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Background Current guidelines support different management of cryptococcosis between severely immunodeficient and immunocompetent populations. However, few studies have focused on cryptococcosis patients with mild-to-moderate immunodeficiency. We performed this study to determine the clinical features of pulmonary (PC) and extrapulmonary cryptococcosis (EPC) and compared them among populations with different immune statuses to support appropriate clinical management of this public health threat. Methods All cases were reported by 14 tertiary teaching hospitals in Jiangsu Province, China from January 2013 to December 2018. The trends in incidence, demographic data, medical history, clinical symptoms, laboratory test indicators, imaging characteristics and diagnostic method of these patients were then stratified by immune status, namely immunocompetent (IC, patients with no recognized underlying disease or those with an underlying disease that does not influence immunity, such as hypertension), mild-to-moderate immunodeficiency (MID, patients with diabetes mellitus, end-stage liver or kidney disease, autoimmune diseases treated with low-dose glucocorticoid therapy, and cancer treated with chemotherapy) and severe immunodeficiency (SID, patients with acquired immunodeficiency syndrome, haematologic malignancies, solid organ transplantation or haematologic stem cell transplantation, idiopathic CD4 lymphocytosis, agranulocytosis, aggressive glucocorticoid or immunosuppressive therapy and other conditions or treatments that result in severe immunosuppression). Results The clinical data of 255 cryptococcosis patients were collected. In total, 66.3% of patients (169) were IC, 16.9% (43) had MID, and 16.9% (43) had SID. 10.1% of the patients (17) with IC were EPC, 18.6% of the patients (8) with MID were EPC, and 74.4% of patients (32) were EPC (IC/MID vs. SID, p Conclusions The clinical presentation of MID patients is intermediate between SID and IC patients and is similar to that of IC patients. The serum CrAg test is more sensitive for the identification of SID or EPC patients.

BackgroundAmong immunocompetent patients, patients with bronchiectasis are considered to be a high-risk group for invasive pulmonary aspergillosis (IPA). Early diagnosis and treatment can improve the prognosis of patients.ObjectivesWe aimed to investigate the diagnostic value of Dectin-1 and IL-17 for diagnosing IPA with bronchiectasis.MethodsWe retrospectively collected data on patients with bronchiectasis who had been hospitalized in the Third Affiliated Hospital of Soochow University between September 2018 to December 2021. Dectin-1, IL-17 and GM were measured by enzyme-linked immunosorbent assays.ResultsA total of 129 patients were analyzed in the study, of whom 33 had proven or probable IPA with bronchiectasis. The remaining 96 patients served as controls. The plasma Dectin-1 and IL-17 levels in the IPA group were significantly higher than that in the control group (P=0.005; PConclusionsPlasma Dectin-1 and IL-17 levels were significantly higher in bronchiectasis patients with IPA. The sensitivity of Dectin-1 and IL-17 was superior to that of GM for the diagnosis of IPA in patients with bronchiectasis. The combination of GM and IL-17 in plasma is helpful for the diagnosis of IPA in bronchiectasis patients who cannot tolerate invasive procedures.

Background The use of galactomannan (GM) testing in plasma and bronchoalveolar lavage fluid (BALF) has improved the diagnosis of invasive pulmonary aspergillosis (IPA) in patients with chronic obstructive pulmonary disease (COPD); however, the high false-positive rate leads to overdiagnosis. Pentraxin 3 (PTX3) as an indicator of inflammation plays an important role in resistance to Aspergillus infections. This study aimed to investigate the diagnostic value of PTX3 for diagnosing IPA with COPD. Methods We retrospectively collected data on patients with suspected COPD and IPA who had been hospitalized in the Third Affiliated Hospital of Soochow University between September 2017 and November 2020. PTX3 and GM were measured using enzyme-linked immunosorbent assays. Results A total of 165 patients were included in the study, of whom 35 had confirmed or probable IPA. The remaining 130 patients served as controls. The median plasma and BALF PTX3 levels were significantly higher in patients with IPA than in control patients (3.74 ng/mL vs. 1.29 ng/mL, P P 90% in patients who were PTX3-positive and GM-positive in plasma and BALF. Conclusions BALF and plasma PTX3 levels were significantly higher in COPD patients with IPA. The sensitivity of PTX3 was superior to that of GM for diagnosing IPA in patients with COPD. The combination of GM and PTX3 is useful for the diagnosis of IPA in patients with COPD.

Fisetin is a natural flavonoid with promising antitumor activity, whereas its clinical application is limited by its hydrophobic property. In this study, we aimed to load fisetin into poly(lactic acid) (PLA) nanoparticles to increase fisetin's solubility and therapeutic efficacy. Based on spontaneous emulsification solvent diffusion (SESD) method, the formulation of PLA nanoparticles was optimized by two successive experimental designs. One-factor-at-a-time variation experiments were first applied to investigate the effects of four process variables on three responses, including drug encapsulation efficiency, average particles size and cumulative drug release ratio, followed by determining the possible ranges of these variables. Subsequently, the combinations of four variables at best levels were evaluated using a Taguchi orthogonal array design with regard to the same three responses. Eventually, the nanoparticle prepared by optimized procedure showed a narrow size distribution around 226.85 ± 4.78 nm with a high encapsulation efficiency of 90.35%. The incorporation of fisetin in nanoparticles was subsequently confirmed by FT-IR and DSC spectroscopy. Furthermore, cytotoxicity assay against HCT116 colon cancer cells in vitro and antitumor test in a xenograft 4T1 breast cancer model in vivo demonstrated that the antitumor effect of drug-loaded nanoparticles was superior to that of free drug solution.

[6]-Gingerol, one of the components of the rhizome of Ginger, has a variety of biological activities such as anticoagulant, antioxidative, antitumor, anti-inflammatory, antihypertensive, and so forth. However, as one of the homologous phenolic ketones, [6]-gingerol is insoluble in water which limits its applications. Herein, we prepared [6]-gingerol proliposomes through modified thin-film dispersion method, which was spherical or oval, and physicochemically stable with narrow size distribution. Surprisingly, in vitro release of [6]-gingerol loaded proliposome compared with the free [6]-gingerol was significantly higher and its oral bioavailability increased 5-fold in vivo. Intriguingly, its antitumor effect was enhanced in the liposome formulation. Thus, our prepared [6]-gingerol proliposome proved to be a novel formulation for [6]-gingerol, which significantly improved its antitumor effect.

The major obstacles opposed to doxorubicin (Dox) based chemotherapy are the induction of drug resistance, together with non-specific toxicities for healthy cells. In this study, we prepared a peptide-Dox conjugate aimed at offering Dox molecules a tumor-specific functionality and improving the therapeutic effects of Dox against resistant tumor cells. A slightly acidic pH-sensitive peptide (SAPSP) with high selectivity for cancer cells was attached to Dox to obtain SAPSP-Dox prodrug. The structures and properties of this prodrug were characterized, confirming several merits, including desirable pH-sensitive property, good serum stability and favorable release behavior. Cellular uptake studies demonstrated that SAPSP-Dox was preferably accumulated in cancer cells (Dox-sensitive MCF-7 and Dox-resistant MCF-7/ADR), followed by displaying 26-fold less toxic toward noncancerous MCF-10A cells than free Dox do. The conjugated peptides enabled Dox to escape the efflux effect of P-glycoprotein mediated pump via endocytotic pathway, giving rise to remarkable cytotoxicity and apoptotic effect on MCF-7/ADR cells. Moreover, the superior inhibition efficacy of SAPSP-Dox in vivo was more evident in the both drug-sensitive and drug-resistant xenograft tumor animal models, which enabled Dox to primarily accumulated in tumor. The conjugates also demonstrated a longer half-life in plasma and a lower side effect, for example, reduced cardiac toxicity. Evidence of this study suggests that SAPSP-Dox has the potential to be a potent prodrug for treating drug resistant cancers.

Cancer is a huge challenge humanity facing today, and single chemical treatments inevitably have shortcomings such as poor selectivity and large side effects. This paper constructed an egg yolk phospholipids modified molybdenum disulfide (MoS

Codelivery of multiple chemotherapeutics has become a versatile strategy in recent cancer treatment, but the antagonistic behavior of combined drugs limited their application. We developed a recombinant high-density lipoprotein (rHDL) nanoparticle for the precise coencapsulation and codelivery of two established drugs and hypothesized that they could act synergistically to improve anticancer efficacy. The coloaded rHDL was formulated by passively incorporating hydrophobic paclitaxel (PTX), and subsequently remotely loading hydrophilic doxorubicin (Dox) into the same nanoparticles. The resultant rHDL system restored targeted delivery function toward cancer cells via scavenger receptor class B (SR-BI), as confirmed by in vitro confocal imaging and flow cytometry. These coloaded rHDL nanoparticles were remarkably effective in increasing the ratiometric accumulation of drugs in cancer cells and enhancing antitumor response at synergistic drug ratios. In particular, they exhibited more efficacious anticancer effects in an in vitro cytotoxicity evaluation and in a xenograft tumor model of hepatoma compared with free drug cocktail solutions. These results confirm that the coloaded rHDL nanoparticles are promising candidates for the synergistic delivery of drugs with diverse physicochemical properties in cancer treatment integrating efficiency and safety considerations.

Combination therapy is a promising treatment for certain advanced drug-resistant cancers. Although effective inhibition of various tumor cells was reported in vitro, combination treatment requires improvement in vivo due to uncontrolled ratiometric delivery. In this study, a tumor-targeting lipodisk nanoparticle formulation was developed for ratiometric loading and the transportation of two hydrophobic model drugs, doxorubicin (DOX) and paclitaxel (PTX), in one single platform. Furthermore, a slightly acidic pH-sensitive peptide (SAPSP) incorporated into lipodisks effectively enhanced the tumor-targeting and cell internalization. The obtained co-loaded lipodisks were approximately 30 nm with a pH-sensitive property. The ratiometric co-delivery of two drugs via lipodisks was confirmed in both the drug-resistant MCF-7/ADR cell line and its parental MCF-7 cell line in vitro, as well as in a tumor-bearing mouse model in vivo compared with a cocktail solution of free drugs. Co-loaded lipodisks exerted improved cytotoxicity to tumor cells in culture, particularly to drug-resistant tumor cells at synergistic drug ratios. In an in vivo xenograft mouse model, the anti-tumor ability of co-loaded lipodisks was evidenced by the remarkable inhibitory effect on tumor growth of either MCF-7 or MCF-7/ADR tumors, which may be attributed to the increased and ratiometric accumulation of both drugs in the tumor tissues. Therefore, tumor-specific lipodisks were crucial for the combination treatment of DOX and PTX to completely exert a synergistic anti-cancer effect. It is concluded that for co-loaded lipodisks, cytotoxicity data in vitro could be used to predict their inhibitory activity in vivo, potentially enhancing the clinical outcome of synergistic therapy.

Ovarian cancer is a leading cause of death worldwide from gynecological malignancies, mainly because there are few early symptoms and the disease is generally diagnosed at an advanced stage. In addition, despite the effectiveness of cytoreductive surgery for ovarian cancer and the high response rates to chemotherapy, survival has improved little over the last 20 years. The management of patients with ovarian cancer also remains similar despite studies showing striking differences and heterogeneity among different subtypes. It is therefore clear that novel targeted therapeutics are urgently needed to improve clinical outcomes for ovarian cancer. To that end, several membrane receptors associated with pivotal cellular processes and often aberrantly overexpressed in ovarian cancer cells have emerged as potential targets for receptor-mediated therapeutic strategies including specific agents and multifunctional delivery systems based on ligand-receptor binding. This review focuses on the profiles and potentials of such strategies proposed for ovarian cancer treatment and imaging.

Mengjie Rui, Yang Qu, Tong Gao, Yanru Ge, Chunlai Feng, Ximing Xu Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, People’s Republic of China Abstract: The development of drug resistance in cancer cells is one of the major obstacles to achieving effective chemotherapy. We hypothesized that the combination of a doxorubicin (Dox) prodrug and microRNA (miR)21 inhibitor might show synergistic antitumor effects on drug-resistant breast cancer cells. In this study, we aimed to develop new high-density lipoprotein-mimicking nanoparticles (HMNs) for coencapsulation and codelivery of this potential combination. Dox was coupled with a nuclear localization signal (NLS) peptide to construct a prodrug (NLS-Dox), thereby electrostatically condensing miR21 inhibitor (anti-miR21) to form cationic complexes. The HMNs were formulated by shielding these complexes with anionic lipids and Apo AI proteins. We have characterized that the coloaded HMNs had uniformly dispersed distribution, favorable negatively charged surface, and high coencapsulation efficiency. The HMN formulation effectively codelivered NLS-Dox and anti-miR21 into Dox-resistant breast cancer MCF7/ADR cells and wild-type MCF7 cells via a high-density-lipoprotein receptor-mediated pathway, which facilitated the escape of Pgp drug efflux. The coloaded HMNs consisting of NLS-Dox/anti-miR21 demonstrated greater cytotoxicity with enhanced intracellular accumulation in resistant MCF7/ADR cells compared with free Dox solution. The reversal of drug resistance by coloaded HMNs might be attributed to the suppression of miR21 expression and the related antiapoptosis network. Furthermore, the codelivery of anti-miR21 and NLS-Dox by HMNs showed synergistic antiproliferative effects in MCF7/ADR-bearing nude mice, and was more effective in tumor inhibition than other drug formulations. These data suggested that codelivery of anti-miR21 and chemotherapeutic agents by HMNs might be a promising strategy for antitumor therapy, and could restore the drug sensitivity of cancer cells, alter intracellular drug distribution, and ultimately enhance chemotherapeutic effects. Keywords: drug resistance, microRNA21 inhibitor, doxorubicin prodrug, nuclear localization signal peptide, lipoprotein-mimicking nanoparticles, breast cancer therapy

G-protein coupled receptors (GPCRs) represent one of the most important families of drug targets in pharmaceutical development. GLIDA is a public GPCR-related Chemical Genomics database that is primarily focused on the integration of information between GPCRs and their ligands. It provides interaction data between GPCRs and their ligands, along with chemical information on the ligands, as well as biological information regarding GPCRs. These data are connected with each other in a relational database, allowing users in the field of Chemical Genomics research to easily retrieve such information from either biological or chemical starting points. GLIDA includes a variety of similarity search functions for the GPCRs and for their ligands. Thus, GLIDA can provide correlation maps linking the searched homologous GPCRs (or ligands) with their ligands (or GPCRs). By analyzing the correlation patterns between GPCRs and ligands, we can gain more detailed knowledge about their conserved molecular recognition patterns and improve drug design efforts by focusing on inferred candidates for GPCR-specific drugs. This article provides a summary of the GLIDA database and user facilities, and describes recent improvements to database design, data contents, ligand classification programs, similarity search options and graphical interfaces. GLIDA is publicly available at http://pharminfo.pharm.kyoto-u.ac.jp/services/glida/. We hope that it will prove very useful for Chemical Genomics research and GPCR-related drug discovery.

Information on CYP-chemical interactions was comprehensively explored by a text-mining technique, to confirm our previous structure-activity relationship model for CYP substrates (Yamashita et al. J. Chem. Inf. Model. 2008, 48, 364-369). The text-mining technique is based on natural language processing and can extract chemical names and their interaction patterns according to sentence context. After chemicals were automatically extracted and classified into CYP substrates, inhibitors, and inducers, 709 substrates were retrieved from the PubChem database and categorized as 216, 145, 136, 217, 156, and 379 substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, respectively. Although the previous classification model was developed using data from only 161 compounds, the model classified the substrates found by text-mining analysis with reasonable accuracy. This confirmed the validity of both the multi-objective classification model for CYP substrates and the text-mining procedure.

Summary Background The 2009 influenza pandemics underscored the need for effective vaccines to block the spread of influenza virus infection. Most live attenuated vaccines utilize cold-adapted, temperature-sensitive virus. An alternative to live attenuated virus is presented here, based on microRNA-induced gene silencing. Methods In this study, miR-let-7b target sequences were inserted into the H1N1 genome to engineer a recombinant virus – miRT-H1N1. Female BALB/c mice were vaccinated intranasally with the miRT-H1N1 and challenged with a lethal dose of homologous virus. Results This miRT-H1N1 virus was attenuated in mice, while it exhibited wild-type characteristics in chicken embryos. Mice vaccinated intranasally with the miRT-H1N1 responded with robust immunity that protected the vaccinated mice from a lethal challenge with the wild-type 2009 pandemic H1N1 virus. Conclusions These results indicate that the influenza virus containing microRNA response elements (MREs) is attenuated in vivo and can be used to design a live attenuated vaccine.