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Kai Man Xu,1 Ryan Cho,1 Toby Yiu Bong Chan2,3 1Faculty of Medicine, McMaster University, Hamilton, Ontario, Canada; 2Division of Ophthalmology, Department of Surgery, McMaster University, Waterloo Regional Campus, Kitchener-Waterloo, Ontario, Canada; 3Ocular Health Centre, Kitchener, Ontario, CanadaCorrespondence: Toby Yiu Bong Chan, Ocular Health Center, Unit 501, 31 Kingsbury Dr, Kitchener, Ontario, N2A0K5, Canada, Tel +1 519 208 8104, Fax +1 519 208 8101, Email toby.yb.chan@gmail.comPurpose: Studies comparing the two different formulations of bimatoprost, 0.03% and 0.01%, have shown similar efficacy, but a better adverse effect profile for bimatoprost 0.01% in patients with primary open-angle glaucoma (POAG) and ocular hypertension (OHT). This study assesses the efficacy and tolerability of switching from bimatoprost 0.01% to 0.03% in a patient population with broader spectrum of diagnoses in a real-world clinical setting.Design: Single-centre retrospective observational switch study.Methods: Selected patients were on initial topical therapy with bimatoprost 0.01% prior to switching to bimatoprost 0.03%. Intraocular pressure (IOP) was collected from their pre-switch visit, 6- and 12-week after switch. Paired two-sample t-test was performed to compare IOP at different time points versus baseline. Worsening of hyperemia and other adverse events after the switch were identified. Subgroup analysis was performed for POAG and OHT, secondary open-angle glaucoma (SOAG, including pseudoexfoliative and pigmentary glaucoma), normal tension glaucoma (NTG), and angle closure glaucoma (ACG).Results: The study population consisted of 248 eyes (143 patients). There was a significant mean IOP reduction of 1.0 ± 3.7 mmHg (p < 0.001, n = 248) from baseline to week-6 and 1.6 ± 4.0 mmHg (p < 0.001, n = 142) from baseline to week-12 after switch. The IOP reduction was statistically significant in patients with POAG and OHT (6-week: 1.0 ± 3.8 mmHg, n = 76; 12-week: 1.5 ± 4.1 mmHg, n = 49), ACG (6-week: 1.5 ± 4.1 mmHg, n = 72; 12-week: 2.3 ± 4.5 mmHg, n = 46), and NTG (6-week: 0.83 ± 2.5 mmHg, n = 42; 12-week: 1.12 ± 2.1 mmHg, n = 25). Patients with SOAG did not show statistically significant reduction in IOP at 6- or 12-week after switch. Forty-two (29%) of 143 patients experienced adverse events, with the most common being hyperemia (16%).Conclusion: Significant reduction in IOP could be seen after switching from bimatoprost 0.01% to bimatoprost 0.03% in various types of glaucoma except SOAG. Intolerance after switch may be experienced, though not in the majority of cases.Keywords: bimatoprost, intraocular pressure, conjunctival hyperemia, glaucoma, ocular hypertension

The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy herald new opportunities for classical oxygen-mimetic radiosensitisers. Only nimorazole is used clinically as a radiosensitiser, and there is a dearth of new radiosensitisers in development. In this report, we augment previous work to present new nitroimidazole alkylsulfonamides and we document their cytotoxicity and ability to radiosensitise anoxic tumour cells in vitro. We compare radiosensitisation with etanidazole and earlier nitroimidazole sulfonamide analogues and we identify 2-nitroimidazole and 5-nitroimidazole analogues with marked tumour radiosensitisation in ex vivo assays of surviving clonogens and with in vivo tumour growth inhibition.

Hypoxia in tumors results in resistance to both chemotherapy and radiotherapy treatments but affords an environment in which hypoxia-activated prodrugs (HAP) are activated upon bioreduction to release targeted cytotoxins. The benzotriazine 1,4-di-N-oxide (BTO) HAP, tirapazamine (TPZ, 1), has undergone extensive clinical evaluation in combination with radiotherapy to assist in the killing of hypoxic tumor cells. Although compound 1 did not gain approval for clinical use, it has spurred on the development of other BTOs, such as the 3-alkyl analogue, SN30000, 2. There is general agreement that the cytotoxin(s) from BTOs arise from the one-electron reduced form of the compounds. Identifying the cytotoxic radicals, and whether they play a role in the selective killing of hypoxic tumor cells, is important for continued development of the BTO class of anticancer prodrugs. In this study, nitrone spin-traps, combined with electron spin resonance, give evidence for the formation of aryl radicals from compounds 1, 2 and 3-phenyl analogues, compounds 3 and 4, which form carbon C-centered radicals. In addition, high concentrations of DEPMPO (5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide) spin-trap the •OH radical. The combination of spin-traps with high concentrations of DMSO and methanol also give evidence for the involvement of strongly oxidizing radicals. The failure to spin-trap methyl radicals with PBN (N-tert-butylphenylnitrone) on the bioreduction of compound 2, in the presence of DMSO, implies that free •OH radicals are not released from the protonated radical anions of compound 2. The spin-trapping of •OH radicals by high concentrations of DEPMPO, and the radical species arising from DMSO and methanol give both direct and indirect evidence for the scavenging of •OH radicals that are involved in an intramolecular process. Hypoxia-selective cytotoxicity is not related to the formation of aryl radicals from the BTO compounds as they are associated with high aerobic cytotoxicity.

Intra-tumor heterogeneity represents a major barrier to anti-cancer therapies. One strategy to minimize this limitation relies on bystander effects via diffusion of cytotoxins from targeted cells. Hypoxia-activated prodrugs (HAPs) have the potential to exploit hypoxia in this way, but robust methods for measuring bystander effects are lacking. The objective of this study is to develop experimental models (monolayer, multilayer, and multicellular spheroid co-cultures) comprising ‘activator’ cells with high expression of prodrug-activating reductases and reductase-deficient ‘target’ cells, and to couple these with agent-based models (ABMs) that describe diffusion and reaction of prodrugs and their active metabolites, and killing probability for each cell. HCT116 cells were engineered as activators by overexpressing P450 oxidoreductase (POR) and as targets by knockout of POR, with fluorescent protein and antibiotic resistance markers to enable their quantitation in co-cultures. We investigated two HAPs with very different pharmacology: SN30000 is metabolized to DNA-breaking free radicals under hypoxia, while the dinitrobenzamide PR104A generates DNA-crosslinking nitrogen mustard metabolites. In anoxic spheroid co-cultures, increasing the proportion of activator cells decreased killing of both activators and targets by SN30000. An ABM parameterized by measuring SN30000 cytotoxicity in monolayers and diffusion-reaction in multilayers accurately predicted SN30000 activity in spheroids, demonstrating the lack of bystander effects and that rapid metabolic consumption of SN30000 inhibited prodrug penetration. In contrast, killing of targets by PR104A in anoxic spheroids was markedly increased by activators, demonstrating that a bystander effect more than compensates any penetration limitation. However, the ABM based on the well-studied hydroxylamine and amine metabolites of PR104A did not fit the cell survival data, indicating a need to reassess its cellular pharmacology. Characterization of extracellular metabolites of PR104A in anoxic cultures identified more stable, lipophilic, activated dichloro mustards with greater tissue diffusion distances. Including these metabolites explicitly in the ABM provided a good description of activator and target cell killing by PR104A in spheroids. This study represents the most direct demonstration of a hypoxic bystander effect for PR104A to date, and demonstrates the power of combining mathematical modeling of pharmacokinetics/pharmacodynamics with multicellular culture models to dissect bystander effects of targeted drug carriers.

BackgroundCeramide kinase-like protein (CERKL) was originally described in retinal tissue. CERKL has been shown to protect cells from oxidative stress, and mutations in CERKL underlie the inherited disease retinitis pigmentosa. CERKL expression maintains cellular sphingolipids via an unknown mechanism.ObjectivesTo determine whether CERKL is expressed in epidermis and cutaneous squamous cell carcinoma (cSCC) and whether CERKL expression affects cSCC sphingolipid metabolism and susceptibility to oxidative stress.MethodsCERKL expression was determined by RNA-Seq, quantitative polymerase chain reaction and immunohistochemistry. CERKL was knocked down in cSCC cells using small interfering RNA. Sphingolipid content was analysed by liquid chromatography-mass spectrometry. Oxidative stress was induced by treatment with H2 O2 , and apoptosis was measured using flow cytometry to determine annexin V binding.ResultsCERKL mRNA and protein are highly expressed in actinic keratosis and cSCC in comparison with normal epidermis. CERKL is also expressed in metabolically active epithelial cells in normal hair bulbs and sebaceous glands. CERKL knockdown in cultured cSCC cells reduces cellular sphingolipid content and enhances susceptibility to oxidative stress.ConclusionsThese findings suggest that CERKL may be important in cSCC progression and could lead to novel strategies for prevention and treatment of cSCC.

BackgroundCeramide Kinase-Like Protein (CERKL) was originally described in retinal tissue. CERKL has been shown to protect cells from oxidative stress, and mutations in CERKL underlie the inherited disease, retinitis pigmentosa. CERKL expression maintains cellular sphingolipids via an unknown mechanism.ObjectivesTo determine whether CERKL is expressed in epidermis and cutaneous squamous cell carcinoma (cSCC) and whether CERKL expression affects cSCC sphingolipid metabolism and susceptibility to oxidative stress.MethodsCERKL expression was determined by RNA-Seq, qPCR and immunohistochemistry. CERKL was knocked down in cSCC cells using siRNA. Sphingolipid content was analyzed by liquid chromatography-mass spectrometry (LC-MS). Oxidative stress was induced by treatment with H2 O2 , and apoptosis was measured using flow cytometry to determine annexin v binding.ResultsCERKL mRNA and protein are highly expressed in actinic keratosis and cSCC in comparison with normal epidermis. CERKL also is expressed in metabolically active epithelial cells in normal hair bulbs and sebaceous glands. CERKL knockdown in cultured cSCC cells reduces cellular sphingolipid content and enhances susceptibility to oxidative stress.ConclusionsThese findings suggest that CERKL may be important in cSCC progression and could lead to novel strategies for prevention and treatment of cSCC.

The pulmonate snail Melampus sincaporensis L. Pfeiffer, 1855 (Gastropoda: Ellobiidae) lives in extreme environments such as salt marshes with limited oxygen. Here, we characterized the complete mitochondrial genome of M. sincaporensis from South Korea. It is 14,962 bp in length and includes 13 protein-coding genes (PCGs), two genes, 21 tRNA genes lacking one tRNA-Ser, and two A + T rich regions. Among these 36 genes, 24 were encoded on the heavy strand and 12 on the light strand. A maximum likelihood tree constructed using nucleotide sequences of the 13 PCGs did not support the monophyly of Ellobiidae. This study could provide useful information for exploring phylogenetic relationships among ellobiids and their related species.

The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy herald new opportunities for classical oxygen-mimetic radiosensitisers. Only nimorazole is used clinically as a radiosensitiser, and there is a dearth of new radiosensitisers in development. In this report, we augment previous work to present new nitroimidazole alkylsulfonamides and we document their cytotoxicity and ability to radiosensitise anoxic tumour cells in vitro. We compare radiosensitisation with etanidazole and earlier nitroimidazole sulfonamide analogues and we identify 2-nitroimidazole and 5-nitroimidazole analogues with marked tumour radiosensitisation in ex vivo assays of surviving clonogens and with in vivo tumour growth inhibition. [ABSTRACT FROM AUTHOR]

The chiton (Polyplacophora) occupies a significant position in molluscan evolutionary history as one of the most primitive groups within the phylum Mollusca. Acanthochitona defilippii (Tapparone-Canefri 1874) (Chitonida: Acanthochitonidae) is a commonly found intertidal chiton species in South Korea. In this study, we characterized the complete mitochondrial genome of A. defilippii (14,999 bp long), comprising 13 protein-coding genes (PCGs), 22 transfer RNA genes, two ribosomal RNA genes, and an A + T rich region (166 bp). The base composition is as follows: 31.82% for A, 11.63% for C, 16.69% for G, and 39.86% for T. We reconstructed a maximum likelihood (ML) tree to elucidate phylogenetic relationships among the eight chitonid families using the nucleotide sequences of all PCGs. The ML tree revealed that A. defilippii clustered with Acanthochitona avicula (BP 100) within the family Acanthochitonidae. Acanthochitonidae formed a sister group with Mopaliidae. The results could provide a valuable understanding the phylogenetic relationships of chitonid species.

The ground beetle Synuchus nitidus (Motschulsky, 1861) (Carabidae: Harpalinae: Sphodrini) is one of the most common species in the forests of South Korea, which has the potential to be utilized as an environmental indicator. Here, we characterized the complete mitochondrial genome (mitogenome) of S. nitidus, which is the first in the harpaline tribe Sphodrini. Its genome is 16,392 bp in length and composed of 13 protein-coding genes (PCGs), 22 tRNA genes, two rRNA genes, and an A + T rich region. In addition, we reconstructed a maximum likelihood tree to elucidate the phylogenetic position of Sphodrini among the seven harpaline tribes using nucleotide sequences of the 13 PCGs. The ML tree supported a monophyletic clade of the subfamily Harpalinae and showed a close relationship between Sphodrini and Lebinii with a low bootstrap value. The complete mitogenome of S. nitidus could be helpful for molecular species identification and exploring phylogenetic relationships among carabids.

Background: Antiadhesion products are essential for postoperative care in patients after thyroidectomy by providing a physical barrier to cover the exposed tissue and thus preventing abnormal adhesion of adjacent tissues. Since thyroidectomy may result in swallowing difficulties arising from damage or inflammation of the surrounding tissues, the use of antiadhesion agents such as MegaShield ® or Guardix-SG ® will help reduce scar formation. This may thus improve postoperative swallowing function in patients. Methods: Patients were enrolled and followed up between October 4, 2018, and March 26, 2020. Patients during the postoperative follow-up sessions were randomly allocated to the standard care with Guardix-SG ® and clinical trial medical device application group with MegaShield ® (test group) in a 1:1 ratio by the permuted block randomization method. Patient performance on penetration aspiration scale (PAS), National Institutes of Health-Swallow Safety Scale (NIH-SSS), videofluoroscopic dysphagia scale (VDS), Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) based on Videofluoroscopic swallowing study (VFSS) were collected. Nonadhesion-reducing agent patient data were used as a control group. Results: No statistical significance was shown ( P > .05) between the 2 groups of MegaShield ® and Guardix-SG ® in various phases from thick semisolid, thin semisolid to liquid for both PAS and NIH-SSS. Several statistical significances were reported in the results comparing various criteria of PAS, NIH-SSS, VDS at different oral and pharyngeal phases, and DIGEST in all 3 stages among MegaShield ® , Guardix-SG ® , and nonadhesion-reducing agent group. Conclusions: These results prove the noninferiority of MegaShield ® compared with Guardix-SG ® as an antiadhesion agent in postthyroidectomy care.

Abstract With the progress of robotic transaxillary thyroid surgery (RTTS), the indications for this procedure have gradually expanded. This study presents the insights gained from performing 10,000 RTTS cases at a single institution, along with the expansion of indications over time. RTTS was performed on 10,000 patients using the da Vinci robot system between October 2007 and April 2023 at the Yonsei University Health System, Seoul, Korea. Among 10,000 patients, 9461 (94.0%) were diagnosed with thyroid cancer, whereas 539 (5.4%) had either a benign thyroid nodule or Graves’ disease. Surgical procedures were performed using four-arm-based robots (da Vinci S, Si, or Xi) for 8408 cases (84.1%), with the remaining 1592 cases (15.9%) being performed using the da Vinci SP surgical robotic system. Notably, for 53 patients with nodules ≥ 5 cm, which were not included in the eligibility criteria of the previous study, RTTS was performed safely without significant complications. The most common postoperative complication was transient hypoparathyroidism (37.91%), and recurrence occurred in 100 patients with thyroid cancer (1.1%). In conclusion, RTTS appears safe and feasible from both surgical and oncological perspectives, and the spectrum of indications suitable for RTTS surgery is progressively expanding.