Protective effect of zinc oxide nanoparticles synthesized using Cassia alata for DSS-induced ulcerative colitis in mice model.

The most prevalent form of inflammatory bowel disease (IBD), ulcerative colitis (UC), is characterized by persistent inflammation of the colorectal mucosa. It is asymptomatic, whereas Crohn's disease (CD) causes patchy lesions in the gastrointestinal tract. Men and women suffer equally from ulcerative colitis, which usually strikes in the second and third decades of life and becomes more common in senior citizens. In the present study, we produced zinc oxide nanoparticles using the natural herbal plant, Cassia alata. Zinc oxide nanoparticles have remarkable antimicrobial and antitumor benefits in the field of biomedical science. Furthermore, the synthesized zinc oxide nanoparticles (ZnO NPs) were characterized using UV, XRD, FTIR, and SEM analyses. The XRD analysis confirmed the crystallite nature and purity of the synthesized nanoparticles. Zinc oxide nanoparticles with a uniform size and partially agglomerated morphology were verified by SEM analysis. We investigated the protective effects of environmentally friendly zinc oxide nanoparticles in dextran sodium sulfate-induced ulcerative colitis mouse models. Green synthesized Cassia alata zinc oxide nanoparticles (CA ZnO NPs) reversed weight loss, disease activity index, colon shortening, and colon histological damage. Zinc oxide nanoparticles reduce hypersensitivity, oxidative stress, and inflammation, and protect the mucosal layer. Green synthesized CA ZnO NPs demonstrated protection against dextran sodium sulfate-induced ulcerative colitis via anti-inflammatory activity.

CAR T cells vs bispecific antibody as third- or later-line large B-cell lymphoma therapy: a meta-analysis.

ABSTRACT: This meta-analysis evaluates the efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We searched MEDLINE, Embase, and Cochrane databases until July 2023 for trials assessing CAR T-cell therapies and CD20×CD3 bispecific antibodies as third or subsequent lines in R/R DLBCL. Random-effects models estimated the complete response (CR) rate and secondary outcomes, with meta-regressions adjusting for relevant covariates. Sixteen studies comprising 1347 patients were included in the pooled analysis. The pooled CR rate for bispecific antibodies was 0.36 (95% confidence interval [CI], 0.29-0.43), compared with 0.51 (95% CI, 0.46-0.56) for CAR T-cell therapy (P < .01). This superiority persisted when comparing the CAR T-cell-naive patients within the bispecific antibody group, with a CR rate of 0.37 (95% CI, 0.32-0.43). Multivariable meta-regression also revealed better efficacy of CAR T cells with adjustment for the proportion of double-hit lymphoma. The pooled 1-year progression-free survival rate mirrored these findings (0.32 [95% CI, 0.26-0.38] vs 0.44 [95% CI, 0.41-0.48]; P < .01). For adverse events of grade ≥3, the bispecific antibody had incidences of 0.02 (95% CI, 0.01-0.04) for cytokine release syndrome, 0.01 (95% CI, 0.00-0.01) for neurotoxicity, and 0.10 (95% CI, 0.03-0.16) for infections. The CAR T cell had rates of 0.08 (95% CI, 0.03-0.12), 0.11 (95% CI, 0.06-0.17), and 0.17 (95% CI, 0.11-0.22), respectively, with significant differences observed in the first 2 categories. In summary, CAR T-cell therapy outperformed bispecific antibody in achieving higher CR rates, although with an increase in severe adverse events.

ThermOxshield ion pair self assembly unleashing suppressed release.

Poly (acrylic acid) (PAA), an anionic polymer was used to prepare ion pair self-assembly (IPSAM) with 4-(methylthio)aniline (MTA), a hydrophobic counter ion, which is responsive to temperature and oxidation. The IPSAM was formed when the carboxylic to amino group molar ratio was 7/3-5/5. The structure of the IPSAM nanoparticle was spherical whose diameter was 30-40 nm on the TEM images. The PAA/MTA ion pair showed the upper critical solution temperature (UCST) that hiked with increasing MTA content. When the MTA of the ion pair was oxidized by H2O2, the UCST was also increased. The amphiphilic property of the ion pair was responsible for interface activity which declined upon the oxidation of the MTA. The surface tension was low for the ratio of PAA/MTA (5/5), which made the 5/5 ratio suitable for further studies. The interaction between PAA and MTA, which was ionic, and the oxidation of MTA was confirmed by FT-IR spectroscopy. The release of payload (i.e. Nile red) in IPSAM was restrained below the UCST but it was triggered above the phase transition temperature possibly due to the disintegration of the IPSAM whereas on MTA oxidation the release was shielded due to more hydrophobicity. The release was found to be higher in tumor environment temperature which could be controlled with the input concentration of H2O2 giving a stable IPSAM. The cell viability results showed that IPSAM has no significant cytotoxicity and can serve as a drug carrier for stimulus-response.

Phytochemical Investigation of Equisetum arvense and Evaluation of Their Anti-Inflammatory Potential in TNFα/INFγ-Stimulated Keratinocytes.

Equisetum arvense L. (Equisetaceae), widely known as 'horsetail', is a perennial plant found extensively across Asia. Extracts of E. arvense have been used in traditional medicine, particularly for the treatment of inflammatory disorders. This study aimed to determine the phytochemical compounds in E. arvense ethanolic extract and their anti-inflammatory properties. Subsequently, we isolated and identified nine secondary metabolites, including kaempferol 3,7-di-O-ß-D-glucopyranoside (1), icariside B2 (2), (Z)-3-hexenyl ß-D-glucopyranoside (3), luteolin 5-O-ß-D-glucopyranoside (4), 4-O-ß-D-glucopyranosyl caffeic acid (5), clemastanin B (6), 4-O-caffeoylshikimic acid (7), (7S,8S)-threo-7,9,9'-trihydroxy-3,3'-dimethoxy-8-O-4'-neolignan-4-O-ß-D-glucopyranoside (8), and 3-O-caffeoylshikimic acid (9). The chemical structures of the isolated compounds (1-9) were elucidated using HR-ESI-MS data, NMR spectra, and ECD data. Next, the anti-inflammatory effects of the isolates were evaluated in tumor necrosis factor (TNF)α/interferon (IFN)γ-induced HaCaT, a human keratinocyte cell line. Among the isolates, compound 3 showed the highest inhibitory effect on the expression of pro-inflammatory chemokines, followed by compounds 6 and 8. Correspondingly, the preceding isolates inhibited TNFα/IFNγ-induced activation of pro-inflammatory transcription factors, signal transducer and activator of transcription 1, and nuclear factor-κB. Collectively, E. arvense could be employed for the development of prophylactic or therapeutic agents for improving dermatitis.

Ca2+-Permeable TRPV1 Receptor Mediates Neuroprotective Effects in a Mouse Model of Alzheimer's Disease via BDNF/CREB Signaling Pathway.

Transient receptor potential vanilloid 1 (TRPV1) protein is a Ca2+-permeable non-selective cation channel known for its pain modulation pathway. In a previous study, it was discovered that a triple-transgenic Alzheimer's disease (AD) mouse model (3xTg-AD+/+) has anti-AD effects. The expression of proteins in the brain-derived neurotrophic factor (BDNF)/cAMP response element binding protein (CREB) pathway in a 3xTg-AD/TRPV1 transgenic mice model was investigated to better understand the AD regulatory effect of TRPV1 deficiency. The results show that TRPV1 deficiency leads to CREB activation by increasing BDNF levels and promoting phosphorylation of tyrosine receptor kinase B (TrkB), extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and CREB in the hippocampus. Additionally, TRPV1 deficiency-induced CREB activation increases the antiapoptotic factor B-cell lymphoma 2 (Bcl-2) gene, which consequently downregulates Bcl-2-associated X (Bax) expression and decreases cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP), which leads to the prevention of hippocampal apoptosis. In conclusion, TRPV1 deficiency exhibits neuroprotective effects by preventing apoptosis through the BDNF/CREB signal transduction pathway in the hippocampus of 3xTg-AD mice.

Efficacy of Salvage Treatments in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Including Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review and Meta-Analysis.

PURPOSE: We intend to evaluate the efficacy of salvage treatments for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) through meta-analysis. Materials and Methods: R/R DLBCL trials were divided into two groups based on eligibility for autologous stem-cell transplantation (ASCT), and meta-analysis of each group was performed. Random effects models were used to estimate the 1-year progression-free survival (PFS) rate, and chimeric antigen receptor (CAR) T-cell therapy was used as reference treatment. RESULTS: Twenty-six ASCT-eligible cohorts from 17 studies comprising 2,924 patients and 59 ASCT-ineligible cohorts from 53 studies comprising 3,617 patients were included in the pooled analysis. In the ASCT-eligible group, the pooled 1-year PFS rate was 0.40 (95% confidence interval [CI], 0.15 to 0.65) for the CAR T-cell group and 0.34 (95% CI, 0.30 to 0.37) for the group with chemotherapy followed by ASCT intention. The two treatments were not significantly different in meta-regression analysis. In the ASCT-ineligible group, the pooled 1-year PFS was 0.40 (95% CI, 0.35 to 0.46) for CAR T-cell, and the highest primary outcome was 0.47 (95% CI, 0.37 to 0.57) for the tafasitamab group. CAR T-cell therapy showed significantly better outcomes than chemotherapy and therapies based on ibrutinib, lenalidomide, and selinexor. However, loncastuximab, polatuzumab plus bendamustine and rituximab, and the tafasitamab group showed no different efficacy than CAR T-cell therapy after adjusting for median number of previous lines of treatment. CONCLUSION: Although several regimens were crudely grouped for classification, CAR T-cell therapy did not outperform chemotherapy followed by ASCT in the second-line setting or several recently developed agents in the ASCT-ineligible setting.

Synergistic therapeutic combination with a CAF inhibitor enhances CAR-NK-mediated cytotoxicity via reduction of CAF-released IL-6.

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) contribute to an impaired functionality of natural killer (NK) cells that have emerged as a promising therapeutic modality. The interaction between CAFs and NK cells within the TME exerts major inhibitory effects on immune responses, indicating CAF-targeted therapies as potential targets for effective NK-mediated cancer killing. METHODS: To overcome CAF-induced NK dysfunction, we selected an antifibrotic drug, nintedanib, for synergistic therapeutic combination. To evaluate synergistic therapeutic efficacy, we established an in vitro 3D Capan2/patient-derived CAF spheroid model or in vivo mixed Capan2/CAF tumor xenograft model. The molecular mechanism of NK-mediated synergistic therapeutic combination with nintedanib was revealed through in vitro experiments. In vivo therapeutic combination efficacy was subsequently evaluated. Additionally, the expression score of target proteins was measured in patient-derived tumor sections by the immunohistochemical method. RESULTS: Nintedanib blocked the platelet-derived growth factor receptor ß (PDGFRß) signaling pathway and diminished the activation and growth of CAFs, markedly reducing CAF-secreted IL-6. Moreover, coadministration of nintedanib improved the mesothelin (MSLN) targeting chimeric antigen receptor-NK-mediated tumor killing abilities in CAF/tumor spheroids or a xenograft model. The synergistic combination resulted in intense NK infiltration in vivo. Nintedanib alone exerted no effects, whereas blockade of IL-6 trans-signaling ameliorated the function of NK cells. The combination of the expression of MSLN and the PDGFRß+-CAF population area, a potential prognostic/therapeutic marker, was associated with inferior clinical outcomes. CONCLUSION: Our strategy against PDGFRß+-CAF-containing pancreatic cancer allows improvements in the therapy of pancreatic ductal adenocarcinoma.

Aruncus dioicus var. kamtschaticus Extract Ameliorates Psoriasis-like Skin Inflammation via Akt/mTOR and JAK2/STAT3 Signaling Pathways in a Murine Model.

Goat's beard (Aruncus dioicus var. kamtschaticus) is a traditional medicinal plant, widely used in Chinese and Korean traditional medicine because of its anti-inflammatory, anti-oxidant, antimicrobial, and anti-cancer activity. However, its effect on skin inflammatory diseases like psoriasis is unknown. The aim of this study was to investigate the therapeutic potency of A. dioicus extract (ADE) in in vitro and in vivo psoriasis models. ADE treatment significantly attenuated skin inflammation and improved skin integrity in imiquimod-treated mice by suppressing keratinocyte hyperproliferation, inhibiting the infiltration of immune cells, and downregulating the expression of psoriatic markers. Further, ADE treatment suppressed protein kinase B/mammalian target of rapamycin (Akt/mTOR) and Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) signaling in HaCaT cells. Overall, the application of ADE relieves psoriasis-like skin inflammation possibly by regulating the Akt/mTOR and JAK2/STAT3 signaling pathways, making it an effective alternative for psoriasis therapy.

Meyeroguilline E, a New Isoindolinone Alkaloid from the Poisonous Mushroom Chlorophyllum molybdites, and Identification of Compounds with Multidrug Resistance (MDR) Reversal Activities.

Three isoindolinone alkaloids (1-3), including one new isoindolinone-type alkaloid, meyeroguilline E (1), and six other known compounds (4-9) were isolated from the poisonous mushroom Chlorophyllum molybdites (Agaricaceae). The structure of the new compound was determined using extensive spectroscopic analyses via one-dimensional (1D) and two-dimensional (2D) NMR data interpretation and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). To the best of our knowledge, compound 1 is the first example of a natural isoindolinone with a butanoic acid moiety, and this study is the first to detect the other known compounds (2-9) in C. molybdites. The isolated compounds (1-9) were examined for their multidrug resistance (MDR) reversal activity against MES-SA, MES-SA/DX5, HCT15, and HCT15/CL02 human cancer cells. Based on the results, 20 µM of compounds 3 and 6 slightly potentiated paclitaxel (TAX)-induced cytotoxicity in MES-SA/DX5, HCT15, and HCT15/CL02 cells; however, the compounds had no effect on the cytotoxicity against MES-SA and nonMDR cells.

Antitumor Potential of Withanolide Glycosides from Ashwagandha (Withania somnifera) on Apoptosis of Human Hepatocellular Carcinoma Cells and Tube Formation in Human Umbilical Vein Endothelial Cells.

Hepatocellular carcinoma (HCC) is the fastest-growing tumor capable of spreading to other organs via blood vessels formed by endothelial cells. Apoptosis and angiogenesis-targeting therapies are attractive for cancer treatment. In this study, we aimed to study the in vitro cytotoxicity of Withania somnifera against human HCC (HepG2) cells, identify potential antitumoral withanolide glycosides from the active fraction, and elucidate cytotoxic molecular mechanisms of identified bioactive compounds. W. somnifera (Solanaceae), well-known as 'ashwagandha', is an Ayurvedic medicinal plant used to promote health and longevity, and the MeOH extract of W. somnifera root exhibited cytotoxicity against HepG2 cells during initial screening. Bioactivity-guided fractionation of the MeOH extract and subsequent phytochemical investigation of the active n-BuOH-soluble fraction resulted in the isolation of five withanolide glycosides (1-5), including one new metabolite, withanoside XIII (1), aided by liquid chromatography-mass spectrometry-based analysis. The new compound structure was determined by 1D and 2D nuclear magnetic resonance spectroscopy, high-resolution electrospray ionization mass spectroscopy, electronic circular dichroism, and enzymatic hydrolysis. In addition, withanoside XIIIa (1a) was identified as the new aglycone (1a) of 1. Isolated withanolide glycosides 1-5 and 1a were cytotoxic toward HepG2 cells; withagenin A diglucoside (WAD) (3) exhibited the most potent cytotoxicity against HepG2 cells, with cell viability less than 50% at 100 µM. WAD cytotoxicity was mediated by both extrinsic and intrinsic apoptosis pathways. Treatment with WAD increased protein expression levels of cleaved caspase-8, cleaved caspase-9, cleaved caspase-3, Bcl-2-associated X protein (Bax), and cleaved poly(ADP-ribose) polymerase (cleaved PARP) but decreased expression levels of B-cell lymphoma 2 (Bcl-2). Moreover, WAD inhibited tubular structure formation in human umbilical vein endothelial cells (HUVECs) by inhibiting the protein expression of vascular endothelial growth factor receptor 2 and its downstream pathways, including extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). These effects were also enhanced by co-treatment with ERK and PI3K inhibitors. Overall, these results indicate that WAD (3) induced HepG2 apoptosis and inhibited HUVEC tube formation, suggesting its potential application in treating liver cancers.

KLHL3 deficiency in mice ameliorates obesity, insulin resistance, and nonalcoholic fatty liver disease by regulating energy expenditure.

Obesity is a growing global epidemic that can cause serious adverse health consequences, including insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). Obesity development can be attributed to energy imbalance and metabolic inflexibility. Here, we demonstrated that lack of Kelch-like protein 3 (KLHL3) mitigated the development of obesity, IR, and NAFLD by increasing energy expenditure. KLHL3 mutations in humans cause Gordon's hypertension syndrome; however, the role of KLHL3 in obesity was previously unknown. We examined differences in obesity-related parameters between control and Klhl3-/- mice. A significant decrease in body weight concomitant with fat mass loss and improved IR and NAFLD were observed in Klhl3-/- mice fed a high-fat (HF) diet and aged. KLHL3 deficiency inhibited obesity, IR, and NAFLD by increasing energy expenditure with augmentation of O2 consumption and CO2 production. Delivering dominant-negative (DN) Klhl3 using adeno-associated virus into mice, thereby dominantly expressing DN-KLHL3 in the liver, ameliorated diet-induced obesity, IR, and NAFLD. Finally, adenoviral overexpression of DN-KLHL3, but not wild-type KLHL3, in hepatocytes revealed an energetic phenotype with an increase in the oxygen consumption rate. The present findings demonstrate a novel function of KLHL3 mutation in extrarenal tissues, such as the liver, and may provide a therapeutic target against obesity and obesity-related diseases.

Thermo-sensitive self-assembly of poly(ethylene imine)/(phenylthio) acetic acid ion pair in surfactant solutions.

Poly(ethylene imine)/(phenylthio) acetic acid (PEI/PTA) ion pairs exhibited an upper critical solution temperature (UCST) behavior in an aqueous solution and the UCST was higher as the PTA content was more. The UCST of the ion pair decreased with increasing Brij S100 (BS 100, a nonionic surfactant) concentration but increased with increasing cetylpridinium chloride (CPC, a cationic surfactant) and sodium lauroylsarcosinate (SLS, an anionic surfactant) concentration. TEM microscopy demonstrated BS 100 markedly reduced the size of PEI/PTA ion pair self-assembly (IPSAM) whereas CPC and SLS had little effect on the size and the integrity of IPSAM. 1H NMR spectroscopy showed the hydrophobic interaction among the phenyl groups of PEI/PTA ion pairs took place. It also demonstrated the hydrophobic interaction between BS 100 and PTA and the electrostatic interaction between CPC and PTA and between SLS and PEI occurred. X-ray photoelectron spectroscopy disclosed the PTA of PEI/PTA IPSAM could be readily oxidized by H2O2 even at a low concentration (e.g. 0.005%). IPSAM released its payload (i.e. nile red) in a temperature and oxidation-responsive manner. The surfactants (i.e. BS 100, CPC, and SLS) suppressed the thermally triggered release in a different way. The effectiveness of the surfactant to suppress the release was in the order of BS 100 > CPC > SLS. IPSAM released its content more extensively as H2O2 (an oxidizing agent) concentration was higher. The ionic surfactants (i.e. CPS and SLS) had little effect on the oxidation-induced release degree but the nonionic surfactant (BS 100) markedly suppressed the release degree.

Next-generation engineered nanogold for multimodal cancer therapy and imaging: a clinical perspectives.

Cancer is one of the significant threats to human life. Although various latest technologies are currently available to treat cancer, it still accounts for millions of death each year worldwide. Thus, creating a need for more developed and novel technologies to combat this deadly condition. Nanoparticles-based cancer therapeutics have offered a promising approach to treat cancer effectively while minimizing adverse events. Among various nanoparticles, nanogold (AuNPs) are biocompatible and have proved their efficiency in treating cancer because they can reach tumors via enhanced permeability and retention effect. The size and shape of the AuNPs are responsible for their diverse therapeutic behavior. Thus, to modulate their therapeutic values, the AuNPs can be synthesized in various shapes, such as spheres, cages, flowers, shells, prisms, rods, clusters, etc. Also, attaching AuNPs with single or multiple targeting agents can facilitate the active targeting of AuNPs to the tumor tissue. The AuNPs have been much explored for photothermal therapy (PTT) to treat cancer. In addition to PTT, AuNPs-based nanoplatforms have been investigated for combinational multimodal therapies in the last few years, including photodynamic therapy, chemotherapy, radiotherapy, immunotherapy, etc., to ablate cancer cells. Thus, the present review focuses on the recent advancements in the functionalization of AuNPs-based nanoconstructs for cancer imaging and therapy using combinatorial multimodal approaches to treat various cancers.

Extract from Black Soybean Cultivar A63 Extract Ameliorates Atopic Dermatitis-like Skin Inflammation in an Oxazolone-Induced Murine Model.

Black soybean has been used in traditional medicine to treat inflammatory diseases, cancer, and diabetes and as a nutritional source since ancient times. We found that Korean black soybean cultivar A63 has more cyanidin-3-O-glucoside, (C3G), procyanidin B2 (PB2), and epicatechin (EPC) contents than other cultivars and has beneficial effects on cell viability and anti-oxidation. Given the higher concentration of anthocyanidins and their strong anti-oxidant activity, we predicted that A63 extract could relieve inflammatory disease symptoms, including those of atopic dermatitis (AD). Here, we evaluated the anti-AD activity of A63 extract in an oxazolone (OXA)-induced mouse model. A63 extract treatment significantly reduced epidermal thickness and inflammatory cell infiltration, downregulated the expression of AD gene markers, including Interleukin (IL)-4 and IL-5, and restored damaged skin barrier tissues. Furthermore, A63 extract influenced the activation of the signal transducer and activator of transcription (STAT) 3 and STAT6, extracellular regulatory kinase (ERK), and c-Jun N-terminal kinase (JNK) signaling pathways, which play a crucial role in the development of AD. Altogether, our results suggest that A63 can ameliorate AD-like skin inflammation by inhibiting inflammatory cytokine production and STAT3/6 and Mitogen-activated protein kinase (MAPK) signaling and restoring skin barrier function.

Hepatitis B virus X protein promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells by regulating SOCS1.

Hepatocellular carcinoma (HCC), a primary type of liver cancer, is one of the leading causes of cancer related deaths worldwide. HCC patients have poor prognosis due to intrahepatic and extrahepatic metastasis. Hepatitis B virus (HBV) infection is one of the major causes of various liver diseases including HCC. Among HBV gene products, HBV X protein (HBx) plays an important role in the development and metastasis of HCC. However, the mechanism of HCC metastasis induced by HBx has not been elucidated yet. In this study, for the first time, we report that HBx interacts with the suppressor of cytokine signaling 1 (SOCS1) which negatively controls NF-κB by degrading p65, a subunit of NF-κB. NF-κB activates the transcription of factors associated with epithelial-mesenchymal transition (EMT), a crucial cellular process associated with invasiveness and migration of cancer cells. Here, we report that HBx physically binds to SOCS1, subsequently prevents the ubiquitination of p65, activates the transcription of EMT transcription factors and enhance cell migration and invasiveness, suggesting a new mechanism of HBV-associated HCC metastasis. [BMB Reports 2022; 55(5): 220-225].

ERK inhibitor ASN007 effectively overcomes acquired resistance to EGFR inhibitor in non-small cell lung cancer.

The emergence of acquired resistance limits the long-term efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs). Thus, development of effective strategies to overcome resistance to EGFR TKI is urgently needed. Multiple mechanisms to reactivate ERK signaling have been successfully demonstrated in acquired resistance models. We found that in EGFR mutant non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR TKIs was accompanied by increased activation of ERK. Increased ERK activation was also found in in vitro models of acquired EGFR TKI resistance. ASN007 is a potent selective ERK1/2 inhibitor with promising antitumor activity in cancers with BRAF and RAS mutations. ASN007 treatment impeded tumor cell growth and the cell cycle in EGFR TKI-resistant cells. In addition, combination treatment with ASN007 and EGFR TKIs significantly decreased the survival of resistant cells, enhanced induction of apoptosis, and effectively inhibited the growth of erlotinib-resistant xenografts, providing the preclinical rationale for testing combinations of ASN007 and EGFR TKIs in EGFR-mutated NSCLC patients. This study emphasizes the importance of targeting ERK signaling in maintaining the long-term benefits of EGFR TKIs by overcoming acquired resistance.

Association of Smoking Status with Efficacy of First-line Immune Checkpoint Inhibitors in Advanced Non-small Cell Lung Cancers: A Systematic Review and Meta-analysis.

Background: Although smoking status has potential as a biomarker for immune checkpoint blockade in advanced non-small cell lung cancer (NSCLC), its clinical significance remains obscure. This meta-analysis aims to assess the impact of the smoking status on the efficacy of first-line immunotherapy and to find better treatment in never-smoker and ever-smoker patients. Methods: We searched the MEDLINE, EMBASE, and Cochrane database for trials comparing immunotherapy with conventional chemotherapy as front-line treatment for advanced NSCLC. Random-effects models were used to pool estimates of hazard ratios (HRs) for overall survival with 95% confidence intervals (CIs). Predefined subgroup analysis was performed to investigate the difference in the efficacy between the single checkpoint blockade and checkpoint inhibitor plus chemotherapy combination in the never-smokers and current/former smokers. Results: Twelve trials involving 6,446 patients were included in the analysis. A statistically significant overall survival benefit over conventional chemotherapy was found for both checkpoint inhibitor monotherapy (HR, 0.71; 95% CI, 0.59-0.85) and checkpoint inhibitor plus chemotherapy (HR, 0.75; 95% CI, 0.63-0.90) in the current/former smoker group. There was no subgroup difference between monotherapy and combination treatment (p=0.67). However, there was an inconsistent survival outcome in the never-smoker group; checkpoint blockade monotherapy did not show significantly better efficacy than chemotherapy alone (HR, 1.05; 95% CI, 0.81-1.37), but combination treatment showed an overall survival benefit (HR, 0.64; 95% CI, 0.43-0.94). A significant subgroup difference existed between monotherapy and combination therapy (p=0.04). Similarly, there was a significant difference in efficacy of monotherapy between the current/former smoker and never-smoker group (p=0.01), but the efficacy of the combination treatment was comparable between the two groups (p=0.45). Conclusion: Smoking status, which is easily available information, could be used as a guide in clinical practice to choose better treatment in the front-line setting for advanced NSCLC patients.

Preventive Effect of M. cochinchinensis on Melanogenesis via Tyrosinase Activity Inhibition and p-PKC Signaling in Melan-A Cell.

Whitening research is of particular interest in the cosmetics market. The main focus of whitening research is on melanogenesis inhibition through tyrosinase activity. The mechanism of melanogenesis is involved with tyrosinase activity and p-PKC signaling. In this study, we used Momordica cochinchinensis (Lour.) spreng, a tropical fruit found throughout Southeast Asia, to investigate the inhibitory effect of melanogenesis. M. cochinchinensis contains a high concentration of polyphenols, flavonoids, and unsaturated fatty acids, which might be related to antioxidant activity. This study aimed to determine whether M. cochinchinensis extracts inhibit melanin synthesis in melan-A cells by inhibiting tyrosinase activity and p-PKC signaling. M. cochinchinensis was divided into pulp and aril and extracted under various conditions, and it was confirmed that all pulp and aril extracts have high contents of both phenols and flavonoids. Melan-A cells were treated with PMA for three days to induce melanin synthesis. After PMA treatment, M. cochinchinensis extracts were added to cultured media in a dose-dependent manner. Melanin contents and MTS were used to determine the amount of melanin in live cells. M. cochinchinensis extracts were evaluated for their effects on tyrosinase activity and p-PKC signaling pathways by Western blotting. It was found that M. cochinchinensis extract treatment decreased the amount of melanin and suppressed p-PKC expression. Additionally, tyrosinase activity was reduced after M. cochinchinensis extract treatment in a dose-dependent manner. Therefore, it was concluded that M. cochinchinensis could be used in antimelanogenesis and functional cosmetic materials to improve whitening.

Comparison of first-line treatments of peripheral T-cell lymphoma according to regimen: A systematic review and meta-analysis.

Peripheral T-cell lymphomas (PTCLs) are known to have an aggressive clinical course and grave prognosis. Several recommended first-line treatment regimens are available, but identification of the superior treatment remain elusive. We conducted a systematic review and meta-analysis to determine which study-level factors and group of regimens affect survival outcomes. The MEDLINE, Embase, and Cochrane databases were searched from inception to January 2021, and phase II or III clinical studies evaluating the efficacy of chemotherapy regimens were included. Random effects models were used to estimate 3-year overall survival rate, complete remission rate, and subgroup differences. Meta-regressions were carried out with adjustments for relevant covariates. Overall, 34 cohorts from 28 studies comprising 1424 PTCL patients were included in the pooled analysis. Chemotherapy regimens were divided into four groups: cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), CHOP plus etoposide, gemcitabine-based, and others. The pooled 3-year overall survival rate was 0.49 (95% confidence interval [CI] 0.43-0.54) for CHOP, 0.61 (95% CI 0.52-0.70) for CHOP plus etoposide, 0.39 (95% CI 0.30-0.47) for gemcitabine-based, and 0.61 (95% CI 0.44-0.78) for others. CHOP plus etoposide was significantly better than CHOP, with the latter used as a reference (coefficient of 0.11; p = 0.035), with adjustment for the proportion of International Prognostic Index score 4-5 in meta-regression analysis. Although grossly divided groups were pooled and analyzed, among four regimen groups for frontline PTCL treatment CHOP plus etoposide showed better survival than CHOP.