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Simple Summary: There is still no effective treatment for advanced prostate cancer. CAR-T therapy is a promising approach; however, many obstacles remain for the treatment of solid tumors due to the complex physical barriers and inhibitory microenvironment in solid tumors. Single CAR-T therapy has a low response rate and a high recurrence rate. With the enhancement of CAR-T itself and the gradual improvement of the immune microenvironment, the number of CAR-T weapons against tumors is increasing. This article discusses the current status and future of CAR-T therapy for prostate cancer. We believe that the enhancement and modification of CAR-T or CAR-T combined with other therapies are expected to be a breakthrough in the treatment of prostate cancer. The incidence rate of prostate cancer is higher in male cancers. With a hidden initiation of disease and long duration, prostate cancer seriously affects men's physical and mental health. Prostate cancer is initially androgen-dependent, and endocrine therapy can achieve good results. However, after 18–24 months of endocrine therapy, most patients eventually develop castration-resistant prostate cancer (CRPC), which becomes metastatic castration resistant prostate cancer (mCRPC) that is difficult to treat. Chimeric Antigen Receptor T cell (CAR-T) therapy is an emerging immune cell therapy that brings hope to cancer patients. CAR-T has shown considerable advantages in the treatment of hematologic tumors. However, there are still obstacles to CAR-T treatment of solid tumors because the physical barrier and the tumor microenvironment inhibit the function of CAR-T cells. In this article, we review the progress of CAR-T therapy in the treatment of prostate cancer and discuss the prospects and challenges of armed CAR-T and combined treatment strategies. At present, there are still many obstacles in the treatment of prostate cancer with CAR-T, but when these obstacles are solved, CAR-T cells can become a favorable weapon for the treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

Context: Lignin has an immense potential for the production of lignin-based functional materials. In this work, effect of 2-chloro-ethyltrimethyl ammonium chloride (AC)-grafted alkali lignin (AL) on the morphologies in water was investigated by dissipative particle dynamics (DPD) simulations. The results showed that AL molecules formed spherical micelles, but the corresponding phenylpropane units of AL were randomly distributed in spherical micelles. However, AC-grafted modification of phenolic hydroxyl groups in AL led to the formation of multilamellar spherical micelles. The formation of multilamellar spherical micelles of AL mainly went through four stages: small clusters, larger aggregates with a core-shell structure, trilaminar, and multilamellar spherical micelles. AL molecules resulted in dimethomorph molecules being randomly distributed in the spherical micelle, while the dimethomorph molecules were perfectly entrapped into the spherical micelles of AC-grafted AL. Various molecular weights of AL had no effect on the formation and size of multilamellar spherical micelles. With increasing the content of AC-grafted AL, small clusters, multilamellar spherical micelles, tube-like, and lamellar aggregates were observed successively. This work highlights the potential of lignin to prepare monodispersed lignin-based functional colloidal spheres. Methods: Coarse-grained beads were performed energy minimization, geometric optimization, NPT ensemble (298 K and 1.0 bar), and NVT ensemble (298 K) calculations. DPD simulations were carried out at 300,000 steps in a 30×30×30 Rc3 cubic box with Materials Studio 7.0 program. [ABSTRACT FROM AUTHOR]

Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to recurrence as castration‐resistant PCa (CRPC), which has high mortality rates and lacks effective treatment modalities. The study confirms the presence of high glutathione peroxidase 4 (GPX4) expression, a key regulator of ferroptosis (i.e., iron‐dependent program cell death) in CRPC cells. Therefore, inducing ferroptosis in CRPC cells might be an effective therapeutic modality for CRPC. However, nonspecific uptake of ferroptosis inducers can result in undesirable cytotoxicity in major organs. Thus, to precisely induce ferroptosis in CRPC cells, a genetic engineering strategy is proposed to embed a prostate‐specific membrane antigen (PSMA)‐targeting antibody fragment (gy1) in the macrophage membrane, which is then coated onto mesoporous polydopamine (MPDA) nanoparticles to produce a biomimetic nanoplatform. The results indicate that the membrane‐coated nanoparticles (MNPs) exhibit high specificity and affinity toward CRPC cells. On further encapsulation with the ferroptosis inducers RSL3 and iron ions, MPDA/Fe/RSL3@M‐gy1 demonstrates superior synergistic effects in highly targeted ferroptosis therapy eliciting significant therapeutic efficacy against CRPC tumor growth and bone metastasis without increased cytotoxicity. In conclusion, a new therapeutic strategy is reported for the PSMA‐specific, CRPC‐targeting platform for ferroptosis induction with increased efficacy and safety. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the association between drug resistance and class I, II and III integrons in Acinetobacter baumannii (ABA). Multilocus sequence typing (MLST) is a tool used to analyze the homology among house-keeping gene clusters in ABA and ABA prevalence and further provides a theoretical basis for hospitals to control ABA infections. A total of 96 clinical isolates of non-repeating ABA were harvested, including 74 carbapenem-resistant ABA (CRABA) and 22 non-CRABA strains, and used for bacterial identification and drug susceptibility analysis. Variable regions were sequenced and analyzed. Then, 7 pairs of housekeeping genes were amplified and sequenced via MLST and sequence alignment was performed against the Pub MLST database to determine sequence types (STs) strains and construct different genotypic evolutionary diagrams. The detection rate of CRABA class I integrons was 13.51% (10/74); no class II and III integrons were detected. However, class I, II and III integrons were not detected in non-CRABA strains. The variable regions of 9 of 10 class I integrons were amplified and 10 gene cassettes including aacC1, aac1, aadDA1, aadA1a, aacA4, dfrA17, aadA5, aadA1, aadA22 and aadA23 were associated with drug resistance. The 96 ABA strains were divided into 21 STs: 74 CRABA strains containing 9 STs, primarily ST208 and ST1145 and 22 non-CRABA strains containing 18 STs, primarily ST1145. Class I integrons are a critical factor underlying drug resistance in ABA. CRABA and non-CRABA strains differ significantly; the former primarily contained ST208 and ST1145, and the latter contained ST1145. Most STs were concentrated in intensive care units (ICUs) and the department of Neurology, with the patients from the ICUs being the most susceptible to bacterial infection. In the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, ABA is potentially horizontally transmitted and MLST can be used for clinical ABA genotyping. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint blockade (ICB) therapy can be effective against clear cell renal cell carcinoma (ccRCC), but many patients show no benefit. Tumor-derived pericytes (TDPs) may promote tumor progression by influencing T cells and are an immunotherapy target; however, they may comprise functionally distinct subtypes. We aimed to identify markers of tumor-promoting TDPs and develop TDP-targeting strategies to enhance ICB therapy effectiveness against ccRCC. Methods: We analyzed the relationship between endosialin (EN) expression and cytotoxic T-lymphocyte (CTL) infiltration in ccRCC tumor samples using flow cytometry and in a ccRCC-bearing mice inhibited for EN via knockout or antibody-mediated blockade. The function of ENhigh TDPs in CTL infiltration and tumor progression was analyzed using RNA-sequencing (RNA-seq) data from ccRCC tissue-derived TDPs and single-cell RNA-seq (scRNA-seq) data from an online database. The role of EN in TDP proliferation and migration and in CTL infiltration was examined in vitro. Finally, we examined the anti-tumor effect of combined anti-EN and anti-programmed death 1 (PD-1) antibodies in ccRCC-bearing mice. Results: High EN expression was associated with low CTL infiltration in ccRCC tissues, and inhibition of EN significantly increased CTL infiltration in ccRCC-bearing mice. RNA-seq and scRNA-seq analyses indicated that high EN expression represented the TDP activation state. EN promoted TDP proliferation and migration and impeded CTL infiltration in vitro. Finally, combined treatment with anti-EN and anti-PD-1 antibodies synergistically enhanced anti-tumor efficacy. Conclusion: ENhigh TDPs are in an activated state and inhibit CTL infiltration into ccRCC tissues. Combined treatment with anti-EN and anti-PD-1 antibodies may improve ICB therapy effectiveness against ccRCC. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma (OS) is the most common malignant bone tumor with a high incidence in children and adolescents. Frequent tumor metastasis and high postoperative recurrence are the most common challenges in OS. However, detailed mechanism is largely unknown. Methods: We examined the expression of CD248 in OS tissue microarrays by immunohistochemistry (IHC) staining. We studied the biological function of CD248 in cell proliferation, invasion and migration of OS cells by CCK8 assay, transwell and wound healing assay. We also studied its function in the metastasis of OS in vivo. At last, we explored the potential mechanism how CD248 promotes OS metastasis by using RNA-seq, western blot, immunofluorescence staining and co-immunoprecipitation using CD248 knockdown OS cells. Results: CD248 was highly expressed in OS tissues and its high expression was correlated with pulmonary metastasis of OS. Knockdown of CD248 in OS cells significantly inhibited cell migration, invasion and metastasis, while had no obvious effect on cell proliferation. Lung metastasis in nude mice was significantly inhibited when CD248 was knocked down. Mechanistically, we found that CD248 could promote the interaction between ITGB1 and extracellular matrix (ECM) proteins like CYR61 and FN, which activated the FAK-paxillin pathway to promote the formation of focal adhesion and metastasis of OS. Conclusion: Our data showed that high CD248 expression is correlated with the metastatic potential of OS. CD248 may promote migration and metastasis through enhancing the interaction between ITGB1 and certain ECM proteins. Therefore, CD248 is a potential marker for diagnosis and effective target for the treatment of metastatic OS. [ABSTRACT FROM AUTHOR]

Evidence of more recent studies should be updated to evaluate the effect of long-term exposure to particulate matter (PM) on blood pressure and hypertension. Studies of long-term effects of PM1, PM2.5 and PM10 on blood pressure (SBP, DBP, MAP), hypertension were searched in Pubmed, Web of Science and Embase before May, 2021. Meta-analysis of 41 studies showed that exposure to PM1, PM2.5 was associated with SBP (1.76 mmHg (95%CI:0.71, 2.80) and 0.63 mmHg (95%CI:0.40, 0.85), per 10 μg/m3 increase in PM), all three air pollutants (PM1, PM2.5, PM10) was associated with DBP (1.16 mmHg (95%CI:0.34, 1.99), 0.31 mmHg (95%CI:0.16, 0.47), 1.17 mmHg (95%CI:0.24, 2.09), respectively. As for hypertension, PM1, PM2.5 and PM10 were all significantly associated with higher risk of hypertension (OR=1.27 (95%CI:1.06, 1.52), 1.15 (95%CI:1.10, 1.20) and 1.11 (95%CI:1.07, 1.16). In conclusion, our study indicated a positive association between long-term exposure to particulate matter and increased blood pressure, hypertension. [ABSTRACT FROM AUTHOR]

Background: Population aging has led to depression becoming a serious public health problem both in China and worldwide. Marital relationships, relationships with their children, and air pollution might play an important role in the process of depressive disorders. In this study, we aimed to reveal the mechanism of the effects of these factors on depression. Methods: Participants were recruited from The China Health and Retirement Longitudinal Study (CHARLS) (wave 4) from July 2018 to March 2019. Depression symptoms were evaluated using the 10-item Center for Epidemiologic Studies depression scale (CESD-10). Marital relationships, relationships with their children, air quality satisfaction, and perceived health status were analyzed using Likert 5-point evaluation methods. Structural equation modeling-path (SEM) models were used to explore these variables' mediation effects on depression symptoms. Results: Marital relationships, relationships with their children, air quality satisfaction, perceived health status, and depression symptoms were significantly associated with each other (P < 0.001). Mediation analysis showed that family relationships (standardized beta = −0.28 [−0.31, −0.26]) and quality satisfaction (standardized beta = −0.03 [−0.05, −0.01]) had negative effects on depression symptoms. The total indirect effects of family relationships and air quality satisfaction on depression symptoms were −0.06 (95% confidence interval (CI) = [−0.07, −0.05]) and −0.016 (95% CI = [−0.02, −0.01]), respectively. Conclusion: Family relationships, air quality satisfaction, and perceived health status influenced depression symptoms. The effects of family relationships and air quality satisfaction on depression symptoms were significantly mediated by perceived health status. Therefore, perceived health status aspects should be considered when conducting targeted intervention toward depression symptoms among middle-aged and elderly adults. [ABSTRACT FROM AUTHOR]

Phase separation is a critical mechanism for partitioning cellular functions by specific aggregation of biological macromolecules. Recent studies have found that phase separation is widely contributed in various biological functions, particularly in RNA related processes. Over 170 different post-transcriptional modifications occur in RNA, which is considered to be one of the most important physiological and pathogenic epigenetic mechanisms. Here, we discuss the role of phase separation in regulating RNA modification processing to ensure orderly RNA metabolism and function. Enzymes responsible for RNA modification undergo compartmentalization, enabling them to traffic client RNAs and amplify modifying efficacy. Meanwhile, altered RNA affects the formation, dissolution, and biophysical properties of phase separation conversely. These findings deeper our understanding of the interplay between phase separation and RNAs that governs a wide range of cellular processes. Finally, we concluded pathological roles of phase separation in RNA modification towards clinical applications and outlined perspectives to research RNA modification through the lens of phase separation. [ABSTRACT FROM AUTHOR]

• CD248 is identified as a specific target gene associated with hypertrophic scar. • CD248 interacts with ECM molecules to regulate hypertrophic scar. • IgG78 targeting CD248 inhibits scar formation and hypertrophy. Hypertrophic scar (HS) presents a significant clinical challenge, frequently arising as a fibrotic sequela of burn injuries and trauma. Characterized by the aberrant activation and proliferation of myofibroblasts, HS lacks a targeted therapeutic approach to effectively reduce this dysregulation. This study offers novel evidence of upregulated expression of CD248 in HS tissues compared to normal skin (NS) tissues. Specifically, the expression of CD248 was predominantly localized to α-SMA+-myofibroblasts in the dermis. To explain the functional role of CD248 in dermal myofibroblast activity, we employed a targeted anti-CD248 antibody, IgG78. Both CD248 intervention and IgG78 treatment effectively suppressed the proliferative, migratory, and ECM-synthesizing activities of myofibroblasts isolated from HS dermis. In addition, IgG78 administration significantly attenuated HS formation in an in vivo rabbit ear model. The LC/MS analysis coupled with co-immunoprecipitation of HS tissues indicated a direct interaction between CD248 and the ECM components Fibronectin (FN) and Collagen I (COL I). These findings collectively suggest that CD248 may function as a pro-fibrotic factor in HS development through its interaction with ECM constituents. The utilization of an anti-CD248 antibody, such as IgG78, represents a promising novel therapeutic strategy for the treatment of HS. [ABSTRACT FROM AUTHOR]

Background: Chronic liver injury induces pathological repair, resulting in fibrosis, during which hepatic stellate cells (HSCs) are activated and transform into myofibroblasts. CD248 is mainly expressed on myofibroblasts and was considered as a promising target to treat fibrosis. The primary aim of this study was to generate a CD248 specific antibody-drug conjugate (ADC) and evaluate its therapeutic efficacy for liver fibrosis and its safety in vivo. Methods: CD248 expression was examined in patients with liver cirrhosis and in mice with CCl4-induced liver fibrosis. The ADC IgG78-DM1, which targets CD248, was prepared and its bioactivity on activated primary HSCs was studied. The anti-fibrotic effects of IgG78-DM1 on liver fibrosis were evaluated in CCl4-induced mice. The reproductive safety and biosafety of IgG78-DM1 were also evaluated in vivo. Results: CD248 expression was upregulated in patients with liver cirrhosis and in CCl4-induced mice, and was mainly expressed on alpha smooth muscle actin (α-SMA)+ myofibroblasts. IgG78-DM1 was successfully generated, which could effectively bind with and kill CD248+ activated HSCs in vitro and inhibit liver fibrosis in vivo. In addition, IgG78-DM1 was demonstrated to have qualified biosafety and reproductive safety in vivo. Conclusions: Our study demonstrated that CD248 could be an ideal target for myofibroblasts in liver fibrosis, and CD248-targeting IgG78-DM1 had excellent anti-fibrotic effects in mice with liver fibrosis. Our study provided a novel strategy to treat liver fibrosis and expanded the application of ADCs beyond tumors. [ABSTRACT FROM AUTHOR]

Bladder cancer (BLCA) is the most common malignancy whose early diagnosis can ensure a better prognosis. However, the predictive accuracy of commonly used predictors, including patients' general condition, histological grade, and pathological stage, is insufficient to identify the patients who need invasive treatment. Autophagy is regarded as a vital factor in maintaining mitochondrial function and energy homeostasis in cancer cells. Whether autophagy-related genes (ARGs) can predict the prognosis of BLCA patients deserves to be investigated. Based on BLCA data retrieved from the Cancer Genome Atlas and ARGs list obtained from the Human Autophagy Database website, we identified prognosis-related differentially expressed ARGs (PDEARGs) through Wilcox text and constructed a PDEARGs-based prognostic model through multivariate Cox regression analysis. The predictive accuracy, independent forecasting capability, and the correlation between present model and clinical variables or tumor microenvironment were evaluated through R software. Enrichment analysis of PDEARGs was performed to explore the underlying mechanism, and a systematic prognostic signature with nomogram was constructed by integrating clinical variables and the aforementioned PDEARGs-based model. We found that the risk score generated by PDEARGs-based model could effectively reflect deteriorated clinical variables and tumor-promoting microenvironment. Additionally, several immune-related gene ontology terms were significantly enriched by PDEARGs, which might provide insights for present model and propose potential therapeutic targets for BLCA patients. Finally, a systematic prognostic signature with promoted clinical utility and predictive accuracy was constructed to assist clinician decision. PDEARGs are valuable prognostic predictors and potential therapeutic targets for BLCA patients. [ABSTRACT FROM AUTHOR]

Background: Carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) causes serious infections with significant morbidity and mortality. However, the epidemiology and transmission mechanisms of CR-hvKP and the corresponding carbapenem-resistant plasmids require further investigation. Herein, we have characterized an ST11 K. pneumoniae strain EBSI041 from the blood sample encoding both hypervirulence and carbapenem resistance phenotypes from a patient in Egypt. Results: K. pneumoniae strain EBSI041 showed multidrug-resistance phenotypes, where it was highly resistant to almost all tested antibiotics including carbapenems. And hypervirulence phenotypes of EBSI041 was confirmed by the model of Galleria mellonella infection. Whole-genome sequencing analysis showed that the hybrid plasmid pEBSI041-1 carried a set of virulence factors rmpA, rmpA2, iucABCD and iutA, and six resistance genes aph(3′)-VI, armA, msr(E), mph(E), qnrS, and sul2. Besides, blaOXA-48 and blaSHV-12 were harboured in a novel conjugative IncL-type plasmid pEBSI041-2. The blaKPC-2-carrying plasmid pEBSI041-3, a non-conjugative plasmid lacking the conjugative transfer genes, could be transferred with the help of pEBSI041-2, and the two plasmids could fuse into a new plasmid during co-transfer. Moreover, the emergence of the p16HN-263_KPC-like plasmids is likely due to the integration of pEBSI041-3 and pEBSI041-4 via IS26-mediated rearrangement. Conclusion: To the best of our knowledge, this is the first report on the complete genome sequence of KPC-2- and OXA-48-coproducing hypervirulent K. pneumoniae from Egypt. These results give new insights into the adaptation and evolution of K. pneumoniae during nosocomial infections. [ABSTRACT FROM AUTHOR]

TIGIT is an emerging novel checkpoint target that is expressed on both tumor-infiltrating T cells and NK cells. Some current investigational antibodies targeting TIGIT have also achieved dramatic antitumor efficacy in late clinical research. Most recently, the relevance of NK cell–associated TIGIT signaling pathway to tumors' evasion of the immune system has been clearly revealed, which endows NK cells with a pivotal role in the therapeutic effects of TIGIT blockade. In this article, we describe a novel anti-TIGIT monoclonal antibody, AET2010, which was acquired from a phage-displayed human single-chain antibody library through a cell panning strategy. With emphasis on its regulation of NK cells, we confirmed the excellent ex vivo and in vivo antitumor immunity of AET2010 mediated by the NK-92MI cells. Intriguingly, our work also revealed that AET2010 displays a lower affinity but parallel avidity and activity relative to MK7684, an investigational monoclonal antibody from MSD, implying a reasonable balance of potency and potential side effects for AET2010. Together, these results are promising and warrant further development of AET2010. • We applied a cell panning strategy to select therapeutic antibodies from a phage-displayed human antibody library. • We identified a novel candidate therapeutic antibody with a low risk of potential side effects but undiminished efficacy. • The novel anti-TIGIT antibody exhibited excellent ex vivo and in vivo antitumor immunity mediated by NK-92MI cells. • This is the first report assessing the activity of TIGIT antibodies in a xenograft model with adoptive injection of NK-92MI. [ABSTRACT FROM AUTHOR]

The study was aimed at assessing the diagnostic performance of 68Ga-PSMA-617 PET/CT in the detection of prostate cancer (PCa) in patients with a prostate-specific antigen (PSA) level of 4–20 ng/ml and to compare its efficacy with that of multiparametric MRI (mpMRI). We analyzed the data of 67 consecutive patients with PSA levels of 4–20 ng/ml who almost simultaneously underwent 68Ga-PSMA-617 PET/CT and mpMRI. 68Ga-PSMA-617 PET/CT and mpMRI diagnostic performances were compared via receiver operating characteristic (ROC) curve analysis. Of the 67 suspected PCa cases, 33 had pathologically confirmed PCa. 68Ga-PSMA-617 PET/CT showed a patient-based sensitivity, specificity, and positive and negative predictive values (PPVs and NPVs) of 87.88%, 88.24%, 87.88%, and 88.24%, respectively. The corresponding values for mpMRI were 84.85%, 52.94%, 63.64%, and 78.26%. The area under the curve values for 68Ga-PSMA-617 PET/CT and mpMRI were 0.881 and 0.689, respectively. 68Ga-PSMA-617 PET/CT showed a better diagnostic performance than mpMRI in the detection of PCa in patients with PSA levels of 4–20 ng/ml. [ABSTRACT FROM AUTHOR]

Cancer is a public health problem and the main cause of human mortality and morbidity worldwide. Complete removal of tumors and metastatic lymph nodes in surgery is significantly beneficial for the prognosis of patients. Tumor-targeted, near-infrared fluorescent (NIRF) imaging is an emerging field of real-time intraoperative cancer imaging based on tumor-targeted NIRF dyes. Targeted NIRF dyes contain NIRF fluorophores and specific binding ligands such as antibodies, peptides and small molecules. The present article reviews recently updated tumor-targeted NIRF dyes for the molecular imaging of malignant tumors in the preclinical stage and clinical trials. The strengths and challenges of NIRF agents with tumor-targeting ability are also summarized. Smaller ligands, near infrared II dyes, dual-modality dyes and activatable dyes may contribute to quicker, deeper, stronger imaging in the nearest future. In this review, we highlighted tumor-targeted NIRF dyes for fluorescence-guided surgery and their potential clinical translation. [ABSTRACT FROM AUTHOR]

The authors Weihong Wen and Weijun Qin should also have been denoted as a corresponding author. B Correction to: Cancer Immunology, Immunotherapy b https://doi.org/10.1007/s00262-023-03372-z The original version of this article unfortunately contained a mistake. Correction to: Endosialin-positive tumor-derived pericytes promote tumor progression through impeding the infiltration of CD8+ T cells in clear cell renal cell carcinoma. [Extracted from the article]

CREPT (cell cycle-related and expression elevated protein in tumor) is highly expressed in many kinds of cancer, and has been shown to be prognostic in certain cancers. However, the clinical significance of CREPT in colorectal cancer (CRC) has not been sufficiently investigated. In this study, we examined the CREPT expression in 225 clinical CRC tissues and paired adjacent normal tissues, and analyzed the correlation between CREPT expression and other clinicopathological features. We also evaluated the biological function of CREPT both in vitro and in vivo using knockdown or overexpressing CRC cells. Our results showed that CREPT expressed in 175 of 225 (77.8%) CRC patients and the CREPT expression was significantly associated with tumor differentiation (P = 0.000), Dukes' stages (P = 0.013) and metastasis (P = 0.038). Patients with high CREPT expression tended to have shorter survival time. Multivariate analysis showed that positive CREPT expression can be used as an independent predictor for CRC prognosis. CREPT knockdown cells showed inhibited cell proliferation and arrested cell cycle, while CREPT overexpressing cells showed increased proliferation and promoted cell cycle. In addition, CREPT overexpression significantly promoted tumor growth in vivo . Mechanism study showed that CREPT may regulate cell proliferation and cell cycle through the regulation on cyclin D3, CDK4 and CDK6. [ABSTRACT FROM AUTHOR]

Prostate specific membrane antigen positron emission tomography (PSMA PET) is an excellent molecular imaging technique for prostate cancer. Currently, PSMA PET for patients with primary prostate cancer is supplementary to conventional imaging techniques, according to guidelines. This supplementary function of PSMA PET is due to a lack of systematic review of its strengths, limitations, and potential development direction. Thus, we review PSMA ligands, detection, T, N, and M staging, treatment management, and false results of PSMA PET in clinical studies. We also discuss the strengths and challenges of PSMA PET. PSMA PET can greatly increase the detection rate of prostate cancer and accuracy of T/N/M staging, which facilitates more appropriate treatment for primary prostate cancer. Lastly, we propose that PSMA PET could become the first-line imaging modality for primary prostate cancer, and we describe its potential expanded application. [ABSTRACT FROM AUTHOR]

Multi-locus sequence typing (MLST) can be used to analyze the homology among the drug resistance gene cassettes in Salmonella and determine the prevalence. Information extracted using this technique can provide a theoretical basis for hospitals to devise protocols to control Salmonella infections. The aim of the present study was to investigate the possible association between drug resistance and integrons in clinical isolates of Salmonella from human fecal samples. Therefore, in the present study, 52 clinical fecal isolates of non-duplicate (i.e., not genome contamination) Salmonella were harvested from children with diarrhea and used for bacterial identification using biochemical tests, drug susceptibility analysis by antibiotic susceptibility testing and serotype identification using an agglutination assay. In total, seven Salmonella housekeeping genes (chorismate synthase, β sliding clamp of DNA polymerase III, uroporphyrinogen-III synthase, histidinol dehydrogenase, phosphoribosylaminoimidazole carboxylase catalytic subunit, 2-oxoglutarate dehydrogenase E1 component and homoserine dehydrogenase) were amplified and sequenced using MLST, before sequence alignment was performed against the Pub MLST database to determine the sequence-typed (ST) strains and construct genotypic evolutionary diagrams. Subsequently, the 52 Salmonella strains were subdivided into 11 serotypes and 11 sequence types. The dominant subtypes were found to be Salmonella typhimurium ST34 and ST19, which were diversely distributed. However, no new subtypes were found. Although the serotypes, including ST19, ST29, ST34, ST40, ST11, ST27, ST469, ST365, ST1499, ST413 and ST588, were closely associated with the MLST subtype, they did not correspond entirely. The detection rate of class I integrons was 38.46% (20/52), but no class II and III integrons were detected. The variable regions of three of 20 class I integrons were found to be amplified, whereas nine gene cassettes, including dihydrofolate reductase A12, open reading frame F, aminoglycoside-adenylyltransferase (aad)A2, aadA22, aadA23, aadA1, cadmium-translocating P-type ATPase 2, lincosamide and linF, were associated with drug resistance. These data suggest that Class I integrons are important factors underlying drug resistance in Salmonella, which may serve a role in the spread of drug resistance and warrant specific focus. In addition, MLST typing and serotyping should be applied cooperatively in epidemiological research. [ABSTRACT FROM AUTHOR]

Abstract: The down-regulation of Notch1 by small interfering RNA (siRNA) can significantly inhibit human prostate cancer cell growth. The delivery of siRNA into specific cells is a key requirement for its clinical application. Recent reports have indicated that antibody-mediated siRNA delivery is an effective approach for targeted knockdown of specific genes in appropriate cells. Prostate-specific membrane antigen (PSMA) is regarded as an ideal target for the delivery of therapeutic agents to prostate cancer cells. The purpose of the present study was to evaluate whether siRNA can be efficiently delivered into PSMA-positive prostate cancer cells using two fusion proteins, s-tP and sFH-tP. These fusion proteins are composed of an anti-PSMA single chain antibody (scFv, abbreviated as an “s”) and a truncated protamine (tP); and in sFH-tP a furin cleavage site and an HA2 fragment sequence (FH) were inserted between the scFv and tP domains. Our results showed that siRNA can be specifically delivered into PSMA-positive LNCaP cells by these two fusion proteins, with the sFH-tP fusion protein being more effective. Efficient knockdown of Notch1 by siNotch1 delivered by either fusion protein was observed in PSMA-positive LNCaP cells and in LNCaP xenografted nude mice. Further experiments confirmed that the fusion protein-delivered siNotch1 could efficiently inhibit PSMA-positive LNCaP cell proliferation and promote apoptosis both in vitro and in vivo. Our data describe a promising strategy for the targeted delivery of siRNA to PSMA-positive prostate cancer cells using anti-PSMA scFv fusion proteins. [Copyright &y& Elsevier]

Abstract: Targeted therapy is needed for hepatitis B virus (HBV)-mediated hepatocellular carcinoma (HCC) which shows overexpression of HBV surface antigen (HBsAg). We previously developed scFv15, a human single-chain antibody against HBsAg. Here we tested the strategic feasibility of scFv15-mediated delivery of apoptotic effectors for HBsAg-targeted HCC therapy and application of HA2 motif of influenza hemagglutinin to enhance endosome escape and antitumor effect. A class of HBsAg-targeted immunoproapoptotic molecule was generated by sequentially fusing scFv15, the furin-cleavable motif from diphtheria toxin (Fdt), HA2 and a truncated apoptotic protein Bid (tBid). The resulting scFv15-Fdt-HA2-tBid was prokaryotically expressed and functionally characterized for HBsAg-binding capacity, endosome escape activity and antitumor effect as compared with scFv15-Fdt-tBid. Both scFv15-Fdt-HA2-tBid and scFv15-Fdt-tBid retained affinity and specificity for HBsAg, and bound and selectively killed HBsAg-positive HCC cells via apoptosis. Notably, the IC50 of scFv15-Fdt-HA2-tBid in HBsAg-positive PLC/PRF/5 cells was 10 times lower than that of scFv15-Fdt-tBid. In vivo imaging of antitumor activity demonstrated 95% growth inhibition of orthotopic HCC by scFv15-Fdt-HA2-tBid compared with 75% suppression by scFv15-Fdt-tBid. This study represents an extended application of the immunoproapoptotic strategy in the treatment of HBsAg-positive HCC and shows significant potential of HA2 as a functional enhancer for endosome-encapsulated antibody-conjugates. [Copyright &y& Elsevier]

Background and Objective: Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are nuclear effectors of the Hippo pathway. Although they are abundantly expressed in the cytoplasm and nuclei of human colorectal cancer (CRC), and related to tumor proliferation status, there have been few studies on the predictive role of YAP and TAZ expression on the overall survival of patients with CRC. This study investigated YAP and TAZ expression in both CRC patients and colon cancer cell lines, and assessed their prognostic value. Methods: Paraffin-embedded specimens from 168 eligible patients were used to investigate YAP and TAZ expression by immunohistochemistry, and compared with experimental results in colon cancer HCT116 cell line to explore their clinical significance in CRC. Results: Statistically significant positive correlations were found between protein expression of YAP and TAZ in CRC tissues. Patients with higher YAP or TAZ expression showed a trend of shorter survival times; more importantly, our cohort study indicated that patients with both YAP and TAZ overexpression presented the worst outcomes. This was supported by multivariate analysis. In HCT116 colon cancer cells, the capacity for proliferation, metastasis, and invasion was dramatically reduced by knockdown of YAP and TAZ expressions by siRNA. Conclusions: Co-overexpression of YAP and TAZ is an independent predictor of prognosis for patients with CRC, and may account for the higher proliferation, metastasis, and poor survival outcome of these patients. [ABSTRACT FROM AUTHOR]

The oncoprotein c-Jun is one of the components of the activator protein-1 (AP-1) transcription factor complex. AP-1 regulates the expression of many genes and is involved in a variety of biological functions such as cell transformation, proliferation, differentiation and apoptosis. AP-1 activates a variety of tumor-related genes and therefore promotes tumorigenesis and malignant transformation. Here, we found that epidermal growth factor (EGF) induces phosphorylation of c-Jun by P21-activated kinase (PAK) 2. Our data showed that PAK2 binds and phosphorylates c-Jun at five threonine sites (Thr2, Thr8, Thr89, Thr93 and Thr286) in vitro and ex vivo. Knockdown of PAK2 in JB6 Cl41 (P+) cells had no effect on c-Jun phosphorylation at Ser63 or Ser73 but resulted in decreases in EGF-induced anchorage-independent cell transformation, proliferation and AP-1 activity. Mutation at all five c-Jun threonine sites phosphorylated by PAK2 decreased the transforming ability of JB6 cells. Knockdown of PAK2 in SK-MEL-5 melanoma cells also decreased colony formation, proliferation and AP-1 activity. These results indicated that PAK2/c-Jun signaling plays an important role in EGF-induced cell proliferation and transformation. [ABSTRACT FROM AUTHOR]

The ribosomal S6 kinase 2 (RSK2) is a well-known serine/threonine kinase and a member of the p90 ribosomal S6 kinase (p90RSK) family of proteins. It is activated downstream of the MEK/ERKs cascade by mitogenic stimuli such as EGF or TPA. Here, we show that RSK2 is activated by treatment with tumor necrosis factor-α (TNF-α) and directly phosphorylates IB at Ser-32, leading to IB degradation. The phosphorylation of IB promotes the activation and translocation of the nuclear factor-ΚB (NF-κB) subunits p65 and p50 to the nucleus. The net result is an increased NF-κB activity, which serves as a mechanism for RSK2 blockade of TNF-α-induced apoptosis and enhanced cell survival. [ABSTRACT FROM AUTHOR]

Abstract: Dendritic cells (DCs) have been widely used as cancer vaccines. However, their functional abilities have often been suppressed by tumor-secreted immunosuppressants such as transforming growth factor-beta (TGF-β). We developed a new strategy using a TGF-β insensitive DC as cancer vaccine. The effect of this vaccine was tested in a murine pulmonary metastases model of renal carcinoma (Renca). Tumor lysate-pulsed DCs (TP-DCs) were infected with retrovirus containing gene of dominant negative TGF-β type II receptor (TβRIIDN) and thus made TGF-β insensitive. Vaccination of the mice bearing Renca pulmonary metastases with the TβRIIDN TP-DC induced powerful tumor-specific cytotoxic T lymphocyte (CTL) responses, suppressed pulmonary metastases, and prolonged survival times. These results suggest TGF-β-insensitive TP-DC vaccine can be used to enhance the antitumor efficacy of DC vaccine. [Copyright &y& Elsevier]

Abstract: To develop reagents for early diagnosis and therapeutic drugs against SARS-associated coronavirus (SARS-CoV), a large (3×109) immunized human antibody library was constructed from peripheral blood mononuclear cells from six SARS convalescent patients. A single chain variable fragment antibody (N18) with high affinity against N protein of SARS-CoV was isolated. Sequence analysis revealed that the VL gene was composed of VL3h (V lambda subgroup) and JL2 regions and the VH gene was composed of VH1-69 (VH1 subgroup), D2-15, D3-22 and JH6 regions. Soluble N18 antibody was expressed in Escherichia coli HB2151, purified by Ni–NTA affinity chromatography and verified by SDS-PAGE and Western blot. The potential application for early diagnosis was evaluated using N protein capture ELISA in which N18 antibody demonstrated high sensitive activity in detecting N protein of SARS-CoV. Finally, the potential usefulness of the N18 antibody in prophylaxis, vaccine design and therapy of SARS is discussed. [Copyright &y& Elsevier]