Case report: The diagnostic pitfall of Warthin-like mucoepidermoid carcinoma.

Warthin-like mucoepidermoid carcinoma (WL-MEC) is a newly reported variant of mucoepidermoid carcinoma. Its histological feature is easy to confused with metaplastic Warthin Tumor, and its relationship with Warthin tumor in histogenesis is controversial. In this study, we presented two cases of WL-MEC, discussing their clinicopathological and molecular features. Notably, one case was initially misdiagnosed during the first onset of the tumor. Case 1 was a 60-year-old female with a mass in the right parotid gland. Case 2 featured a 29-year-old male who developed a lump at the original surgical site 6 months after a "Warthin tumor" resection from the submandibular gland. Histologically, both tumor exhibited a prominent lymphoid stroma and cystic pattern, accompanied by various amounts of epithelial nests composed of squamoid cells, intermediate cells and mucinous cells. The characteristic eosinophilic bilayer epithelium of Warthin tumor was not typically presented in either case. Both cases tested positive for MAML2 gene rearrangement. To contextualize our findings, we conducted a comprehensive review of forty-eight WL-MEC cases documented in the English literature, aiming to synthesizing a reliable differential diagnostic approach. WL-MEC is a rare yet clinically relevant variant, posing a diagnostic pitfall for pathologists. Our study underscores the importance of a meticulous evaluation of both clinical and histological features, coupled with the detection of MAML2 rearrangement, as a credible method for distinguishing WL-MEC from other benign and malignant lesions, particularly metaplastic Warthin tumor.

Bioactive Metal Ion-Coordinated Dynamic Hydrogel with Antibacterial, Immunomodulatory, and Angiogenic Activities for Infected Wound Repair.

The repair of infected wounds is a complex physiopathologic process. Current studies on infected wound treatment have predominantly focused on infection treatment, while the factors related to delayed healing caused by vascular damage and immune imbalance are commonly overlooked. In this study, an extracellular matrix (ECM)-like dynamic and multifunctional hyaluronic acid (HA) hydrogel with antimicrobial, immunomodulatory, and angiogenic capabilities was designed as wound dressing for the treatment of infected skin wounds. The dynamic network in the hydrogel dressing was based on reversible metal-ligand coordination formed between sulfhydryl groups and bioactive metal ions. In our design, antibacterial silver and immunomodulatory zinc ions were employed to coordinate with sulfhydrylated HA and a vasculogenic peptide. In addition to the desired bioactivities for infected wounds, the hydrogel could also exhibit self-healing and injectable abilities. Animal experiments with infected skin wound models indicated that the hydrogel dressings enabled minimally invasive injection and seamless skin wound covering and then facilitated wound healing by efficient bacterial killing, continuous inflammation inhibition, and improved blood vessel formation. In conclusion, the metal ion-coordinated hydrogels with wound-infection-desired bioactivities and ECM-like dynamic structures represent a class of tissue bionic wound dressings for the treatment of infected and chronic inflammation wounds.

Tailor-made molecular imprints for biological event intervention.

Molecular imprints, which are crosslinked architectures containing specific molecular recognition cavities for targeting compounds, have recently transitioned from in vitro diagnosis to in vivo treatment. In current application scenarios, it has become an important topic to create new biomolecular recognition pathways through molecular imprinting, thereby inhibiting the pathogenesis and regulating the development of diseases. This review starts with a pathological analysis, mainly focusing on the corresponding artificial enzymes, enzyme inhibitors and antibody mimics with enhanced functions that are created by molecular imprinting strategies. Recent advances are highlighted in the use of molecular imprints as tailor-made nanomedicines for the prevention of three major diseases: metabolic syndrome, cancer, and bacterial/viral infections.

Case report: Tall cell carcinoma with reversed polarity of the breast: an additional case and review of the literature.

Objective: The aim of this report was to comprehensively investigate the clinicopathological features, histological characteristics, and differential diagnosis of tall cell carcinoma with reversed polarity of the breast (TCCRP) to enhance the understanding of this tumour for precise therapeutic interventions. Methods: The clinicopathological characteristics and differential diagnosis of a patient with TCCRP were retrospectively analysed, and a systematic literature review was extracted from relevant published studies on PubMed. Results: All patients included in the study were female, with a median age of 51 years. Microscopically, the tumour cells exhibited a solid papillary growth pattern with tall columnar morphology and reversed nuclear polarity. Immunohistochemistry revealed that the tumours were triple-negative breast cancer (negative for ER, PR, and HER-2), with a low Ki-67 proliferation index. Different degrees of expression were observed for CK7, Calretinin, and S-100 markers; however, CK5/6 showed high expression levels. Conclusions: TCCRP is an uncommon invasive carcinoma subtype found in the breast. Its histological morphology resembles that of tall cell subtype papillary thyroid carcinoma. Accurate diagnosis requires the integration of histomorphological assessment along with immunohistochemistry and molecular genetics analysis.

An Oral Nanomedicine Elicits In Situ Vaccination Effect against Colorectal Cancer.

Oral administration is the most preferred approach for treating colon diseases, and in situ vaccination has emerged as a promising cancer therapeutic strategy. However, the lack of effective drug delivery platforms hampered the application of in situ vaccination strategy in oral treatment of colorectal cancer (CRC). Here, we construct an oral core-shell nanomedicine by preparing a silk fibroin-based dual sonosensitizer (chlorin e6, Ce6)- and immunoadjuvant (imiquimod, R837)-loaded nanoparticle as the core, with its surface coated with plant-extracted lipids and pluronic F127 (p127). The resultant nanomedicines (Ce6/R837@Lp127NPs) maintain stability during their passage through the gastrointestinal tract and exert improved locomotor activities under ultrasound irradiation, achieving efficient colonic mucus infiltration and specific tumor penetration. Thereafter, Ce6/R837@Lp127NPs induce immunogenic death of colorectal tumor cells by sonodynamic treatment, and the generated neoantigens in the presence of R837 serve as a potent in situ vaccine. By integrating with immune checkpoint blockades, the combined treatment modality inhibits orthotopic tumors, eradicates distant tumors, and modulates intestinal microbiota. As the first oral in situ vaccination, this work spotlights a robust oral nanoplatform for producing a personalized vaccine against CRC.

MCM6 is a Poor Prognostic Biomarker and Promotes Progression in Breast Cancer.

BACKGROUND: Breast cancer is the commonest global malignancy and the primary cause of carcinoma death. MCM6 is vital to carcinogenesis, but the pathogenesis of MCM6 remains unclear. METHODS: MCM6 expression in patients with breast cancer was examined through The Cancer Genome Atlas (TCGA) database, immunohistochemistry, Quantitative Real-Time PCR (qRT‒PCR) and Western blotting. The prognostic factors were assessed by the Kaplan‒Meier method and Cox regression. On the basis of the key factors selected by multivariable Cox regression analysis, a nomogram risk prediction model was adopted for clinical risk assessment. The TCGA database was utilized to determine how MCM6 is correlated with chemotherapy sensitivity, immune checkpoint-related genes (ICGs), tumor-infiltrating immune cells, along with tumor mutation burden (TMB) and methylation. The impact of MCM6 on carcinoma cells was investigated in terms of proliferation, cell cycle as well as migrating and invasive behavior through CCK assays, flow cytometry, wound healing assays, Transwell assays and xenotransplantation experiments. RESULTS: MCM6 expression was upregulated, which is closely associated with the size of the tumor (p = 0.001) and lymph node metastasis (p = 0.012) in patients with breast cancer. Multivariate analysis revealed MCM6 to be an independent risk factor for prognosis in patients with breast carcinoma. The nomograph prediction model included MCM6, age, ER, M and N stage, which displayed good discrimination with a C index of 0.817 and good calibration. Overexpression of MCM6 correlated with chemotherapy sensitivity, immune checkpoint-related genes (ICGs), tumor-infiltrating immune cells, tumor mutation burden (TMB), and methylation. Silencing MCM6 significantly inhibited proliferation, prolonged the G1 phase of the cell cycle, and restrained the proliferation, migration and invasive behavior of cancerous cells and inhibited tumor growth in vivo. CONCLUSIONS: Our research shows that MCM6 is highly expressed in breast cancer and can be used as an independent prognostic factor, which is expected to become a new target for the treatment of breast cancer in the future.

Multivalency-enhanced enzyme inhibitors with biomolecule-responsive activity.

This work reports a polymeric adenosine triphosphate (ATP)-responsive trypsin inhibitor. The polymeric inhibitor was rationally obtained by optimizing the benzamidine and phenylboronic acid monomers, which could synergistically bind with the phosphate and ribose groups in ATP. The ATP-responsive trypsin activity shows its potential as a therapeutic drug for cancer-targeting cell inhibition.

An Update on Adipose-Derived Stem Cells for Regenerative Medicine: Where Challenge Meets Opportunity.

Over the last decade, adipose-derived stem cells (ADSCs) have attracted increasing attention in the field of regenerative medicine. ADSCs appear to be the most advantageous cell type for regenerative therapies owing to their easy accessibility, multipotency, and active paracrine activity. This review highlights current challenges in translating ADSC-based therapies into clinical settings and discusses novel strategies to overcome the limitations of ADSCs. To further establish ADSC-based therapies as an emerging platform for regenerative medicine, this review also provides an update on the advancements in this field, including fat grafting, wound healing, bone regeneration, skeletal muscle repair, tendon reconstruction, cartilage regeneration, cardiac repair, and nerve regeneration. ADSC-based therapies are expected to be more tissue-specific and increasingly important in regenerative medicine.

Case Report: Clinicopathological Analysis of Minute Pulmonary Meningothelial-Like Nodules: Report of 7 Cases.

Objective: To investigate the clinical manifestations, radiologic features, pathological features, and immunophenotype of minute pulmonary meningothelial-like nodules (MPMNs). Method: This is a retrospective observational study. We collected the clinical data of 7 cases of MPMNs, and performed comprehensive characterization using a combination of clinical, morphological, radiologic and immunohistochemical assessments. Results: Of the 7 cases of MPMNs, 6 were female and 1 was male. The median age was 55 years. All MPMNs were multiple in lung with the size from 0,01 to 0,5cm. Chest CT examination showed ground-glass attenuation or solid nodules. Four cases were concomitant with carcinoma and/or pneumonia, and 3 cases occurred alone. Four of the 7 patients had no obvious symptoms; 3 patients had chest pain or cough or shortness of breath or hemoptysis. Multiple white nodules were found macroscopically, and the diseased cells grew along the alveolar septum, with relatively normal morphology, rich cytoplasm, unclear cell boundary, and uniform nucleus with delicate chromatin and without atypia; and the diseased cells showed nest or whorls distribution. EMA, PR, CD56 and vimentin were positive in all cases by immunohistochemistry. Conclusions: MPMNs are rare benign lesions in the lung, often multiple, usually less than 0.5cm in diameter, most of which have no obvious clinical symptoms. MPMNs are often found by chest CT, and occur independently or concomitant with other lesions. The positive immunohistochemical staining of EMA, PR, CD56, vimentin supports the diagnosis.

Mussel-Inspired Clickable Antibacterial Peptide Coating on Ureteral Stents for Encrustation Prevention.

Long-term indwelling catheters or stents often cause complications like infection, encrustation, hematuria, pain, and so on. The source of these problems is bacteria, which can form biofilms on the stents to reduce antibiotic sensitivity and produce urease to form encrustation by increasing the urine pH. Urinary tract infection (UTI) can aggravate the body damage and even seriously endanger lives, and the encrustation will block the stents, which can cause hydronephrosis and renal function damage. Therefore, the prevention of UTI and encrustation represents a great challenge in clinical ureteral stent uses. In this work, a clickable mussel-inspired peptide and antimicrobial peptide (AMP) were used to functionalize the commercial stents' surfaces to inhibit long-term infection and encrustation caused by bacteria. Copper (Cu) ions were used to coordinate the mussel-inspired peptide to improve the stability. The AMP with an azido group was clicked to the mussel-inspired Cu-coordinated peptide coating through click chemistry. The bio-inspired antibacterial coating was constructed with excellent stability, bactericidal properties, and improved biological compatibility. In in vitro and in vivo experiments, it was further found that the coating showed bactericidal and encrustation reduction abilities. This study thus developed an effective, safe, and stable AMP coating on urinary stents/catheters capable of long-term antibacterial and encrustation inhibition.

Characterization of Pathway-Specific Regulator NigR for High Yield Production of Nigericin in Streptomyces malaysiensis F913.

Nigericin is a polyether antibiotic with potent antibacterial, antifungal, antimalarial and anticancer activity. NigR, the only regulator in the nigericin biosynthetic gene cluster in Streptomyces malaysiensis F913, was identified as a SARP family regulator. Disruption of nigR abolished nigericin biosynthesis, while complementation of nigR restored nigericin production, suggesting that NigR is an essential positive regulator for nigericin biosynthesis. Overexpression of nigR in Streptomyces malaysiensis led to significant increase in nigericin production compared to the wild-type strain. Nigericin production in the overexpression strain was found to reach 0.56 g/L, which may be the highest nigericin titer reported to date. Transcriptional analysis suggested that nigR is required for the transcription of structural genes in the nig gene cluster; quantitative RT-PCR analysis revealed that the expression of structural genes was upregulated in the nigR overexpression strain. Our study suggested that NigR acts in a positive manner to modulate nigericin production by activating transcription of structural genes and provides an effective strategy for scaling up nigericin production.

Mussel-Inspired Ligand Clicking and Ion Coordination on 2D Black Phosphorus for Cancer Multimodal Imaging and Therapy.

As a promising 2D nanocarrier, the biggest challenge of bare black phosphorus nanosheets (BP NSs) lies in the inherent instability, while it can be improved by surface modification strategies to a great extent. Considering the existing infirm BP NSs surface modification strategies, A mussels-inspired strong adhesive biomimetic peptide with azide groups for surface modification to increase the stability of BP NSs is synthesized. The azide groups on the peptide can quickly and precisely bind to the targeting ligand through click chemistry, solving the problem of nonspecificity of secondary modification of other mussel-mimicking materials. Besides, a catechol-Gd3+ coordination network is further constructed for magnetic resonance imaging (MRI) and inducing intracellular endo/lysosome escape. The fabricated BP-DOX@Gd/(DOPA)4 -PEG-TL nanoplatform exhibits enhanced antitumor abilities through synergetic chemo/photothermal effects both in vitro and in vivo.

Bio-inspired antibacterial coatings on urinary stents for encrustation prevention.

Urinary tract infection (UTI) represents one of the most common nosocomial infections, which is mainly related to indwelling catheters or stents. In addition to the formation of biofilms to reduce antibiotic sensitivity, the urease-producing bacteria can also increase urine pH, causing Ca2+ and Mg2+ deposition and finally catheter obstruction. The prevention of UTIs and its complication (i.e., encrustation) thus is a great challenge in design of catheters and ureteral stents. In this work, a metal-catechol-assisted mussel chemistry (i.e., dopamine self-polymerization) was employed for surface functionalization of commercially available catheters with antimicrobial peptides (AMP), for the purpose of long-term anti-infection and encrustation prevention. To improve the stability of the polydopamine coating on polymeric stents, we used Cu2+-coordinated dopamine self-polymerization. Then, a cysteine-terminated AMP was introduced on the polydopamine coating through Michael addition. We found that the Cu2+-coordinated polydopamine coating showed improved stability and antibacterial effect. The cytotoxicity test confirmed that the bioinspired antibacterial coating showed good biocompatibility and no obvious toxicity. The results confirmed that the stents with AMP could in situ inhibit bacterial growth and biofilm formation, and finally reduce the deposition of struvite and hydroxyapatite crystals both in vitro and in vivo. We anticipate that this bioinspired strategy would develop a safe, stable and effective antibacterial coating on urinary tract medical devices for long-term bacterial inhibition and encrustation prevention.

Bioinspired peptide adhesion on Ti implants alleviates wear particle-induced inflammation and improves interfacial osteogenesis.

In the inflammatory peri-implant microenvironment, excessive polarization of macrophages to the proinflammatory M1 phenotype can trigger the secretion of inflammatory cytokines, which promote bone resorption and impede osteogenesis around implants. The direct consequence of this process is the failure of prosthetic implants due to aseptic loosening. To reverse the inflammatory microenvironment and prevent prosthesis loosening, a mussel adhesion-inspired surface strategy was used for bioengineering of titanium implants with integrin-binding ability. In our design, a mussel-inspired catecholic peptide with tetravalent 3,4-dihydroxy-l-phenylalanine (DOPA) and Arg-Gly-Asp (RGD) sequences was synthesized. The peptide can easily anchor to the surface of medical titanium materials through a mussel adhesive mechanism. We found that peptide-decorated titanium implants could effectively inhibit peri-implant inflammation in a wear particle model and could promote the polarization of macrophages to a pro-healing M2 phenotype by interfering with integrin-α2ß1 and integrin-αvß3. Moreover, the peptide coating increased the adherence of osteoblasts and promoted osteogenesis on titanium implants even under inflammatory conditions. This work suggested that this biomimetic catecholic integrin-binding peptide can provide facile tactics for surface bioengineering of medical prostheses with improved interfacial osteogenesis under inflammatory conditions, which might contribute greatly to the prevention of prosthesis loosening and the improvement of clinical outcomes.

Bioclickable Mussel-Derived Peptides With Immunoregulation for Osseointegration of PEEK.

Polyether ether ketone (PEEK)-based biomaterials have been widely used in the field of spine and joint surgery. However, lack of biological activity limits their further clinical application. In this study, we synthesized a bioclickable mussel-derived peptide Azide-DOPA4 as a PEEK surface coating modifier and further combined bone morphogenetic protein 2 functional peptides (BMP2p) with a dibenzylcyclooctyne (DBCO) motif through bio-orthogonal reactions to obtain DOPA4@BMP2p-PEEK. As expected, more BMP2p can be conjugated on PEEK after Azide-DOPA4 coating. The surface roughness and hydrophilicity of DOPA4@BMP2p-PEEK were obviously increased. Then, we optimized the osteogenic capacity of PEEK substrates. In vitro, compared with the BMP2p-coating PEEK material, DOPA4@BMP2p-PEEK showed significantly higher osteogenic induction capability of rat bone marrow mesenchymal stem cells. In vivo, we constructed a rat calvarial bone defect model and implanted PEEK materials with a differently modified surface. Micro-computed tomography scanning displayed that the DOPA4@BMP2p-PEEK implant group had significantly higher new bone volume and bone mineral density than the BMP2p-PEEK group. Histological staining of hard tissue further confirmed that the DOPA4@BMP2p-PEEK group revealed a better osseointegrative effect than the BMP2p-PEEK group. More importantly, we also found that DOPA4@BMP2p coating has a synergistic effect with induced Foxp3+ regulatory T (iTreg) cells to promote osteogenesis. In summary, with an easy-to-perform, two-step surface bioengineering approach, the DOPA4@BMP2p-PEEK material reported here displayed excellent biocompatibility and osteogenic functions. It will, moreover, offer insights to engineering surfaces of orthopedic implants.

Helicobacter pylori promotes gastric cancer progression by upregulating semaphorin 5A expression via ERK/MMP9 signaling.

Helicobacter pylori (H. pylori) infection is the strongest risk factor for the occurrence and development of gastric carcinoma. However, the molecular mechanism underlying H. pylori-induced pathogenesis has not yet been fully characterized. Here, we explored whether H. pylori upregulates semaphorin 5A to promote gastric cancer progression via the extracellular regulated protein kinases/matrix metalloproteinase (ERK/MMP9) signaling pathway. In this study, H. pylori upregulated semaphorin 5A expression in vitro and in vivo. Using the human gastric carcinoma cell lines SGC7901, SGC7901-siScrambled, and SGC7901-siSema 5A, our studies showed that H. pylori increased the proliferation, growth, migration, and invasiveness of gastric cancer cells via its effects on semaphorin 5A and that H. pylori increased the expression of MMP9 in gastric cancer cells via the semaphorin 5A-mediated ERK signaling pathway. Further analysis revealed that the ERK inhibitor PD98059 and MMP9 antibody (Ab) attenuated H. pylori-induced gastric cancer cell invasion and metastasis in vitro through a semaphorin 5A-dependent mechanism. In conclusion, H. pylori could promote gastric cancer progression in a semaphorin 5A-dependent manner via the ERK/MMP9 signaling pathway. Semaphorin 5A and its related signaling molecules potentially represent latent targets for H. pylori-related gastric cancer therapy.

miR-142-3p Modulates Cell Invasion and Migration via PKM2-Mediated Aerobic Glycolysis in Colorectal Cancer.

Decreased expression of miR-142-3p was observed in human cancers. However, the function and mechanism of miR-142-3p in human colorectal cancer remain obscure. The expressions of miR-142-3p in human colorectal cancer tissues and cell lines were measured by RT-qPCR. The effects of miR-142-3p on cell invasion and migration were detected by transwell assays. The efficiency of aerobic glycolysis was determined by glucose consumption and lactate production. Dual-luciferase reporter assays were performed to confirm the correlation between miR-142-3p and pyruvate kinase isozyme M2 (PKM2). The level of PKM2 was assessed by western blotting. Our results showed that the expression of miR-142-3p was decreased both in human colorectal cancer tissues and in cells. Overexpression of miR-142-3p in cell line attenuated colorectal cancer cell invasion and migration. About the underlying mechanism, we found that miR-142-3p modulated aerobic glycolysis via targeting pyruvate kinase M2 (PKM2). In addition, we demonstrated PKM2 and PKM2-mediated aerobic glycolysis contributes to miR-142-3p-mediated colorectal cancer cell invasion and migration. Hence, these data suggested that miR-142-3p was a potential therapeutic target for the treatment of human colorectal cancer.

A versatile pH-responsive peptide based dynamic biointerface for tracking bacteria killing and infection resistance.

Herein we reported a versatile dynamic biointerface based on pH-responsive peptide self-assembly and disassembly to capture the bacteria to avoid bacteria further infected tissue around that can release peptides from the surface in a slightly acidic environment to kill the bacteria with the specificity. The exposed biointerface still presented infection resistance.

Evolution of Molecularly Imprinted Enzyme Inhibitors: From Simple Activity Inhibition to Pathological Cell Regulation.

Molecular imprinting represents one of the most promising strategies to design artificial enzyme inhibitors. However, the study of molecularly imprinted enzyme inhibitors (MIEIs) remains at a primary stage. Advanced applications of MIEIs for cell regulation have rarely been explored. Using a solid-phase oriented imprinting strategy so as to leave the active site of the enzymes accessible, we synthesized two MIEIs that exhibit high specificity and potent inhibitory effects (inhibition constant at low nM range) towards trypsin and angiogenin. The trypsin MIEI inhibits trypsin activity, tryptic digestion-induced extracellular matrix lysis and cell membrane destruction, indicating its utility in the treatment of active trypsin-dependent cell injury. The angiogenin MIEI blocks cancer cell proliferation by suppressing the ribonuclease activity of angiogenin and decreasing the angiogenin level inside and outside HeLa cells. Our work demonstrates the versatility of MIEIs for both enzyme inhibition and cell fate manipulation, showing their great potential as therapeutic drugs in biomedicine.