Tyrosine kinase inhibitors (TKIs) are currently the first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. These patients receive platinum-based chemotherapy as the second-line treatment after they develop resistance to TKIs. Many patients regain sensitivity to the TKIs used in the first-line treatment after the failure of chemotherapy. However, the molecular mechanism for the regain of TKI sensitivity is largely unknown. In this study, we established gefitinib-resistant PC9 and HCC827 cell lines, which did not harbor the EGFR T790M mutation and MET amplification but exhibited the epithelial-mesenchymal transition (EMT) phenotype. Overexpression of EMT inducers, Snail or Slug, in the parental lines promoted their resistance to gefitinib. The gefitinib-resistant cell lines regained their sensitivity to gefitinib and displayed reverse EMT phenotypes after long-term culture in gefitinib-free culture medium. Blockage of reverse EMT by stable expression of Snail or Slug prevented the regain of TKI sensitivity. In conclusion, reverse EMT is one of the major mechanisms for the regain of TKI sensitivity in TKI-resistant NSCLC cells, suggesting that the development of small molecules targeting the EMT process may prolong the efficacy of TKIs in NSCLC patients with EGFR mutations.
IMPORTANCEPrehospital advanced airway management with either initial endotracheal intubation (ETI) or initial supraglottic airway (SGA) insertion in patients with out-of-hospital cardiac arrest (OHCA) remains controversial. OBJECTIVE To compare the effectiveness of ETI and SGA in patients with nontraumatic OHCA. DESIGN, SETTING, AND PARTICIPANTS The Supraglottic Airway Device vs Endotracheal intubation (SAVE) trial was a multicenter cluster randomized clinical trial conducted in Taipei City, Taiwan. Individuals aged 20 years or older who experienced nontraumatic OHCA requiring advanced airway management and were treated by participating emergency medical service agencies were enrolled from No-
Autosomal Dominant polycystic kidney disease (ADPKD) is the most common inherited adult kidney disease. Although ADPKD is primarily caused by PKD1 and PKD2, the identification of several novel causative genes in recent years has revealed more complex genetic heterogeneity than previously thought. To study the disease-causing mutations of ADPKD, a total of 920 families were collected and their diagnoses were established via clinical and image studies by Taiwan PKD Consortium investigators. Amplicon-based library preparation with next-generation sequencing, variant calling, and bioinformatic analysis was used to identify disease-causing mutations in the cohort. Microsatellite analysis along with genotyping and haplotype analysis was performed in the PKD2 p.Arg803* family members. The age of mutation was calculated to estimate the time at which the mutation occurred or the founder arrived in Taiwan. Disease-causing mutations were identified in 634 families (68.9%) by detection of 364 PKD1, 239 PKD2, 18 PKHD1, 7 GANAB, and 6 ALG8 pathogenic variants. 162 families (17.6%) had likely causative but non-diagnostic variants of unknown significance (VUS). A single PKD2 p.Arg803* mutation was found in 17.8% (164/920) of the cohort in Taiwan. Microsatellite and array analysis showed that 80% of the PKD2 p.Arg803* families shared the same haplotype in a 250 kb region, indicating those families may originate from a common ancestor 300 years ago. Our findings provide a mutation landscape as well as evidence that a founder effect exists and has contributed to a major percentage of the ADPKD population in Taiwan.
Background
The effects of early integration of point-of-care ultrasound (PoCUS) into patient care are uncertain. This study aims to investigate the effects of early PoCUS on patients with acute flank pain.
Methods
Adult non-traumatic patients with acute flank pain receiving PoCUS were enrolled. Expert physicians reviewed the medical records and made the “final diagnosis” for the cause of acute flank pain. The primary outcome was the relationship between the door to ultrasound (US) time and length of stay (LOS). The secondary outcomes included the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the sonographic diagnosis, compared with the final diagnosis.
Results
Eight hundred and eighty-eight patients were included in the analysis. Patients receiving early PoCUS (≤120 min) had a shorter LOS (128 vs. 217 min, p < 0.0001). Patients in the late POCUS group (> 120 min) had a trend to receive more CT scans. The disease distribution, sensitivity, specificity, PPV, and NPV were similar in patients receiving early or late PoCUS for target diagnoses. After adjusting for the confounders, early PoCUS (OR, 2.77, 95% CIs, 1.93–3.98) had a positive impact on shorter LOS. In addition, the effect of early PoCUS became more prominent (OR, 4.91, 95% CIs, 3.39–7.13) on LOS in less than 3 h.
Conclusions
Early integration of PoCUS is significantly related to shorter LOS in patients with acute flank pain without increasing morbidity and mortality. Our results suggested “PoCUS early” in these patients to possibly alleviate emergency department crowding.
Trial registration NCT04149041 at the ClinicalTrial.gov.
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