Corrigendum: The utility of high-frequency 18 MHz ultrasonography for preoperative evaluation of acral melanoma thickness in Chinese patients.

[This corrects the article DOI: 10.3389/fonc.2023.1185389.].

Chronic Stress Dampens Lactobacillus Johnsonii-Mediated Tumor Suppression to Enhance Colorectal Cancer Progression.

Colorectal cancer development and outcome are impacted by modifiable risk factors, including psychologic stress. The gut microbiota has also been shown to be linked to psychologic factors. Here, we found a marked deteriorative effect of chronic stress in multiple colorectal cancer models, including chemically induced (AOM/DSS), genetically engineered (APCmin/+), and xenograft tumor mouse models. RNA sequencing data from colon tissues revealed that expression of stemness-related genes was upregulated in the stressed colorectal cancer group by activated ß-catenin signaling, which was further confirmed by results from ex vivo organoid analyses as well as in vitro and in vivo cell tumorigenicity assays. 16S rRNA sequencing of the gut microbiota showed that chronic stress disrupted gut microbes, and antibiotic treatment and fecal microbiota transplantation abolished the stimulatory effects of chronic stress on colorectal cancer progression. Stressed colorectal cancer mice displayed a significant decrease in Lactobacillus johnsonii (L. johnsonii) abundance, which was inversely correlated with tumor load. Moreover, protocatechuic acid (PCA) was identified as a beneficial metabolite produced by L. johnsonii based on metabolome sequencing and LC/MS-MS analysis. Replenishment of L. johnsonii or PCA blocked chronic stress-induced colorectal cancer progression by decreasing ß-catenin expression. Furthermore, PCA activated the cGMP pathway, and the cGMP agonist sildenafil abolished the effects of chronic stress on colorectal cancer. Altogether, these data identify that stress impacts the gut microbiome to support colorectal cancer progression. SIGNIFICANCE: Chronic stress stimulates cancer stemness by reducing the intestinal abundance of L. johnsonii and its metabolite PCA to enhance ß-catenin signaling, forming a basis for potential strategies to circumvent stress-induced cancer aggressiveness. See related commentary by McCollum and Shah, p. 645.

The utility of high-frequency 18 MHz ultrasonography for preoperative evaluation of acral melanoma thickness in Chinese patients.

Background: Despite the increasing use of preoperative ultrasound evaluation for melanoma, there is limited research on the use of this technique for Acral Melanoma (AM). Methods: This retrospective study analyzed the electronic medical records of patients who underwent preoperative evaluation for cutaneous melanoma maximum thickness using an 18 MHz probe and histopathological examination between December 2017 and March 2021 at the Department of Dermatology in Xiangya Hospital, Central South University. Results: A total of 105 patients were included in the study. The mean tumor thickness was 3.9 mm (s.d., 2.3), with 63% of the specimens showing ulceration and 44 patients showing lymph node metastasis. The results showed a good correlation between the high-frequency ultrasonography (HFUS) and histopathological thickness measurements, with a Spearman's correlation coefficient of 0.83 [(95% CI 0.73-0.90) (P < 0.001)]. The positive predictive value (PPV) of sonography in identifying tumor thickness was also found to be high. Conclusion: Our study suggests that high-frequency 18 MHz ultrasonography is an effective tool for the preoperative evaluation of AM thickness. The HFUS measurements correlated well with the histopathological thickness measurements, making it a valuable and reliable method for clinicians to assess the thickness of melanoma lesions preoperatively.

Beta-adrenergic receptor blocker propranolol triggers anti-tumor immunity and enhances irinotecan therapy in mice colorectal cancer.

Colorectal cancer (CRC) stands as the second leading cause of cancer-related deaths worldwide with limited available medicines. While drug repurposing comes as a promising strategy for cancer treatment, we discovered that propranolol (Prop), a non-selective ß1 and ß2 adrenergic receptor blocker, significantly inhibited the development of subcutaneous CT26 CRC and AOM/DSS-induced CRC models. The RNA-seq analysis highlighted the activated immune pathways after Prop treatment, with KEGG analysis enriched in T-cell differentiation. Routine analyses of blood revealed a decrease in neutrophil to lymphocyte ratio, a biomarker of systemic inflammation, and a prognostic indicator in the Prop-treated groups in both CRC models. Analysis of the tumor-infiltrating immune cells exhibited that Prop regressed the exhaustion of CD4+ and CD8+ T cells in the CT26-derived graft models, which was further corroborated in the AOM/DSS-induced models. Furthermore, bioinformatic analysis fitted well with the experimental data, showing that ß2 adrenergic receptor (ADRB2) was positively correlated with T-cell exhaustion signature in various tumors. The in vitro experiment showed no direct effect of Prop on CT26 cell viability, while T cells were activated with significantly-upregulated production of IFN-γ and Granzyme B. Consistently, Prop was unable to restrain CT26 tumor growth in nude mice. At last, the combination of Prop and the chemotherapeutic drug Irinotecan acted out the strongest inhibition in CT26 tumor progress. Collectively, we repurpose Prop as a promising and economical therapeutic drug for CRC treatment and highlight T-cell as its target.

Photodynamic therapy combined with surgery versus Mohs micrographic surgery for the treatment of difficult-to-treat basal cell carcinoma: a retrospective clinical study.

BACKGROUND: Mohs micrographic surgery (MMS) is the preferable surgery for difficult -to-treat basal cell carcinoma (BCC) but is an expensive, labor-intensive, and time-consuming technique. The aim of this study is to compare the efficacy and safety of photodynamic therapy combined with surgery(S-PDT) versus Mohs micrographic surgery (MMS) for the treatment of difficult-to-treat BCC. METHODS: This was a retrospective, comparative study. A total of 32 patients, 16 patients with 48 lesions, were treated with S-PDT, and the other 16 patients with 17 lesions treated by MMS were enrolled in this study. Follow-up was at least 36 months posttreatment. RESULTS: The recurrence rate was no statistical difference between the S-PDT and MMS (p = 1.000, Fishers exact test). The median follow-up was 42.5 months (range 36-63 months). The mean healing time in the S-PDT [17.9 d (SD 9.8)] is longer than in MMS [7.5 d (SD 1.5)] during follow-up (p＜.001, Independent T-test). On the whole, the cosmetic outcome of patients in S-PDT was statistically no significant difference with that in MMS according to a 4-point scale (p = .719, chi-squared test). CONCLUSIONS: S-PDT is a safe, effective, and novel cosmetic treatment, which holds the potential to be an alternative treatment to MMS for some cases.

TRPC absence induces pro-inflammatory macrophages and gut microbe disorder, sensitizing mice to colitis.

The transient receptor potential canonical (TRPC) channels, encoded in seven non-allelic genes, are important contributors to calcium fluxes, are strongly associated with various diseases. Here we explored the consequences of ablating all seven TRPCs in mice focusing on colitis. We discovered that absence of all seven TRPC proteins in mice (TRPC HeptaKO mice) promotes the development of dextran sulfate sodium (DSS)-induced colitis. RNA-sequence analysis highlighted an extremely pro-inflammatory profile in colons of DSS-treated TRPC HeptaKO mice, with an amount of increased pro-inflammatory cytokines and chemokines. Flow cytometry analysis showed that the infiltration of Ly6Chi monocytes and neutrophils in colonic lamina propria was significantly increased in DSS-treated TRPC HeptaKO mice. Results also revealed that macrophages from TRPC HeptaKO mice exhibited M1 polarization and enhanced secretion of pro-inflammatory factors. In addition, the composition of gut microbiota was markedly disturbed in DSS-treated TRPC HeptaKO mice. However, upon antibiotic cocktail (Abx)-treatment, TRPC HeptaKO mice showed no significant differences with WT mice in disease severity. Collectively, these data suggest that ablation of all TRPCs promotes the development of DSS-induced colitis by inducing pro-inflammatory macrophages and gut microbiota disorder.

Preoperative Ultrasound-Guided Incisional Biopsy Enhances the Pathological Accuracy of Incisional Biopsy of Cutaneous Melanoma: A Prospective Clinical Trial in Chinese Patients.

OBJECTIVES: To assess the feasibility of preoperative ultrasound (US)-guided incisional biopsy through a prospective controlled clinical trial. METHODS: This was a prospective, double-arm, single-center study of Chinese patients. Thirty patients were enrolled in the study. Fourteen patients received incisional biopsies for which the choice of biopsy area relied on a clinical evaluation, and 16 patients received incisional biopsies for which the choice of biopsy area relied on a US-guided evaluation. The following procedure was used in the US-guided incisional biopsy group: 1) clinical and dermoscopic evaluation of skin lesions; 2) US examination; 3) incisional biopsy; 4) surgical excision; and 5) histopathological examination. The same procedure was used in the non-US-guided group except without US examination. RESULTS: In the non-US-guided group, the mean tumor thicknesses obtained from incisional biopsy and postoperative histopathological examination were 2.1 and 4.1 mm, respectively. Seven melanomas were underestimated by incisional biopsy, resulting in margins narrower than currently recommended. In the US-guided group, the mean tumor thicknesses obtained from US, incisional biopsy, and postoperative histopathological examination were 3.4, 2.9, and 2.7 mm, respectively. In only 3 melanomas was the tumor thickness of the incisional biopsy less than that of the postoperative histopathological examination, demonstrating that US-guided biopsy obtains the maximum thickness area. CONCLUSIONS: Preoperative US-guided incisional biopsy can enhance the pathological accuracy of incisional biopsy, which may allow us to better perform surgical excision with safe peripheral surgical margins.

The Classification of Six Common Skin Diseases Based on Xiangya-Derm: Development of a Chinese Database for Artificial Intelligence.

BACKGROUND: Skin and subcutaneous disease is the fourth-leading cause of the nonfatal disease burden worldwide and constitutes one of the most common burdens in primary care. However, there is a severe lack of dermatologists, particularly in rural Chinese areas. Furthermore, although artificial intelligence (AI) tools can assist in diagnosing skin disorders from images, the database for the Chinese population is limited. OBJECTIVE: This study aims to establish a database for AI based on the Chinese population and presents an initial study on six common skin diseases. METHODS: Each image was captured with either a digital camera or a smartphone, verified by at least three experienced dermatologists and corresponding pathology information, and finally added to the Xiangya-Derm database. Based on this database, we conducted AI-assisted classification research on six common skin diseases and then proposed a network called Xy-SkinNet. Xy-SkinNet applies a two-step strategy to identify skin diseases. First, given an input image, we segmented the regions of the skin lesion. Second, we introduced an information fusion block to combine the output of all segmented regions. We compared the performance with 31 dermatologists of varied experiences. RESULTS: Xiangya-Derm, as a new database that consists of over 150,000 clinical images of 571 different skin diseases in the Chinese population, is the largest and most diverse dermatological data set of the Chinese population. The AI-based six-category classification achieved a top 3 accuracy of 84.77%, which exceeded the average accuracy of dermatologists (78.15%). CONCLUSIONS: Xiangya-Derm, the largest database for the Chinese population, was created. The classification of six common skin conditions was conducted based on Xiangya-Derm to lay a foundation for product research.

Graphene oxide exacerbates dextran sodium sulfate-induced colitis via ROS/AMPK/p53 signaling to mediate apoptosis.

BACKGROUND: Graphene oxide (GO), a novel carbon-based nanomaterial, has promising applications in biomedicine. However, it induces potential cytotoxic effects on the gastrointestinal (GI) tract cells, and these effects have been largely uncharacterized. The present study aimed to explore the toxic effects of GO on the intestinal tract especially under pre-existing inflammatory conditions, such as inflammatory bowel disease (IBD), and elucidate underlying mechanisms. RESULTS: Our findings indicated that oral gavage of GO worsened acute colitis induced by 2.5% dextran sodium sulfate (DSS) in mice. In vitro, GO exacerbated DSS-induced inflammation and apoptosis in the FHC cell line, an ideal model of intestinal epithelial cells (IECs). Further, the potential mechanism underlying GO aggravated mice colitis and cell inflammation was explored. Our results revealed that GO treatment triggered apoptosis in FHC cells through the activation of reactive oxygen species (ROS)/AMP-activated protein kinase (AMPK)/p53 pathway, as evidenced by the upregulation of cytochrome c (Cytc), Bax, and cleaved caspase-3 (c-cas3) and the downregulation of Bcl-2. Interestingly, pretreatment with an antioxidant, N-acetyl-L-cysteine, and a specific inhibitor of AMPK activation, Compound C (Com.C), effectively inhibited GO-induced apoptosis in FHC cells. CONCLUSIONS: Our data demonstrate that GO-induced IECs apoptosis via ROS/AMPK/p53 pathway activation accounts for the exacerbation of colitis in vivo and aggravation of inflammation in vitro. These findings provide a new insight into the pathogenesis of IBD induced by environmental factors. Furthermore, our findings enhance our understanding of GO as a potential environmental toxin, which helps delineate the risk of exposure to patients with disturbed intestinal epithelial barrier/inflammatory disorders such as IBD.

Graphene oxide aggravated dextran sulfate sodium-induced colitis through intestinal epithelial cells autophagy dysfunction.

Graphene oxide (GO) is one of the most promising nanomaterials used in biomedicine. However, studies about its adverse effects on the intestine in state of inflammation remain limited. This study aimed to explore the underlying effects of GO on intestinal epithelial cells (IECs) in vitro and colitis in vivo. We found that GO could exert toxic effects on NCM460 cells in a dose- and time-dependent manner and promote inflammation. Furthermore, GO caused lysosomal dysfunction and then blockaded autophagy flux. Moreover, pharmacological autophagy inhibitor 3-Methyladenine could reverse GO-induced LC3B and p62 expression levels, reduce expression levels of IL-6, IL-8, TLR4, and CXCL2, and increase the level of IL-10. In vivo, C57BL/6 mice were treated with 2.5% dextran sulfate sodium (DSS) in drinking water for five consecutive days to induce colitis. Then, GO at 60 mg/kg dose was administered through the oral route every two days from day 2 to day 8. These results showed that GO aggravated DSS-induced colitis, characterized by shortening of the colon and severe pathological changes, and induced autophagy. In conclusion, GO caused the abnormal autophagy in IECs and exacerbated DSS-induced colitis in mice. Our research indicated that GO may contribute to the development of intestinal inflammation by inducing IECs autophagy dysfunction.

M2 Macrophage-Derived Exosomal miR-590-3p Attenuates DSS-Induced Mucosal Damage and Promotes Epithelial Repair via the LATS1/YAP/ ß-Catenin Signalling Axis.

BACKGROUND AND AIMS: M2 phenotype macrophages are involved in the resolution of inflammation and intestinal repair. Exosomes are emerging as important mediators of intercellular communication in the mucosal microenvironment. METHODS: M2 macrophages were transfected with or without miR-590-3p. Exosomes derived from M2 macrophages were isolated and identified. Proliferation and wound healing were tested in vitro and compared between groups. The mechanism involving LATS1, and activation of YAP and ß-catenin signalling was investigated by using plasmid transfection, western blotting, immunofluorescence and luciferase reporter assays. The effect of exosomes in vivo was detected in dextran saline sulphate [DSS]-induced murine colitis. RESULTS: First, we demonstrated that M2 macrophages promoted colonic epithelial cell proliferation in an exosome-dependent manner. Epithelial YAP mediated the effect of M2 macrophage-derived exosomes [M2-exos] in epithelial proliferation. Moreover, miR-590-3p, which was significantly enriched in M2-exos, could be transferred from macrophages into epithelial cells, resulting in the enhanced proliferation and wound healing of epithelial cells. Mechanistically, miR-590-3p suppressed the expression of LATS1 by binding to its coding sequence and subsequently activated the YAP/ß-catenin-modulated transcription process to improve epithelial cell wound-healing ability. miR-590-3p also inhibited the induction of pro-inflammatory cytokines, including tumour necrosis factor-α, interleukin-1ß [IL-1ß] and IL-6. More importantly, repression of miR-590-3p in M2-exos resulted in more severe mucosal damage and impaired colon repair of mice compared with those in M2-exo-treated mice after DSS-induced colitis. CONCLUSION: M2 macrophage-derived exosomal miR-590-3p reduces inflammatory signals and promotes epithelial regeneration by targeting LATS1 and subsequently activating YAP/ß-catenin-regulated transcription, which could offer a new opportunity for clinical therapy for ulcerative colitis.

TLR 7/8 agonist reverses oxaliplatin resistance in colorectal cancer via directing the myeloid-derived suppressor cells to tumoricidal M1-macrophages.

Resistance to oxaliplatin is a major obstacle hindering the clinical treatment of colorectal cancer, but the underlying immunological mechanism has not yet been well illustrated. As a pivotal immunosuppressive component in tumor microenvironment, myeloid-derived suppressor cells (MDSCs) and their differentiated tumor-associated macrophages (TAMs) have been considered to be associated with resistance to chemotherapy. The aim of current study was to investigate the role of MDSCs in oxaliplatin-resistance and antitumor activity in colorectal cancer. Here, we found that tumor-bearing mice treated with oxaliplatin performed remarkably decreasing M-MDSCs and M1-type TAMs differentiated from MDSCs in tumor site, which inspired us to combine immunotherapy that activates M1-like TAMs to conquer oxaliplatin resistance. In addition, this study further confirmed a dose-dependent improvement of M1-like macrophage supernatants on enhancing pro-apoptotic effect and inhibiting migration and invasion of cancer cells incubated with oxaliplatin. Administration of oxaliplatin combined with Toll-like receptors agonists R848 reversed the functional orientation of MDSCs towards M1-like macrophages and strengthened antitumor effect of oxaliplatin. In this study, we uncovered novel immunological mechanism of oxaliplatin-resistance and showed the great potential of TLR7/8 agonist as a new immunologic adjuvant in chemotherapy for oxaliplatin-resistant colorectal cancer.

Anti-gastric cancer effect of Salidroside through elevating miR-99a expression.

Salidroside is an active ingredient extracted from Rhodiola rosea that has anti-tumor activities. The current paper attempted to assess the impact of Salidroside on gastric cancer (GC) and explore the potential mechanism. GC cell lines (SNU-216 and MGC803) and gastric epithelial cell line GES-1 were treated with Salidroside. CCK-8 assay, colony formation assay, flow cytometry and Transwell assay were respectively performed to evaluate GC cells phenotype. qRT-PCR and western blot were conducted to reveal the downstream genes and signaling of Salidroside. We found that 800 µM Salidroside was capable of reducing GC cells viability, while has no such impacts on GES-1 cells. Salidroside inhibited GC cells proliferation, migration, invasion and promoted apoptosis, which coupled with the down-regulation of p21, Bcl-2, MMP2, RhoA, p-ROCK1, Vimentin and the up-regulations of CyclinD1, Bax, cleaved caspases. miR-99a was found to be highly expressed in response to Salidroside treatment. Besides, the inhibition of MAPK/ERK and PI3K/AKT signaling induced by Salidroside was attenuated by miR-99a silence and in this process, IGF1R worked as a target of miR-99a. The anti-GC effect of Salidroside was also confirmed in a mouse model of GC. The promoting effect of Salidroside on miR-99a expression was also verified in vivo. Furthermore, Salidroside promoted the cisplatin-sensitivity of SGC7901/DDP cells. In conclusion, this study demonstrated that Salidroside possessed anti-GC effects through regulating miR-99a/IGF1R axis and inhibiting MAPK/ERK and PI3K/AKT pathways.

ALDH2 Protects Against Ischemic Stroke in Rats by Facilitating 4-HNE Clearance and AQP4 Down-Regulation.

Aldehyde dehydrogenase 2 (ALDH2) is a new therapeutic target in the central nervous system. However, the association between ALDH2 and brain edema following ischemic stroke (IS) remains unclear. The present study was investigated to whether active ALDH2 can attenuate brain edema by using a rat model of IS, with the aim of clarifying the underlying mechanisms involved. Rats were administered the ALDH2 agonist Alda-1, vehicle or the ALDH2 inhibitor cyanamide (CYA) 15 min prior to a 1.5 h middle cerebral artery occlusion (MCAO) surgery. The effects of ALDH2 were subsequently investigated 24 h after reperfusion by evaluating neurological function, infarct sizes, brain edema volumes, 4-hydroxy-2-nonenal (4-HNE) levels, and aquaporin 4 (AQP4) protein expression. The results demonstrated that increasing ALDH2 activity significantly improved neurological deficits, reduced infarct sizes, and attenuated brain edema after MCAO. Alda-1 administration led to decreased 4-HNE levels and inhibited AQP4 protein expression in the peri-infarct section of the brain. Whereas, CYA administration increased 4-HNE levels, AQP4 expression, and simultaneously aggravated brain edema following MCAO. In conclusion, increasing ALDH2 activity can improve brain edema, infarct volumes, and reduce neurological impairment in a rat IS model. The therapeutic benefits of ALDH2 are related to 4-HNE clearance and AQP4 down-regulation.

High-temperature solvent-free sulfidation of MoO3 confined in a polypyrrole shell: MoS2 nanosheets encapsulated in a nitrogen, sulfur dual-doped carbon nanoprism for efficient lithium storage.

Hierarchical nanostructured metal sulfides in a rectangular prism shape are highly attractive as a promising electrode material for lithium ion energy storage. Herein, we develop a simultaneous pyrolysis and sulfidation strategy to synthesize yolk-shelled MoS2@nitrogen, sulfur dual-doped carbon (MoS2@NSC) nanoprisms. Upon encapsulating MoO3 nanoprisms into a polypyrrole (PPy) shell, a high-temperature solvent-free sulfidation reaction from MoO3 to hierarchical MoS2 nanosheets could take place within the PPy nanoreactor, and the PPy nanoreactor simultaneously converted into NSC hollow nanoprisms. Owing to the compositional and structural superiority, the MoS2@NSC nanoprisms with a well-defined sheet-in-prism superstructure manifested enhanced electrochemical activity as a promising anode material for lithium-ion batteries including a high reversible capacity (960 mA h g-1 at 0.1 A g-1), excellent cycling stability (800 mA h g-1 at 0.1 A g-1 up to 300 cycles), and superior rate capability (440 mA h g-1 at 2 A g-1).

Factors associated with psychological characteristics in patients with hepatic malignancy before interventional procedures.

OBJECTIVE: To investigate the psychological characteristics of hepatic malignancy patients before interventional procedures and assess associations with related factors. METHODS: Two hundred and thirteen patients requiring interventional procedure for hepatic malignancy were asked to complete a survey of health knowledge and psychological symptom on health knowledge questionnaire and SCL-90 before interventional procedure. Logistic regression analysis was employed to determine the association of various demographic, clinical and health knowledge factors with the presence of psychological symptoms in patients. RESULTS: Eight psychological symptom scores, i.e. somatization, obsessive-compulsive tendencies, depression, anxiety, hostility, phobia, paranoid ideations and psychotic states, were significantly higher than the normal range (P< 0.001). Of 213 cases in the study, 49 families (23.00%) concealed the diagnoses of hepatic carcinoma from patients; 135 patients (63.38%) described the prognosis of the disease correctly. It was demonstrated that the correlations between psychological symptoms and related factors, i.e. age, gender, education, interventional procedure times and health knowledge, were statistically significant (P< 0.05). CONCLUSION: Psychological distress is severe in hepatic malignancy patients before interventional procedures. Age, gender, education, interventional procedure times and health knowledge are associated with psychological symptoms which are significant different from the normal range in Chinese.

Psychological intervention reduces postembolization pain during hepatic arterial chemoembolization therapy: a complementary approach to drug analgesia.

AIM: To assess whether psychological intervention reduces postembolization pain during hepatic arterial chemoembolization therapy. METHODS: Two hundred and sixty-two patients, who required hepatic arterial chemoembolization for hepatic malignancy and postembolization pain, were randomized into control group (n = 46, receiving medication) and intervention group (n = 216, receiving psychological intervention and medication in turn). The symptom checklist-90 (SCL-90) was used to scale the psychological symptoms of the patients before operation. Pain was scored with a 0 to 10 numeric rating scale (NRS-10) before and after analgesia as well as after psychological intervention (only in intervention group). RESULTS: All psychological symptomatic scores measured with SCL-90 in the intervention group were higher than the normal range in Chinese (P < 0.05). The somatization, phobia and anxiety symptomatic scores were associated with pain numerical rating score before analgesia (r = 0.141, 0.157 and 0.192, respectively, P < 0.05). Patients in both groups experienced pain relief after medication, psychotherapy or psychotherapy combined with medication during the procedure (P < 0.01). Only some patients in the intervention group reported partial or entire pain relief (29.17% and 2.31%) after psychological intervention. The pain score after analgesia in the intervention group was significantly lower than that in the control group (P < 0.01). CONCLUSION: Severe psychological distress occurs in patients with hepatic malignancy. Psychological intervention reduces pain scores significantly during hepatic arterial chemoembolization therapy and is thus, highly recommended as a complementary approach to drug analgesia.