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We chose the "natural laboratory" provided by high-altitude native ethnic Tibetan women who had completed childbearing to examine the hypothesis that multiple oxygen delivery traits were associated with lifetime reproductive success and had genomic associations. Four hundred seventeen (417) women aged 46 to 86 y residing at ≥3,500 m in Upper Mustang, Nepal, provided information on reproductive histories, sociocultural factors, physiological measurements, and DNA samples for this observational cohort study. Simultaneously assessing multiple traits identified combinations associated with lifetime reproductive success measured as the number of livebirths. Women with the most livebirths had distinctive hematological and cardiovascular traits. A hemoglobin concentration near the sample mode and a high percent of oxygen saturation of hemoglobin raised arterial oxygen concentration without risking elevated blood viscosity. We propose ongoing stabilizing selection on hemoglobin concentration because extreme values predicted fewer livebirths and directional selection favoring higher oxygen saturation because higher values had more predicted livebirths. EPAS1, an oxygen homeostasis locus with strong signals of positive natural selection and a high frequency of variants occurring only among populations indigenous to the Tibetan Plateau, associated with hemoglobin concentration. High blood flow into the lungs, wide left ventricles, and low hypoxic heart rate responses aided effective convective oxygen transport to tissues. Women with physiologies closer to unstressed, low altitude values had the highest lifetime reproductive success. This example of ethnic Tibetan women residing at high altitudes in Nepal links reproductive fitness with trait combinations increasing oxygen delivery under severe hypoxic stress and demonstrates ongoing natural selection., Competing Interests: Competing interests statement:The authors declare no competing interest.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disorder with two main subtypes: ulcerative colitis (UC) and Crohn's disease (CD). The pathogenesis involves genetic predisposition, dysbiosis, and immune dysregulation. Complications include perianal lesions, strictures, fistulas, perforations, and an increased risk of colon cancer. Clinical classification ranges from mild to fulminant and recurrent disease, with common symptoms such as abdominal discomfort, rectal bleeding, diarrhea, and weight loss. Extraintestinal manifestations include arthritis, erythema nodosum, pyoderma gangrenosum, and uveitis. Conventional treatments using aminosalicylates, corticosteroids, and immunomodulators have limitations. Biologics, introduced in the 1990s, offer improved efficacy and specificity, targeting factors like TNF-α, integrins, and cytokines. Monoclonal antibodies play a crucial role in IBD management, aiming to reduce relapses, hospitalizations, and surgeries. In conclusion, this review is aimed at summarizing the latest knowledge, advantages, and drawbacks of IBD therapies, such as small molecules, biologics, and monoclonal antibodies, to provide a basis for further research in the IBD field.

Introduction: Since the initial identification of Miller Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis (BBE),significant milestones have been achieved in understanding these diseases.Discoveries of common serum antibodies (IgG anti-GQ1b), antecedent infections, neurophysiological data, andneuroimaging suggested a shared autoimmune pathogenetic mechanism rather than distinct pathogenesis, leadingto the hypothesis that both diseases are part of a unified syndrome, termed "Fisher-Bickerstaff syndrome". The subsequent identification of atypical anti-GQ1b-positive forms expanded the classification to a broader condition known as "Anti-GQ1b-Antibody syndrome"., Methods: An exhaustive literature review was conducted, analyzing a substantial body of research spanning from the initialdescriptions of the syndrome's components to recent developments in diagnostic classification and researchperspectives., Results: Anti-GQ1b syndrome encompasses a continuous spectrum of conditions defined by a common serological profilewith varying degrees of peripheral (PNS) and central nervous system (CNS) involvement. MFS and BBE represent theopposite ends of this spectrum, with MFS primarily affecting the PNS and BBE predominantly involving the CNS.Recently identified atypical forms, such as acute ophthalmoparesis, acute ataxic neuropathy withoutophthalmoparesis, Guillain-Barré syndrome (GBS) with ophthalmoparesis, MFS-GBS and BBE-GBS overlap syndromes,have broadened this spectrum., Conclusion: This work aims to provide an extensive, detailed, and updated overview of all aspects of the anti-GQ1b syndromewith the intention of serving as a stepping stone for further shaping thereof. Special attention was given to therecently identified atypical forms, underscoring their significance in redefining the boundaries of the syndrome., (© 2024. Fondazione Società Italiana di Neurologia.)

Objectives: The aim of this study was to explore the effectiveness of a less-invasive posterior spine decompression in complex deformities. We studied the potential advantages of the microendoscopic approach, supplemented by the piezoelectric technique, to decompress both sides of the vertebral canal from a one-sided approach to preserve spine stability, ensuring adequate neural decompression., Methods: A series of 32 patients who underwent a tailored stability-preserving microendoscopic decompression for lumbar spine degenerative disease was retrospectively analyzed. The patients underwent selective bilateral decompression via a monolateral approach, without the skeletonization of the opposite side. For omo- and the contralateral decompression, we used a microscopic endoscopy-assisted approach, with the assistance of piezosurgery, to work safely near the exposed dura mater. Piezoelectric osteotomy is extremely effective in bone removal while sparing soft tissues., Results: In all patients, adequate decompression was achieved with a high rate of spine stability preservation. The approach was essential in minimizing the opening, therefore reducing the risk of spine instability. Piezoelectric osteotomy was useful to safely perform the undercutting of the base of the spinous process for better contralateral vision and decompression without damaging the exposed dura. In all patients, a various degree of neurologic improvement was observed, with no immediate spine decompensation., Conclusions: In selected cases, the tailored microendoscopic monolateral approach for bilateral spine decompression with the assistance of piezosurgery is adequate and safe and shows excellent results in terms of spine decompression and stability preservation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Brain metastases (BMs) represent the most frequent brain tumors in adults. The identification of key prognostic factors is essential for choosing the therapeutic strategy tailored to each patient. Epilepsy can precede several months of other clinical presentations of BMs. This work aimed to study the impact of epilepsy and other prognostic factors on BMs patients' survival., Methods: This retrospective study included 51 patients diagnosed with BMs and who underwent neurosurgery between 2010 and 2021. The impact of BM features and patient's clinical characteristics on the overall survival (OS) was analyzed through uni- and multivariate analysis., Results: The average OS was 25.98 months and differed according to the histology of the primary tumor. The primary tumor localization and the presence of extracranial metastases had a statistically significant impact on the OS, and patients with single BM showed a superior OS to those with multifocal lesions. The localization of BMs in the temporal lobe correlated with the highest OS. The OS was significantly higher in patients who presented seizures in their clinical onset and in those who had better post-surgical Karnofsky performance status, no post-surgical complications, and who underwent post-surgical treatment., Conclusion: Our study has highlighted prognostically favorable patient and tumor factors. Among those, a clinical onset with epileptic seizures can help identify brain metastasis hitherto silent. This could lead to immediate diagnostic-therapeutic interventions with more aggressive therapies after appropriate multidisciplinary evaluation., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Surgical Neurology International.)

Background: Bone flap resorption is a known complication of postdecompressive autologous cranioplasty. Although several potential etiopathogenetic factors have been investigated, their role is still under discussion. To further complicate things, resorption is not an all-or-nothing event, patients frequently presenting with different degrees of flap remodeling. Focus of this paper was to describe the elaboration of a score quantifying bone resorption according to a set of clinical and radiological criteria, hopefully allowing prompt identification of patients needing resurgery before the development of adverse events., Methods: In a 10-year period, 281 autologous cranioplasties were performed at our institution following decompressive craniectomy. Pertinent clinical and radiological information was registered. A set of 3 clinical and 3 radiological parameters was established to score the degree of resorption, identified under the acronym FIS (Flap Integrity Score). Three groups of patients emerged, respectively showing no (208), partial (32), and advanced (41) resorption., Results: An overall 14.6% incidence of advanced bone resorption was found in our series. Younger age, bone multifragmentation, higher postcranioplasty Glasgow Outcome Scale scores, <2 cm distance of medial craniectomy border from the midline, and cause leading to decompressive craniectomy were associated to a statistically significant higher risk of developing a relevant bone flap resorption. The first three variables were confirmed as risk factors in multivariate analysis. Flap Integrity Score well discriminated the 3 different groups., Conclusions: Autologous bone repositioning is still a valuable, low-cost, cosmetically and functionally satisfactory procedure. Nonetheless, although resorption affects a minor percentage of patients, its early identification and treatment can improve long-term results., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Glioblastoma multiforme (GBM) is probably the most malignant and aggressive brain tumor belonging to the class of astrocytomas. The considerable aggressiveness and high malignancy of GBM make it a tumor that is difficult to treat. Here, we report the synthesis and biological evaluation of eighteen novel cinnamoyl derivatives (3a-i and 4a-i) to obtain more effective antitumor agents against GBM., Methods: The chemical structures of novel cinnamoyl derivatives (3a-i and 4a-i) were confirmed by NMR and MS analyses. The physicochemical properties and evaluation of the ADME profile of 3a-i and 4a-i were performed by the preADMETlab2.0 web program. Cinnamoyl derivatives 3a-i and 4a-i were tested in vitro for their cytotoxicity against the human healthy fibroblast (HDFa) cells using an MTT cell viability assay. Derivatives with no toxicity on HDFa cells were tested both on human glioblastoma (U87MG) and neuroblastoma (SHSY- 5Y) cells, chosen as an experimental model of brain tumors. Cell death mechanisms were analyzed by performing flow cytometry analyses., Results: Cinnamoyl derivatives 3a-i and 4a-i showed good physicochemical and ADME properties suggesting that these compounds could be developed as oral drugs endowed with a high capability to cross the blood-brain barrier. Compounds (E)-1-methoxy-4-(2-(phenylsulfonyl)vinyl)benzene (2c) and (E)-N-benzyl-N-(2- (cyclohexylamino)-2-oxoethyl)-3-(3,4,5-trimethoxyphenyl)acrylamide (3e) did not show cytotoxicity on healthy human fibroblast cells up to 100 μg/mL. The most anticarcinogenic molecule, compound 3e, emerged as the most potent anticancer candidate in this study. Flow cytometry results showed that compound 3e (25 μg/mL) application resulted in nearly 86% and 84% cytotoxicity in the U87MG and the SHSY-5Y cell lines, respectively. Compound 2c (25 μg/mL) resulted in 81% and 82% cytotoxicity in the U87MG and the SHSY-5Y cell lines, respectively., Conclusion: Cinnamoyl derivative 3e inhibits the proliferation of cultured U87MG and SHSY-5Y cells by inducing apoptosis. Further detailed research will be conducted to confirm these data in in vivo experimental animal models., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Summary: Background. International guidelines suggested skin tests with Polyethylene-glycol (PEG) and polysorbate 80 (PS-80), to investigate a possible hypersensitivity to these excipients either to identify subjects at risk of developing allergic reactions to Covid-19 vaccines, or in patients with suspected IgE mediated hypersensitivity reactions (HR) to the Covid-19 vaccine. The main purpose of this study was to investigate the prevalence of PEG and PS sensitization in patients with a clinical history of HR to drugs containing PEG/PS and in patients with a suspected Covid-19 vaccine immediate HR. Methods. This was a multicenter retrospective study conducted by allergists belonging to 20 Italian medical centers. Skin testing was performed in 531 patients with either a clinical history of suspected hypersensitivity reaction (HR) to drugs containing PEG and/or PS-80 (group 1:362 patient) or a suspected HR to Covid-19 vaccines (group 2: 169 patient), as suggested by the AAIITO/SIAAIC guidelines for the "management of patients at risk of allergic reactions to Covid-19 vaccines" [1]. Results. 10/362 (0.02%) had positive skin test to one or both excipients in group 1, 12/169 (7.1%) in group 2 (p less than 0.01). In group 2 HRs to Covid-19 vaccines were immediate in 10/12 of cases and anaphylaxis occurred in 4/12 of patients. Conclusions. The positivity of skin test with PEG and or PS before vaccination is extremely rare and mostly replaceable by an accurate clinical history. Sensitization to PEG and PS has to be investigated in patients with a previous immediate HR to a Covid-19 vaccine, in particular in patients with anaphylaxis.

Background: The global health pandemic has affected the increasing older adult population, especially those with mental illnesses. It is necessary to prevent cases of cognitive impairment in adults early on, and this requires the support of information and communication technologies for evaluating and training cognitive functions. This can be achieved through computer applications designed for cognitive assessment., Objective: In this review, we aimed to assess the state of the art of the current platforms and digital test applications for cognitive evaluation, with a focus on older adults., Methods: A systematic literature search was conducted on 3 databases (Web of Science, PubMed, and Scopus) to retrieve recent articles on the applications of digital tests for cognitive assessment and analyze them based on the methodology used. Four research questions were considered. Through the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology, following the application of inclusion and exclusion criteria, a total of 20 articles were finally reviewed., Results: Some gaps and trends were identified regarding the types of digital applications and technologies used, the evaluated effects on cognitive domains, and the psychometric parameters and personal characteristics considered for validation., Conclusions: Computerized tests (similar to paper-and-pencil tests) and test batteries (on computers, tablets, or web platforms) were the predominant types of assessments. Initial studies with simulators, virtual environments, and daily-life activity games were also conducted. Diverse validation methods and psychometric properties were observed; however, there was a lack of evaluations that involved specific populations with diverse education levels, cultures, and degrees of technology acceptance. In addition, these evaluations should consider emotional and usability aspects., (©Claudio Cubillos, Antonio Rienzo. Originally published in JMIR Mental Health (https://mental.jmir.org), 08.12.2023.)

Background: Decompressive craniectomy (DC) is still controversial in neurosurgery. According to the most recent trials, DC seems to increase survival in case of refractory intracranial pressure. On the other hand, the risk of postsurgical poor outcomes remain high. The present study aimed to evaluate a series of preoperative factors potentially impacting on long-term follow-up of traumatic brain injury (TBI) patients treated with DC., Methods: We analyzed the first follow-up year of a series of 75 TBI patients treated with DC at our department in five years (2015-2019). Demographic, clinical, and radiological parameters were retrospectively collected from clinical records. Blood examinations were analyzed to calculate the preoperative neutrophil-to-lymphocyte ratio (NLR). Disability rating scale (DRS) was used to classify patients' outcomes (good outcome [G.O.] if DRS ≤11 and poor outcome [P.O.] if DRS ≥12) at 6 and 12 months., Results: At six months follow-up, 25 out of 75 patients had DRS ≤11, while at 12 months, 30 out of 75 patients were included in the G.O. group . Admission Glasgow Coma Scale (GCS) >8 was significantly associated with six months G.O. Increased NLR values and the interval between DC and cranioplasty >3 months were significantly correlated to a P.O. at 6- and 12-month follow-up., Conclusion: Since DC still represents a controversial therapeutic strategy, selecting parameters to help stratify TBI patients' potential outcomes is paramount. GCS at admission, the interval between DC and cranioplasty, and preoperative NLR values seem to correlate with the long-term outcome., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Surgical Neurology International.)

Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simultaneous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands σR/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (K i σ 1 R = 38 ± 3.7; K i σ 2 R = 2917 ± 769 and HDACs IC 50  = 0.59 µM) is the most promising candidate as an antiproliferative agent with an IC 50 of 0.9 µM on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over σ 1 R and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

In this study, combining the thiazole and cinnamoyl groups into the styryl-thiazole scaffold, a series of novel styryl-thiazole hybrids (6a-p) was rationally designed, synthesized, and evaluated by the multi-target-directed ligands strategy as potential candidates for the treatment of Alzheimer's disease (AD). Hybrids 6e and 6i are the most promising among the synthesized hybrids since they are able to significantly increase cell viabilities in Aβ 1-42 -exposed-human neuroblastoma cell line (6i at the concentration of 50 μg mL -1 and 6e at the concentration of 25 μg mL -1 resulted in ∼34% and ∼30% increase in cell viabilities, respectively). Compounds 6e and 6i exhibit highly AChE inhibitory properties in the experimental AD model at 375.6 ± 18.425 mU mL -1 and 397.6 ± 32.152 mU mL -1 , respectively. Moreover, these data were also confirmed by docking studies and in vitro enzyme inhibition assays. Compared to hybrid 6e and according to the results, 6i also has the highest potential against Aβ 1-42 aggregation with over 80% preventive activity. The in silico prediction of the physicochemical properties confirms that 6i possesses a better profile compared to 6e. Therefore, compound 6i presents a promising multi-targeted active molecular profile for treating AD considering the multifactorial nature of AD, and it is reasonable to deepen its mechanisms of action in an in vivo experimental model of AD., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Ventricular walls penetration frequently occurs in periventricular gliomas surgery. Even when aimed at maximal tumor resection, it can lead to several complications, including CSF leak, delayed wound healing and, potentially, distant tumor dissemination, with a negative impact on overall survival. Several authors have claimed damaged ventricular walls always need repair, especially when the additional use of intrathecal chemotherapy is scheduled. Fibrin sponge has been consistently used in the past to address small ventricular walls defects but more recently attention has been focused on TachoSilTM, that seems to be a valid alternative to close up to 1.5 cm gaps. After an accurate review of literature, we were unable to find any report describing the use of autologous pericranium to the same aim. We report the case of a 54 years-old patient who presented with symptoms of intracranial hypotension four weeks after his last surgery (performed at another Institution) for a relapsing right frontal grade III astrocytoma,. Pre-operative MRI showed a huge gap in the roof of the right frontal ventricular horn, associated to a large subdural hygroma and a massive subcutaneous CSF collection. The gap was repaired using a layer of autologous pericranium, sutured by pial stitches to the surrounding brain and reinforced by fibrin glue. Full and permanent leak sealing was obtained within the next 2 weeks, but patient immediately and fully recovered from his symptoms. Although limited by the single case experience, we believe that pericranium might be considered as an alternative to artificial materials in cases of large ventricular walls openings, being easily intraoperatively retrievable, granting maximal biocompatibility, not significantly impacting on surgery duration and overall costs.

Background: Ventriculoperitoneal (VP) shunt exposure is rare. Small series reporting on managing this complication mainly focus on the pediatric population, where wound breaks over cerebrospinal fluid (CSF) chambers are observed most frequently. However, case series on adult patients are missing., Methods: Between June 2004 and December 2019, 18 patients underwent VP shunt revision due to implant exposure. Pertinent data were retrospectively collected from the hospital database. Their full clinical history, laboratory values, neuroradiological imaging, pretreatment CSF characteristics, photographic and video material, and surgery types were reviewed., Results: The ventricular catheter was exposed in 8 patients (the frontal region in 6 and the occipital region in 2), the valve chamber at the retroauricular region in 6, the shunt tube in 7 (at the neck in 4, the supraclavicular region in 2, and the abdominal incision in 1). Multiple exposure sites were found in 2 cases. Two patients with CSF infections benefitted from system removal and temporary external ventricular drainage until infection control was achieved. The remaining 16 patients underwent on-ward revision (wound curettage, skin mobilisation, and resuture over the exposed part of the shunt), which was effective in 14 patients, but further revision was required in 2 patients., Conclusions: While rare, VP shunt exposure is a serious complication. In our experience, a prompt and accurate on-ward revision could save the implant in most patients without CSF infections., (Copyright © 2023 Elsevier Inc. All rights reserved.)

(1) Background: Obesity, a complex metabolic disease resulting from an imbalance between food consumption and energy expenditure, leads to an increase in adipocytes and chronic inflammatory conditions. The aim of this paper was to synthesize a small series of carvacrol derivatives ( CD1-3 ) that are able to reduce both adipogenesis and the inflammatory status often associated with the progression of the obesity disease. (2) Methods: The synthesis of CD1-3 was performed using classical procedures in a solution phase. Biological studies were performed on three cell lines: 3T3-L1, WJ-MSCs, and THP-1. The anti-adipogenic properties of CD1-3 were evaluated using western blotting and densitometric analysis by assessing the expression of obesity-related proteins, such as ChREBP. The anti-inflammatory effect was estimated by measuring the reduction in TNF-α expression in CD1-3 -treated THP-1 cells. (3) Results: CD1-3 -obtained through a direct linkage between the carboxylic moiety of anti-inflammatory drugs (Ibuprofen, Flurbiprofen, and Naproxen) and the hydroxyl group of carvacrol-have an inhibitory effect on the accumulation of lipids in both 3T3-L1 and WJ-MSCs cell cultures and an anti-inflammatory effect by reducing TNF- α levels in THP-1 cells. (4) Conclusions: Considering the physicochemical properties, stability, and biological data, the CD3 derivative-obtained by a direct linkage between carvacrol and naproxen-resulted in the best candidate, displaying anti-obesity and anti-inflammatory effects in vitro.

Recently, there has been an increasing interest in finding new approaches to manage oral wound healing. Although resveratrol (RSV) exhibited many biological properties, such as antioxidant and anti-inflammatory activities, its use as a drug is limited by unfavorable bioavailability. This study aimed to investigate a series of RSV derivatives ( 1a - j ) with better pharmacokinetic profiles. At first, their cytocompatibility at different concentrations was tested on gingival fibroblasts (HGFs). Among them, derivatives 1d and 1h significantly increased cell viability compared to the reference compound RSV. Thus, 1d and 1h were investigated for cytotoxicity, proliferation, and gene expression in HGFs, endothelial cells (HUVECs), and oral osteoblasts (HOBs), which are the main cells involved in oral wound healing. For HUVECs and HGFs, the morphology was also evaluated, while for HOBs ALP and mineralization were observed. The results showed that both 1d and 1h did not exert negative effects on cell viability, and at a lower concentration (5 µM) both even significantly enhanced the proliferative rate, compared to RSV. The morphology observations pointed out that the density of HUVECs and HGFs was promoted by 1d and 1h (5 µM) and mineralization was promoted in HOBs. Moreover, 1d and 1h (5 µM) induced a higher eNOS mRNA level in HUVECs, higher COL1 mRNA in HGFs, and higher OCN in HOBs, compared to RSV. The appreciable physicochemical properties and good enzymatic and chemical stability of 1d and 1h , along with their promising biological properties, provide the scientific basis for further studies leading to the development of RSV-based agents useful in oral tissue repair.

Pancreatic cancer (PC) is one of the deadliest malignancies, with an increasing incidence and limited response to current therapeutic options. Therefore, more effective and low-toxic agents are needed to improve PC patients' outcomes. Resveratrol (RSV) is a natural polyphenol with multiple biological properties, including anticancer effects. In this study, we explored the antiproliferative activities of newly synthetized RSV analogues in a panel of PC cell lines and evaluated the physicochemical properties of the most active compound. This derivative exhibited marked antiproliferative effects in PC cells through mechanisms involving DNA damage, apoptosis induction, and interference in cell cycle progression, as assessed using flow cytometry and immunoblot analysis of cell cycle proteins, PARP cleavage, and H2AX phosphorylation. Notably, the compound induced a consistent reduction in the PC cell subpopulation with a CD133 + EpCAM + stem-like phenotype, paralleled by dramatic effects on cell clonogenicity. Moreover, the RSV derivative had negligible toxicity against normal HFF-1 cells and, thus, good selectivity index values toward PC cell lines. Remarkably, its higher lipophilicity and stability in human plasma, as compared to RSV, might ensure a better permeation along the gastrointestinal tract. Our results provide insights into the mechanisms of action contributing to the antiproliferative activity of a synthetic RSV analogue, supporting its potential value in the search for effective and safe agents in PC treatment.

In our overall goal to develop anti-Parkinson drugs, we designed novel diketopiperazines (DKP1-6) aiming to both reach the blood-brain barrier and counteract the oxidative stress related to Parkinson's Disease (PD). The anti-Parkinson properties of DKP 1-6 were evaluated using neurotoxin-treated PC12 cells, as in vitro model of PD, while their cytotoxicity and genotoxicity potentials were investigated in newborn rat cerebral cortex (RCC) and primary human whole blood (PHWB) cell cultures. The response against free radicals was evaluated by the total antioxidant capacity (TAC) assay. Comet assay was used to detect DNA damage while the content of 8-hydroxyl-2'-deoxyguanosine (8-OH-dG) was determined as a marker of oxidative DNA damage. PAMPA-BBB and Caco-2 assays were employed to evaluate the capability of DKP1-6 to cross the membranes. Stability studies were conducted in simulated gastric and intestinal fluids and human plasma. Results showed that DKP5-6 attenuate the MPP  +  -induced cell death on a nanomolar scale, but a remarkable effect was observed for DKP6 on Nrf2 activation that leads to the expression of genes involved in oxidative stress response thus increasing glutathione biosynthesis and ROS buffering. DKP5-6 resulted in no toxicity for RCC neurons and PHWB cells exposed to 10-500 nM concentrations during 24 h as determined by MTT and LDH assays and TAC levels were not altered in both cultured cell types. No significant difference in the induction of DNA damage was observed for DKP5-6. Both DKPs resulted stable in simulated gastric fluids (t 1/2  > 22h). In simulated intestinal fluids, DKP5 underwent immediate hydrolysis while DKP6 showed a half-life higher than 3 h. In human plasma, DKP6 resulted quite stable. DKP6 displayed both high BBB and Caco-2 permeability confirming that the DKP scaffold represents a useful tool to improve the crossing of drugs through the biological membranes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In Tibetans, noncoding alleles in EPAS1 -whose protein product hypoxia-inducible factor 2α (HIF-2α) drives the response to hypoxia-carry strong signatures of positive selection; however, their functional mechanism has not been systematically examined. Here, we report that high-altitude alleles disrupt the activity of four EPAS1 enhancers in one or more cell types. We further characterize one enhancer (ENH5) whose activity is both allele specific and hypoxia dependent. Deletion of ENH5 results in down-regulation of EPAS1 and HIF-2α targets in acute hypoxia and in a blunting of the transcriptional response to sustained hypoxia. Deletion of ENH5 in mice results in dysregulation of gene expression across multiple tissues. We propose that pleiotropic adaptive effects of the Tibetan alleles in EPAS1 underlie the strong selective signal at this gene.

Pleural mesothelioma (PM) is a rare and aggressive disease that arises from the mesothelial cells lining the pleural cavity. Approximately 80% of PM patients have a history of asbestos exposure. The long latency period of 20-40 years from the time of asbestos exposure to diagnosis, suggests that multiple somatic genetic alterations are required for the tumorigenesis of PM. The genomic landscape of PM has been characterized by inter- and intratumor heterogeneity associated with the impairment of tumor suppressor genes such as CDKN2A , NF2 , and BAP1 . Current systemic therapies have shown only limited efficacy, and none is approved for patients with relapsed PM. Advances in understanding of the molecular landscape of PM has facilitated several biomarker-driven clinical trials but so far, no predictive biomarkers for targeted therapies are in clinical use. Recent advances in the PM genetics have provided optimism for successful molecular strategies in the future. Here, we summarize the molecular mechanism underlying PM pathogenesis and review potential therapeutic targets.

Hypoxia plays a crucial role in tumorigenesis and drug resistance, and it is recognised as a major factor affecting patient clinical outcome. Therefore, the detection of hypoxic areas within the tumour micro-environment represents a useful way to monitor tumour growth and patients' responses to treatments, properly guiding the choice of the most suitable therapy. To date, non-invasive hypoxia imaging probes have been identified, but their applicability in vivo is strongly limited due to an inadequate resistance to the low oxygen concentration and the acidic pH of the tumour micro-environment. In this regard, nucleic acid aptamers represent very powerful tools thanks to their peculiar features, including high stability to harsh conditions and a small size, resulting in easy and efficient tumour penetration. Here, we describe a modified cell-SELEX (Systematic Evolution of Ligands by EXponential enrichment) approach that allows the isolation of specific RNA aptamers for the detection of the hypoxic phenotype in breast cancer (BC) cells. We demonstrated the effectiveness of the proposed method in isolating highly stable aptamers with an improved and specific binding to hypoxic cells. To our knowledge, this is the first example of a cell-SELEX approach properly designed and modified to select RNA aptamers against hypoxia-related epitopes expressed on tumour cell surfaces. The selected aptamers may provide new effective tools for targeting hypoxic areas within the tumour with great clinical potential., Competing Interests: Author MI was employed by Bracco Imaging S.p.A. Author AA was employed by Percuros B.V. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nuzzo, Iaboni, Ibba, Rienzo, Musumeci, Franzese, Roscigno, Affinito, Petrillo, Quintavalle, Ciccone, Esposito and Catuogno.)

Background: Surgical treatment of spinal metastases should be tailored to provide pain control, neurological deficit improvement, and vertebral stability with low operative morbidity and mortality. The aim of this study was to analyze the predictive value of some preoperative factors on overall survival in patients undergoing surgery for spinal metastases., Methods: We retrospectively analyzed a consecutive series of 81 patients who underwent surgery for spinal metastases from 2015 and 2021 in the Clinic of Neurosurgery of Ancona (Italy). Data regarding patients' baseline characteristics, preoperative Karnofsky Performance Status Score (KPS), and Frankel classification grading system, histology of primary tumor, Tokuhashi revised and Tomita scores, Spine Instability Neoplastic Score, and Epidural Spinal Cord Compression Classification were collected. We also evaluated the interval time between the diagnosis of the primary tumor and the onset of spinal metastasis, the type of surgery, the administration of adjuvant therapy, postoperative pain and Frankel grade, and complications after surgery. The relationship between patients' overall survival and predictive preoperative factors was analyzed by the Kaplan-Meier method. For the univariate and multivariate analysis, the log-rank test and Cox regression model were used. P ≤ 0.05 was considered as statistically significant., Results: After surgery, the median survival time was 13 months. In our series, the histology of the primary tumor ( P < 0.001), the Tomita ( P < 0.001) and the Tokuhashi revised scores ( P < 0.001), the preoperative KPS ( P < 0.001), the adjuvant therapy ( P < 0.001), the postoperative Frankel grade ( P < 0.001), and the postoperative pain improvement ( P < 0.001) were significantly related to overall survival in the univariate analysis. In the multivariate analysis, the Tomita ( P < 0.001), Tokuhashi revised scores ( P < 0.001), and the adjuvant therapy were confirmed as independent prognostic factors., Conclusion: These data suggest that patients with limited extension of primitive tumor and responsive to the adjuvant therapy are the best candidates for surgery with better outcome., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Surgical Neurology International.)

Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies., (©2022 American Association for Cancer Research.)

Background: In order to evaluate the efficacy of intranasal mometasone furoate in patients with non-allergic rhinitis (NAR), a real-life, observational, prospective study is performed., Methods: Thirty-one patients (age 18-64 years) receive intranasal (mometasone furoate, 200 µg b.i.d. for 15 consecutive days per month for 6 consecutive months), plus isotonic nasal saline. The cytologic pattern of local inflammation, nasal airflow, through peak nasal inspiratory flow (PNIF), quality of life (QoL), through the rhinitis quality of life questionnaire (RQLQ), the sinonasal outcome test (SNOT-22), the short-form 36-item health survey (SF-36v2), and the combined symptom medication score (CSMS), and, finally, olfactory function, through Sniffin' sticks-16 identification test (SSIT-16), are evaluated at baseline and after treatment., Results: NARNE is the most frequent cytological pattern (48% of the total sample). The therapeutic response shows improvement in olfactory function and QoL., Conclusions: The results of this study confirm that intranasal mometasone furoate is an effective treatment for patients with NAR.

The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact., (Copyright © 2022 International Association for the Study of Lung Cancer. All rights reserved.)

Introduction: The use of hydroxyapatite cranioplasties has grown progressively over the past few decades. The peculiar biological properties of this material make it particularly suitable for patients with decompressive craniectomy where bone reintegration is a primary objective. However, hydroxyapatite infection rates are similar to those of other reconstructive materials., Research Question: We investigated if infected hydroxyapatite implants could be saved or not., Materials and Methods: We present a consecutive series over a 10-year period of nine patients treated for hydroxyapatite cranioplasty infection. Clinical and radiological data from admission and follow-up, photo and video material documenting the different phases of infection assessment and treatment, and final outcomes were retrospectively reviewed in an attempt to identify the best options and possible pitfalls in a case-by-case decision-making process., Results: Five unilateral and four bifrontal implants became infected. Wound rupture with cranioplasty exposure was the most common presentation. At revision, all implants were ossified, requiring a new craniotomy to clean the purulent epidural collections. The cranioplasty was fully saved in one hemispheric and 2 bifrontal implants and partially saved in the remaining 2 bifrontal implants. A complete cranioplasty removal was needed in the other 4 cases, but immediate cranial reconstruction was possible in 2. Skin defects were covered by free flaps in 3 cases. Four patients underwent adjunctive hyperbaric therapy, which was effective in one case., Discussion and Conclusion: In our experience, infected hydroxyapatite cranioplasty management is complex and requires a multidisciplinary approach. Salvage of a hydroxyapatite implant is possible under specific circumstances., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

We must embrace a multidimensional, continuous view of ancestry and move away from continental ancestry categories.

Present-day Tibetans have adapted both genetically and culturally to the high altitude environment of the Tibetan Plateau, but fundamental questions about their origins remain unanswered. Recent archaeological and genetic research suggests the presence of an early population on the Plateau within the past 40 thousand years, followed by the arrival of subsequent groups within the past 10 thousand years. Here, we obtain new genome-wide data for 33 ancient individuals from high elevation sites on the southern fringe of the Tibetan Plateau in Nepal, who we show are most closely related to present-day Tibetans. They derive most of their ancestry from groups related to Late Neolithic populations at the northeastern edge of the Tibetan Plateau but also harbor a minor genetic component from a distinct and deep Paleolithic Eurasian ancestry. In contrast to their Tibetan neighbors, present-day non-Tibetan Tibeto-Burman speakers living at mid-elevations along the southern and eastern margins of the Plateau form a genetic cline that reflects a distinct genetic history. Finally, a comparison between ancient and present-day highlanders confirms ongoing positive selection of high altitude adaptive alleles., (© 2022. The Author(s).)

The main antimicrobial resistance (AMR) nosocomial strains (ESKAPE pathogens such as Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter spp.) are the most widespread bacteria in cutaneous infections. In this work we report the synthesis, in silico skin permeability prediction, antimicrobial, antibiofilm, and wound healing properties of novel cinnamic acid-based antimicrobials ( DM1-11 ) as novel antibacterial drugs for the treatment of ESKAPE-related skin infections. Antimicrobial and wound healing scratch assays were performed to evaluate the antibacterial properties of DM1-11 . In silico skin permeability capabilities of DM1-11 were evaluated using Swiss-ADME online database. Cytotoxicity assays were performed on keratinocytes and fibroblasts. DM2 , bearing a catechol group on the aromatic ring of the cinnamic portion of the molecule, possesses a significant antibacterial activity against S. aureus (MIC range 16-64 mg/L) and contrasts the biofilm-mediated S. epidermidis infection at low concentrations. Wound healing assays showed that wound closure in 48 h was observed in DM2 -treated keratinocytes with a better healing pattern at all the used concentrations (0.1, 1.0, and 10 µM). A potential good skin permeation for DM2 , that could guarantee its effectiveness at the target site, was also observed. Cytotoxicity studies revealed that DM2 may be a safe compound for topical use. Taking together all these data confirm that DM2 could represent a safe wound-healing topical agent for the treatment of skin wound infections caused by two of main Gram-positive bacteria belonging to ESKAPE microorganisms.

Introduction: During COVID-19 pandemic, the massive use of Personal Protective Equipment could provoke severe adverse reactions in latex allergy patients and could negatively affect their quality of life. Methods: Trough a survey the study aimed: (a) to evaluate the incidence of allergic reactions in patients with latex allergy during the SARS-CoV-2 pandemic; (b) to evaluate the protective role of continuous latex sublingual immunotherapy (SLIT) during this period; and (c) to evaluate quality of life of natural rubber latex allergy (NRLA) patients during the pandemic. Results: 67 patients (9 males and 58 females, mean age of 45.9 ± 11.4 years) suffering from latex allergy were included in the present study. We recorded among our patients 13 cases (34.2%) of urticarial/angioedema (U/A), 9 cases (23.6%) of respiratory symptoms (dyspnoea, shortness of breath and wheezing) and 7 cases (18.4%) of anaphylaxis. In patients who underwent continuous SLIT, we observed less cases of U/A ( p < 0.001), respiratory symptoms ( p < 0.001), anaphylaxis ( p = 0.003), hospitalizations ( p = 0.014) and a lower therapy administration. We compared the results of SF-36 questionnaire in patients who underwent continuous and not-continuous SLIT with a significance differences score between these two groups. Conclusions: Our study is the first that investigated the clinical and quality of life effects of COVID-19 pandemic in NRLA patients.

Background: Ventriculoperitoneal (VP) shunting is widely accepted as the gold-standard treatment for idiopathic normal pressure hydrocephalus (iNPH). However, a restricted group of patients experience only minimal or no improvement after the operation. In such cases, the question whether the diagnosis was incorrect or the shunt is malfunctioning remains unanswered., Methods: We retrospectively collected data on a 10-year series of VP-shunted patients with iNPH showing transient or minimal improvement of symptoms within 3 weeks from surgery. A full workup (including noninvasive diagnostic, cognitive, and invasive tests) was performed. After ruling out mechanical malfunction, we performed a tap test followed by a Katzman test 2 weeks later. The confirmed persistence of disturbance of cerebrospinal fluid dynamics was treated by shunt revision and, if found working, by its replacement into the atrial cavity., Results: Twenty patients were diagnosed with shunt insufficiency. At surgery, the distal end of the shunt was easily extruded and found working in all cases. It was then repositioned into the right atrium (the first 8 patients of the series also underwent failed contralateral abdominal replacement). Early postoperative clinical improvement was always confirmed. In 1 case, shunt overdrainage was corrected by valve upregulation., Conclusions: According to our experience, inadequate distal end placement of a shunt might be one of the reasons needing investigation in patients with iNPH failing improvement after surgery. In such situations, the conversion to a ventriculoatrial shunt proved to be a low-cost and successful treatment option., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Holospinal epidural abscesses (HEAs) are rare with potentially devastating consequences. Urgent bony decompression and abscess evacuation with long-term antibiotic therapy are typically the treatment of choice., Methods: We reviewed cases of holospinal HEAs operated on between 2009 and 2018. Variables studied included preoperative laboratories, CT/MR studies plus clinical and radiographic follow-up for between 34 and 60 postoperative months., Results: We utilized skip hemilaminectomies to minimize the risks of segmental instability. Targeted antibiotic therapy was also started immediately and maintained for 6 postoperative weeks. MR/CT studies documented full radiographic and neurological recovery between 6 and 12-months later., Conclusion: HEAs may be treated utilizing multilevel skip hemilaminectomies to help maintain spinal stability while offering adequate abscess decompression/resolution., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Surgical Neurology International.)

Introduction: Prognostic models for malignant pleural mesothelioma have been limited to demographics, symptoms, and laboratory values. We hypothesize higher accuracy using both tumor and patient characteristics. The mesothelioma prognostic test (MPT) and molecular subtype based on claudin-15-to-vimentin expression ratio are molecular signatures associated with survival. Tumor volume (TV) has improved performance compared with clinical staging, whereas neutrophil-to-lymphocyte ratio (NLR) is prognostic for malignant pleural mesothelioma., Methods: Tumor specimens and clinical data were collected prospectively from patients who underwent extrapleural pneumonectomy (EPP) or pleurectomy and decortication (PD) during 2007 to 2014. MPT and claudin-15-to-vimentin ratio were determined by real-time quantitative polymerase chain reaction, whereas TV was assessed from preoperative scans. Risk groups were derived from combinations of adverse factors on the basis of the Cox model. Predictive accuracy was assessed using Harrell's c-index., Results: MPT, molecular subtype, TV, and NLR were independently prognostic in patients with EPP (N = 191), suggesting equal weighting in a final three-group model (c = 0.644). In the PD cohort (N = 193), MPT poor risk combined with TV greater than 200 cm 3 was associated with triple the risk compared with other subgroups (hazard ratio = 2.94, 95% confidence interval: 1.70-5.09, p < 0.001) persisting when adjusted for molecular subtype, NLR, performance status, and serum albumin to yield a final three-group model (c = 0.641). The EPP and PD models achieved higher accuracy than published models (c ≤ 0.584, c ≤ 0.575) and pathologic staging (c = 0.554, c = 0.571)., Conclusions: The novel models use pretreatment parameters obtained from minimally invasive biopsy, imaging, and blood tests to evaluate the expected outcome of each type of surgery in newly diagnosed patients and improve stratification on clinical trials., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Despite potential advantages, broad carbon dioxide (CO 2 ) laser diffusion in neurosurgery was historically prevented by several operative limitations. Nonetheless, in recent decades, significant improvements, in particular the development of surgical scanners, have made CO 2 laser surgery easier and reproducible. The aim of this study was to report our preliminary experience with the SmartXide 2 CO 2 laser system., Methods: The SmartXide 2 laser system is a CO 2 laser with a radiofrequency-excited laser source, a surgical scanner, and a high-precision micromanipulator, which are connected to the surgical microscope. Ten different brain and spinal tumors were treated to evaluate the laser system potential in different neurosurgical scenarios. Four illustrative cases were presented., Results: The CO 2 laser was used together with the traditional instruments in every step of the procedures, from the initial pial incision (intra-axial tumors) or early debulking (extra-axial lesions), to progressive tumor removal, and, lastly, for surgical cavity hemostasis. No injury to the surrounding neurovascular structures was observed. Postoperative neuroimaging confirmed complete tumor removal and showed a marked reduction of preoperative surrounding edema without signs of cerebral/medullary contusions., Conclusions: In selected cases, the SmartXide 2 CO 2 laser system could be a helpful, reliable, and safe surgical instrument to treat different cerebral and spinal lesions. It addresses some of the limitations of laser systems and is able to cut/ablate and coagulate the tissue simultaneously, with minimal lateral thermal spread, preserving the surrounding eloquent neurovascular structures. Moreover, having no consumable accessories, it is also cost-effective., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Novel boron-based compounds (BBCs) were synthesized and evaluated as potential candidates for the development of novel drugs against Alzheimer's disease (AD). The neuroprotective profile of novel BBCs was evaluated using Aβ1-42-treated-SH-SY5Y cells while their antioxidant activity was evaluated by total antioxidant capacity (TAC) and total oxidative status (TOS) assays. Results showed that BLA (a novel boron-based hybrid containing an antioxidant portion) inhibited cell death induced by Aβ1-42-exposure in differentiated SH-SY5Y cells, resulting in an increase in cell viability by 25-33% (MTT assay) and by 63-71% (LDH assay) in a concentration range of 25-100 μM. Antioxidant assays demonstrated a good capability of BLA to counteract the oxidative status. Moreover, BLA possessed a significant ability to inhibit acetylcholinesterase (AChE) (22.96% at 50 μM), an enzyme whose enzymatic activity is increased in AD patients. In the present work, absorption and distribution properties of boron-based hybrids were predicted using Pre-ADMET software. In vitro preliminary results suggested that boron-based hybrids could be new structural scaffolds for the development of novel drugs for the management of AD., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Recently, mineral healing clays have gained much attention for wound-dressing applications. Here, we selected halloysite (HAL) clay as a biocompatible, non-toxic material that is useful as a drug delivery system to enhance the healing properties of water-soluble terpenoids 1-3 ( T1-3 ). Terpenoids-loaded HAL clay ( TH1-3 ) was prepared and characterized by adsorption equilibrium studies, X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, and release studies. The results reveal that T1-3 were adsorbed at the HAL surface with good efficiency. The prevalent mechanism of drug retention is due to the adsorption via electrostatic interactions between the cationic groups of the T1-3 and the HAL's external surface. Release studies demonstrated that T3 was released in a higher percentage (>60%) compared to T1-2 (≈50%). Additionally, TH1-3 were assessed for their antimicrobial activity and capability to promote the re-epithelialization of scratched HaCat monolayers, through the time-kill test and the wound-healing assays, respectively. The results reveal that all the tested formulations were able to reduce the microbial growth after 1 h of incubation and that they ensured complete wound closure after 48 h. Furthermore, at the concentration of 1 µg/mL, TH3 exhibited 45% wound closure at 24 h, compared to TH1 (27%) and TH2 (30%), proving to be the best candidate in making the tissue-repair process easier and faster.

Dura mater repair represents a final and crucial step in neurosurgery: an inadequate dural reconstruction determines dreadful consequences that significantly increase morbidity and mortality rates. Different dural substitutes have been used with suboptimal results. To overcome this issue, in previous studies, we proposed a laser-based approach to the bonding of porcine dura mater, evidencing the feasibility of the laser-assisted procedure. In this work, we present the optimization of this approach in ex vivo experiments performed on porcine dura mater. An 810-nm continuous-wave AlGaAs (Aluminium Gallium Arsenide) diode laser was used for welding Indocyanine Green-loaded patches (ICG patches) to the dura. The ICG-loaded patches were fabricated using chitosan, a resistant, pliable and stable in the physiological environment biopolymer; moreover, their absorption peak was very close to the laser emission wavelength. Histology, thermal imaging and leak pressure tests were used to evaluate the bonding effect. We demonstrated that the application of 3 watts (W), pulsed mode (T on 30 ms, T off 3.5 ms) laser light induces optimal welding of the ICG patch to the dura mater, ensuring an average fluid leakage pressure of 216 ± 105 mmHg, falling within the range of physiological parameters. This study demonstrated that the thermal effect is limited and spatially confined and that the laser bonding procedure can be used to close the dura mater. Our results showed the effectiveness of this approach and encourage further experiments in in vivo models.

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with limited therapeutic options beyond surgery and cytotoxic chemotherapy. The success of immune checkpoint inhibition has been found to correlate with expression of immune-related genes such as CD274 (PD-L1) in lung and other solid cancers. However, only a small subset of MPM patients respond to checkpoint inhibition, and this response has been varied and unpredictable across several clinical trials. Recent advances in next-generation sequencing (NGS) technology have improved our understanding of the molecular features of MPM, also with respect to its genetic signature and how this impacts the immune microenvironment. This article will review current evidence surrounding the interplay between MPM genetics, including epigenetics and transcriptomics, and the immune response., Competing Interests: RB reports research grants and clinical trials support from MedGenome, Roche, Verastem, Genentech, Merck, Gritstone, Epizyme, Siemens, National Institutes of Health, and Department of Defense. In addition, RB holds 4 patents through Brigham and Women’s Hospital and equity in Navigation Sciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wadowski, Bueno and De Rienzo.)

The optimal management of cranioplasty infections remains a matter of debate. Most authors have suggested that the infected bone/implant removal is mandatory, combined with prolonged antibiotic therapy before reconstruction. However, failures can occur, even with 12-18-month intervals between the surgeries. Longer wait times before cranial reconstruction increase the risks of socioeconomic burdens and further complications, as observed in decompressed patients hosting shunts. In our department, we treated 48 cranioplasty infections over a period of 8 years, divided into two groups. For Group A (n = 26), the treatment consisted of cranioplasty removal and debridement, followed by a delayed reconstruction. Group B (n = 22) received 2 weeks of broad-spectrum antibiotics, followed by an "aggressive" field debridement and immediate cranioplasty. All patients received a minimum of 8 weeks of post-operative antibiotic therapy and were scheduled for clinic-radiological follow-ups for at least 36 months. Significant differences were observed between Groups A and B with respect to the number of failures (respectively 7 versus 1), the global operative time (significantly longer for Group B), germ identification (respectively 7 versus 13), and the overall length of hospital stay (on average, 61.04 days in Group A versus 47.41 days in Group B). Three shunted patients in Group A developed sinking flap syndrome. Shunt resetting allowed symptom control until cranioplasty in one subject, whereas two did not improve, even after reconstruction. In selected patients, an aggressive field debridement, followed by the immediate replacement of an infected cranioplasty, may represent a safe and valuable option.

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas.

This paper is based on one idea and built around one clinical experience that helped me to broaden my comprehension of it. The idea, underlying the work of several authors, is that when the analytic field is saturated with primitive and unintegrated mental contents, the analyst's somatic countertransference is a precious indicator of a deep, dissociated form of communication. The clinical experience concerns the difficult elaboration of a complex, multifaceted countertransference that took place during the early stages of the analysis of a sensitive patient who used to communicate in a very dissociated way and that I found hard to contain. This experience, closely described in the article, led me to formulate the clinical idea that the transference field may be made of distinct layers (psychoid, affective, verbal), and that each one of them may potentially convey dissociated, even contrasting bits of information. The corollary of this is that the analyst should be ready to accept contrasting sensations, feelings and thoughts at the same time, as they might be the basic ingredients of a complex reverie. The analyst could find himself/herself in front of his/her own internal unelaborated multiplicity before a symbolic image may emerge to link the scattered pieces of the experience. Nevertheless, the heart of this paper is not about suggesting an idea, but in the sharing of a complex working through, which fostered the birth of a new, more human relational perspective: the capacity of being together in time, in a transitional space where there is neither total separation nor fusion., (© 2021, The Society of Analytical Psychology.)

Sex differences in incidence, prognosis, and treatment response have been described for many cancers. In malignant pleural mesothelioma (MPM), a lethal disease associated with asbestos exposure, men outnumber women 4 to 1, but women consistently live longer than men following surgery-based therapy. This study investigated whether tumor expression of genes associated with estrogen signaling could potentially explain observed survival differences. Two microarray datasets of MPM tumors were analyzed to discover estrogen-related genes associated with survival. A validation cohort of MPM tumors was selected to balance the numbers of men and women and control for competing prognostic influences. The RAS like estrogen regulated growth inhibitor ( RERG ) gene was identified as the most differentially-expressed estrogen-related gene in these tumors and predicted prognosis in discovery datasets. In the sex-matched validation cohort, low RERG expression was significantly associated with increased risk of death among women. No association between RERG expression and survival was found among men, and no relationship between estrogen receptor protein or gene expression and survival was found for either sex. Additional investigations are needed to elucidate the molecular mechanisms underlying this association and its sex specificity.

Introduction: Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM., Methods: Microarray, real-time quantitative reverse transcription-polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression., Results: UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-sequencing experiments exhibited the pleiotropic effects of UHRF1 down-regulation and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM., Conclusions: UHRF1 is an epigenetic driver in MPM. These findings support the efforts to target UHRF1 expression or activity for mesothelioma therapy., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

BRCA1-associated protein-1 (BAP1) expression is commonly lost in several tumors including malignant pleural mesothelioma (MPM). Presence or absence of immunohistochemical BAP1 nuclear staining in tumor cells is currently used for differential diagnosis of MPM. In this study, a large cohort of 596 MPM tumors with available clinical data was analyzed to examine associations of BAP1 staining pattern with clinical and molecular features that may reflect the impact of BAP1 mutation on MPM biology. Cases were classified according to the BAP1 staining pattern of tumor cells. Exome and RNA-sequencing data were available for subsets of cases. Levels of mRNA encoding claudin 15 (CLDN15) and vimentin (VIM) were determined using RT-qPCR on 483 cases to estimate the relative proportions of epithelial-like and mesenchymal-like components in each tumor. Four BAP1 staining patterns were observed: single-pattern nuclear staining (36%), single-pattern cytoplasmic staining (25%), single-pattern absent staining (12%), and combinations of these staining patterns (27%). This study confirmed prior reports that nuclear BAP1 is more frequently associated with wild-type BAP1 and sarcomatoid histology. However, no associations between BAP1 staining pattern(s) and mutations in specific protein domains and/or mutation type were observed. BAP1 staining patterns were significantly associated (p < 0.001) with BAP1 gene expression, MPM histologic subtypes, molecular clusters, and markers of epithelial-to-mesenchymal transition. Frequent observation of combinations of BAP1 staining patterns in MPM tumors indicated intra-tumoral heterogeneity of BAP1 status. Cytoplasmic BAP1 staining was identified as a putative indicator of favorable prognosis in non-epithelioid MPM. In conclusion, novel significant associations among different BAP1 staining patterns and subgroups of MPM tumors were observed, suggesting that the role of BAP1 in tumor progression may be more complex than its presumed tumor suppressor function. Cytoplasmic staining was identified as a putative indicator of favorable prognosis in non-epithelioid MPM, potentially addressing a critical need in clinical decision-making in this disease. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland., (© 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.)

Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural lining associated with asbestos exposure in greater than 80% of cases. It is characterized by molecular heterogeneity both between patients and within individual tumors. Next-generation sequencing technology and novel computational techniques have resulted in a greater understanding of the epigenetic, genetic, and transcriptomic hallmarks of MPM. This article reviews these features and discusses the implications of advances in MPM molecular biology in clinical practice., Competing Interests: Disclosure The authors disclose no potential conflicts of interest. Dr. Bueno reports research grants and clinical trials support from MedGenome, Roche, Verastem, Genentech, Merck, Gritstone, Epizyme, Siemens, NIH, and DOD. In addition, Dr. Bueno has 4 patents through the BWH (no royalties to date) and Equity in a new start-up company, Navigation Sciences., (Copyright © 2020 Elsevier Inc. All rights reserved.)