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This article discusses a study that examines the genetic and molecular characteristics of lung cancer patients who have transformed from one type of lung cancer to another. The study identifies two distinct subtypes based on the RB1 gene status of the patients. The findings suggest that RB1 and SMAD4 alterations are important factors in this transformation, and patients with RB1 mutations tend to have a longer time before the transformation occurs. The article highlights the importance of understanding the heterogeneity within this patient population in order to develop new treatments and improve outcomes. Additionally, the study develops a predictive model to assess the risk of transformation in patients with specific gene mutations. Overall, this research provides valuable insights into the biology of transformed lung cancer and potential targets for therapy. [Extracted from the article]

Background: Some studies of dual-targeted therapy (DTT) targeting epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) have shown promising efficacy in non-small-cell lung cancer (NSCLC). Consequently, patient management following DTT resistance has gained significance. However, the underlying resistance mechanisms and clinical outcomes in these patients remain unclear. Objectives: This study aimed to delineate the molecular characteristics and survival outcomes of patients with NSCLC harboring EGFR mutations and acquired MET amplification after developing resistance to DTT. Design: We conducted a retrospective analysis of patients with NSCLC with EGFR mutations and acquired MET amplification who exhibited resistance to EGFR/MET DTT. Methods: Next-generation sequencing (NGS) was performed on patients with available tissue samples before and/or after the development of resistance to DTT. Stratified analyses were carried out based on data sources and subsequent salvage treatments. Univariate/multivariate Cox regression models and survival analyses were employed to explore potential independent prognostic factors. Results: The study included 77 NSCLC patients, with NGS conducted on 19 patients. We observed many resistance mechanisms, including EGFR-dependent pathways (4/19, 21.1%), MET-dependent pathways (2/19, 10.5%), EGFR/MET co-dependent pathways (2/19, 10.5%), and EGFR/MET-independent resistance mechanisms (11/19, 57.9%). Post-progression progression-free survival (pPFS) and post-progression overall survival (pOS) significantly varied among patients who received the best supportive care (BSC), targeted therapy, or chemotherapy (CT), with median pPFS of 1.5, 3.9, and 4.9 months, respectively (p = 0.003). Median pOS were 2.3, 7.7, and 9.2 months, respectively (p < 0.001). The number of treatment lines following DTT resistance and the Eastern Cooperative Oncology Group performance status emerged as the independent prognostic factors. Conclusion: This study revealed a heterogeneous landscape of resistance mechanisms to EGFR/MET DTT, with a similar prevalence of on- and off-target mechanisms. Targeted therapy or CT, as compared to BSC, exhibited the potential to improve survival outcomes for patients with advanced NSCLC following resistance to DTT. [ABSTRACT FROM AUTHOR]

A simple liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI/MS) method has been developed to analyze oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (ox-PAPC) products on the lipoproteins of uremic patients. The native PAPC standard was in vitro oxidized by the Fenton reaction, and the ox-PAPC products were analyzed by LC- ESI/MS. For LC, a C8 column and a mobile phase (acetonitrile-isopropanol containing 0.1% formic acid (70:30, v/v)) were selected. For ESI/MS, the optimal conditions included sheath gas pressure (10 psi), capillary temperature (270 °C), and injection time (1000 ms). The identification of ox-PAPC products on human lipoproteins was based on the extracted ion chromatograms (EICs) and the ESI-MS spectra of the in vitro oxidation products of PAPC standard. The EICs and ESI-MS spectra showed good repeatability and sensitivity. A total of 21 ox-PAPC products was determined. Linear analysis has been performed for the phospholipid standard, 1, 2-Di-O-hexadecyl-sn-glycero-3-phosphocholine (PC(O-16:0/O-16:0)). The linear range was 5.0–100.0 µg/mL, and the coefficient of determination (R2) was 0.989. The concentration limit of detection (LOD) was 1.50 µg/mL, and the concentration limit of quantitation (LOQ) was 4.54 µg/mL. The selected 21 ox-PAPC products have been identified and quantified in very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) of uremic and healthy subjects. Interestingly, the results showed that the levels of 18 products in VLDL, one product in LDL, and 19 products in HDL were significantly higher for uremic patients than healthy controls. This simple LC-ESI/MS method might accelerate the searching for biomarkers of uremia in the future. [ABSTRACT FROM AUTHOR]

Background: MET dysregulation has been implicated in the development of primary and secondary resistance to EGFR tyrosine kinase inhibitor (TKI) therapy. However, the clinicopathological characteristics and outcomes of patients harboring EGFR‐sensitive mutations and de novo MET amplifications still need to be explored. Methods: A total of 54 patients from our hospital with non‐small cell lung cancer harboring EGFR‐sensitive mutations and/or de novo MET amplifications were included in this study. Survival rates were estimated by the Kaplan–Meier method with log‐rank statistics. Lung cancer organoids (LCOs) were generated from patient‐derived malignant pleural effusion to perform drug sensitivity assays. Results: Fifty‐four patients with the appropriate clinicopathological characteristics were enrolled. MET FISH was performed in 40 patients who were stratified accordingly into two groups: EGFR+/METamp‐ (n = 22) and EGFR+/METamp + (n = 18). Survival rates for EGFR+/METamp‐ and EGFR+/METamp + patients respectively, were as follows: the median progression‐free survival (PFS) was 12.1 and 1.9 months (p<0.001); the median post‐progression overall survival (pOS) was 25.6 and 11.6 months (p = 0.023); the median overall survival (OS) was 33.2 and 12.7 months (p = 0.013). Drug testing conducted in LCOs derived from malignant pleural effusion from EGFR+/METamp + patients showed that dual targeted therapy was more effective than TKI monotherapy. Conclusion: EGFR+/METamp + patients treated with first‐line TKI monotherapy had poor clinical outcomes. Dual targeted therapy showed potent anticancer activity in the LCO drug testing assay, suggesting that it is a promising first‐line treatment for EGFR+/METamp + patients. Randomized controlled trials are needed to further validate these results. [ABSTRACT FROM AUTHOR]

Proinflammatory immune cell subsets constitute the majority in the local microenvironment after spinal cord injury (SCI), leading to secondary pathological injury. Previous studies have demonstrated that inflammasomes act as an important part of the inflammatory process after SCI. Probenecid, an inhibitor of the Pannexin-1 channel, can inhibit the activation of inflammasomes. This article focuses on the effects of probenecid on the local immune microenvironment, histopathology, and behavior of SCI. Our data show that probenecid inhibited the expression and activation of nucleotide-binding oligomerization domain receptor pyrindomain-containing 1 (NLRP1), apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1, interleukin-1β (IL-1β), and caspase-3 proteins associated with inflammasomes, thereby suppressing the proportion of M1 cells. And consequently, probenecid reduced the lesion area and demyelination in SCI. Moreover, the drug increased the survival of motor neurons, which resulted in tissue repair and improved locomotor function in the injured SC. Altogether, existing studies indicated that probenecid can alleviate inflammation by blocking Pannexin-1 channels to inhibit the expression of caspase-1 and IL-1β, which in turn restores the balance of immune cell subsets and exerts neuroprotective effects in rats with SCI. [ABSTRACT FROM AUTHOR]

Aim: Hydroxychloroquine (HCQ) is used to control proteinuria in IgA Nephropathy (IgAN) However, its efficacy and safety in pregnant IgAN patients remains unknown. This study aimed to verify the safety of HCQ in pregnant IgAN patients and compare renal function and pregnancy outcomes with those of patients not treated with HCQ. Methods: We retrospectively reviewed medical records of all pregnant IgAN patients and singleton gestations at Peking University First Hospital from 2003–2021. Patients who did and did not receive HCQ treatment during pregnancy were compared. Results: We found no significant pre‐ or post‐pregnancy differences in proteinuria or renal function between the two groups. However, the HCQ (+) group had higher proteinuria at the time of kidney biopsy (2.04 [1.26, 2.56] g/d vs. 0.80 [0.44, 1.11] g/d, P <.001); the proteinuria level at HCQ therapy initiation was also higher than that at the beginning of pregnancy (1.87 [1.30, 2.59] g/d vs. 1.08 [0.75, 1.50] g/d, P =.001). Despite no difference in preterm birth, birth weight, preeclampsia or postpartum haemorrhage, the proportion of patients with a previous history of spontaneous abortion was higher in the HCQ (+) group than in the HCQ (−) group (48.0% vs. 20.6%, P =.010). The eGFR (regression coefficient, 0.981; 95%CI 0.964–0.998) was a predictive factor for obstetrical complications. Conclusion: HCQ is safe for IgAN treatment during pregnancy with effective reduction of proteinuria. HCQ might also be helpful in patients with a history of spontaneous abortion. SUMMARY AT A GLANCE: In this retrospective comparison of 25 pregnant patients with IgA nephropathy treated with hydroxychloroquine (HCQ) versus 65 other pregnant IgAN patients who were not given HCQ, it was found that HCQ is safe and effective in reducing proteinuria. Multivariate regression shows that baseline eGFR is a predictor of obstetric complications. [ABSTRACT FROM AUTHOR]