Treatment Patterns and Prognosis of Palliative Chemotherapy Combined With Targeting Agents in Patients With Unresectable Metastatic Colorectal Cancer: CHOICE, A Multicenter Longitudinal Observational Study.

BACKGROUND/AIM: This study investigated the treatment patterns and prognosis of patients with metastatic or unresectable colorectal cancer (mCRC) treated with chemotherapy with targeting agents. PATIENTS AND METHODS: This longitudinal multicenter study included 963 patients with mCRC who were treated in Korea between 2016 and 2020. Treatment patterns and efficacy were compared according to the mutation status and clinical factors. RESULTS: As first-line therapy, most of the patients (83.5%) received FOLFOX plus bevacizumab (35.4%), followed by FOLFIRI plus bevacizumab (18.8%), FOLFIRI plus cetuximab (17.0%), and FOLFOX plus cetuximab (12.3%). Bevacizumab was the most frequent agent (78.8%) combined with chemotherapy in RAS-mutated CRC, while cetuximab (57.2%) in RAS wild-type CRC. Cetuximab was frequently combined with a doublet regimen in patients with left-sided CRC than in those with right-sided CRC (34.4% vs. 16%). As second-line therapy, most patients (63.4%) also received doublet regimens with bevacizumab, and FOLFIRI plus aflibercept was administered in 15.1%. The objective response rate with FOLFIRI plus cetuximab was significantly higher in patients with left-sided CRC than in those with right-sided CRC (59.2% vs. 30.8%, p=0.008) and marginally higher in patients with RAS wild-type CRC than in those with RAS-mutated CRC (55.6% vs. 0.0%, p=0.092). Progression-free survival (PFS) with FOLFOX plus bevacizumab was significantly shorter than that with FOLFIRI plus bevacizumab (p=0.030) in RAS-mutated CRC, whereas there were no significant differences between regimens in RAS wild-type CRC. CONCLUSION: In patients with unresectable metastatic colorectal cancer, doublet chemotherapy with targeting agents is the most common therapy and efficacy depends on the mutation status as well as clinical factors.

Prognostic impact of pretreatment skeletal muscle index and CONUT score in diffuse large B-cell Lymphoma.

BACKGROUND: Although the prognostic value of the Controlling Nutritional Status (CONUT) score in diffuse large B-cell lymphoma (DLBCL) has been reported in several previous studies, its clinical relevance for the presence of sarcopenia has not been assessed. METHODS: In this study, 305 DLBCL patients were reviewed. They were categorized into normal/mild (n = 219) and moderate/severe (n = 86) CONUT groups. Sarcopenia was assessed using the L3-skeletal muscle index measured by baseline computed tomography imaging. Based on CONUT score and sarcopenia, patients were grouped: A (normal/mild CONUT and no sarcopenia), B (either moderate/severe CONUT or sarcopenia, but not both), and C (both moderate/severe CONUT and sarcopenia). RESULTS: The moderate/severe CONUT group showed higher rates of ≥ grade 3 febrile neutropenia, thrombocytopenia, non-hematologic toxicities, and early treatment discontinuation not related to disease progression, compared to the normal/mild CONUT group. The moderate/severe CONUT group had a lower complete response rate (58.1% vs. 80.8%) and shorter median overall survival (18.5 vs. 162.6 months) than the normal/mild group. Group C had the poorest prognosis with a median survival of 8.6 months, while groups A and B showed better outcomes (not reached and 60.1 months, respectively). Combining CONUT score and sarcopenia improved the predictive accuracy of the Cox regression model (C-index: 0.763), compared to the performance of using either CONUT score (C-index: 0.754) or sarcopenia alone (C-index: 0.755). CONCLUSIONS: In conclusion, the moderate/severe CONUT group exhibited treatment intolerance, lower response, and poor prognosis. Additionally, combining CONUT score and sarcopenia enhanced predictive accuracy for survival outcomes compared to individual variables.

Safety and effectiveness of aflibercept in combination with FOLFIRI in Korean patients with metastatic colorectal cancer who received oxaliplatin-containing regimen.

PURPOSE: To evaluate the safety and effectiveness of aflibercept in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in Korean patients with metastatic colorectal cancer (mCRC) who progressed with oxaliplatin-containing regimen. METHODS: This was a prospective observational study conducted at 22 sites across Korea between February 2018 and September 2019. Patients aged > 19 years with a diagnosis of mCRC who were prescribed aflibercept plus FOLFIRI, after progression with an oxaliplatin-containing regimen were included. Disease assessment was performed every 6 weeks. RESULTS: A total of 185 patients were included (males, 58.9%; right-sided tumors, 23.8%; and ECOG performance factor ≥ 1, 68.6%). A total of 514 adverse events (AEs) occurred in 134 patients, of which 206 (49.2%; 95% CI 42.0%, 56.4%) events were considered as adverse drug reactions (ADRs), 172 unexpected AEs (49.7%; 95% CI 42.5%, 56.9%), and 53 serious AEs (22.2%; 95% CI16.2%, 28.2%). The most common serious ADR was pneumonia (n = 2, 1.6%). The most common all grade hematological AE and non-hematological AE were neutropenia (21.6%) and nausea (16.2%), respectively. Over a median follow-up of 5.6 months, a total of five grade 5 (1.0%) AEs were reported. Median OS was 9.4 months, and median progression-free survival (PFS) was 7.3 months. The overall response rate was 14.6%. Right-sided tumor location and prior bevacizumab treatment were independent factors of poor PFS in multivariate analysis. CONCLUSION: Aflibercept in combination with FOLFIRI was effective and showed an acceptable safety profile in Korean patients with mCRC in daily clinical practice.

API-2-Induced Cell Migration Is Overcome by Small Molecular Approaches Inhibiting ß-Catenin.

Frequent mutation of APC (90%) in advanced colorectal cancer (CRC) results in the simultaneous activation of Wnt/ß-catenin and AKT signaling pathways, and the current therapeutic limitations of the AKT inhibitors for treating CRC patients are nuclear ß-catenin-induced EMT and bypassing apoptosis. In this study, we discover that the combinatorial treatment of an AKT inhibitor and KY1022, a ß-catenin destabilizer, effectively overcomes the current limitations of API-2, an AKT inhibitor, by reducing nuclear ß-catenin. Taken together, we demonstrate that the simultaneous suppression of Wnt/ß-catenin with the AKT signaling pathways is an ideal strategy for suppressing the AKT-inhibitor-mediated metastasis and for maximizing the therapeutic effects of AKT inhibitors.

Endothelial activation and stress index (EASIX) as a predictive biomarker in small cell lung cancer.

BACKGROUND: Endothelial activation and insult may contribute to the aggressive clinical course of small-cell lung cancer (SCLC); however, no predictive biomarker for this pathogenesis has been identified. OBJECTIVE: To evaluate the clinical impact of the endothelial activation and stress index (EASIX) in SCLC. METHODS: In this retrospective study, the EASIX was calculated from measurements of serum lactate dehydrogenase, creatinine, and platelet levels. A total of 264 patients with SCLC treated with platinum-based chemotherapy were stratified into high and low EASIX groups. RESULTS: Complete and objective response rates in the limited-stage (LD) were 19.5% vs. 33.3% (P= 0.050) and 85.4% vs. 97.9% (P= 0.028) in the high and low EASIX groups, respectively. There was no significant difference in the response rate between the two groups in the extensive-stage (ED). The median overall survival was 9.8 vs. 40.5 months in LD (P< 0.001) and 7.2 vs. 11.9 months in ED (P< 0.001) in the high and low EASIX groups, respectively. In multivariate analyses, a high EASIX level was an independent prognostic factor for worse progression-free and overall survival irrespective of stage. CONCLUSION: EASIX may be a potential predictive biomarker of SCLC.

Cachexia index as a potential biomarker for cancer cachexia and a prognostic indicator in diffuse large B-cell lymphoma.

BACKGROUND: Cancer cachexia is known to adversely affect the clinical course in patients with malignant lymphoma. The cachexia index (CXI) is a potential biomarker of cancer cachexia, and its implications for the prognosis and treatment outcome of lung cancer and aggressive lymphoma has been assessed in previous studies. METHODS: A total of 267 patients diagnosed with diffuse large B-cell lymphoma who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy were retrospectively reviewed. The CXI was calculated as the skeletal muscle index (SMI) × serum albumin/neutrophil-lymphocyte ratio (NLR). Although previous studies measured the SMI using the muscles of the L3 vertebral level, the present study used both the L3 vertebral muscles and the pectoralis muscles (PM) at the T4 vertebral level to measure the SMI. Depending on the type of muscles used, the CXI was termed the L3-CXI or PM-CXI. Using sex-specific cutoff values for CXI, the patients were categorized as follows: (i) high-CXI group (high L3-CXI and high PM-CXI), (ii) intermediate-CXI group (high L3-CXI and low PM-CXI), and (iii) low-CXI group (low L3-CXI and low PM-CXI). RESULTS: Complete responses to R-CHOP were obtained in 145/173 (83.8%), 25/36 (69.4%), and 27/57 (47.4%) patients in the high-CXI, intermediate-CXI, and low-CXI groups, respectively (P < 0.001). Treatment-related anaemia (15.6%, 30.6%, and 26.3%, P = 0.038), thrombocytopenia (21.4%, 36.1%, and 43.9%, P < 0.001), febrile neutropenia (23.7%, 44.4%, and 36.8%, P = 0.022), and any nonhaematologic toxicity (31.2%, 44.4%, and 54.4%, P = 0.001) of Grade 3 or more were more common in the lower CXI groups than in the higher-CXI groups. Early treatment discontinuation for reasons other than lymphoma progression also occurred more frequently in the low-CXI group (24/57, 42.1%) compared with the intermediate-CXI (5/36, 13.9%) and high-CXI (18/173, 10.4%) groups (P < 0.001). Median overall survival in the high-CXI, intermediate-CXI, and low-CXI groups was not reached, 50.6 months, and 14.5 months, respectively (p < 0.001). Multivariable analysis showed that low CXI was an independent negative prognostic factor for overall survival (hazard ratio 2.103, 95% confidence interval 1.278-3.460, P = 0.003). CONCLUSIONS: We suggest that in patients with diffuse large B-cell lymphoma, the CXI is a biomarker for cancer cachexia that can predict survival, treatment response, treatment-related toxicity, and compliance with R-CHOP. Patients were more clearly stratified by this new CXI category compared with the classifications described in previous studies.

Discovery of a novel CDK7 inhibitor YPN-005 in small cell lung cancer.

In contrast to non-small cell lung cancer, there has been no significant progress in the development of therapies for the small cell lung cancer (SCLC) in recent decades. Although various targeted agents, including immunotherapies, have recently been developed for testing in clinical trials, novel therapeutic agents are still needed for SCLC. We developed a potent inhibitor of cyclin-dependent kinase 7 (CDK7), designated YPN-005, and sought to determine whether it showed any anticancer effects in SCLC cells, cisplatin or etoposide-resistant cells, or organoids derived from SCLC patients. In a panel of kinases assay, YPN-005 was highly selective for CDK7 and showed antiproliferative effects in SCLC and cells with acquired resistance to conventional anticancer drugs. Similar to other CDK7 inhibitors, YPN-005 treatment significantly decreased the phosphorylation of the carboxyl-terminal domain of RNA polymerase II. Consistent with the in vitro results, YPN-005 treatment showed a significant inhibition of tumor growth through the suppression of RNA polymerase II phosphorylation. Finally, YPN-005 showed potent anticancer effects in organoids derived from SCLC patients compared to another CDK7 inhibitor, THZ1. Therapeutic targeting of CDK7 in SCLC might be suitable for clinical investigation, and YPN-005 may be a promising therapeutic option for primary SCLC and SCLC with acquired resistance to conventional therapy.

Exosomal miR-1260b derived from non-small cell lung cancer promotes tumor metastasis through the inhibition of HIPK2.

Tumor-derived exosomes (TEXs) contain enriched miRNAs, and exosomal miRNAs can affect tumor growth, including cell proliferation, metastasis, and drug resistance through cell-to-cell communication. We investigated the role of exosomal miR-1260b derived from non-small cell lung cancer (NSCLC) in tumor progression. Exosomal miR-1260b induced angiogenesis by targeting homeodomain-interacting protein kinase-2 (HIPK2) in human umbilical vein endothelial cells (HUVECs). Furthermore, exosomal miR-1260b or suppression of HIPK2 led to enhanced cellular mobility and cisplatin resistance in NSCLC cells. In patients with NSCLC, the level of HIPK2 was significantly lower in tumor tissues than in normal lung tissues, while that of miR-1260b was higher in tumor tissues. HIPK2 and miR-1260b expression showed an inverse correlation, and this correlation was strong in distant metastasis. Finally, the expression level of exosomal miR-1260b in plasma was higher in patients with NSCLC than in healthy individuals, and higher levels of exosomal miR-1260b were associated with high-grade disease, metastasis, and poor survival. In conclusion, exosomal miR-1260b can promote angiogenesis in HUVECs and metastasis of NSCLC by regulating HIPK2 and may serve as a prognostic marker for lung cancers.

Estrogen-related receptor-gamma influences Helicobacter pylori infection by regulating TFF1 in gastric cancer.

Helicobacter pylori infection is a crucial factor in the development of gastric cancer (GC). Molecular therapeutic targets and mechanisms contributing to H. pylori infection-associated GC induction are poorly understood and this study aimed to fill that research gap. We found that the nuclear receptor estrogen-related receptor gamma (ESRRG) is a candidate factor influencing H. pylori infection-driven GC. ESRRG suppressed H. pylori infection and cell growth induced by H. pylori infection in GC cells and organoid models In addition, H. pylori infection downregulates ESRRG expression. Gene expression profiling revealed that trefoil factor 1 (TFF1), a well-known tumor suppressor in GC, is a downstream target of ESRRG. Mechanistically, ESRRG directly binds to the TFF1 promoter and induces TFF1 gene expression. Furthermore, TFF1 activation by ESRRG was inhibited by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/p65, which is induced by inflammation, such as by H. pylori infection. Our current study provides new molecular insights into how ESRRG regulates H. pylori infection, contributing to GC development. We suggest that modulation of ESRRG-suppressing H. pylori infection could be a therapeutic target for the treatment of GC patients.

Efficacy of the CDK7 Inhibitor on EMT-Associated Resistance to 3rd Generation EGFR-TKIs in Non-Small Cell Lung Cancer Cell Lines.

Epithelial to mesenchymal transition (EMT) is associated with resistance during EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Here, we investigated whether EMT is associated with acquired resistance to 3rd generation EGFR-TKIs, and we explored the effects of cyclin-dependent kinase 7 (CDK7) inhibitors on EMT-mediated EGFR-TKIs resistance in non-small cell lung cancer (NSCLC). We established 3rd generation EGFR-TKI resistant cell lines (H1975/WR and H1975/OR) via repeated exposure to WZ4002 and osimertinib. The two resistant cell lines showed phenotypic changes to a spindle-cell shape, had a reduction of epithelial marker proteins, an induction of vimentin expression, and enhanced cellular mobility. The EMT-related resistant cells had higher sensitivity to THZ1 than the parental cells, although THZ1 treatment did not inhibit EGFR activity. This phenomenon was also observed in TGF-ß1 induced EMT cell lines. THZ1 treatment induced G2/M cell cycle arrest and apoptosis in all of the cell lines. In addition, THZ1 treatment led to drug-tolerant, EMT-related resistant cells, and these THZ1-tolerant cells partially recovered their sensitivity to 3rd generation EGFR-TKIs. Taken together, EMT was associated with acquired resistance to 3rd generation EGFR-TKIs, and CDK7 inhibitors could potentially be used as a therapeutic strategy to overcome EMT associated EGFR-TKI resistance in NSCLC.

Epigenetic regulation of miR-29a/miR-30c/DNMT3A axis controls SOD2 and mitochondrial oxidative stress in human mesenchymal stem cells.

The use of human mesenchymal stem cells (hMSCs) in clinical applications requires large-scale cell expansion prior to administration. However, the prolonged culture of hMSCs results in cellular senescence, impairing their proliferation and therapeutic potentials. To understand the role of microRNAs (miRNAs) in regulating cellular senescence in hMSCs, we globally depleted miRNAs by silencing the DiGeorge syndrome critical region 8 (DGCR8) gene, an essential component of miRNA biogenesis. DGCR8 knockdown hMSCs exhibited severe proliferation defects and senescence-associated alterations, including increased levels of reactive oxygen species (ROS). Transcriptomic analysis revealed that the antioxidant gene superoxide dismutase 2 (SOD2) was significantly downregulated in DGCR8 knockdown hMSCs. Moreover, we found that DGCR8 silencing in hMSCs resulted in hypermethylation in CpG islands upstream of SOD2. 5-aza-2'-deoxycytidine treatment restored SOD2 expression and ROS levels. We also found that these effects were dependent on the epigenetic regulator DNA methyltransferase 3 alpha (DNMT3A). Using computational and experimental approaches, we demonstrated that DNMT3A expression was regulated by miR-29a-3p and miR-30c-5p. Overexpression of miR-29a-3p and/or miR-30c-5p reduced ROS levels in DGCR8 knockdown hMSCs and rescued proliferation defects, mitochondrial dysfunction, and premature senescence. Our findings provide novel insights into hMSCs senescence regulation by the miR-29a-3p/miR-30c-5p/DNMT3A/SOD2 axis.

RNA-binding protein NONO contributes to cancer cell growth and confers drug resistance as a theranostic target in TNBC.

Breast cancer (BC) is one of the most common cancers in women. TNBC (Triple-negative breast cancer) has limited treatment options and still lacks viable molecular targets, leading to poor outcomes. Recently, RNA-binding proteins (RBPs) have been shown to play crucial roles in human cancers, including BC, by modulating a number of oncogenic phenotypes. This suggests that RBPs represent potential molecular targets for BC therapy. Methods: We employed genomic data to identify RBPs specifically expressed in TNBC. NONO was silenced in TNBC cell lines to examine cell growth, colony formation, invasion, and migration. Gene expression profiles in NONO-silenced cells were generated and analyzed. A high-throughput screening for NONO-targeted drugs was performed using an FDA-approved library. Results: We found that the NONO RBP is highly expressed in TNBC and is associated with poor patient outcomes. NONO binds to STAT3 mRNA, increasing STAT3 mRNA levels in TNBC. Surprisingly, NONO directly interacts with STAT3 protein increasing its stability and transcriptional activity, thus contributing to its oncogenic function. Importantly, high-throughput drug screening revealed that auranofin is a potential NONO inhibitor and inhibits cell growth in TNBC. Conclusions: NONO is an RBP upstream regulator of both STAT3 RNA and protein levels and function. It represents an important and clinically relevant promoter of growth and resistance of TNBCs. NONO is also therefore a potential therapeutic target in TNBC.

Papillary Thyroid Cancer Tumor Spheres Cultured by Passaging Without Sorting Exhibit Cancer Stemness.

AIM: Cancer stem-like cell (CSC) markers and the role of CSCs derived from papillary thyroid carcinoma (PTC) in pathogenesis are unclear. This study aimed to investigate CSC properties using tumor spheres from passaged PTC cells but without sorting CSCs. MATERIALS AND METHODS: To identify the properties of CSCs derived from PTC, the expression of SRY-box transcription factor 2(SOX2), octamer-binding transcription factor 4 (OCT4), Nanog homeobox (NANOG), thyroglobulin (TG), thyroid-stimulating hormone receptor (TSHR), E-cadherin, YES-associated protein 1 (YAP1), and signal transducer and activator of transcription 3 (STAT3) was investigated in tumor spheres serially passaged without sorting CSCs. RESULTS: The cultured tumor spheres had cancer stemness; high expression of OCT4, SOX2, NANOG, and YAP1; low expression of E-cadherin; and varied expression of TG, TSHR, and STAT3. PTC tumor spheres transfected with small interfering RNA targeting YAP1 had fewer CSC properties than the non-transfected tumor spheres did. CONCLUSION: Tumor spheres derived from PTC cells by passaging without sorting CSCs have more stem-like cell properties, and less differentiation potential. Thus, this simple and cost-effective method can be used for the enrichment of PTC stemness for employment in cell-based models, reducing the need for use of animal models.

Prognostic model based on the geriatric nutritional risk index and sarcopenia in patients with diffuse large B-cell lymphoma.

BACKGROUND: Systemic inflammation and cachexia are associated with adverse clinical outcomes in diffuse large B-cell lymphoma (DLBCL). The Geriatric Nutritional Risk Index (GNRI) is one of the main parameters used to assess these conditions, but its efficacy in DLBCL is inconclusive. METHODS: We retrospectively reviewed 228 DLBCL patients who were treated with R-CHOP immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). The patients were stratified according to GNRI score (> 98, 92 to 98, 82 to < 92, and < 82) as defined in previous studies. Additionally, the extent of sarcopenia was categorized as sarcopenia-both, sarcopenia-L3/PM alone, and non-sarcopenia-both according to skeletal muscle index. RESULTS: Survival curves plotted against a combination of GNRI and sarcopenia scores revealed two clear groups as follows: high cachexia risk (HCR) group (GNRI < 82, sarcopenia-both, or GNRI 82-92 with sarcopenia-L3/PM alone) and low cachexia risk (LCR) group (others). The HCR group had a lower complete response rate (46.5% vs. 86.6%) and higher frequency of treatment-related mortality (19.7% vs. 3.8%) and early treatment discontinuation (43.7% vs. 8.3%) compared with the LCR group. The median progression-free survival (PFS) (not reached vs. 10.3 months, p <  0.001) and overall survival (OS) (not reached vs. 12.9 months, p <  0.001) were much shorter in the HCR group than in the LCR group. On multivariable analyses, the HCR group was shown to be an independent negative prognostic factor for PFS and OS after adjusting the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI). CONCLUSIONS: A combined model of GNRI and sarcopenia may provide prognostic information independently of the NCCN-IPI in DLBCL.

Luminescent silicon nanoparticles for distinctive tracking of cellular targeting and trafficking.

Developing therapeutic nanoparticles that actively target disease cells or tissues by exploiting the binding specificity of receptors presented on the cell surface has extensively opened up biomedical applications for drug delivery and imaging. An ideal nanoparticle for biomedical applications is required to report confirmation of relevant targeting and the ultimate fate in a physiological environment for further verification, e.g. to adapt dosage or predict response. Herein, we demonstrate tracking of silicon nanoparticles through intrinsic photoluminescence (PL) during the course of cellular targeting and uptake. Time-resolved analysis of PL characteristics in cellular microenvironments provides dynamic information on the physiological conditions where the silicon nanoparticles are exposed. In particular, the PL lifetime of the silicon nanoparticles is in the order of microseconds, which is significantly longer than the nanosecond lifetimes exhibited by fluorescent molecules naturally presented in cells, thus allowing discrimination of the nanoparticles from the cellular background autofluorescence in time-gated imaging. The PL lifetime is a physically intensive property that reports the inherent characteristics of the nanoparticles regardless of surrounding noise. Furthermore, we investigate a unique means to inform the lifespan of the biodegradable silicon nanoparticles responsive to local microenvironment in the course of endocytosis. A multivalent strategy of nanoparticles for enhanced cell targeting is also demonstrated with complementary analysis of time-resolved PL emission imaging and fluorescence correlation spectroscopy. The result presents the promising potential of the photoluminescent silicon nanoparticles toward advanced cell targeting systems that simultaneously enable tracking of cellular trafficking and tissue microenvironment monitoring.

Photoluminescent and biodegradable porous silicon nanoparticles for biomedical imaging.

Porous silicon nanoparticles (PSiNPs) have attracted increasing interest as biomedical probes for drug delivery and imaging. In particular, a set of unique properties including biodegradability, intrinsic photoluminescence, and favorable mesoporous structure providing high drug loading allow PSiNPs to address current challenges of translational nanomedicine. In this review, the important features of PSiNPs considered as a biomedical imaging probe will be concisely discussed along with recent advances in fabrication and theranostic applications. Firstly, an overview of PSiNP fabrication with controllable geometry through top-down or bottom-up strategies is provided. Next, intrinsic photoluminescence, the key element allowing application of PSiNPs as an imaging agent, is highlighted with near-infrared emission and micro-second scale lifetime. Emerging technologies for biodegradable nanomedicine based on PSiNPs are then presented. Advances of PSiNPs for disease treaments including photodynamic and photothermal therapeutics are also discussed to open up potential translational medical strategies. In addition, the versatile surface chemistry and modification of PSiNPs in the context of biomedical applications are extensively discussed. Overall, the promising characteristics of PSiNPs encourage further exploration for biomedical research and translational medical platforms, particularly in biomedical imaging.

Priming with Toll-like receptor 3 agonist or interferon-gamma enhances the therapeutic effects of human mesenchymal stem cells in a murine model of atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease. Great efforts have been recently made to treat AD using mesenchymal stem cells (MSCs), which have immunomodulatory functions. However, the immunomodulatory effects of MSCs need to be enhanced for clinical application in the treatment of AD. OBJECTIVES: To evaluate and characterise the therapeutic effects of human Wharton's jelly-derived MSCs (WJ-MSCs) primed with the Toll-like receptor 3 agonist poly I:C or interferon-γ (IFN-γ) in a murine model of AD. METHODS: Mice were treated with Aspergillus fumigatus extract to induce AD and then subcutaneously injected with non-primed, poly I:C-primed or IFN-γ-primed WJ-MSCs. Clinical symptom scores, transepidermal water loss (TEWL), histological characteristics and cytokine levels were determined. Transcriptome profiling and pathway analyses of primed WJ-MSCs were conducted. RESULTS: The clinical symptom score and TEWL in skin lesions were reduced in mice administered non-primed and primed WJ-MSCs. Epidermal thickness and inflammatory cell infiltration in skin lesions were reduced more in mice administered primed WJ-MSCs than in mice administered non-primed WJ-MSCs. Secretion of interleukin-17 was significantly reduced in skin draining lymph nodes of mice administered primed WJ-MSCs. Genomics and bioinformatics analyses demonstrated the enrichment of certain pathways specifically in WJ-MSCs primed with poly I:C or IFN-γ. CONCLUSIONS: Priming with poly I:C- or IFN-γ improved the therapeutic effects of WJ-MSCs in a murine model of AD. This study suggests that priming with poly I:C or IFN-γ enhances the immunomodulatory functions of WJ-MSCs and can be used as a novel therapeutic approach for AD.

Clinical impact of prognostic nutritional index in diffuse large B cell lymphoma.

We evaluated the association between the prognostic nutritional index (PNI) and the clinical features of diffuse large B cell lymphoma (DLBCL) and developed a novel prognostic model using a nomogram including the PNI and other biomarkers for cancer cachexia. A total of 228 DLBCL patients treated with first-line R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) were retrospectively reviewed. PNI was calculated as 10 × serum levels of albumin (g/dL) + 0.005 × absolute lymphocyte count (/mm3). Patients were categorized into low- and high-PNI groups based on a cut-off value of 40. The nomogram for predicting overall survival (OS) was constructed using a Cox regression model. PNI was positively correlated with skeletal muscle index, body mass index, and serum levels of albumin. The low-PNI group had a lower complete response rate (60.3% vs. 87.6%), increased treatment-related toxicity, and more frequent treatment discontinuation (43.5% vs. 8.8%) than the high-PNI group. The median OS was shorter in the low-PNI group than the high-PNI group (15.6 months vs. not reached; p < 0.001). Multivariate Cox regression analyses showed that PNI, sarcopenia, and the international prognostic index (IPI) were independent prognostic factors for OS. The nomogram developed using this regression model showed excellent discriminatory ability for predicting OS (c-index, 0.80) compared to the IPI alone (c-index, 0.75). Low PNI was associated with adverse clinical features of DLBCL. The proposed nomogram supports the clinical impact of cachexia on survival and may contribute to individualized therapy in DLBCL.

Anti-metastatic effect of metformin via repression of interleukin 6-induced epithelial-mesenchymal transition in human colon cancer cells.

Metformin, a first-line drug used to treat type 2 diabetes, has also been shown to have anticancer effects against a variety of malignancies, including colorectal cancer. Although inhibition of the mTOR pathway is known to be the most important mechanism for the antitumor effects of metformin, other mechanisms remain unclear. The purpose of this study was to identify the antitumor mechanism of metformin in colorectal cancer using high-throughput data, and then test the mechanism experimentally. We identified the gene signature of metformin-treated colon cancer cells. This signature was processed for prediction using colon adenocarcinoma patient data from the Cancer Genome Atlas to classify the patients showing a gene expression pattern similar to that in metformin-treated cells. This patient group showed better overall and disease-free survival. Furthermore, pathway analysis revealed that the metformin-predicted group was characterized by decreased interleukin (IL)-6 pathway signaling, epithelial-mesenchymal transition, and colon cancer metastatic signaling. We induced epithelial-mesenchymal transition in colon cancer cell lines via IL-6 treatment, which increased cell motility and promoted invasion. However, these effects were blocked by metformin. These findings suggest that blockade of IL-6-induced epithelial-mesenchymal transition is an antitumor mechanism of metformin.