The challenge of survivors of gynecological carcinomas: a retrospective study on occurrence of second tumors.

OBJECTIVE: To clarify the epidemiologic characteristics and risk of other tumors in survivors of gynecological tumors. MATERIALS AND METHODS: This is a retrospective study based on the Surveillance, Epidemiology, and End Results database (SEER). RESULTS: The morbidity of other malignant tumors in patients with gynecological cancer was 8.07%. The most common subsequent tumors are breast, lung, colorectal, thyroid, and bladder cancers. Taking the incidence rate of the general population as reference, the second tumor with the highest relative risk in patients with cervical cancer is vulvar cancer. Bladder cancer is the second tumor with the highest relative risk value both in patients with corpus and ovarian cancer. The median period from the diagnosis of the initial tumor to the diagnosis of the second tumor was 5 years. Most patients with other tumors following gynecological cancer showed worse prognosis than patients with gynecological tumors only. However, thyroid cancer following ovarian cancer is a protective factor in survival. CONCLUSION: Patients with gynecological tumors have a significantly higher risk of malignant tumors in other systems compared to ordinary population. It is necessary to be vigilant against subsequent high-risk tumors and tumors with poor prognosis within 5 years of initial diagnosis.

Abnormal glycosylation in glioma: related changes in biology, biomarkers and targeted therapy.

Glioma is a rapidly growing and aggressive primary malignant tumor of the central nervous system that can diffusely invade the brain tissue around, and the prognosis of patients is not significantly improved by traditional treatments. One of the most general posttranslational modifications of proteins is glycosylation, and the abnormal distribution of this modification in gliomas may shed light on how it affects biological behaviors of glioma cells, including proliferation, migration, and invasion, which may be produced by regulating protein function, cell-matrix and cell‒cell interactions, and affecting receptor downstream pathways. In this paper, from the perspective of regulating protein glycosylation changes and abnormal expression of glycosylation-related proteins (such as glycosyltransferases in gliomas), we summarize how glycosylation may play a crucial role in the discovery of novel biomarkers and new targeted treatment options for gliomas. Overall, the mechanistic basis of abnormal glycosylation affecting glioma progression remains to be more widely and deeply explored, which not only helps to inspire researchers to further explore related diagnostic and prognostic markers but also provides ideas for discovering effective treatment strategies and improving glioma patient survival and prognosis.

Diabetes mellitus induces a novel inflammatory network involving cancer progression: Insights from bioinformatic analysis and in vitro validation.

Background: Patients with diabetes mellitus (DM) have a higher incidence of malignant tumors than people without diabetes, but the underlying molecular mechanisms are still unclear. Methods: To investigate the link between DM and cancer, we screened publicly available databases for diabetes and cancer-related genes (DCRGs) and constructed a diabetes-based cancer-associated inflammation network (DCIN). We integrated seven DCRGs into the DCIN and analyzed their role in different tumors from various perspectives. We also investigated drug sensitivity and single-cell sequencing data in colon adenocarcinoma as an example. In addition, we performed in vitro experiments to verify the expression of DCRGs and the arachidonic acid metabolic pathway. Results: Seven identified DCRGs, including PPARG, MMP9, CTNNB1, TNF, TGFB1, PTGS2, and HIF1A, were integrated to construct a DCIN. The bioinformatics analysis showed that the expression of the seven DCRGs in different tumors was significantly different, which had varied effects on diverse perspectives. Single-cell sequencing analyzed in colon cancer showed that the activity of the DCRGs was highest in Macrophage and the lowest in B cells among all cell types in adenoma and carcinoma tissue. In vitro experiments showed that the DCRGs verified by western bolt and PEG2 verified by ELISA were all highly expressed in COAD epithelial cells stimulated by high glucose. Conclusion: This study, for the first time, constructed a DCIN, which provides novel insights into the underlying mechanism of how DM increases tumor occurrence and development. Although further research is required, our results offer clues for new potential therapeutic strategies to prevent and treat malignant tumors.

lncRNA-associated ceRNA network revealing the potential regulatory roles of ferroptosis and immune infiltration in Alzheimer's disease.

Background: Alzheimer's disease (AD) is the most common form of dementia characterized by a prominent cognitive deterioration of sufficient magnitude to impair daily living. Increasing studies indicate that non-coding RNAs (ncRNAs) are involved in ferroptosis and AD progression. However, the role of ferroptosis-related ncRNAs in AD remains unexplored. Methods: We obtained the intersection of differentially expressed genes in GSE5281 (brain tissue expression profile of patients with AD) from the GEO database and ferroptosis-related genes (FRGs) from the ferrDb database. Least absolute shrinkage and selection operator model along with weighted gene co-expression network analysis screened for FRGs highly associated with AD. Results: A total of five FRGs were identified and further validated in GSE29378 (area under the curve = 0.877, 95% confidence interval = 0.794-0.960). A competing endogenous RNA (ceRNA) network of ferroptosis-related hub genes (EPT1, KLHL24, LRRFIP1, CXCL2 and CD44) was subsequently constructed to explore the regulatory mechanism between hub genes, lncRNAs and miRNAs. Finally, CIBERSORT algorithms were used to unravel the immune cell infiltration landscape in AD and normal samples. M1 macrophages and mast cells were more infiltrated whereas memory B cells were less infiltrated in AD samples than in normal samples. Spearman's correlation analysis revealed that LRRFIP1 was positively correlated with M1 macrophages (r = -0.340, P < 0.001) whereas ferroptosis-related lncRNAs were negatively correlated with immune cells, wherein miR7-3HG correlated with M1 macrophages and NIFK-AS1, EMX2OS and VAC14-AS1 correlated with memory B cells (|r| > 0.3, P < 0.001). Conclusion: We constructed a novel ferroptosis-related signature model including mRNAs, miRNAs and lncRNAs, and characterized its association with immune infiltration in AD. The model provides novel ideas for the pathologic mechanism elucidation and targeted therapy development of AD.

The Biosynthetic Gene Cluster of Mushroom-Derived Antrocin Encodes Two Dual-Functional Haloacid Dehalogenase-like Terpene Cyclases.

(-)-Antrocin (1), produced by the medicinal mushroom Antrodia cinnamomea, is a potent antiproliferative compound. The biosynthetic gene cluster of 1 was identified, and the pathway was characterized by heterologous expression. We characterized a haloacid dehalogenase-like terpene cyclase AncC that biosynthesizes the drimane-type sesquiterpene (+)-albicanol (2) from farnesyl pyrophosphate (FPP). Biochemical characterization of AncC, including kinetic studies and mutagenesis, demonstrated the functions of two domains: a terpene cyclase (TC) and a pyrophosphatase (PPase). The TC domain first cyclizes FPP to albicanyl pyrophosphate, and the PPase domain then removes the pyrophosphate to form 2. Intriguingly, AncA (94 % sequence identity to AncC), in the same gene cluster, converts FPP into (R)-trans-γ-monocyclofarnesol instead of 2. Notably, Y283/F375 in the TC domain of AncA serve as a gatekeeper in controlling the formation of a cyclofarnesoid rather than a drimane-type scaffold.

Dietary energy restriction in neurological diseases: what's new?

Energy-restricted diet is a specific dietary regimen, including the continuous energy-restricted diet and the intermittent energy-restricted diet. It has been proven effective not only to reduce weight and extend the lifespan in animal models, but also to regulate the development and progression of various neurological diseases such as epilepsy, cerebrovascular diseases (stroke), neurodegenerative disorders (Alzheimer's disease and Parkinson's disease) and autoimmune diseases (multiple sclerosis). However, the mechanism in this field is still not clear and a systematic neurological summary is still missing. In this review, we first give a brief summary of the definition and mainstream strategies of energy restrictions. We then review evidence about the effects of energy-restricted diet from both animal models and human trials, and update the current understanding of mechanisms underlying the biological role of energy-restricted diet in the fight against neurological diseases. Our review thus contributes to the modification of dietary regimen and the search for special diet mimics.

Lactobacillus and intestinal diseases: Mechanisms of action and clinical applications.

The gut microbial ecosystem, which is a collection of the host-microbiota interactions and the inter-species interplay among bacteria-dominated microbiota, has become a research hotspot due to its contribution to host health in recent years. Lactobacillus, which has worldwide usage in fermented dairy products, has aroused increasing attention and becomes one of the commonly used probiotics given its promising applications in intestinal health and disease, though it occupies a relatively small proportion of the intestinal microbiota. In the review, we first update the current understanding of determinants of Lactobacillus abundance in the intestinal tract. We then review evidence from animal models to human trials that provided insights into Lactobacillus's applications in common intestinal disorders including the Helicobacter pylori infection, colorectal cancer, diarrhea, inflammatory bowel disease, and irritable bowel syndrome. Mechanisms underlying the probiotic role of Lactobacillus are finally discussed in five aspects: microbial interactions, the improvement of intestinal barrier function, the immunoregulation, the anticancer activity, and the metabolic regulation. This review aims to yield a profound understanding of how Lactobacillus will contribute to disease prevention and individualized therapies in future clinical practice, and to inspire novel microbial strategies utilizing both probiotics and their products in the fields of biology and medicine.

Extracranial 125I Seed Implantation Allows Non-invasive Stereotactic Radioablation of Hippocampal Adult Neurogenesis in Guinea Pigs.

Adult hippocampal neurogenesis (AHN) is important for multiple cognitive functions. We sort to establish a minimal or non-invasive radiation approach to ablate AHN using guinea pigs as an animal model. 125I seeds with different radiation dosages (1.0, 0.8, 0.6, 0.3 mCi) were implanted unilaterally between the scalp and skull above the temporal lobe for 30 and 60 days, with the radiation effect on proliferating cells, immature neurons, and mature neurons in the hippocampal formation determined by assessment of immunolabeled (+) cells for Ki67, doublecortin (DCX), and neuron-specific nuclear antigen (NeuN), as well as Nissl stain cells. Spatially, the ablation effect of radiation occurred across the entire rostrocaudal and largely the dorsoventral dimensions of the hippocampus, evidenced by a loss of DCX+ cells in the subgranular zone (SGZ) of dentate gyrus (DG) in the ipsilateral relative to contralateral hemispheres in reference to the 125I seed implant. Quantitatively, Ki67+ and DCX+ cells at the SGZ in the dorsal hippocampus were reduced in all dosage groups at the two surviving time points, more significant in the ipsilateral than contralateral sides, relative to sham controls. NeuN+ neurons and Nissl-stained cells were reduced in the granule cell layer of DG and the stratum pyramidale of CA1 in the groups with 0.6-mCi radiation for 60 days and 1.0 mCi for 30 and 60 days. Minimal cranial trauma was observed in the groups with 0.3- 1.0-mCi radiation at 60 days. These results suggest that extracranial radiation with 125I seed implantation can be used to deplete HAN in a radioactivity-, duration-, and space-controllable manner, with a "non-invasive" stereotactic ablation achievable by using 125I seeds with relatively low radioactivity dosages.

Reproduction-Associated Hormones and Adult Hippocampal Neurogenesis.

The levels of reproduction-associated hormones in females, such as estrogen, progesterone, prolactin, and oxytocin, change dramatically during pregnancy and postpartum. Reproduction-associated hormones can affect adult hippocampal neurogenesis (AHN), thereby regulating mothers' behavior after delivery. In this review, we first briefly introduce the overall functional significance of AHN and the methods commonly used to explore this front. Then, we attempt to reconcile the changes of reproduction-associated hormones during pregnancy. We further update the findings on how reproduction-related hormones influence adult hippocampal neurogenesis. This review is aimed at emphasizing a potential role of AHN in reproduction-related brain plasticity and its neurobiological relevance to motherhood behavior.

Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer's Disease.

Shank3 is a postsynaptic scaffolding protein of excitatory synapses. Mutations or variations of SHANK3 are associated with various psychiatric and neurological disorders. We set to determine its normal expression pattern in the human brain, and its change, if any, with age and Alzheimer's disease (AD)-type ß-amyloid (Aß) and Tau pathogenesis. In general, Shank3 immunoreactivity (IR) exhibited largely a neuropil pattern with differential laminar/regional distribution across brain regions. In youth and adults, subsets of pyramidal/multipolar neurons in the cerebrum, striatum, and thalamus showed moderate IR, while some large-sized neurons in the brainstem and the granule cells in the cerebellar cortex exhibited light IR. In double immunofluorescence, Shank3 IR occurred at the sublemmal regions in neuronal somata and large dendrites, apposing to synaptophysin-labeled presynaptic terminals. In aged cases, immunolabeled neuronal somata were reduced, with disrupted neuropil labeling seen in the molecular layer of the dentate gyrus in AD cases. In immunoblot, levels of Shank3 protein were positively correlated with that of the postsynaptic density protein 95 (PSD95) among different brain regions. Levels of Shank3, PSD95, and synaptophysin immunoblotted in the prefrontal, precentral, and cerebellar cortical lysates were reduced in the aged and AD relative to youth and adult groups. Taken together, the differential Shank3 expression among brain structures/regions indicates the varied local density of the excitatory synapses. The enriched Shank3 expression in the forebrain subregions appears inconsistent with a role of this protein in the modulation of high cognitive functions. The decline of its expression in aged and AD brains may relate to the degeneration of excitatory synapses.

ER stress modulates apoptosis in A431 cell subjected to EtNBSe-PDT via the PERK pathway.

Photodynamic therapy (PDT) is a promising modality against various cancers including squamous cell carcinoma (SCC) with which the induction of apoptosis is an effective mechanism. Here, we initially describe the preclinical activity of 5-ethylamino-9-diethylaminobenzo [a] phenoselenazinium(EtNBSe)-mediated PDT treatment in SCC. Results of our studies suggest that EtNBSe-PDT provokes a cellular state of endoplasmic reticulum (ER) stress triggering the PERK/ eIF2α signaling pathway and induces the appearance of apoptosis in A431 cells at the meantime. With ER stress inhibitor 4-PBA or eIF2α inhibitor ISRIB, suppressing the EtNBSe-PDT induced ER stress substantially promotes apoptosis of A431 cells. Furthermore, we demonstrate that ATF4, whose expression is ER-stress-inducible and elevated in response to the PERK/eIF2α signaling pathway activation, contributes to cytoprotection against EtNBSe-PDT induced apoptosis. In a mouse model bearing A431 cells, EtNBSe shows intense phototoxicity and when associated with decreased ER stress, EtNBSe-PDT ameliorates tumor growth. Taken together, our study reveals an antagonistic activity of ER stress against EtNBSe-PDT treatment via inhibiting apoptosis in A431 cells. With further development, these results provide a proof-of-concept that downregulation of ER stress response has a therapeutic potential to improve EtNBSe-PDT sensitivity in SCC patients via the promotion of induced apoptosis.

An Enzyme-Mediated Aza-Michael Addition Is Involved in the Biosynthesis of an Imidazoyl Hybrid Product of Conidiogenone B.

Meleagrin B is a terpene-alkaloid hybrid natural product that contains both the conidiogenone and meleagrin scaffold. Their derivatives show diverse biological activities. We characterized the biosynthesis of (-)-conidiogenone B (1), which involves a diterpene synthase and a P450 monooxygenase. In addition, an α,ß-hydrolase (Con-ABH) was shown to catalyze an aza-Michael addition between 1 and imidazole to give 3S-imidazolyl conidiogenone B (6). Compound 6 was more potent than 1 against Staphylococcus aureus strains.

Suppression of Drug-Resistant Non-Small-Cell Lung Cancer with Inhibitors Targeting Minichromosomal Maintenance Protein.

Drug resistance has been a major threat in cancer therapies that necessitates the development of new strategies to overcome this problem. We report here a cell-based high-throughput screen of a library containing two-million molecules for the compounds that inhibit the proliferation of non-small-cell lung cancer (NSCLC). Through the process of phenotypic screening, target deconvolution, and structure-activity relationship (SAR) analysis, a compound of furanonaphthoquinone-based small molecule, AS4583, was identified that exhibited potent activity in tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant NSCLC cells (IC50 = 77 nM) and in xenograft mice. The mechanistic studies revealed that AS4583 inhibited cell-cycle progression and reduced DNA replication by disrupting the formation of the minichromosomal maintenance protein (MCM) complex. Subsequent SAR study of AS4583 gave compound RJ-LC-07-48 which exhibited greater potency in drug-resistant NSCLC cells (IC50 = 17 nM) and in mice with H1975 xenograft tumor.