceedings of the National Academy of Sciences - PNAS,
03/2006, Letnik:
103, Številka:
10
Journal Article
Recenzirano
Odprti dostop
MicroRNAs (miRNAs) are a class of small noncoding RNAs that have important regulatory roles in multicellular organisms. The public miRNA database contains 321 human miRNA sequences, 234 of which have ...been experimentally verified. To explore the possibility that additional miRNAs are present in the human genome, we have developed an experimental approach called miRNA serial analysis of gene expression (miRAGE) and used it to perform the largest experimental analysis of human miRNAs to date. Sequence analysis of 273,966 small RNA tags from human colorectal cells allowed us to identify 200 known mature miRNAs, 133 novel miRNA candidates, and 112 previously uncharacterized miRNA* forms. To aid in the evaluation of candidate miRNAs, we disrupted the Dicer locus in three human colorectal cancer cell lines and examined known and novel miRNAs in these cells. These studies suggest that the human genome contains many more miRNAs than currently identified and provide an approach for the large-scale experimental cloning of novel human miRNAs in human tissues.
In this paper, we report the development of a portable energy-efficient interrogator (Perrogator) for wavelength-based optical sensors. The interrogator is based on a compact solution encompassing a ...white light source and the spectral convolution between the sensor and a tunable filter, which is acquired by a photodetector, where a microcontroller has two functions: (i) To control the filter tuning and to (ii) acquire the photodetector signal. Then, the data is sent to a single-board computer for further signal processing. Furthermore, the employed single-board computer has a Wi-Fi module, which can be used to send the sensors data to the cloud. The proposed approach resulted in an interrogator with a resolution as high as 3.82 pm (for 15.64 nm sweeping range) and maximum acquisition frequency of about 210 Hz (with lower resolution ~15.30 pm). Perrogator was compared with a commercial fiber Bragg grating (FBG) interrogator for strain measurements and good agreement between both devices was found (1.226 pm/µε for the commercial interrogator and 1.201 pm/µε for the proposed approach with root mean square error of 0.0144 and 0.0153, respectively), where the Perrogator has the additional advantages of lower cost, higher portability and lower energy consumption. In order to demonstrate such advantages in conjunction with the high acquisition frequency allowed us to demonstrate two wearable applications using the proposed interrogation device over FBG and Fabry-Perot interferometer (FPI) sensors. In the first application, an FBG-embedded smart textile for knee angle assessment was used to analyze the gait of a healthy person. Due to the capability of reconstructing the FBG spectra, it was possible to employ a technique based on the FBG wavelength shift and reflectivity to decouple the effects of the bending angle and axial strain on the FBG response. The measurement of the knee angle as well as the estimation of the angular and axial displacements on the grating that can be correlated to the variations of the knee center of rotation were performed. In the second application, a FPI was embedded in a chest band for simultaneous measurement of breath and heart rates, where good agreement (error below 5%) was found with the reference sensors in all analyzed cases.
The MiniBooNE experiment at Fermilab reports results from an analysis of ν_{e} appearance data from 12.84×10^{20} protons on target in neutrino mode, an increase of approximately a factor of 2 over ...previously reported results. A ν_{e} charged-current quasielastic event excess of 381.2±85.2 events (4.5σ) is observed in the energy range 200<E_{ν}^{QE}<1250 MeV. Combining these data with the νover ¯_{e} appearance data from 11.27×10^{20} protons on target in antineutrino mode, a total ν_{e} plus νover ¯_{e} charged-current quasielastic event excess of 460.5±99.0 events (4.7σ) is observed. If interpreted in a two-neutrino oscillation model, ν_{μ}→ν_{e}, the best oscillation fit to the excess has a probability of 21.1%, while the background-only fit has a χ^{2} probability of 6×10^{-7} relative to the best fit. The MiniBooNE data are consistent in energy and magnitude with the excess of events reported by the Liquid Scintillator Neutrino Detector (LSND), and the significance of the combined LSND and MiniBooNE excesses is 6.0σ. A two-neutrino oscillation interpretation of the data would require at least four neutrino types and indicate physics beyond the three neutrino paradigm. Although the data are fit with a two-neutrino oscillation model, other models may provide better fits to the data.
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