Context-dependent T-BOX transcription factor family: from biology to targeted therapy.

T-BOX factors belong to an evolutionarily conserved family of transcription factors. T-BOX factors not only play key roles in growth and development but are also involved in immunity, cancer initiation, and progression. Moreover, the same T-BOX molecule exhibits different or even opposite effects in various developmental processes and tumor microenvironments. Understanding the multiple roles of context-dependent T-BOX factors in malignancies is vital for uncovering the potential of T-BOX-targeted cancer therapy. We summarize the physiological roles of T-BOX factors in different developmental processes and their pathological roles observed when their expression is dysregulated. We also discuss their regulatory roles in tumor immune microenvironment (TIME) and the newly arising questions that remain unresolved. This review will help in systematically and comprehensively understanding the vital role of the T-BOX transcription factor family in tumor physiology, pathology, and immunity. The intention is to provide valuable information to support the development of T-BOX-targeted therapy.

Morphological and phylogenetic analyses reveal a new species of Anthracophyllum (Omphalotaceae, Agaricales) in Zhejiang Province, China.

During the investigations of macrofungi resources in Zhejiang Province, China, an interesting wood rot fungus was collected. Based on morphological and molecular phylogenetic studies, it is described as a new species, Anthracophyllum sinense. A. sinense is characterized by its sessile, charcoal black and pleurotoid pileus, sparse lamellae occasionally branching, clavate basidia with long sterigmata [(3-)6-7(-8) µm], and non-heteromorphous cystidia. A. sinense establishes a separate lineage close to A. archeri and A. lateritium in the phylogenetic tree.

Retiboletus atrofuscus (Boletaceae, Boletales), a new species from China.

Based on morphological and phylogenetic analyses, an ectomycorrhizal fungus collected from Jiangxi, China, is described as a new species. R. atrofuscus is morphological characterized by a dark gray to black pileus, white to pale yellowish white hymenophore, a grayish brown to pale yellow context, which turning orange-yellow to rusty yellow when injured, a prominently and coarsely white to pale yellow to black reticulation on upper 3/4 or entire stipe, grayish yellow to pale yellow to yellowish brown basidiospores in KOH with measuring (7-)7.5-13(-13.5) × (3-)3.5-5(-5.5) µm. Phylogenetic analysis results showed that R. atrofuscus formed an independent lineage within Retiboletus. Descriptions and hand drawings of the new species and comparisons with similar species are presented.

Aquapteridospora jiangxiensis, a new aquatic hyphomycetous fungus from a freshwater habitat in China.

During an investigation of freshwater fungi in Jiangxi province, China, a new hyphomycetous fungus, Aquapteridospora jiangxiensis, was collected and isolated. Aquapteridospora jiangxiensis is characterized by its unbranched and guttulate conidiophores with multi-septa swollen at the base, polyblastic conidiogenous cells with sympodial proliferations, and denticles, and guttulate conidia with a sheath. A photo plate of the macro- and micro-morphology and a muti-loci (ITS, LSU, SSU, TEF1 and RPB2) phylogenetic tree are provided. A key to the species of Aquapteridospora is also presented in this paper.

Immunotherapy for type 1 diabetes mellitus by adjuvant-free Schistosoma japonicum-egg tip-loaded asymmetric microneedle patch (STAMP).

BACKGROUND: Type 1 diabetes mellitus (T1DM) is an autoimmune disease mediated by autoreactive T cells and dominated by Th1 response polarization. Insulin replacement therapy faces great challenges to this autoimmune disease, requiring highly frequent daily administration. Intriguingly, the progression of T1DM has proven to be prevented or attenuated by helminth infection or worm antigens for a relatively long term. However, the inevitable problems of low safety and poor compliance arise from infection with live worms or direct injection of antigens. Microneedles would be a promising candidate for local delivery of intact antigens, thus providing an opportunity for the clinical immunotherapy of parasitic products. METHODS: We developed a Schistosoma japonicum-egg tip-loaded asymmetric microneedle patch (STAMP) system, which serves as a new strategy to combat TIDM. In order to improve retention time and reduce contamination risk, a specific imperfection was introduced on the STAMP (asymmetric structure), which allows the tip to quickly separate from the base layer, improving reaction time and patient's comfort. After loading Schistosoma japonicum-egg as the immune regulator, the effects of STAMP on blood glucose control and pancreatic pathological progression improvement were evaluated in vivo. Meanwhile, the immunoregulatory mechanism and biosafety of STAMP were confirmed by histopathology, qRT-PCR, ELISA and Flow cytometric analysis. RESULTS: Here, the newly developed STAMP was able to significantly reduce blood glucose and attenuate the pancreatic injury in T1DM mice independent of the adjuvants. The isolated Schistosoma japonicum-eggs micron slowly degraded in the skin and continuously released egg antigen for at least 2 weeks, ensuring localization and safety of antigen stimulation. This phenomenon should be attributed to the shift of Th2 immune response to reduce Th1 polarization. CONCLUSION: Our results exhibited that STAMP could significantly regulate the blood glucose level and attenuate pancreatic pathological injury in T1DM mice by balancing the Th1/Th2 immune responses, which is independent of adjuvants. This technology opens a new window for the application of parasite products in clinical immunotherapy.

Roles of metformin-mediated girdin expression in metastasis of epithelial ovarian cancer.

Antimetastatic effect of Metformin has been documented in epithelial ovarian cancer (EOC). Presently, we investigated the regulatory mechanism of Metformin in EOC metastasis. First, Girdin was significantly enhanced in EOC tumorous tissues and cell lines. Seconded, knockdown of Girdin significantly suppressed EOC cell viability, migration, and invasion, while upregulation of Girdin produced the opposite effects in vitro and facilitated lung metastasis in EOC cell xenograft in vivo. In addition, we confirmed that the inhibitory effect of Metformin on Girdin expression. Mechanistically, the oncogenic effects of Girdin could be reversed by LY294002 (an AKT pathway inhibitor) and Metformin. These results suggested that Metformin attenuated EOC metastasis through Girdin and targeting Girdin may be a promising therapeutic strategy for EOC in the future.

Questioning the Yelp Effect: Mixed Methods Analysis of Web-Based Reviews of Urgent Cares.

BACKGROUND: Providers of on-demand care, such as those in urgent care centers, may prescribe antibiotics unnecessarily because they fear receiving negative reviews on web-based platforms from unsatisfied patients-the so-called Yelp effect. This effect is hypothesized to be a significant driver of inappropriate antibiotic prescribing, which exacerbates antibiotic resistance. OBJECTIVE: In this study, we aimed to determine the frequency with which patients left negative reviews on web-based platforms after they expected to receive antibiotics in an urgent care setting but did not. METHODS: We obtained a list of 8662 urgent care facilities from the Yelp application programming interface. By using this list, we automatically collected 481,825 web-based reviews from Google Maps between January 21 and February 10, 2019. We used machine learning algorithms to summarize the contents of these reviews. Additionally, 200 randomly sampled reviews were analyzed by 4 annotators to verify the types of messages present and whether they were consistent with the Yelp effect. RESULTS: We collected 481,825 reviews, of which 1696 (95% CI 1240-2152) exhibited the Yelp effect. Negative reviews primarily identified operations issues regarding wait times, rude staff, billing, and communication. CONCLUSIONS: Urgent care patients rarely express expectations for antibiotics in negative web-based reviews. Thus, our findings do not support an association between a lack of antibiotic prescriptions and negative web-based reviews. Rather, patients' dissatisfaction with urgent care was most strongly linked to operations issues that were not related to the clinical management plan.

Molecular techniques reveal more secrets of fermented foods.

Fermented foods were likely to have been the first among all types of processed foods consumed by human beings. The role that fermented food plays is not only related to the development of civilizations and cultural relationships between countries but also related to the nutritional importance of its population. Of course, the early manufacturers of fermented foods didn't take into account the advantages of modern sciences, because enzymes and microorganisms were discovered just 150-200 years ago. For that reason, we can conclude why the ancient fermentation techniques were known to philosophers and alchemists, but not to biologists. It demonstrated that the fermentation mechanisms involved many secrets still undiscovered. Recently, applications of molecular techniques for analyzing and study the fermented foods have been explored. In this review, we provide answers with a critical vision to many questions for understanding the role of molecular techniques to discover the secrets of fermented foods such as how to evaluate the traditional fermented foods? Why using molecular techniques to study the fermented foods not else? Is the future will carry to us a boom in molecular technologies contribute to the detection of more secrets of the fermented food?

Upregulation of microRNA-133a and downregulation of connective tissue growth factor suppress cell proliferation, migration, and invasion in human glioma through the JAK/STAT signaling pathway.

Recently, microRNA-133a (miR-133a) has been found to function in many diseases in previous studies, yet few studies have been focused on its role in glioma. This study aims to investigate the mechanism of miR-133a/CTGF on regulating the malignant phenotypes of glioma cells via the JAK/STAT signaling pathway. Sixty-five human glioma specimens were collected and 30 normal brain tissues were selected as controls. The expression of connective tissue growth factor (CTGF) and miR-133a in tissues was detected, and the relationship between their expression and the clinicopathological features as well as prognosis of glioma was analyzed. MiR-133a and CTGF expression in U87, A172, and HEB cell lines was determined. The expression of CTGF, signaling pathway-, proliferation-, migration-, invasion-, apoptosis- and epithelial-mesenchymal transition (EMT)-related factors was detected. A number of assays were used to detect cell proliferation, migration, invasion, cell cycle, apoptosis, glioma growth, and the targeting site between CTGF and miR-133a. MiR-133a was downregulated and CTGF was upregulated in human glioma tissues and cells. MiR-133a and CTGF expression was related to glioma's WHO staging and size. Downregulated miR-133a and upregulated CTGF caused unfavorable prognosis in glioma. Upregulated miR-133a suppressed CTGF expression and the activation of JAK/STAT signaling pathway, thereby constraining cell colony formation, proliferation, migration and invasion, and promoting apoptosis in glioma. Our study reveals that upregulated miR-133a and downregulated CTGF suppress cell proliferation, migration, and invasion in human glioma through the inhibition of the JAK/STAT signaling pathway.

Selective 14-3-3γ Upregulation Promotes Beclin-1-LC3-Autophagic Influx via ß-Catenin Interaction in Starved Neurons In Vitro and In Vivo.

Lack of blood or glucose supply is the most common pathological factor in the brain. To cope with such an energy stress, initiating programmed autophagic processes in neurons is required. However, the mechanisms controlling neuronal autophagy during starvation remain far from clear. Here, we report an essential role of 14-3-3γ in starvation-activated neuronal autophagic influx signaling and elucidate the underlying mechanism. Double-fluorescent immunostaining demonstrates that 14-3-3γ protein elevation is well co-localized with Beclin-1 and LC3 elevation in cortical neurons in ischemic brains. Starvation treatment activates autophagic influx and upregulates Beclin-1 and only the γ isoform of 14-3-3 in N2a cells and cultured cortical neurons. Suppressing overall 14-3-3 function by difopein overexpression or knocking-out the γ isoform of 14-3-3 is sufficient to abolish starvation-induced Beclin-1 induction and LC3 activation while overexpressing 14-3-3γ but no other 14-3-3 isoform significantly upregulate Beclin-1-LC3 signaling. Upon starvation, 14-3-3γ binds more p-ß-catenin but less Beclin-1. Finally, overexpressing 14-3-3γ reactivates ß-catenin-suppressed Beclin-1-LC3 signaling in neuronal cells. Taken together, our data reveal that starvation-induced 14-3-3γ is required for ß-catenin-Beclin-1-LC3-autophagy in starved neurons in vitro and in vivo, which may provide insights in the treatment of neurologic diseases such as stoke.

PD-L1 confers glioblastoma multiforme malignancy via Ras binding and Ras/Erk/EMT activation.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor due to the lack of effective therapeutic drugs. Cancer therapy targeting programmed cell death protein 1 (PD-1) or programmed death ligand-1 (PD-L1) is of revolutionary. However, the role of intrinsic PD-L1, which determines immune-therapy outcomes, remains largely unclear. Here we demonstrated an oncogenic role of PD-L1 via binding and activating Ras in GBM cells. RNA-sequencing transcriptome data revealed that PD-L1 significantly altered gene expression enriched in cell growth/migration/invasion pathways in human GBM cells. PD-L1 overexpression and knockout or knockdown demonstrated that PD-L1 promoted GBM cell proliferation and migration in vitro and in vivo. Mechanistically, PD-L1 prominently activated epithelial mesenchymal transition (EMT) process in a MEK/Erk- but not PI3K/Akt-dependent manner. Further, we identified intracellular interactions of PD-L1 and H-Ras, which led to Ras/Erk/EMT activation. Finally, we demonstrated that PD-L1 overexpression promoted while knockdown abolished GBM development and invasion in orthotopic GBM models of rodents. Taken together, we found that intracellular PD-L1 confers GBM cell malignancy and aggressiveness via binding Ras and activating the downstream Erk-EMT signaling. Thus, these results shed important insights in improving efficacy of immune therapy for GBM as well as other malignant tumors.

Advances in Hypoxia-Mediated Mechanisms in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common and the third most deadly malignant tumor worldwide. Hypoxia and related oxidative stress are heavily involved in the process of HCC development and its therapies. However, direct and accurate measurement of oxygen concentration and evaluation of hypoxic effects in HCC prove difficult. Moreover, the hypoxia-mediated mechanisms in HCC remain elusive. Here, we summarize recent major evidence of hypoxia in HCC lesions shown by measuring partial pressure of oxygen (pO2), the clinical importance of hypoxic markers in HCC, and recent advances in hypoxia-related mechanisms and therapies in HCC. For the mechanisms, we focus mainly on the roles of oxygen-sensing proteins (i.e., hypoxia-inducible factor and neuroglobin) and hypoxia-induced signaling proteins (e.g., matrix metalloproteinases, high mobility group box 1, Beclin 1, glucose metabolism enzymes, and vascular endothelial growth factor). With respect to therapies, we discuss mainly YQ23, sorafenib, 2-methoxyestradiol, and celastrol. This review focuses primarily on the results of clinical and animal studies.

Identification of repaglinide as a therapeutic drug for glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients.

Piperlongumine suppresses bladder cancer invasion via inhibiting epithelial mesenchymal transition and F-actin reorganization.

Piperlongumine (PL), a natural alkaloid isolated from longer pepper plants, is recently found to be a potent selective anti-cancer compound. We first tested its anti-cancer effects on bladder cancer, the fifth most common and aggressive cancer worldwide, to further explore the therapeutic spectrum and molecular mechanisms of PL. PL significantly suppressed bladder cancer cell proliferation, the transition of G2/M phase to next phase, migration/invasion in vitro and bladder cancer growth/development in vivo. PL markedly elevated reactive oxygen species (ROS) and the administration of antioxidants abolished PL induced cell proliferation inhibition, G2/M phase arrest and migration suppression on bladder cancer cells. In vivo studies demonstrated that PL inhibited epithelial mesenchymal transition with profoundly decreased level of Slug, ß-catenin, ZEB1 and N-Cadherin. Further, we first reported PL effects on cytoskeleton with prominently reduced lamellipodia formation and decreased F-actin intensity in bladder cancer cells. Taken together, our results first revealed that PL suppressed bladder cancer proliferation and migration in vivo and in vitro, suggesting novel mechanism underlying PL's anti-cancer effect and providing a new anticancer drug strategy for bladder cancer therapy.

14-3-3 Isoforms Differentially Regulate NFκB Signaling in the Brain After Ischemia-Reperfusion.

Mammalian 14-3-3 isoforms exist predominantly in the brain and are heavily involved in neurological diseases. However, the isoform-specific role of 14-3-3 proteins in the brain remains largely unclear. Here, we investigated the role of 14-3-3 isoforms in rat brains after transient middle cerebral artery occlusion and reperfusion. 14-3-3ß, η, γ and ζ but not ε or τ were selectively upregulated in cerebral cortical neurons after ischemia-reperfusion (I/R). Selectively, 14-3-3ß, γ and ζ were translocated from cytoplasm into the nuclei of neurons after I/R. 14-3-3 bound to p65 and suppressed p65 expression in N2a cells. In the brain, 14-3-3 could either colocalize with p65 in the nuclei of neurons or segregate from p65 expression in cortical neurons after I/R. All evidence together suggests that 14-3-3 isoforms are differentially induced to enter into the nuclei of neurons after I/R, which might regulate NFκB signaling directly or indirectly. Since 14-3-3 proteins are essential for cell survival and NFκB is a key transcriptional factor, our data suggest that the 14-3-3/p65 signaling pathway might be a potential therapeutic target for stroke.

An overview of Melanommataceae (Pleosporales, Dothideomycetes): Current insight into the host associations and geographical distribution with some interesting novel additions from plant litter.

Melanommataceous species exhibit high diversity with a cosmopolitan distribution worldwide and show a prominent saprobic lifestyle. In this study, we explored five saprobic species collected from plant litter substrates from terrestrial habitats in China and Thailand. A combination of morphological characteristics and multi-locus phylogenetic analyses was used to determine their taxonomic classifications. Maximum Likelihood and Bayesian Inference analyses of combined LSU, SSU, ITS and tef1-α sequence data were used to clarify the phylogenetic affinities of the species. Byssosphaeriapoaceicola and Herpotrichiazingiberacearum are introduced as new species, while three new host records, Bertiellafici, By.siamensis and Melanommapopulicola are also reported from litter of Cinnamomumverum, Citrustrifoliata and Fagussylvatica, respectively. Yet, despite the rising interest in the melanommataceous species, there is a considerable gap in knowledge on their host associations and geographical distributions. Consequently, we compiled the host-species associations and geographical distributions of all the so far known melanommataceous species.

Eccrine porocarcinoma in the tempus of an elderly woman: A case report.

BACKGROUND: Eccrine porocarcinoma (EPC) is a rare skin tumor that mainly affects the elderly population. Tumors often present with slow growth and a good prognosis. EPCs are usually distinguished from other skin tumors using histopathology and immunohistochemistry. However, surgical management alone may be inadequate if the tumor has metastasized. However, currently, surgical resection is the most commonly used treatment modality. CASE SUMMARY: A seventy-four-year-old woman presented with a slow-growing nodule in her left temporal area, with no obvious itching or pain, for more than four months. Histopathological examination showed small columnar and short spindle-shaped cells; thus, basal cell carcinoma was suspected. However, immunohistochemical analysis revealed the expression of cytokeratin 5/6, p63 protein, p16 protein, and Ki-67 antigen (40%), and EPC was taken into consideration. The skin biopsy was repeated, and hematoxylin and eosin staining revealed ductal differentiation in some cells. Finally, the patient was diagnosed with EPC, and Mohs micrographic surgery was performed. We adapted follow-up visits in a year and not found any recurrence of nodules. CONCLUSION: This case report emphasizes the diagnosis and differentiation of EPC.

Biphasic photobiomodulation of inflammation in mouse models of common wounds, infected wounds, and diabetic wounds.

Bidirectional photobiomodulation (PBM) therapy is an active research area. However, most studies have focused on its dependence on optical parameters rather than on its tissue-dependent effects. We constructed mouse models of wounds in three inflammatory states (normal, low, and high levels of inflammations) to assess the bidirectional regulatory effect of PBM on inflammation. Mice were divided into three groups to prepare common wounds, diabetic wounds, and bacteria-infected wounds. The same PBM protocol was used to regularly irradiate the wounds over a 14 d period. PBM promoted healing of all three kinds of wounds, but the inflammatory manifestations in each were significantly different. In common wounds, PBM slightly increased the aggregation of inflammatory cells and expression of IL-6 but had no effect on the inflammatory score. For wounds in a high level of inflammation caused by infection, PBM significantly increased TNF-α expression in the first 3 d of treatment but quickly eliminated inflammation after the acute phase. For the diabetic wounds in a low level of inflammation, PBM intervention significantly increased inflammation scores and prevented neutrophils from falling below baseline levels at the end of the 14 d observation period. Under fixed optical conditions, PBM has a bidirectional (pro- or anti-inflammatory) effect on inflammation, depending on the immune state of the target organism and the presence of inflammatory stimulants. Our results provide a basis for the formulation of clinical guidelines for PBM application.

Multi-gene phylogenetic analyses revealed two novel species and one new record of Trichobotrys (Pleosporales, Dictyosporiaceae) from China.

The rotting wood in freshwater is a unique eco-environment favoring various fungi. During our investigation of freshwater fungi on decaying wood, three hyphomycetes were collected from Jiangxi and Guangxi Provinces, China. Based on the morphological observations and phylogenetic analysis of a combined DNA data containing ITS, LSU, SSU and tef1-α sequences, two new Trichobotrys species, T.meilingensis and T.yunjushanensis, as well as a new record of T.effusa, were introduced. Additionally, a comprehensive description of the genus with both morphological and molecular data was first provided.

Transcription factor BACH1 in cancer: roles, mechanisms, and prospects for targeted therapy.

Transcription factor BTB domain and CNC homology 1 (BACH1) belongs to the Cap 'n' Collar and basic region Leucine Zipper (CNC-bZIP) family. BACH1 is widely expressed in mammalian tissues, where it regulates epigenetic modifications, heme homeostasis, and oxidative stress. Additionally, it is involved in immune system development. More importantly, BACH1 is highly expressed in and plays a key role in numerous malignant tumors, affecting cellular metabolism, tumor invasion and metastasis, proliferation, different cell death pathways, drug resistance, and the tumor microenvironment. However, few articles systematically summarized the roles of BACH1 in cancer. This review aims to highlight the research status of BACH1 in malignant tumor behaviors, and summarize its role in immune regulation in cancer. Moreover, this review focuses on the potential of BACH1 as a novel therapeutic target and prognostic biomarker. Notably, the mechanisms underlying the roles of BACH1 in ferroptosis, oxidative stress and tumor microenvironment remain to be explored. BACH1 has a dual impact on cancer, which affects the accuracy and efficiency of targeted drug delivery. Finally, the promising directions of future BACH1 research are prospected. A systematical and clear understanding of BACH1 would undoubtedly take us one step closer to facilitating its translation from basic research into the clinic.