Compartmentalized metabolism supports midgestation mammalian development.

Mammalian embryogenesis requires rapid growth and proper metabolic regulation1. Midgestation features increasing oxygen and nutrient availability concomitant with fetal organ development2,3. Understanding how metabolism supports development requires approaches to observe metabolism directly in model organisms in utero. Here we used isotope tracing and metabolomics to identify evolving metabolic programmes in the placenta and embryo during midgestation in mice. These tissues differ metabolically throughout midgestation, but we pinpointed gestational days (GD) 10.5-11.5 as a transition period for both placenta and embryo. Isotope tracing revealed differences in carbohydrate metabolism between the tissues and rapid glucose-dependent purine synthesis, especially in the embryo. Glucose's contribution to the tricarboxylic acid (TCA) cycle rises throughout midgestation in the embryo but not in the placenta. By GD12.5, compartmentalized metabolic programmes are apparent within the embryo, including different nutrient contributions to the TCA cycle in different organs. To contextualize developmental anomalies associated with Mendelian metabolic defects, we analysed mice deficient in LIPT1, the enzyme that activates 2-ketoacid dehydrogenases related to the TCA cycle4,5. LIPT1 deficiency suppresses TCA cycle metabolism during the GD10.5-GD11.5 transition, perturbs brain, heart and erythrocyte development and leads to embryonic demise by GD11.5. These data document individualized metabolic programmes in developing organs in utero.

Mutant IDH1 regulates the tumor-associated immune system in gliomas.

Gliomas harboring mutations in isocitrate dehydrogenase 1/2 (IDH1/2) have the CpG island methylator phenotype (CIMP) and significantly longer patient survival time than wild-type IDH1/2 (wtIDH1/2) tumors. Although there are many factors underlying the differences in survival between these two tumor types, immune-related differences in cell content are potentially important contributors. In order to investigate the role of IDH mutations in immune response, we created a syngeneic pair mouse model for mutant IDH1 (muIDH1) and wtIDH1 gliomas and demonstrated that muIDH1 mice showed many molecular and clinical similarities to muIDH1 human gliomas, including a 100-fold higher concentration of 2-hydroxygluratate (2-HG), longer survival time, and higher CpG methylation compared with wtIDH1. Also, we showed that IDH1 mutations caused down-regulation of leukocyte chemotaxis, resulting in repression of the tumor-associated immune system. Given that significant infiltration of immune cells such as macrophages, microglia, monocytes, and neutrophils is linked to poor prognosis in many cancer types, these reduced immune infiltrates in muIDH1 glioma tumors may contribute in part to the differences in aggressiveness of the two glioma types.

A Feedback Loop between TGF-ß1 and ATG5 Mediated by miR-122-5p Regulates Fibrosis and EMT in Human Trabecular Meshwork Cells.

Autophagy is a cell's evolutionary conserved process for degrading and recycling cellular proteins and removing damaged organelles. There has been an increasing interest in identifying the basic cellular mechanism of autophagy and its implications in health and illness during the last decade. Many proteinopathies such as Alzheimer's and Huntington's disease are reported to be associated with impaired autophagy. The functional significance of autophagy in exfoliation syndrome/exfoliation glaucoma (XFS/XFG), remains unknown though it is presumed to be impaired autophagy to be responsible for the aggregopathy characteristic of this disease. In the current study we have shown that autophagy or ATG5 is enhanced in response to TGF-ß1 in human trabecular meshwork (HTM) cells and TGF-ß1 induced autophagy is necessary for increased expression of profibrotic proteins and epithelial to mesenchymal (EMT) through Smad3 that lead to aggregopathy. Inhibition of ATG5 by siRNA mediated knockdown reduced profibrotic and EMT markers and increased protein aggregates in the presence of TGF-ß1 stimulation. The miR-122-5p, which was increased upon TGF exposure, was also reduced upon ATG5 inhibition. We thus conclude that TGF-ß1 induces autophagy in primary HTM cells and a positive feedback loop exists between TGF-ß1 and ATG5 that regulated TGF downstream effects mainly mediated by Smad3 signaling with miR-122-5p also playing a role.

Development of a Medical Complexity Score for Pediatric Aerodigestive Patients.

OBJECTIVE: To develop a complexity scoring system to characterize the diverse population served in pediatric aerodigestive clinics and help predict their treatment outcomes. STUDY DESIGN: A 7-point medical complexity score was developed through an iterative group consensus of relative stakeholders to capture the spectrum of comorbidities among the aerodigestive population. One point was assigned for each comorbid diagnosis in the following categories: airway anomaly, neurologic, cardiac, respiratory, gastrointestinal, genetic diagnoses, and prematurity. A retrospective chart review was conducted of patients seen in the aerodigestive clinic who had ≥2 visits between 2017 and 2021. The predictive value of the complexity score for the selected outcome of feeding progression among children with dysphagia was analyzed with univariate and multivariable logistic regression. RESULTS: We analyzed 234 patients with complexity scores assigned, showing a normal distribution (Shapiro Wilk P = .406) of the scores 1-7 (median, 4; mean, 3.50 ± 1.47). In children with dysphagia, there was waning success in the improvement of oral feeding with increasing complexity scores (OR, 0.66; 95% CI, 0.51-0.84; P = .001). Tube-fed children with higher complexity scores were incrementally less likely to achieve full oral diet (OR, 0.60; 95% CI, 0.40-0.89; P = .01). On multivariable analysis, neurologic comorbidity (OR, 0.26; P < .001) and airway malformation (OR, 0.35; P = .01) were associated with a decreased likelihood to improve in oral feeding. CONCLUSIONS: We propose a novel complexity score for the pediatric aerodigestive population that is easy to use, successfully stratifies diverse presentations, and shows promise as a predictive tool to assist in counseling and resource use.

Non-linguistic auditory speech processing.

OBJECTIVES: A method for testing auditory processing of non-linguistic speech-like stimuli was developed and evaluated. DESIGN: Monosyllabic words were temporally reversed and distorted. Stimuli were matched for spectrum and level. Listeners discriminated between distorted and undistorted stimuli. STUDY SAMPLE: Three groups were tested. The Normal group was comprised of 12 normal-hearing participants. The Senior group was comprised of 12 seniors. The Hearing Loss group was comprised of 12 participants with thresholds of at least 35 dB HL at one or more frequencies. RESULTS: The Senior group scored lower than the Normal group, and the Hearing Loss group scored lower than the Senior group. Scores for forward compressed speech were slightly higher than backward compressed speech but the difference was not statistically significant. Retest scores were slightly higher than scores on the first test, but the difference was not statistically significant. CONCLUSIONS: Large differences in discrimination of distorted speech were observed among the three groups. Age and hearing loss separately affected performance. The depressed performance of the Senior group may be a result of "hidden hearing loss" that is attributed to cochlear synaptopathy. The backward-distorted speech task may be a useful non-linguistic test of speech processing that is language independent.

Alternate Causes for Pathogenesis of Exfoliation Glaucoma, a Multifactorial Elastotic Disorder: A Literature Review.

Exfoliation glaucoma (XFG) is the most recognizable form of secondary open-angle glaucoma associated with a high risk of blindness. This disease is characterized by white flaky granular deposits in the anterior chamber that leads to the elevation of intraocular pressure (IOP) and subsequent glaucomatous optic nerve damage. Conventionally, XFG is known to respond poorly to medical therapy, and surgical intervention is the only management option in most cases. Various genetic and nongenetic factors are known to be linked to the development of XFG. Despite decades of research on the genetic factors in exfoliation syndrome (XFS) by study groups and global consortia involving different ethnic populations, the pathogenesis of XFS and the mechanism of onset of glaucoma still remains an unsolved mystery. The key lies in understanding how the function of a gene (or set of genes) is altered by environmental triggers, along with other molecular events that underlie the key disease attributes, namely, oxidative stress and the disruption of the blood-aqueous barrier (BAB). It remains a challenge to evolve a theory encompassing all factions of molecular events occurring independently or parallelly that determine the disease manifestation (phenotype) or the stage of the disease in the eye (or in any tissue) in exfoliation. Our enhanced understanding of the underlying molecular pathophysiology of XFG, beyond the known genes or polymorphisms involved in the disease, will lead to improved diagnosis and management and the ability to recognize how the environment influences these key events that lead to the disease phenotype or disease progression. This review summarizes the recent observations and discoveries of four key factors that may hold the answers to the non-lysyl oxidase-like 1 (LOXL1) mechanisms behind XFG pathogenesis, namely, the epigenetic factor miRNA, disordered autophagy along with the potential involvement of mitochondrial mutations, and a compromised aqueous-blood barrier.

Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.

In vivo efficacy of decitabine as a natural killer cell-mediated immunotherapy against isocitrate dehydrogenase mutant gliomas.

OBJECTIVE: Isocitrate dehydrogenase (IDH) mutations are found in more than 80% of low-grade gliomas and in the majority of secondary glioblastomas. IDH mutation (IDHmut) leads to aberrant production of an oncogenic metabolite that promotes epigenetic dysregulation by inducing hypermethylation to suppress transcription of various tumor suppressor genes. Hypermethylation in IDHmut gliomas leads to transcriptional repression of NKG2D ligands, especially UL16-binding protein (ULBP)-1 and ULBP-3, and subsequent evasion of natural killer (NK) cell-mediated lysis. The demethylating agent 5-aza-2'deoxycytodine (decitabine [DAC]) is a DNA methyltransferase 1 inhibitor that prevents hypermethylation and is capable of restoring NKG2D ligand expression in IDHmut gliomas to resensitize them to NK cells. Given its capacity for sustained epigenetic reprogramming, the authors hypothesized that DCA would be an effective immunotherapeutic agent in treating IDHmut gliomas in an NK cell-dependent manner by upregulating epigenetically repressed activating NKG2D ligands in IDHmut tumors. In this study, the authors sought to use a glioma stem cell, preclinical animal model to determine the efficacy of DAC in IDHmut and IDH wild-type (IDHwt) tumors, and to characterize whether the activity of DAC in gliomas is dependent on NK cell function. METHODS: Xenograft models of IDHwt and IDHmut gliomas were established in athymic-nude mice. When tumors were grossly visible and palpable, mice were treated with either DCA or dimethylsulfoxide intraperitoneally every 7 days. Tumor sizes were measured every 2 to 3 days. After the animals were euthanized, xenografts were harvested and analyzed for the following: tumor expression of NKG2D ligands, tumor susceptibility to human and murine NK cells, immunohistochemistry for NK infiltration, and tumor-infiltrating lymphocyte characterization. RESULTS: DAC significantly inhibited the growth of IDHmut xenografts in the athymic nude mice. This effect was abrogated with NK cell depletion. Ex vivo analysis of tumor cells from harvested xenografts confirmed that DAC increased NKG2D ligand ULBP-1 and ULBP-3 expressions, and enhanced susceptibility to lysis of both human and murine IDHmut glial cells with corresponding NK cells. Immunohistochemical analysis of the xenografts indicated that DCA-treated IDHmut gliomas had a greater level of NK infiltration into the tumor compared with the negative control. Finally, DCA radically altered the tumor-infiltrating lymphocyte landscape of IDHmut glioma xenografts by increasing NK cells, dendritic cells, and M1 macrophages, while decreasing suppressive monocyte infiltration. CONCLUSIONS: DCA displayed novel immunotherapeutic functions in IDHmut gliomas. This effect was critically dependent on NK cells. Additionally, DCA significantly altered the tumor immune landscape in IDHmut gliomas from suppressive to proinflammatory.

Adenosine receptors regulate exosome production.

Exosomes, small-sized extracellular vesicles, carry components of the purinergic pathway. The production by cells of exosomes carrying this pathway remains poorly understood. Here, we asked whether type 1, 2A, or 2B adenosine receptors (A1Rs, A2ARs, and A2BRs, respectively) expressed by producer cells are involved in regulating exosome production. Preglomerular vascular smooth muscle cells (PGVSMCs) were isolated from wildtype, A1R-/-, A2AR-/-, and A2BR-/- rats, and exosome production was quantified under normal or metabolic stress conditions. Exosome production was also measured in various cancer cells treated with pharmacologic agonists/antagonists of A1Rs, A2ARs, and A2BRs in the presence or absence of metabolic stress or cisplatin. Functional activity of exosomes was determined in Jurkat cell apoptosis assays. In PGVSMCs, A1R and A2AR constrained exosome production under normal conditions (p = 0.0297; p = 0.0409, respectively), and A1R, A2AR, and A2BR constrained exosome production under metabolic stress conditions. Exosome production from cancer cells was reduced (p = 0.0028) by the selective A2AR agonist CGS 21680. These exosomes induced higher levels of Jurkat apoptosis than exosomes from untreated cells or cells treated with A1R and A2BR agonists (p = 0.0474). The selective A2AR antagonist SCH 442416 stimulated exosome production under metabolic stress or cisplatin treatment, whereas the selective A2BR antagonist MRS 1754 reduced exosome production. Our findings indicate that A2ARs suppress exosome release in all cell types examined, whereas effects of A1Rs and A2BRs are dependent on cell type and conditions. Pharmacologic targeting of cancer with A2AR antagonists may inadvertently increase exosome production from tumor cells.

Comparison of Thresholds Obtained With the Radioear B-71 and B-81 Bone-Conduction Transducers.

OBJECTIVES: A new bone conduction transducer, the Radioear B-81, has been designed to be an improvement over the commonly used transducer, the Radioear B-71. Reference Equivalent Threshold Force Levels (RETFLs) were obtained with the new Radioear B-81. DESIGN: Thresholds were obtained in accordance with ANSI-S3.6-2018 (Annex D) and participants were selected as prescribed in ISO 389.9-2009. Thresholds were obtained with automatic audiometry using circumaural earphones (Radioear DD450) and forehead placement of the bone vibrators. RESULTS: Mean bone conduction thresholds obtained using the B-81 and B-71 bone oscillators for frequencies from 250 to 4000 Hz were not statistically different. RETFLs for the B-81 are identical to the values in ANSI S3.6-2018 for the B-71 bone vibrator. Air-bone gaps were observed for both transducers at low frequencies (250 and 500 Hz) due to occlusion effects produced by the circumaural earphone and at high frequencies (3000 and 4000 Hz), previously reported in several studies that used standard RETFLs. Test-retest differences for air conduction thresholds were analyzed and the results are presented in the Appendix A (Supplemental Digital Content 1, http://links.lww.com/EANDH/A639). CONCLUSIONS: RETFLs in ANSI S3.6-2018 and ISO 389.3-2016 are appropriate for use with the B-81 bone vibrator.

Outcomes of Ahmed glaucoma valve FP8 versus FP7 in adult secondary glaucoma.

AIM: To compare the outcomes of Ahmed glaucoma valve (AGV) pediatric FP8 versus the large-sized adult FP7 implants in an adult secondary glaucoma. METHODS: Patients who underwent AGV implantation from January 2011 to December 2016 for adult secondary glaucoma (due to causes other than post-vitreoretinal/buckle surgery glaucoma) with a follow-up of 6 months were included for this retrospective study. Success was defined as IOP > 6 mm Hg and < 21 mm Hg without any loss of vision, with or without the need of anti-glaucoma medications or additional procedures for control of IOP. Hypertensive phase was defined as IOP > 21 mmHg at any visit in the first 6 months of postoperative follow-up period, while failure was defined as IOP > 21 mm Hg even after medications or additional procedures, need of removal of implant or loss of light perception. Cumulative survival rates and intraoperative or postoperative complications along with IOP profiles were compared between the implants. RESULTS: Of 43 patients, 19 patients underwent FP7 and 24 patients underwent FP8 Ahmed Glaucoma valve implantation. The IOP significantly reduced in both groups from baseline (31 ± 8.2 mm Hg in FP7 eyes and 37 ± 13.1 mm Hg in FP8 eyes) by a mean of 64 ± 23.5% in FP8 and 64 ± 21.5% in FP7 group, respectively, p = 0.8 with comparable final IOP of 16.5 mm Hg and 16.9 mm Hg, respectively, p = 0.9. Both groups had 75% qualified success rates at 20 months after surgery with similar rates of need for postoperative medications or incidence of hypertensive phase. The FP8 eyes had more frequent conjunctiva-related complications in eyes with prior surgeries and preoperative conjunctival scarring while the other complications were similar in the two groups. CONCLUSION: Surgical outcomes of adult FP7 and pediatric FP8 AGV in adult secondary glaucoma seem to achieve similar IOP control and success rates. This suggests that smaller-sized FP8 can be used in adult glaucoma with good surgical outcomes albeit with careful case selection in eyes with extensive preoperative scarring to avoid conjunctival thinning-related complications postoperatively.

Asthma treatment and outcomes for children in the emergency department and hospital.

OBJECTIVE: To describe and compare the treatment of acute asthma exacerbations in children given in the emergency department (ED) and admitted to acute care floor in the hospital or intensive care unit (ICU). METHODS: A retrospective chart review of visits for acute exacerbation of asthma treated at Phoenix Children's Hospital between January 1, 2014 and December 31, 2016. RESULTS: A total of 287 asthma exacerbation cases were identified including 106 (37%) ED visits, 134 (47%) hospital floor and 47 (16%) ICU admissions. A history of a previous ED visit (ED 88%, Floor 60% and ICU 68%; p < 0.0001) and prior pulmonology inpatient consultation (ED 30%, Floor 19% and ICU 15%; p = 0.05) varied significantly. Pulmonology inpatient consultations were performed more frequently in the ICU than on the hospital floor (54% versus 8%; p < 0.0001). Although overall 145 (51%) of the cases were already on inhaled corticosteroids (ICS) at the time of visit with no differences across locations, ICS initiation/step-up was greater in the ICU (72%) than on the hospital floor (54%) and ED (2%) (p < 0.0001). A recommendation given to the family for follow-up with pulmonology was more frequent for patients who had been admitted to the ICU (68%) as compared to those only admitted to the floor (31%) or ED (4%) (p < 0.0001). Readmission rates were similar for patients previously admitted to the hospital (Floor 42%; ICU 40%), but significantly higher for previous ED visits (77%) (p < 0.0001). CONCLUSIONS: Physicians in the ED have an opportunity to provide preventative care in the acute care setting and should be encouraged to initiate treatment with ICS. Consideration should be given to develop a program or clinical pathway focused on long-term asthma management and maintenance to reduce readmissions and long hospital stays.

Conjunctival changes in different clinical variants of early pseudoexfoliation.

PURPOSE: To evaluate the conjunctival signs in different forms of pseudoexfoliation (PXF) syndrome to identify signs predicting early forms of the disease. METHODS: This observational study included patients with newly diagnosed PXF screened in the outpatient department of glaucoma services. Slit lamp photographs were captured in low and high magnification after full dilatation, and details like melanotic pigmentation, vascularity and tortuosity of vessels, scarring if any, presence of pterygium and actinic changes along with basal Schirmer's test were analysed. Variables in each subtype of PXF previously described by us, namely radial pigmentary (group A), combined pigmentary and classical (group B) and classical PXF (group C), were analysed and compared to age-matched controls. The differences between manifest (group B + C) and unmanifest or early form (group A) were also compared. RESULTS: A total of 89 eyes from 55 patients (M/F = 38:17, 21 unilateral, 34 bilateral, 48 group A, 10 group B and 31 group C) were compared with 40 controls. The Schirmer's test was statically lower in patients with manifest PXF (10 ± 1.4 mm) and unmanifest PXF (14 ± 0.6 mm), p < 0.001. The most frequent conjunctival finding (n = 88) in this cohort was lightly pigmented melanotic pigmentation present close to limbus without evidence of any feeder vessels or actinic changes and associated with pupillary ruff atrophy in the same quadrant. Analysing different PXF forms, there was conjunctival melanosis in one or all quadrants in all forms of PXF which was more prominent in manifest PXF, present in a mean 2 ± 1.7 quadrants in unmanifest and manifest PXF, p = 0.01. CONCLUSION: Conjunctival melanosis with associated pupillary ruff atrophy in the same quadrant may be the earliest signs of early pseudoexfoliation.

Neural Correlates of Selective Attention With Hearing Aid Use Followed by ReadMyQuips Auditory Training Program.

OBJECTIVES: The objectives of this study were to investigate the effects of hearing aid use and the effectiveness of ReadMyQuips (RMQ), an auditory training program, on speech perception performance and auditory selective attention using electrophysiological measures. RMQ is an audiovisual training program designed to improve speech perception in everyday noisy listening environments. DESIGN: Participants were adults with mild to moderate hearing loss who were first-time hearing aid users. After 4 weeks of hearing aid use, the experimental group completed RMQ training in 4 weeks, and the control group received listening practice on audiobooks during the same period. Cortical late event-related potentials (ERPs) and the Hearing in Noise Test (HINT) were administered at prefitting, pretraining, and post-training to assess effects of hearing aid use and RMQ training. An oddball paradigm allowed tracking of changes in P3a and P3b ERPs to distractors and targets, respectively. Behavioral measures were also obtained while ERPs were recorded from participants. RESULTS: After 4 weeks of hearing aid use but before auditory training, HINT results did not show a statistically significant change, but there was a significant P3a reduction. This reduction in P3a was correlated with improvement in d prime (d') in the selective attention task. Increased P3b amplitudes were also correlated with improvement in d' in the selective attention task. After training, this correlation between P3b and d' remained in the experimental group, but not in the control group. Similarly, HINT testing showed improved speech perception post training only in the experimental group. The criterion calculated in the auditory selective attention task showed a reduction only in the experimental group after training. ERP measures in the auditory selective attention task did not show any changes related to training. CONCLUSIONS: Hearing aid use was associated with a decrement in involuntary attention switch to distractors in the auditory selective attention task. RMQ training led to gains in speech perception in noise and improved listener confidence in the auditory selective attention task.

Targeting metabolic reprogramming as a potential therapeutic strategy in melanoma.

Metabolic reprogramming is a recognized hallmark of cancer. In order to support continued proliferation and growth, tumor cells must metabolically adapt to balance their bioenergetic and biosynthetic needs. To achieve this, cancer cells switch from mitochondrial oxidative phosphorylation to predominantly rely on glycolysis, a process known as the "Warburg effect". The BRAF oncogene has recently emerged as a critical regulator of this process in melanoma, bringing to the fore the importance of metabolic reprogramming in the pathogenesis and treatment of metastatic melanoma. In this review, we summarize our current understanding of oncogenic reprogramming of metabolism in BRAF and NRAS mutant melanoma, and highlight emerging evidence supporting a metabolic basis for MAPK pathway inhibitor resistance and metabolic vulnerabilities that may be exploited to overcome this.

Peptide receptor chemoradionuclide therapy in small cell carcinoma: from bench to bedside.

PURPOSE: Small cell cancers (SmCC), whether pulmonary (SCLC) or extrapulmonary, have a poor prognosis unless localised at diagnosis. Given a proportion of these cancers express somatostatin receptor subtype 2 (SSTR2), we aimed to investigate the efficacy of targeted peptide receptor chemoradionuclide therapy (PRCRT). METHODS: In this preclinical study, we used a SCLC xenograft mouse model with high expression of SSTR2 to investigate the effect of peptide receptor radionuclide therapy (PRRT) with chemotherapy compared to either alone. We subsequently explored the clinical utility in a patient with SmCC with high SSTR expression treated with PRCRT. RESULTS: Robust expression of SSTR2 in NCI-H69 SCLC xenografts was documented by (68)Ga-DOTA-octreotate (GaTate) (tumour to background uptake ratio = 35). The combination of PRRT using (177)Lu-DOTA-octreotate (LuTate) with carboplatin/etoposide (C/E) chemotherapy was more effective than either LuTate or C/E alone for regression of the NCI-H69 model (p value < 0.05). PRCRT was associated with significantly prolonged survival versus PRRT (p value = 0.0001) or chemotherapy alone (p value = 0.0058). In the subsequent case study, a patient with relapsed SmCC with high SSTR2 expression on GaTate PET underwent PRCRT with radiosensitising etoposide with evidence of a complete metabolic response for 4 months. CONCLUSION: Given the limited treatment options in this setting, PRCRT is a promising therapeutic option for SSTR2-expressing SmCC.

New insights of superoxide dismutase inhibition of pyrogallol autoxidation.

Autoxidation of pyrogallol in alkaline medium is characterized by increases in oxygen consumption, absorbance at 440 nm, and absorbance at 600 nm. The primary products are H2O2 by reduction of O2 and pyrogallol-ortho-quinone by oxidation of pyrogallol. About 20 % of the consumed oxygen was used for ring opening leading to the bicyclic product, purpurogallin-quinone (PPQ). The absorbance peak at 440 nm representing the quinone end-products increased throughout at a constant rate. Prolonged incubation of pyrogallol in alkali yielded a product with ESR signal. In contrast the absorbance peak at 600 nm increased to a maximum and then declined after oxygen consumption ceased. This represents quinhydrone charge-transfer complexes as similar peak instantly appeared on mixing pyrogallol with benzoquinones, and these were ESR-silent. Superoxide dismutase inhibition of pyrogallol autoxidation spared the substrates, pyrogallol, and oxygen, indicating that an early step is the target. The SOD concentration-dependent extent of decrease in the autoxidation rate remained the same regardless of higher control rates at pyrogallol concentrations above 0.2 mM. This gave the clue that SOD is catalyzing a reaction that annuls the forward electron transfer step that produces superoxide and pyrogallol-semiquinone, both oxygen radicals. By dismutating these oxygen radicals, an action it is known for, SOD can reverse autoxidation, echoing the reported proposal of superoxide:semiquinone oxidoreductase activity for SOD. The following insights emerged out of these studies. The end-product of pyrogallol autoxidation is PPQ, and not purpurogallin. The quinone products instantly form quinhydrone complexes. These decompose into undefined humic acid-like complexes as late products after cessation of oxygen consumption. SOD catalyzes reversal of autoxidation manifesting as its inhibition. SOD saves catechols from autoxidation and extends their bioavailability.

Optic nerve head characteristics in eyes with papillomacular bundle defects in glaucoma.

To evaluate the pattern of retinal nerve fibre layer defects (RNFLD) with regard to involvement of papillomacular bundle (PMB) in glaucoma. This observational study included patients attending glaucoma imaging services at our centre from 2011 to 2012. All images were exported to Image J software for analysis and rescaled to a unified scale for measurement of degree of RNFLD defined by its angular width, pattern of involvement with regard to involvement or sparing of PMB in particular and horizontal and vertical distance of central vessel trunk (CVT) from the disc margin. Association of clinical data with pattern of defects with regard to PMB involvement was analysed. Sixty-two fundus photographs with discernible nerve fibre layer defects on red free images were selected, including 48 normal tension glaucoma, two primary angle closure glaucoma (PACG) and 12 primary open angle glaucoma (POAG) eyes. Discernible PMB involvement was seen in 35 eyes which included 31 defects in inferior quadrant while CVT exit was placed in the quadrant opposite to the quadrant of RNFLD in that eye. The mean vertical distance from the nearest disc margin was greater in eyes without PMB involvement, 0.4 ± 0.02 mm, than eyes with PMB defects, 0.3 ± 0.01 mm, p < 0.001. On multivariate logistic regression, PMB involvement was significantly associated with decreased linear horizontal of the CVT from the disc margin, p = 0.003. Selective involvement of superior and inferior PMB suggests different retinotopic representation within the optic disc. Exit of the CVT towards the disc margin may be a predisposing factor for RNFLD and involvement of the PMB.