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Pancreatic cancer (PC) is highly resistant to chemo and radiotherapy. Radiation-induced fibrosis (RIF) is a major cause of clinical concern for various malignancies, including PC. In this study, we aimed to evaluate the radiosensitizing and anti-RIF potential of fluvastatin in PC. Short-term viability and clonogenic survival assays were used to evaluate the radiosensitizing potential of fluvastatin in multiple human and murine PC cell lines. The expression of different proteins was analyzed to understand the mechanisms of fluvastatin-mediated radiosensitization of PC cells and its anti-RIF effects in both mouse and human pancreatic stellate cells (PSCs). Finally, these effects of fluvastatin and/or radiation were assessed in an immune-competent syngeneic murine model of PC. Fluvastatin radiosensitized multiple PC cell lines, as well as radioresistant cell lines in vitro, by inhibiting radiation-induced DNA damage repair response. Nonmalignant cells, such as PSCs and NIH3T3 cells, were less sensitive to fluvastatin-mediated radiosensitization than PC cells. Interestingly, fluvastatin suppressed radiation and/or TGF-β-induced activation of PSCs, as well as the fibrogenic properties of these cells in vitro. Fluvastatin considerably augmented the antitumor effect of external radiation therapy and also suppressed intra-tumor RIF in vivo. These findings suggested that along with radiation, fluvastatin co-treatment may be a potential therapeutic approach against PC. Fluvastatin, a cholesterol-lowering drug, radiosensitizes pancreatic cancer (PC) cells partly by inhibiting DNA damage response and/or autophagic flux. Fluvastatin also significantly suppresses intra-tumor radiation-induced fibrosis, as it inhibits radiation/TGF-β-induced activation of pancreatic stellate cells. Together, fluvastatin and radiation co-treatment may be a potential therapeutic approach against PC and warrants further clinical evaluation.

The exchange of CO2 between the air–water interfaces of estuaries is crucial from the perspective of the global carbon cycle and climate change feedback. In this regard, we evaluated the air–water CO2 exchanges in two major estuaries—the Mahanadi estuary (ME) and the Dhamra estuary (DE) in the northern part of the Bay of Bengal, India. Biogeochemical properties of these estuarine waters were quantified in three distinct seasons, namely, pre-monsoon (March to May), monsoon (June to October), and post-monsoon (November to February). The significant properties of water, such as the water temperature, pH, salinity, nutrients, dissolved oxygen, chlorophyll-a (chl a), and photosynthetic pigment fluorescence of phytoplankton, were estimated and correlated with CO2 fluxes. We found that the ME acted as a source of CO2 fluxes in the monsoon and post-monsoon, while DE acted as a sink during the monsoon. The stepwise regression model showed that the fluxes were primarily driven by water temperature, pH, and salinity, and they correlated well with the phytoplankton characteristics. The chl a content, fluorescence yield, and phycobilisomes-to-photosystem II fluorescence ratios were major drivers of the fluxes. Therefore, for predicting air–water CO2 exchanges precisely in a large area over a seasonal and annual scale in the estuaries of the Bay of Bengal, India, critical key parameters such as water temperature, pH, salinity, chl a, and fluorescence yield of phytoplankton should be taken into consideration. However, the responses of phytoplankton, both in terms of production and CO2 capture, are critical research areas for a better understanding of air–water CO2 exchanges in coastal ecology under climate change scenarios.

Background This systematic review and meta-analysis aimed to compare the efficacy and safety of cangrelor as compared to ticagrelor in patients with ST-elevated myocardial infarction (STEMI) who underwent percutaneous intervention. Methods PubMed, Embase, Scopus, Web of Science, Cochrane CENTRAL, and ClinicalTrials.gov databases were searched for relevant head-on-comparison or swapping studies. The primary outcome was the rate of high platelet reactivity (HPR) at specific time intervals after stopping cangrelor infusion during the first 24 h. Secondary outcomes were the risks of thrombosis, all-cause mortality and bleeding. Pooled odds ratios (ORs) were calculated using random-effects models. Results A total of 1018 studies were screened and eight were included in the analysis. There were four head-on-comparison studies and four swapping studies. There was no significant difference in the proportion of patients achieving a high platelet reactivity in swapping studies [OR, 0.71 (95% CI 0.04, 13.87), p  = 0.82, i 2  = 88%]. In head-on-comparison studies, PRU from Fig.  2 B shows there was no significant reduction in high platelet reactivity [mean difference – 77.83 (95% CI − 238.84, 83.18), p  < 0.001, i 2  = 100%]. PRU results from (Fig.  2 C) show a mean difference of 7.38 (95% CI − 29.74, 44.51), p  < 0.001, i 2  = 97%. There was no significant difference in the risks of thrombosis [OR, 0.91 (95% CI 0.20, 4.13), p  = 0.81, i 2  = 0%], all-cause mortality [OR, 3.52 (95% CI 0.44, 27.91), p  = 0.24, i 2  = 26%] and bleeding [OR, 0.89 (95% CI 0.37, 2.17), p  = 0.93, i 2  = 0%] between the two groups as revealed in the head-on-comparison studies. Conclusion The efficacy and safety profiles of cangrelor and ticagrelor were similar in patients with STEMI.

The study focuses on two breeds of dog namely Labrador retriever and German shepherd to investigate the different haematological parameters. Blood samples were collected from these two breeds of dog, and haematological parameters such as haemoglobin (Hb), total erythrocyte count (TEC), total leukocyte count (TLC), packed cell volume (PCV), mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) were investigated. Though literatures on haematological profiling of dogs are in record, a comparative study between two breeds namely Labrador retriever and German has not been explained adequately. So, this study was undertaken to establish a comparative analysis of haematological parameters of two breeds of dog. Sex-wise variations in the haematological values as well as a significant correlation between different parameters have been reported in these two breeds of dog.

Hypericum perforatum L., commonly known as St. John’s wort is an important medicinal plant, belonging to family Hypericaceae. Among all species of Hypericum, H. perforatum is most investigated and exploited. It is sold as one of the world’s topmost retailing antidepressants. This plant possesses antibacterial, antiviral, anti-inflammatory, and anticancerous properties. These medicinal properties are attributed to the presence of bioactive compounds, such as hypericins and pseudohypericins (naphthodianthrones), hyperforin and adhyperforin (prenylated acylphloroglucinols), quercetin, rutin, isoquercetin, and catechin (flavonoids), chlorogenic acid, caffeic acid, and tannic acid (phenols) and xanthones. The conventional methods of propagation of H. perforatum are time consuming and field grown plants are exposed to biotic and abiotic challenges which affect its phytochemical constituents. Moreover, these methods are also unable to meet the commercial demand of secondary metabolites. Therefore, in order to meet the growing raw material demand of pharmaceutical industries there is a need to develop effecient in vitro plant regeneration protocols for large scale production of H. perforatum plants and other biotechnological methods (cell, tissue and organ culture, cell suspension culture, hairy root culture, elicitation, etc.) for improvement of target bioactive compounds. The present review provides a comprehensive account of the available information on in vitro plant regeneration and biotechnological approaches used to enhance the secondary metabolite(s) content in H. perforatum during the past years. It also deals with the unexplored areas which might be exploited for drug discovery.

A combination of chemotherapy with immunotherapy has been proposed to have better clinical outcomes in Pancreatic Ductal Adenocarcinoma (PDAC). On the other hand, chemotherapeutics is known to have certain unwanted effects on the tumor microenvironment that may mask the expected beneficial effects of immunotherapy. Here, we have investigated the effect of gemcitabine (GEM), on two immune checkpoint proteins (PD-L1 and PD-L2) expression in cancer associated fibroblasts (CAFs) and pancreatic cancer cells (PCCs). Findings of in vitro studies conducted by using in-culture activated mouse pancreatic stellate cells (mPSCs) and human PDAC patients derived CAFs demonstrated that GEM significantly induces PD-L1 and PD-L2 expression in these cells. Moreover, GEM induced phosphorylation of STAT1 and production of multiple known PD-L1-inducing secretory proteins including IFN-γ in CAFs. Upregulation of PD-L1 in PSCs/CAFs upon GEM treatment caused T cell inactivation and apoptosis in vitro. Importantly, Statins suppressed GEM-induced PD-L1 expression both in CAFs and PCCs while abrogating the inactivation of T-cells caused by GEM-treated PSCs/CAFs. Finally, in an immunocompetent syngeneic orthotopic mouse pancreatic tumor model, simvastatin and GEM combination therapy significantly reduced intra-tumor PD-L1 expression and noticeably reduced the overall tumor burden and metastasis incidence. Together, the findings of this study have provided experimental evidence that illustrates potential unwanted side effects of GEM that could hamper the effectiveness of this drug as mono and/or combination therapy. At the same time the findings also suggest use of statins along with GEM will help in overcoming these shortcomings and warrant further clinical investigation.

In patients with pancreatic cancer (PC), the peritoneal cavity is the second-most common site of metastasis after the liver. Peritoneal macrophages (PMs) have been demonstrated to play a significant role in the peritoneal metastases of different cancers. Gemcitabine (GEM) is known to affect PC-associated immune cells, including macrophages. However, its effect on PMs and its possible clinical implication is yet to be investigated. In this study, mouse-derived PMs were treated with GEM ex vivo to analyze the polarization status. Production of GEM-induced reactive oxygen species (ROS) and reactive nitrogen species was evaluated using DCFH-DA, DAF-FM, and Griess assay. Antitumor effects of PMs on UN-KC-6141and UN-KPC-961 murine PC cells were evaluated in presence and absence of GEM in vitro. Similarly, effect of GEM on human THP-1 macrophage polarization and its tumoricidal effect was studied in vitro. Furthermore, the effect of GEM-treated PMs on peritoneal metastasis of UN-KC-6141 cells was evaluated in a syngeneic mouse model of PC. GEM upregulated M1 phenotype-associated molecular markers (Tnf-α and Inos) in vitro in PMs obtained from naïve mouse. Moreover, IL-4-induced M2-like PMs reverted to M1-like after GEM treatment. Co-culture of UN-KC-6141 and UN-KPC-961 cancer cells with PMs in the presence of GEM increased apoptosis of these cells, whereas cell death was markedly reduced after N-acetyl-l-cysteine treatment. Corroborating these findings co-culture of GEM-treated human THP-1 macrophages also induced cell death in MIAPaCa-2 cancer cells. GEM-treated PMs injected intraperitoneally along with UN-KC-6141 cells into mice extended survival period, but did not stop disease progression and mortality. Together, GEM induced M1-like polarization of PMs from naive and/or M2-polarized PMs in a ROS-dependent manner. GEM-induced M1-like PMs prompted cytotoxicity in PC cells and delayed disease progression in vivo.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that increasingly is being studied in cancers and inflammatory diseases. Though murine models have been instrumental in understanding the functional role of MIF in different pathological conditions, the information obtained from these models is biased towards a specific species. In experimental science, results obtained from multiple clinically relevant animal models always provide convincing data that might recapitulate in humans. Syrian golden hamster ( Mesocricetus auratus ), is a clinically relevant animal model for multiple human diseases. Hence, the major objectives of this study were to characterize the structure and function of  Mesocricetus auratus MIF (MaMIF) and finally evaluate its effect on pancreatic tumor growth in vivo . Initially, the recombinant MaMIF was cloned, expressed and purified in a bacterial expression system. The MaMIF primary sequence, biochemical properties, and crystal structure analysis showed greater similarity with human MIF. The crystal structure of MaMIF illustrates that it forms a homotrimer as known in human and mouse. However, MaMIF exhibits some minor structural variations when compared to human and mouse MIF. The in vitro functional studies show that MaMIF has tautomerase activity and enhances activation and migration of hamster peripheral blood mononuclear cells (PBMCs). Interestingly, injection of MaMIF into HapT1 pancreatic tumor-bearing hamsters significantly enhanced the tumor growth and tumor-associated angiogenesis. Together, the current study shows a structural and functional similarity between the hamster and human MIF. Moreover, it has demonstrated that a high level of circulating MIF originating from non-tumor cells might also promote pancreatic tumor growth in vivo .