UNASSIGNED: Kidney transplant recipients expect to survive the procedure with sufficient renal function for reliable dialysis freedom.
UNASSIGNED: Transplant outcomes (survival and estimated renal function) were assessed after live and deceased donor transplantation from the US national database. Outcomes were stratified by age (donor and recipient) and donor type.
UNASSIGNED: Aggregate recipient outcomes were better transplanting living vs deceased donated kidneys. However, when stratified by the one-year renal function (within KDIGO CKD stage stratifications), surviving recipients had clinically similar dialysis-freedom, irrespective of donor type or age. The major outcome differences for recipients of age-stratified live and deceased kidneys was 1) the increasing frequency of one-year graft failures and 2) the increasing likelihood of severely limited renal function (CKD 4/5) with advancing donor age. Over 30% of recipients of deceased kidneys >65 years had either one-year graft failure or severely limited renal function contrasted to less than 15% of recipients of live kidneys aged >65 years.
UNASSIGNED: Evolving techniques to reduce adverse events after urgent vs elective procedures, plus improved transplant outcome predictability with increased-age deceased donor kidneys using advanced predictive analytics (using age-stratified live kidney transplantation outcomes as a relevant reference point) should facilitate similar kidney transplant outcomes, irrespective of donor type.

BACKGROUND: Renal outcomes in patients with type 2 diabetes following treatment with sodium-glucose co-transporter-2 inhibitors (SGLT2is) or glucagon-like peptide-1 receptor agonists (GLP1RAs) have not been directly compared. This study compared the impact of SGLT2i and GLP1RA therapy on renal function and metabolic parameters.
METHODS: Patients with type 2 diabetes who initiated SGLT2i or GLP1RA therapy in a tertiary hospital between January 2009 and August 2023 were included to assess composite renal outcomes, such as a 40% decline in estimated glomerular filtration rate (eGFR), onset of end-stage renal disease, renal death, or new-onset macroalbuminuria. Alterations in blood pressure, glucose regulation parameters, lipid profile, and anthropometric parameters, including body fat and muscle masses, were examined over 4-years.
RESULTS: A total of 2,112 patients were enrolled using a one-to-three propensity-score matching approach (528 patients for GLP1RAs, 1,584 patients for SGLT2i). SGLT2i treatment was favoured over GLP1RA treatment, though not significantly, for composite renal outcomes (hazard ratio [HR], 0.63; p = 0.097). SGLT2i therapy preserved renal function effectively than GLP1RAs (decrease in eGFR, ≥ 40%; HR, 0.46; p = 0.023), with improving albuminuria regression (HR, 1.72; p = 0.036). SGLT2i therapy decreased blood pressure and body weight to a greater extent. However, more patients attained HbA1c levels < 7.0% with GLP1RAs than with SGLT2is (40.6% vs 31.4%; p < 0.001). GLP1RA therapy enhanced β-cell function and decreased LDL-cholesterol levels below baseline values.
CONCLUSIONS: SGLT2is were superior for preserving renal function and reducing body weight, whereas GLP1RAs were better for managing glucose dysregulation and dyslipidaemia.

In order to survive and replicate, Salmonella has evolved mechanisms to gain access to intestinal epithelial cells of the crypt. However, the impact of Salmonella Typhimurium on stem cells and progenitors, which are responsible for the ability of the intestinal epithelium to renew and protect itself, remains unclear. Given that intestinal organoids growth is sustained by stem cells and progenitors activity, we have used this model to document the effects of Salmonella Typhimurium infection on epithelial proliferation and differentiation, and compared it to an in vivo model of Salmonella infection in mice. Among gut segments, the caecum was preferentially targeted by Salmonella. Analysis of infected crypts and organoids demonstrated increased length and size, respectively. mRNA transcription profiles of infected crypts and organoids pointed to upregulated EGFR-dependent signals, associated with a decrease in secretory cell lineage differentiation. To conclude, we show that organoids are suited to mimic the impact of Salmonella on stem cells and progenitors cells, carrying a great potential to drastically reduce the use of animals for scientific studies on that topic. In both models, the EGFR pathway, crucial to stem cells and progenitors proliferation and differentiation, is dysregulated by Salmonella, suggesting that repeated infections might have consequences on crypt integrity and further oncogenesis.

Bioactive compounds derived from natural products demonstrate a wide range of beneficial properties in cancer treatment. One popular approach to inhibiting cancer cell growth is by stimulating apoptosis. Interestingly, our research has discovered that traditional mushroom and isolated compounds from traditional herbs can induce apoptosis in A549 cells while inhibiting tyrosine kinase activities. We have identified two extracts from traditional mushrooms, Phallus indusiatus and Fomes rimosus (Berk.) Cooke, which exhibit promising abilities to activate apoptotic events in cells. Additionally, isolated compounds such as Chamuangone, Cannabigerol (CBG), Cannabidiol (CBD), and NP1-cyclic peptide have also demonstrated significant apoptotic activation capabilities. To further our understanding, we analyzed phosphoprotein changes in A549 cells exposed to these extracts and compounds, both with and without epidermal growth factor (EGF) stimulation. Our positive controls were two known drugs, Afatinib and Osimertinib, which are tyrosine kinase inhibitors with apoptotic stimulation abilities. In order to enrich our understanding of the kinase pathway, we conducted phosphoprotein enrichment analysis and identified altered phosphoproteins using LC-MS/MS. Across these testing conditions, we found that 1228 phosphoproteins were altered, providing valuable insights into the biochemical mechanisms underlying cell apoptosis in A549 cells through post-translational modifications of proteins. Furthermore, our findings not only shed light on the mechanisms of cell apoptosis in A549 cells but also offer promising avenues for future research and therapeutic development.

Nasopharyngeal carcinoma (NPC), primarily found in the southern region of China, is a malignant tumor known for its highly metastatic characteristics. The high mortality rates caused by the distant metastasis and disease recurrence remain unsolved clinical problems. In clinic, the berberine (BBR) compound has widely been in NPC therapy to decrease metastasis and disease recurrence, and BBR was documented as a main component with multiple anti-NPC effects. However, the mechanism by which BBR inhibits the growth and metastasis of nasopharyngeal carcinoma remains elusive. Herein, we show that BBR effectively inhibits the growth, metastasis, and invasion of NPC via inducing a specific super enhancer (SE). From a mechanistic perspective, the RNA sequencing (RNA-seq) results suggest that the RAS-RAF1-MEK1/2-ERK1/2 signaling pathway, activated by the epidermal growth factor receptor (EGFR), plays a significant role in BBR-induced autophagy in NPC. Blockading of autophagy markedly attenuated the effect of BBR-mediated NPC cell growth and metastasis inhibition. Notably, BBR increased the expression of EGFR by transcription, and knockout of EGFR significantly inhibited BBR-induced microtubule associated protein 1 light chain 3 (LC3)-II increase and p62 inhibition, proposing that EGFR plays a pivotal role in BBR-induced autophagy in NPC. Chromatin immunoprecipitation sequencing (ChIP-seq) results found that a specific SE existed only in NPC cells treated with BBR. This SE knockdown markedly repressed the expression of EGFR and phosphorylated EGFR (EGFR-p) and reversed the inhibition of BBR on NPC proliferation, metastasis, and invasion. Furthermore, BBR-specific SE may trigger autophagy by enhancing EGFR gene transcription, thereby upregulating the RAS-RAF1-MEK1/2-ERK1/2 signaling pathway. In addition, in vivo BBR effectively inhibited NPC cells growth and metastasis, following an increase LC3 and EGFR and a decrease p62. Collectively, this study identifies a novel BBR-special SE and established a new epigenetic paradigm, by which BBR regulates autophagy, inhibits proliferation, metastasis, and invasion. It provides a rationale for BBR application as the treatment regime in NPC therapy in future.

UNASSIGNED: Despite the need, measuring glomerular filtration rate (mGFR) is not routinely performed for adults with cerebral palsy (CP), possibly due to unknown feasibility given the secondary complications of CP. This study aimed to assess the feasibility and reliability of mGFR and explore factors associated with eGFR-mGFR discordance among young adults with mild-to-moderate CP.
UNASSIGNED: This single-center, cross-sectional study included 18- to 40-year-olds with CP gross motor function classification system (GMFCS) I-III. The participants were excluded if they were pregnant/lactating, had cognitive impairments, or had contraindications to mGFR. A routine clinical protocol for mGFR and eGFR was used. mGFR feasibility was assessed based on the number of participants who completed testing. mGFR reliability was assessed using the coefficient of variation (CV) across the four 30 min intervals. The association between age, sex, and GMFCS and the percentage of eGFR-mGFR discordance was assessed.
UNASSIGNED: Of the 19 participants enrolled, 18 completed the testing [mean age (SD), 29.9 (7.4) years, n = 10 female participants, n = 10/3/5 for GMFCS I/II/III] and most (n = 15) of the participants had an mGFR >90 mL/min; 14 participants (77.8%) had a CV <20%, 2 had a CV between 20 and 25%, and 2 had a CV >50%. eGFR overestimated mGFR by a median (interquartile range) of approximately 17.5% (2-38%); the full range of mis-estimation was -20.5 to 174.3%. Increasing age and GMFCS levels exhibited notable, but weak-to-modest, associations with a larger eGFR-mGFR discordance.
UNASSIGNED: Obtaining mGFR was feasible and reasonably reliable within this small sample. eGFR overestimated mGFR by a notable amount, which may be associated with patient-level factors.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor. Standard treatments including surgical resection, radiotherapy, and chemotherapy, have failed to significantly improve the prognosis of glioblastoma patients. Currently, immunotherapeutic approaches based on vaccines, chimeric antigen-receptor T-cells, checkpoint inhibitors, and oncolytic virotherapy are showing promising results in clinical trials. The combination of different immunotherapeutic approaches is proving satisfactory and promising. In view of the challenges of immunotherapy and the resistance of glioblastomas, the treatment of these tumors requires further efforts. In this review, we explore the obstacles that potentially influence the efficacy of the response to immunotherapy and that should be taken into account in clinical trials. This article provides a comprehensive review of vaccine therapy for glioblastoma. In addition, we identify the main biomarkers, including isocitrate dehydrogenase, epidermal growth factor receptor, and telomerase reverse transcriptase, known as potential immunotherapeutic targets in glioblastoma, as well as the current status of clinical trials. This paper also lists proposed solutions to overcome the obstacles facing immunotherapy in glioblastomas.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and is associated with high recurrence rates, a high incidence of distant metastases and poor overall survival. The aim of this study was to investigate the role of PD-L1, EGFR and AR expression in TNBC promotion and progression. To that end, we analyzed the immunohistochemical expression of these genes in 125 TNBC patients and their relation to clinicopathological parameters and survival. An elevated expression of PD-L1 was significantly correlated with higher tumor and nuclear grade, while a low expression was correlated with loco-regional recurrence without any influence on survival. Contrary to this, the expression of AR showed a positive impact on the DFI and a negative association with tumor grade. Furthermore, PD-L1 and AR demonstrated simultaneous expression, and further co-expression analysis revealed that a positive expression of PD-L1/AR notably correlates with tumor and nuclear grade and has a significant impact on a longer DFI and OS, while a negative PD-L1/AR expression is significantly associated with metastases. Therefore, our results suggest that positive PD-L1/AR expression is beneficial for TNBC patients. In addition, an elevated expression of EGFR contributes to metastases and a worse DFI and OS. In conclusion, we think that low PD-L1/low AR/high EGFR expression followed by high Ki67 expression constitutes a \'high risk\' profile of TNBC.

Raf Kinase Inhibitor Protein (RKIP) is recognized as a bona fide tumor suppressor gene, and its diminished expression or loss is associated with the progression and poor prognosis of various solid tumors. It exerts multifaceted roles in carcinogenesis by modulating diverse intracellular signaling pathways, including those governed by HER receptors such as MAPK. Given the significance of HER receptor overexpression in numerous tumor types, we investigated the potential oncogenic relationship between RKIP and HER receptors in solid tumors. Through a comprehensive in silico analysis of 30 TCGA PanCancer Atlas studies encompassing solid tumors (10,719 samples), we uncovered compelling evidence of an inverse correlation between RKIP and EGFR expression in solid tumors observed in 25 out of 30 studies. Conversely, a predominantly positive association was noted for the other HER receptors (ERBB2, ERBB3, and ERBB4). In particular, cervical cancer (CC) emerged as a tumor type exhibiting a robust inverse association between RKIP and EGFR expression, a finding that was further validated in a cohort of 202 patient samples. Subsequent in vitro experiments involving pharmacological and genetic modulation of EGFR and RKIP showed that RKIP depletion led to significant upregulation of EGFR mRNA levels and induction of EGFR phosphorylation. Conversely, EGFR overactivation decreased RKIP expression in CC cell lines. Additionally, we identified a common molecular signature among patients depicting low RKIP and high EGFR expression and demonstrated the prognostic value of this inverse correlation in CC patients. In conclusion, our findings reveal an inverse association between RKIP and EGFR expression across various solid tumors, shedding new light on the underlying molecular mechanisms contributing to the aggressive phenotype associated with RKIP and EGFR in cervical cancer.

BACKGROUND: Lazertinib is a third-generation tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI) that selectively inhibit common EGFR mutation and T790M mutation in non-small-cell lung cancer (NSCLC) patients. No previous studies have compared lazertinib to platinum-based chemotherapy. We have compared lazertinib with platinum-based chemotherapy in EGFR-mutated NSCLC patients after previous EGFR-TKI therapy.
METHODS: We retrospectively compared 200 patients from LASER201, LASER301, and LASER-PMS studies to 334 patients who were treated with platinum-based chemotherapy after previous EGFR-TKI from the Samsung Medical Center. After propensity score matching (PSM), we selected 156 patients from each group. The primary outcome was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and time to treatment discontinuation (TTD) as secondary outcomes.
RESULTS: The median follow-up of PFS was 15.61 months in the lazertinib group and 21.67 months in the external control group. The PFS was significantly longer in patients who were treated with lazertinib than those treated with platinum-based chemotherapy (10.97 months vs. 5.10 months; adjusted hazard ratio (HR) 0.40; 95% confidence interval (CI), 0.29-0.55; p < 0.01) after PSM. Lazertinib showed superior OS (32.23 months vs. 18.73 months; adjusted HR 0.45; 95% CI, 0.29-0.69; p < 0.001), ORR (64.1% vs. 47.4%), and TTD (11.66 months vs. 6.73 months; adjusted HR 0.54; 95% CI, 0.39-0.75; p < 0.001) compared to platinum-based chemotherapy.
CONCLUSIONS: Based on this retrospective, external control study, lazertinib has demonstrated significantly better efficacy compared with platinum-based chemotherapy. The external controls provide important context to evaluate efficacy in single-arm studies.