Unveiling ferroptosis: a new frontier in skin disease research.

Ferroptosis, a form of regulated cell death distinct from apoptosis, necrosis, and autophagy, is increasingly recognized for its role in skin disease pathology. Characterized by iron accumulation and lipid peroxidation, ferroptosis has been implicated in the progression of various skin conditions, including psoriasis, photosensitive dermatitis, and melanoma. This review provides an in-depth analysis of the molecular mechanisms underlying ferroptosis and compares its cellular effects with other forms of cell death in the context of skin health and disease. We systematically examine the role of ferroptosis in five specific skin diseases, including ichthyosis, psoriasis, polymorphous light eruption (PMLE), vitiligo, and melanoma, detailing its influence on disease pathogenesis and progression. Moreover, we explore the current clinical landscape of ferroptosis-targeted therapies, discussing their potential in managing and treating skin diseases. Our aim is to shed light on the therapeutic potential of modulating ferroptosis in skin disease research and practice.

TMK4-mediated FIP37 phosphorylation regulates auxin-triggered N6-methyladenosine modification of auxin biosynthetic genes in Arabidopsis.

The dynamics of N6-methyladenosine (m6A) mRNA modification are tightly controlled by the m6A methyltransferase complex and demethylases. Here, we find that auxin treatment alters m6A modification on auxin-responsive genes. Mechanically, TRANSMEMBRANE KINASE 4 (TMK4), a component of the auxin signaling pathway, interacts with and phosphorylates FKBP12-INTERACTING PROTEIN 37 (FIP37), a core component of the m6A methyltransferase complex, in an auxin-dependent manner. Phosphorylation of FIP37 enhances its interaction with RNA, thereby increasing m6A modification on its target genes, such as NITRILASE 1 (NIT1), a gene involved in indole-3-acetic acid (IAA) biosynthesis. 1-Naphthalacetic acid (NAA) treatment accelerates the mRNA decay of NIT1, in a TMK4- and FIP37-dependent manner, which leads to inhibition of auxin biosynthesis. Our findings identify a regulatory mechanism by which auxin modulates m6A modification through the phosphorylation of FIP37, ultimately affecting mRNA stability and auxin biosynthesis in plants.

Impact of Body Composition on Clinical Outcomes in Patients with Esophageal Squamous Cell Carcinoma Receiving Neoadjuvant Immunotherapy Plus Chemotherapy.

AIM: Some studies have reported that body composition profiles affect clinical outcomes of multidisciplinary treatments in several types of cancers; however, a paucity of data exists on the association in neoadjuvant immunotherapy. In the present study, we aimed to investigate the effect of body composition on the clinical outcomes of patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunotherapy plus chemotherapy (nICT). METHODS: Clinicopathological data and computed tomography (CT) images of 85 patients with locally advanced ESCC who underwent esophagectomy after nICT were collected. At diagnosis and before surgery, the CT scan of the third lumbar vertebra was chosen to evaluate the skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), the subcutaneous and the visceral adiposity index. The relationships between body composition and tumor response after nICT and postoperative complications were analyzed. RESULTS: The clinical stage (Odds Ratio (OR) 0.345, 95% confidence interval (CI) 0.141-0.844, p = 0.020) and change in SMI (∆SMI, OR 1.394, 95% CI 1.061-1.832, p = 0.017) were associated with tumor remission after nICT. Moreover, the multivariate logistic analysis revealed that ∆SMI (OR 0.598, 95% CI 0.433-0.828, p = 0.002) was associated with the incidence of postoperative complications. Patients with ∆SMI <-1 had a higher rate of postoperative complications (56% vs 15%, p < 0.001). CONCLUSIONS: For ESCC, ∆SMI is associated with the pathological response after nICT and postoperative complications. Further analysis is needed to clarify whether nutritional intervention during neoadjuvant therapy increases SMI and thus improves clinical outcomes.

Diversity and growth-promoting characteristics of rhizosphere bacteria of three naturally growing plants at the sand iron ore restoration area in Qinghe County.

It is a great challenge to restore northern mines after mining and achieve optimal results due to the extremely harsh environment and climate, as in Qinghe County of Xinjiang Province, China. Qinghe County has a climate of drought, cold, strong winds, and high altitude. After sand and iron mining, the soil in this area contains a large amount of sand and gravel with extremely low organic matter, nitrogen deficiency, and a high pH of 9.26. Our preliminary studies disclosed that only three plants, including Caligonum junceum, Atraphaxis virgata, and Melilotus albus Medic, can grow naturally in this environment without any artificial management. For effective ecology restoration, this study explored the mechanism of plant-microbial interaction and stress resistance in this environment. It was found that although the soil condition in the sand iron ore landfill area is extreme, the bacterial diversity remained high, with Shannon and Simpson indices reaching 9.135 and 0.994, respectively. The planting of three types of remediation plants did not significantly improve, or even decreased, the soil bacterial diversity index, but greatly changed the composition of dominant bacterial genera. Significant differences in the composition of rhizosphere soil bacterial communities among these three remediation plants were observed. Potential new bacterial species accounted for 9.8 %, and the proportion of unique genera reached 30 % or 50 %, respectively. Among all the isolated strains, 74 % had nitrogen fixation and other growth-promoting properties. In summary, the soil microbial community structure in this extreme environment is unique and diverse. The types of remediation plants play a major role in the composition of the rhizosphere bacterial community structure, and the recruited growth-promoting bacteria are diverse and functional. This study may offer valuable information for further studies in vegetation restoration and aid in ecology restoration, especially under extreme conditions.

Multivariate prognostic index and triplet regimen efficacy predictive index in locally advanced and metastatic gastric cancer: pooled analysis from three clinical trials using individual patient data.

Background: To construct an effective prognostic index to predict overall survival (OS) and triplet regimen efficacy for advanced gastric cancer (AGC) patients treated with platinum-based and fluorouracil-based chemotherapy. Objectives: Between 2011 and 2021, 679 patients from two randomized phase III trials and one phase II trial were enrolled. Designs: We collected 11 baseline clinicopathological and 14 hematological parameters to establish a prognostic index. Methods: Univariate and multivariate Cox analyses were used to screen prognostic factors, and a prognostic index nomogram was conducted. Results: Seven prognostic factors were identified: primary tumor site in the non-proximal gastric area, signet-ring cell carcinoma (SRCC)/mucinous carcinoma, peritoneal metastasis, neutrophil count higher than the upper limit of normal value (ULN), lymphocyte count lower than the lower limit of normal value, lactate dehydrogenase level higher than the ULN, and alkaline phosphatase level higher than the ULN as significant for prognosis. A prognostic nomogram named the Fudan advanced gastric cancer prognostic risk score (FARS) index was constructed, and patients in the high-risk group had significantly shorter OS than those in the low-risk group (median OS, 15.5 versus 8.0 months, p < 0.001). The areas under the curve of the FARS index for 1-, 2-, and 3-year OS were 0.70, 0.72, and 0.77, respectively. A validation and external cohort verified the prognostic value of the FARS index. Moreover, three triplet regimen efficacy parameters were identified: SRCC/mucinous adenocarcinoma, primary tumor location in the non-proximal gastric area, and peripheral neutrophil count higher than the ULN; a TRIS index was subsequently conducted. In patients with any two of the three parameters, the triplet regimen showed significantly longer OS than the doublet regimen (p = 0.018). Conclusion: The constructed FARS index to predict the OS of AGC patients and the TRIS index to screen out the dominant population for triplet regimens can be used to aid clinical decision-making and individual risk stratification.

A prognostic index in locally advanced and metastatic gastric cancer To date, no recognized systematic prognostic score has been established for advanced gastric cancer (AGC). Our research aims to construct an effective prognostic index to predict overall survival (OS) for AGC patients to aid clinical decision-making and individual risk stratification. In our research, seven prognostic factors were identified: primary tumor site in the non-proximal gastric area, signet-ring cell carcinoma (SRCC)/mucinous carcinoma, peritoneal metastasis, neutrophil count higher than the upper limit of normal value (ULN), lymphocyte count lower than the lower limit of normal value, lactate dehydrogenase level higher than the ULN, and alkaline phosphatase level higher than the ULN as significant for prognosis. A prognostic index named the Fudan advanced gastric cancer prognostic risk score (FARS) index was constructed, and patients in the high-risk group had significantly shorter OS than those in low-risk group (median OS, 15.5 months vs. 8.0 months, P < 0.001). Moreover, three triplet regimen efficacy parameters were identified: SRCC/mucinous adenocarcinoma, primary tumor location in the non-proximal gastric area, and peripheral neutrophil count higher than the ULN; a TRIS index was subsequently conducted. In patients with any two of the three parameters, the triplet regimen showed significantly longer OS than the doublet regimen (P = 0.018).

Learning curve in relation to health-related quality of life in long-term, disease free survivors after McKeown minimally invasive esophagectomy.

BACKGROUND: The potential impact of learning curve on long-term health-related quality of life (QoL) after esophagectomy for cancer has not been investigated. The aim of this article is to investigate the relationship between learning curve for McKeown minimally invasive esophagectomy (MIE) and health-related quality of life (QoL) in long-term, disease free survivors up to 10 years after esophageal cancer resection. METHODS: Esophageal cancer patients who underwent McKeown MIE between 2009 and 2019 were identified in which 280 who were free of disease at the time of survey and completed health-related QoL and symptom questionnaires, including EORTC QLQ-C30, EORTC QLQ-OES18, and Digestive Symptom Questionnaire. Patients were assessed in 3 cohorts according to the learning phases of expertise reported by our previous study: initial phase; plateau phase, and; experienced phase. RESULTS: Median time from operation to survey was 5.8 years (interquartile range 4.6-8.2). The QLQ-C30 mean scores of functional scales, and symptom scales of respiratory and digestive systems including dyspnea (P = 0.006), shortness of breath (P = 0.003), and dysphagia (P = 0.031) were significantly better in experienced phase group. Furthermore, in the subgroup analyses for patients without postoperative major complications, patients in the initial learning phase remained suffering from more symptoms of dyspnea (P = 0.040) and shortness of breath (P = 0.001). CONCLUSION: Esophageal cancer patients undergoing McKeown MIE in initial learning phase tend to suffer from a deterioration in long-term health-related QoL and higher symptomatic burden as compared to experienced learning phase, which did not improved over time and warranted more attention.

A liquid biopsy signature of circulating extracellular vesicles-derived RNAs predicts response to first line chemotherapy in patients with metastatic colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most threatening tumors in the world, and chemotherapy remains dominant in the treatment of metastatic CRC (mCRC) patients. The purpose of this study was to develop a biomarker panel to predict the response of the first line chemotherapy in mCRC patients. METHODS: Totally 190 mCRC patients treated with FOLFOX or XEOLX chemotherapy in 3 different institutions were included. We extracted the plasma extracellular vesicle (EV) RNA, performed RNA sequencing, constructed a model and generated a signature through shrinking the number of variables by the random forest algorithm and the least absolute shrinkage and selection operator (LASSO) algorithm in the training cohort (n = 80). We validated it in an internal validation cohort (n = 62) and a prospective external validation cohort (n = 48). RESULTS: We established a signature consisted of 22 EV RNAs which could identify responders, and the area under the receiver operating characteristic curve (AUC) values was 0.986, 0.821, and 0.816 in the training, internal validation, and external validation cohort respectively. The signature could also identify the progression-free survival (PFS) and overall survival (OS). Besides, we constructed a 7-gene signature which could predict tumor response to first-line oxaliplatin-containing chemotherapy and simultaneously resistance to second-line irinotecan-containing chemotherapy. CONCLUSIONS: The study was first to develop a signature of EV-derived RNAs to predict the response of the first line chemotherapy in mCRC with high accuracy using a non-invasive approach, indicating that the signature could help to select the optimal regimen for mCRC patients.

Multiphase CT radiomics nomogram for preoperatively predicting the WHO/ISUP nuclear grade of small (< 4 cm) clear cell renal cell carcinoma.

BACKGROUND: Small (< 4 cm) clear cell renal cell carcinoma (ccRCC) is the most common type of small renal cancer and its prognosis is poor. However, conventional radiological characteristics obtained by computed tomography (CT) are not sufficient to predict the nuclear grade of small ccRCC before surgery. METHODS: A total of 113 patients with histologically confirmed ccRCC were randomly assigned to the training set (n = 67) and the testing set (n = 46). The baseline and CT imaging data of the patients were evaluated statistically to develop a clinical model. A radiomics model was created, and the radiomics score (Rad-score) was calculated by extracting radiomics features from the CT images. Then, a clinical radiomics nomogram was developed using multivariate logistic regression analysis by combining the Rad-score and critical clinical characteristics. The receiver operating characteristic (ROC) curve was used to evaluate the discrimination of small ccRCC in both the training and testing sets. RESULTS: The radiomics model was constructed using six features obtained from the CT images. The shape and relative enhancement value of the nephrographic phase (REV of the NP) were found to be independent risk factors in the clinical model. The area under the curve (AUC) values for the training and testing sets for the clinical radiomics nomogram were 0.940 and 0.902, respectively. Decision curve analysis (DCA) revealed that the radiomics nomogram model was a better predictor, with the highest degree of coincidence. CONCLUSION: The CT-based radiomics nomogram has the potential to be a noninvasive and preoperative method for predicting the WHO/ISUP grade of small ccRCC.

Development of PLA/Lignin Bio-Composites Compatibilized by Ethylene Glycol Diglycidyl Ether and Poly (ethylene glycol) Diglycidyl Ether.

Poly (lactic acid) (PLA) is a promising green substitute for conventional petroleum-based plastics in a variety of applications. However, the wide application of PLA is still limited by its disadvantages, such as slow crystallization rate, inadequate gas barrier, thermal degradation, etc. In this study, lignin (1, 3, 5 PHR) was incorporated into PLA to improve the thermal, mechanical, and barrier properties of PLA. Two low-viscosity epoxy resins, ethylene glycol diglycidyl ether (EGDE) and poly (ethylene glycol) diglycidyl ether (PEGDE), were used as compatibilizers to enhance the performance of the composites. The addition of lignin improved the onset degradation temperature of PLA by up to 15 °C, increased PLA crystallinity, improved PLA tensile strength by approximately 15%, and improved PLA oxygen barrier by up to 58.3%. The addition of EGDE and PEGDE both decreased the glass transition, crystallization, and melting temperatures of the PLA/lignin composites, suggesting their compatabilizing and plasticizing effects, which contributed to improved oxygen barrier properties of the PLA/lignin composites. The developed PLA/lignin composites with improved thermal, mechanical, and gas barrier properties can potentially be used for green packaging applications.

Comparing effectiveness and safety of paclitaxel plus raltitrexed vs. paclitaxel alone in second-line palliative chemotherapy for metastatic gastric adenocarcinoma: A randomized phase II clinical trial.

OBJECTIVE: Paclitaxel (P) is a standard second-line chemotherapy in the treatment of advanced gastric cancer. This study compared the clinical outcome of a paclitaxel plus raltitrexed (RP) regimen as second-line treatment in metastatic gastric cancer (MGC) patients. METHODS: An open, randomized, multi-center phase II clinical trial was conducted involving 148 patients who were randomly assigned and treated with RP [raltitrexed (3 mg/m2 on day 1) and paclitaxel (135 mg/m2 on day 1 every 3 weeks)] or P [paclitaxel (135 mg/m2 on day 1 every 3 weeks)] as 2nd-line chemotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), and safety. RESULTS: PFS had a tendency to be prolonged with RP compared to P (2.7 months vs. 1.7 months; P = 0.148). OS was also prolonged with RP compared to P (10.2 months vs. 6.1 months; P = 0.140). The ORR was equal in the RP and P groups (6.8% and 4.0%; P = 0.72). The disease control rate (DCR) in the RP and P groups was 56.2% and 36.0%, respectively. Grade 3-4 treatment-related adverse events occurred in 36.2% (RP) and 28.2% (P) of patients. Frequent grade 3-4 toxicities for RP and P were neutropenia (11.0% and 4.0%), anemia (1.4% and 4.0%), and thrombocytopenia (1.4% and 5.3%), and all grades of peripheral neurotoxicity (12.3% vs. 17.3%). All grades of hepatic toxicity were demonstrated for the RP and P groups based on elevated aminotransferase levels (27.4% and 14.1%). Subgroup analysis shows if MGC was combined with ascites or peritoneal involvement, the OS of the RP regimen was longer (P = 0.05). CONCLUSIONS: Second-line palliative chemotherapy with RP was shown to prolong the PFS and OS, especially among patients with ascites or peritoneal involvement, which warrants confirmation using larger sample studies.

Integrating ferroptosis-related genes (FRGs) and prognostic models to enhance UCEC outcome prediction and therapeutic insights.

Ferroptosis is closely associated with uterine corpus endometrial carcinoma (UCEC) development. This project aimed to identify new potential biomarkers to predict the prognosis of UCEC. In this work, UCEC transcriptome data along with clinical information was retrieved from the TCGA database including a total of 382 FRGs. We performed univariate Cox regression analysis to evaluate ferroptosis-related genes (FRGs) for prognostic significance. The genes with prognostic significance were then analyzed using LASSO-Cox to construct a prognosis model. The model genes were further characterized through various proteomic analyses and expression detection in clinical samples. A multivariate Cox regression model was constructed containing four FRGs (CDKN1A, CDKN2A, CEBPG, NOS2). Among four FRGs, higher expressions of CDKN2A, CEBPG, and NOS2 were associated with poorer overall survival probability, while higher expression of CDKN1A was associated with better overall survival probability. The area under the receiver operating characteristic curve of the risk model was 0.617, 0.688, and 0.693 for 1 year, 3 years, and 5 years, respectively. Moreover, proteomic analysis showed that the protein expression of CDKN1A, CDKN2A, and CEBPG was higher in tumor tissues than that in normal tissues. Higher protein expression of CDKN1A and CDKN2A predicted poorer survival probability. Besides, CDKN1A protein had an interaction relationship with CDKN2A protein or NOS2 protein. In clinical samples, all four FRGs were upregulated in UCEC tissues, regardless of gene expression or protein expression. Our four FRGs risk model provides new insights for predicting the prognosis of UCEC patients.

Effectiveness of rb-bFGF Eye Drops for Post-Cataract Surgery Dry Eye and Observation of Changes in Tear Secretion and Corneal Damage in Patients.

Objective: Dry eye syndrome after cataract surgery is a common complication that may affect the patient's visual comfort and quality of life. Because the surgery may affect the secretion and quality of tears in the eye, resulting in dry and uncomfortable eyes.This study aimed to investigate the therapeutic effects of recombinant bovine basic fibroblast growth factor (rb-bFGF) eye drops on dry eye syndrome after cataract surgery and to analyze its impact on tear secretion and corneal injury. Methods: This is a retrospective study. A total of 126 patients (126 eyes) with dry eye syndrome after cataract surgery were treated between January 2021 and October 2022. patients were randomly divided into a study group (64 patients, 64 eyes) and a control group (62 patients, 62 eyes). Both groups were treated with sodium hyaluronate eye drops, while the study group received rb-bFGF eye drops for four weeks in addition to the sodium hyaluronate eye drops. The clinical efficacy, results of tear secretion test (SIT), tear film break-up time (BUT), corneal fluorescein staining, corneal topography examination, oxidative stress indicators, ocular surface disease index (OSDI) score, and drug adverse reactions were compared between the two groups. Results: The study group exhibited a significantly higher total effective treatment rate (96.88%) compared to the control group (85.48%), suggesting the enhanced efficacy of rb-bFGF eye drops. Moreover, the study group demonstrated extended tear secretion length and tear film break-up time, indicating improved tear film stability and ocular surface health. Additionally, the study group showed reduced corneal fluorescein staining score and improved corneal surface regularity index, indicative of enhanced corneal integrity and smoothness. Notably, tear superoxide dismutase levels were elevated, while lipid peroxide levels were lowered in the study group, underscoring the potential antioxidative effects of rb-bFGF. The study group also exhibited a lower OSDI score, suggesting reduced ocular discomfort and improved quality of life. Although the study group had a slightly higher incidence of adverse reactions (9.38%) compared to the control group (8.06%), the difference was not statistically significant. Particularly significant is the statistical significance highlighting the heightened total effective treatment rate in the study group, indicating the potential of rb-bFGF eye drops in promoting favorable therapeutic outcomes. Conclusion: rb-bFGF eye drops are safe and effective in treating dry eye syndrome after cataract surgery. They can help regulate tear secretion, repair corneal damage, and improve dry eye symptoms. Despite the retrospective design and relatively small sample size of this study, further randomized controlled trials and larger sample size may be needed to verify the robustness of the results, but this study is important for guiding the treatment strategy and optimizing patient care for dry eye after cataract surgery.

Prevalence and severity of thrombocytopenia in patients with hyperferritinemia.

BACKGROUND: In patients with tumors, inflammation, and blood disorders, hyperferritinemia has been associated with the severity of the underlying disease and is frequently accompanied by a co-occurring low platelet count or thrombocytopenia. Despite this, no established correlation has been identified between hyperferritinemia and platelet count. In this retrospective, double-center study, we sought to describe the prevalence and severity of thrombocytopenia in patients with hyperferritinemia. STUDY AND DESIGN: A total of 901 samples were enrolled in this study, all of which had significantly high ferritin levels (>2000 µg/L) between January 2019 and June 2021. We analyzed the general distribution, incidence of thrombocytopenia in patients with hyperferritinemia, and the relationship between ferritin level and platelet count. p-values < 0.05 were considered statistically significant. RESULTS: The total incidence of thrombocytopenia in patients with hyperferritinemia was 64.7%. Hematological diseases were the most frequent cause of hyperferritinemia (43.1%), followed by solid tumors (29.5%) and infectious diseases (11.7%). Patients with thrombocytopenia (<150 × 109/L) had significantly higher ferritin levels than those with platelet counts exceeding 150 × 109/L, with median ferritin levels of 4011 and 3221 µg/L, respectively (P < 0.001). Additionally, the results showed that the incidence of thrombocytopenia was higher in hematological patients with chronic transfusion than in those without chronic blood transfusions (93% vs 69%). CONCLUSIONS: In conclusion, our results suggest that hematological diseases are the most common cause of hyperferritinemia and that patients with chronic blood transfusions are more susceptible to thrombocytopenia. Elevated ferritin levels may act as a trigger for thrombocytopenia.

The spatiotemporal matching pattern of Ezrin/Periaxin involved in myoblast differentiation and fusion and Charcot-Marie-Tooth disease-associated muscle atrophy.

BACKGROUND: Clinically, Charcot-Marie-Tooth disease (CMT)-associated muscle atrophy still lacks effective treatment. Deletion and mutation of L-periaxin can be involved in CMT type 4F (CMT4F) by destroying the myelin sheath form, which may be related to the inhibitory role of Ezrin in the self-association of L-periaxin. However, it is still unknown whether L-periaxin and Ezrin are independently or interactively involved in the process of muscle atrophy by affecting the function of muscle satellite cells. METHOD: A gastrocnemius muscle atrophy model was prepared to mimic CMT4F and its associated muscle atrophy by mechanical clamping of the peroneal nerve. Differentiating C2C12 myoblast cells were treated with adenovirus-mediated overexpression or knockdown of Ezrin. Then, overexpression of L-periaxin and NFATc1/c2 or knockdown of L-periaxin and NFATc3/c4 mediated by adenovirus vectors were used to confirm their role in Ezrin-mediated myoblast differentiation, myotube formation and gastrocnemius muscle repair in a peroneal nerve injury model. RNA-seq, real-time PCR, immunofluorescence staining and Western blot were used in the above observation. RESULTS: For the first time, instantaneous L-periaxin expression was highest on the 6th day, while Ezrin expression peaked on the 4th day during myoblast differentiation/fusion in vitro. In vivo transduction of adenovirus vectors carrying Ezrin, but not Periaxin, into the gastrocnemius muscle in a peroneal nerve injury model increased the numbers of muscle myosin heavy chain (MyHC) I and II type myofibers, reducing muscle atrophy and fibrosis. Local muscle injection of overexpressed Ezrin combined with incubation of knockdown L-periaxin within the injured peroneal nerve or injection of knockdown L-periaxin into peroneal nerve-injured gastrocnemius muscle not only increased the number of muscle fibers but also recovered their size to a relatively normal level in vivo. Overexpression of Ezrin promoted myoblast differentiation/fusion, inducing increased MyHC-I+ and MyHC-II + muscle fiber specialization, and the specific effects could be enhanced by the addition of adenovirus vectors for knockdown of L-periaxin by shRNA. Overexpression of L-periaxin did not alter the inhibitory effects on myoblast differentiation and fusion mediated by knockdown of Ezrin by shRNA in vitro but decreased myotube length and size. Mechanistically, overexpressing Ezrin did not alter protein kinase A gamma catalytic subunit (PKA-γ cat), protein kinase A I alpha regulatory subunit (PKA reg Iα) or PKA reg Iß levels but increased PKA-α cat and PKA reg II α levels, leading to a decreased ratio of PKA reg I/II. The PKA inhibitor H-89 remarkably abolished the effects of overexpressing-Ezrin on increased myoblast differentiation/fusion. In contrast, knockdown of Ezrin by shRNA significantly delayed myoblast differentiation/fusion accompanied by an increased PKA reg I/II ratio, and the inhibitory effects could be eliminated by the PKA reg activator N6-Bz-cAMP. Meanwhile, overexpressing Ezrin enhanced type I muscle fiber specialization, accompanied by an increase in NFATc2/c3 levels and a decrease in NFATc1 levels. Furthermore, overexpressing NFATc2 or knocking down NFATc3 reversed the inhibitory effects of Ezrin knockdown on myoblast differentiation/fusion. CONCLUSIONS: The spatiotemporal pattern of Ezrin/Periaxin expression was involved in the control of myoblast differentiation/fusion, myotube length and size, and myofiber specialization, which was related to the activated PKA-NFAT-MEF2C signaling pathway, providing a novel L-Periaxin/Ezrin joint strategy for the treatment of muscle atrophy induced by nerve injury, especially in CMT4F.

A Clinical Radiomics Nomogram Was Developed by Integrating Radiomics Signatures and Clinical Variables to Distinguish High-Grade ccRCC from Type 2 pRCC.

Purpose: A nomogram was constructed by combining clinical factors and a CT-based radiomics signature to discriminate between high-grade clear cell renal cell carcinoma (ccRCC) and type 2 papillary renal cell carcinoma (pRCC). Methods: A total of 142 patients with 71 in high-grade ccRCC and seventy-one in type 2 pRCC were enrolled and split into a training cohort (n = 98) and a testing cohort (n = 44). A clinical factor model containing patient demographics and CT imaging characteristics was designed. By extracting the radiomics features from the precontrast phase, corticomedullary phase (CMP), and nephrographic phase (NP) CT images, a radiomics signature was established, and a Rad-score was computed. By combining the Rad-score and significant clinical factors using multivariate logistic regression analysis, a clinical radiomics nomogram was subsequently developed. The diagnostic performance of these three models was evaluated by using data from both the training and testing groups using a receiver operating characteristic (ROC) curve analysis. Results: The radiomics signature contained eight validated features from the CT images. The relative enhancement value of CMP (REV1) was an independent risk factor in the clinical factor model. The area under the curve (AUC) value of the clinical radiomics nomogram was 0.974 and 0.952 in the training and testing cohorts, respectively. In the training cohort, the decision curves of the nomogram demonstrated an added overall net advantage compared to the clinical factor model. Conclusion: A noninvasive prediction tool termed radiomics nomogram, combining clinical criteria and the radiomics signature, may accurately predict high-grade ccRCC and type 2 pRCC before surgery. It also has some importance in assisting clinicians in determining future treatment strategies.

Differential Diagnosis of Type 1 and Type 2 Papillary Renal Cell Carcinoma Based on Enhanced CT Radiomics Nomogram.

Objectives: To construct a contrast-enhanced CT-based radiomics nomogram that combines clinical factors and a radiomics signature to distinguish papillary renal cell carcinoma (pRCC) type 1 from pRCC type 2 tumours. Methods: A total of 131 patients with 60 in pRCC type 1 and 71 in pRCC type 2 were enrolled and divided into training set (n=91) and testing set (n=40). Patient demographics and enhanced CT imaging characteristics were evaluated to set up a clinical factors model. A radiomics signature was constructed and radiomics score (Rad-score) was calculated by extracting radiomics features from contrast-enhanced CT images in corticomedullary phase (CMP) and nephrographic phase (NP). A radiomics nomogram was then built by incorporating the Rad-score and significant clinical factors according to multivariate logistic regression analysis. The diagnostic performance of the clinical factors model, radiomics signature and radiomics nomogram was evaluated on both the training and testing sets. Results: Three validated features were extracted from the CT images and used to construct the radiomics signature. Boundary blurring as an independent risk factor for tumours was used to build clinical factors model. The AUC value of the radiomics nomogram, which was based on the selected clinical factors and Rad-score, were 0.855 and 0.831 in the training and testing sets, respectively. The decision curves of the radiomics nomogram and radiomics signature in the training set indicated an overall net benefit over the clinical factors model. Conclusion: Radiomics nomogram combining clinical factors and radiomics signature is a non-invasive prediction method with a good prediction for pRCC type 1 tumours and type 2 tumours preoperatively and has some significance in guiding clinicians selecting subsequent treatment plans.

Corrigendum: Longitudinal Circulating Tumor DNA Profiling in Metastatic Colorectal Cancer During Anti-EGFR Therapy.

[This corrects the article DOI: 10.3389/fonc.2022.830816.].

Longitudinal Circulating Tumor DNA Profiling in Metastatic Colorectal Cancer During Anti-EGFR Therapy.

Background: Metastatic colorectal cancer (mCRC) is a heterogenous disease with limited precision medicine and targeted therapy options. Monoclonal antibodies against epidermal growth factor receptor (EGFR) have been a crucial treatment option for mCRC. However, proper biomarkers for predicting therapeutic response remain unknown. As a non-invasive test, circulating tumor DNA (ctDNA) is appropriately positioned to reveal tumor heterogeneity and evolution, as it can be used in real-time genomic profiling. To evaluate the significance of ctDNA in monitoring the dynamic therapeutic response and prognosis of mCRC, we detected the baseline and dynamic changes of ctDNA in mCRC patients receiving anti-EGFR therapies. Methods: A single-center study was conducted retrospectively. Plasma samples from mCRC patients who received anti-EGFR therapies were collected at baseline and continuous treatment points. The ctDNA was extracted and sequenced with a target panel of tumor-related genes via next-generation sequencing (NGS). Clinical information was also collected and analyzed. Results: We conducted dynamic sampling of 22 mCRC patients, analyzed 130 plasma samples, obtained a baseline genomic mutation profile of the patients. In total, 54 variations were detected in 22 plasma samples, with a positive rate of 77.3% (17/22). TP53 was the most mutated gene (59.1%, 13/22), followed by APC (18.2%, 4/22). There was a high concordance rate of genomic characteristics between the tumor tissue test by polymerase chain reaction and ctDNA test by NGS. The mutation discrepancy increased with an extended course of treatment. During remission TP53 and APC were the most frequently decreased clonal mutations and KRAS, NRAS, ERBB2 and PIK3CA were the most decreased subclonal mutations. Both mutation types were increased during progression. The ctDNA decreased earlier than did the responses of computed tomography and traditional tumor markers (carbohydrate antigen 19-9 and carcinoembryonic antigen [CEA]). Lactate dehydrogenase level (P = 0.041), CEA level (P = 0.038), and primary lesion site (P = 0.038) were independent risk factors that influenced overall survival. Moreover, patients with RAS mutations tended to have a worse prognosis (P = 0.072). Conclusions: This study demonstrates that ctDNA is a promising biomarker for monitoring the dynamic response to treatment and determining the prognosis of mCRC.

Induction Chemotherapy Followed by Primary Tumor Resection Did Not Bring Survival Benefits in Colon Cancer Patients With Asymptomatic Primary Lesion and Synchronous Unresectable Metastases.

BACKGROUND: It is still controversial whether primary tumor resection (PTR) improves survival in colorectal cancer (CRC) patients with unresectable metastases. METHODS: Colon cancer patients were enrolled and randomly allocated to with or without PTR after induction chemotherapy with XELOX or mFOLFOX6, and those with chemotherapy failure were excluded. The primary endpoint was TTF (time to strategy failure) on an intent-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02291744. RESULTS: Between April 2015 and July 2020, 140 patients were enrolled, and 54 patients were excluded due to colon obstruction (16), perforation (1), disease progression (22), death (1), radical resection (3), or other reasons (11). After induction chemotherapy, 86 patients were randomized into group A (the resection group, n = 42) or group B (chemotherapy-alone group, n = 44). The median TTF was 143 days (95% CI: 104.9-181.1) in group A and 196 days (95% CI: 96.5-295.5) in group B (HR: 0.930 95% CI: 0.589-1.468, p = 0.755), and there was no significant difference in PFS, OS, and incidence of chemotherapy-related adverse events between two groups. The primary lesion-related events after PTR in group A were significantly fewer than those in group B. Patients with a tumor regression grade (TRG) score of 2 had longer TTF and PFS than those with score of 3. CONCLUSION: PTR after induction chemotherapy could not bring survival benefits for colon cancer patients with unresectable metastases, and it is not recommended routinely. However, it also requires individualized treatment as colon obstruction or perforation occurred in some patients and PTR could reduce primary tumor-related events, and the TRG score might help for selection of beneficial patients.