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Currently, there are no specific antiviral therapeutic approaches targeting Human papillomaviruses (HPVs), which cause around 5% of all human cancers. Specific antiviral reagents are particularly needed for HPV-related oropharyngeal cancers (HPV + OPCs) whose incidence is increasing and for which there are no early diagnostic tools available. We and others have demonstrated that the estrogen receptor alpha (ERα) is overexpressed in HPV + OPCs, compared to HPV-negative cancers in this region, and that these elevated levels are associated with an improved disease outcome. Utilizing this HPV + -specific overexpression profile, we previously demonstrated that estrogen attenuates the growth and cell viability of HPV + keratinocytes and HPV + cancer cells in vitro . Expansion of this work in vivo failed to replicate this sensitization. The role of stromal support from the tumor microenvironment (TME) has previously been tied to both the HPV lifecycle and in vivo therapeutic responses. Our investigations revealed that in vitro co-culture with fibroblasts attenuated HPV + -specific estrogen growth responses. Continuing to monopolize on the HPV + -specific overexpression of ERα, our co-culture models then assessed the suitability of the selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen, and showed growth attenuation in a variety of our models to one or both of these drugs in vitro . Utilization of these SERMs in vivo closely resembled the sensitization predicted by our co-culture models. Therefore, the in vitro fibroblast co-culture model better predicts in vivo responses. We propose that utilization of our co-culture in vitro model can accelerate cancer therapeutic drug discovery., Importance: Human papillomavirus-related cancers (HPV + cancers) remain a significant public health concern, and specific clinical approaches are desperately needed. In translating drug response data from in vitro to in vivo , the fibroblasts of the adjacent stromal support network play a key role. Our study presents the utilization of a fibroblast 2D co-culture system to better predict translational drug assessments for HPV + cancers. We also suggest that this co-culture system should be considered for other translational approaches. Predicting even a portion of treatment paradigms that may fail in vivo with a co-culture model will yield significant time, effort, resource, and cost efficiencies., Competing Interests: The authors declare no conflict of interest.

The mpox outbreak of 2022-2023 represented a new global health challenge and recognition of mpox as a sexually transmitted disease. The majority of cases were reported in men who have sex with men (MSM), but women are also susceptible, especially during pregnancy. We evaluated the reproductive tracts of a subset of macaques from a large rechallenge study of mpox infection with virus from the 2022 outbreak and identified intraabdominal mpox replication associated with endometriosis. Mpox virus (MPXV) was found not only in skin, but in the cervix, the uterus, and periovarian endometriotic lesions of the affected macaque. Mpox replication preferentially targeted vimentin-positive poorly differentiated endometriotic stromal tissue and infiltrating macrophages in the reproductive tract. Mpox tropism for stromal cells and macrophages has broad implications for mpox pathogenesis and associated clinical syndromes. In addition, women with endometriosis may be at heightened risk for adverse outcomes associated with mpox infection. The rhesus macaque provides rare insight into this disease and the potential complications of mpox infection in the context of genitourinary tract disease., (© 2024. The Author(s).)