Inhibition of PIM kinase in tumor associated macrophages suppresses inflammasome activation and sensitizes prostate cancer to immunotherapy.

Immunotherapy has changed the treatment paradigm for many types of cancer, but immune checkpoint inhibitors (ICIs) have not shown benefit in prostate cancer (PCa). Chronic inflammation contributes to the immunosuppressive prostate tumor microenvironment (TME) and is associated with poor response to ICIs. The primary source of inflammatory cytokine production is the inflammasome.

PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer.

PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy.

MASTL regulates EGFR signaling to impact pancreatic cancer progression.

Pancreatic cancer (PC) remains a major cause of cancer-related deaths primarily due to its inherent potential of therapy resistance. Checkpoint inhibitors have emerged as promising anti-cancer agents when used in combination with conventional anti-cancer therapies. Recent studies have highlighted a critical role of the Greatwall kinase (microtubule-associated serine/threonine-protein kinase-like (MASTL)) in promoting oncogenic malignancy and resistance to anti-cancer therapies; however, its role in PC remains unknown.

Direct phosphorylation and stabilization of HIF-1α by PIM1 kinase drives angiogenesis in solid tumors.

Angiogenesis is essential for the sustained growth of solid tumors. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of angiogenesis and constitutive activation of HIF-1 is frequently observed in human cancers. Therefore, understanding the mechanisms governing the activation of HIF-1 is critical for successful therapeutic targeting of tumor angiogenesis.

Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer.

Objective: This study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer.

Design: Patient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic syngeneic models.

Synergistic antitumor effect of 5-fluorouracil and withaferin-A induces endoplasmic reticulum stress-mediated autophagy and apoptosis in colorectal cancer cells.

The development of chemo-resistance against 5-fluorouracil (5-FU) in tumor cells is one of the main debacles in colorectal cancer (CRC) patients. A recent combination of 5-FU with oxaliplatin or cetuximab drastically improves the survival rate in CRC patients; however, the toxicity issue cannot be evaded completely. Thus, searching for novel drug combinations with high specificity and low toxicity is seemingly important.

PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer.

Resistance to chemotherapy represents a major obstacle to the successful treatment of non-small-cell lung cancer (NSCLC). The goal of this study was to determine how PIM kinases impact mitochondrial dynamics, ROS production, and response to chemotherapy in lung cancer. Live-cell imaging and microscopy were used to determine the effect of PIM loss or inhibition on mitochondrial phenotype and ROS.

Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC), like many KRAS-driven tumors, preferentially loses CDKN2A that encodes an endogenous CDK4/6 inhibitor to bypass the RB-mediated cell cycle suppression. Analysis of a panel of patient-derived cell lines and matched xenografts indicated that many pancreatic cancers have intrinsic resistance to CDK4/6 inhibition that is not due to any established mechanism or published biomarker. Rather, there is a KRAS-dependent rapid adaptive response that leads to the upregulation of cyclin proteins, which participate in functional complexes to mediate resistance.

Dual Inhibition of Bruton's Tyrosine Kinase and Phosphoinositide-3-Kinase p110 as a Therapeutic Approach to Treat Non-Hodgkin's B Cell Malignancies.

Although new targeted therapies, such as ibrutinib and idelalisib, have made a large impact on non-Hodgkin's lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies, or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors, possibly prolonging the duration of the response and reducing resistance.

Ethanol and age enhances fluoride toxicity through oxidative stress and mitochondrial dysfunctions in rat intestine.

Fluoride toxicity and alcohol abuse are the two serious public health problems in many parts of the world. The current study was an attempt to investigate the effect of alcohol administration and age on fluoride toxicity in rat intestine. Six and 18 months old female Sprague Dawley rats were exposed to sodium fluoride (NaF, 25 mg/kg), 30 % ethanol (EtOH, 1 ml/kg), and NaF+EtOH (25 mg/kg+1 ml/kg) for a period of 20, 40, and 90 days.

Growth inhibition and apoptosis induction by (+)-Cyanidan-3-ol in hepatocellular carcinoma.

The objective of this study was to evaluate the cytotoxicity of (+)-cyanidan-3-ol (CD-3) in human hepatocellular carcinoma cell line (HepG2) and chemopreventive potential against hepatocellular carcinoma (HCC) in Balb/c mice. The HepG2 cell line was treated with CD-3 at various concentrations and the proliferation of the HepG2 cells was measure by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT), sulforhodamine B (SRB) and lactate dehydrogenase (LDH) assays. Cell apoptosis was detected by Hoechst 33258 (HO), Acridine orange/ethylene dibromide (AO/EB) staining, DNA fragmentation analysis and the apoptosis rate was detected by flow cytometry.

Effects of fluoride and ethanol administration on lipid peroxidation systems in rat brain.

Exposure to fluoride and excessive ethanol consumption has been identified as a serious public health problem in many parts of the world, including India. Thus, the effect of co-exposure to fluoride and ethanol for 3-6 weeks was studied on lipid peroxidation (LPO) and oxidative stress related parameters in the rat brain. After 3 weeks, co-treated animals showed 95% increase in LPO levels compared to control.

Modulation of intestinal brush border membrane chemical composition during postnatal development in rats: effect of gestational diabetes.

There was a significant increase in fucose (52%), total hexoses (16%) and hexosamine (56%) except sialic acid, which was reduced (77%) in the microvillus membrane of infants born to rat mothers made diabetic by injecting alloxan on day 3 of gestation. Expressed on the protein basis there were a significant increase in membrane, triglyceride, total cholesterol, and phospholipids content of brush border in pups from diabetic group between 5-45 days of postnatal age. Intestinal morphology in diabetic group showed, regression of tubular glands, distorted cellular organization of mucosal cells, reduction in the mucosal cell height and number of secretory goblet cells.

Gestational diabetes affects postnatal development of transport and enzyme functions in rat intestine.

The effect of alloxan-induced gestational diabetes on the postnatal development of brush border disaccharidases and D-glucose transport in rat intestine was studied. Pups born to diabetic mothers showed 92-22% increase in blood sugar levels compared with the controls. Western blot and RT-PCR analyses revealed that the activities of brush border sucrase, lactase and Sodium Glucose Co-transporter 1 (SGLT1) correlates with protein and mRNA levels in intestine of pups born to diabetic rat mothers after 5-45 days of birth.

Modulation of lipid peroxidation and antioxidant defense systems in rat intestine by subchronic fluoride and ethanol administration.

Excessive consumption of fluoride and ethanol has been identified as injurious to human health. Fluoride and ethanol co-exposures are commonly seen among the alcoholics residing in endemic fluoride areas worldwide. This study was undertaken to examine the modulation of lipid peroxidation and antioxidant defense systems in rat intestine by subchronic fluoride and ethanol administration.