There is a need to develop new, more efficient therapies for head and neck cancer (HNSCC) patients. It is currently unclear whether defects in DNA repair genes play a role in HNSCCs' resistance to therapy. PARP1 inhibitors (PARPi) were found to be "synthetic lethal" in cancers deficient in BRCA1/2 with impaired homologous recombination. Since tumors rarely have these particular mutations, there is considerable interest in finding alternative determinants of PARPi sensitivity. Effectiveness of combined irradiation and PARPi olaparib was evaluated in ten HNSCC cell lines, subdivided into HR-proficient and HR-deficient cell lines using a GFP-based reporter assay. Both groups were equally sensitive to PARPi alone. Combined treatment revealed stronger synergistic interactions in the HR-deficient group. Because HR is mainly active in S-Phase, replication processes were analyzed. A stronger impact of treatment on replication processes (p = 0.04) and an increased number of radial chromosomes (p = 0.003) were observed in the HR-deficient group. We could show that radiosensitization by inhibition of PARP1 strongly correlates with HR competence in a replication-dependent manner. Our observations indicate that PARP1 inhibitors are promising candidates for enhancing the therapeutic ratio achieved by radiotherapy via disabling DNA replication processes in HR-deficient HNSCCs.

There is a need to develop new, more efficient therapies for head and neck cancer (HNSCC) patients. It is currently unclear whether defects in DNA repair genes play a role in HNSCCs' resistance to therapy. PARP1 inhibitors (PARPi) were found to be "synthetic lethal" in cancers deficient in BRCA1/2 with impaired homologous recombination. Since tumors rarely have these particular mutations, there is considerable interest in finding alternative determinants of PARPi sensitivity. Effectiveness of combined irradiation and PARPi olaparib was evaluated in ten HNSCC cell lines, subdivided into HR-proficient and HR-deficient cell lines using a GFP-based reporter assay. Both groups were equally sensitive to PARPi alone. Combined treatment revealed stronger synergistic interactions in the HR-deficient group. Because HR is mainly active in S-Phase, replication processes were analyzed. A stronger impact of treatment on replication processes (p = 0.04) and an increased number of radial chromosomes (p = 0.003) were observed in the HR-deficient group. We could show that radiosensitization by inhibition of PARP1 strongly correlates with HR competence in a replication-dependent manner. Our observations indicate that PARP1 inhibitors are promising candidates for enhancing the therapeutic ratio achieved by radiotherapy via disabling DNA replication processes in HR-deficient HNSCCs.

BACKGROUND: Precancerous high-grade squamous intraepithelial lesion (HSIL), the current consensus terminology for anogenital squamous cell carcinoma in situ (SCCIS), often presents with distinctive histopathologic findings that may be a function of anatomic site or associated human papillomavirus infection.

METHODS: Fifty-six specimens of anogenital HSIL were compared with an equal number of specimens of SCCIS from non-anogenital sites in regard to the presence of parakeratosis, flag sign in the stratum corneum, compact stratum corneum, hypergranulosis, koilocytes, small blue cells, clonal populations of keratinocytes, pagetoid scatter of atypical keratinocytes, clear cell change, glassy red cytoplasm, pigmentation, nuclear/cytoplasmic(N/C) ratio >2/1, nuclear hyperchromasia, pleomorphic nuclei, mitotic figures, abnormal mitotic figures, dyskeratotic keratinocytes, involvement of skin appendages, acantholysis and amyloid deposition.

RESULTS: Hypergranulosis, koilocytes, small blue cells, pigmentation, nuclear hyperchromasia, dyskeratotic keratinocytes and amyloid deposition were more frequently noted in anogenital HSIL. Parakeratosis, clear cell change, pleomorphic nuclei, skin appendages involvement and acantholysis were strongly associated with non-anogenital location. There was no significant difference in the incidence of the remaining features.

CONCLUSION: The strongest predicators of an anogenital location included hypergranulosis, koilocytes, small blue cells and nuclear hyperchromasia. Pigmentation and amyloid deposition were also strongly associated with an anogenital location.

PURPOSE: To assess the prevalence and causes of visual impairment in children of South Sinai, and to evaluate outcomes of rehabilitation programs.

METHODS: Population-based, cross-sectional analysis of 2070 healthy school children screened for visual impairment from 2009 through 2010 in cities of South Sinai and their surrounding Bedouin settlements. Visual acuity (VA) was tested using Snellen charts followed by cycloplegic autorefractometry for cases with presenting VA ≤ 6/9. Appropriate eyeglasses were prescribed and VA re-evaluated.

RESULTS: This study included 1047 boys and 1023 girls, mean age 10.7 ± 3.1 years. Visual impairment (uncorrected VA ≤ 6/9) was detected in 29.4% of children, while 2.0% had moderate-severe visual impairment (uncorrected VA ≤ 6/24). There were statistically significant differences in prevalence of visual impairment between the studied cities (p < 0.05), with the highest prevalence in Abu Redis. Prevalence of visual impairment was significantly higher among girls (p < 0.05) and those with positive consanguinity (p < 0.05). Bedouin children showed significantly lower prevalences of visual impairment. Only age was a reliable predictor of visual impairment (odds ratio 0.94, p < 0.0001). Ophthalmic examination revealed other disorders, e.g. dry eye (4.74%), squint (2.37%), exophthalmos (1.58%) and ptosis (0.79%). VA significantly improved in children who received spectacles (p < 0.001).

CONCLUSION: A total of 29.4% of South Sinai children had some form of visual impairment, 90.32% of which comprised refractive errors (mainly astigmatism) which were significantly corrected with eyeglasses. VA screening and correction of refractive errors are of the utmost importance for ensuring better visual outcomes and improved school performance.

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