Pterostilbene: a potential therapeutic agent for fibrotic diseases.

Fibrosis is a prevailing pathology in chronic diseases and accounts for 45% of deaths in developed countries. This condition is primarily identified by the transformation of fibroblasts into myofibroblasts and the overproduction of extracellular matrix (ECM) by myofibroblasts. Pterostilbene (PTS) is a natural analogue of resveratrol and is most commonly found in blueberries. Research has shown that PTS exerts a wide range of pharmacological effects, such as antioxidant, anti-inflammatory, and anticancer effects. As a result, PTS has the potential to prevent and cure numerous diseases. Emerging evidence has indicated that PTS can alleviate myocardial fibrosis, renal fibrosis, pulmonary fibrosis, hepatic fibrosis, and colon fibrosis via the inhibition of inflammation, oxidative stress, and fibrogenesis effects in vivo and in vitro, and the potential mechanisms are linked to various pathways, including transforming growth factor-ß1 (TGF-ß1)/small mother against decapentaplegic proteins (Smads) signalling, the reactive oxygen species (ROS)-driven Pitx2c/mir-15b pathway, nuclear factor kappa B (NF-κB) signalling, Kelch-like epichlorohydrin-associated protein-1 (Keap-1)/NF-E2-related factor-2 (Nrf2) cascade, the NLR family pyridine structure domain 3 (NLRP3) pathway, the Janus kinase-2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, and the Src/STAT3 pathway. In this review, we comprehensively summarize the antifibrotic effects of PTS both in vivo and in vitro and the pharmacological mechanisms, pharmacokinetics, and toxicology of PTS and provide insights into and strategies for exploring promising agents for the treatment of fibrosis.

The pharmacological role of Ginsenoside Rg3 in liver diseases: A review on molecular mechanisms.

Liver diseases are a significant global health burden and are among the most common diseases. Ginssennoside Rg3 (Rg3), which is one of the most abundant ginsenosides, has been found to have significant preventive and therapeutic effects against various types of diseases with minimal side effects. Numerous studies have demonstrated the significant preventive and therapeutic effects of Rg3 on various liver diseases such as viral hepatitis, acute liver injury, nonalcoholic liver diseases (NAFLD), liver fibrosis and hepatocellular carcinoma (HCC). The underlying molecular mechanism behind these effects is attributed to apoptosis, autophagy, antioxidant, anti-inflammatory activities, and the regulation of multiple signaling pathways. This review provides a comprehensive description of the potential molecular mechanisms of Rg3 in the development of liver diseases. The article focuses on the regulation of apoptosis, oxidative stress, autophagy, inflammation, and other related factors. Additionally, the review discusses combination therapy and liver targeting strategy, which can accelerate the translation of Rg3 from bench to bedside. Overall, this article serves as a valuable reference for researchers and clinicians alike.

HIIT Promotes M2 Macrophage Polarization and Sympathetic Nerve Density to Induce Adipose Tissue Browning in T2DM Mice.

Browning of white adipose tissue (WAT) is a focus of research in type 2 diabetes mellitus (T2DM) and metabolism, which may be a potential molecular mechanism for high-intensity interval training (HIIT) to improve T2DM. In this study, male C57BL/6J wild-type mice were subjected to an 8-week HIIT regimen following T2DM induction through a high-fat diet (HFD) combined with streptozotocin (STZ) injection. We found that HIIT improved glucose metabolism, body weight, and fat mass in T2DM mice. HIIT also decreased adipocyte size and induced browning of WAT. Our data revealed a decrease in TNFα and an increase in IL-10 with HIIT, although the expression of chemokines MCP-1 and CXCL14 was increased. We observed increased pan-macrophage infiltration induced by HIIT, along with a simultaneous decrease in the expression of M1 macrophage markers (iNOS and CD11c) and an increase in M2 macrophage markers (Arg1 and CD206), suggesting that HIIT promotes M2 macrophage polarization. Additionally, HIIT upregulated the expression of Slit3 and neurotrophic factors (BDNF and NGF). The expression of the sympathetic marker tyrosine hydroxylase (TH) and the nerve growth marker GAP43 was also increased, demonstrating the promotion of sympathetic nerve growth and density by HIIT. Notably, we observed macrophages co-localizing with TH, and HIIT induced the accumulation of M2 macrophages around sympathetic nerves, suggesting a potential association between M2 macrophages and increased density of sympathetic nerves. In conclusion, HIIT induces adipose tissue browning and improves glucose metabolism in T2DM mice by enhancing M2 macrophage polarization and promoting sympathetic nerve growth and density.

Protein aggregation and biomolecular condensation in hypoxic environments (Review).

Due to molecular forces, biomacromolecules assemble into liquid condensates or solid aggregates, and their corresponding formation and dissolution processes are controlled. Protein homeostasis is disrupted by increasing age or environmental stress, leading to irreversible protein aggregation. Hypoxic pressure is an important factor in this process, and uncontrolled protein aggregation has been widely observed in hypoxia­related conditions such as neurodegenerative disease, cardiovascular disease, hypoxic brain injury and cancer. Biomolecular condensates are also high­order complexes assembled from macromolecules. Although they exist in different phase from protein aggregates, they are in dynamic balance under certain conditions, and their activation or assembly are considered as important regulatory processes in cell survival with hypoxic pressure. Therefore, a better understanding of the relationship between hypoxic stress, protein aggregation and biomolecular condensation will bring marked benefits in the clinical treatment of various diseases. The aim of the present review was to summarize the underlying mechanisms of aggregate assembly and dissolution induced by hypoxic conditions, and address recent breakthroughs in understanding the role of aggregates in hypoxic­related diseases, given the hypotheses that hypoxia induces macromolecular assemblage changes from a liquid to a solid phase, and that adenosine triphosphate depletion and ATP­driven inactivation of multiple protein chaperones play important roles among the process. Moreover, it is anticipated that an improved understanding of the adaptation in hypoxic environments could extend the overall survival of patients and provide new strategies for hypoxic­related diseases.

Natural killer cells immunosenescence and the impact of lifestyle management.

Natural killer cells (NKs) are lymphocytes of the innate immune system that quickly respond to viruses, infections, and tumors during their short cell life cycle. However, it was recently found that NKs undergo quantitative, distributional, structural, and functional phenotypic changes during aging that suppress immune responses, which is known as immunosenescence. The aging host environment, cytokine regulation, cytomegalovirus status, and hypothalamic‒pituitary‒adrenal axis have significant effects on NK function. Different lifestyle management interventions modulate the number and cytotoxic activity of NKs, which are essential for rebuilding the immune barrier against pathogens in elderly individuals. Based on recent studies, we review the phenotypic changes of and potential threats of NKs during aging and explore the underlying mechanisms. By summarizing the effects of lifestyle management on NKs and their application prospects, we aim to provide evidence for enhancing immune system function against immune diseases in elderly individuals.

Anti-Melanogenic and Antioxidant Activity of Bifidobacterium longum Strain ZJ1 Extracts, Isolated from a Chinese Centenarian.

Melanin produced by melanocytes protects our skin against ultraviolet (UV) radiation-induced cell damage and oxidative stress. Melanin overproduction by hyperactivated melanocytes is the direct cause of skin hyperpigmentary disorders, such as freckles and melasma. Exploring natural whitening agents without the concern of toxicity has been highly desired. In this study, we focused on a Bifidobacterium longum strain, ZJ1, isolated from a Chinese centenarian, and we evaluated the anti-melanogenic activity of the distinctive extracts of ZJ1. Our results demonstrated that whole lysate (WL) and bacterial lysate (BL) of ZJ1 ferments efficiently reduce α-melanocyte-stimulating hormone (α-MSH)-induced melanin production in B16-F10 cells as well as the melanin content in zebrafish embryos. BL and WL downregulate melanogenesis-related gene expression and indirectly inhibit intracellular tyrosinase activity. Furthermore, they both showed antioxidant activity in a menadione-induced zebrafish embryo model. Our results suggest that ZJ1 fermentation lysates have application potential as therapeutic reagents for hyperpigmentary disorders and whitening agents for cosmetics.

Development of an antibody-ligand fusion protein scFvCD16A-sc4-1BBL in Komagataella phaffii with stimulatory activity for Natural Killer cells.

BACKGROUND: Natural killer (NK) cell-based immunotherapies have demonstrated substantial potential for the treatment of hematologic malignancies. However, its application is limited due to the difficulty in the production of a large number of NK cells in vitro and the insufficient therapeutic efficacy against solid tumors in vivo. Engineered antibodies or fusion proteins targeting activating receptors and costimulatory molecules of NK cells have been developed to encounter these problems. They are mostly produced in mammalian cells with high cost and long processing times. Yeast systems, such as Komagataella phaffii, present a convenient manipulation of microbial systems with the key advantages of improved folding machinery and low cost. RESULTS: In this study, we designed an antibody fusion protein scFvCD16A-sc4-1BBL, composed of the single chain variant fragment (scFv) of anti-CD16A antibody and the three extracellular domains (ECDs) of human 4-1BBL in a single-chain format (sc) with the GS linker, aiming to boost NK cell proliferation and activation. This protein complex was produced in the K. phaffii X33 system and purified by affinity chromatography and size exclusion chromatography. The scFvCD16A-sc4-1BBL complex showed comparable binding abilities to its two targets human CD16A and 4-1BB as its two parental moieties (scFvCD16A and monomer ECD (mn)4-1BBL). scFvCD16A-sc4-1BBL specifically stimulated the expansion of peripheral blood mononuclear cell (PBMC)-derived NK cells in vitro. Furthermore, in the ovarian cancer xenograft mouse model, adoptive NK cell infusion combined with intraperitoneal (i.p) injection of scFvCD16A-sc4-1BBL further reduced the tumor burden and prolonged the survival time of mice. CONCLUSION: Our studies demonstrate the feasibility of the expression of the antibody fusion protein scFvCD16A-sc4-1BBL in K. phaffii with favourable properties. scFvCD16A-sc4-1BBL stimulates PBMC-derived NK cell expansion in vitro and improves the antitumor activity of adoptively transferred NK cells in a murine model of ovarian cancer and may serve as a synergistic drug for NK immunotherapy in future research and applications.

Astaxanthin: A promising therapeutic agent for organ fibrosis.

Fibrosis is the end-stage pathological manifestation of many chronic diseases. Infiltration of inflammatory cells and activation of myofibroblasts are the most prominent features of fibrosis, with excessive deposition of extracellular matrix (ECM) in tissues leading to organ tissue damage, which eventually progresses to organ failure and leads to high mortality rates. At present, a large number of studies have been conducted on tissue fibrosis, and the pathological mechanism of fibrosis development has generally been recognized. However, the prevention and treatment of fibrosis is still an unsolved problem, and a shortage of drugs that can be used in the clinic persists. Astaxanthin (ASTX), a carotenoid, is widely known for its strong antioxidant capacity. ASTX also has other biological properties, such as anti-inflammatory, antiaging and anticancer properties. Recently, many papers have reported that ASTX inhibits the occurrence and development of fibrosis by regulating signaling molecular pathways, such as transforming growth factor-ß/small mother against decapentaplegic protein (TGF-ß1/Smad), sirtuin 1 (SIRT1), nuclear factor kappa-B (NF-κB), microRNA, nuclear factor-E2-related factor 2/antioxidant response element (Nrf 2/ARE) and reactive oxygen species (ROS) pathways. By targeting these molecular signaling pathways, ASTX may become a potential drug for the treatment of fibrotic diseases. In this review, we summarize the therapeutic effects of ASTX on organ fibrosis and its underlying mechanisms of action. By reviewing the results from in vitro and in vivo studies, we analyzed the therapeutic prospects of ASTX for various fibrotic diseases and provided insights into and strategies for exploring new drugs for the treatment of fibrosis.

Effects of Multiscale Mechanical Pulverization on the Physicochemical and Functional Properties of Black Tea.

Black tea leaves were pulverized at an organ-scale (~mm), tissue-scale (500−100 µm) and cell-scale (<50−10 µm) to investigate their physicochemical and functional properties. The results showed that cell-scale powders exhibited a bright brown color compared with organ- or tissue-scale powders with the highest total color difference (∆E) of 39.63 and an L value of 55.78. There was no obvious difference in the oil-holding capacity (OHC) of the organ- and tissue-scale powders (3.71−3.74 g/g), while the OHC increased significantly to 4.08 g/g in cell-scale powders. The soluble dietary fiber (SDF) content of cell-scale powders increased remarkably to 10.41%, indicating a potential application as a high-SDF food. Further, cell-scale pulverization of black tea enhanced its DPPH scavenging activity and ferric-ion-reducing antioxidant power (FRAP). However, the polyphenol content (13.18−13.88%) and the protein content (27.63−28.09%), as well as the Pb2+ adsorption capacity (1.97−1.99 mg/g) were not affected by multiscale pulverizations. The mean particle size (D50) correlated linearly with tap density (TD), color parameters of L and b, SDF content, DPPH scavenging activity and FRAP. The results indicate that black tea powders pulverized at a cell-scale can be used as a soluble fiber-rich functional food additive with a bright color, enhanced OHC and antioxidant capacity.

Advances in NK cell production.

Immunotherapy based on natural killer (NK) cells is a promising approach for treating a variety of cancers. Unlike T cells, NK cells recognize target cells via a major histocompatibility complex (MHC)-independent mechanism and, without being sensitized, kill the cells directly. Several strategies for obtaining large quantities of NK cells with high purity and high cytotoxicity have been developed. These strategies include the use of cytokine-antibody fusions, feeder cells or membrane particles to stimulate the proliferation of NK cells and enhance their cytotoxicity. Various materials, including peripheral blood mononuclear cells (PBMCs), umbilical cord blood (UCB), induced pluripotent stem cells (iPSCs) and NK cell lines, have been used as sources to generate NK cells for immunotherapy. Moreover, genetic modification technologies to improve the proliferation of NK cells have also been developed to enhance the functions of NK cells. Here, we summarize the recent advances in expansion strategies with or without genetic manipulation of NK cells derived from various cellular sources. We also discuss the closed, automated and GMP-controlled large-scale expansion systems used for NK cells and possible future NK cell-based immunotherapy products.

Anti-Tumor Activity of Expanded PBMC-Derived NK Cells by Feeder-Free Protocol in Ovarian Cancer.

Natural killer (NK) cells have shown great therapeutic potential against a wide range of cancers due to their pan-specific target recognition. Numerous reports indicate that NK cell immunotherapy is an effective therapeutic approach for treating hematological malignancies, but shows limited effects against solid tumors. In this study, several models of ovarian cancer (OC) were used to test the anti-cancer effects of NK cells derived from human peripheral blood mononuclear cells and expanded using a feeder cell-free expansion system (eNKs). The results show that eNKs exhibit potent inhibitory activity on tumor growth in different ovarian cancer xenograft mice (i.e., solid tumors, abdominal metastatic tumors, and ascites), importantly, in a dose-dependent manner. Moreover, adoptive transfer of eNKs resulted in significant reduction in ascites formation in OC peritoneal tumor models, and especially in reducing intraperitoneal ascites. We found that eNKs could migrate to the tumor site, retain their activity, and proliferate to maintain high cell counts in cutaneous xenograft mice. In addition, when increased the infusion with a high dose of 12 × 107 cells/mouse, Graft-versus-host disease could be induced by eNK. These data show that eNK cell immunotherapy could be a promising treatment strategy for ovarian cancers, including solid tumors and ascites.

Chimeric antigen receptor- and natural killer cell receptor-engineered innate killer cells in cancer immunotherapy.

Chimeric antigen receptor (CAR)-engineered T-cell (CAR-T) therapy has demonstrated impressive therapeutic efficacy against hematological malignancies, but multiple challenges have hindered its application, particularly for the eradication of solid tumors. Innate killer cells (IKCs), particularly NK cells, NKT cells, and γδ T cells, employ specific antigen-independent innate tumor recognition and cytotoxic mechanisms that simultaneously display high antitumor efficacy and prevent tumor escape caused by antigen loss or modulation. IKCs are associated with a low risk of developing GVHD, thus offering new opportunities for allogeneic "off-the-shelf" cellular therapeutic products. The unique innate features, wide tumor recognition range, and potent antitumor functions of IKCs make them potentially excellent candidates for cancer immunotherapy, particularly serving as platforms for CAR development. In this review, we first provide a brief summary of the challenges hampering CAR-T-cell therapy applications and then discuss the latest CAR-NK-cell research, covering the advantages, applications, and clinical translation of CAR- and NK-cell receptor (NKR)-engineered IKCs. Advances in synthetic biology and the development of novel genetic engineering techniques, such as gene-editing and cellular reprogramming, will enable the further optimization of IKC-based anticancer therapies.

Fe-Mn Plaque Formation Mechanism Underlying the Inhibition of Cadmium Absorption by Rice Under Oxygation Conditions.

Oxygation (O) is a water-saving and energy-saving irrigation method that can also influence the absorption of cadmium (Cd) by rice, but the related mechanism is still unclear. In this study, the relationship between O method and Fe-Mn plaque formation was tested through pot experiments. The Fe-Mn plaque content and Cd concentration were measured during different rice growth periods, and the fitted models based on their correlation were established. The results show that, Fe-Mn plaque formation was the most significant factor affecting Cd accumulation in rice under O conditions. The content of rice root Fe-Mn plaque was higher after the application of O during the filling and maturity stages of rice growth, and Fe-Mn plaque inhibited Cd accumulation in the rice roots and grains and reduced the translocation factors (TFs) from the rice dithionite-citrate-bicarbonate extract (DCB) to the roots (TFDCB-R) and from the roots to the straw (TFStraw-G). O may influence the Fe-Mn plaque formation on the root surface to impede Cd absorption by rice. This research provides theoretical support for the Cd absorption under O conditions.

Development of IL-15/IL-15Rα sushi domain-IgG4 Fc complexes in Pichia pastoris with potent activities and prolonged half-lives.

BACKGROUND: Interleukin-15 (IL-15) is a critical cytokine for the development, proliferation, and function of natural killer (NK) cells, NKT cells, and CD8+ memory T cells and has become one of the most promising protein molecules for the treatment of cancer and viral diseases. However, there are several limitations in applying IL-15 in therapy, such as its low yield in vitro, limited potency, and short half-life in vivo. To date, there are several recombinant IL-15 agonists based on configurational modifications that are being pursued in the treatment of cancer, such as ALT-803, which are mainly produced from mammalian cells. RESULTS: In this study, we designed two different forms of the IL-15 complex, which were formed by the noncovalent assembly of IL-15 with dimeric or monomeric sushi domain of IL-15 receptor α (SuIL-15Rα)-IgG4 Fc fusion protein and designated IL-15/SuIL-15Rα-dFc and IL-15/SuIL-15Rα-mFc, respectively. The two IL-15 complexes were expressed in Pichia pastoris (P. pastoris), and their activities and half-lives were evaluated and compared. Pharmacokinetic analysis showed that IL-15/SuIL-15Rα-dFc had a half-life of 14.26 h while IL-15/SuIL-15Rα-mFc had a half-life of 9.16 h in mice, which were much longer than the 0.7-h half-life of commercial recombinant human IL-15 (rhIL-15). Treatment of mice with intravenous injection of the two IL-15 complexes resulted in significant increases in NK cells, NKT cells, and memory CD8+ T cells, which were not observed after rhIL-15 treatment. Treatment of human peripheral blood mononuclear cells (PBMCs) from healthy donors with the two IL-15 complexes yielded enhanced NK and CD8+ T cell activation and proliferation, which was comparable to the effect of rhIL-15. CONCLUSIONS: These findings indicate that the IL-15/SuIL-15Rα-dFc and IL-15/SuIL-15Rα-mFc produced in P. pastoris exhibit potent activities and prolonged half-lives and may serve as superagonists for immunotherapy in further research and applications.

Blockade of checkpoint receptor PVRIG unleashes anti-tumor immunity of NK cells in murine and human solid tumors.

BACKGROUND: Although checkpoint-based immunotherapy has shown exciting results in the treatment of tumors, around 70% of patients have experienced unresponsiveness. PVRIG is a recently identified immune checkpoint receptor and blockade of which could reverse T cell exhaustion to treat murine tumor; however, its therapeutic potential via NK cells in mice and human remains seldom reported. METHODS: In this study, we used patient paraffin-embedded colon adenocarcinoma sections, various murine tumor models (MC38 colon cancer, MCA205 fibrosarcoma and LLC lung cancer), and human NK cell- or PBMC-reconstituted xenograft models (SW620 colon cancer) to investigate the effect of PVRIG on tumor progression. RESULTS: We found that PVRIG was highly expressed on tumor-infiltrating NK cells with exhausted phenotype. Furthermore, either PVRIG deficiency, early blockade or late blockade of PVRIG slowed tumor growth and prolonged survival of tumor-bearing mice by inhibiting exhaustion of NK cells as well as CD8+ T cells. Combined blockade of PVRIG and PD-L1 showed better effect in controlling tumor growth than using either one alone. Depletion of NK or/and CD8+ T cells in vivo showed that both cell types contributed to the anti-tumor efficacy of PVRIG blockade. By using Rag1-/- mice, we demonstrated that PVRIG blockade could provide therapeutic effect in the absence of adaptive immunity. Further, blockade of human PVRIG with monoclonal antibody enhanced human NK cell function and inhibited human tumor growth in NK cell- or PBMC-reconstituted xenograft mice. CONCLUSIONS: Our results reveal the importance of NK cells and provide novel knowledge for clinical application of PVRIG-targeted drugs in future.

A Review of the Clinical Characteristics and Novel Molecular Subtypes of Endometrioid Ovarian Cancer.

Ovarian cancer is one of the most common gynecologic cancers that has the highest mortality rate. Endometrioid ovarian cancer, a distinct subtype of epithelial ovarian cancer, is associated with endometriosis and Lynch syndrome, and is often accompanied by synchronous endometrial carcinoma. In recent years, dysbiosis of the microbiota within the female reproductive tract has been suggested to be involved in the pathogenesis of endometrial cancer and ovarian cancer, with some specific pathogens exhibiting oncogenic having been found to contribute to cancer development. It has been shown that dysregulation of the microenvironment and accumulation of mutations are stimulatory factors in the progression of endometrioid ovarian carcinoma. This would be a potential therapeutic target in the future. Simultaneously, multiple studies have demonstrated the role of four molecular subtypes of endometrioid ovarian cancer, which are of particular importance in the prediction of prognosis. This literature review aims to compile the potential mechanisms of endometrioid ovarian cancer, molecular characteristics, and molecular pathological types that could potentially play a role in the prediction of prognosis, and the novel therapeutic strategies, providing some guidance for the stratified management of ovarian cancer.

Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity.

T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8+ tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10-Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8+ tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10-Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.

CDH17+/CDX2+ Can be Helpful in Providing Support for Small Intestinal Origin Versus Pancreatic or Biliary Origin.

Because of the distinct and complex anatomy of the ampullary region, the exact origin of the periampullary tumors was often difficult to ascertain. In this study, we evaluated 78 patient samples, including 26 small intestinal adenocarcinomas, 35 pancreatic ductal adenocarcinomas, and 17 cholangiocarcinomas by immunohistochemical detection of cadherin-17 (CDH17), CDX2, CK20, and CK19 protein expression. The result showed that CDH17 and CDX2 expression was higher in small intestinal adenocarcinoma (73.1% and 65.4%) than in pancreatic (14.3% and 2.9%) and bile duct (41.2% and 23.5%) cancers, respectively. CK20 expression was low in 78 tumor tissues, but relatively high in small intestinal adenocarcinoma (42.3%). CK19 showed a strong positive expression in all 78 adenocarcinoma tissues. The CDH17-high/CDX2-high pattern was predominantly expressed in small intestinal cancer tissues (75%), whereas the CDH17-low/CDX2-low pattern was observed in pancreatic cancers (63.8%) and bile duct cancers (20.9%). The study concluded that CDH17-high/CDX2-high adenocarcinomas more likely originated from small intestine versus pancreas or bile duct, whereas CDH17-low/CDX2-low ones are more likely of pancreatic origin. The combined use of CDH17 and CDX2 could be helpful in providing support for the histologic origin of periampullary adenocarcinoma.

Energy restriction causes metaphase delay and chromosome mis-segregation in cancer cells.

ATP metabolism during mitosis needs to be coordinated with numerous energy-demanding activities, especially in cancer cells whose metabolic pathways are reprogramed to sustain rapid proliferation in a nutrient-deficient environment. Although strategies targeting the energy metabolic pathways have shown therapeutic efficacy in preclinical cancer models, how normal cells and cancer cells differentially respond to energy shortage is unclear. In this study, using time-lapse microscopy, we found that cancer cells displayed unique mitotic phenotypes in a dose-dependent manner upon decreasing ATP (i.e. energy) supply. When reduction in ATP concentration was moderate, chromosome movements in mitosis were barely affected, while the metaphase-anaphase transition was significantly prolonged due to reduced tension between the sister-kinetochores, which delayed the satisfaction of the spindle assembly checkpoint. Further reduction in ATP concentration led to a decreased level of Aurora-B at the centromere, resulting in increased chromosome mis-segregation after metaphase delay. In contrast to cancer cells, ATP restriction in non-transformed cells induced cell cycle arrest in interphase, rather than causing mitotic defects. In addition, data mining of cancer patient database showed a correlation between signatures of energy production and chromosomal instability possibly resulted from mitotic defects. Together, these results reveal that energy restriction induces differential responses in normal and cancer cells, with chromosome mis-segregation only observed in cancer cells. This points to targeting energy metabolism as a potentially cancer-selective therapeutic strategy.

Updates of Pathogenesis, Diagnostic and Therapeutic Perspectives for Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC) is a special pathological type of epithelial ovarian carcinoma (EOC) and has a high prevalence in Asia without specific molecular subtype classification. Endometriosis is a recognized precancerous lesion that carries 3-fold increased risk of OCCC. Ovarian endometrioid carcinoma, which also originates from endometriosis, shares several features with OCCC, including platinum resistance and younger age at diagnosis. Patients with OCCC have about a 2.5 to 4 times greater risk of having a venous thromboembolism (VTE) compared with other EOC, and OCCC tends to metastasize through lymphatic vesicular and peritoneal spread as opposed to hematogenous metastasis. There is only mild elevation of the conventional biomarker CA125. Staging surgery or optimal cytoreduction combined with chemotherapy is a common therapeutic strategy for OCCC. However, platinum resistance commonly portends a poor prognosis, so novel treatments are urgently needed. Targeted therapy and immunotherapy are currently being studied, including PARP, EZH2, and ATR inhibitors combined with the synthetic lethality of ARID1A-dificiency, and MAPK/PI3K/HER2, VEGF/bFGF/PDGF, HNF1ß, and PD-1/PD-L1 inhibitors. Advanced stage, suboptimal cytoreduction, platinum resistance, lymph node metastasis, and VTE are major prognostic predictors for OCCC. We focus on update pathogenesis, diagnostic methods and therapeutic approaches to provide future directions for clinical diagnosis and treatment of OCCC.