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The endogenous cannabinoid anandamide was identified as an agonist for the recombinant human VR1 (hVR1) by screening a large array of bioactive substances using a FLIPR‐based calcium assay. Further electrophysiological studies showed that anandamide (10 or 100 μM) and capsaicin (1 μM) produced similar inward currents in hVR1 transfected, but not in parental, HEK293 cells. These currents were abolished by capsazepine (1 μM). In the FLIPR anandamide and capsaicin were full agonists at hVR1, with pEC50 values of 5.94±0.06 (n=5) and 7.13±0.11 (n=8) respectively. The response to anandamide was inhibited by capsazepine (pKB of 7.40±0.02, n=6), but not by the cannabinoid receptor antagonists AM630 or AM281. Furthermore, pretreatment with capsaicin desensitized the anandamide‐induced calcium response and vice versa. In conclusion, this study has demonstrated for the first time that anandamide acts as a full agonist at the human VR1. British Journal of Pharmacology (2000) 129, 227–230; doi:10.1038/sj.bjp.0703050

Vanilloid receptor-1 (VR1, also known as TRPV1) is a thermosensitive, nonselective cation channel that is expressed by capsaicin-sensitive sensory afferents and is activated by noxious heat, acidic pH and the alkaloid irritant capsaicin 1 . Although VR1 gene disruption results in a loss of capsaicin responses, it has minimal effects on thermal nociception 2 , 3 . This and other experiments—such as those showing the existence of capsaicin-insensitive heat sensors in sensory neurons 4 —suggest the existence of thermosensitive receptors distinct from VR1. Here we identify a member of the vanilloid receptor/ TRP gene family, vanilloid receptor-like protein 3 (VRL3, also known as TRPV3), which is heat-sensitive but capsaicin-insensitive. VRL3 is coded for by a 2,370-base-pair open reading frame, transcribed from a gene adjacent to VR1 , and is structurally homologous to VR1. VRL3 responds to noxious heat with a threshold of about 39 °C and is co-expressed in dorsal root ganglion neurons with VR1. Furthermore, when heterologously expressed, VRL3 is able to associate with VR1 and may modulate its responses. Hence, not only is VRL3 a thermosensitive ion channel but it may represent an additional vanilloid receptor subunit involved in the formation of heteromeric vanilloid receptor channels.

Cytokines are known to shape the tumor microenvironment and although progress has been made in understanding their role in carcinogenesis, much remains to learn regarding their role in tumor growth and progression. We have identified granulocyte colony-stimulating factor (G-CSF) as one such cytokine, showing that G-CSF is linked with metastasis in human gastrointestinal tumors and neutralizing G-CSF in a mouse model of colitis-associated cancer is protective. Here, we set out to identify the role of G-CSF and its receptor, G-CSFR, in CD4 and CD8 T cell responses in the tumor microenvironment. MC38 colon cancer cells were injected into WT, G-CSFR mice, or Rag2 mice. Flow cytometry, Real Time PCR and Multiplex cytokine array analysis were used for T cell phenotype analysis. Adoptive transfer of WT or G-CSFR CD4 of CD8 T cells were performed. Mouse tumor size, cytokine expression, T cell phenotype, and cytotoxic activity were analyzed. We established that in G-CSFR mice, tumor growth of MC38 colon cancer cells is significantly decreased. T cell phenotype and cytokine production were also altered, as both and approaches revealed that the G-CSF/G-CSFR stimulate IL-10-producing, FoxP3-expressing CD4 and CD8 T cells, whereas G-CSFR T cells exhibit increased IFNγ and IL-17A production, leading to increased cytotoxic activity in the tumor microenvironment. Furthermore, peritumoral injection of recombinant IFNγ or IL-17A inhibited colon and pancreas tumor growth compared to controls. Taken together, our data reveal an unknown mechanism by which G-CSF, through its receptor G-CSFR, promotes an inhibitory Treg phenotype that limits tumor immune responses and furthermore suggest that targeting this cytokine/receptor axis could represent a novel therapeutic approach for gastrointestinal, and likely other tumors with high expression of these factors.

The vanilloid receptor-1 (VR1) is a heat-gated ion channel that is responsible for the burning sensation elicited by capsaicin. A similar sensation is reported by patients with esophagitis when they consume alcoholic beverages or are administered alcohol by injection as a medical treatment. We report here that ethanol activates primary sensory neurons, resulting in neuropeptide release or plasma extravasation in the esophagus, spinal cord or skin. Sensory neurons from trigeminal or dorsal root ganglia as well as VR1-expressing HEK293 cells responded to ethanol in a concentration-dependent and capsazepine-sensitive fashion. Ethanol potentiated the response of VR1 to capsaicin, protons and heat and lowered the threshold for heat activation of VR1 from ∼42°C to ∼34°C. This provides a likely mechanistic explanation for the ethanol-induced sensory responses that occur at body temperature and for the sensitivity of inflamed tissues to ethanol, such as might be found in esophagitis, neuralgia or wounds.

The pharmacology of various peptide and non‐peptide ligands was studied in Chinese hamster ovary (CHO) cells stably expressing human orexin‐1 (OX1) or orexin‐2 (OX2) receptors by measuring intracellular calcium ([Ca2+]i) using Fluo‐3AM. Orexin‐A and orexin‐B increased [Ca2+]i in CHO‐OX1 (pEC50=8.38±0.04 and 7.26±0.05 respectively, n=12) and CHO‐OX2 (pEC50=8.20±0.03 and 8.26±0.04 respectively, n=8) cells. However, neuropeptide Y and secretin (10 pM – 10 μM) displayed neither agonist nor antagonist properties in either cell‐line. SB‐334867‐A (1‐(2‐Methyylbenzoxanzol‐6‐yl)‐3‐[1,5]naphthyridin‐4‐yl‐urea hydrochloride) inhibited the orexin‐A (10 nM) and orexin‐B (100 nM)‐induced calcium responses (pKB=7.27±0.04 and 7.23±0.03 respectively, n=8), but had no effect on the UTP (3 μM)‐induced calcium response in CHO‐OX1 cells. SB‐334867‐A (10 μM) also inhibited OX2 mediated calcium responses (32.7±1.9% versus orexin‐A). SB‐334867‐A was devoid of agonist properties in either cell‐line. In conclusion, SB‐334867‐A is a non‐peptide OX1 selective receptor antagonist. British Journal of Pharmacology (2001) 132, 1179–1182; doi:10.1038/sj.bjp.0703953

A major risk factor for colon cancer growth and progression is chronic inflammation. We have shown that the MAPK-activated protein kinase 2 (MK2) pathway is critical for colon tumor growth in colitis-associated and spontaneous colon cancer models. This pathway is known to regulate expression of the tumor-promoting cytokines, IL-1, IL-6, and TNF-α. However, little is known about the ability of MK2 to regulate chemokine production. This is the first study to demonstrate this pathway also regulates the chemokines, MCP-1, Mip-1α, and Mip-2α (MMM). We show that these chemokines induce tumor cell growth and invasion and that MK2 inhibition suppresses tumor cell production of chemokines and reverses the resulting pro-tumorigenic effects. Addition of MMM to colon tumors significantly enhances tumor growth in control tumors and restores tumor growth in the presence of MK2 inhibition. We also demonstrate that MK2 signaling is critical for chemokine expression and macrophage influx to the colon tumor microenvironment. MK2 signaling in macrophages was essential for inflammatory cytokine/chemokine production, whereas MK2 macrophages or MK2 inhibition suppressed cytokine expression. We show that addition of bone marrow-derived macrophages to the tumor microenvironment enhances tumor growth in control tumors and restores tumor growth in tumors treated with MK2 inhibitors, while addition of MK2 macrophages had no effect. This is the first study to demonstrate the critical role of the MK2 pathway in chemokine production, macrophage influx, macrophage function, and tumor growth.

The vanilloid receptor-1 (VR1) is a heat-gated ion channel that is responsible for the burning sensation elicited by capsaicin. A similar sensation is reported by patients with esophagitis when they consume alcoholic beverages or are administered alcohol by injection as a medical treatment. We report here that ethanol activates primary sensory neurons, resulting in neuropeptide release or plasma extravasation in the esophagus, spinal cord or skin. Sensory neurons from trigeminal or dorsal root ganglia as well as VR1-expressing HEK293 cells responded to ethanol in a concentration-dependent and capsazepine-sensitive fashion. Ethanol potentiated the response of VR1 to capsaicin, protons and heat and lowered the threshold for heat activation of VR1 from similar to 42 degree C to similar to 34 degree C. This provides a likely mechanistic explanation for the ethanol-induced sensory responses that occur at body temperature and for the sensitivity of inflamed tissues to ethanol, such as might be found in esophagitis, neuralgia or wounds.

We have studied the performances of (a) a two-way coupled atmosphere–ocean modeling system and (b) one-way coupled ocean model (forced by the atmosphere model), as compared to the available in situ measurements during and after a strong Adriatic bora wind event in February 2012, which led to extreme air–sea interactions. The simulations span the period between January and March 2012. The models used were ALADIN (Aire Limitée Adaptation dynamique Développement InterNational) (4.4 km resolution) on the atmosphere side and an Adriatic setup of Princeton ocean model (POM) (1°∕30 × 1°∕30 angular resolution) on the ocean side. The atmosphere–ocean coupling was implemented using the OASIS3-MCT model coupling toolkit. Two-way coupling ocean feedback to the atmosphere is limited to sea surface temperature. We have compared modeled atmosphere–ocean fluxes and sea temperatures from both setups to platform and CTD (conductivity, temperature, and depth) measurements from three locations in the northern Adriatic. We present objective verification of 2 m atmosphere temperature forecasts using mean bias and standard deviation of errors scores from 23 meteorological stations in the eastern part of Italy. We show that turbulent fluxes from both setups differ up to 20 % during the bora but not significantly before and after the event. When compared to observations, two-way coupling ocean temperatures exhibit a 4 times lower root mean square error (RMSE) than those from one-way coupled system. Two-way coupling improves sensible heat fluxes at all stations but does not improve latent heat loss. The spatial average of the two-way coupled atmosphere component is up to 0.3 °C colder than the one-way coupled setup, which is an improvement for prognostic lead times up to 20 h. Daily spatial average of the standard deviation of air temperature errors shows 0.15 °C improvement in the case of coupled system compared to the uncoupled. Coupled and uncoupled circulations in the northern Adriatic are predominantly wind-driven and show no significant mesoscale differences.

To assess the prevalence of abortion among population groups and changes in rates between 2008 and 2014. We used secondary data from the Abortion Patient Survey, the American Community Survey, and the National Survey of Family Growth to estimate abortion rates. We used information from the Abortion Patient Survey to estimate the lifetime incidence of abortion. Between 2008 and 2014, the abortion rate declined 25%, from 19.4 to 14.6 per 1000 women aged 15 to 44 years. The abortion rate for adolescents aged 15 to 19 years declined 46%, the largest of any group. Abortion rates declined for all racial and ethnic groups but were larger for non-White women than for non-Hispanic White women. Although the abortion rate decreased 26% for women with incomes less than 100% of the federal poverty level, this population had the highest abortion rate of all the groups examined: 36.6. If the 2014 age-specific abortion rates prevail, 24% of women aged 15 to 44 years in that year will have an abortion by age 45 years. The decline in abortion was not uniform across all population groups.