Deep Candida albicans infection is one of the major causes of death in immunosuppressed hosts. Remodeling macrophages to phenotype M1 can decrease fungus burden and facilitate combating C. albicans under an immunosuppressive state. In this study, a nanotrinity was exploited to direct fungicidal macrophage polarization by leveraging the regulation pathways in macrophage redifferentiation. Conventional chemotherapeutic imatinib, which can abrogate M2 macrophage polarization via “shutting off” the STAT6 phosphorylation pathway, was encapsulated in biodegradable polymeric nanoparticles. In house-customized dual functional mannosylated chitosan oligosaccharides were then coated on the surface of the imatinib-laden nanoparticles, and thus, a mannosylated nanotrinity was achieved with ternary functions for macrophage remodeling: (i) imatinib-blocked STAT6 phosphorylation pathway for decreasing M2 macrophage population; (ii) chitosan oligosaccharides-mediated TLR-4 pathway activation that could promote macrophage redifferentiation to M1 phenotype; (iii) mannose motif-enhanced macrophage targeting. After physiochemical characterization, regulatory effects of the mannosylated nanotrinity on macrophages and the anti-C. albicans efficacy were evaluated at the cellular level and animal level, respectively. The results demonstrated that our mannosylated nanotrinity could efficiently induce macrophage polarization toward the M1 phenotype, decrease M2 phenotype production, and markedly lessen fungus burden and increased the median survival time of mice infected with C. albicans. Therefore, the mannosylated nanotrinity developed in this study could significantly induce macrophage remodeling in situ by the two-pronged process, “turning on” M1 phenotype polarization meanwhile “shutting off” M2 phenotype polarization, and thus allowed to eradicate C. albicans infection.

Background: A number of mutations in key oncogenes have been identified as important for the initiation and maintenance of lung adenocarcinoma (LAC). This study elucidated the prevalence and prognostic significance of mutations in the epidermal growth factor receptor gene (EGFR) and rearrangements in the anaplastic lymphoma kinase gene (ALK) in patients with surgically resected primary LAC.Patients and Methods: We retrospectively analyzed 675 consecutive patients who underwent radical resection at a single institution. We concurrently analyzed mutations in EGFR and the Kirsten rat sarcoma viral oncogene homolog gene (KRAS) by reverse transcription (RT)-PCR, and investigated ALK rearrangements by immunohistochemistry. LAC with or without various oncogenic mutations was studied for clinicopathological features and their association with disease-free survival (DFS) and overall survival (OS).Result: ALK rearrangements and EGFR mutations were detected in 75 and 312 patients, respectively, with coexistence in 5 cases. ALK rearrangements and mutations in EGFR and KRAS were mutually exclusive. Compared with patients with EGFR mutations, ALK rearrangements were more common in younger patients, and those with advanced tumors, lymph node metastases, and higher rates of postoperative adjuvant therapy. Histologically, EGFR mutations were more common than ALK rearrangements in patients with the acinar predominant subtype and the lepidic predominant subtype of LAC, whereas ALK rearrangements were more frequent in the solid predominant subtype with mucin production and invasive mucinous adenocarcinomas. ALK-positive patients had a significantly worse DFS than those with EGFR mutations and wild-type (WT) patients. The mean OS after surgical procedures was significantly longer in EGFR-mutated versus WT patients. No significant differences were found in patients with ALK-positive tumors compared with EGFR-mutated and WT patients.Conclusion: Clinicopathological features of LAC with ALK rearrangements differ from those of LAC with EGFR mutations. Patients with ALK rearrangements had a significantly worse DFS than those harboring EGFR mutations. Thus, ALK rearrangements are an adverse prognostic factor in surgically-resected LAC patients, while EGFR mutations are associated with a better prognosis.

IntroductionThis study determined the prevalence of anaplastic lymphoma kinase (ALK) rearrangement, and identified the associations of ALK rearrangement with clinicopathologic characteristics and treatment outcomes in patients with surgically-resected stage I-III lung adenocarcinoma.MethodsA total of 534 surgically-resected lung adenocarcinoma patients were studied. The prevalence of ALK protein over-expression was determined by a fully-automated immunochemistry assay (with mouse monoclonal Ventana D5F3 antibody), and the associations of ALK rearrangement with clinicopathologic characteristics and treatment outcomes were analyzed.ResultsForty-two (7.9%) of the 534 lung adenocarcinoma patients were ALK IHC-positive. ALK rearrangement was significantly associated with younger age (P = 0.011), high T-stage (P = 0.025), high pathologic stage (P = 0.002), solid predominant adenocarcinoma with mucin production (P = 0.006), invasive mucinous adenocarcinoma (P = 0.009), and receipt of adjuvant therapy after surgery (P = 0.036), but no significant associations were found between the ALK rearrangement and sex or smoking status. ALK IHC-positivity was significantly associated with a shorter disease-free survival, tumor-specific survival, and overall survival (P = 0.001, 0.026, and 0.007, respectively). Multivariate analysis showed that ALK IHC-positivity was an adverse prognostic factor for disease-free survival (HR, 1.80; 95% CI 1.18-2.77; P = 0.007), tumor-specific survival (HR, 2.59; 95% CI 1.35-4.97; P = 0.004), and overall survival (HR, 1.92; 95% CI 1.07-3.44; P = 0.030).ConclusionThe clinical characteristics of patients with ALK-positive lung adenocarcinoma were similar to those of EGFR-mutated patients. ALK rearrangement was an adverse prognostic factor in surgically-resected lung adenocarcinoma patients.

Angiogenesis is important in the development of solid tumors. Vasohibin-1 (VASH-1) is an endothelium-derived protein that acts as an inhibitor of angiogenesis in many different types of cancer. However, the expression of VASH-1 and its clinical value in bladder cancer remain unknown. The current study analyzed the expression of VASH-1, as well as the expression of the angiogenesis-related factors vascular endothelial growth factor-A, hypoxia inducible factor-1α and cluster of differentiation 34 in bladder cancer tissues from 50 patients using immunohistochemistry. The associations between the expression of these factors and the clinicopathological characteristics of the patients were assessed. The current study demonstrated that VASH-1 is primarily expressed in the cytoplasm of bladder cancer cells and in a fraction of vascular endothelial cells. Furthermore, the expression of VASH-1 was positively associated with the tumor stage (P<0.01), pathological grade (P<0.01) and distant metastasis (P<0.05) but not with patient age or sex (P>0.05). Spearman rank correlation tests indicated that levels of those four factors were positively correlated with each other. Kaplan-Meier analysis indicated that high expression of these four factors was significantly associated with lower 5-year overall survival and progression-free survival rates. Collectively, the results of the current study suggest that VASH-1 is clinically significant in bladder cancer and its high expression may predict the progression and prognosis of patients with bladder cancer. The present study also implies that VASH-1 may be a novel target for vascular targeting therapy.

A 47‐year‐old female with ALK‐rearranged lung adenocarcinoma developed leptomeningeal metastasis (LM) after progression on first‐line crizotinib. Alectinib 300 mg was commenced and the patient achieved clinical and radiographic improvements. After nine months of alectinib 300 mg, she started to experience symptomatic LM. Two concurrent non‐EML4‐ALK rearrangements, LOC388942‐ALK and LINC00211‐ALK, were identified from the CSF but not from the plasma samples. With the primary lung lesions remaining stable, the alectinib dose was increased to 600 mg twice daily which alleviated the clinical symptoms of symptomatic LM. After 7.6 months of alectinib 600 mg, the patient again experienced CNS progression. With both CSF and plasma samples revealing no druggable mutations, the alectinib dose was re‐escalated to 900 mg twice daily, resulting in clinical benefits lasting for two months. Her therapy was then switched to lorlatinib which controlled the disease for 8.7 months until her demise. The LINC00211‐ALK fusion, which retains the ALK kinase domain, detected from the CSF was the mechanism of treatment efficacy in this patient. The central nervous system (CNS) has been increasingly recognized as a site of treatment failure in multiple cancers, including non‐small cell lung cancer (NSCLC). Our case demonstrated that alectinib dose‐escalation and lorlatinib overcame ALK inhibitor resistance in the CNS in an ALK‐positive LM patient. Furthermore, we provide the first clinical evidence of the efficacy of sequential ALK inhibitors in targeting LINC00211‐ALK in a patient with LM.

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