Research Progress of SN38 Drug Delivery System in Cancer Treatment.

The active metabolite of irinotecan (CPT-11), 7-ethyl-10-hydroxycamptothecin (SN38), is 100-1000 times more active than CPT-11 and has shown inhibitory effects on a range of cancer cells, including those from the rectal, small cell lung, breast, esophageal, uterine, and ovarian malignancies. Despite SN38's potent anticancer properties, its hydrophobicity and pH instability have caused substantial side effects and anticancer activity loss, which make it difficult to use in clinical settings. To solve the above problems, the construction of SN38-based drug delivery systems is one of the most feasible methods to improve drug solubility, enhance drug stability, increase drug targeting ability, improve drug bioavailability, enhance therapeutic efficacy and reduce adverse drug reactions. Therefore, based on the targeting mechanism of drug delivery systems, this paper reviews SN38 drug delivery systems, including polymeric micelles, liposomal nanoparticles, polymeric nanoparticles, protein nanoparticles, conjugated drug delivery systems targeted by aptamers and ligands, antibody-drug couplings, magnetic targeting, photosensitive targeting, redox-sensitive and multi-stimulus-responsive drug delivery systems, and co-loaded drug delivery systems. The focus of this review is on nanocarrier-based SN38 drug delivery systems. We hope to provide a reference for the clinical translation and application of novel SN38 medications.

[Effects of Long-term Combined Application of Organic and Inorganic Fertilizers on Soil Carbon Pool and Greenhouse Gas Emissions in Orchards].

Applying organic fertilizer can increase the contents of soil organic carbon (SOC) and active organic carbon, which are crucial for strengthening soil quality and fertility. Four treatments were established:no fertilization (CK), single application of organic fertilizer (M), single application of chemical fertilizer (NPK), and combined application of organic and inorganic fertilizers (MNPK). The changes in SOC and active components under long-term combined application of organic and inorganic fertilizers were investigated, as were the effects of various fertilization measures on greenhouse gas emissions. Moreover, we evaluated the variation in the soil carbon pool management index (CPMI). Total organic carbon (TOC), microbial biomass carbon (MBC), dissolved organic carbon (DOC), easily oxidized organic carbon (EOC), and particulate organic carbon (POC) increased by 82.84%, 66.30%, 21.12%, 93.28%, and 145.80%, respectively, when compared to those in the CK treatment. The NPK treatment had no discernible effect on SOC and organic carbon components. The combined application of organic and inorganic materials could enhance LI, CPI, and the soil carbon pool management index, with the increase in LI and CPI being the primary reason for the increase in CPMI. Correlation analyses revealed that soil organic carbon components and CPMI were significantly positively correlated with greenhouse gas emissions. The combined application of organic and inorganic materials enhanced cumulative CO2 emissions and warming potential (GWP) but decreased GHGI and yielded a maximum of 56365 kg·hm-2. Compared with that in the CK treatment (29073 kg·hm-2), apple yield in MNPK increased by 93.87%. Therefore, applying organic and inorganic fertilizers in dryland apple orchards can improve the accumulation of organic carbon and stabilize the soil carbon pool, which is more beneficial to the sustainable development of orchards.

Development of curcumin-loaded galactosylated chitosan-coated nanoparticles for targeted delivery of hepatocellular carcinoma.

Curcumin (CUR) has good antitumor effects, but its poor aqueous solubility severely limits its clinical application and the systemic nonspecific distribution of the free drug in tumor patients is a key therapeutic challenge. In order to overcome the limitations of free drugs and improve the therapeutic efficacy, we developed novel galactosylated chitosan (GC)-modified nanoparticles (GC@NPs) based on poly (ethylene glycol) methyl ether-block-poly (lactide-co-glycolide) (PEG-PLGA), which can target asialoglycoprotein receptor (ASGPR) expressed on hepatocellular carcinoma cells and have excellent biocompatibility. The results showed that the drug loading (DL) of CUR was approximately 4.56 %. A favorable biosafety profile was maintained up to concentrations of 500 µg/mL. Furthermore, in vitro cellular assays showed that GC@NPs could be efficiently internalized by HepG2 cells via ASGPR-mediated endocytosis and successfully released CUR for chemotherapy. More importantly, in vivo anti-tumor experiments revealed that GC@NPs were able to accumulate effectively within tumor sites through EPR effect and ASGPR-mediated endocytosis, leading to superior inhibition of tumor growth compared to free CUR. Overall, GC@NPs are a promising CUR nanocarrier for enhanced tumor therapy with a good biosafety profile.

The mycobiome: interactions with host and implications in diseases.

Over the past decade, our understanding of the composition and function of the human mucosal surface-associated fungal community (i.e. the mycobiome) has rapidly expanded. Fungi colonize at various sites of the mucosal surface at birth and play important roles in the development and homeostasis of immune system throughout adulthood. Here, we review the recent research progresses in the human mycobiome at different body sites, including the gastrointestinal (GI) tract, the respiratory tract, the urogenital tract, the oral cavity, the skin surface, and the tumor tissues. Researchers have made extensive effort in characterizing the interactions between mycobiome and immune system, especially in the GI tract. We discuss the mycobiome dysbiosis and its implications to the progression of diseases such as inflammatory bowel diseases, alcoholic liver diseases, systemic infections, cancers, and so on, indicating the potential of mycobiome-targeting intervention strategy for life-threatening diseases.

Targeted Drug Delivery Systems for Curcumin in Breast Cancer Therapy.

Breast cancer (BC) is the most prevalent type of cancer in the world and the main reason women die from cancer. Due to the significant side effects of conventional treatments such as chemotherapy and radiotherapy, the search for supplemental and alternative natural drugs with lower toxicity and side effects is of interest to researchers. Curcumin (CUR) is a natural polyphenol extracted from turmeric. Numerous studies have demonstrated that CUR is an effective anticancer drug that works by modifying different intracellular signaling pathways. CUR's therapeutic utility is severely constrained by its short half-life in vivo, low water solubility, poor stability, quick metabolism, low oral bioavailability, and potential for gastrointestinal discomfort with high oral doses. One of the most practical solutions to the aforementioned issues is the development of targeted drug delivery systems (TDDSs) based on nanomaterials. To improve drug targeting and efficacy and to serve as a reference for the development and use of CUR TDDSs in the clinical setting, this review describes the physicochemical properties and bioavailability of CUR and its mechanism of action on BC, with emphasis on recent studies on TDDSs for BC in combination with CUR, including passive TDDSs, active TDDSs and physicochemical TDDSs.

Targeted drug delivery systems for elemene in cancer therapy: The story thus far.

Elemene (ELE) is a group of broad-spectrum anticancer active ingredients with low toxicity extracted from traditional Chinese medicines (TCMs), such as Curcumae Rhizoma and Curcuma Radix, which can exert antitumour activities by regulating various signal pathways and targets. However, the strong hydrophobicity, short half-life, low bioavailability and weak in vivo targeting ability of ELE restrict its use. Targeted drug delivery systems based on nanomaterials are among the most viable methods to overcome these shortcomings. In this review, we first summarize recent studies on the clinical uses of ELE as an adjunct antitumour drug. ELE-based combination strategies have great promise for enhancing efficacy, reducing adverse reactions, and improving patients' quality of life and immune function. Second, we summarize recent studies on the antitumour mechanisms of ELE and ELE-based combination strategies. The potential mechanisms include inducing pyroptosis and ferroptosis, promoting senescence, regulating METTL3-mediated m6A modification, suppressing the Warburg effect, and inducing apoptosis and cell cycle arrest. Most importantly, we comprehensively summarize studies on the combination of targeted drug delivery systems with ELE, including passively and actively targeted drug delivery systems, stimuli-responsive drug delivery systems, and codelivery systems for ELE combined with other therapies, which have great promise in improving drug bioavailability, increasing drug targeting ability, controlling drug release, enhancing drug efficacy, reducing drug adverse effects and reversing MDR. Our summary will provide a reference for the combination of TCMs such as ELE with advanced targeted drug delivery systems in the future.

Worldwide emergence of fluconazole-resistant Candida parapsilosis: current framework and future research roadmap.

Candida parapsilosis is one of the most commen causes of life-threatening candidaemia, particularly in premature neonates, individuals with cancer of the haematopoietic system, and recipients of organ transplants. Historically, drug-susceptible strains have been linked to clonal outbreaks. However, worldwide studies started since 2018 have reported severe outbreaks among adults caused by fluconazole-resistant strains. Outbreaks caused by fluconazole-resistant strains are associated with high mortality rates and can persist despite strict infection control strategies. The emergence of resistance threatens the efficacy of azoles, which is the most widely used class of antifungals and the only available oral treatment option for candidaemia. The fact that most patients infected with fluconazole-resistant strains are azole-naive underscores the high potential adaptability of fluconazole-resistant strains to diverse hosts, environmental niches, and reservoirs. Another concern is the multidrug-resistant and echinocandin-tolerant C parapsilosis isolates, which emerged in 2020. Raising awareness, establishing effective clinical interventions, and understanding the biology and pathogenesis of fluconazole-resistant C parapsilosis are urgently needed to improve treatment strategies and outcomes.

Recent progress in the development of nanomaterials targeting multiple cancer metabolic pathways: a review of mechanistic approaches for cancer treatment.

Cancer is a very heterogeneous disease, and uncontrolled cell division is the main characteristic of cancer. Cancerous cells need a high nutrition intake to enable aberrant growth and survival. To do so, cancer cells modify metabolic pathways to produce energy and anabolic precursors and preserve redox balance. Due to the importance of metabolic pathways in tumor growth and malignant transformation, metabolic pathways have also been given promising perspectives for cancer treatment, providing more effective treatment strategies, and target-specific with minimum side effects. Metabolism-based therapeutic nanomaterials for targeted cancer treatment are a promising option. Numerous types of nanoparticles (NPs) are employed in the research and analysis of various cancer therapies. The current review focuses on cutting-edge strategies and current cancer therapy methods based on nanomaterials that target various cancer metabolisms. Additionally, it highlighted the primacy of NPs-based cancer therapies over traditional ones, the challenges, and the future potential.

Profiling the Fungal Microbiome after Fecal Microbiota Transplantation for Graft-versus-Host Disease: Insights from a Phase 1 Interventional Study.

Disruption of the intestinal bacterial microbiota is frequently observed in the context of allogeneic hematopoietic cell transplantation (HCT) and is particularly pronounced in patients who develop graft-versus-host disease (GVHD). Donor fecal microbiota transplantation (FMT) restores gut microbial diversity and reduces GVHD in HCT recipients. The composition of the intestinal fungal community in patients with GVHD, and whether fungal taxa are transferred during FMT are currently unknown. We performed a secondary analysis of our clinical trial of FMT in patients with steroid-refractory GVHD with a focus on the mycobiota. We characterized the fecal mycobiota of 17 patients and healthy FMT donors using internal transcribed spacer amplicon sequencing. The donor who provided the majority of FMT material in our study represents an n-of-one study of the intestinal flora over time. In this donor, mycobiota composition fluctuated over time while the bacterial microbiota remained stable over 16 months. Fungal DNA was detected more frequently in baseline stool samples from patients with steroid-refractory GVHD than in patients with steroid-dependent GVHD. We could detect fungal taxa in the majority of samples but did not see evidence of mycobiota transfer from donor to recipient. Our study demonstrates the feasibility of profiling the mycobiota alongside the more traditional bacterial microbiota, establishes the methodology, and provides a first insight into the mycobiota composition of patients with GVHD.

Review targeted drug delivery systems for norcantharidin in cancer therapy.

Norcantharidin (NCTD) is a demethylated derivative of cantharidin (CTD), the main anticancer active ingredient isolated from traditional Chinese medicine Mylabris. NCTD has been approved by the State Food and Drug Administration for the treatment of various solid tumors, especially liver cancer. Although NCTD greatly reduces the toxicity of CTD, there is still a certain degree of urinary toxicity and organ toxicity, and the poor solubility, short half-life, fast metabolism, as well as high venous irritation and weak tumor targeting ability limit its widespread application in the clinic. To reduce its toxicity and improve its efficacy, design of targeted drug delivery systems based on biomaterials and nanomaterials is one of the most feasible strategies. Therefore, this review focused on the studies of targeted drug delivery systems combined with NCTD in recent years, including passive and active targeted drug delivery systems, and physicochemical targeted drug delivery systems for improving drug bioavailability and enhancing its efficacy, as well as increasing drug targeting ability and reducing its adverse effects.

Systematic Analysis of Copy Number Variations in the Pathogenic Yeast Candida parapsilosis Identifies a Gene Amplification in RTA3 That is Associated with Drug Resistance.

We analyzed the genomes of 170 C. parapsilosis isolates and identified multiple copy number variations (CNVs). We identified two genes, RTA3 (CPAR2_104610) and ARR3 (CPAR2_601050), each of which was the target of multiple independent amplification events. Phylogenetic analysis shows that most of these amplifications originated only once. For ARR3, which encodes a putative arsenate transporter, 8 distinct CNVs were identified, ranging in size from 2.3 kb to 10.5 kb with 3 to 23 copies. For RTA3, 16 distinct CNVs were identified, ranging in size from 0.3 kb to 4.5 kb with 2 to ~50 copies. One unusual amplification resulted in a DUP-TRP/INV-DUP structure similar to some human CNVs. RTA3 encodes a putative phosphatidylcholine (PC) floppase which is known to regulate the inward translocation of PC in Candida albicans. We found that an increased copy number of RTA3 correlated with resistance to miltefosine, an alkylphosphocholine drug that affects PC metabolism. Additionally, we conducted an adaptive laboratory evolution experiment in which two C. parapsilosis isolates were cultured in increasing concentrations of miltefosine. Two genes, CPAR2_303950 and CPAR2_102700, coding for putative PC flippases homologous to S. cerevisiae DNF1 gained homozygous protein-disrupting mutations in the evolved strains. Overall, our results show that C. parapsilosis can gain resistance to miltefosine, a drug that has recently been granted orphan drug designation approval by the United States Food and Drug Administration for the treatment of invasive candidiasis, through both CNVs or loss-of-function alleles in one of the flippase genes. IMPORTANCE Copy number variations (CNVs) are an important source of genomic diversity that have been associated with drug resistance. We identify two unusual CNVs in the human fungal pathogen Candida parapsilosis. Both target a single gene (RTA3 or ARR3), and they have occurred multiple times in multiple isolates. The copy number of RTA3, a putative floppase that controls the inward translocation of lipids in the cell membrane, correlates with resistance to miltefosine, a derivative of phosphatidylcholine (PC) that was originally developed as an anticancer drug. In 2021, miltefosine was designated an orphan drug by the United States Food and Drug Administration for the treatment of invasive candidiasis. Importantly, we find that resistance to miltefosine is also caused by mutations in flippases, which control the outward movement of lipids, and that many C. parapsilosis isolates are prone to easily acquiring an increased resistance to miltefosine.

Urokinase-type plasminogen activator receptor (uPAR) as a therapeutic target in cancer.

Urokinase-type plasminogen activator receptor (uPAR) is an attractive target for the treatment of cancer, because it is expressed at low levels in healthy tissues but at high levels in malignant tumours. uPAR is closely related to the invasion and metastasis of malignant tumours, plays important roles in the degradation of extracellular matrix (ECM), tumour angiogenesis, cell proliferation and apoptosis, and is associated with the multidrug resistance (MDR) of tumour cells, which has important guiding significance for the judgement of tumor malignancy and prognosis. Several uPAR-targeted antitumour therapeutic agents have been developed to suppress tumour growth, metastatic processes and drug resistance. Here, we review the recent advances in the development of uPAR-targeted antitumor therapeutic strategies, including nanoplatforms carrying therapeutic agents, photodynamic therapy (PDT)/photothermal therapy (PTT) platforms, oncolytic virotherapy, gene therapy technologies, monoclonal antibody therapy and tumour immunotherapy, to promote the translation of these therapeutic agents to clinical applications.

Haematopoietic cell transplantation outcomes are linked to intestinal mycobiota dynamics and an expansion of Candida parapsilosis complex species.

Allogeneic haematopoietic cell transplantation (allo-HCT) induces profound shifts in the intestinal bacterial microbiota. The dynamics of intestinal fungi and their impact on clinical outcomes during allo-HCT are not fully understood. Here we combined parallel high-throughput fungal ITS1 amplicon sequencing, bacterial 16S amplicon sequencing and fungal cultures of 1,279 faecal samples from a cohort of 156 patients undergoing allo-HCT to reveal potential trans-kingdom dynamics and their association with patient outcomes. We saw that the overall density and the biodiversity of intestinal fungi were stable during allo-HCT but the species composition changed drastically from day to day. We identified a subset of patients with fungal dysbiosis defined by culture positivity (n = 53) and stable expansion of Candida parapsilosis complex species (n = 19). They presented with distinct trans-kingdom microbiota profiles, characterized by a decreased intestinal bacterial biomass. These patients had worse overall survival and higher transplant-related mortality independent of candidaemia. This expands our understanding of the clinical significance of the mycobiota and suggests that targeting fungal dysbiosis may help to improve long-term patient survival.

Tanshinone IIA derivatives induced S-phase arrest through stabilizing c-myc G-quadruplex DNA to regulate ROS-mediated PI3K/Akt/mTOR pathway.

Herein, a derivate from tanshinone IIA, 1,6,6-trimethyl-11-phenyl-7,8,9,10-tetrahydro-6H-furo[2',3':1,2]phenanthro[3,4-d]imidazole (TA25), has been synthesized and investigated as potential inhibitor against the proliferation, migration and invasion of lung cancer cells. MTT assay and cell colony formation assay results showed that TA25 exhibits acceptable inhibitory effect against the proliferation of lung cancer A549 cells, and the value of IC50 was about 17.9 µM. This result was further confirmed by the inhibition of TA25 against the growth of xenograft lung cancer cells on zebrafish bearing tumor (A549 lung cancer cells). The results of wound-healing assay and FITC-gelatin invasion assay displayed that TA25 could inhibit the migration and invasion of lung cancer A549 cells. Moreover, the studies on the binding properties of TA25 interact with c-myc G-quadruplex DNA suggested that TA25 can bind in the G-quarter plane formed from G7, G11, G16 and G20 with c-myc G-quadruplex DNA through π-π stacking. Further study of the potential anti-cancer mechanism indicated that TA25 can induce S-phase arrest in lung cancer A549 cells, and this phenomenon resulted from the promotion of the production of reactive oxygen species and DNA damage in A549 cells under the action of TA25. Further research revealed that TA25 could inhibit the PI3K/Akt/mTOR signal pathway and increase the expression of p53 protein. Overall, TA25 can be developed into a promising inhibitor against the proliferation, migration and invasion of lung cancer cells and has potential clinical application in the near future.

[Doxorubicin Hydrochloride Liposome-Based CHOP Regimen in the Initial Treatment of Elderly Patients with Diffuse Large B-Cell Lymphoma: A Retrospective Study].

OBJECTIVE: To evaluate the efficacy and safety of CHOP regimen based on doxorubicin hydrochloride liposome in the initial treatment of elderly patients with diffuse large B-cell lymphoma (DLBCL). METHODS: Thirty-one patients with DLBCL treated from January 1, 2012 to December 31, 2019 were analyzed retrospectively, their median age was 83 (71-95) years old, and all of them were in Ⅲ-Ⅳ stage, including 17 cases who had international prognostic index (IPI) ≥ 3. The patients were treated with R-CHOP and CHOP regimens based on doxorubicin hydrochloride liposome. The efficacy and safety were evaluated during and after treatment. RESULTS: A total of 219 chemotherapy cycles and 7 median cycles were performed in 31 patients. The overall response (OR) rate and complete remission (CR) rate was 80.7% (25/31) and 61.3% (19/31), respectively, as well as 2 cases (6.5%) stable, 4 cases (12.9%) progressive. The main toxicities were as follows: the incidence of grade Ⅲ -Ⅳ neutropenia was 29% (9/31); two patients (6.5%) developed degree Ⅰ-Ⅱ cardiac events, which were characterized by new degree Ⅰ atrioventricular block; there were no cardiac events requiring emergency treatment and discontinuation of chemotherapy. The 1-year, 2-year and 3-year overall survival rate was 83.9%, 77.4% and 61.3%, respectively. The 1-year, 2-year and 3-year progression-free survival rate was 77.4%, 64.5% and 61.3%, respectively. CONCLUSION: The chemotherapy regimen based on doxorubicin hydrochloride liposome has better efficacy and higher cardiac safety for elderly patients with DLBCL.

Mycobiota dysbiosis and gastric tumorigenesis.

The gastrointestinal tract contains a vast and diverse microbial reservoir composed of bacteria, fungi, and viruses that contribute positively to human health. There is growing evidence that perturbation of the normal microbiota can promote a variety of human disease states that include tumorigenesis. Whether the fungal component of the gut microbiota (i.e., the mycobiota) can influence tumor development has not been investigated in detail. In the recent issue of the Theranostics, Zhong et al (2021) shed light on an association between mycobiota dysbiosis and gastric cancer. These findings implicate the mycobiota in gastric carcinogenesis and set the stage for future mechanistic studies to explore whether fungal dysbiosis is a cause or consequence of gastric carcinogenesis, with important implications for preventative strategies.

Gm40600 promotes CD4+ T-cell responses by interacting with Ahnak.

It is important to characterize novel proteins involved in T- and B-cell responses. Our previous study demonstrated that a novel protein, Mus musculus Gm40600, reduced the proliferation of Mus musculus plasmablast (PB)-like SP 2/0 cells and B-cell responses induced in vitro by LPS. In the present study, we revealed that Gm40600 directly promoted CD4+ T-cell responses to indirectly up-regulate B-cell responses. Importantly, we found that CD4+ T-cell responses, including T-cell activation and differentiation and cytokine production, were increased in Gm40600 transgenic (Tg) mice and were reduced in Gm40600 knockout (KO) mice. Finally, we demonstrated that Gm40600 promoted the Ahnak-mediated calcium signalling pathway by interacting with Ahnak to maintain a cytoplasmic lateral location of Ahnak in CD4+ T cells. Collectively, our data suggest that Gm40600 promotes CD4+ T-cell activation to up-regulate the B-cell response via interacting with Ahnak to promote the calcium signalling pathway. The results suggest that targeting Gm40600 may be a means to control CD4+ T-cell-related diseases.

Hspa13 Promotes Plasma Cell Production and Antibody Secretion.

The generation of large numbers of plasma cells (PCs) is a main factor in systemic lupus erythematosus (SLE). We hypothesize that Hspa13, a member of the heat shock protein family, plays a critical role in the control of PC differentiation. To test the hypothesis, we used lipopolysaccharide (LPS)-activated B cells and a newly established mouse line with a CD19cre-mediated, B cell-specific deletion of Hspa13: Hspa13 cKO mice. We found that Hspa13 mRNA was increased in PCs from atacicept-treated lupus-prone mice and in LPS-stimulated plasmablasts (PBs) and PCs. A critical finding was that PBs and PCs [but not naïve B cells and germinal center (GC) B cells] expressed high levels of Hspa13. In contrast, the Hspa13 cKO mice had a reduction in BPs, PCs, and antibodies induced in vitro by LPS and in vivo by sheep red blood cells (SRCs)- or 4-hydroxy-3-nitrophenylacetyl (NP)-immunization. Accordingly, the Hspa13 cKO mice had reduced class-switched and somatically hypermutated antibodies with defective affinity maturation. Our work also showed that Hspa13 interacts with proteins (e.g., Bcap31) in the endoplasmic reticulum (ER) to positively regulate protein transport from the ER to the cytosol. Importantly, Hspa13 mRNA was increased in B220+ cells from patients with multiple myeloma (MM) or SLE, whereas Hspa13 cKO led to reduced autoantibodies and proteinuria in both pristane-induced lupus and lupus-prone MRL/lpr mouse models. Collectively, our data suggest that Hspa13 is critical for PC development and may be a new target for eliminating pathologic PCs.

High-resolution mycobiota analysis reveals dynamic intestinal translocation preceding invasive candidiasis.

The intestinal microbiota is a complex community of bacteria, archaea, viruses, protists and fungi1,2. Although the composition of bacterial constituents has been linked to immune homeostasis and infectious susceptibility3-7, the role of non-bacterial constituents and cross-kingdom microbial interactions in these processes is poorly understood2,8. Fungi represent a major cause of infectious morbidity and mortality in immunocompromised individuals, although the relationship of intestinal fungi (that is, the mycobiota) with fungal bloodstream infections remains undefined9. We integrated an optimized bioinformatics pipeline with high-resolution mycobiota sequencing and comparative genomic analyses of fecal and blood specimens from recipients of allogeneic hematopoietic cell transplant. Patients with Candida bloodstream infection experienced a prior marked intestinal expansion of pathogenic Candida species; this expansion consisted of a complex dynamic between multiple species and subspecies with a stochastic translocation pattern into the bloodstream. The intestinal expansion of pathogenic Candida spp. was associated with a substantial loss in bacterial burden and diversity, particularly in the anaerobes. Thus, simultaneous analysis of intestinal fungi and bacteria identifies dysbiosis states across kingdoms that may promote fungal translocation and facilitate invasive disease. These findings support microbiota-driven approaches to identify patients at risk of fungal bloodstream infections for pre-emptive therapeutic intervention.

Gm40600 suppressed SP 2/0 isograft tumor by reducing Blimp1 and Xbp1 proteins.

BACKGROUND: Multiple myeloma (MM), characterized by cancerous proliferation of plasmablasts (PB) and plasma cells (PC), remains incurable in many patients. Differentially expressed molecules between MM PCs and healthy PCs have been explored in order to identify novel targets for treating MM. In the present study, we searched for novel MM therapeutic targets by comparing mRNA expression patterns between the Mus musculus myeloma plasmablast-like SP 2/0 cell line and LPS-induced PB/PC. METHODS: Gene expression profiles of LPS-induced PB/PC and SP 2/0 cells were determined using RNA-sequencing. A predicted gene (Gm40600) was found to be expressed at a low level in SP 2/0 cells. To study the role of Gm40600 in malignant PC, Gm40600 cDNA was cloned into a lentiviral vector (LV201) containing a puromycin selectable marker that was then transfected into SP 2/0 cells. Stable Gm40600-expressing SP 2/0 cells were selected using puromycin. The effect of Gm40600 on SP 2/0 cell proliferation, cell cycle/apoptosis, and tumor progression was assessed by cell counting kit-8 (CCK8), flow cytometry (FACS), and the SP 2/0 isograft mouse model, respectively. The effect of Gm40600 on mRNA and protein expression was evaluated by RNA-sequencing and western blotting, respectively. RESULTS: We found that SP 2/0 cells expressed lower level of Gm40600 mRNA as compared to LPS-induced PB/PC. Overexpression of Gm40600 significantly suppressed SP 2/0 cell proliferation and isograft tumor progression in an isograft mouse model by promoting apoptosis. In addition, Gm40600 overexpression suppressed transcription of the gene encoding Bcl2. Gm40600 overexpression also reduced the expression of PC-associated transcription factors Blimp1 and Xbp1, which promote transcription of the gene that encodes Bcl2. CONCLUSIONS: Gm40600 reduced SP 2/0 cell proliferation and isograft tumor growth and progression by suppressing Blimp1 and Xbp1-mediated Bcl2 transcription to induce apoptosis. Thus, regulation of a human homolog of Gm40600, or associated factors, may be a potential therapeutic approach for treating MM.