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Purpose: To describe a surgical approach for the resection of schwannomas occurring in the medial aspect of the orbit and to review a series of patients who underwent this novel technique., Methods: This retrospective, non-comparative case series presents the surgical technique and outcomes of patients who underwent removal of a medial orbital schwannoma via an endoscopic endonasal approach combined with a small-incision medial orbitotomy by a team of two surgeons (BSB and SKF). Patient demographics, pre- and post-operative clinical examination findings, visual field testing, and radiographic studies were reviewed. Operative reports were reviewed for technical details and complications., Results: The patients included a 12 year-old male, 73 year-old female and 8 year-old male. Indications for surgery included: decreased visual acuity, diplopia, proptosis and Humphrey visual field (HVF) deficit, in the presence of a medial orbital biopsy-proven schwannoma. The surgical approach in all three patients was primarily endoscopic endonasal. Additionally, two had transcaruncular orbitotomies and one had a small-incision medial lid crease orbitotomy to assist with lateral tumor dissection. Tumor resection was complete in one case and near-total in two cases. There were no intra-operative surgical complications. Average resected specimen volume was 3.41 cm 3  ± 2.20. All patients had post-operative improvement in visual acuity (VA) and proptosis. Post-operative follow-up intervals were 27.5 months, 12.3 months and 3.5 months, respectively., Conclusion: Resection of orbital schwannomas using an endoscopic endonasal approach with small-incision medial transorbital assistance is a safe and effective option for a multidisciplinary surgical team.

Malignant epidural spinal cord compression (MESCC) represents the most common indication for emergent radiotherapy. First-year residents must quickly gain competence in managing this condition prior to taking call for the department. We sought to develop a hybrid didactic/simulation exercise to assist first-year radiation oncology residents in developing a skillset relevant to treating a MESCC case in an emergency situation. This was a prospective, qualitative survey study conducted at the University of California, Los Angeles, during the years 2014-2016. Following an introductory lecture during orientation for academic years 2014-2016, residents completed a simulated consultation on a patient with suspected MESCC. Subsequently, they worked with radiation therapists to complete the clinical treatment procedure (including field placement and manual calculation of monitor units needed to deliver the prescribed dose) to a phantom placed on a linear accelerator. Residents were then surveyed about whether the exercise increased confidence in their ability to successfully complete a consult, and urgent treatment if needed, for MESCC. All residents agreed or strongly agreed that this exercise had improved this ability, and all agreed or strongly agreed that the exercise was valuable and should be retained in the curriculum. Simulated consultation and treatment of MESCC provides new residents with increased confidence and knowledge regarding this relatively common indication for emergent radiation., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Education and Health Promotion.)

Purpose: To report two cases of macular choroidal macrovessel with description of multimodal imaging and review of published cases., Methods: Medical and imaging records were retrospectively reviewed. A literature review was performed to identify other cases of macular choroidal macrovessel published between 1990 and 2018., Results: There were 2 patients referred for evaluation of a potential choroidal tumor, including a 55-year-old white woman with no visual symptoms and a 68-year-old white woman with blurred vision. Funduscopic examination in each case revealed a focal area of choroidal elevation in the temporal foveal area with a single, dilated, slightly tortuous choroidal vessel, estimated to measure 250 μm and 300 μm, respectively, at widest girth, and extending temporally toward the equator with a tapering width. Optical coherence tomography showed an optically hollow choroidal lesion elevating the retinal pigment epithelium with overlying ellipsoid zone mottling. Both cases demonstrate shallow subretinal fluid, sparing the foveola. Fluorescein angiography showed faint staining along the course of the vessel in both cases. Indocyanine green angiography demonstrated clear visualization of the ectatic vessel with early filling and late staining without leakage. Both patients retained visual acuity of 20/25 in the affected eye and did not require treatment., Conclusion: Macular choroidal macrovessel is a rare vascular anomaly presenting as a single, dilated, tortuous choroidal vessel, originating in the temporal foveal region and extending temporally to the equator. This finding can simulate a choroidal neoplasm or parasitic track. Optical coherence tomography and indocyanine green angiography have diagnostic value demonstrating the vascular nature of this lesion and delineating the vascular course.

Competing Interests: There are no conflicts of interest.

Objectives: The objective of this study was to analyze outcomes for patients with soft tissue sarcoma of the extremities using neoadjuvant ifosfamide-based chemotherapy and hypofractionated reduced dose radiotherapy, followed by limb-sparing surgery., Materials and Methods: An Institutional Review Board (IRB)-approved retrospective review of patients treated at a single institution between 1990 and 2013 was performed. In total, 116 patients were identified who received neoadjuvant ifosfamide-based chemotherapy and 28 Gy in 8 fractions of preoperative radiation (equivalent dose in 2 Gray fractions, 31.5 Gy [α/β 10] 36.4 Gy [α/β 3]) followed by limb-sparing surgery. Local recurrence (LR), distant failure (DF), and overall survival (OS) were calculated. Univariate and multivariate analysis for LR, DF, and OS were performed using Cox analysis. Statistical significance was set at a P<0.05., Results: Median follow-up was 5.9 years (range, 0.3 to 24 y). Actuarial LR at 3/6 years was 11%/17%, DF at 3/6 years was 25%/35%, and OS at 3/6 years was 82%/67%. On multivariate analysis, only a positive surgical margin was significantly correlated with worse local control (P=0.005; hazard ratio [HR], 18.33; 95% confidence interval (CI), 2.41-139.34). Age over 60 years (P=0.03; HR, 2.34; 95% CI, 1.10-4.98) and tumor size over 10 cm compared with tumor size ≤5 cm (P=0.03; HR, 3.32; 95% CI, 1.15-9.61) were associated with worse OS., Conclusions: Soft tissue extremity sarcoma patients treated using reduced dose hypofractionated preoperative radiotherapy in combination with ifosfamide-based chemotherapy shows acceptable local control and warrants further investigation.

Competing Interests: There are no conflicts of interest

Primary conjunctival rhabdomyosarcoma (RMS) is a rare entity that can present with or without papillomatous features. A 5-year-old Asian boy was referred for a rapidly growing conjunctival tumor in the superior fornix of the left eye. Surgical excision yielded a 28 mm multilobulated papillomatous specimen that exhibited histopathologic and immunohistochemical features consistent with embryonal (botryoid) RMS. Molecular analysis revealed the absence of the PAX3/FOXO1 fusion gene, indicating favorable prognosis. After surgery, he was promptly treated with systemic chemotherapy and proton beam radiotherapy., Competing Interests: There are no conflicts of interest.

Purpose: We compared the dosimetry of brachyablation (BA) and stereotactic ablative radiotherapy (SABR) in the treatment of liver metastases., Methods and Materials: Treatment plans for 10 consecutive liver metastasis patients, treated with SABR, were replanned for BA. BA treatment was planned using five 12 Gy fractions to the same planning target volume (PTV) used for SABR. Dosimetric parameters were compared using a Student's paired t test., Results and Conclusions: BA and SABR plans had similar mean volume receiving 100% of the prescribed dose (94.1% vs. 93.9% of PTV, p = 0.8). Mean volume receiving 150% of the prescribed dose for BA was 63.6%, whereas for SABR it was 0. The minimum dose to the PTV was 65.8% for BA, whereas for SABR it was 87.4% (p = 0.0002). Liver volume receiving ≥15 Gy was similar for BA and SABR (278 vs. 256 cc, p = 0.3). Small bowel mean dose, as percent prescription dose, was higher for BA (10.8% vs. 7.1%, p = 0.006). Stomach mean dose was similar (4.9% vs. 4.8% of prescription dose, p = 0.98). Right kidney mean dose was greater for BA (6.7% vs. 4.2%, p = 0.07). BA leads to a higher target dose, similar dose to organs at risk, but potentially with lower target coverage compared with SABR. Further work is needed to determine ideal suitability for mono vs. combination therapy with this approach., (Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Aims: Adenosine triphosphate (ATP) synthase uses chemiosmotic energy across the inner mitochondrial membrane to convert adenosine diphosphate and orthophosphate into ATP, whereas genetic deletion of Sirt3 decreases mitochondrial ATP levels. Here, we investigate the mechanistic connection between SIRT3 and energy homeostasis., Results: By using both in vitro and in vivo experiments, we demonstrate that ATP synthase F1 proteins alpha, beta, gamma, and Oligomycin sensitivity-conferring protein (OSCP) contain SIRT3-specific reversible acetyl-lysines that are evolutionarily conserved and bind to SIRT3. OSCP was further investigated and lysine 139 is a nutrient-sensitive SIRT3-dependent deacetylation target. Site directed mutants demonstrate that OSCP(K139) directs, at least in part, mitochondrial ATP production and mice lacking Sirt3 exhibit decreased ATP muscle levels, increased ATP synthase protein acetylation, and an exercise-induced stress-deficient phenotype., Innovation: This work connects the aging and nutrient response, via SIRT3 direction of the mitochondrial acetylome, to the regulation of mitochondrial energy homeostasis under nutrient-stress conditions by deacetylating ATP synthase proteins., Conclusion: Our data suggest that acetylome signaling contributes to mitochondrial energy homeostasis by SIRT3-mediated deacetylation of ATP synthase proteins.

Cryoamputation, or physiologic amputation, is a well-described procedure typically used to amputate gangrenous lower extremities. In such cases the patient is too unstable for transport to the operating room, so cryoamputation using dry ice or other refrigerant allows for immediate bedside intervention and later operative amputation when the patient is more stable. In this study the authors describe the use of cryoamputation to stabilize a burn patient with a nonviable upper extremity considered to be contributing significantly to his metabolic acidosis. This experience suggests that cryoamputation may be a reasonable technique to consider when a burn patient presents with a nonviable extremity but is too unstable for immediate operative amputation.

One fundamental observation in cancer etiology is that the rate of malignancies in any mammalian population increases exponentially as a function of age, suggesting a mechanistic link between the cellular processes governing longevity and carcinogenesis. In addition, it is well established that aberrations in mitochondrial metabolism, as measured by increased reactive oxygen species (ROS), are observed in both aging and cancer. In this regard, genes that impact upon longevity have recently been characterized in S. cerevisiae and C. elegans, and the human homologs include the Sirtuin family of protein deacetylases. Interestingly, three of the seven sirtuin proteins are localized into the mitochondria suggesting a connection between the mitochondrial sirtuins, the free radical theory of aging, and carcinogenesis. Based on these results it has been hypothesized that Sirt3 functions as a mitochondrial fidelity protein whose function governs both aging and carcinogenesis by modulating ROS metabolism. Sirt3 has also now been identified as a genomically expressed, mitochondrial localized tumor suppressor and this review will outline potential relationships between mitochondrial ROS/superoxide levels, aging, and cell phenotypes permissive for estrogen and progesterone receptor positive breast carcinogenesis.

Genetic deletion of the mitochondrial deacetylase sirtuin-3 (Sirt3) results in increased mitochondrial superoxide, a tumor-permissive environment, and mammary tumor development. MnSOD contains a nutrient- and ionizing radiation (IR)-dependent reversible acetyl-lysine that is hyperacetylated in Sirt3⁻/⁻ livers at 3 months of age. Livers of Sirt3⁻/⁻ mice exhibit decreased MnSOD activity, but not immunoreactive protein, relative to wild-type livers. Reintroduction of wild-type but not deacetylation null Sirt3 into Sirt3⁻/⁻ MEFs deacetylated lysine and restored MnSOD activity. Site-directed mutagenesis of MnSOD lysine 122 to an arginine, mimicking deacetylation (lenti-MnSOD(K122-R)), increased MnSOD activity when expressed in MnSOD⁻/⁻ MEFs, suggesting acetylation directly regulates function. Furthermore, infection of Sirt3⁻/⁻ MEFs with lenti-MnSOD(K122-R) inhibited in vitro immortalization by an oncogene (Ras), inhibited IR-induced genomic instability, and decreased mitochondrial superoxide. Finally, IR was unable to induce MnSOD deacetylation or activity in Sirt3⁻/⁻ livers, and these irradiated livers displayed significant IR-induced cell damage and microvacuolization in their hepatocytes., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3(-/-) mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3(-/-) MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3(-/-) MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3(-/-) mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Cellular longevity is a complex process relevant to age-related diseases including but not limited to chronic illness such as diabetes and metabolic syndromes. Two gene families have been shown to play a role in the genetic regulation of longevity; the Sirtuin and FOXO families. It is also established that nuclear Sirtuins interact with and under specific cellular conditions regulate the activity of FOXO gene family proteins. Thus, we hypothesize that a mitochondrial Sirtuin (SIRT3) might also interact with and regulate the activity of the FOXO proteins. To address this we used HCT116 cells overexpressing either wild-type or a catalytically inactive dominant negative SIRT3. For the first time we establish that FOXO3a is also a mitochondrial protein and forms a physical interaction with SIRT3 in mitochondria. Overexpression of a wild-type SIRT3 gene increase FOXO3a DNA-binding activity as well as FOXO3a dependent gene expression. Biochemical analysis of HCT116 cells over expressing the deacetylation mutant, as compared to wild-type SIRT3 gene, demonstrated an overall oxidized intracellular environment, as monitored by increase in intracellular superoxide and oxidized glutathione levels. As such, we propose that SIRT3 and FOXO3a comprise a potential mitochondrial signaling cascade response pathway.

We have previously shown that hydrogen peroxide-resistant permanent (OC-14) cells are resistant to the cytotoxicity of several exogenous oxidative and anticancer agents including H(2)O(2), etoposide, and cisplatin; and we refer to this process as an oxidative multimodality-resistant phenotype (MMRP). Furthermore, OC-14 cells contain increased activator protein 1 activity, and inhibition of activator protein 1 reversed the MMRP. In this study, we show that permanent Rat-1 cell lines genetically altered to overexpress c-Fos also displayed a similar MMRP to H(2)O(2), etoposide, and cisplatin as OC-14 cells. Gene expression analysis of the OC-14 cells and c-Fos-overexpressing cells showed increased DNMT1 expression. Where OC-14 and c-Fos-overexpressing cells were exposed to 5-aza-2'-deoxycytidine, which inhibits DNMT activity, a significant but incomplete reversal of the MMRP was observed. Thus, it seems logical to suggest that DNMT1 might be at least one target in the MMRP. Rat-1 cells genetically altered to overexpress DNMT1 were also shown to be resistant to the cytotoxicity of H(2)O(2), etoposide, and cisplatin. Finally, somatic HCT116 knockout cells that do not express either DNMT1 (DNMT1(-/-)) or DNMT3B (DNMT3B(-/-)) were shown to be more sensitive to the cytotoxicity of H(2)O(2), etoposide, and cisplatin compared with control HCT116 cells. This work is the first example of a role for the epigenome in tumor cell resistance to the cytotoxicity of exogenous oxidative (H(2)O(2)) or systemic (etoposide and cisplatin) agents and highlights a potential role for DNMT1 as a potential molecular target in cancer therapy.

Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered intracellular processes including cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. Metabolites from these processes result in significant cellular oxidative stress that must be buffered to prevent permanent cell damage and cell death. Tumor cells depend on a complex set of respiratory pathways to generate the necessary energy as well as redox-sensitive pro-survival signaling pathways and factors to cope with and defend against the detrimental effects of oxidative stress. It has been hypothesized that redox-sensitive signaling factors such as thioredoxin reductase-1 (TR) and thioredoxin (TRX) may represent central pro-survival factors that would allow tumor cells to evade the damaging and potentially cytotoxic effects of endogenous and exogenous agents that induce oxidative stress. The overarching theme of this review is an extension of the hypothesis that tumor cells use these redox sensitive pro-survival signaling pathways/factors, which are up-regulated due to increased tumor cell respiration, to evade the cytotoxic effects of anticancer agents. These observations suggest that redox-sensitive signaling factors may be potential novel molecular targets for drug discovery.

Purpose: There is a growing awareness that radiation-induced normal tissue injury in late-responding organs, such as the brain, kidney, and lung, involves complex and dynamic responses between multiple cell types that not only lead to targeted cell death but also acute and chronic alterations in cell function. The specific genes involved in the acute and chronic responses of these late-responding normal tissues remain ill defined; understanding these changes is critical to understanding the mechanism of organ damage. As such, the aim of the present study was to identify candidate genes involved in the development of radiation injury in the murine kidney and brain using microarray analysis., Experimental Design: A multimodality experimental approach combined with a comprehensive expression analysis was done to determine changes in normal murine tissue gene expression at 8 and 24 hours after irradiation., Results: A comparison of the gene expression patterns in normal mouse kidney and brain was strikingly different. This observation was surprising because it has been long assumed that the changes in irradiation-induced gene expression in normal tissues are preprogrammed genetic changes that are not affected by tissue-specific origin., Conclusions: This study shows the potential of microarray analysis to identify gene expression changes in irradiated normal tissue cells and suggests how normal cells respond to the damaging effects of ionizing radiation is complex and markedly different in cells of differing origin.

Tumor cells undergoing proliferation, de-differentiation and progression depend on a complex set of respiratory pathways to generate the necessary energy. The metabolites from these pathways produce significant oxidative stress and must be buffered to prevent permanent cell damage and cell death. It is now clear that, in order to cope with and defend against the detrimental effects of oxidative stress, a series of redox-sensitive, pro-survival signaling pathways and factors regulate a complex intracellular redox buffering network. This review develops the hypothesis that tumor cells use these redox-sensitive, pro-survival signaling pathways and factors - up-regulated due to increased tumor cell respiration - to evade the damaging and cytotoxic effects of specific anticancer agents. It further suggests that redox-sensitive, signaling factors may be potential novel targets for drug discovery.

Two-component regulatory systems, typically composed of a sensor kinase to detect a stimulus and a response regulator to execute a response, are widely used by microorganisms for signal transduction. Response regulators exhibit a high degree of structural similarity and undergo analogous activating conformational changes upon phosphorylation. The activity of particular response regulators can be increased by specific amino acid substitutions, which either prolong the lifetime or mimic key features of the phosphorylated state. We probed the universality of response regulator activation by amino acid substitution. Thirty-six mutations that activate 11 different response regulators were identified from the literature. To determine whether the activated phenotypes would be retained in the context of a different response regulator, we recreated 51 analogous amino acid substitutions at corresponding positions of CheY. About 55% of the tested substitutions completely or partially inactivated CheY, approximately 30% were phenotypically silent, and approximately 15% activated CheY. Three previously uncharacterized activated CheY mutants were found. The 94NS (and presumably 94NT) substitutions resulted in resistance to CheZ-mediated dephosphorylation. The 113AP substitution led to enhanced autophosphorylation and may increase the fraction of non-phosphorylated CheY molecules that populate the activated conformation. The locations of activating substitutions on the response regulator three-dimensional structure are generally consistent with current understanding of the activation mechanism. The best candidates for potentially universal activating substitutions of response regulators identified in this study were 13DK and 113AP.

A motion-sensitive en-face-scanning 3-D optical coherence microscope (OCM) has been designed and constructed to study critical events in the early development of plants and animals. We describe the OCM instrument and present time-lapse movies of frog gastrulation, an early developmental event in which three distinct tissue layers are established that later give rise to all major organ systems. OCM images constructed with fringe-amplitude data show the mesendoderm migrating up along the blastocoel roof, thus forming the inner two tissue layers. Motion-sigma data, measuring the random motion of scatterers, is used to construct complementary images that indicate the presence of Brownian motion in the yolk cells of the endoderm. This random motion provides additional intrinsic contrast that helps to distinguish different tissue types. Depth penetration at 850 nm is sufficient for studies of the outer ectoderm layer, but is not quite adequate for detailed study of the blastocoel floor, about 500 to 800 mum deep into the embryo. However, we measure the optical attenuation of these embryos to be about 35% less at 1310 nm. 2-D OCT images at 1310 nm are presented that promise sufficient depth penetration to test current models of cell movement near the blastocoel floor during gastrulation.

[formula: see text] Isoapoptolidin was isolated from crude fermentation extracts of the apoptolidin-producing microorganism Nocardiopsis sp. Apoptolidin isomerizes to isoapoptolidin upon treatment with methanolic triethylamine to establish a 1.4:1 equilibrium mixture of isoapoptolidin and apoptolidin. Semisynthesis of a peracetylated and deglycosylated derivative of apoptolidin is also described.