Simpson-Golabi-Behmel syndrome.

The Simpson-Golabi-Behmel syndrome (SGBS; OMIM 312870) is an overgrowth/multiple congenital anomalies/dysplasia condition, inherited as an X-linked semi-dominant trait, with variable expressivity in males and reduced penetrance and expressivity in females. The clinical spectrum is broad, ranging from mild manifestations in both males and females to multiple malformations and neonatal death in the more severely affected cases. An increased risk of neoplasia is reported, requiring periodical surveillance. Intellectual development is normal in most cases. SGBS is caused by a loss-of-function mutation of the GPC3 gene, either deletions or point mutations, distributed all over the gene. Notably, GPC3 deletion/point mutations are not found in a significant proportion of clinically diagnosed SGBS cases. The protein product GPC3 is a glypican functioning as a receptor for Hh at the cell surface, involved in the Hh-Ptc-Smo signaling pathway, a regulator of cellular growth.

Personal journeys to and in human genetics and dysmorphology.

Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.

Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders.

Mitochondria are involved in multiple aspects of neurodevelopmental processes and play a major role in the pathogenetic mechanisms leading to neuro-degenerative diseases. Fragile-X-related disorders (FXDs) are genetic conditions that occur due to the dynamic expansion of CGG repeats of the FMR1 gene encoding for the RNA-binding protein FMRP, particularly expressed in the brain. This gene expansion can lead to premutation (PM, 56-200 CGGs), full mutation (FM, >200 CGGs), or unmethylated FM (UFM), resulting in neurodegeneration, neurodevelopmental disorders, or no apparent intellectual disability, respectively. To investigate the mitochondrial mechanisms that are involved in the FXD patients, we analyzed mitochondrial morphology and bioenergetics in fibroblasts derived from patients. Donut-shaped mitochondrial morphology and excessive synthesis of critical mitochondrial proteins were detected in FM, PM, and UFM cells. Analysis of mitochondrial oxidative phosphorylation in situ reveals lower respiration in PM fibroblasts. Importantly, mitochondrial permeability transition-dependent apoptosis is sensitized to reactive oxygen species in FM, PM, and UFM models. This study elucidated the mitochondrial mechanisms that are involved in the FXD phenotypes, and indicated altered mitochondrial function and morphology. Importantly, a sensitization to permeability transition and apoptosis was revealed in FXD cells. Overall, our data suggest that mitochondria are novel drug targets to relieve the FXD symptoms.

Absorption and Fluorescence Emission Investigations on Supramolecular Assemblies of Tetrakis-(4-sulfonatophenyl)porphyrin and Graphene Quantum Dots.

The one-pot synthesis of N-doped graphene quantum dots (GQDs), capped with a positively charged polyamine (trien), has been realized through a microwave-assisted pyrolysis on solid L-glutamic acid and trien in equimolar amounts. The resulting positively charged nanoparticles are strongly emissive in aqueous solutions and are stable for months. The interaction with the anionic tetrakis(4-sulphonatophenyl)porphyrin (TPPS4) has been investigated at neutral and mild acidic pH using a combination of UV/vis absorption spectroscopy together with static and time-resolved fluorescence emission. At pH = 7, the experimental evidence points to the formation of a supramolecular adduct mainly stabilized by electrostatic interactions. The fluorescence emission of the porphyrin is substantially quenched while GQDs remain still emissive. On decreasing the pH, protonation of TPPS4 leads to formation of porphyrin J-aggregates through the intermediacy of the charged quantum dots.

Deep Learning in Neovascular Age-Related Macular Degeneration.

Background and objectives: Age-related macular degeneration (AMD) is a complex and multifactorial condition that can lead to permanent vision loss once it progresses to the neovascular exudative stage. This review aims to summarize the use of deep learning in neovascular AMD. Materials and Methods: Pubmed search. Results: Deep learning has demonstrated effectiveness in analyzing structural OCT images in patients with neovascular AMD. This review outlines the role of deep learning in identifying and measuring biomarkers linked to an elevated risk of transitioning to the neovascular form of AMD. Additionally, deep learning techniques can quantify critical OCT features associated with neovascular AMD, which have prognostic implications for these patients. Incorporating deep learning into the assessment of neovascular AMD eyes holds promise for enhancing clinical management strategies for affected individuals. Conclusion: Several studies have demonstrated effectiveness of deep learning in assessing neovascular AMD patients and this has a promising role in the assessment of these patients.

Impact of soluble tumor necrosis factor-related apoptosis-inducing ligand released by engineered adipose mesenchymal stromal cells on white blood cells.

BACKGROUND AIMS: The proapoptotic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is physiologically expressed by immune cells and performs regulatory functions in infections, autoimmune diseases and cancer, where it acts as a tumor suppressor. Adipose-derived mesenchymal stromal cells (AD-MSCs) also may play immunomodulatory roles in both primary and acquired immune responses. We have previously demonstrated the efficacy of an anticancer gene therapy based on AD-MSC engineered to secrete a soluble TRAIL variant (sTRAIL) against pancreatic cancer. However, the impact of AD-MSC sTRAIL on leukocyte subsets has been not yet considered also to predict a possible immunotoxicity profile in the clinical translation of this cell-based anticancer strategy. METHODS: Monocytes, polymorphonuclear cells and T lymphocytes were freshly isolated from the peripheral blood of healthy donors. Immunophenotype and functional (DR4 and DR5) and decoy (DcR1 and DcR2) TRAIL receptors were tested by flow cytometry. The viability of white blood cells treated with sTRAIL released by gene-modified AD-MSC or co-cultured with AD-MSC sTRAIL was then evaluated by both metabolic assays and flow cytometry. In addition, cytokine profile in co-cultures was analyzed by multiplex enzyme-linked immunosorbent assay. RESULTS: Monocytes and polymorphonuclear cells showed high positivity for DR5 and DcR2, respectively, whereas T cells revealed negligible expression of all TRAIL receptors. Irrespective of TRAIL receptors' presence on the cell membrane, white blood cells were refractory to the proapoptotic effect displayed by sTRAIL secreted by gene-modified AD-MSC, and direct cell-to-cell contact with AD-MSC sTRAIL had negligible impact on T-cell and monocyte viability. Cytokine crosstalk involving interleukin 10, tumor necrosis factor alpha, and interferon gamma secreted by T lymphocytes and vascular endothelial growth factor A and interleukin 6 released by AD-MSC was highlighted in T-cell and AD-MSC sTRAIL co-cultures. CONCLUSIONS: In summary, this study demonstrates the immunological safety and thus the clinical feasibility of an anticancer approach based on AD-MSC expressing the proapoptotic molecule sTRAIL.

Ethanol-Gas-Sensing Performances of Built-in ZrO2/Co3O4 Hybrid Nanostructures.

The development of novel nanomaterials as highly efficient gas-sensing materials is envisaged as one of the most important routes in the field of gas-sensing research. However, developing stable, selective, and efficient materials for these purposes is a highly challenging task requiring numerous design attempts. In this work, a ZrO2/Co3O4 composite is reported, for the first time, as a gas-sensing material for the detection of ethanol. The sensitive and selective detection of ethanol gas at 200 °C has been demonstrated for the ZrO2/Co3O4 (0.20 wt%/0.20 wt%)-based sensor. Furthermore, the sensor showed a very low response/recovery time of 56 s and 363 s, respectively, in response to a pulse of 20 ppm of ethanol and good stability. The interesting gas-sensing property of ZrO2/Co3O4 can be ascribed to both the porous structure, which facilitates the interaction between the target gas and the sensing site, and the p-p-junction-induced built-in electric field. These results indicate that the ZrO2/Co3O4 composite can serve as a heterostructured nanomaterial for the detection of ethanol gas.

Dermatological manifestations, management, and care in RASopathies.

RASopathies are rare genetic disorders caused by germline pathogenic variants in genes belonging to the RAS/MAPK pathway, which signals cell proliferation, differentiation, survival and death. The dysfunction of such signaling pathway causes syndromes with overlapping clinical manifestations. Skin and adnexal lesions are the cardinal clinical signs of RASopathies, such as cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, formerly known as LEOPARD syndrome, Costello syndrome, neurofibromatosis (NF1), Legius syndrome, Noonan-like syndrome with loose anagen hair (NSLH) and Noonan syndrome. As NF1, one of the most common RASopathies, described in 1882, has its clinical features well delineated, we will focus on the dermatological diagnosis, management and care of non-NF1 RASopathies, which are less known and more recently described. Dermatological manifestations are important clinical diagnostic elements that can aid differential diagnosis among RASopathies. They can affect dermis and epidermis, causing pigmented lesions (melanocytic nevi, café-au-lait spots, and lentigines), hyperkeratosis (keratosis pilaris, ulerythema ophryogenes, and palmoplantar keratosis) or hyperplasia. To date there are rare known links to malignancy, but oftentimes skin lesions require close attention because they can highly affect quality of life.

Factors associated with the transition of adolescent inpatients from an intensive residential ward to adult mental health services.

Transition of young people from Child and Adolescent Mental Health Services (CAMHS) to Adult Mental Health Services (AMHS) is a complex process. Transition rates are heterogeneously reported, with wide definitions and ranges. Few data are available regarding predictive factors of a successful transition. We explored factors associated with transition in a cohort of former inpatients of a Children and Adolescents Intensive Treatment Ward (CAITW). Socio-demographic and clinical features of patients previously admitted to CAITW were matched to AMHS data for those patients having reached age requirements. We built multiple logistic regression models to identify factors associated with transfer to AMHS (either inpatient or outpatient) and with successful retention in treatment (RIT) at six (short RIT), 12 (intermediate RIT) and 24 months after transfer (long RIT). From a cohort of 322 inpatients, 126 reached the age threshold for transfer to AMHS in the study period. The transfer rate was 50%. Two years after transition-age boundary, CAMHS-AMHS continuity of care was found in 40% and disengagement in 6% of cases. Longer and multiple hospitalizations, atypical antipsychotics prescription and a diagnosis of psychotic disorders were factors associated with short and intermediate RIT. A positive psychiatric family history was negatively associated with successful short and intermediate RIT. Diagnosis of psychosis and learning-supported school attendance were associated with long RIT. Young adults with a history of psychiatric inpatient admission as children or adolescents have a relatively high rate of transition to AMHS. A diagnosis of psychosis seems to be the strongest predictor for transition in these patients. Further research should focus on patients' schooling needs and on children of parents with mental health problems to enhance family and educational system engagement.

Development of a Conductometric Sensor Based on Al,Ca-Doped ZnO for the Detection of Formaldehyde.

In the present study, the development of a conductometric gas sensor based on Al,Ca-doped zinc oxide composite which is finalized to the detection of formaldehyde (HCHO) at a low concentration in air is investigated. The electrical and sensing properties of the composite based on ZnO doped with different loadings of Al and/or Ca (from 0 up to 5 at%) were evaluated. The gas-sensing mechanism of Al,Ca-doped zinc oxide nanocomposite-based sensors was also discussed. The optimized 3%Al,3%Ca-ZnO sensor displayed a formaldehyde response of 3.5 (@ 4 ppm HCHO/air) and an experimental low detection limit of 125 ppb HCHO/air, at the operating temperature of 400 °C. The sensor was also shown to be selective to HCHO with respect to many interferent indoor gases, but NO2 changed the baseline resistance in an opposite way compared to the target gas. The developed device for monitoring HCHO in indoor and workplace environments has the advantage of a simple planar structure and can be easily fabricated for mass production by using low-cost materials and easy fabrication methods.

On the Electroanalytical Detection of Zn Ions by a Novel Schiff Base Ligand-SPCE Sensor.

A novel bidentate Schiff base (L) is here proposed for the detection of Zn ions in water. The structure of the synthesized Schiff base L was characterized by FT-IR, 1H NMR and 13C NMR. Optical characteristics were addressed by UV-Visible spectroscopy and Photoluminescence (PL) measurements. PL demonstrated that L displays a "turn-off" type fluorescence quenching in the presence of Zn2+ ion in aqueous solution, indicating its ability to preferentially coordinate this ion. Based on these findings, an L-M (where M is a suitable membrane) modified screen-printed carbon electrode (SPCE) was developed to evaluate the electrochemical behavior of the Schiff base (L) with the final objective of undertaking the electroanalytical determination of Zn ions in water. Using various electrochemical techniques, the modified L-M/SPCE sensor demonstrates high sensitivity and selectivity to Zn ions over some common interferents ions, such as Ca2+, Mg2+, K+, Ni++ and Cd++. The potentiometric response of the L-M/SPCE sensor to Zn ions was found to be linear over a relatively wide concentration range from 1 µM to 100 mM.

Dissecting Immunotherapy Strategies for Small Cell Lung Cancer: Antibodies, Ionizing Radiation and CAR-T.

Small cell lung cancer (SCLC) is a highly aggressive malignancy that accounts for about 14% of all lung cancers. Platinum-based chemotherapy has been the only available treatment for a long time, until the introduction of immune checkpoint inhibitors (ICIs) recently changed first-line standard of care and shed light on the pivotal role of the immune system. Despite improved survival in a subset of patients, a lot of them still do not benefit from first-line chemo-immunotherapy, and several studies are investigating whether different combination strategies (with both systemic and local treatments, such as radiotherapy) may improve patient outcomes. Moreover, research of biomarkers that may be used to predict patients' outcomes is ongoing. In addition to ICIs, immunotherapy offers other different strategies, including naked monoclonal antibodies targeting tumor associated antigens, conjugated antibody, bispecific antibodies and cellular therapies. In this review, we summarize the main evidence available about the use of immunotherapy in SCLC, the rationale behind combination strategies and the studies that are currently ongoing in this setting, in order to give the reader a clear and complete view of this rapidly expanding topic.

Overgrowth in myth and art.

Individuals with overgrowth have been the subjects of numerous myths and art pieces in various cultures, often depicted as deities or creatures of divine origin, such as giants or titans. In more recent times, however, subjects with signs of generalized or segmental overgrowth have been considered as "freaks of nature," in the disparaging language of the time, and represented in artworks as elements of entertainment or amusement. The different meanings assigned to overgrowth in myth and art through time provide an interesting perspective of the sociocultural approach to dysmorphic traits and genetic disorders.

The earliest depictions of a PIK3CA-Related Overgrowth Spectrum disorder: 17th-18th century prints of women with severe limb overgrowth.

We report two prints (a woodcut from the 17th century and an engraving from the 18th century) that likely show individuals with PIK3CA-Related Overgrowth Spectrum (PROS). These prints are likely the earliest known depictions of this complex condition.

Chromosome 14 deletions, rings, and epilepsy genes: A riddle wrapped in a mystery inside an enigma.

The ring 14 syndrome is a rare condition caused by the rearrangement of one chromosome 14 into a ring-like structure. The formation of the ring requires two breakpoints and loss of material from the short and long arms of the chromosome. Like many other chromosome syndromes, it is characterized by multiple congenital anomalies and developmental delays. Typical of the condition are retinal anomalies and drug-resistant epilepsy. These latter manifestations are not found in individuals who are carriers of comparable 14q deletions without formation of a ring (linear deletions). To find an explanation for this apparent discrepancy and gain insight into the mechanisms leading to seizures, we reviewed and compared literature cases of both ring and linear deletion syndrome with respect to both their clinical manifestations and the role and function of potentially epileptogenic genes. Knowledge of the epilepsy-related genes in chromosome 14 is an important premise for the search of new and effective drugs to combat seizures. Current clinical and molecular evidence is not sufficient to explain the known discrepancies between ring and linear deletions.

CNT/Al2O3 core-shell nanostructures for the electrochemical detection of dihydroxybenzene isomers.

We report CNT/Al2O3 core-shell nanostructures for the electrochemical detection of dihydroxybenzene (DHB) isomers. Amorphous films of Al2O3 (1.2-15.4 nm in thickness) are uniformly deposited onto the inner and outer walls of CNTs by atomic layer deposition. The effect of the Al2O3 shell thickness on the electrochemical detection of dihydroxybenzene isomers was explored using cyclic and square-wave voltammetry. The best sensing properties are found at a shell thickness of approx. 2.4 nm (CNT/Al2O3(9) sensor), where the oxidation peak currents (sensor-signal) increased ca. 10 times as compared to a sensor fabricated with non-coated CNTs. All of the three DHB isomers (hydroquinone, catechol and resorcinol) are independently detected in the concentration ranges of 2-1000 µmol L-1, 0.5-700 µmol L-1 and 3.5-500 µmol L-1, respectively. The sensors show reliable repeatability, reproducibility, long-term stability, and applicability in the analysis of real samples. Based on these findings, a plausible mechanism is proposed highlighting the role of the Al2O3-shell.

Fabrication of a Novel Electrochemical Sensor Based on Carbon Cloth Matrix Functionalized with MoO3 and 2D-MoS2 Layers for Riboflavin Determination.

The preparation and characterization of a hybrid composite, based on carbon cloth (CC) matrix functionalized with two-dimensional (2D) MoS2 flakes and MoO3, and its use for developing an electrochemical sensor for the determination of riboflavin (RF) is here reported. The 2D-MoS2-MoO3CC composite was prepared by depositing 2D-MoS2 nanosheets, obtained by liquid phase exfoliation (LPE), on the surface of a carbon cloth fiber network, previously functionalized with a layer of molybdenum oxide (α-MoO3) by radio-frequency magnetron reactive sputtering technique. The 2D-MoS2-MoO3CC composite was characterized by scanning electron microscopy and energy dispersive X-ray analysis (SEM-EDX), and Raman spectroscopy. An electrochemical sensor has been then fabricated by fixing a slice of the 2D-MoS2-MoO3CC composite on the working electrode of a screen-printed carbon electrode (SPCE). The 2D-MoS2-MoO3-CC/SPCE sensor display good electrochemical characteristics which have been exploited, for the first time, in the electroanalytical determination of riboflavin (RF). The sensitivity to RF, equal to 0.67 µA mM-1 in the linear range from 2 to 40 µM, and a limit of detection (LOD) of 1.5 µM at S/N = 3, demonstrate the promising characteristics of the proposed 2D-MoS2-MoO3-CC/SPCE electrochemical sensor for the determination of riboflavin.

Metal-Oxide Based Nanomaterials: Synthesis, Characterization and Their Applications in Electrical and Electrochemical Sensors.

Pure, mixed and doped metal oxides (MOX) have attracted great interest for the development of electrical and electrochemical sensors since they are cheaper, faster, easier to operate and capable of online analysis and real-time identification. This review focuses on highly sensitive chemoresistive type sensors based on doped-SnO2, RhO, ZnO-Ca, Smx-CoFe2-xO4 semiconductors used to detect toxic gases (H2, CO, NO2) and volatile organic compounds (VOCs) (e.g., acetone, ethanol) in monitoring of gaseous markers in the breath of patients with specific pathologies and for environmental pollution control. Interesting results about the monitoring of biochemical substances as dopamine, epinephrine, serotonin and glucose have been also reported using electrochemical sensors based on hybrid MOX nanocomposite modified glassy carbon and screen-printed carbon electrodes. The fundamental sensing mechanisms and commercial limitations of the MOX-based electrical and electrochemical sensors are discussed providing research directions to bridge the existing gap between new sensing concepts and real-world analytical applications.

LRG1 Expression Is Elevated in the Eyes of Patients with Neovascular Age-Related Macular Degeneration.

Leucine-rich a-2-glycoprotein 1 (LRG1) is a candidate therapeutic target for treating the neovascular form of age-related macular degeneration (nvAMD). In this study we examined the expression of LRG1 in eyes of nvAMD patients. Choroidal neovascular membranes (CNVMs) from patients who underwent submacular surgery for retinal pigment epithelium-choroid graft transplantation were collected from 5 nvAMD patients without any prior intravitreal anti-VEGF injection, and from six patients who received intravitreal anti-VEGF injections before surgery. As controls free of nvAMD, retina sections were obtained from the eyes resected from a patient with lacrimal sac tumor and from a patient with neuroblastoma. CNVMs were immunostained for CD34, LRG1, and α-smooth muscle actin (α-SMA). Aqueous humor samples were collected from 58 untreated-naïve nvAMD patients prior to the intravitreal injection of anti-VEGF and 51 age-matched cataract control patients, and LRG1 concentration was measured by ELISA. The level of LRG1 immunostaining is frequently high in both the endothelial cells of the blood vessels, and myofibroblasts in the surrounding tissue of CNVMs of treatment-naïve nvAMD patients. Furthermore, the average concentration of LRG1 was significantly higher in the aqueous humor of nvAMD patients than in controls. These observations provide a strong experimental basis and scientific rationale for the progression of a therapeutic anti-LRG1 monoclonal antibody into clinical trials with patients with nvAMD.

Altered mitochondrial function in cells carrying a premutation or unmethylated full mutation of the FMR1 gene.

Fragile X-related disorders are due to a dynamic mutation of the CGG repeat at the 5' UTR of the FMR1 gene, coding for the RNA-binding protein FMRP. As the CGG sequence expands from premutation (PM, 56-200 CGGs) to full mutation (> 200 CGGs), FMRP synthesis decreases until it is practically abolished in fragile X syndrome (FXS) patients, mainly due to FMR1 methylation. Cells from rare individuals with no intellectual disability and carriers of an unmethylated full mutation (UFM) produce slightly elevated levels of FMR1-mRNA and relatively low levels of FMRP, like in PM carriers. With the aim of clarifying how UFM cells differ from CTRL and FXS cells, a comparative proteomic approach was undertaken, from which emerged an overexpression of SOD2 in UFM cells, also confirmed in PM but not in FXS. The SOD2-mRNA bound to FMRP in UFM more than in the other cell types. The high SOD2 levels in UFM and PM cells correlated with lower levels of superoxide and reactive oxygen species (ROS), and with morphological anomalies and depolarization of the mitochondrial membrane detected through confocal microscopy. The same effect was observed in CTRL and FXS after treatment with MC2791, causing SOD2 overexpression. These mitochondrial phenotypes reverted after knock-down with siRNA against SOD2-mRNA and FMR1-mRNA in UFM and PM. Overall, these data suggest that in PM and UFM carriers, which have high levels of FMR1 transcription and may develop FXTAS, SOD2 overexpression helps to maintain low levels of both superoxide and ROS with signs of mitochondrial degradation.