Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer.

Ferroptosis is an iron-dependent, non-apoptotic form of cell death resulting from the accumulation of lipid peroxides. Colorectal cancer (CRC) accumulates high levels of intracellular iron and reactive oxygen species (ROS), thereby sensitizing cells to ferroptosis. The selenoprotein glutathione peroxidase (GPx4) is a key enzyme in the detoxification of lipid peroxides and can be inhibited by the compound (S)-RSL3 ([1S,3R]-RSL3). However, the stereoisomer (R)-RSL3 ([1R,3R]-RSL3), which does not inhibit GPx4, exhibits equipotent activity to (S)-RSL3 across a panel of CRC cell lines. Utilizing CRC cell lines with an inducible knockdown of GPx4, we demonstrate that (S)-RSL3 sensitivity does not align with GPx4 dependency. Subsequently, a biotinylated (S)-RSL3 was then synthesized to perform affinity purification-mass spectrometry (AP-MS), revealing that (S)-RSL3 acts as a pan-inhibitor of the selenoproteome, targeting both the glutathione and thioredoxin peroxidase systems as well as multiple additional selenoproteins. To investigate the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC, we employed further chemical and genetic approaches to disrupt selenoprotein function. The findings demonstrate that the selenoprotein inhibitor Auranofin can induce ferroptosis and/or oxidative cell death both in-vitro and in-vivo. Consistent with this data we observe that AlkBH8, a tRNA-selenocysteine methyltransferase required for the translational incorporation of selenocysteine, is essential for CRC growth. In summary, our research elucidates the complex mechanisms underlying ferroptosis in CRC and reveals that modulation of the selenoproteome provides multiple new therapeutic targets and opportunities in CRC.

Protective roles of tRNA-derived small RNA tRF-Ile-AAT-019 in pathological progression of psoriasis.

Psoriasis is a chronic recurrent inflammatory skin disease that is characterized by abnormal proliferation and differentiation of keratinocytes (KCs), angiogenesis and skin inflammation. Transfer RNA fragments (tRFs) are tRNA-derived small RNAs (tsRNAs), which possess regulatory functions in many diseases. Their potential roles in the pathological development of psoriasis have not been established. We first identified differentially expressed (DE) tRFs from psoriatic skin lesions using small RNA sequencing, and collected additional clinical samples for validation. Then, we investigated the function and mechanism of target tRFs in vitro. As a result of our investigation: we identified 234 DE transcripts in psoriatic skin lesions compared with normal controls. Further functional analysis showed the downregulation of tRF-Ile-AAT-019 in psoriatic lesions plays a critical role in pathogenesis since it could target 3'UTR of the serine protease serpin protein E1 (SERPINE1) gene. We next demonstrated that tRF-Ile-AAT-019 could suppress SERPINE1, thus leading to decreased expressions of vascular endothelial growth factor but increased expressions of keratinocytes (KCs) differentiation markers including Keratin1 and Involucrin. In conclusion, tRF-Ile-AAT-019 plays a protective role in the pathological progression of psoriasis via targeting SERPINE1, resulting in regulation of KCs differentiation and vascular proliferation biomarkers and providing a potential novel targeting pathway for the disease treatment.

Evaluation of in vivo reflectance confocal microscopy in the diagnosis of extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy that most commonly affects the apocrine glands of older men and women. Because it is associated with other cancers, early diagnosis and evaluation are needed. This study is to evaluate the value of reflectance confocal microscopy (RCM) in diagnosing EMPD. A total of 73 patients with clinically suspicious diagnosis of EMPD were enrolled in this study, and the RCM device imaged their lesions. Moreover, 67 patients underwent skin biopsies to confirm the diagnosis. We retrospectively analyzed the results of RCM and histological diagnosis and then evaluated the RCM value of biopsy-confirmed lesions. Based on the RCM image analysis, 54 of 73 (74.0%) patients were diagnosed with EMPD. Of all 67 biopsied lesions, 52 (77.6%) were EMPD. Then, we analyzed the RCM characteristics of 52 cases of biopsy-confirmed EMPD, compared their RCM image characteristics of three different lesions of EMPD, and further concluded the key points of EMPD under RCM microscopy based on the 52 EMPD cases. Finally, we focused on the differential diagnosis of EMPD from other skin diseases. RCM showed great diagnostic value in diagnosing EMPD.

In vivo reflectance confocal microscopy for monitoring actinic keratosis treated with 5-aminolevulinic acid photodynamic therapy.

BACKGROUND: Actinic keratosis (AK) occurs frequently in sun-exposed skin while its diagnosis and treatment were still in exploration. MATERIALS AND METHODS: Thirty two patients with facial AK lesions were selected and examined with reflective confocal microscopy (RCM) firstly, followed by biopsy at the same site. RCM was used to observe AK lesions before 5-aminolevulinic acid photodynamic therapy (ALA-PDT) treatment, after the first treatment, after 4 treatments, and at 1 and 6 months follow-up. Retrospective analysis of RCM images was performed. RESULTS: Thirty two AK cases showed initial RCM microscopic features including disorderly arranged epidermal cells (100%), atypical keratinocytes (100%), and blurry border between the epidermis and dermis (100%). 4 patients quitted trail. After treatments, 24 cases showed basically regular arrangement of epidermal cells, absent atypical keratinocytes, and clear border between epidermis and dermis, while 4 cases improved little. At 1 and 6 months follow-up, 23 cases remained relapse-free while 1 case developed recurrent symptoms. Effective rate of 4 ALA-PDT treatments for AK was 100%; recurrence and cure rates were 4.2% and 82.1%, respectively. CONCLUSION: ALA-PDT is effective to treat AK, while RCM can be recommended for in vivo evaluating and monitoring the effect of ALA-PDT on AK.

The influence of nodule size on the aggressiveness of thyroid carcinoma varies with patient's age.

BACKGROUND: Thyroid nodule size is one of the key parameters that determines the operative approach for thyroid carcinoma. It is necessary to evaluate the influence of nodule size on the aggressiveness of thyroid carcinoma. The eighth edition of staging system has updated the prognostic age cutoff from 45 to 55 years old. It is needed to re-evaluate the difference in aggressiveness of thyroid carcinoma between younger (<55 years old) and older (≥55 years old) patients. Importantly, whether the influence of nodule size on the aggressiveness of thyroid carcinoma varies according to the new age stratification remains to be explored. METHODS: Medical records from patients were retrospectively reviewed. Patients with a documented thyroid ultrasonography (US), US-guided fine needle aspiration (FNA) and histopathology were included. The risks of unfavorable events such as central-compartment neck lymph node (CLN) metastasis, lateral-compartment neck lymph node (LLN) metastasis and gross extrathyroidal extension (ETE) were analyzed in four subsets of patients according to size and age. RESULTS: Large nodule size (≥10 mm) significantly increased the frequencies of CLN metastasis, LLN metastasis and gross ETE (P<0.05). The frequency of CLN metastasis was significantly higher in younger patients compared with that in older ones. Logistic regression analysis recognized large nodule size as an independent risk factor for all CLN metastasis (OR: 3.304, 95% CI: 2.473-4.415), LLN metastasis (OR: 9.673, 95% CI: 4.542-20.597), and gross ETE (OR: 2.430, 95% CI: 1.508-3.916). Secondly, in younger patients, frequencies of all CLN metastasis, LLN metastasis and gross ETE were significantly higher in nodules ≥10 mm than in nodules <10 mm (P<0.001). However, in older patients, no significant difference was found in the frequencies of LLN metastasis or gross ETE between nodules <10 mm and ≥10 mm. Logistic regression analysis showed, in younger patients, large nodule size was an independent risk factor for all CLN metastasis (OR: 3.241, 95% CI: 2.393-4.389), LLN metastasis (OR: 12.495, 95% CI: 5.281-29.562), and gross ETE (OR: 2.591, 95% CI: 1.519-4.419), while in older patients large nodule size was recognized as an independent risk factor for CLN metastasis (OR: 3.924, 95% CI: 1.413-10.899) but not for LLN metastasis or gross ETE. CONCLUSIONS: Large nodule size is significantly related to high aggressiveness of thyroid carcinoma. The correlation between large nodule size and high aggressiveness varies according to patient's age, indicating that the presence of unfavorable events has different clinical significance for patients of varied ages. These findings contribute to accurately assessing the prognosis of individual patient and developing a better management strategy.

The diagnostic value of in vivo reflectance confocal microscopy in actinic keratosis.

BACKGROUND: Actinic keratosis (AK) is a pre-neoplastic skin damage caused by sun exposure with a risk of transforming squamous cell carcinoma (SCC) ranging from 0.1%-20%, while it should be differentiated with many diseases such as seborrheic keratosis (SK), discoid lupus erythematosus (DLE), Bowen's disease, and basal cell carcinoma(BCC) et al. Reflectance confocal microscopy (RCM) as a non-invasive method is showing an increasing diagnostic accuracy. Currently, there are a few studies that summarized the characteristics of AK with RCM. AIM: The study aimed to find the diagnostic value of diagnosing actinic keratosis by reflectance confocal microscopy. METHODS: A total of 92 patients with clinical suspicious diagnosis of actinic keratosis were enrolled in this study, and RCM device imaged their lesions. Fifty-three of these patients underwent skin biopsies to confirm the diagnosis. We retrospectively analyzed the results of RCM and histological diagnosis and then summarized the RCM characteristics of biopsy-confirmed lesions. RESULTS: Based on RCM images, 76 of 92 (82.6%) patients were diagnosed with AK, 9 of 92 (9.8%) patients could not be diagnosed by the dermatologist according to RCM. Of all 53 biopsied lesions, 42 (79.2%) were AK, 1 was seborrheic keratosis, 3 were basal cell carcinoma, three were discoid lupus erythematosus, 1 was Bowen's disease, and three were squamous cell carcinoma. CONCLUSION: The value of RCM in the diagnosis and differential diagnosis of AK is good and worthy of clinical application.

Ultrasonic evaluation of congenital vaginal oblique septum syndrome: A study of 21 cases.

The aim of the present study was to investigate the ultrasound features and classify the lesion types of congenital vaginal oblique septum syndrome (CVOS) in 21 patients prior to surgery. Grey-scale pelvic ultrasound was performed to evaluate the uterus, vagina and kidneys in 21 patients with suspected CVOS. Ultrasound features, including the presence of a double uterus, hematocolpos masses and renal absence, in CVOS types I, II and III were studied and compared with intra-operative results and the results of surgery. Ultrasound identified the presence of double uteruses and cervices with ipsilateral renal agenesis on the oblique septum side in all 21 patients. There were 14 hematocolpos lesions on the right and 7 on the left of the vagina. Type I CVOS was diagnosed in 15 patients with a large hematocolpos mass (volume, 64-268 ml) and these diagnoses were confirmed by surgery. Furthermore, there were 4 patients with type II and 2 patients with type III CVOS exhibiting small hematocolpos lesions (volume, 5-36 ml) identified by ultrasound, which were all confirmed by surgery. Therefore, ultrasound imaging is useful tool to evaluate the abnormal features of CVOS and determine the type of CVOS in patients prior to surgical intervention.

Methicillin-resistant Staphylococcus aureus bacteremia among liver transplant recipients: epidemiology and associated risk factors for morbidity and mortality.

Bacteremia due to Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), complicates the clinical course of liver transplantation and is associated with high morbidity and mortality. Intravascular catheters had been reported to be the most frequent source of MRSA bacteremia. Among bacteremic liver recipients, 26.3%-100% of S. aureus were MRSA. Previous studies identified pre-transplant and post-transplant acquired S. aureus carriage, greater severity of liver disease, hepatocellular carcinoma and infection with immuno-modulatory viruses as predictors of S. aureus bacteremia in liver recipients. MRSA bacteremia accompanied by pneumonia and abdominal infections was related to mortality. Vancomycin, as well as daptomycin, is a first-line antibiotic for MRSA bacteremia. The purpose of this review is to better understand the characteristics of MRSA bacteremia by summarizing the epidemiology and antimicrobial resistance of S. aureus, the primary source, and related risk factors for morbidity and mortality of MRSA bacteremia. We have also explored the diagnostic, therapeutic and preventive measures for MRSA bacteremia to improve the outcomes of liver recipients.

Facile fabrication of zinc oxide coated superhydrophobic and superoleophilic meshes for efficient oil/water separation.

Zinc oxide (ZnO) coated superhydrophobic and superoleophilic stainless steel meshes are facilely fabricated via chemical immersion growth and subsequent surface modification. The as-prepared meshes show good mechanical durability, chemical stability and corrosion-resistant properties due to a combination of the hierarchical ZnO structure and the low surface energy modification. More importantly, the as-prepared meshes are used for highly efficient separation of various oil/water mixtures. Meanwhile, a new oil skimmer based on the as-prepared mesh is proposed to spontaneously collect floating oil with high separation efficiency and desirable durability.