Atovaquone attenuates experimental colitis by reducing neutrophil infiltration of colonic mucosa.

Ulcerative colitis (UC) is a chronic relapsing disease featuring aberrant accumulation of neutrophils in colonic mucosa and the luminal space. Although significant advances in UC therapy have been made with the development of novel biologics and small molecules targeting immune responses, success of most current therapies is still limited, with significant safety concerns. Thus, there is a need to develop additional safe and effective therapies for the treatment of UC. Antimalarial drugs have been safely used for many years to resolve tissue inflammation and the associated pathologies. Atovaquone is a recent FDA-approved antimalarial drug that has shown anti-viral and tumor-suppressive properties in vitro however, its role in mucosal inflammation has not been evaluated. Using pre-clinical murine DSS-induced colitis model combined with complementary in vivo peritonitis and ex vivo human neutrophil activation and chemotaxis assays we investigated functional and mechanistic impacts of atovaquone on disease resolution and neutrophil trafficking. We demonstrate that atovaquone promotes resolution of DSS-induced murine colitis by reducing neutrophil accumulation in the inflamed colonic mucosa. Mechanistically, we show that atovaquone suppressed induction of CD11b expression in neutrophils, reducing their polarization and migratory ability. Thus, our findings identify a new role of atovaquone in promoting resolution of mucosal inflammation, supporting the idea of potential repurposing of this FDA-approved drug as UC therapeutic.

Liver transplantation for hepatocellular carcinoma following checkpoint inhibitor therapy with nivolumab.

Limited case series describe conflicting results regarding the safety of checkpoint inhibitors (CPI) prior to liver transplantation (LT). We reviewed single-center data on all consecutive patients who underwent LT for hepatocellular carcinoma treated with CPI between January 1, 2018, and January 30, 2021. Time from CPI to LT, immunosuppression, biopsy-proven acute cellular rejection (BPACR), graft loss and death were evaluated. Five patients with a mean age 65 (range 61-71) years underwent LT after CPI with nivolumab. Time from last CPI to LT ranged from 0.3 to 11 months. Two patients with <3 months from the last dose of CPI to LT developed BPACR and severe hepatic necrosis, one of whom required retransplantation with recurrent BPACR but without recurrent graft loss over 38 months of follow up. None of the patients who underwent LT >3 months from the last dose of CPI had BPACR. In conclusion, pretransplant use of CPIs, particularly within 90 days of LT, was associated with BPACR and immune-mediated hepatic necrosis. Future multicenter studies should consider a sufficient interval from the last dose of CPI to LT to mitigate the risk for adverse immune-mediated outcomes and graft loss.

Rescue liver re-transplantation after graft loss due to severe rejection in the setting of pre-transplant nivolumab therapy.

Immune checkpoint inhibitors (ICI) have been used to treat hepatocellular carcinoma (HCC) since 2017. The safety of ICIs in the setting of solid organ transplantation remains controversial. When used in the post-transplant setting, ICIs have been associated with high allograft rejection rates, but there are few published reports on the use of ICIs prior to transplant. We present the first reported case of rescue liver re-transplantation after loss of the first allograft due to severe acute rejection with extensive hepatic necrosis in the setting of pre-transplant ICI therapy with the PD-1 inhibitor nivolumab. It is likely that the durable immune response triggered by nivolumab contributes to graft rejection, therefore extreme caution should be taken when using ICIs before transplant until further investigation has been conducted on their safety in the pre-transplant setting.

Symmetry Breaking in an Edgeless Epithelium by Fat2-Regulated Microtubule Polarity.

Planar cell polarity (PCP) information is a critical determinant of organ morphogenesis. While PCP in bounded epithelial sheets is increasingly well understood, how PCP is organized in tubular and acinar tissues is not. Drosophila egg chambers (follicles) are an acinus-like "edgeless epithelium" and exhibit a continuous, circumferential PCP that does not depend on pathways active in bounded epithelia; this follicle PCP directs formation of an ellipsoid rather than a spherical egg. Here, we apply an imaging algorithm to "unroll" the entire 3D tissue surface and comprehensively analyze PCP onset. This approach traces chiral symmetry breaking to plus-end polarity of microtubules in the germarium, well before follicles form and rotate. PCP germarial microtubules provide chiral information that predicts the direction of whole-tissue rotation as soon as independent follicles form. Concordant microtubule polarity, but not microtubule alignment, requires the atypical cadherin Fat2, which acts at an early stage to translate plus-end bias into coordinated actin-mediated collective cell migration. Because microtubules are not required for PCP or migration after follicle rotation initiates, while dynamic actin and extracellular matrix are, polarized microtubules lie at the beginning of a handoff mechanism that passes early chiral PCP of the cytoskeleton to a supracellular planar polarized extracellular matrix and elongates the organ.

Refractive error in school children in an urban and rural setting in Cambodia.

PURPOSE: To assess the prevalence of refractive error in schoolchildren aged 12-14 years in urban and rural settings in Cambodia's Phnom Penh and Kandal provinces. METHODS: Ten schools from Phnom Penh Province and 26 schools from Kandal Province were randomly selected and surveyed in October 2010. Children were examined by teams of Australian and Cambodian optometrists, ophthalmic nurses and ophthalmologists who performed visual acuity (VA) testing and cycloplegic refraction. RESULTS: A total of 5527 children were included in the study. The prevalence of uncorrected, presenting and best-corrected VA ≤ 6/12 in the better eye were 2.48% (95% confidence interval [CI] 2.02-2.83%), 1.90% (95% CI 1.52-2.24%) and 0.36% (95% CI 0.20-0.52%), respectively; 43 children presented with glasses whilst a total of 315 glasses were dispensed. The total prevalence of refractive error was 6.57% (95% CI 5.91-7.22%), but there was a significant difference between urban (13.7%, 95% CI 12.2-15.2%) and rural (2.5%, 95% CI 2.03-3.07%) schools (P < 0.0001). Refractive error accounted for 91.2% of visually impaired eyes, cataract for 1.7%, and other causes for 7.1%. Myopia (spherical equivalent ≤ -0.50 diopters [D] in either eye) was associated with increased age, female gender and urban schooling. CONCLUSIONS: The prevalence of refractive error was significantly higher in urban Phnom Penh schools than rural schools in Kandal Province. The prevalence of refractive error, particularly myopia was relatively low compared to previous reports in Asia. The majority of children did not have appropriate correction with spectacles, highlighting the need for more effective screening and optical intervention.