Characterization of endoplasmic reticulum stress unveils ZNF703 as a promising target for colorectal cancer immunotherapy.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant tumors globally, with high morbidity and mortality. Endoplasmic reticulum is a major organelle responsible for protein synthesis, processing, and transport. Endoplasmic reticulum stress (ERS) refers to the abnormal accumulation of unfolded and misfolded proteins in the endoplasmic reticulum, which are involved in tumorigenesis and cancer immunity. Nevertheless, the clinical significance of ERS remains largely unexplored in CRC. METHODS: In present study, we performed an unsupervised clustering to identify two types of ERS-related subtypes [ERS clusters, and ERS-related genes (ERSGs) clusters] in multiple large-scale CRC cohorts. Through the utilization of machine learning techniques, we have successfully developed an uncomplicated yet robust gene scoring system (ERSGs signature). Furthermore, a series of analyses, including GO, KEGG, Tumor Immune Dysfunction and Exclusion (TIDE), the Consensus Molecular Subtypes (CMS), were used to explore the underlying biological differences and clinical significance between these groups. And immunohistochemical and bioinformatics analyses were performed to explore ZNF703, a gene of ERSGs scoring system. RESULTS: We observed significant differences in prognosis and tumor immune status between the ERS clusters as well as ERSGs clusters. And the ERSGs scoring system was an independent risk factor for overall survival; and exhibited distinct tumor immune status in multicenter CRC cohorts. Besides, analyses of TNM stages, CMS groups demonstrated that patients in advanced stage and CMS4 had higher ERSGs scores. In addition, the ERSGs scores inversely correlated with positive ICB response predictors (such as, CD8A, CD274 (PD-L1), and TIS), and directly correlated with negative ICB response predictors (such as, TIDE, T cell Exclusion, COX-IS). Notably, immunohistochemical staining and bioinformatics analyses revealed that ZNF70 correlated with CD3 + and CD8 + T cells infiltration. CONCLUSION: Based on large-scale and multicenter transcriptomic data, our study comprehensively revealed the essential role of ERS in CRC; and constructed a novel ERSGs scoring system to predict the prognosis of patients and the efficacy of ICB treatment. Furthermore, we identified ZNF703 as a potentially promising target for ICB therapy in CRC.

Fusobacterium nucleatum upregulates MMP7 to promote metastasis-related characteristics of colorectal cancer cell via activating MAPK(JNK)-AP1 axis.

BACKGROUND: Colorectal cancer (CRC) is the third most common malignant tumor. Fusobacterium nucleatum (F. nucleatum) is overabundant in CRC and associated with metastasis, but the role of F. nucleatum in CRC cell migration and metastasis has not been fully elucidated. METHODS: Differential gene analysis, protein-protein interaction, robust rank aggregation analysis, functional enrichment analysis, and gene set variation analysis were used to figure out the potential vital genes and biological functions affected by F. nucleatum infection. The 16S rDNA sequencing and q-PCR were used to detect the abundance of F. nucleatum in tissues and stools. Then, we assessed the effect of F. nucleatum on CRC cell migration by wound healing and transwell assays, and confirmed the role of Matrix metalloproteinase 7 (MMP7) induced by F. nucleatum in cell migration. Furthermore, we dissected the mechanisms involved in F. nucleatum induced MMP7 expression. We also investigated the MMP7 expression in clinical samples and its correlation with prognosis in CRC patients. Finally, we screened out potential small molecular drugs that targeted MMP7 using the HERB database and molecular docking. RESULTS: F. nucleatum infection altered the gene expression profile and affected immune response, inflammation, biosynthesis, metabolism, adhesion and motility related biological functions in CRC. F. nucleatum was enriched in CRC and promoted the migration of CRC cell by upregulating MMP7 in vitro. MMP7 expression induced by F. nucleatum infection was mediated by the MAPK(JNK)-AP1 axis. MMP7 was highly expressed in CRC and correlated with CMS4 and poor clinical prognosis. Small molecular drugs such as δ-tocotrienol, 3,4-benzopyrene, tea polyphenols, and gallic catechin served as potential targeted therapeutic drugs for F. nucleatum induced MMP7 in CRC. CONCLUSIONS: Our study showed that F. nucleatum promoted metastasis-related characteristics of CRC cell by upregulating MMP7 via MAPK(JNK)-AP1 axis. F. nucleatum and MMP7 may serve as potential therapeutic targets for repressing CRC advance and metastasis.

N6-Methyladenosine Regulators Are Involved in the Progression of and Have Clinical Impact on Breast Cancer.

BACKGROUND N6-methyladenosine (m6A) modification has been widely studied in various cancers, and m6A regulators, such as METTL3, METTL14, WTAP, and YTHDF1, play crucial roles in breast cancer. However, a comprehensive study of m6A regulators in breast cancer is still lacking. MATERIAL AND METHODS Expression data of m6A regulators and clinicopathological information were acquired from The Cancer Genome Atlas (TCGA) program. Protein interaction was collected from the STRING database. Data on tumor purity and correlation among m6A regulators were obtained from the TIMER database. LASSO, consensus clustering, and gene set enrichment analysis (GSEA) were used to evaluate the role of m6A regulators. Moreover, the prognostic value of m6A-related genomic targets in breast cancer was analyzed by Kaplan-Meier analysis and Cox regression models. RESULTS We found most m6A regulators were associated with key clinicopathological parameters, such as tumor staging, Nottingham prognostic index (NPI), and cellularity. Also, consensus clustering analysis-based grouping could effectively predict patients' overall survival. Correlation analysis also showed that these regulators interacted with each other. Patients were further split into a high-risk group and low-risk group based on Cox and LASSO analysis. High-risk patients had a significantly worse overall survival than did low-risk patients. Moreover, AKT1 and MYC were enriched in patients in the high-risk group, according to GSEA analysis. The patients in the high-risk group also displayed resistance to chemoradiotherapy or hormone therapy. CONCLUSIONS The m6A regulators are critical participants in the development and progression of breast cancer and are likely to be used to predict prognosis and develop treatment strategies.

Long-term oncologic safety of immediate reconstructive surgery in patients with invasive breast cancer: a retrospective matched-cohort study.

OBJECTIVE: Immediate reconstruction (IR) is a safe and effective surgical treatment for patients with breast cancer. We aimed to assess the prognosis, aesthetic outcomes, and patient satisfaction of IR compared with breast conservation surgery (BCS) and total mastectomy (TM). METHODS: This retrospective matched-cohort study was conducted between May 2005 and December 2014. We established two cohorts according to the tumor (T) size of breast cancer. In the T≤3cm group, cases (IR) and controls (BCS or TM) were matched for age, pathological tumor size, and pathologic nodal status in a 1:1:1 ratio. In the T>3cm group, cases (IR) and controls (TM) were matched with the same factors and ratio. The primary outcome was the 5-year disease-free survival (DFS). The secondary outcome was patient satisfaction and quality of life. RESULTS: A total of 12,678 breast cancer patients were assessed for eligibility, of which 587 were included (T≤3 cm group: 155 IR vs 155 BCS vs 155 TM; T>3cm group: 61 IR vs 61 TM). In the T≤3 cm cohort, patients who underwent IR had no difference compared with those who underwent BCS or TM regarding the 5-year DFS (P=0.539); however, an improved aesthetic satisfaction, psychosocial, and sexual well-being were achieved in the IR group (P<0.001). In the T>3 cm cohort, the IR group had a worse median 5-year DFS (P=0.044), especially for Her2+ or triple-negative breast carcinoma (TNBC) subtypes compared with the TM group. CONCLUSIONS: IR improves aesthetic satisfaction, psychosocial, and sexual well-being for breast cancer patients with T≤3 cm. For patients with T > 3 cm invasive breast cancer, TM is superior to IR as it predicts a better 5-year DFS.

CRISPR-Cas12a Coupled with Platinum Nanoreporter for Visual Quantification of SNVs on a Volumetric Bar-Chart Chip.

Methods that can detect and quantify single nucleotide variations (SNVs)/single nucleotide polymorphisms (SNPs) are greatly needed in the bioanalytical measurement of gene mutations and polymorphisms. Herein a visual and instrument-free SNV quantification platform is developed. Platinum nanoparticles tethered to magnetic beads by single-stranded DNAs are designed as quantitative readout reporters for a CRISPR-Cas12a nucleic acid detection system. The integration of platinum nanoreporter and CRISPR-Cas system with a volumetric bar-chart chip realizes the volumetric quantification of nucleic acids. This platform enables quantification of multiple cancer mutations in pure DNA samples and mock cell-free DNA samples in serum, with allelic fractions as low as 0.01%. This platform could have great potential in the quantification of SNVs/SNPs as well as other types of nucleic acid targets at the point of care.

Androgen Receptor Expression and Bicalutamide Antagonize Androgen Receptor Inhibit ß-Catenin Transcription Complex in Estrogen Receptor-Negative Breast Cancer.

BACKGROUND/AIMS: Little is known about the potential mechanism of action for androgen receptor (AR) targeting treatment in estrogen receptor (ER)-negative breast cancer. This study aimed to evaluate AR status and its prognosis in four breast cancer subtypes. Bicalutamide has been identified as an AR antagonist and used for treating AR+/ER- breast cancer in a phase II trial. Our studies will clarify its mechanism in breast cancer treatment. METHODS: A total of 510 consecutive cases of invasive ductal cancer (IDC) were evaluated in this study. The expression of AR was analyzed by immunohistochemistry and compared with patient survival, and its implications were evaluated in four subtypes of IDC. We examined bicalutamide as an AR antagonist to inhibit proliferation and increased apoptosis in AR+/ER- breast cancer cell lines. We explored the tumor suppressive functions of bicalutamide in vitro and vivo and its related mechanisms in AR+/ER- breast cancer. RESULTS: AR expression was related to that of ER (P<0.001), PR (P<0.001), Her2 (P=0.017), Ki-67(P=0.020) and to four subtypes (P<0.001). AR retained independent prognostic signifcance (P=0.007, ER- cases; P=0.001, ER+ cases; P=0.001, total cases). We found that bicalutamide significantly decreased viability and increased apoptosis in vitro and vivo. The mechanistic analysis revealed that bicalutamide blocked androgen-stimulated oncogenic AR and Wnt/ß-catenin signaling and inhibited the growth of AR+/ER- breast cancer. CONCLUSION: Our studies provide novel insights into bicalutamide as an antagonist of AR function in AR+/ER- breast cancer and reveal the mechanistic basis for targeting AR as a therapeutic opportunity for patients with AR+/ER- breast cancer.

ATAD2 overexpression is associated with progression and prognosis in colorectal cancer.

OBJECTIVES: ATPase family AAA domain-containing 2 plays an important role in tumor progression including cell cycle, proliferation, apoptosis and chemoresistance. However, the expression of ATPase family AAA domain-containing 2 in colorectal cancer and its significance are still unclear. The aim of this study was to examine the expression of ATPase family AAA domain-containing 2 in colorectal cancer. METHODS: Immunohistochemistry was used to determine the expression of ATPase family AAA domain-containing 2 in 155 colorectal cancer and 30 matched adjacent noncancerous tissues. The correlation of ATPase family AAA domain-containing 2 expression with clinicopathological variables was assessed using chi-square test. Patient survival was analyzed using the Kaplan-Meier and log-rank tests. Cox regression was performed for the multivariate analysis of prognostic factors. RESULTS: High expression of ATPase family AAA domain-containing 2 was detected in 58.1% of the colorectal cancers and was significantly associated with advanced tumor-node-metastasis stage (P = 0.044), poor differentiation (P = 0.028), deep infiltration (P < 0.001), lymphovascular invasion (P = 0.006), lymph node metastasis (P = 0.024) and recurrence (P = 0.022). Patients with high ATPase family AAA domain-containing 2 expression had significantly poorer overall survival and disease-free survival (both P < 0.001) when compared with patients with low expression of ATPase family AAA domain-containing 2. The multivariate analysis showed that ATPase family AAA domain-containing 2 was an independent factor for both overall survival (P = 0.003; hazard ratio (HR): 2.356; 95% confidence interval (CI): 1.335-4.158) and disease-free survival (P = 0.001; HR: 2.643; 95% CI: 1.489-4.693). CONCLUSIONS: These results showed that ATPase family AAA domain-containing 2 overexpression was associated with progression and prognosis of colorectal cancer.

Elevated expression of HABP1 is a novel prognostic indicator in triple-negative breast cancers.

Hyaluronan-binding protein 1 (HABP1) has been documented to overexpress in several malignancies. The aim of our study is to investigate the expression of HABP1 protein in triple-negative breast cancer (TNBC) and its clinical significance. Using immunohistochemistry, HABP1 expression was evaluated in 139 TNBC specimens. The association between HABP1 expression with clinicopathological parameters was assessed using chi-square test. The survival status of patients was analyzed using the Kaplan-Meier and log-rank tests. Cox regression was used for the multivariate analysis of prognostic factors. The results showed that HABP1 overexpression correlated with higher histological grade (P = 0.004), advanced TNM stage (P = 0.008), greater tumor size (P = 0.016), metastasis of lymph node (P < 0.001), and recurrence (P = 0.040). Furthermore, it indicated that patients with HABP1 overexpression had significantly poorer overall survival (OS) and disease-free survival (DFS) compared with patients (P < 0.001 for both). Multivariate Cox regression analysis revealed that elevated HABP1 expression was an independent prognostic factor for both OS (P = 0.035) and DFS (P = 0.013). In contrast to the effect of HABP1 in TNBCs with lymph node metastasis, HABP1 overexpression significantly affects prognosis (OS, P = 0.002; DFS, P = 0.003) in TNBCs without lymph node metastasis. In conclusion, HABP1 protein high expression may contribute to the tumor progression and poor prognosis of TNBC, especially in predicting prognosis in TNBCs without lymph node metastasis.

Study of circulating antibodies against CD25 and FOXP3 in breast cancer.

Our recent work suggests that circulating levels of anti-CD25 and anti-FOXP3 antibodies were significantly increased in patients with either lung cancer or esophageal cancer. To confirm if these two autoantibodies are specific for certain types of malignant tumors, the present work was thus undertaken to examine an alteration of anti-CD25 and anti-FOXP3 IgG levels in breast cancer. A total of 152 patients with breast cancer and 112 control subjects were recruited in this study. The levels of circulating anti-CD25 and anti-FOXP3 IgG antibodies were tested using an in-house enzyme-linked immunosorbent assay (ELISA). Student's t test showed no significant differences in the levels of either anti-CD25 IgG or anti-FOXP3 IgG between patients with breast cancer and control subjects, although patients at stage I had increased levels of anti-CD25 IgG compared with control subjects (t = 2.11, P = 0.037); there was no significant association of the anti-FOXP3 IgG levels with stages of breast cancer. In conclusion, circulating IgG autoantibody to CD25 instead of FOXP3 may be a potential biomarker for early diagnosis of breast cancer but further investigation remains needed to replicate this initial finding.

Surgical treatment of gynecomastia: mastectomy compared to liposuction technique.

BACKGROUND: Gynecomastia is a benign enlargement of the male breast. Yet enlarged breasts cause anxiety, embarrassment, psychosocial discomfort, and fear of breast cancer. The aim of this study was to assess the experience of gynecomastia patients undergoing mastectomy and liposuction surgery. METHODS: Seven hundred thirty-three patients were analyzed for age, chief complaint, position, grade, operation approach, biopsy, and complication between mastectomy group and liposuction group, from 1990 to 2010. RESULTS: Four hundred two patients (436 breasts) were treated with mastectomy and 331 patients (386 breasts) were treated with liposuction techniques. Three hundred thirty (82%) patients complained of breast lump and lump with pain in mastectomy group, and 204 (61%) patients complained of enlargement breast and enlargement with pain in liposuction group (P < 0.05). All excision specimens were performed for routine histological analysis which showed pathologic diagnosis in patients with mastectomy (100%). One hundred fifty-nine (41%) patients with liposuction acquired pathologic diagnosis through fine needle aspiration and/or core biopsy (P < 0.05). The reoperation rates in mastectomy group and liposuction group were 1.4% and 0.5%, respectively. There were no nipple/areola necrosis and scars in liposuction group. CONCLUSIONS: The surgical treatment of gynecomastia required an individual approach, depending on symptoms (lump or enlargement) and requirements of patients. Patients who chose mastectomy were looking for reassurance that their pathologic diagnosis was benign. The increase in the number of liposuction patients was reflected in our study because it was associated with superior esthetic results and few complications.

Type I photodynamic antimicrobial therapy: Principles, progress, and future perspectives.

The emergence of drug-resistant bacteria has significantly diminished the efficacy of existing antibiotics in the treatment of bacterial infections. Consequently, the need for finding a strategy capable of effectively combating bacterial infections has become increasingly urgent. Photodynamic therapy (PDT) is considered one of the most promising emerging antibacterial strategies due to its non-invasiveness, low adverse effect, and the fact that it does not lead to the development of drug resistance. However, bacteria at the infection sites often exist in the form of biofilm instead of the planktonic form, resulting in a hypoxic microenvironment. This phenomenon compromises the treatment outcome of oxygen-dependent type-II PDT. Compared to type-II PDT, type-I PDT is not constrained by the oxygen concentration in the infected tissues. Therefore, in the treatment of bacterial infections, type-I PDT exhibits significant advantages over type-II PDT. In this review, we first introduce the fundamental principles of type-I PDT in details, including its physicochemical properties and how it generates reactive oxygen species (ROS). Next, we explore several specific antimicrobial mechanisms utilized by type-I PDT and summarize the recent applications of type-I PDT in antimicrobial treatment. Finally, the limitations and future development directions of type-I photosensitizers are discussed. STATEMENT OF SIGNIFICANCE: The misuse and overuse of antibiotics have accelerated the development of bacterial resistance. To achieve the effective eradication of resistant bacteria, pathfinders have devised various treatment strategies. Among these strategies, type I photodynamic therapy has garnered considerable attention owing to its non-oxygen dependence. The utilization of non-oxygen-dependent photodynamic therapy not only enables the effective elimination of drug-resistant bacteria but also facilitates the successful eradication of hypoxic biofilms, which exhibits promising prospects for treating biofilm-associated infections. Based on the current research status, we anticipate that the novel type I photodynamic therapy agent can surmount the biofilm barrier, enabling efficient treatment of hypoxic biofilm infections.

Rising rainfall intensity induces spatially divergent hydrological changes within a large river basin.

Droughts or floods are usually attributed to precipitation deficits or surpluses, both of which may become more frequent and severe under continued global warming. Concurring large-scale droughts in the Southwest and flooding in the Southeast of China in recent decades have attracted considerable attention, but their causes and interrelations are not well understood. Here, we examine spatiotemporal changes in hydrometeorological variables and investigate the mechanism underlying contrasting soil dryness/wetness patterns over a 54-year period (1965-2018) across a representative mega-watershed in South China-the West River Basin. We demonstrate that increasing rainfall intensity leads to severe drying upstream with decreases in soil water storage, water yield, and baseflow, versus increases therein downstream. Our study highlights a simultaneous occurrence of increased drought and flooding risks due to contrasting interactions between rainfall intensification and topography across the river basin, implying increasingly vulnerable water and food security under continued climate change.

Hypoxia stimulates CTC-platelet cluster formation to promote breast cancer metastasis.

Circulating tumor cell clusters/micro-emboli (CTM) possess greater metastatic capacity and survival advantage compared to individual circulating tumor cell (CTC). However, the formation of CTM subtypes and their role in tumor metastasis remain unclear. In this study, we used a microfluidic Cluster-Chip with easy operation and high efficiency to isolate CTM from peripheral blood, which confirmed their correlation with clinicopathological features and identified the critical role of CTC-platelet clusters in breast cancer metastasis. The correlation between platelets and CTM function was further confirmed in a mouse model and RNA sequencing of CTM identified high-expressed genes related to hypoxia stimulation and platelet activation which possibly suggested the correlation of hypoxia and CTC-platelet cluster formation. In conclusion, we successfully developed the Cluster-Chip platform to realize the clinical capture of CTMs and analyze the biological properties of CTC-platelet clusters, which could benefit the design of potential treatment regimens to prevent CTM-mediated metastasis and tumor malignant progression.

Unique clinicopathological features of metaplastic breast carcinoma compared with invasive ductal carcinoma and poor prognostic indicators.

BACKGROUND: Metaplastic breast carcinoma is a rare aggressive malignant neoplasm. The purposes of this study are to review the pathologic features and clinical outcomes of metaplastic breast carcinoma compared to invasive ductal carcinoma and to evaluate the prognosis of metaplastic breast carcinoma. METHODS: The cases of 55 patients with metaplastic breast carcinoma presenting between 1991 and 2006 were analyzed and compared to the cases of 767 age-matched patients with invasive ductal carcinoma from the same time period. RESULTS: The group of patients with metaplastic breast carcinoma presented with a larger tumor size, lower lymph node involvement, higher percentage of triple-negative (estrogen receptor-, progesterone receptor- and human epidermal growth factor receptor-2-negative) cases, and Ki-67 over-expression compared with the group of patients with invasive ductal carcinoma and triple-negative invasive ductal carcinomas. Patients in the metaplastic breast carcinoma group tended to have more local (often chest wall) recurrences (P = 0.038) and distant (often lung) metastases (P = 0.001) than those in the invasive ductal carcinomas group. The prognosis of metaplastic breast carcinoma was poorer than that of invasive ductal carcinoma and triple-negative invasive ductal carcinomas; the 5-year overall survival rate was 54.5% in metaplastic breast carcinoma versus 85.1% in invasive ductal carcinoma, and 73.3% in triple-negative invasive ductal carcinomas (P <0.001). The 5-year disease-free survival rate was 45.5% in metaplastic breast carcinoma versus 71.2% in invasive ductal carcinoma, and 60.3% in triple-negative invasive ductal carcinomas (P <0.001). Multivariate analysis revealed tumor size larger than 5.0 cm, lymph node involvement and Ki-67≥14% were significantly related to 5-year overall survival (P = 0.010; P = 0.010; P = 0.035) and 5-year disease-free survival (P = 0.020; P = 0.018; P = 0.049). CONCLUSIONS: Metaplastic breast carcinoma shows a poorer prognosis than both invasive ductal carcinoma and triple-negative invasive ductal carcinomas. Tumor size larger than 5.0 cm, lymph node involvement and Ki-67 ≥14% indicate a poor prognosis in patients with metaplastic breast carcinoma.

Nanotherapeutics with immunoregulatory functions for the treatment of bacterial infection.

The advent of drug-resistant pathogens results in the occurrence of stubborn bacterial infections that cannot be treated with traditional antibiotics. Antibacterial immunotherapy by reviving or activating the body's immune system to eliminate pathogenic bacteria has confirmed promising therapeutic strategies in controlling bacterial infections. Subsequent studies found that antimicrobial immunotherapy has its own benefits and limitations, such as avoiding recurrence of infection and autoimmunity-induced side effects. Current studies indicate that the various antibacterial therapeutic strategies inducing immune regulation can achieve superior therapeutic efficacy compared with monotherapy alone. Therefore, summarizing the recent advances in nanomedicine with immunomodulatory functions for combating bacterial infections is necessary. Herein, we briefly introduce the crisis caused by drug-resistant bacteria and the opportunity for antibacterial immunotherapy. Then, immune-involved multimodal antibacterial therapy for the treatment of infectious diseases was systematically summarized. Finally, the prospects and challenges of immune-involved combinational therapy are discussed.

The tremendous clinical potential of the microbiota in the treatment of breast cancer: the next frontier.

Although significant advances have been made in the diagnosis and treatment of breast cancer (BC) in recent years, BC remains the most common cancer in women and one of the main causes of death among women worldwide. Currently, more than half of BC patients have no known risk factors, emphasizing the significance of identifying more tumor-related factors. Therefore, we urgently need to find new therapeutic strategies to improve prognosis. Increasing evidence demonstrates that the microbiota is present in a wider range of cancers beyond colorectal cancer. BC and breast tissues also have different types of microbiotas that play a key role in carcinogenesis and in modulating the efficacy of anticancer treatment, for instance, chemotherapy, radiotherapy, and immunotherapy. In recent years, studies have confirmed that the microbiota can be an important factor directly and/or indirectly affecting the occurrence, metastasis and treatment of BC by regulating different biological processes, such as estrogen metabolism, DNA damage, and bacterial metabolite production. Here, we review the different microbiota-focused studies associated with BC and explore the mechanisms of action of the microbiota in BC initiation and metastasis and its application in various therapeutic strategies. We found that the microbiota has vital clinical value in the diagnosis and treatment of BC and could be used as a biomarker for prognosis prediction. Therefore, modulation of the gut microbiota and its metabolites might be a potential target for prevention or therapy in BC.

Tumor Microenvironment-Responsive Nanoherb Delivery System for Synergistically Inhibition of Cancer Stem Cells.

Multidrug resistance in cancer stem cells (CSCs) is a major barrier to chemotherapy; hence, developing CSC-specific targeted nanocarriers for efficient drug delivery is critical. In this study, monodisperse hollow-structured MnO2 (H-MnO2) with a mesoporous shell was created for efficient targeted drug delivery. An effective therapeutic compound isoliquiritigenin (ISL) was confirmed to inhibit the lung cancer stem-cell phenotype by natural compound screening based on integrated microfluidic devices. The resultant H-MnO2 showed a high drug-loading content of the potent CSC-targeting compound ISL and near-infrared fluorescent dye indocyanine green (ICG). In addition, H-MnO2 was successively modified with hyaluronic acid (HA) to enhance targeting CSCs with high CD44 expression levels. The H-MnO2@(ICG + ISL)@HA nanocomposites displayed promising chemotherapeutic and photothermal treatment capabilities, as well as NIR-triggered drug release, which showed excellent CSC-killing effects and tumor inhibition efficacy. Meanwhile, the development of the tumor was effectively restrained by NIR-triggered phototherapy and prominent chemotherapy without obvious side effects after tail vein injection of the nanocomposites in vivo. In summary, the prepared nanocomposites accomplished synergistic cancer therapy that targets CSCs, offering a versatile platform for lung cancer diagnosis and treatment.

Recent progress in nanozymes for the treatment of diabetic wounds.

The slow healing of diabetic wounds has seriously affected human health. Meanwhile, the open wounds are susceptible to bacterial infection. Clinical therapeutic methods such as antibiotic therapy, insulin treatment, and surgical debridement have made great achievements in the treatment of diabetic wounds. However, drug-resistant bacteria will develop after long-term use of antibiotics, resulting in decreased efficacy. To improve the therapeutic effect, increasing drug concentration is a common strategy in clinical practice, but it also brings serious side effects. In addition, hyperglycemia control or surgical debridement can easily bring negative effects to patients, such as hypoglycemia or damage of normal tissue. Therefore, it is essential to develop novel therapeutic strategies to effectively promote diabetic wound healing. In recent years, nanozyme-based diabetic wound therapeutic systems have received extensive attention because they possess the advantages of nanomaterials and natural enzymes. For example, nanozymes have the advantages of a small size and a high surface area to volume ratio, which can enhance the tissue penetration of nanozymes and increase the reactive active sites. Moreover, compared with natural enzymes, nanozymes have more stable catalytic activity, lower production cost, and stronger operability. In this review, we first reviewed the basic characteristics of diabetic wounds and then elaborated on the catalytic mechanism and action principle of different types of nanozymes in diabetic wounds from three aspects: controlling bacterial infection, controlling hyperglycemia, and relieving inflammation. Finally, the challenges, prospects and future implementation of nanozymes for diabetic wound healing are outlined.

A Bidirectional Single-Cell Migration and Retrieval Chip for Quantitative Study of Dendritic Cell Migration.

Dendritic cell (DC) migration is a fundamental step during execution of its adaptive immunity functions. Studying DC migration characteristics is critical for development of DC-dependent allergy treatments, vaccines, and cancer immunotherapies. Here, a microfluidics-based single-cell migration platform is described that enables high-throughput and precise bidirectional cell migration assays. It also allows selective retrieval of cell subpopulations that have different migratory potentials. Using this microfluidic platform, DC migration is investigated in response to different chemoattractants and inhibitors, quantitatively describe DC migration patterns and retrieve DC subpopulations of different migratory potentials for differential gene expression analysis. This platform opens an avenue for precise characterization of cell migration and potential discovery of therapeutic modulators.