Pulmonary sarcomatoid carcinoma: A rare case report, diagnostic dilemma and review of literature.

RATIONALE: Pulmonary sarcomatoid carcinoma (PSC), a rare tumor, comprises 0.1% to 0.4% of all malignant lung tumors. Given the rarity of PSC, its clinical course, therapeutic guidelines, and patient outcomes remain largely unknown. Therefore, it is imperative to alert clinicians to this extremely rare and instructive early-onset cancer. PATIENT CONCERNS: This report describes a 28-year-old woman with PSC, who was initially misdiagnosed with Whipple's disease. A conclusive diagnosis of PSC was made following careful clinical examination, imaging, and histopathological evaluation of the patient's biopsy sample. Radiological imaging revealed multiple nodules and mass formations in the left upper lobe of the patient's lung, with the largest measuring of 5.4 × 3.2 cm. DIAGNOSIS: Histopathological examination indicated the presence of a malignant neoplasm associated with necrosis suggestive of sarcoma, which was pathologically staged as cT4N1M1. INTERVENTIONS AND OUTCOMES: A regimen of doxorubicin and ifosfamide was administered therapeutically, resulting in a stable disease state. LESSONS: The rarity and tumor origin challenge the diagnosis, which emphasizes the imperative role of histological examination, immunohistochemistry, and flow cytometry in achieving an accurate diagnosis. This report summarizes the existing publications to provide a comprehensive overview of PSC, including its clinical manifestations, radiographic imaging, pathologic features, diagnostic challenges, treatment strategies, and prognosis, and aims to improve the understanding of PSC.

Efficacy and Safety of Conservative Treatment Compared With Surgical Treatment for Thoracolumbar Fracture With Score 4 Thoracolumbar Injury Classification and Severity (TLICS): A Systematic Review and Meta-analysis.

STUDY DESIGN: This was a systematic review and meta-analysis. OBJECTIVE: The clinical outcomes, radiologic outcome, and complications were compared between surgical treatment and conservative treatment of thoracolumbar fractures with a Thoracolumbar Injury Classification and Severity (TLICS) score of 4. SUMMARY OF BACKGROUND DATA: The thoracolumbar fracture is the main reason leading to the spinal cord injury. Some studies suggested that the treatment of TLICS=4 is a "gray zone." Hence, the efficacy and safety of surgical treatment and conservative treatment of thoracolumbar fractures with scores 4 TLICS was still debated. MATERIALS AND METHODS: A comprehensive search of PubMed, Embase, and the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Chongqing VIP Database (VIP), and Wan Fang Database was performed up to October 2021. Relevant studies were identified using specific eligibility criteria and data was extracted and analyzed based on primary and secondary outcomes. RESULTS: A total of 10 studies involving 555 patients were included (3 randomized controlled trials and 7 retrospective studies). There was no significant difference of hospital time (standardized mean difference=0.24, 95% CI: -1.50 to 1.97, P=0.79) and Oswestry Disability Index (mean difference=2.97, 95% CI: -1.07 to 7.01, P=0.15) between surgery and nonsurgery. The length of returning to work was shorter in surgical treatment (standardized mean difference=1.27, 95% CI: 0.07-2.46, P=0.04). Visual Analog Scale in surgical treatment was lower at 1, 3, and 6 months (respectively, P<0.00001, P=0.003, and P=0.02). However, there existed no significant difference between surgical treatment and nonsurgical treatment at 12 and >24 months (respectively, P=0.18 and 0.17). Cobb angle was lower in surgical treatment at postoperative at 6, 12, and >24 months (respectively, P=0.005, P<0.00001, P=0.002, and P=0.0002). Finally, the surgical treatment had a lower incidence of complications (odds ratio=3.89, 95% CI: 1.90-7.94, P=0.0002). CONCLUSIONS: Current evidence recommended that surgical treatment is superior to conservative treatment of TLICS score of 4 at the early follow-up. Surgical treatment had lower Cobb angle, Visual Analog Scale scores, and complications compared with a nonsurgical TLICS score of 4. However, these findings needed to be verified further by multicenter, double-blind, and large-sample randomized controlled trials.

Prognostic Value of the Neutrophil-to-Lymphocyte Ratio in Patients Treated with Definitive Chemoradiotherapy for Locally Advanced Oesophageal Squamous Cell Carcinoma.

Background: The neutrophil-to-lymphocyte ratio (NLR) has been shown to have prognostic value in several common cancers. This study aimed to investigate the prognostic value of NLR in patients with advanced oesophageal squamous cell carcinoma (ESCC) after definitive chemoradiotherapy (dCRT). Methods: A retrospective analysis was performed on 158 patients with advanced ESCC who received dCRT from January 2012 to December 2018. The NLR for different treatment stages was calculated based on laboratory test results. The Kaplan-Meier (KM) method and Cox proportional regression model were used to analyse the relationship between NLR and overall survival (OS). Results: The mean NLR of 158 patients with ESCC was 3.403 ± 2.479. The pre-treatment NLR cut-off was 4.839, and patients were divided into the low NLR group (NLR < 4.839) and the high NLR group (NLR ≥ 4.839). NLR in patients with ESCC was related to N stage (P < 0.05). The KM analysis showed that the median OS of all enrolled patients was 29.3 months, the median OS periods of patients in the high and low NLR groups were 15.6 and 35.8 months, respectively, and the OS of the low NLR group was better than that of the high NLR group (P < 0.001). In the multivariate analysis, NLR was an independent prognostic factor that affects the prognosis of patients with ESCC receiving dCRT. Furthermore, patients who maintained a high NLR before and after treatment showed worse clinical outcomes than the other groups. Conclusion: Our findings suggest that NLR can effectively assess the prognosis of patients with advanced ESCC undergoing dCRT.

A 21.3%-Efficiency Clipped-Sinusoid UWB Impulse Radio Transmitter With Simultaneous Inductive Powering and Data Receiving.

An ultra-wide-band impulse-radio (UWB-IR) transmitter (TX) for low-energy biomedical microsystems is presented. High power efficiency is achieved by modulating an LC tank that always resonates in the steady state during transmission. A new clipped-sinusoid scheme is proposed for on-off keying (OOK)-modulation, which is implemented by a voltage clipper circuit with on-chip biasing generation. The TX is designed to provide a high data-rate wireless link within the 3-5 GHz band. The chip was fabricated in 130 nm CMOS technology and fully characterized. State-of-the-art power efficiency of 21.3% was achieved at a data-rate of 230 Mbps and energy consumption of 21pJ/b. A bit-error-rate (BER) of less than 10 -6 was measured at a distance of 1 m without pulse averaging. In addition, simultaneous wireless powering and VCO-based data transmission are supported. A potential extension to a VCO-free all-wireless mode to further reduce the power consumption is also discussed.

Efficacy and safety of electroacupuncture for carpal tunnel syndrome (CTS): A systematic review and meta-analysis of randomized controlled trials.

Aim: We carried out a systematic review and meta-analysis to evaluate the safety and efficacy of electroacupuncture for patients with carpal tunnel syndrome. Methods: We searched PubMed, Embase, Cochrane Library, Scopus, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Chongqing VIP Database (VIP), and Wan Fang Database up to May 2022 for relevant studies. Relevant studies were identified by using specific eligibility criteria and data were extracted. Results: A total of 26 randomized controlled trials (RCTs) with 1,698 patients were included. Compared with routine treatment, electroacupuncture treatment had lower visual analog scale (VAS) score [mean difference = -0.79, 95% confidence interval (CI): -1.11 to -0.47, P < 0.00001], and the symptom severity scale and function status scale in electroacupuncture group were significantly lower than the control group (P = 0.0001 and P = 0.006). Moreover, the electrophysiological parameters in the electroacupuncture group were better than the control group. The electroacupuncture group had higher total effective rate than the control group (odds ratio = 4.94, 95% CI: 3.44-7.08, P < 0.00001). Conclusion: Our meta-analysis indicated that electroacupuncture had lower VAS score, higher total effective rate, a lower the scores of symptoms and function and electroacupuncture had better electrophysiological parameters. However, these findings needed to be verified further by multicenter, double-blind, and large-sample RCTs.

Activation of HIF-1α/VEGF-A pathway by deferoxamine ameliorates retinal hypoxia in a rat subarachnoid hemorrhage model.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) is associated with sustained vasoconstriction in retinal vessels and vasoconstriction leads to retinal ischemia and hypoxia. Our previous finding also revealed the changes in hypoxia-related elements in the retina after SAH, further lending weight to the hypothesis that retinal vasospasm and hypoxia after SAH. Deferoxamine is a high-affinity iron chelator with reported neuroprotective effects against stroke. Here, we aimed to explore the effects of deferoxamine on retinal hypoxia after SAH. METHODS: SAH was established and deferoxamine was injected intraperitoneally for 3 days in the treatment group. To detect retinal new vessels, platelet endothelial cell adhesion molecule (CD31) was labeled by immunofluorescence and immunohistochemistry. Furthermore, the effects of deferoxamine on the expression of vascular endothelial growth factor A (VEGF-A) and hypoxia-inducible factor-1α (HIF-1α) were revealed by western blot analysis. RESULTS: The immunofluorescence and immunohistochemical staining of CD31 revealed a marked increase in new vessels in the retinal ganglion cell layer after deferoxamine treatment. By western blot analysis, HIF-1α and VEGF-A increased gradually in the first day and then rebounded to a new level on day 7. A deferoxamine-induced increase in HIF-1α/VEGF-A expression was also confirmed by western blot. CONCLUSIONS: Our findings suggest that modulating the application of deferoxamine may offer therapeutic approaches to alleviate retinal complications after SAH.

Erratum: "miR-182 promotes cell proliferation and invasion by inhibiting APC in melanoma".

[This corrects the article on p. 1900 in vol. 11, PMID: 31938296.].

Inhibition of TRPA1 Attenuates Oxidative Stress-induced Damage After Traumatic Brain Injury via the ERK/AKT Signaling Pathway.

Neuron apoptosis is a feature of secondary injury after traumatic brain injury (TBI). Evidence implies that excess calcium (Ca2+) ions and reactive oxidative species (ROS) play critical roles in apoptosis. In reaction to increased ROS, the anti-oxidative master transcription factor, Transient receptor potential Ankyrin 1 (TRPA1) allows Ca2+ ions to enter cells. However, the effect of TBI on the expression of TRPA1 and the role of TRPA1 in TBI are unclear. In the present study, TBI in the mouse brain was simulated using the weight-drop model. The process of neuronal oxidative stress was simulated in HT22 neuronal cells by treatment with hydrogen peroxide. We found that TRPA1 was significantly upregulated in neurons at 24 h after TBI. Neuronal apoptosis was increased in the in vivo and in vitro models; however, this increase was reduced by the functional inhibition of TRPA1 in both models. After TBI, TRPA1 was upregulated via nuclear factor, erythroid 2 like 2 (Nrf2) in neurons. TRPA1-mediated neuronal apoptosis after TBI might be achieved in part through the CaMKII/AKT/ERK signaling pathway. To sum up, TBI-triggered TRPA1 upregulation in neurons is mediated by Nrf2 and the functional blockade of TRPA1 attenuates neuronal apoptosis and improves neuronal dysfunction, partially mediated through the activation of the calcium/calmodulin dependent protein kinase II (CaMKII) extracellular regulated kinase (ERK)/protein kinase B (AKT) signaling pathway. Our results suggest that functional blockade of TRPA1 might be a promising therapeutic intervention related to ROS and Nrf2 in TBI.

Efficacy and safety of anterior transposition of the ulnar nerve for distal humerus fractures: A systematic review and meta-analysis.

Background: This systematic review and meta-analysis was performed to summarize available evidence of anterior transposition of the ulnar nerve for patients with distal humerus fractures. Materials and Methods: The databases were searched from PubMed, Cochrane, Embase, Scopus, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Chongqing VIP Database (VIP), and Wan Fang Database up to June 2022. The clinical outcome included operation time, fracture healing time, hospital stays, elbow joint function, and ulnar neuritis rate. Statistical analysis was performed with Review Manager 5.3 (Cochrane Collaboration). Results: A total of 17 studies were included (8 RCTs and 9 retrospective studies), and 1280 patients were analyzed. The results of this meta-analysis showed anterior transposition group had longer operation time (MD = 20.35 min, 95%CI: 12.56-28.14, P < 0.00001). There was no significant difference in fracture healing time (SMD = -0.50, 95%CI: -1.50-0.50, P = 0.33), hospital stays (MD = -1.23 days, 95%CI: -2.72--0.27, P = 0.11), blood loss (MD = 2.66 ml, 95%CI: -2.45-7.76, P = 0.31), and ulnar neuritis rate (OR = 1.23, 95%CI: 0.63-2.42, P = 0.54) between two groups. Finally, elbow joint motion, elbow joint function, fracture nonunion, and post-operative infection (P > 0.05) between two groups were not significantly statistic difference. Conclusion: This meta-analysis showed that anterior transposition group is not superior to non-transposition group for patients with distal humerus fractures without ulnar nerve injury. On the contrary, non-transposition group have shorter operation time than that of anterior transposition group. Non-transposition group did not increase the post-operative ulnar neuritis rate. Therefore, both anterior transposition group and non- transposition group are the treatment options for patients with distal humerus fractures without ulnar nerve injury. Besides, these findings need to be further verified by multi-center, double-blind, and large sample RCTs.

MC1R Is a Prognostic Marker and Its Expression Is Correlated with MSI in Colorectal Cancer.

Melanocortin 1 receptor (MC1R) is thought to be a marker of poor prognosis and a potential target for the treatment of melanoma. Studies have found that MC1R promotes several tumor behaviors, including cell proliferation and differentiation, pigment formation, and genome damage repair. Some single-nucleotide polymorphisms (SNPs) of MC1R are involved in the occurrence and development of melanoma. A few studies have reported a relationship between MC1R and colorectal cancer (CRC). In this research, our objective was to examine MC1R expression and MC1R SNPs and investigate their correlation with the clinicopathological features of human CRC tissues. We evaluated MC1R mRNA expression by performing bioinformatic analyses on human CRC expression datasets. We used Western blotting and RT-qPCR to compare MC1R expression in CRC tissues with that in normal tissues, and MC1R SNPs in CRC tissues were detected by PCR-direct sequencing (DS). The expression of MC1R was significantly decreased in CRC tissues compared with normal tissue, and its expression was negatively associated with P53 expression, MLH1 expression, and PMS2 expression, and high MC1R expression was significantly associated with microsatellite instability (MSI). MC1R SNPs were also associated with the clinicopathological characteristics of CRC; for example, the rs2228479 locus genotype was correlated with Ki67 status, and the rs885479 locus genotype was correlated with age and T stage. In conclusion, MC1R plays a crucial role in the progression of CRC and may be a marker of poor prognosis in CRC.

Pseudomonas Exotoxin A-Based Immunotherapy Targeting CCK2R-Expressing Colorectal Malignancies: An In Vitro and In Vivo Evaluation.

Cholecystokinin-2 receptor (CCK2R) has been proven to be a specific biomarker for colorectal malignancies. Immunotoxins are a valuable class of immunotherapy agents consisting of a targeting element and a bacterial or plant toxin. Previous work demonstrated that targeting CCK2R is a good therapeutic strategy for the treatment of colorectal cancer (CRC). In the present study, we developed a new version of CCK2R-targeting immunotoxin GD9P using a targeted peptide, GD9, as the binding motif and a truncated Pseudomonas exotoxin A (PE38) as the cytokiller. BALB/c nude mice were treated with different doses of GD9P, and pharmacodynamics, pharmacokinetic, and toxicological data were obtained throughout this study. Compared to the parental immunotoxin rCCK8PE38, GD9P exhibited about 1.5-fold yield, higher fluorescence intensity, and increased antitumor activity against human CRC in vitro and in vivo. The IC50 values of GD9P in vitro ranged from 1.61 to 4.55 nM. Pharmacokinetic studies were conducted in mice with a T1/2 of 69.315 min. When tumor-bearing nude mice were treated with GD9P at doses ≥2 mg/kg for five doses, a rapid shrinkage in tumor volume and, in some cases, complete remission was observed. A preliminary safety evaluation demonstrated a good safety profile of GD9P as a Pseudomonas exotoxin A-based immunotherapy. The therapy in combination with oxaliplatin can increase the antitumor efficacy and reduce the toxic side effects caused by chemotherapy. In conclusion, the data support the use of GD9P as a promising immunotherapy targeting CCK2R-expressing colorectal malignancies.

Expression of FOXO transcription factors in the brain following traumatic brain injury.

Traumatic brain injury (TBI) is a substantial clinical and social problem worldwide, causing high morbidity and mortality along with significant economic and medical costs. Forkhead box O transcription factors (FOXOs) have been found to play a critical role in the regulation of cell functions, such as nutrient metabolism, programmed cell death, and tumor suppression. In the central nervous system, FOXOs are reported to be pivotal regulators of learning and memory, neurite outgrowth, and axonal degeneration. However, the role of FOXOs in TBI is still unknown. Here, we investigate changes in the expression of FOXOs in the acute stage following TBI. First, we evaluated the expression of FOXO proteins in the brains of humans after TBI. A TBI model was then established in mice, and the ipsilateral cerebral cortex was collected at 3 h, 6 h, 9 h, 12 h, 24 h, and 72 h post-TBI. The dynamic expression of Foxo proteins was observed. Neuron-specific localization of Foxos was detected by double immunofluorescence staining. Following TBI, FOXO proteins in the brains of humans were significantly increased. In mice, Foxo protein levels generally peaked at 24 h. By examining co-localization with neurons, the proportion of Foxo(+) neurons was found to increase following TBI and peak at 24 h. This study reveals the time-dependent and neuron-specific expression of Foxos following TBI in mice, providing insight to enhance understanding of the role of Foxos in TBI.

Deferoxamine reduces amyloid-beta peptides genesis and alleviates neural apoptosis after traumatic brain injury.

Traumatic brain injury (TBI) is recognized as the most influential risk factor for neurodegenerative diseases later in life, including Alzheimer's disease. The aberrant genesis of amyloid-ß peptides, which is triggered by TBI, is associated with the development of Alzheimer's disease. Evidence suggests that iron plays a role in both the production of amyloid-ß and its neurotoxicity, and iron overload has been noted in the brain after TBI. We therefore investigated the effects of an iron-chelating treatment on amyloid-ß genesis in a weight-drop model of TBI in mice. Human brain samples were obtained from patients undergoing surgery for severe brain trauma. The Institute of Cancer Research mice were treated with deferoxamine by intraperitoneal injection after TBI induction. Changes in amyloid-ß(1-42) were assessed using western blot and immunohistochemical staining. Ferritin was also detected using western blot to investigate iron deposition in the mice brain. Immunofluorescent terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was also performed to evaluate neural apoptosis. The amyloid-ß(1-42) was markedly elevated after TBI in both humans and mice. Deferoxamine treatment in mice significantly decreased the levels of both amyloid-ß(1-42) and ferritin in the brain, and reduced TBI-induced neural cell apoptosis. The iron chelator deferoxamine can alleviate the increase of amyloid-ß(1-42) in the brain after TBI, and may therefore be a potential therapeutic strategy to prevent TBI patients from undergoing neurodegenerative processes.

Lactic acid promotes metastatic niche formation in bone metastasis of colorectal cancer.

BACKGROUND: To investigate the effect of lactic acid (LA) on the progression of bone metastasis from colorectal cancer (CRC) and its regulatory effects on primary CD115 (+) osteoclast (OC) precursors. METHODS: The BrdU assay, Annexin-V/PI assay, TRAP staining and immunofluorescence were performed to explore the effect of LA on the proliferation, apoptosis and differentiation of OC precursors in vitro and in vivo. Flow cytometry was performed to sort primary osteoclast precursors and CD4(+) T cells and to analyze the change in the expression of target proteins in osteoclast precursors. A recruitment assay was used to test how LA and Cadhein-11 regulate the recruitment of OC precursors. RT-PCR and Western blotting were performed to analyze the changes in the mRNA and protein expression of genes related to the PI3K-AKT pathway and profibrotic genes. Safranin O-fast green staining, H&E staining and TRAP staining were performed to analyze the severity of bone resorption and accumulation of osteoclasts. RESULTS: LA promoted the expression of CXCL10 and Cadherin-11 in CD115(+) precursors through the PI3K-AKT pathway. We found that CXCL10 and Cadherin-11 were regulated by the activation of CREB and mTOR, respectively. LA-induced overexpression of CXCL10 in CD115(+) precursors indirectly promoted the differentiation of osteoclast precursors through the recruitment of CD4(+) T cells, and the crosstalk between these two cells promoted bone resorption in bone metastasis from CRC. On the other hand, Cadherin-11 mediated the adhesion between osteoclast precursors and upregulated the production of specific collagens, especially Collagen 5, which facilitated fibrotic changes in the tumor microenvironment. Blockade of the PI3K-AKT pathway efficiently prevented the progression of bone metastasis caused by lactate. CONCLUSION: LA promoted metastatic niche formation in the tumor microenvironment through the PI3K-AKT pathway. Our study provides new insight into the role of LA in the progression of bone metastasis from CRC. Video Abstract.

Transcription elongation factor A-like 7, regulated by miR-758-3p inhibits the progression of melanoma through decreasing the expression levels of c-Myc and AKT1.

BACKGROUND: Ectopic expression of transcription elongation factor A (SII)-like 7 (TCEAL7) has been observed in several kinds of cancers, but its role in melanoma is still unclear. This study was carried out to investigate TCEAL7 role in melanoma progression, and uncover the underlying mechanisms. METHODS: TCEAL7 expression levels in melanoma tissues and cells were determined by using real-time quantitative PCR (RT-PCR) and western blotting. CCK-8, transwell chambers, flow cytometry, starch assay and tumorigenesis assay were applied to detect cell growth, invasion, apoptosis, migration and tumorigenesis, respectively. RESULTS: A low expression level of TCEAL7 was observed in melanoma tissues and cells, which was associated with malignant clinical process and poor prognosis. TCEAL7 negatively modulated AKT1, AKT2, c-Myc, N-cadherin and PCNA expression and inhibited cancer progression via decreasing AKT1 and c-Myc levels. In addition, TCEAL7 was negatively modulated by miR-758-3p which promoted melanoma progression. Moreover, overexpression of TCEAL7 abolished miR-758-3p role in promoting melanoma progression. CONCLUSION: This study demonstrated that TCEAL7, regulated by miR-758-3p inhibited melanoma progression through decreasing the expression levels of c-Myc and AKT1.

Retinal hypoxia after experimental subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The patients who survive subarachnoid hemorrhage (SAH) often have long-term neurological complications. There are no reports about the pathological change of retina after SAH. METHODS: An experimental model of SAH was established by injecting autologous blood into the prechiasmatic cistern of Sprague-Dawley rats. Hematoxylin and eosin (HE) staining was performed to show the alternation of morphology in retina after SAH. To detect the retinal new vessels (NVs), CD31 was labelled by immunofluorescence and immunohistochemistry. The time-course expressions of vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor-1α (HIF-1 α) was also revealed by Western blot analysis. RESULTS: A clear reduction of retinal ganglion cells (RGCs) was noticed after SAH. The immunofluorescence and immunohistochemical staining of CD31 reveals a large number of NVs in RGC layer after SAH compared with the normal controls. The level of VEGF-A in the retina after SAH was increased and peaked at 12h and 14 d. The expression of HIF-1α in the retina increased as early as 3 h after SAH, reached a peak at 12 h after SAH. CONCLUSIONS: The results showed that SAH induced the retina hypoxia resulting in the reduction of RGCs, increase of NVs and activation of NVs related HIF-1α/VEGF-A pathway.

Stealth Strategies of Mycobacterium tuberculosis for Immune Evasion.

Tuberculosis is a devastating disease causing high mortality all over the world, especially in the developing countries. Mycobacterium tuberculosis (M. tb) is the causative agent of tuberculosis which replicates in the intracellular environment of host macrophages. Although the host immune system is capable of completely eliminating the pathogen, co-evolution of M. tb with humans has resulted in its ability to hijack the host innate and adaptive immune systems in numerous ways. Limited recent progress has been made in the understanding of M. tb immune escape mechanisms, hence exploration of survival strategies of M. tb has been critically reviewed with an insight into understanding its pathogenesis. We summarized the recent studies regarding the modulation of innate immune response, adaptive immune response, epigenetics and the role of miRNA. All of these advancements suggest that M. tb is well-familiarize with the host immune system and possess the ability to hijack it for intracellular survival.

α-MSH-PE38KDEL Kills Melanoma Cells via Modulating Erk1/2/MITF/TYR Signaling in an MC1R-Dependent Manner.

BACKGROUND/OBJECTIVE: The immunotoxin α-MSH-PE38KDEL consisting of α-MSH and PE38KDEL showed high cytotoxicity on MSH receptor-positive melanoma cells, suggesting that α-MSH-PE38KDEL might be a potent drug for the treatment of melanoma. Herein, we explored whether the Erk1/2/MITF/TYR signaling, a verified target of α-MSH/MC1R, was involved in α-MSH-PE38KDEL-mediated cytotoxicity. METHODS: Human melanoma cell line A375, mouse melanoma cell line B16-F10, human breast cancer cell line MDA-MB-231 and human primary epidermal melanocytes (HEMa) with different expression levels of MC1R were used in this study. Cell apoptosis and viability were determined by using flow cytometry and MTT assays. Protein expressions were tested by Western blotting. RESULTS: The expression levels of MC1R in A375 and B16-F10 cells were significantly higher than that of MDA-MB-231 and HEMa. α-MSH-PE38KDEL treatment induced a significant inhibition in cell viability in A375 and B16-F10 cells, while showed no obvious influence in the viability of MDA-MB-231 and HEMa cells. However, knockdown of MC1R abolished α-MSH-PE38KDEL role in promoting cell apoptosis in A375 and B16-F10 cells, and upregulation of MC1R endowed α-MSH-PE38KDEL function to promote cell apoptosis in MDA-MB-231 and HEMa cells. Additionally, α-MSH-PE38KDEL treatment increased the phosphorylation levels of Erk1/2 and MITF (S73), and decreased MITF and TYR expressions in an MC1R-dependent manner. All of the treatments, including inhibition of Erk1/2 with PD98059, MC1R downregulation and MITF overexpression weakened the anti-tumor role of α-MSH-PE38KDEL in melanoma. CONCLUSION: Collectively, this study indicates that α-MSH-PE38KDEL promotes melanoma cell apoptosis via modulating Erk1/2/MITF/TYR signaling in an MC1R-dependent manner.

Neuroprotective role of glutathione peroxidase 4 in experimental subarachnoid hemorrhage models.

BACKGROUND AND PURPOSE: Early brain injury is an essential pathological process after subarachnoid hemorrhage (SAH), with many cell death modalities. Ferroptosis is a newly discovered regulated cell death caused by the iron-dependent accumulation of lipid peroxidation, which can be prevented by glutathione peroxidase 4 (GPX4). Our study aimed to investigate the role of GPX4 in neuronal cell death after experimental SAH. METHODS: In vivo experimental SAH was induced by injecting autologous arterial blood into the prechiasmatic cistern in male Sprague-Dawley rats. Meanwhile, the in vitro SAH model was performed with primary rat cortical neurons cultured in medium containing hemoglobin (Hb). Adenovirus was used to overexpress GPX4 before experimental SAH. GPX4 expression was detected by western blot and immunofluorescence experiments. Malondialdehyde (MDA) was measured to evaluate the level of lipid peroxidation. Nissl staining was employed to assess cell death in vivo, whereas lactate dehydrogenase (LDH) release was used to evaluate cell damage in vitro. The brain water content and neurological deficits were evaluated to determine brain injury. RESULTS: Endogenous GPX4 was mainly expressed in neurons, and its expression decreased at 24 h after experimental SAH. Overexpression of GPX4 significantly reduced lipid peroxidation and cell death in the experimental SAH models both in vivo and in vitro. Moreover, overexpression of GPX4 ameliorated brain edema and neurological deficits at 24 h after SAH. CONCLUSIONS: The decrease of GPX4 expression potentially plays an important role in ferroptosis during early brain injury after SAH. Overexpression of GPX4 has a neuroprotective effect after SAH.

Mutations in COMP cause familial carpal tunnel syndrome.

Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment syndrome, affecting a large proportion of the general population. Genetic susceptibility has been implicated in CTS, but the causative genes remain elusive. Here, we report the identification of two mutations in cartilage oligomeric matrix protein (COMP) that segregate with CTS in two large families with or without multiple epiphyseal dysplasia (MED). Both mutations impair the secretion of COMP by tenocytes, but the mutation associated with MED also perturbs its secretion in chondrocytes. Further functional characterization of the CTS-specific mutation reveals similar histological and molecular changes of tendons/ligaments in patients' biopsies and the mouse models. The mutant COMP fails to oligomerize properly and is trapped in the ER, resulting in ER stress-induced unfolded protein response and cell death, leading to inflammation, progressive fibrosis and cell composition change in tendons/ligaments. The extracellular matrix (ECM) organization is also altered. Our studies uncover a previously unrecognized mechanism in CTS pathogenesis.