RESUMO
RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral genome. We screened lipophilic small-interfering RNA (siRNA) conjugates targeting highly conserved regions of the SARS-CoV-2 genome and identified leads targeting outside of the spike-encoding region capable of achieving [≥]3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single-siRNA approach. A two-siRNA combination delivered intranasally protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach to limit SARS-CoV-2 infection that may help combat emergent variants, complement existing interventions, or protect populations where vaccines are less effective. Most importantly, this strategy has implications for developing medicines that may be valuable in protecting against future coronavirus pandemics.
RESUMO
BACKGROUND: Although most cutaneous squamous cell carcinoma (SCC) is curable by a variety of treatment modalities, a small subset of tumors recur, metastasize, and result in death. Although risk factors for metastasis have been described, there are little data available on appropriate workup and staging of patients with high-risk SCC. OBJECTIVE: We reviewed reported cases and case series of SCC in which sentinel lymph node biopsy (SLNB) was performed to determine whether further research is warranted in developing SLNB as a staging tool for patients with high-risk SCC. METHODS: The English medical literature was reviewed for reports of SLNB in patients with cutaneous SCC. Data from anogenital and nonanogenital cases were collected and analyzed separately. The percentage of cases with a positive sentinel lymph node (SLN) was calculated. False negative and nondetection rates were tabulated. Rates of local recurrence, nodal and distant metastasis, and disease-specific death were reported. RESULTS: A total of 607 patients with anogenital SCC and 85 patients with nonanogenital SCC were included in the analysis. A SLN could not be identified in 3% of anogenital and 4% of nonanogenital cases. SLNB was positive in 24% of anogenital and 21% of nonanogenital patients. False-negative rates as determined by completion lymphadenectomy were 4% (8/213) and 5% (1/20), respectively. Most false-negative results were reported in studies from 2000 or earlier in which the combination of radioisotope and blue dye was not used in the SLN localization process. Complications were reported rarely and were limited to hematoma, seroma, cutaneous lymphatic fistula, wound infection, and dehiscence. CONCLUSIONS: Owing to the lack of controlled studies, it is premature to draw conclusions regarding the utility of SLNB in SCC. The available data, however, suggest that SLNB accurately diagnoses subclinical lymph node metastasis with few false-negative results and low morbidity. Controlled studies are needed to demonstrate whether early detection of subclinical nodal metastasis will lead to improved disease-free or overall survival for patients with high-risk SCC.