C-H Functionalization-Enabled 11-Step Semisynthesis of (-)-Veragranine A and Characterization of Synthetic Analogs in Osteoarthritis-related Pain Treatment.

We report an efficient semisynthesis of the cholestane steroidal alkaloid (-)-veragranine A with a 6/6/6/5/6/6 hexacyclic ring system, eight stereocenters, and a unique C12-C23 linkage. Our synthesis features a Schönecker-Baran C-H oxidation at C12, a Suzuki-Miyaura cross-coupling to form the C12-C23 bond, and a hydrogen atom transfer (HAT)-initiated Minisci C-H cyclization to forge the C20-C22 bond with desired stereochemistry at C20. These enabling transformations significantly enhanced the overall synthetic efficiency and delivered (-)-veragranine A in 11 steps and over 200 mg from cheap and readily available dehydroepiandrosterone. In addition, this approach allowed flexible syntheses of novel synthetic analogs for biological evaluations in sensory neurons in vitro and in an in vivo model of arthritic pain, from which two novel lead compounds were identified for further development.

Evaluation of a novel phantom for the quality assurance of a six-degree-of-freedom couch 3D-printed at multiple centres.

This study aimed to validate a bespoke 3D-printed phantom for use in quality assurance (QA) of a 6 degrees-of-freedom (6DoF) treatment couch. A novel phantom design comprising a main body with internal cube structures, was fabricated at five centres using Polylactic Acid (PLA) material, with an additional phantom produced incorporating a PLA-stone hybrid material. Correctional setup shifts were determined using image registration by 3D-3D matching of high HU cube structures between obtained cone-beam computer tomography (CBCT) images to reference CTs, containing cubes with fabricated rotational offsets of 3.5°, 1.5° and -2.5° in rotation, pitch, and roll, respectively. Average rotational setup shifts were obtained for each phantom. The reproducibility of 3D-printing was probed by comparing the internal cube size as well as Hounsfield Units between each of the uniquely produced phantoms. For the five PLA phantoms, the average rot, pitch and roll correctional differences from the fabricated offsets were -0.3 ± 0.2°, -0.2 ± 0.5° and 0.2 ± 0.3° respectively, and for the PLA hybrid these differences were -0.09 ± 0.14°, 0.30 ± 0.00° and 0.03 ± 0.10°. There was found to be no statistically significant difference in average cube size between the five PLA printed phantoms, with the significant difference (P < 0.05) in HU of one phantom compared to the others attributed to setup choice and material density. This work demonstrated the capability producing a novel 3D-printed 6DoF couch QA phantom design, at multiple centres, with each unique model capable of sub-degree couch correction.

Misdiagnosis of persistent left superior vena cava with unroofed coronary sinus as a coronary sinus-type atrial septal defect.

Key Clinical Message: Awareness of persistent left superior vena cava (PLSVC) with unroofed coronary sinus is crucial. Pre- and perioperative evaluation of this association is necessary for surgical plan. Creating an intra-atrial tunnel to divert LSVC to right atrium without obstructing the mitral valve or the pulmonary veins is the safe surgical approach. Abstract: Unroofed coronary sinus syndrome is a rare congenital heart defect representing less than 1% of all atrial septal defect (ASD) types, and may be associated with persistent left superior vena cava (PLSVC) which may be missed during preoperative diagnosis. Herein, we present a case of a 2-year-old patient who underwent an operation for repair of a coronary sinus-type ASD; however, PLSVC was detected intraoperatively. An antra-atrial tunnel has created to divert the flow of PLSVC into the right atrium along with the repair of the ASD.

Brain insulin resistance as a mechanistic mediator links peripheral metabolic disorders with declining cognition.

BACKGROUND AND AIMS: Studies continue to investigate the underlying mechanism of the association between the increased risk of different types of cognitive decline and metabolic dysregulation. Brain insulin resistance (BIR) has been suggested to explain this association. The vital role of insulin in the body has been examined intensively and extensively; however, its role in the brain requires further investigation. Herein, we confined our focus to summarize the role of brain insulin signaling and the negative effect of dysmetabolism on insulin functioning in the brain. METHODS: Published scientific manuscripts between 1998 and 2020 that discussed the effect of selected metabolic disorder conditions such as obesity, type 2 diabetes mellitus (T2DM), and high-fat diet (HFD) on brain functions were reviewed. The main keywords used were insulin resistance, brain insulin resistance, obesity, T2DM, and cognition. RESULTS: Various metabolic disorders were linked to the increased risk of BIR, and was suggested to increase the probability of cognition impairment occurrence. Several proposed mechanisms explain this association among which insulin resistance and hyperinsulinemia were primary factors attributed to an increased risk of BIR among various metabolic disorders. CONCLUSIONS: Understanding the trajectory of the association between metabolic disorders and alternation in cognition status could expand our vision of those overlapping conditions and pave the road to both treatment and preventative strategies for cognitive disorders.

Risk of radiation-induced second malignant neoplasms from photon and proton radiotherapy in paediatric abdominal neuroblastoma.

BACKGROUND AND PURPOSE: State-of-the-art radiotherapy modalities have the potential of reducing late effects of treatment in childhood cancer survivors. Our aim was to investigate the carcinogenic risk associated with 3D conformal (photon) radiation (3D-CRT), intensity modulated arc therapy (IMAT) and pencil beam scanning proton therapy (PBS-PT) in the treatment of paediatric abdominal neuroblastoma. MATERIALS AND METHODS: The risk of radiation-induced second malignant neoplasm (SMN) was estimated using the concept of organ equivalent dose (OED) for eleven organs (lungs, rectum, colon, stomach, small intestine, liver, bladder, skin, central nervous system (CNS), bone, and soft tissues). The risk ratio (RR) between radiotherapy modalities and lifetime absolute risks (LAR) were reported for twenty abdominal neuroblastoma patients (median, 4y; range, 1-9y) historically treated with 3D-CRT that were also retrospectively replanned for IMAT and PBS-PT. RESULTS: The risk of SMN due to primary radiation was reduced in PBS-PT against 3D-CRT and IMAT for most patients and organs. The RR across all organs ranged from 0.38 ± 0.22 (bladder) to 0.98 ± 0.04 (CNS) between PBS-PT and IMAT, and 0.12 ± 0.06 (rectum and bladder) to 1.06 ± 0.43 (bone) between PBS-PT and 3D-CRT. The LAR for most organs was within 0.01-1% (except the colon) with a cumulative risk of 21 ± 13%, 35 ± 14% and 35 ± 16% for PBS-PT, IMAT and 3D-CRT, respectively. CONCLUSIONS: PBS-PT was associated with the lowest risk of radiation-induced SMN compared to IMAT and 3D-CRT in abdominal neuroblastoma treatment. Other clinical endpoints and plan robustness should also be considered for optimal plan selection.

Atlas construction and spatial normalisation to facilitate radiation-induced late effects research in childhood cancer.

Reducing radiation-induced side effects is one of the most important challenges in paediatric cancer treatment. Recently, there has been growing interest in using spatial normalisation to enable voxel-based analysis of radiation-induced toxicities in a variety of patient groups. The need to consider three-dimensional distribution of doses, rather than dose-volume histograms, is desirable but not yet explored in paediatric populations. In this paper, we investigate the feasibility of atlas construction and spatial normalisation in paediatric radiotherapy. We used planning computed tomography (CT) scans from twenty paediatric patients historically treated with craniospinal irradiation to generate a template CT that is suitable for spatial normalisation. This childhood cancer population representative template was constructed using groupwise image registration. An independent set of 53 subjects from a variety of childhood malignancies was then used to assess the quality of the propagation of new subjects to this common reference space using deformable image registration (i.e. spatial normalisation). The method was evaluated in terms of overall image similarity metrics, contour similarity and preservation of dose-volume properties. After spatial normalisation, we report a dice similarity coefficient of 0.95 ± 0.05, 0.85 ± 0.04, 0.96 ± 0.01, 0.91 ± 0.03, 0.83 ± 0.06 and 0.65 ± 0.16 for brain and spinal canal, ocular globes, lungs, liver, kidneys and bladder. We then demonstrated the potential advantages of an atlas-based approach to study the risk of second malignant neoplasms after radiotherapy. Our findings indicate satisfactory mapping between a heterogeneous group of patients and the template CT. The poorest performance was for organs in the abdominal and pelvic region, likely due to respiratory and physiological motion and to the highly deformable nature of abdominal organs. More specialised algorithms should be explored in the future to improve mapping in these regions. This study is the first step toward voxel-based analysis in radiation-induced toxicities following paediatric radiotherapy.

Electromagnetic Field in Alzheimer's Disease: A Literature Review of Recent Preclinical and Clinical Studies.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive loss of neurons leading to cognitive and memory decay. The main signs of AD include the irregular extracellular accumulation of amyloid-beta (Aß) protein in the brain and the hyper-phosphorylation of tau protein inside neurons. Changes in Aß expression or aggregation are considered key factors in the pathophysiology of sporadic and early-onset AD and correlate with the cognitive decline seen in patients with AD. Despite decades of research, current approaches in the treatment of AD are only symptomatic in nature and are not effective in slowing or reversing the course of the disease. Encouragingly, recent evidence revealed that exposure to electromagnetic fields (EMF) can delay the development of AD and improve memory. This review paper discusses findings from in vitro and in vivo studies that investigate the link between EMF and AD at the cellular and behavioural level, and highlights the potential benefits of EMF as an innovative approach for the treatment of AD.

Radiobiological Implications of Nanoparticles Following Radiation Treatment.

Materials with a high atomic number (Z) are shown to cause an increase in the level of cell kill by ionizing radiation when introduced into tumor cells. This study uses in vitro experiments to investigate the differences in radiosensitization between two cell lines (MCF-7 and U87) and three commercially available nanoparticles (gold, gadolinium, and iron oxide) irradiated by 6 MV X-rays. To assess cell survival, clonogenic assays are carried out for all variables considered, with a concentration of 0.5 mg mL-1 for each nanoparticle material used. This study demonstrates differences in cell survival between nanoparticles and cell line. U87 shows the greatest enhancement with gadolinium nanoparticles (2.02 ± 0.36), whereas MCF-7 cells have higher enhancement with gold nanoparticles (1.74 ± 0.08). Mass spectrometry, however, shows highest elemental uptake with iron oxide and U87 cells with 4.95 ± 0.82 pg of iron oxide per cell. A complex relationship between cellular elemental uptake is demonstrated, highlighting an inverse correlation with the enhancement, but a positive relation with DNA damage when comparing the same nanoparticle between the two cell lines.

Recommendations for clinical translation of nanoparticle-enhanced radiotherapy.

A multi-disciplinary cooperative for nanoparticle-enhanced radiotherapy (NERT) has been formed to review the current status of the field and identify key stages towards translation. Supported by the Colorectal Cancer Healthcare Technologies Cooperative, the cooperative comprises a diverse cohort of key contributors along the translation pathway including academics of physics, cancer and radio-biology, chemistry, nanotechnology and clinical trials, clinicians, manufacturers, industry, standards laboratories, policy makers and patients. Our aim was to leverage our combined expertise to devise solutions towards a roadmap for translation and commercialisation of NERT, in order to focus research in the direction of clinical implementation, and streamline the critical pathway from basic science to the clinic. A recent meeting of the group identified barriers to and strategies for accelerated clinical translation. This commentary reports the cooperative's recommendations. Particular emphasis was given to more standardised and cohesive research methods, models and outputs, and reprioritised research drivers including patient quality of life following treatment. Nanoparticle design criteria were outlined to incorporate scalability of manufacture, understanding and optimisation of biological mechanisms of enhancement and in vivo fate of nanoparticles, as well as existing design criteria for physical and chemical enhancement. In addition, the group aims to establish a long-term and widespread international community to disseminate key findings and create a much-needed cohesive body of evidence necessary for commercial and clinical translation.

Thinking about brain insulin resistance.

INTRODUCTION: Dementia and type 2 diabetes mellitus (T2DM) are two of the epidemics of our time; in which insulin resistance (IR) is playing the central role. Epidemiological studies found that different types of dementia development may be promoted by the presence of T2DM. OBJECTIVES: We aimed in this review to highlight the role of insulin and the IR in the brain as a pathophysiological factor of dementia development and also to expand our understanding of T2DM as a mediator of IR in the brain and to review the possible mechanisms of action that may explain the association. METHODOLOGY: A critical review of the relevant published English articles up to 2018, using PubMed, Google Scholar, Science Direct, ADI, and WHO database was carried out. Keywords were included insulin resistance, T3DM, T2DM, dementia, brain insulin resistance were used. CONCLUSION: The rapidly increased prevalence of dementia concurrently with T2DM and obesity need urgent action to illustrate guidelines for prevention, modifying, and treatment based on mechanistic studies.

Association between complement component C3 and body composition: a possible obesity inflammatory biomarker for insulin resistance.

BACKGROUND AND OBJECTIVES: The C3 complement component (C3) is increasingly recognized as a cardiometabolic risk factor. We aimed to examine the role of C3 in insulin resistance (IR) and its association with adiposity. METHODS AND STUDY DESIGN: Sixty-seven obese (18-35 years) participants were matched with normal weight participants from the University of Jordan. BMI, waist-hip ratio (WHpR), and waist-height ratio (WHtR) were calculated. Body percent fat mass (%FM) was determined using the bioelectrical impedance analysis. C3, insulin, and glucose serum concentrations were measured. IR was assessed by the homeostasis model assessment of IR (HOMA-IR). RESULTS: Serum concentrations of C3 and IR were significantly higher in the obese group than that in the normal body weight, regardless of gender (women: 1.2±0.08 and men: 1.2±0.08 vs women: 0.88±0.07 and men: 0.94±0.05, p<0.01; women: 3.6±0.34 and men: 3.9±0.43 vs women: 1.7±0.12 and men: 2.0±0.24, respectively; p<0.001). After adjustment for the potential confounders, BMI, waist circumference, WHtR and %FM were correlated positively with C3 (r=0.44; 0.42; 0.47; 0.43, respectively; p<0.001), and with IR (r=0.67; 0.61; 0.59; 0.59, respectively; p<0.001). C3 was correlated with IR (r=0.35, p<0.001). In linear regression analysis, C3 was not associated with IR independent of BMI (p>0.05). CONCLUSIONS: C3 may be a marker of chronic inflammatory process independently underlying IR obese individuals regardless of gender, which may have a role in the progression of IR during obesity.

Vitamin D Insufficiency Predicts Elevated Levels of Complement 3 Independent of Insulin Resistance and BMI.

This study was to determine serum 25-hydroxyvitamin D (25(OH)D), the complement 3 (C3), and C-reactive protein (CRP) levels, and their association with the risk of insulin resistance (IR). A case-control study was carried out among 134 participants with body mass index (BMI) ≥30 kg/m2 and BMI=18.5-24.99 kg/m2. Anthropometric and body composition indicators were measured. Serum levels of C3, CRP, 25(OH)D, insulin, and glucose were also measured. IR was assessed by the homeostasis model assessment (HOMA-IR). C3, CRP, insulin, and HOMA-IR levels were higher in participants with obesity than that of controls (p<0.001). After adjustment for the potential confounders, anthropometric and body composition indicators were correlated positively with C3 (p<0.001), and negatively with 25(OH)D (p<0.05). C3, and 25(OH)D were correlated with HOMA-IR (r=0.350; r=-0.212; p<0.05). In logistic regression analyses, C3 and CRP were significantly related to increased odds of IR among participants with obesity as compared to controls after progressively adjusting for the potential confounders (p<0.001), whereas 25(OH)D was negatively, but insignificantly, related to decreased odds of IR among participants with obesity (p>0.05). C3 was associated positively with 25(OH)D insufficiency/deficiency independent of HOMA-IR and/or BMI (ß=0.183, p<0.05). Obesity is associated with elevated levels of proinflammatory biomarkers and IR. 25(OH)D insufficiency/deficiency was associated with C3 regardless of HOMA-IR or BMI, which could in turn, have a role in the augmentation of IR during obesity.

Complement 3 serum levels as a pro-inflammatory biomarker for insulin resistance in obesity.

INTRODUCTION: Obesity is frequently characterized by chronic inflammation and insulin resistance (IR). Obesity-associated inflammation is responsible for the complement system activation of which the third component (C3) plays the central role. OBJECTIVE: to discuss several aspects of the central component of the complement system in relation to obesity and obesity-associated IR. METHODS: A critical review of the relevant published English articles from 2003- 2014 was carried out using several search engines including PubMed, Google Scholar, and ScienceDirect. Keywords were used, including complement system, C3, obesity-induced inflammation, IR, ASP, and adipose tissue. CONCLUSION: The defect in the adipose tissue secretory function during obesity may result in different metabolic disorders including IR. The C3 role during obesity-associated inflammation in IR is emerging. More longitudinal studies are warranted to evaluate the role of C3 among other pro-inflammatory biomarkers for IR.