Intralesional Cidofovir: A Systematic Review of Administration Protocols and Long-term Recurrence Rates in Adult and Juvenile Recurrent Respiratory Papillomatosis.

OBJECTIVE: This is a systematic review aimed to explore Cidofovir administration protocols, recurrence rates, and long-term effectiveness for severe cases of recurrent respiratory papillomatosis (RRP). The primary goal was to identify current practices, determine the preferred protocol, and assess the adjuvant therapy's ability to prevent long-term papilloma recurrence in juvenile and adult-onset disease. METHODS: The following databases were searched: Pubmed, Google Scholar (pages 1-10), EMBASE, Scopus, ISI (clarivate), Cochrane Library, and Journal Storage from 1996 to June 2022. Articles that reported the use of intralesional Cidofovir in RRP and reported remission/recurrence rates with follow-up were included in the review. The systematic review was registered through PROSPERO and contains the detailed protocol for the conduction of the review. RESULTS: A total of 389 records were identified, 126 titles and abstracts screened, 45 studies fully read, and 30 studies met the inclusion criteria. Two hundred and fourteen adult-onset RRP (AORRP) and 126 juvenile-onset RRP (JORRP) cases were treated with Cidofovir across the included studies. There was no universal protocol for administering Cidofovir, with variations in concentration, treatment period, number and interval of injections, and follow-up duration. Most lesions showed human papilloma virus types 6 and 11. Recurrence rates varied, and other outcomes reported included remission rates, lesion reduction, surgical intervals, and side effects. Some studies demonstrated significant improvements in disease severity and extended intervals between recurrences after Cidofovir administration. CONCLUSIONS: The analysis of 30 studies reveals the need for greater consistency in reporting treatment parameters and outcomes. The use of recurrence-free period as an outcome measure and the potential benefits of a concentration of 7.5 mg/mL are identified. Additionally, the importance of viral typing within papilloma lesions is emphasized. To further enhance understanding and establish optimal protocols, future research should focus on uniform reporting, including severity, dosage, interval, treatment duration, functional outcome, and related procedures. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022299549.

Individual cells generate their own self-reinforcing contact guidance cues through local matrix fiber remodeling.

Directed cell migration arises from cells following a microenvironmental gradient (e.g. of a chemokine) or polarizing feature (e.g. a linear structure). However cells not only follow, but in many cases, also generate directionality cues by modifying their microenvironment. This bi-directional relationship is seen in the alignment of extracellular matrix (ECM) fibers ahead of invading cell masses. The forces generated by many migrating cells cause fiber alignment, which in turn promotes further migration in the direction of fiber alignment via contact guidance and durotaxis. While this positive-feedback relationship has been widely described for cells invading en masse, single cells are also able to align ECM fibers, as well as respond to contact guidance and durotaxis cues, and should therefore exhibit the same relationship. In this study, we directly tested this hypothesis by studying the migration persistence of individual HT-1080 fibrosarcoma cells migrating in photocrosslinked collagen matrices with limited remodeling potential. Our results demonstrate that this positive-feedback relationship is indeed a fundamental aspect of cell migration in fibrillar environments. We observed that the cells' inability to align and condense fibers resulted in a decrease in persistence relative to cells in native collagen matrices and even relative to isotropic (glass) substrates. Further experiments involving 2D collagen and electrospun polymer scaffolds suggest that substrates composed of rigid, randomly oriented fibers reduce cells' ability to follow another directionality cue by forcing them to meander to follow the available adhesive area (i.e. fibers). Finally, our results demonstrate that the bi-directional relationship between cell remodeling and migration is not a "dimensionality" effect, but a fundamental effect of fibrous substrate structure.

Trpm1: Novel function at the intersection of light and pain response in the iris.

In mammals, the retina is the photosensitive tissue that is responsible for the capture of light and the transduction of the light-initiated signals to the brain. These visual signals help to drive image and non-image forming behaviors. The pupillary light reflex (PLR) is an involuntary non-image forming behavior which involves the constriction of the iris muscle tissue in response to ambient light intensity. A subset of photosensitive retinal ganglion cells provides the principal pathway for all light input to the olivary pretectal nucleus which directs the neuronal input to drive iris constriction. Transient receptor potential melastatin 1 (Trpm1) knockout mice have a severe defect in PLR, but it remains unclear how the Trpm1 channel contributes to this behavior. We have demonstrated that the reduced PLR in Trpm1-/- mice at scotopic and photopic intensities is due to a functional loss of Trpm1 in the retina as well as the iris sphincter muscle. We have also tested constriction in isolated eyes and have shown that light-driven constriction independent of signaling from the brain also requires Trpm1 expression. In both the in vivo PLR and the iris photomechanical response, melanopsin is required for the light-dependent activation. Finally, pharmacological experiments using capsaicin to activate pain afferents in the eye demonstrate that Trpm1 expression is required for all sensory driven iris constriction. Our results demonstrate for the first time that Trpm1 has a novel and necessary role in iridial cells and is required for all sensory-driven constriction in the iris.