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In recent years, tumor metabolism has become a prevalent research topic for scientists and pharmaceutical companies. As research in the field has progressed, the metabolism-based therapy of tumors has ushered in new opportunities. Most tumors emerge and evolve under selective pressure from their microenvironment, which promotes the diversification of both neoplastic and non-neoplastic compartments of the tumor microenvironment (TME), and finally reaches a certain degree of intratumoral heterogeneity. As a result of the tumor intratumoral heterogeneity, tumor cells often possess a complex energy metabolism phenotype. During tumor progression, the metabolism for both tumor parenchyma and stroma is reprogrammed. The tumor stroma mainly consists of the extracellular matrix, fibroblasts, and immune cells. Interestingly, tumor-infiltrating immune cells utilize different metabolites based on their subtype and function, and these immunometabolic pathways can be modified in the TME. In particular, interleukins play a vital role in the activation and differentiation of immune cells and have exhibited multiple effects on tumor cell neoplasia, invasion, and metastasis. In this review, we summarize the common mechanisms of interleukins affecting the tumor and tumor-infiltrating immune cells metabolically and discuss how these mechanisms may lead to novel therapeutic opportunities. This review might contribute to the novel development of cancer immunotherapy.

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.

Prostate cancer is the most common cancer among men in the USA. A peptide derived from the active site of alpha-fetoprotein (AFP), known as AFPep, has been shown to be efficacious in inhibiting breast cancer growth. The role of this derived peptide AFPep in the development of prostate cancer has yet to be studied. To investigate the role of AFPep on prostate cancer, we used the PC-3 and DU-145 cell lines. We found that through key anti-apoptosis and pro-proliferation molecules, AFPep enhances the proliferation of DU-145 prostate cancer cells. The anti-proliferative molecules p18, p21, and p27, along with the pro-apoptotic molecules Fas and Bax, were all down-regulated in DU-145 cell lines treated with AFPep. Conversely, AFPep was not found to have a proliferative effect on the PC-3 prostate cancer cell line. This finding suggests the effects of AFPep to be cell line-specific in prostate cancer. Further investigation into the effects of AFPep could lead to new areas of treating prostate cancer.

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.

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.

Interleukins are signaling molecules involved in the immune system, and they play a variety of roles in different diseases and cancers. Acute myeloid leukemia (AML) is the most common type of leukemia in adults, and survival rate after diagnosis is very low. Investigating the role interleukins play in AML can help understand the progression of the disease. There exists a need for more effective treatment of AML. Interleukins can be used to guide immunotherapy for AML. This review article will examine how specific interleukins play a role in AML disease progression and how they can be utilized as a future treatment option.

Non-Hodgkin's lymphoma is a relatively common cancer with malignant tendencies. Although there is no current cure for the disease, research has been successful in figuring out the mechanisms of how the disease progresses, however, there is still a lot of unknowns, and more research must be done to find the ultimate cause of the disease. Interleukins and various cytokines play unique roles in the development of cancer. This review article summarizes the pathophysiology between certain interleukins and non-Hodgkin's lymphoma. Although TNF-α is not an interleukin, the article examines TNF-α due to its high correspondence with cancer. The article also describes a promising immunotherapy for the disease, while looking at immunotherapies that have been successful in other types of cancer and disease.

Skin cancers are the most common cancers in the world and among the different types of skin cancers, melanoma is the deadliest and incidence is rising. Previous studies have shown promising in vitro and human evidence of kiwifruit exhibiting anti-cancer effects. This study was designed to investigate if kiwifruit extract (KE) has any effect on CRL-11147 melanoma cancer cells and to investigate the possible mechanisms behind the results. The effects of KE on CRL-11147 melanoma cell survival, proliferation, and apoptosis was investigated using clonogenic survival assay, cell proliferation, and caspase-3 activity kits. Potential anti-tumor molecular mechanisms were elucidated using RT-PCR and IHC. Addition of KE decreased CRL-11147 cell colonies percentages indicated by a decreased optical density value of cancer cells when compared to control. Furthermore, treatment with KE increased relative caspase-3 activity in cancer cells, which indicated increased apoptosis of cancer cells. The anti-proliferative effect of KE on cancer cells corresponded with decreased expression of the pro-proliferative molecule Cyclin E and CDK4, while increased expression of the pro-apoptotic molecule TRAILR1 corresponded with the pro-apoptotic effect. KE decreases CRL-11147 melanoma cell growth via downregulation of Cyclin E and CDK4 and upregulation in TRAILR1. Our study suggests a potential use for KE in treatment of melanoma.

Background COVID-19 caused by SARS-CoV-2 has been inducing an ongoing global health and economic emergency. Although viral pneumonia is the most striking presentation for COVID-19 patients, it has been noticed that some patients may also be accompanied with an abnormal liver function. Methods CT was performed in both lungs, and routine bloodwork and the blood metabolic panel were measured. Results Here, we report on a young male patient without any history of live diseases who suffered simultaneously both SARS-CoV-2 caused pneumonia and hepatitis as evidenced by increased serum bilirubin together with increased serum transaminases. Conclusions Studies on mechanisms whereby SARS-CoV-2 causing liver damages might provide more information about the pathogenesis of COVID-19 and help management of this global health emergency.

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 Nocardia infection is a very rare bacterial infection caused by Gram-positive, aerobic nocardia species. However, in recent years, it has become a serious infection in immunocompromised patients. Earlier diagnosis plays a pivotal in the effective treatment of nocardia infection. Methods In this study, we reported a 65-year-old male patient with nephrotic syndrome who had disseminated abscesses in the lungs, right lower limb, and right cheek. Results Bacterial culture from these lesions confirmed the presence of nocardia. Timely administration of sensitive antibiotics resulted in a quick recovery for this patient. Conclusions Nocardia infection should be considered in the differential diagnosis of infectious lesions, especially when a patient has multiple abscesses and an underlying disorder in which the immune function of the patient may be compromised.

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.

Background Primary hepatic tuberculosis is a very rare clinical form of tuberculosis, with atypical clinical presentations and nonspecific imaging features. This results in great difficulty to reach a correct and timely clinical diagnosis. Traditionally, liver biopsy is the gold standard for its diagnosis. Here we assessed the effectiveness of using a T-SPOT.TB test in the early diagnosis of primary hepatic tuberculosis. Methods We report a case of primary hepatic tuberculosis whose location of hepatic lesion renders it hard to perform a biopsy. Instead, a T-SPOT.TB test was utilized to help in the early diagnosis of this rare form of tuberculosis. A conventional fourdrug regimen for anti-tubercular therapy together with vitamin B6 was initiated and maintained for 6 months. Results The T-SPOT.TB test was highly positive for ESAT-6 (87 > 20) and CFP-10 (89 > 20). Dull pain in the upper right abdomen was gone 2 months post treatment. The abnormal lesions shown in an MRI reduced significantly 4 months post treatment. Spot count for ESAT-6 and CFP-10 decreased 6 months post treatment. Conclusions The results of this study suggest the critical role of T-SPOT.TB test in the earlier diagnosis of prima¬ry hepatic tuberculosis for those patients who have difficulties having a hepatic biopsy.

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.

Pancreatic cancer is the most lethal digestive cancer and the fourth leading cause of cancer death in the US. IL-39, a heterodimer of p19 and EBI3, is a newly found cytokine and its role in the pathogenesis of neoplasia has not been studied yet. This study was designed to investigate the direct role of IL-39 in the growth of pancreatic cancer. Clonogenic survival assay, cell proliferation, and caspase-3 activity kits were used to evaluate the direct effects of IL-39 on cell survival, proliferation and apoptosis of the widely studied pancreatic cancer cell line MiaPaCa-2. We further investigated the possible molecular mechanisms by using RT-PCR and IHC. The percentage of colonies of pancreatic cancer cells increased significantly in the presence of IL-39. This was paralleled with the increase in the OD value of cancer cells in the presence of IL-39. Interestingly, the relative caspase-3 activity in cancer cells decreased significantly in the presence of IL-39. Furthermore, the pro-tumor effect of IL-39 on pancreatic cancer cells correlated with decreased anti-proliferative molecule p21.The anti-apoptotic effect of IL-39 correlated with decreased pro-apoptotic molecule TRAILR1. These results suggest that IL-39 favors growth of pancreatic cancer by promoting growth and inhibiting apoptosis of cancer cells. This suggests that IL-39 acts as a friend to pancreatic cancer. Thus, inhibition of effect of IL-39 on cells might be a promising strategy to treat pancreatic 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.

Background IL-9 is a pleiotropic cytokine produced mainly by Th9 cells. IL-9 may have an anti-proliferative role in murine melanoma, however, its effect on human melanoma is unknown. Methods We examined the effects of IL-9 on proliferation and apoptosis in four human melanoma cell lines, HTB-65, HTB-72, CRL-11147, and SK-Mel-5. Clonogenic assay, PCNA staining, Quick Cell Proliferation assay, TUNEL staining and caspase-3 activity assay were used to assess proliferation and apoptosis, as appropriate. Results We found that IL-9 decreased the percentage of colonies of HTB-72 and SK-Mel-5 cells but not that of HTB-65 or CRL-11147 cells. PCNA mRNA, PCNA+ cells, PCNA staining intensity, and the OD value of HTB-72 melanoma cells were consistently decreased in the present of IL-9. IL-9 also increased TUNEL+ cells and the relative caspase-3 activity in HTB-72 melanoma cells. We further investigated the possible molecular mechanisms using RT-PCR and immunohistochemical staining. The anti-proliferative effect of IL-9 on HTB-72 cells correlated with higher expression of anti-proliferative molecule p21. Its pro-apoptotic effect on HTB-72 cells correlated with higher expression of the pro-apoptotic molecule TRAIL. Conclusions IL-9 inhibits melanoma HTB-72 cell growth by upregulation of p21 and TRAIL. Understanding the interactions between IL-9 and melanoma may help direct strategies for cytokine-based immunotherapy development. J. Surg. Oncol. 2015 111:969–974. © 2015 Wiley Periodicals, Inc.

Interleukin-21 (IL-21), produced predominantly by CD4+ T cells and natural killer T (NKT) cells, is a newly discovered member of the common γ-chain family of cytokines. It has been implicated in many immunological processes and has been linked to autoimmune diseases, allergies and other inflammatory diseases. In recent years, the role for IL-21 in the pathogenesis of cancer has also been extensively studied. In this review, we will discuss recent advances concerning the role of IL-21 in immunological processes and the pathogenesis of cancer.

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.

Prostate cancer (PCa) is the most common non-cutaneous cancer in men in the USA. Radiation therapy (RT) is widely considered the standard treatment for PCa. IL-37 is an IL-1 family member, and it has been extensively studied in immunity. However, no studies have been done regarding its potential as a radiosensitizer. This study is designed to investigate the direct effect of IL-37 on growth of DU145 and PC-3, two widely studied PCa cell lines, and to investigate whether IL-37 could be used as a radiosensitizer for PCa. Clonogenic survival and quick cell proliferation assays along with immunohistochemistry, TUNEL staining, and caspace-3 activity assay kits as well as RT-PCR were used in this study. Our results showed that IL-37 has little direct effect on growth of PCa. However, IL-37/RT enhanced RT-induced inhibition of cell proliferation and apoptosis in both cell lines. We further found that IL-37/RT upregulated the mRNA expression of p27, Fas, and Bax, while downregulating the mRNA expression of cdk2 in DU145 cells. These findings suggest that IL-37 has the potential to be used as a radiosensitizer for PCa and warrants further investigation.

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.

Background Up to 25% of diabetic patients will develop a diabetic foot ulcer. Chronic wounds such as diabetic foot ulcers often fail to heal with conventional therapies. In recent years, it has been identified that chronic wounds are usually associated with elevated level of matrix metalloproteinases (MMPs). Doxycycline, a cheap tetracycline antibiotic, has been shown to inhibit MMPs both in vitro and in vivo independent of its antimicrobial property. Methods We undertook a search through PUBMED for peer-reviewed research literature with doxycycline, chronic wound, diabetes, MMPs as key words. Results Seventy papers were included in the review. This review identified doxycycline is a very promising drug to be used in patients with diabetic foot ulcers because higher efficacy even in a very low dosage, little side effects in a lower dosage, inhibition of MMP as well as prevention/treatment of infection in the ulcers, beneficial to cardiovascular complications and cheap to manufacture. Conclusion In this review, we provide an overview of the roles of MMPs in the pathogenesis of chronic wounds and explore the potential application of doxycycline as a treatment option in managing chronic wounds such as diabetic foot ulcers.

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.

IL-33 is a member of the IL-1 family of cytokines, and no study has been performed to address its direct anti-tumor effect. This study is designed to investigate whether IL-33 has any direct effect on pancreatic cancer. Clonogenic survival assay, immunohistochemistry, TUNEL staining, proliferation, caspase-3 activity kits and RT-PCR were used to evaluate the effects of IL-33 on cell survival, proliferation and apoptosis of a pancreatic cancer cell line, MIA PaCa-2. We found that the percentage of colonies of MIA PaCa-2 cells, PCNA+ cells and the OD value of cancer cells were all decreased in the presence of IL-33. TUNEL+ cells and the relative caspase-3 activity in cancer cells were increased in the presence of IL-33. We further found that its anti-proliferative effect on cancer cells correlated with downregulation of pro-proliferative molecules cdk2 and cdk4 and upregulation of anti-proliferative molecules p15, p21 and p53. Its pro-apoptotic effect correlated with downregulation of anti-apoptotic molecule FLIP and upregulation of pro-apoptotic molecule TRAIL. These results suggest that IL-33 presents significant anti-tumor effects by inhibition of proliferation and induction of apoptosis of MIA PaCa-2 pancreatic cancer cells. Thus, strength of IL-33/ST2 signal pathway might be a promising way to treat pancreatic cancer.

Melanoma is the leading cause of death among all skin cancers and its incidence continues to rise rapidly worldwide in the past decades. The available treatment options for melanoma remain limited despite extensive clinical research. Melanoma is an immunogenic tumor and great advances in immunology in recent decades allow for the development of immunotherapeutic agents against melanoma. In recent years, immunotherapy utilizing cytokines has been particularly successful in certain cancers and holds promise for patients with advanced melanoma. In this review, an overview of the current status and emerging perspectives on cytokine immunotherapy for melanoma are discussed in details. Such a study will be helpful to unveil the mysterious mask of cytokine-based immunotherapy for melanoma.

Prostate cancer (PCA) is the most common malignancy in men in USA, and the role of Trichomonas vaginalis (T. vag) in the development of PCA is still controversial. Clonogenic assay, PCNA staining, TUNEL staining and caspase-3 activity assay were used to investigate the in vitro role of T. vag in human prostate cancer. We further investigated the possible molecular mechanisms using RT-PCR and immunohistochemical staining. Culture supernatant of T. vag inhibits growth of PC-3 prostate cancer cells, and this correlated with upregulation of p21. Culture supernatant of T. vag induced apoptosis of PC-3 cells, and this correlated with downregulation of Bcl-2. The growth inhibition effect of culture supernatant of T. vag is also demonstrated in another prostate cancer cell line DU145, suggesting that its effect is not specific to one prostate cancer cell line. Culture supernatant of T. vag inhibits growth of prostate cancer by inhibition of proliferation and promotion of apoptosis. Such a study might be helpful to address the association between PCA and infection of T. vag.

Acinetobacter baumannii has been becoming a great challenge to clinicians due to their resistance to almost all available antibiotics. In this study, we sequenced the genome from a multiple antibiotics resistant Acinetobacter baumannii stain which was named A. baumannii-1isolated from China by SMRT sequencing technology to explore its potential mechanisms to antibiotic resistance. We found that several mechanisms might contribute to the antibiotic resistance of Acinetobacter baumannii. Specifically, we found that SNP in genes associated with nucleotide excision repair and ABC transporter might contribute to its resistance to multiple antibiotics; we also found that specific genes associated with bacterial DNA integration and recombination, DNA-mediated transposition and response to antibiotics might contribute to its resistance to multiple antibiotics; Furthermore, specific genes associated with penicillin and cephalosporin biosynthetic pathway and specific genes associated with CHDL and MBL β-lactamase genes might contribute to its resistance to multiple antibiotics. Thus, the detailed mechanisms by which Acinetobacter baumannii show extensive resistance to multiple antibiotics are very complicated. Such a study might be helpful to develop new strategies to control Acinetobacter baumannii infection.

Intercellular communications between lung epithelial cells and alveolar macrophages play an essential role in host defense against acute lung injury. Hyperoxia-induced oxidative stress is an established model to mimic human lung injury. We show that after hyperoxia-associated oxidative stress, a large amount of extracellular vesicles (EVs) are detectable in bronchoalveolar lavage fluid (BALF) and culture medium of lung epithelial cells. Microvesicles (MVs), but not exosomes (Exos) or apoptotic bodies (Abs), are the main type of EVs found in the early stages after hyperoxia. Among all the MV compositions, small RNAs are altered the most significantly after hyperoxia-associated oxidative stress. We further confirmed that hyperoxia up-regulates the levels of certain specific miRNAs in the epithelial cell-derived MVs, such as the miR-320a and miR-221. Functionally, the hyperoxia-induced epithelial MVs promote macrophage activation in vitro and facilitate the recruitment of immunomodulatory cells in vivo detected in BALF. Using MV as a cargo, delivery of the specific miRNA-enriched epithelial MVs (miR-221 and/or miR-320a) also triggers macrophage-mediated pro-inflammatory effects. Collectively, epithelial cell-derived MVs promote macrophage-regulated lung inflammatory responses via MV-shuttling miRNAs.

Prostate cancer (PCa) is the most common non-cutaneous cancer in the United States. There is currently a lack of safe and effective radiosensitizers that can enhance the effectiveness of radiation treatment (RT) for Pca. Clonogenic assay, PCNA staining, Quick Cell Proliferation assay, TUNEL staining and caspase-3 activity assay were used to assess proliferation and apoptosis in DU145 Pca cells. RT-PCR/IHC were used to investigate the mechanisms. We found that the percentage of colonies, PCNA staining intensity, and the optical density value of DU145 cells were decreased (RT/GT vs. RT). TUNEL + cells and the relative caspase-3 activity were increased (RT/GT vs. RT). Compared to RT, the anti-proliferative effect of RT/GT correlated with increased expression of the anti-proliferative molecule p16. Compared to RT, the pro-apoptotic effect of RT/GT correlated with decreased expression of the anti-apoptotic molecule Bcl-2. GT enhances RT sensitivity of DU145 by inhibiting proliferation and promoting apoptosis.

Cervical cancer (CC) is a leading cause of death in women worldwide. Radiation therapy (RT) for CC is an effective alternative, but its toxicity remains challenging. Blueberry is amongst the most commonly consumed berries in the United States. We previously showed that resveratrol, a compound in red grapes, can be used as a radiosensitizer for prostate cancer. In this study, we found that the percentage of colonies, PCNA expression level and the OD value of cells from the CC cell line SiHa were all decreased in RT/Blueberry Extract (BE) group when compared to those in the RT alone group. Furthermore, TUNEL+ cells and the relative caspase-3 activity in the CC cells were increased in the RT/BE group compared to those in the RT alone group. The anti-proliferative effect of RT/BE on cancer cells correlated with downregulation of pro-proliferative molecules cyclin D and cyclin E. The pro-apoptotic effect of RT/BE correlated with upregulation of the pro-apoptotic molecule TRAIL. Thus, BE sensitizes SiHa cells to RT by inhibition of proliferation and promotion of apoptosis, suggesting that blueberry might be used as a potential radiosensitizer to treat CC.

Lung cancer is the most common cancer in the world and the leading cause of tumor death among males. MicroRNAs (miRNAs) are single-stranded RNAs of approximately 22 nucleotides and constituted a new class of gene regulators in humans. As a novel class of emerging biomarkers, the aberrant expression of miRNA has been detected in various tumors. miRNAs are secreted into circulation by microvesicles from the broken tumor cells and act as either oncogenes or tumor suppressors in tumor tissues. In this review, we summarized different circulating miRNAs and their expression level as well as predictable values in lung cancer patients which were investigated in recent 5 years. Circulating miRNAs are found to be dysregulated and have association with clinicopathological parameters and overall survival in lung cancer patients. In conclusion, circulating miRNAs have the potential for distinguishing lung cancer patients from healthy individuals, with the advantages of stabilities, noninvasiveness and cost-effectiveness.

Reactive oxygen species (ROS) participate in various physiological and pathological functions following generation from different types of cells. Here we explore ROS functions on spontaneous tail regeneration using gecko model. ROS were mainly produced in the skeletal muscle after tail amputation, showing a temporal increase as the regeneration proceeded. Inhibition of the ROS production influenced the formation of autophagy in the skeletal muscles, and as a consequence, the length of the regenerating tail. Transcriptome analysis has shown that NADPH oxidase (NOX2) and the subunits (p40phox and p47phox) are involved in the ROS production. ROS promoted the formation of autophagy through regulation of both ULK and MAPK activities. Our results suggest that ROS produced by skeletal muscles are required for the successful gecko tail regeneration.

IFN-γ(-/-) NOD.H-2h4 mice develop autoimmune disease with extensive hyperplasia and proliferation of thyroid epithelial cells (TEC H/P) and fibrosis. Splenic T cells from donors with severe TEC H/P transfer TEC H/P to SCID recipients. The goal of this study was to determine what factors control TEC H/P development/progression by examining T cells, markers of apoptosis, senescence and proliferation in thyroids of SCID recipients over time. At 28days, T cell infiltration was maximal, thyrocytes were proliferating, and fibrosis was moderate. At days 60 and 90, thyroids were larger with more fibrosis. T cells, cytokines and thyrocyte proliferation decreased, and cell cycle inhibitor proteins, and anti-apoptotic molecules increased. T cells and thyrocytes had foci of phosphorylated histone protein H2A.X, indicative of cellular senescence, when TEC H/P progressed and thyrocyte proliferation declined. Some thyrocytes were regenerating at day 90, with irregularly shaped empty follicles and ciliated epithelium. Proliferating thyrocytes were thyroid transcription factor (TTF1)-positive, suggesting they derived from epithelial cells and not brachial cleft remnants.

In this study, a new subunit vaccine that comprised native F1 and recombinant rV270 was evaluated for protective efficacy using mouse, guinea pig and rabbit models in comparison with the live attenuated vaccine EV76. Complete protection against challenging with 10 6 colony-forming units (CFU) of virulent Yersinia pestis strain 141 was observed for mice immunized with the subunit vaccines and EV76 vaccine. In contrast, the subunit vaccine recipes VII (F1-20 μg + rV270-10 μg) and IX (F1-40 μg + rV270-20 μg) and EV76 vaccine provided 86%, 79% and 93% protection against the same level of challenge in guinea pigs and 100%, 83% and 100% protection in rabbits, respectively. The immunized mice with the vaccines had significantly higher IgG titres than the guinea pigs and rabbits, and the immunized guinea pigs developed significantly higher IgG titres than the rabbits, but the anti-F1 response in guinea pigs was more variable than in the mice and rabbits, indicating that guinea pig is not an ideal model for evaluating protective efficacy of plague subunit vaccine, instead the rabbits could be used as an alternative model. All the immunized animals with EV76 developed a negligible IgG titre to rV270 antigen. Furthermore, analysis of IgG subclasses in the immunized animals showed a strong response for IgG1, whereas those receiving EV76 immunization demonstrated predominant production of IgG1 and IgG2a isotypes. The subunit vaccine and EV76 vaccine are able to provide protection for animals against Y. pestis challenge, but the subunit vaccines have obvious advantages over EV76 in terms of safety of use.

To investigate the effects of two different dosages of sildenafil on patients with erectile dysfunction (ED), a total of 3,674 patients with ED were recruited to answer questionnaires designed specifically for this study. There were 977 patients in the 50 mg group and there were 2,697 patients in the 100 mg group. Both 50 mg and 100 mg of sildenafil therapy increased the ED patients’ average monthly frequency of sexual intercourse, improved erectile function state in self-assessment, and elevated sexual satisfaction and enjoyment. Despite a higher rate of concomitant diseases, patients in the higher dosage of sildenafil group had a better outcome in the average monthly frequency of sexual intercourse and sexual enjoyment compared with those in the lower dosage. Such a study might be helpful for health care providers to choose sildenafil dosage for patients with ED.

Phytochemicals are chemical compounds from fruits, vegetables, or grains and they have been used to treat various diseases for thousands of years. More than one million people in the United States get cancer each year. Although recent advances in medicine have improved the outcomes for cancer patients, there is still a need for novel approaches in the fight against cancer. One such approach that has shown promise in recent years is the use of phytochemicals alone or as synergistic agents. In this review, we will discuss the use of phytochemicals as therapeutic agents against cancer with an emphasis on apple extract.

Interleukin-11 (IL-11) is a member of the glycoprotein-130 (GP-130) cytokines that utilizes the GP-130 signaling pathway shared by other cytokines of the same family. Traditionally regarded as an anti-inflammatory cytokine, IL-11 also demonstrates its role as a proinflammatory cytokine, suggesting its complex role in immune response. In recent years, IL-11 has an emerging role in various inflammation-associated cancers. In this review, we aim to discuss IL-11 signaling pathway, to explore the role of IL-11 in immunity and various cancers, and to provide a therapeutic perspective of strategies utilized to interfere IL-11 signaling in cancer cells.

Interleukin-10 (IL-10) produced by a wide-variety of cells is a highly pleiotropic cytokine. It has been implicated in the pathogenesis and/or development of autoimmune diseases and cancer, although it displays differential effects that seem to be contradictory sometimes. The ultimate role of this cytokine in disease, however, cannot be fully determined until the immunological contexts that regulate its function are further elucidated. In this review, we will discuss a wide variety of evidence of IL-10 in immunity and cancer in an effort to illuminate the remaining mysteries in the function of this cytokine that, when fully understood, may prove to be a powerful tool in the battle against cancer.