Search

Purpose: Mutant isocitrate dehydrogenase 1 (mIDH1) alters the epigenetic regulation of chromatin, leading to a hypermethylation phenotype in adult glioma. This work focuses on identifying gene targets epigenetically dysregulated by mIDH1 to confer therapeutic resistance to ionizing radiation (IR). Experimental Design: We evaluated changes in the transcriptome and epigenome in a radioresistant mIDH1 patient-derived glioma cell culture (GCC) following treatment with an mIDH1-specific inhibitor, AGI-5198. We identified Zinc Finger MYND-Type Containing 8 (ZMYND8) as a potential target of mIDH1 reprogramming. We suppressed ZMYND8 expression by shRNA knockdown and genetic knockout (KO) in mIDH1 glioma cells and then assessed cellular viability to IR. We assessed the sensitivity of mIDH1 GCCS to pharmacologic inhibition of ZMYND8-interacting partners: HDAC, BRD4, and PARP. Results: Inhibition of mIDH1 leads to an upregulation of gene networks involved in replication stress. We found that the expression of ZMYND8, a regulator of DNA damage response, was decreased in three patient-derived mIDH1 GCCs after treatment with AGI-5198. Knockdown of ZMYND8 expression sensitized mIDH1 GCCs to radiotherapy marked by decreased cellular viability. Following IR, mIDH1 glioma cells with ZMYND8 KO exhibit significant phosphorylation of ATM and sustained γH2AX activation. ZMYND8 KO mIDH1 GCCs were further responsive to IR when treated with either BRD4 or HDAC inhibitors. PARP inhibition further enhanced the efficacy of radiotherapy in ZMYND8 KO mIDH1 glioma cells. Conclusions: These findings indicate the impact of ZMYND8 in the maintenance of genomic integrity and repair of IR-induced DNA damage in mIDH1 glioma. See related commentary by Sachdev et al., p. 1648

In recent years, estimating customer value for airline companies has attracted much scholarly attention. Many researchers have tried to classify customer rankings based on different commercial models [1-2] (e.g., Huang & Liu, 2016; Liu & Du, 2010). However, few studies have quantified specific value rankings and designed tailored strategies. This project aims to fractionate customer value rankings and make corresponding strategies depending on their features. The whole project can be divided into two parts. First, customer values are quantified and six value rankings (Rank A to F) are developed by applying factor analysis method and regression models. Second, researchers use K-means algorithm to find out customer features for each value ranking. Customers are classified into two or three feature groups within each value ranking. Budgets were allocated based on value rankings and tailored strategies were made according to feature groups. The results of this project can assist the airline company in allocating resources and attracting customers.

Supplementary Figures and Figure Legends

Table S2. Liquid Chromatography and Mass Spectrometry Measurement of 2-hydroxyglutarate in the Conditioned Media of mIDH1 GCCs untreated, treated with vehicle (DMSO), or mIDH1 inhibitor (AGI-5198 or DS1001b)

Purpose:Mutant isocitrate dehydrogenase 1 (mIDH1) alters the epigenetic regulation of chromatin, leading to a hypermethylation phenotype in adult glioma. This work focuses on identifying gene targets epigenetically dysregulated by mIDH1 to confer therapeutic resistance to ionizing radiation (IR).Experimental Design:We evaluated changes in the transcriptome and epigenome in a radioresistant mIDH1 patient-derived glioma cell culture (GCC) following treatment with an mIDH1-specific inhibitor, AGI-5198. We identified Zinc Finger MYND-Type Containing 8 (ZMYND8) as a potential target of mIDH1 reprogramming. We suppressed ZMYND8 expression by shRNA knockdown and genetic knockout (KO) in mIDH1 glioma cells and then assessed cellular viability to IR. We assessed the sensitivity of mIDH1 GCCS to pharmacologic inhibition of ZMYND8-interacting partners: HDAC, BRD4, and PARP.Results:Inhibition of mIDH1 leads to an upregulation of gene networks involved in replication stress. We found that the expression of ZMYND8, a regulator of DNA damage response, was decreased in three patient-derived mIDH1 GCCs after treatment with AGI-5198. Knockdown of ZMYND8 expression sensitized mIDH1 GCCs to radiotherapy marked by decreased cellular viability. Following IR, mIDH1 glioma cells with ZMYND8 KO exhibit significant phosphorylation of ATM and sustained γH2AX activation. ZMYND8 KO mIDH1 GCCs were further responsive to IR when treated with either BRD4 or HDAC inhibitors. PARP inhibition further enhanced the efficacy of radiotherapy in ZMYND8 KO mIDH1 glioma cells.Conclusions:These findings indicate the impact of ZMYND8 in the maintenance of genomic integrity and repair of IR-induced DNA damage in mIDH1 glioma.See related commentary by Sachdev et al., p. 1648

Supplementary Methods

Background: Recently developed vaccines for the SARS-CoV-2 virus utilize endogenous production of the virus’ spike protein (SP), allowing the host to develop an immune response. As a result of the novelty of this virus and its vaccines, little is known overall about the potential effects of the SP on the pathogenesis of neoplasia, either from vaccination or from infection. This study was designed to investigate if SARS-CoV-2 SP has any direct effect on SiHa cervical cancer cells. Methods: The effects of SARS-CoV-2 SP on cervical cancer cell proliferation and apoptosis were investigated by using clonogenic cell survival assay, quick cell proliferation assay, and caspase-3 activity kits in a widely used cervical cancer cell line, SiHa. RT-PCR and immunohistochemistry were also performed to determine the potential molecular mechanisms. Results: The growth and proliferation of SiHa cancer cells were inhibited by SARS-CoV-2 SP. SARS-CoV-2 SP also induced apoptosis in SiHa cancer cells. The anti-proliferative effect of SARS-CoV-2 SP on SiHa cancer cells was associated with the upregulation of the anti-proliferative molecule p53. The pro-apoptotic effect of SARS-CoV-2 SP on SiHa cells was associated with the upregulation of the pro-apoptotic molecule TRAIL. Conclusion: SARS-CoV-2 SP inhibits the growth of cervical cancer via upregulation of p53 and TRAIL. Further studies are needed to elaborate on the potential effects of the SARS-CoV-2 SP on other cancer cell lines and other normal physiological cell lines to compare.

Activation of the nod-like receptor protein 3 (NLRP3) inflammasome by monosodium urate (MSU) crystals has been identified as the molecular basis for the acute inflammatory response in gouty arthritis. However, MSU crystals alone are not sufficient to induce acute gouty arthritis (AGA). Adenosine triphosphate (ATP) is an endogenous signaling molecule involved in the NLRP3 inflammasome activation. We aimed to explore the role of ATP in MSU crystal-induced AGA development. In peripheral blood mononuclear cell-derived macrophages obtained from gout patients, we observed a synergistic effect of ATP on MSU crystal-induced IL-1β release. Furthermore, in a rat model of spontaneous gout, we demonstrated that a synergistic effect of ATP and MSU crystals, but not MSU crystals alone, is essential for triggering AGA. Mechanistically, this synergistic effect is achieved through the purinergic receptor P2X7 (P2X7R). Blockade of P2X7R prevented AGA induction in rats after local injection of MSU crystals, and carrying the mutant hP2X7R gene contributed to the inhibition of NLRP3 inflammasome activation induced by costimulation of MSU crystals and ATP in vitro. Taken together, these results support the synergistic effect of ATP on MSU crystal-induced NLRP3 inflammasome activation facilitating inflammatory episodes in AGA. In this process, P2X7R plays a key regulatory role, suggesting targeting P2X7R to be an attractive therapeutic strategy for the treatment of AGA.

Background Cervical cancer (CC) is the second deadliest for women between the ages of 20 to 39 years. Even with prevention tactics for screening, incident rates and mortality of CC remain high. Olive has been shown to have many beneficial effects in humans concerning cardiovascular disease and inflammation. Despite these promising benefits, little is known about its effect on CC. This study examined the effects and mechanism of effects of olive extract (OE) on the HeLa cervical cancer cell line. Methods We utilized clonogenic survival assay, quick cell proliferation assay, and caspase-3 activity to investigate the effect of OE on proliferation and apoptosis of CC cell line HeLa. To investigate the mechanisms behind these findings, RT-PCR and immunohistochemistry (IHC) were performed. Results OE inhibited the growth and proliferation of HeLa cells. In comparison to the control, the percentage of colonies as well as the optical density of the CC cells was found to be decreased. In addition, the relative activity of caspase-3, a marker for apoptosis, was increased after treatment with OE. The anti-proliferative effect of OE on HeLa cells correlated with the increase of an anti-proliferative molecule p21. However, the pro-apoptotic effect of OE was not correlated with change of major pro-apoptotic or anti-apoptotic molecules examined in this study. Conclusion Our study suggests that OE inhibits growth of HeLa CC cells by upregulation of p21. Further study on the effects of OE on CC and other cancers is warranted by these results.

BackgroundCiliated muconodular papillary tumor (CMPT) is an incredibly rare pulmonary tumor. Currently, little is known about CMPT, and it has not yet been classified by the World Health Organization. The clinical manifestation of CMPT is nonspecific and the diagnosis is only based on pathology. CMPT has been documented in limited reports as a benign tumor, thus the treatment is typically with surgical excision if a solid tumor is identifiable. The prognosis of CMPT is very positive, as no recurrence has been reported in the limited literature available. However, CMPT accompanied with adenocarcinoma in situ has not been reported previously in the literature.Case presentationIn this report, we presented a case of a 53-year-old male smoker with CMPT associated with adenocarcinoma in situ. This diagnosis was confirmed by pathological examination, including immunohistostaining. No solid resectable lesion was identified on CT scan; therefore, no surgery was performed. The patient’s adenocarcinoma in situ was disseminated in both lungs, thus chemotherapeutic treatment with cisplatin and pemetrexed was given. The patient will be continually followed up closely on a wait-and-watch basis.ConclusionsIn summary, our report reveals a unique case of CMPT in conjunction with adenocarcinoma in situ, potentially revealing an association between CMPT and malignancy which has not been previously reported. More similar case studies will be beneficial to determine the authentic relationship between CMPT and adenocarcinoma in situ.

Branched-chain amino acids (BCAAs) supply both carbon and nitrogen in pancreatic cancers, and increased levels of BCAAs have been associated with increased risk of pancreatic ductal adenocarcinomas (PDACs). It remains unclear, however, how stromal cells regulate BCAA metabolism in PDAC cells and how mutualistic determinants control BCAA metabolism in the tumour milieu. Here, we show distinct catabolic, oxidative and protein turnover fluxes between cancer-associated fibroblasts (CAFs) and cancer cells, and a marked reliance on branched-chain α-ketoacid (BCKA) in PDAC cells in stroma-rich tumours. We report that cancer-induced stromal reprogramming fuels this BCKA demand. The TGF-β-SMAD5 axis directly targets BCAT1 in CAFs and dictates internalization of the extracellular matrix from the tumour microenvironment to supply amino-acid precursors for BCKA secretion by CAFs. The in vitro results were corroborated with circulating tumour cells (CTCs) and PDAC tissue slices derived from people with PDAC. Our findings reveal therapeutically actionable targets in pancreatic stromal and cancer cells.

To investigate the effects of isolated SARS-CoV-2 spike protein on prostate cancer cell survival. The effects of SARS-CoV-2 spike protein on LNCaP prostate cancer cell survival were assessed using clonogenic cell survival assay, quick cell proliferation assay, and caspase-3 activity kits. RT-PCR and immunohistochemistry were performed to investigate underlying molecular mechanisms. SARS-CoV-2 spike protein was found to inhibit prostate cancer cell proliferation as well as promote apoptosis. Further investigation revealed that anti-proliferative effects were associated with downregulation of the pro-proliferative molecule cyclin-dependent kinase 4 (CDK4). The increased rate of apoptosis was associated with the upregulation of pro-apoptotic molecule Fas ligand (FasL). SARS-CoV-2 spike protein inhibits the growth of LNCaP prostate cancer cells in vitro by a two-pronged approach of downregulating the expression of CDK4 and upregulating FasL. The introduction of SARS-CoV-2 spike protein into the body via COVID-19 vaccination may have the potential to inhibit prostate cancer in patients. This potential beneficial association between COVID-19 vaccines and prostate cancer inhibition will require more extensive studies before any conclusions can be drawn about any in vivo effects in a human model.

We show that G-equivariant K-semistability (resp. G-equivariant K-polystability) implies K-semistability (resp. K-polystability) for log Fano pairs when G is a finite group., Comment: 17 pages. Comments are very welcome

BACKGROUND Melanoma is the deadliest variant of skin cancer and its incidence continues to increase. There are limited treatment options for advanced and metastatic cases of melanoma, despite advances in immunotherapy and chemotherapy. Melanoma is notorious as a radioresistant tumor. Previous studies found that phytochemicals, such as resveratrol and those found in green tea and blueberry, can sensitize various cancer cells, including melanoma, to radiotherapy. Our previous study also revealed that kiwifruit extract (KE) has antitumor activity to melanoma cells. This study was designed to expand upon our previous investigation and determine KE's potential as a radiosensitizer on CRL-11147 melanoma cancer cells and elucidate the possible mechanisms behind its potential. MATERIALS AND METHODS Proliferation and apoptosis of CRL-11147 melanoma cells under radiation therapy (RT) plus KE versus RT alone were investigated using Proliferative cell nuclear antigen (PCNA) staining, quick cell proliferation assay, clonogenic assay, and caspase-3 activity assay. Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) were then used to investigate the mechanisms behind the observed results. RESULTS The percentage of CRL-11147 colonies, PCNA staining intensity, and the optic density value of CRL-11147 cells decreased with RT/KE vs. RT alone. Relative caspase-3 activity was increased with RT/KE vs. RT alone. Increased expression of the anti-proliferative molecule p27 and pro-apoptotic molecule TRAILR1 correlated with the anti-tumor effect seen in the RT/KE group versus the RT alone group. CONCLUSION KE augments radiosensitivity of CRL-11147 by up-regulating both p27 and TRAILR1 to inhibit proliferation and increase apoptosis, respectively.

Design for emotion aims to improve human well-being. Design for emotion is a multi-disciplinary or interdisciplinary research field, including art, design, computer science, psychology, education, engineering, and other fields. In the last ten years, there has been an increasing focus on design for emotion in various areas. However, there is no comprehensive literature review to set up a design for emotion research framework. To address this gap, this paper presents a descriptive review of 66 related papers on this topic and then proposes a research framework for emotional design.

Based on deep RNA sequencing of distal segments of lesioned sciatic nerves, a huge number of differentially expression genes (DEGs) were thus obtained and functionally analyzed. The inflammatory response was denoted as one of most significant biological processes following sciatic nerve injury. In the present study, ingenuity pathway analysis (IPA) demonstrated that macrophage migration inhibitory factor (MIF) was identified as a core regulator of inflammatory response through interaction with CD74 membrane receptor. By establishment of rat sciatic nerve transection model, we displayed that MIF was upregulated following sciatic nerve axotomy, in colocalization with Schwann cells (SCs). MIF promoted migration, proliferation, together with inflammatory responses of SCs in vitro. Immunoprecipitation showed that MIF interacted with CD74 receptor, through which to activate intracellular ERK and JNK signaling pathways. Interference of CD74 receptor using specific siRNA showed that the transcription of proinflammatory cytokines including TNF-α, IL-1β, as well as cytokine receptor TLR4 in SCs was significantly attenuated, supporting an participation of MIF/CD74 signal axis in SCs inflammatory response. The data provide a novel role of MIF in eliciting inflammatory response of peripheral nerve injury, which might be beneficial for precise therapy of peripheral nerve inflammation.

To investigate the artificial vaginal microecological features in patients who underwent laparoscopic peritoneal vaginoplasty. 54 cases of patients with artificial vagina after laparoscopic peritoneal vaginoplasty were included in this study. Microecosystem evaluation was performed. Artificial vaginal functional tests and biopsy from vaginal walls were performed. After laparoscopic peritoneal vaginoplasty, the artificial vaginal flora intensity was level II∼III (88.9%); the vaginal flora diversity was level II∼III (72.2%); the predominant vaginal bacteria were gram-positive macrobacillus (27.8%); approximately 57.4% of the patients had vaginal pH ≤ 4.5; there was no pathogenic bateria or other pathogens; dysbiosis accounted for 53.7% of the patients (64.5% of the patients who had the vaginoplasty operation less than 2 years ago exhibited dysbiosis; 39.1% of the patients who had the operation at least 2 years ago exhibited dysbiosis). Vaginal dysbiosis is common after laparoscopic peritoneal vaginoplasty. However, as time goes by, the artificial vaginal microecological condition gradually becomes normal. Evaluation of vaginal microenvironment after laparoscopic peritoneal vaginoplasty might play an important role in reproductive tract infection prevention and neovagina health care.

Background/aim Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive type of primary brain tumor and a cornerstone in its treatment is radiotherapy (RT). However, RT for GBM is largely ineffective at clinically safe doses, thus, the study of radiosensitizers is of great significance. Materials and methods With accumulating evidence for the anticancer effect of compounds from cranberry, this study was designed to investigate if cranberry extract (CE) sensitizes GBM to RT in the widely used human glioblastoma cell line U87. We utilized clonogenic survival assays, cell proliferation assays, and caspase-3 activity kits. Potential proliferative and apoptotic molecular mechanisms were evaluated by reverse transcription-polymerase chain reaction. Results We found that CE alone had little effect on the survival of U87 cells. However, RT supplemented by CE significantly inhibited proliferation and promoted apoptosis of U87 cells when compared with RT alone. The proliferation-inhibitory effect of RT/CE might be attributable to the up-regulation of p21, along with the down-regulation of cyclin B and cyclin-dependent kinase 4. This pro-apoptotic effect might additionally be attributable to the down-regulation of survivin. Conclusion These results warrant further study of the potential radiosensitizing capacity of CE in glioblastoma and other cancer types.

Background Cervical cancer (CC) is one of the leading causes of mortality worldwide. Previously, we reported that blueberry extract constrains the growth of CC. Raspberry is a widely consumed fruit that exhibits antitumor properties against several cancer types but little is known about its direct effect on CC. This study was designed to investigate the potential antitumor effect of raspberry extract (RE) on CC cells and to elucidate the possible mechanisms behind it. Materials and methods Clonogenic survival assay and caspase-3 activity kits were used to evaluate the effects of RE on cell survival, proliferation, and apoptosis of a widely used CC cell line, HeLa. Possible molecular mechanisms were investigated using reverse transcription-polymerase chain reaction. Results The percentage of colonies and optic density value of HeLa cells decreased in the presence of RE in comparison to controls. Relative caspase-3 activity in cancer cells increased in the presence of RE in comparison to controls. The antitumor effect displayed on HeLa cells by RE was associated with the increased expression of antiproliferative molecule P53 and the increased expression of pro-apoptotic molecule tumor necrosis factor receptor superfamily member 6 (FAS). Conclusion RE displays anticancer activity against CC HeLa cells. The mechanism behind this is by up-regulation of anti-proliferative molecule P53 and pro-apoptotic molecule FAS.

Immunoaffinity based EV isolation technologies use antibodies targeting surface markers on EVs to provide higher isolation specificity and purity compared to existing approaches. One standing challenge for researchers is how to release captured EVs from the substrate to increase downstream and biological studies. The strong binding between the antibody and antigen or the antibody and substrate is commonly unbreakable without operating at conditions outside of the critical physiological range, making the release of EVs problematic. Additionally, immuno-affinity approaches are usually low-throughput due to their low flow velocity to ensure adequate time for antibody-antigen binding. To overcome these limitations, we modified the OncoBean chip, a previously reported circulating tumor cell isolation microfluidic device. The OncoBean chip is a radial flow microfluidic device with bean-shape microposts functionalized with biotin-conjugated EPCAM antibody through biotin-avidin link chemistry. It was demonstrated that the high surface area and varying shear rate provided by the bean-shaped posts and the radial flow design in the chip, enabled efficient capture of CTCs at high flow rate. We replace the anti-EPCAM with antibodies that recognize common EV surface markers to achieve high-throughput EV isolation. Moreover, by incorporating desthiobiotin-conjugated antibodies, EVs can be released from the device after capture, which offers a significant improvement over the existing isolation. The released EVs were found to be functional by confirming their uptake by cells using flow cytometry and fluorescent microscopy. We believe the proposed technology can facilitate both the study of EVs as cell-to-cell communicators and the further identification of EV markers.

Background/aim Cervical cancer is one of the deadliest gynecological cancers in USA. The role of Trichomonas Vaginalis (T. Vag) in the etiology or pathogenesis of cervical cancer is still poorly understood and controversial. Materials and methods Clonogenic assay, PCNA staining, TUNEL staining and caspase-3 activity assay were used to investigate the direct in vitro effect of T. Vag on human cervical cancer by using HeLa cells. We further investigated the potential molecular mechanisms using RT-PCR and immunohistochemical staining. Results We found that culture supernatant of T. Vag inhibited growth of HeLa cervical cancer cells and this correlated with up-regulation of p15. We also found that culture supernatant of T. Vag induced apoptosis of HeLa cells and this correlated with up-regulation of Fas, TRAIL and TRAILR1. Conclusion Culture supernatant of T. Vag inhibits growth of HeLa cervical cancer cells by inhibition of proliferation and promotion of apoptosis. Our study might be helpful to address the association between the development of cervical cancer and infection of T. Vag.

Ziwen Zhu,1–3 Weiguo Dong1–3 1Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Hubei Key Laboratory of Digestive System Disease, Wuhan, People’s Republic of China; 3Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China Background: Colorectal carcinoma (CRC) is one of the most common malignancies, and immunotherapy has opened a new field of cancer treatment in recent years. Generally, CRC does not benefit from immunotherapy. HHLA2, a member of the B7 family, is a novel immune checkpoint molecule, and the prognostic value of HHLA2 in CRC patients and the association between HHLA2 expression and clinicopathological characteristics remains unknown. Materials and methods: This study included 63 patients diagnosed with CRC, and their resected specimens were obtained and constructed as a tissue microarray. Expression of HHLA2 and CD8 was detected by the double immunohistochemistry method. Based on follow-up data, correlations of HHLA2 expression and clinicopathological features, including overall survival, in CRC patients were evaluated. Results: High HHLA2 expression was detected in CRC tumor tissues, compared to the adjacent noncancerous tissues. HHLA2 expression level was significantly related to the depth of invasion (P=0.044) and CD8+ T-cell infiltration status (P=0.016), and predicted high mortality rate (P=0.035). HHLA2 acted as an independent predictive factor in the overall survival of CRC patients (P=0.039, hazard ratio=2.162, 95% CI 1.041–3.084). Conclusion: HHLA2 expression is upregulated in CRC patients, and HHLA2 is an independent prognostic factor of overall survival of CRC patients. High HHLA2 expression is closely correlated with CD8 T-cell infiltration status and can predict poor prognosis in CRC patients. Keywords: colorectal carcinoma, HHLA2, immune checkpoint, prognosis

The mechanisms by which steatosis of the liver progresses to non-alcoholic steatohepatitis, and end-stage liver disease remain elusive. Metabolic derangements in hepatocytes controlled by SIRT1 plays a role in the development of fatty liver in inbred-animals. The ability to perform similar studies using human tissue has been limited by the genetically variability in man. We generated human induced pluripotent stem (iPS)-cells with controllable expression of SIRT1. By differentiating edited-iPS cells into hepatocytes and knocking down SIRT1, we found increased fatty acid biosynthesis that exacerbates fat accumulation. To model human fatty livers, we repopulated decellularized rat livers with human mesenchymal cells, fibroblasts, macrophages, and human SIRT1-knockdown iPS-derived hepatocytes and found that the human iPS-derived liver tissue developed macrosteatosis, acquired proinflammatory phenotype and shared a similar lipid and metabolic profiling to human fatty livers. Biofabrication of genetically-edited human liver tissue may become an important tool for investigating human liver biology and disease.

The treatment of renal cell carcinoma (RCC) has evolved tremendously over the past decades. Localized disease is often curative with surgical resection of the malignancy. However, in cases where the primary tumor has metastasized, immunotherapy is becoming a more prevalent means to combat metastatic renal cell carcinoma (mRCC). Cytokine and checkpoint inhibitor immunotherapy have been demonstrated to stimulate the immune response through a number of different mechanisms. These drugs have been used as a monotherapy, combination therapy, or as successive treatments to systemic therapies. This review summarizes the success of previous and current therapeutic targets, while also leading to the direction of future therapies. This review might be helpful in improving the management of mRCC.

Background/aim Pancreatic cancer is the most lethal cancer of the digestive system. IL-29 is a new member of the IFNλ family and well-known for its strong antiviral activity. However, its direct effect on pancreatic cancer is still unclear. This study was performed to investigate if IL-29 has any direct effect on Pan-48 pancreatic cancer cells. Materials and methods Clonogenic survival assay, cell proliferation, and caspase-3 activity kits were used to evaluate the effects of IL-29 on cell survival, proliferation, and apoptosis of Pan-48 pancreatic cancer cells. RT-PCR and IHC were subsequently performed to explore IL-29's potential molecular mechanisms. Results The percentage of colonies of Pan-48 cells was decreased following the addition of IL-29. This was consistent with a decreased optical density (OD) value of cancer cells. Furthermore, the relative caspase-3 activity in cancer cells was increased after the addition of IL-29, indicating increased apoptosis of cancer cells. The anti-proliferative effect of IL-29 on cancer cells correlated with increased expression of the anti-proliferative molecule p21. The pro-apoptotic effect of IL-29 on cancer cells correlated with an increased expression of the pro-apoptotic molecule Bax. Conclusion IL-29 constrains Pan-48 pancreatic cell growth via up-regulation of p21 and Bax. Our study suggests a potential use of IL-29 in immunotherapy for pancreatic cancer treatment.

The original version of this article unfortunately contained a mistake in the text of the entire article. The word "IL-39" should read as "meteorin-like protein". This has been corrected with this correction.

Interluekin-9 (IL-9) is produced predominantly by helper T cells such as Th2 and Th9 cells. It normally functions through the activation of a JAK/STAT pathway and plays a critical role in immunity and the pathogenesis of cancer. In cancer, it yields different responses depending on the cancer cell line involved. This review is a summary of what is known about the involvement of IL-9 in various cancer cell lines as well as its role in immunity with a focus on allergic responses.

Additional structural pictures, EDX spectrums and sample's BET date.

IL-37 is a newly discovered cytokine belonging to IL-1 family consisting of 11 members, which have similar β-barrel structures and associate with Ig-like receptors. Extensive studies have been done with IL-37 since its discovery. These studies suggest that IL-37 does not only play a role in tumorigenesis, but also has anti-inflammatory properties in immune responses through the down regulation of pro-inflammatory molecules. We have previously reviewed the role of IL-37 in cancer. Here, we will focus on the role of IL-37 in non-cancerous Diseases. Such a study might be helpful to design new strategies to treat IL-37 associated diseases.

Highlights • IL-29 activates the JAK-STAT signaling pathway through STAT1 and STAT2. • IL-29 can either induce tumor promoting effects or tumor inhibiting effects depending on the cancer cell type being affected. • IL-29 could be a potential therapeutic target in cancer treatment., Interleukin-29 (IL-29) is a new member of the recently discovered interferon λ (IFNλ) family. It is produced predominantly by maturing dendritic cells and macrophages. It has been implicated in numerous immunological responses and has shown antiviral activity similar to the Type I interferons, although its target cell population is more limited than the Type I interferons. In recent years, the role of IL-29 in the pathogenesis of various cancers has also been extensively studied. In this review, we will discuss the recent advances of IL-29 in immunological processes and the pathogenesis of various cancer.

Interleukin-33 (IL-33), a damage-associated molecular pattern molecule, is a cytokine within the IL-1 interleukin family that binds to the plasma membrane receptor suppression of tumorigenicity 2 on numerous cell types. IL-33 has been extensively studied in its role in autoimmune diseases, host responses to pathogens and allergens, and has been associated with tumorigenic effects in cancer research. The present study was performed to investigate the effects of IL-33 on colon cancer cells, based off the previous data that have demonstrated an anti-tumor effect of IL-33 on pancreatic cancer cells. The effects of IL-33 on proliferation, cell survival and apoptosis on human HCT-116 colon cancer cells were examined using clonogenic survival assays, proliferation and caspase-3 activity kits, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and immunocytochemistry. It was determined that the HCT-116 cells demonstrated an notable decrease in optical density value upon incubation with IL-33, along with a decrease in the number of colonies, compared with the controls. It was further determined that the anti-proliferative effect of IL-33 on HCT-116 cells was associated with downregulation of the pro-proliferative molecules cyclin B, cyclin D and cyclin dependent kinase 2. An apoptosis-inducing effect of IL-33 on HCT-116 cells was associated with downregulation of the anti-apoptotic molecules Flice-like inhibitory protein and B-cell lymphoma 2. Taken together, the results indicated that IL-33 inhibits the growth of colon cancer by suppressing cellular proliferation, whilst simultaneously promoting apoptosis.

Ovarian cancer is the leading cause of cancer‑ associated mortality in the female reproductive system. Interleukin (IL)‑33 and its receptor IL 1 receptor like 1 (also termed ST2) are expressed by many cell types including epithelial cells. The role of IL‑33 in the pathogenesis of neoplasia remains controversial. The authors previously demonstrated that IL‑33 inhibits the growth of pancreatic cancer cells. The present study was performed to explore if IL‑33 has any direct effects on ovarian cancer cells. A clonogenic survival assay, immunohistochemistry (IHC), proliferation kit and caspase‑3 activity kit were all used to evaluate the direct effects of IL‑33 on cell proliferation and apoptosis of a widely studied ovarian cancer cell line, A2780. The possible molecular mechanisms were further evaluated with reverse transcription‑polymerase chain reaction and IHC. It was demonstrated that the percentage of colonies and the optical density value of cancer cells were all increased in the presence of IL‑33; however, the relative caspase‑3 activity in cancer cells was decreased in the presence of IL‑33. Molecular mechanism studies revealed that the pro‑proliferative effect of IL‑33 on cancer cells was associated with decreased levels of p27, and the anti‑apoptotic effect of IL‑33 was associated with levels of Fas cell surface death receptor (Fas) and tumor necrosis factor‑related apoptosis‑inducing ligand receptor 1 (TRAILR1). Therefore, IL‑33 promoted proliferation and inhibited apoptosis of ovarian cancer cells by downregulation of p27, Fas and TRAILR1. Contrary to previous studies demonstrating an anti‑tumor effort in pancreatic cancer, the results of the present study indicated that IL‑33 exhibited a significant onco‑promoting effect on ovarian cancer. Accordingly, the inhibition of IL‑33 may be a promising therapeutic strategy for ovarian cancer.

Nearly 40% of men and women will be diagnosed with cancer during their lifetime. Thus, there is a rapidly growing need for novel therapies to combat this deadly disease. One such method is the consumption of blueberries. Long coveted for their powerful antioxidant properties, more recent studies have demonstrated that blueberries also exhibit inherent abilities to prevent carcinogenesis, inhibit the proliferation of neoplastic cells, and reduce the risks of recurrence in patients in remission. This review will focus on the specific activities of blueberry derivatives in cancer cells across many different forms of cancer. Ultimately, such research could be helpful in the development of new strategies to treat cancer.

We generalize the definition of alpha invariant to arbitrary codimension. We also give a lower bound of these alpha invariants for K-semistable Q-Fano varieties and show that we can characterize projective spaces among all K-semistable Fano manifolds in terms of higher codimensional alpha invariants. Our results demonstrate the relation between alpha invariants of any codimension and volumes of Fano manifolds in the characterization of projective spaces., Comment: 14 pages. Second version: deleted Proposition 3.7 due to a gap in the proof and modified corresponding statements throughout the article. To appear in Internat. J. Math

Circulating tumor cells (CTCs) has an important role in the spread of cancers and metastasis. CTCs are believed to be the most promising model to understand metastatic progression in patients with cancer. Glutamine, an alternative carbon source to glucose, has recently been shown to be important for the cancer cell survival, growth and progression. The role of glutamine metabolism in CTCs is not known. MicroRNAs (miRNAs) are a group of highly conserved noncoding RNAs and approximately 22 nucleotides in length. Here, we postulate that CTCs have unique microRNAs (miRNAs) expression compared to resident tumor cells. And miRNAs control CTC glutamine metabolism for the metastasis. In this study, we used 3 primary CTC cultures to study how miRNA controlling glutamine metabolism. We identified several miRNAs have high expressions in CTCs and these miRNAs are regulating glutamine metabolism in CTCs. Our results demonstrate the metabolic miRNA targets of CTCs on cancer progression. These insights will present a unique opportunity for diagnosing and treating cancer through CTCs. Note: This abstract was not presented at the meeting. Citation Format: Ziwen Zhu, Sarah N. Owen, Abhinav Achreja, Sunitha Nagrath, Deepak Nagrath. Role of microRNAs in circulating tumor cells glutamine metabolism pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1850.

Interleukin-7 (IL-7) is a cytokine that has been known since long in immunology, mainly regarding its effects on T-cells and B-cells. IL-7 has been demonstrated to be necessary for both B-cell and T-cell proliferation and lack of IL-7 causes immature immune cell arrest. Interestingly, in recent years, certain studies have strongly suggested that the role of IL-7 is far beyond the field of immunology, it might have direct or indirect effect on cancer. This review aims to summarize the role of IL-7 in immunity and its role in the pathogenesis of neoplasia.