Description of a new method to calculate the equator of the crystalline lens using AS-OCT images: Accuracy in non-dilated measurements.

OBJECTIVE: To establish a methodology for objectively estimating the Lens Equatorial Plane (LEP) from clinical images, comparing LEP with dilated versus non-dilated pupils. METHODS: A cohort of 91 eyes from 60 patients undergoing preoperative assessments for cataract surgery was evaluated. Anterior Segment Optical Coherence Tomography (AS-OCT) images were analysed under conditions of pharmacologically induced pupil dilation versus a non-dilated pupil. Geometrical parameters, including LEP, intersection diameter (ID), lens thickness (LT), anterior and posterior lens thickness were automatically calculated by applying standard image processing techniques to clinical AS-OCT images. RESULTS: Significant differences in lens parameters, including LEP, were observed between dilated and non-dilated conditions (all p < 0.001). A strong linear correlation was found across all geometrical variables under both conditions (r[LEP] = 0.64, r[ID] = 0.78, r[LT] = 0.99, all p < 0.001); enabling reliable correction of these differences. CONCLUSION: The study introduces an objective methodology for LEP calculation, emphasising the need to consider the eye's physiological state during preoperative measurements. Incorporating LEP into future intraocular lens (IOL) power calculation formulas and replacing the habitual effective lens position may potentially improve the accuracy of IOL power estimation and thus postoperative visual outcomes.

Glutaminase isoforms expression switches microRNA levels and oxidative status in glioblastoma cells.

BACKGROUND: Glutaminase isoenzymes GLS and GLS2 play apparently opposing roles in cancer: GLS acts as an oncoprotein, while GLS2 (GAB isoform) has context specific tumour suppressive activity. Some microRNAs (miRNAs) have been implicated in progression of tumours, including gliomas. The aim was to investigate the effect of GLS and GAB expression on both miRNAs and oxidative status in glioblastoma cells. METHODS: Microarray profiling of miRNA was performed in GLS-silenced LN229 and GAB-transfected T98G human glioblastoma cells and their wild-type counterparts. Results were validated by real-time quantitative RT-PCR. Oxidative status and antioxidant enzymes were determined by spectrophotometric or fluorescence assays in GLS-silenced LN229 and T98G, and GAB-transfected LN229 and T98G. RESULTS: MiRNA-146a-5p, miRNA-140-3p, miRNA-21-5p, miRNA-1260a, and miRNA-92a-3p were downregulated, and miRNA-1246 was upregulated when GLS was knocked down. MiRNA-140-3p, miRNA-1246, miRNA-1260a, miRNA-21-5p, and miRNA-146a-5p were upregulated when GAB was overexpressed. Oxidative status (lipid peroxidation, protein carbonylation, total antioxidant capacity, and glutathione levels), as well as antioxidant enzymes (catalase, superoxide dismutase, and glutathione reductase) of silenced GLS glioblastoma cells and overexpressed GAB glioblastoma cells significantly changed versus their respective control glioblastoma cells. MiRNA-1246, miRNA-1260a, miRNA-146a-5p, and miRNA-21-5p have been characterized as strong biomarkers of glioblastoma proliferation linked to both GLS silencing and GAB overexpression. Total glutathione is a reliable biomarker of glioblastoma oxidative status steadily associated to both GLS silencing and GAB overexpression. CONCLUSIONS: Glutaminase isoenzymes are related to the expression of some miRNAs and may contribute to either tumour progression or suppression through certain miRNA-mediated pathways, proving to be a key tool to switch cancer proliferation and redox status leading to a less malignant phenotype. Accordingly, GLS and GAB expression are especially involved in glutathione-dependent antioxidant defence.

Glutamine Addiction In Gliomas.

Cancer cells develop and succeed by shifting to different metabolic programs compared with their normal cell counterparts. One of the classical hallmarks of cancer cells is their higher glycolysis rate and lactate production even in the presence of abundant O2 (Warburg effect). Another common metabolic feature of cancer cells is a high rate of glutamine (Gln) consumption normally exceeding their biosynthetic and energetic needs. The term Gln addiction is now widely used to reflect the strong dependence shown by most cancer cells for this essential nitrogen substrate after metabolic reprogramming. A Gln/glutamate (Glu) cycle occurs between host tissues and the tumor in order to maximize its growth and proliferation rates. The mechanistic basis for this deregulated tumor metabolism and how these changes are connected to oncogenic and tumor suppressor pathways are becoming increasingly understood. Based on these advances, new avenues of research have been initiated to find novel therapeutic targets and to explore strategies that interfere with glutamine metabolism as anticancer therapies. In this review, we provided an updated overview of glutamine addiction in glioma, the most prevalent type of brain tumor.

Glutamate and Brain Glutaminases in Drug Addiction.

Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement, and relapse. Although most of the interest has been centered in post-synaptic glutamate receptors, the presynaptic synthesis of glutamate through brain glutaminases may also contribute to imbalances in glutamate homeostasis, a key feature of the glutamatergic hypothesis of addiction. Glutaminases are the main glutamate-producing enzymes in brain and dysregulation of their function have been associated with neurodegenerative diseases and neurological disorders; however, the possible implication of these enzymes in drug addiction remains largely unknown. This mini-review focuses on brain glutaminase isozymes and their alterations by in vivo exposure to drugs of abuse, which are discussed in the context of the glutamate homeostasis theory of addiction. Recent findings from mouse models have shown that drugs induce changes in the expression profiles of key glutamatergic transmission genes, although the molecular mechanisms that regulate drug-induced neuronal sensitization and behavioral plasticity are not clear.

Expression of Gls and Gls2 glutaminase isoforms in astrocytes.

The expression of glutaminase in glial cells has been a controversial issue and matter of debate for many years. Actually, glutaminase is essentially considered as a neuronal marker in brain. Astrocytes are endowed with efficient and high capacity transport systems to recapture synaptic glutamate which seems to be consistent with the absence of glutaminase in these glial cells. In this work, a comprehensive study was devised to elucidate expression of glutaminase in neuroglia and, more concretely, in astrocytes. Immunocytochemistry in rat and human brain tissues employing isoform-specific antibodies revealed expression of both Gls and Gls2 glutaminase isozymes in glutamatergic and GABAergic neuronal populations as well as in astrocytes. Nevertheless, there was a different subcellular distribution: Gls isoform was always present in mitochondria while Gls2 appeared in two different locations, mitochondria and nucleus. Confocal microscopy and double immunofluorescence labeling in cultured astrocytes confirmed the same pattern previously seen in brain tissue samples. Astrocytic glutaminase expression was also assessed at the mRNA level, real-time quantitative RT-PCR detected transcripts of four glutaminase isozymes but with marked differences on their absolute copy number: the predominance of Gls isoforms over Gls2 transcripts was remarkable (ratio of 144:1). Finally, we proved that astrocytic glutaminase proteins possess enzymatic activity by in situ activity staining: concrete populations of astrocytes were labeled in the cortex, cerebellum and hippocampus of rat brain demonstrating functional catalytic activity. These results are relevant for the stoichiometry of the Glu/Gln cycle at the tripartite synapse and suggest novel functions for these classical metabolic enzymes.

GLS and GLS2 Glutaminase Isoenzymes in the Antioxidant System of Cancer Cells.

A pathway frequently altered in cancer is glutaminolysis, whereby glutaminase (GA) catalyzes the main step as follows: the deamidation of glutamine to form glutamate and ammonium. There are two types of GA isozymes, named GLS and GLS2, which differ considerably in their expression patterns and can even perform opposing roles in cancer. GLS correlates with tumor growth and proliferation, while GLS2 can function as a context-dependent tumor suppressor. However, both isoenzymes have been described as essential molecules handling oxidant stress because of their involvement in glutathione production. We reviewed the literature to highlight the critical roles of GLS and GLS2 in restraining ROS and regulating both cellular signaling and metabolic stress due to their function as indirect antioxidant enzymes, as well as by modulating both reductive carboxylation and ferroptosis. Blocking GA activity appears to be a potential strategy in the dual activation of ferroptosis and inhibition of cancer cell growth in a ROS-mediated mechanism.

Biometric description of 34 589 eyes undergoing cataract surgery: sex differences.

PURPOSE: To describe gender differences in the biometric parameters of a large sample of patients with cataract. Cataract surgery has evolved from a vision restoration to a refractive procedure, and population-based studies are vital to optimize normative databases and postsurgical outcomes. SETTING: Miguel Servet University Hospital, Zaragoza, Spain. DESIGN: Retrospective single-center observational study. METHODS: The study included 34 589 eyes (20 004 patients with cataract). Biometric data were obtained from IOL Master 700 and Pentacam HR. Linear mixed models were used to account for intereye correlation. HofferQST formula was used to calculate the hypothetical distribution of intraocular lens (IOL) power (arbitrary lens; A = 119.2). RESULTS: Most biometric variables showed significant differences between sexes ( P < .0001), such as 0.53 mm shorter eyes found in females, of which 0.16 mm are explained by shorter aqueous depth. Steeper anterior keratometries (∼0.75 diopter [D]) were found in women, to end up in no difference on anterior astigmatism magnitude, but different orientation ( P < .0001). The distribution of IOL power differed between sexes ( P < .001), with the interquartile range shifting 1 D toward more powerful lenses in women and odds ratio (power >26 D) = 2.26, P < .0001 (Fisher). CONCLUSIONS: Large sample size studies provide smaller margin of error, higher power, and controlled risk of reporting false (negative or positive) findings. Highly significant differences between sexes in ocular biometry were found; this supports the idea that including sex as a parameter in IOL calculation should be explored and may improve results. In addition, the distribution of IOL powers was provided, which may be useful for manufacturers and hospital stock planning.

Metabolic Adjustments following Glutaminase Inhibition by CB-839 in Glioblastoma Cell Lines.

Most tumor cells can use glutamine (Gln) for energy generation and biosynthetic purposes. Glutaminases (GAs) convert Gln into glutamate and ammonium. In humans, GAs are encoded by two genes: GLS and GLS2. In glioblastoma, GLS is commonly overexpressed and considered pro-oncogenic. We studied the metabolic effects of inhibiting GLS activity in T98G, LN229, and U87MG human glioblastoma cell lines by using the inhibitor CB-839. We performed metabolomics and isotope tracing experiments using U-13C-labeled Gln, as well as 15N-labeled Gln in the amide group, to determine the metabolic fates of Gln carbon and nitrogen atoms. In the presence of the inhibitor, the results showed an accumulation of Gln and lower levels of tricarboxylic acid cycle intermediates, and aspartate, along with a decreased oxidative labeling and diminished reductive carboxylation-related labeling of these metabolites. Additionally, CB-839 treatment caused decreased levels of metabolites from pyrimidine biosynthesis and an accumulation of intermediate metabolites in the de novo purine nucleotide biosynthesis pathway. The levels of some acetylated and methylated metabolites were significantly increased, including acetyl-carnitine, trimethyl-lysine, and 5-methylcytosine. In conclusion, we analyzed the metabolic landscape caused by the GLS inhibition of CB-839 in human glioma cells, which might lead to the future development of new combination therapies with CB-839.

Effects of reminiscence therapy on anxiety and depression during acute hospitalization in older patients: Controlled study.

BACKGROUND/OBJECTIVES: Hospitalization due to acute illness in older patients is often associated with anxiety or depressive symptoms. In these circumstances, given that pharmacologic treatment should be avoided to reduce interactions with ongoing medication regimes, psychotherapy techniques should be considered. The purpose of this study was to evaluate the effectiveness of group reminiscence therapy (RT) on the reduction of anxiety and depressive symptoms in acutely hospitalized older patients. METHODS: Controlled and prospective study conducted on the Acute Geriatric Unit of a university hospital. Patients included in the intervention group (RT Group) attended a group session focused on RT, whereas those included in the control group (UC) received usual hospital care. Exclusion criteria were severe cognitive impairment, impossibility to mobilize, and clinical/hemodynamic instability. The intervention was based on a multi-task daily group session of reminiscence activities. The severity of anxiety (Hamilton Anxiety Rating Scale, HAM-A), depressive symptoms (15-item Geriatric Depression Scale, GDS-15), loneliness (ESTE-II social loneliness scale), and fear of death (Collet-Lester scale) was assessed at admission and discharge in both groups. RESULTS: The intervention was effective in reducing the proportion of patients with anxiety and depressive symptoms during hospitalization. The proportion of patients with moderate-severe anxiety at discharge was 32.1% in the UC and 13.4% in the RT Group (p < 0.001), whereas the proportion of patients with depressive symptoms at discharge was 49.1% in the UC and 19.5% in the RT Group (p < 0.001). The intervention was independently associated with benefits on anxiety levels (RR 2.45, 95% CI 1.83-3.28) and depression (RR 3.71, 95% CI 2.22-6.19) at discharge. No differences were found in loneliness or fear of death. CONCLUSIONS: A group reminiscence activity reduces the proportion of patients with anxiety and depressive symptoms during hospitalization for an acute disease. Absolute changes in both anxiety and depression scores, even though significant, were relatively small.

Oxidative stress in apoptosis and cancer: an update.

The oxygen paradox tells us that oxygen is both necessary for aerobic life and toxic to all life forms. Reactive oxygen species (ROS) touch every biological and medical discipline, especially those involving proliferative status, supporting the idea that active oxygen may be increased in tumor cells. In fact, metabolism of oxygen and the resulting toxic byproducts can cause cancer and death. Efforts to counteract the damage caused by ROS are gaining acceptance as a basis for novel therapeutic approaches, and the field of prevention of cancer is experiencing an upsurge of interest in medically useful antioxidants. Apoptosis is an important means of regulating cell numbers in the developing cell system, but it is so important that it must be controlled. Normal cell death in homeostasis of multicellular organisms is mediated through tightly regulated apoptotic pathways that involve oxidative stress regulation. Defective signaling through these pathways can contribute to both unbalance in apoptosis and development of cancer. Finally, in this review, we discuss new knowledge about recent tools that provide powerful antioxidant strategies, and designing methods to deliver to target cells, in the prevention and treatment of cancer.

Global Oncology Authorship and Readership Patterns.

PURPOSE: Global Oncology is the movement to improve equitable access to cancer control and care, recognizing challenges because of economic and social factors between high-, middle-, and low-income countries (HIC, MIC, and LIC, respectively). The JCO Global Oncology (JCO GO) is a major platform dedicated to publishing peer-reviewed research relevant to populations with limited resources. To assess the success of its goals of encouraging global interaction and increasing MIC and LIC engagement, we analyzed authorship and readership patterns. METHODS: Metadata of logged views between January 1, 2018, and June 30, 2019, of articles published in 2018 by JCO GO were identified using Google Analytics. The country of origin of each author and those who accessed the journal were categorized according to the 2019 income group World Bank Classification (WBC). RESULTS: One hundred thirty-two articles were published in JCO GO in 2018. Corresponding authors came from 34 nations: 35% HIC, 47% MIC, and 18% LIC. The top publishing countries were the United States, India, Brazil, Mexico, and Nigeria. Article authors were solely from within one WBC group in 41% (23% HIC, 16% MIC, and 2% LIC). In those with mixed-WBC authorship origins, collaborations were 42% HIC + MIC, 11% HIC + LIC, and 6% HIC + MIC + LIC, but none with MIC + LIC. Regarding viewing, 87,860 views originated from 180 countries (82% of the WBC list): 35% HIC, 51% MIC, and 14% LIC. The most common accessing nations were the United States, India, the United Kingdom, Brazil, and Ethiopia. CONCLUSION: More than half of JCO GO's authorship comes from mixed WBC groups, with viewership extending to most of the world's nations. Areas to address are low level of LIC corresponding authors, few papers from authors across all WBC groups, no publications from MIC + LIC collaborations, and a low percentage of readership by LIC. These data provide focus to target interventions aimed at reducing the academic segregation of LIC and improving interactions across all WBC countries.

Pacinian Corpuscles as a Diagnostic Clue of Ledderhose Disease-A Case Report and Mapping of Pacinian Corpuscles of the Sole.

BACKGROUND: Plantar fibromatosis, known as Ledderhose disease, is a neoplastic disease characterized by a locally-aggressive bland fibroblastic proliferation. Although Pacinian corpuscles alterations are commonly described in palmar fibromatosis, there are still no references about Pacinian corpuscles alterations in the rarer plantar version. METHODS: We present a case report where a wide cutaneous resection, including the plantar fascia was performed, allowing a detailed study of Pacinian corpuscles. Pacinian corpuscles were analyzed using immunohistochemistry for neurofilament proteins, S100 protein, CD34, vimentin, glucose transporter 1, epithelial membrane antigen, neural-cell adhesion molecule, actin, desmin, type IV collagen, and high-affinity neurotrophin Trk-receptors. Moreover, the density and the size of the corpuscles were determined. RESULTS: A clear increase in the number (hyperplasia) of Pacinian corpuscles was evidenced in the Ledderhose disease plantar fascia in comparison with similarly aged normal subjects. Pacinian hypertrophy was not demonstrated, but a significant decrease in the number of corpuscular lamellae was noted, with a subsequent increase in the interlamellar spaces. Pacinian corpuscles from the pathological plantar fascia showed an abnormal structure and immunohistochemical profile, generally without identifiable axons, and also absence of an inner core or an intermediate layer. Moreover, other molecules related with trophic maintenance of corpuscles were also absent. Finally, a vascular proliferation was commonly noted in some corpuscles, which involved all corpuscular constituents. CONCLUSION: The observed Pacinian corpuscles hyperplasia could be considered a diagnostic clue of plantar fibromatosis.

Oncofertility and Fertility Preservation in Cancer Patients Across the Twitterverse.

Purpose: Infertility is a major problem affecting children, adolescents, and young adults (AYAs) with cancer, either due to the disease itself or because of oncologic treatment. Oncofertility (OF) focuses on counseling cancer patients about fertility risks and preservation options. However, OF and fertility preservation (FP) conversations on Twitter and their impact are unknown. We aim to characterize the users and type of content of these conversations. Materials and Methods: This observational study analyzed tweets with the hashtags "#Oncofertility" and "#FertilityPreservation" over eight months. We classified Twitter accounts by user type and country. Tweets were categorized by content type, and retweets and likes were quantified. Descriptive statistics were used for analysis. Results: A total of 399 tweets from 223 different accounts were evaluated. Twitter accounts comprised 22 countries and stemmed from high, upper-middle, and lower-middle-income countries in 86.5%, 5.4%, and 6.3%, respectively; no accounts from low-income countries were found. Accounts were mostly from physicians (37%) and healthcare centers (20%); we did not find any patient accounts. The most common content category was informative tweets directed to patients (30.8%), followed by discussion/sharing of medical papers (25.6%). Only 14.5% of tweets contained information about children and adolescents. Still, only 4.5% were aimed at children. Retweets were absent in 16.5% of the tweets, and 80.7% did not have comments. Conclusion: OF and FP discussions on Twitter were limited to interactions among medical professionals. Also, advocacy groups showed limited activity on social media. Even though a significant proportion of tweets directed to patients were found, no active involvement of patients was observed. Finally, limited number of tweets (4.5%) were directed to children and adolescents. There is a need to raise awareness about the effects of cancer on fertility in this group. Currently, Twitter is not a resource of information for children and AYAs with cancer who need OF counseling and fertility preservation. Our results open a debate on how to promote the use of social media in the future to improve the quality of OF information available, awareness, and care since there is an unmet need for fertility preservation access in young cancer patients.

Tuning the activity of Pt(111) for oxygen electroreduction by subsurface alloying.

To enable the development of low temperature fuel cells, significant improvements are required to the efficiency of the Pt electrocatalysts at the cathode, where oxygen reduction takes place. Herein, we study the effect of subsurface solute metals on the reactivity of Pt, using a Cu/Pt(111) near-surface alloy. Our investigations incorporate electrochemical measurements, ultrahigh vacuum experiments, and density functional theory. Changes to the OH binding energy, ΔE(OH), were monitored in situ and adjusted continuously through the subsurface Cu coverage. The incorporation of submonolayer quantities of Cu into Pt(111) resulted in an 8-fold improvement in oxygen reduction activity. The most optimal catalyst for oxygen reduction has an ΔE(OH) ≈ 0.1 eV weaker than that of pure Pt, validating earlier theoretical predictions.

The Pt(111)/electrolyte interface under oxygen reduction reaction conditions: an electrochemical impedance spectroscopy study.

The Pt(111)/electrolyte interface has been characterized during the oxygen reduction reaction (ORR) in 0.1 M HClO(4) using electrochemical impedance spectroscopy. The surface was studied within the potential region where adsorption of OH* and O* species occur without significant place exchange between the adsorbate and Pt surface atoms (0.45-1.15 V vs RHE). An equivalent electric circuit is proposed to model the Pt(111)/electrolyte interface under ORR conditions within the selected potential window. This equivalent circuit reflects three processes with different time constants, which occur simultaneously during the ORR at Pt(111). Density functional theory (DFT) calculations were used to correlate and interpret the results of the measurements. The calculations indicate that the coadsorption of ClO(4)* and Cl* with OH* is unlikely. Our analysis suggests that the two-dimensional (2D) structures formed in O(2)-free solution are also formed under ORR conditions.

Shine-Dalgarno interaction prevents incorporation of noncognate amino acids at the codon following the AUG.

During translation, usually only one in approximately 400 misincorporations affects the function of a nascent protein, because only chemically similar near-cognate amino acids are misincorporated in place of the cognate one. The deleterious misincorporation of a chemically dissimilar noncognate amino acid during the selection process is precluded by the presence of a tRNA at the ribosomal E-site. However, the selection of first aminoacyl-tRNA, directly after initiation, occurs without an occupied E-site, i.e., when only the P-site is filled with the initiator tRNA and thus should be highly error-prone. Here, we show how bacterial ribosomes have solved this accuracy problem: In the absence of a Shine-Dalgarno (SD) sequence, the first decoding step at the A-site after initiation is extremely error-prone, even resulting in the significant incorporation of noncognate amino acids. In contrast, when a SD sequence is present, the incorporation of noncognate amino acids is not observed. This is precisely the effect that the presence of a cognate tRNA at the E-site has during the elongation phase. These findings suggest that during the initiation phase, the SD interaction functionally compensates for the lack of codon-anticodon interaction at the E-site by reducing the misincorporation of near-cognate amino acids and prevents noncognate misincorporation.

Antioxidant responses related to temozolomide resistance in glioblastoma.

Glioblastoma remains one of the most challenging and devastating cancers, with only a very small proportion of patients achieving 5-year survival. The current standard of care consists of surgery, followed by radiation therapy with concurrent and maintenance chemotherapy with the alkylating agent temozolomide. To date, this drug is the only one that provides a significant survival benefit, albeit modest, as patients end up acquiring resistance to this drug. As a result, tumor progression and recurrence inevitably occur, leading to death. Several factors have been proposed to explain this resistance, including an upregulated antioxidant system to keep the elevated intracellular ROS levels, a hallmark of cancer cells, under control. In this review, we discuss the mechanisms of chemoresistance -including the important role of glioblastoma stem cells-with emphasis on antioxidant defenses and how agents that impair redox balance (i.e.: sulfasalazine, erastin, CB-839, withaferin, resveratrol, curcumin, chloroquine, and hydroxychloroquine) might be advantageous in combined therapies against this type of cancer.