Exploring New Molecular Targets in Advanced Ovarian Cancer: The Aryl Hydrocarbon Receptor (AhR) and Antitumor Benzothiazole Ligands as Potential Therapeutic Candidates

Antitumor benzothiazoles, including 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203; NSC 703786), non-fluorinated parent compound DF 203 (NSC 674495), and Phortress (NSC 710305), the lysyl amide prodrug of 5F 203, are experimental anticancer agents with activity in ovarian and breast cancer models in vitro and in vivo. These compounds require (and induce their own) metabolism by cytochrome P450 (CYP) enzymes (e.g., CYP1A1) for antitumor action. The aryl hydrocarbon receptor (AhR) is the main transcriptional regulator of CYP1A1, and we have previously demonstrated that DF 203 and 5F 203 are potent AhR ligands and trigger activation of AhR signaling in sensitive breast and ovarian cancer cells, causing nuclear translocation of AhR. We propose that AhR may represent a new molecular target in the treatment of ovarian tumors, and 5F 203 may exemplify a potential novel treatment. Furthermore, putative biomarkers of sensitivity to this agent have been identified

The Role of Aryl Hydrocarbon Receptor and Crosstalk with Estrogen Receptor in Response of Breast Cancer Cells to the Novel Antitumor Agents Benzothiazoles and Aminoflavone

Many estrogen-receptor- (ER-) expressing breast cancers become refractory to ER-based therapies. New antitumor drugs like aminoflavone (AF) and benzothiazoles (Bzs) have been developed and have exquisite antitumor activity in ER+MCF-7 and T47D cells and in a MCF-7 nude mouse model. ER(−) breast cancer cells like MDA-MB-231 are less susceptible. We previously found in MCF-7 cells that these drugs activate the aryl hydrocarbon receptor (AhR) via translocation to the nucleus, induction of AhR-specific DNA binding activity, and expression of CYP1A1, whose transcription is controlled by the AhR-ARNT transcription factor. CYP1A1 metabolizes AF and Bz to a species which directly or after further metabolism damages DNA. In contrast an AhR-deficient variant of MCF-7 or cells with predominantly nuclear AhR expression, such as MDA-MB 231, are resistant. Thus, these drugs, unlike other neoplastic agents, require AhR-mediated signaling to cause DNA damage. This is a new treatment strategy for breast cancers with intact AhR signaling

COVID-19 policy analysis: labour structure dictates lockdown mobility behaviour

Countries and cities around the world have resorted to unprecedented mobility restrictions to combat COVID-19 transmission. Here we exploit a natural experiment whereby Colombian cities implemented varied lockdown policies based on ID number and gender to analyse the impact of these policies on urban mobility. Using mobile phone data, we find that the restrictiveness of cities' mobility quotas (the share of residents allowed out daily according to policy advice) does not correlate with mobility reduction. Instead, we find that larger, wealthier cities with more formalized and complex industrial structure experienced greater reductions in mobility. Within cities, wealthier residents are more likely to reduce mobility, and commuters are especially more likely to stay at home when their work is located in wealthy or commercially/industrially formalized neighbourhoods. Hence, our results indicate that cities' employment characteristics and work-from-home capabilities are the primary determinants of mobility reduction. This finding underscores the need for mitigations aimed at lower income/informal workers, and sheds light on critical dependencies between socio-economic classes in Latin American cities

The Exchange of Orientifold Two-Planes in M-theory

We propose an M-theory lift picture of the exchange among type IIA orientifold two-planes. This consists in wrapping a M5-brane on a three-cycle in the transverse space of the M-theory orientifold plane OM2. A flux quantization condition for the three-form self-dual field strength, on the worldvolume of the M5-brane is computed. This condition establishes the value which explains the relative charge between two different OM2-planes. Also, we find that the exchange of the four types of orientifold two-planes in string theory, has a common picture in M-theory. Moreover, we find that the assignment of the extra charge is fixed by cohomology and by the flux quantization of the field strength G in M-theory. We conclude that cohomology is sufficient to describe some orientifold properties in M-theory, that at string theory level, only K-theory is able to explain.Comment: 23+1 pages, 6 figures. v2: typos corrected, references adde