Characterization of the pleural microenvironment niche and cancer transition using single-cell RNA sequencing in EGFR-mutated lung cancer.

Background: Lung cancer is associated with a high mortality rate and often complicated with malignant pleural effusion (MPE), which has a very poor clinical outcome with a short life expectancy. However, our understanding of cell-specific mechanisms underlying the pathobiology of pleural metastasis remains incomplete. Methods: We analyzed single-cell transcriptomes of cells in pleural effusion collected from patients with lung cancer and congestive heart failure (as a control), respectively. Soluble and complement factors were measured using a multiplex cytokine bead assay. The role of ferroptosis was evaluated by GPX4 small interfering RNA (siRNA) transfection and overexpression. Results: We found that the mesothelial-mesenchymal transition (MesoMT) of the pleural mesothelial cells contributed to pleural metastasis, which was validated by lung cancer/mesothelial cell co-culture experiments. The ferroptosis resistance that protected cancer from death which was secondary to extracellular matrix detachment was critical for pleural metastasis. We found a universal presence of immune-suppressive lipid-associated tumor-associated macrophages (LA-TAMs) with complement cascade alteration in the MPE of the lung cancer patients. Specifically, upregulated complement factors were also found in the MPE, and C5 was associated with poor overall survival in the lung cancer patients with epidermal growth factor receptor mutation. Plasmacytoid dendritic cells (pDCs) exhibited a dysfunctional phenotype and pro-tumorigenic feature in the primary cancer. High expression of the gene set extracted from pDCs was associated with a poor prognosis in the lung cancer patients. Receptor-ligand interaction analysis revealed that the pleural metastatic niche was aggravated by cross-talk between mesothelial cells-cancer cells/immune cells via TNC and ICAM1. Conclusions: Taken together, our results highlight cell-specific mechanisms involved in the pathobiological development of pleural metastasis in lung cancer. These results provide a large-scale and high-dimensional characterization of the pleural microenvironment and offer a useful resource for the future development of therapeutic drugs in lung cancer.

TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway.

INTRODUCTION: Acral melanoma is a predominant and aggressive subtype of melanoma in non-Caucasian populations. There is a lack of genotype-driven therapies for over 50% of patients. TRPM1 (transient receptor potential melastatin 1), a nonspecific cation channel, is mainly expressed in retinal bipolar neurons and skin. Nonetheless, the function of TRPM1 in melanoma progression is poorly understood. OBJECTIVES: We investigated the association between TRPM1 and acral melanoma progression and revealed the molecular mechanisms by which TRPM1 promotes tumor progression and malignancy. METHODS: TRPM1 expression and CaMKII phosphorylation in tumor specimens were tested by immunohistochemistry analysis and scored by two independent investigators. The functions of TRPM1 and CaMKII were assessed using loss-of-function and gain-of-function approaches and examined by western blotting, colony formation, cell migration and invasion, and xenograft tumor growth assays. The effects of a CaMKII inhibitor, KN93, were evaluated using both in vitro cell and in vivo xenograft mouse models. RESULTS: We revealed that TRPM1 protein expression was positively associated with tumor progression and shorter survival in patients with acral melanoma. TRPM1 promoted AKT activation and the colony formation, cell mobility, and xenograft tumor growth of melanoma cells. TRPM1 elevated cytosolic Ca2+ levels and activated CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) to promote the CaMKIIδ/AKT interaction and AKT activation. The functions of TRPM1 in melanoma cells were suppressed by a CaMKII inhibitor, KN93. Significant upregulation of phospho-CaMKII levels in acral melanomas was related to increased expression of TRPM1. An acral melanoma cell line with high expression of TRPM1, CA11, was isolated from a patient to show the anti-tumor activity of KN93 in vitro and in vivo. CONCLUSIONS: TRPM1 promotes tumor progression and malignancy in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway. CaMKII inhibition may be a potential therapeutic strategy for treating acral melanomas with high expression of TRPM1.

Progress in Microdermal Grafting for Color Regeneration of White Scars.

BACKGROUND: Microdermal grafting with knife-cut, partially de-epithelialized skin can regenerate color in white (hypopigmented) scars. However, the scalp has more melanocytes, and dermabrasion can preserve more melanocytes than knife cutting during partial de-epithelialization. OBJECTIVES: The aim of this study was to evaluate the color regeneration results and complications of various microdermal grafting procedures for white scar color regeneration. METHODS: Two refinements to an existing microdermal grafting technique for treating white scars were described: dermabrasion, rather than knife cutting, was used to partially de-epithelialize skin, and melanocyte donor sites were harvested from the scalp, rather than from skin. A review was performed of 65 cases in which various combinations of these refinements were used to treat scars on the face and forearms. RESULTS: Sixty-five patients (36 forearms; 29 faces) were treated, 40 receiving 1 session, 23 receiving 2 sessions, and 2 receiving 3 sessions of treatment. The follow-up was 6.5 months (range, 4-16 months). The use of both technique refinements produced approximately 15% better color generation than the original procedure after 1 session of treatment and approximately 20% better than the original procedure after 2 sessions. Histologic immunostaining showed that the dermabrasion method preserved more melanocytes around the epidermal-dermal region, and that the scalp has richer melanocytes than skin. The complication rate was reduced. CONCLUSIONS: The use of the scalp as the donor site and partial de-epithelialization by dermabrasion can be safely incorporated into a previously developed microdermal grafting procedure for better color regeneration of white scars.

Low Galectin-3 Expression Level in Primary Tumors Is Associated with Metastasis in T1 Lung Adenocarcinoma.

BACKGROUND AND OBJECTIVE: Although nodal and distant metastasis is rare in T1 lung adenocarcinoma, it is related to poor clinical prognosis. Association between galectin-3 (Gal-3) expression level, and clinical outcome of T1 lung adenocarcinoma has not been clarified. METHODS: From January 2009 to December 2014, 74 patients with surgically resected T1 lung adenocarcinoma were enrolled in this retrospective cohort study. Patient outcomes were followed up until December 2019. Gal-3 expression level in primary tumors was assessed immunohistochemically and evaluated based on the staining intensity and percentage. Patient characteristics and correlation between Gal-3 expression level and clinical outcomes were reviewed. RESULTS: Low Gal-3 expression was associated with increased metastatic events (p = 0.03), especially distant metastasis (p = 0.007), and mortality rate (p = 0.04). Kaplan-Meier analysis revealed that high Gal-3 expression level was associated with favorable recurrence-free survival in T1 lung adenocarcinoma (log-rank p = 0.048) and T1a (≤ 2 cm, American Joint Committee on Cancer (AJCC) 7th edition) lung adenocarcinoma (log-rank p = 0.043). Gal-3 expression along with tumor size showed a larger area under curve (AUC) than tumor size alone for predicting metastatic events (AUC = 0.747 vs. 0.681) and recurrence (AUC = 0.813 vs. 0.766) in T1a lung adenocarcinoma in the receiver-operating characteristic curve. CONCLUSION: Low Gal-3 expression level in primary tumors was remarkably associated with increased metastatic events and reduced recurrence-free survival in T1 lung adenocarcinoma. We suggest that Gal-3 expression level in addition to tumor size may potentially be stronger than tumor size alone in predicting metastasis in T1a lung adenocarcinoma patients.

Cecal lipoma with subclinical appendicitis: A case report.

BACKGROUND: Colonic lipomas are rare, slow-growing benign tumors. Colonic lipomas are generally asymptomatic and are found incidentally. Although cases of cecal lipoma have been sporadically reported in the literature, the disease has not been systematically reviewed. CASE SUMMARY: We present a 44-year-old man who underwent a routine physical check-up during which colonoscopic examination revealed an asymptomatic 1.5-cm cecal mass at the appendiceal orifice. Laparoscopic exploration was performed that also demonstrated a congested and erythematous appendix. En bloc resection of both the cecum and vermiform appendix was performed because of the suspicion of malignancy. Histopathological examination revealed a cecal lipoma composed of mature adipose tissue, and the appendix showed subclinical inflammation. Our procedures and findings were discussed, along with relevant English literature that was retrieved from the PubMed database from 2000 to 2017. Twenty-six cases, including ours, were reported. Consistent with the findings of the literature, it is difficult to obtain a definitive diagnosis by colonoscopic biopsy. CONCLUSION: Surgery remains the treatment of choice for this condition. Intraoperative frozen pathological sectioning helped the surgeon decide the extent of surgery, and radical surgery was avoided. Excision of benign lesions occupying the appendiceal orifice may be indicated for the prevention of later development of acute appendicitis. The prognosis is generally good, with only one of the 26 reported patients complicated with acute appendicitis, who subsequently succumbed due to severe comorbidities and sepsis.