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Headache is a very common disorder in children and adolescents. While migraine and tension headaches are well-known and diagnosed by pediatricians, a group of primary headaches in children, rare in frequency, are poorly understood and likely underestimated by physicians, resulting in delayed diagnosis and treatment. This review aims to provide an updated overview of these clinical forms, considering new evidence. We will present the main clinical, therapeutic, and pathophysiological aspects and possible future hypotheses, with specific reference to pediatric cases of the following clinical forms: cough headache, thunderclap headache, cold headache, primary stabbing headache, nummular headache, hypnic headache, red ear syndrome, and non-odontogenic orofacial pain. These clinical forms currently pose a major diagnostic challenge for pediatricians and represent a source of serious disability for children and adolescents.

Headache represents one of the most prevalent and disabling conditions in the pediatric population, with significant repercussions on mental and psychological well-being, as well as on academic achievement and social functioning, ultimately leading to a marked reduction in quality of life. Currently, the diagnosis of headache is based on the clinical criteria of the third edition of the International Classification of Headache Disorders (ICHD-3). However, the characteristics of headache may differ between adults and children, as well as the ability of children to provide a complete description of the pain and associated symptoms. The immature narrative skills of children can represent a limitation in defining the clinical phenotype of headache, making the diagnosis more complex. This is even more challenging when extracting information about the characteristics of the headache in children whose verbal expression is poorly developed or completely absent. Given these limitations, clinical psychology has long used drawing as an effective diagnostic instrument to bypass verbal communication barriers. This tool provides unique access to children’s psychological and emotional states, as a direct window into their inner world and as an expressive medium that often generates more detailed, accurate, and clinically actionable information, compared to verbal reports alone. For these reasons, drawing has been recognized as a valuable diagnostic tool for decades, with multiple studies demonstrating specificity and accuracy rates comparable to standard clinical assessments. Particularly for young children, drawings may give access to fundamental information that might otherwise remain inaccessible, thereby allowing both accurate diagnosis and individualized treatment planning. Multiple studies have highlighted and confirmed the graphic differences between representations of various types of headaches and the undeniable utility of an “artistic diagnosis” alongside the clinical one. Furthermore, the literature suggests and encourages the use of drawing in clinical practice, both in the diagnostic process and during subsequent follow-up, as an effective, enjoyable, easy-to-use, and low-cost resource. Accordingly, we propose a narrative review accompanied by a curated collection of drawings that may help identify and categorize specific correlations between graphic representations and clinical phenotypes, such as pain location, quality, intensity, association with nausea and vomiting, photophobia and phonophobia, and types of migraine aura. Our goal is to create a visual reference that can aid clinicians in the accurate interpretation of children’s drawings. Additionally, we aim to promote the integration of this method into routine clinical practice to improve diagnostic precision and support a more child-centered model of care. We also hope to propose new iconographic models to further enrich the diagnostic framework.

Abstract IntroductionDementia with Lewy bodies (DLB) may represent a diagnostic challenge, since its clinical picture overlaps with other dementia. Two toolkits have been developed to aid the clinician to diagnose DLB: the Lewy Body Composite Risk Score (LBCRS) and the Assessment Toolkit for DLB (AT-DLB). We aim to evaluate the reliability of these two questionnaires, and their ability to enhance the interpretation of the international consensus diagnostic criteria.MethodsLBCRS and AT-DLB were distributed to 135 Italian Neurological Centers for Cognitive Decline and Dementia (CDCDs), with the indication to administer them to all patients with dementia referred within the subsequent 3 months. We asked to subsequently apply consensus criteria for DLB diagnosis, to validate the diagnostic accuracy of the two toolkits.ResultsA total of 23 Centers joined the study; 1854 patients were enrolled. We found a prevalence of possible or probable DLB of 13% each (26% total), according to the consensus criteria. LBCRS toolkit showed good reliability, with a Cronbach alpha of 0.77, stable even after removing variables from the construct. AT-DLB toolkit Cronbach alpha was 0.52 and, after the subtraction of the “cognitive fluctuation” criterion, was only 0.31. Accuracy, sensitivity, and specificity were higher for LBCRS vs. AT-DLB. However, when simultaneously considered in the logistic models, AT-DLB showed a better performance (p < 0.001). Overall, the concordance between LBCRS positive and AT-DLB possible/probable was of 78.02%ConclusionsIn a clinical setting, the LBCRS and AT-DLB questionnaires have good accuracy for DLB diagnosis.

Aberrant glycosylation has long been known to be associated with cancer, since it is involved in key mechanisms such as tumour onset, development and progression. This review will focus on protein glycosylation studies in cells, tissue, urine and serum in the context of prostate cancer. A dedicated section will cover the glycoforms of prostate specific antigen, the molecule that, despite some important limitations, is routinely tested for helping prostate cancer diagnosis. Our aim is to provide readers with an overview of mass spectrometry-based glycoproteomics of prostate cancer. From this perspective, the first part of this review will illustrate the main strategies for glycopeptide enrichment and mass spectrometric analysis. The molecular information obtained by glycoproteomic analysis performed by mass spectrometry has led to new insights into the mechanism linking aberrant glycosylation to cancer cell proliferation, migration and immunoescape.

Background Diabetic polyneuropathy (DPN) is the most common and early developing complication of diabetes mellitus, and the key contributor for foot ulcers development, with no specific therapies available. Different studies have shown that mesenchymal stem cell (MSC) administration is able to ameliorate DPN; however, limited cell survival and safety reasons hinder its transfer from bench to bedside. MSCs secrete a broad range of antioxidant, neuroprotective, angiogenic, and immunomodulatory factors (known as conditioned medium), which are all decreased in the peripheral nerves of diabetic patients. Furthermore, the abundance of these factors can be boosted in vitro by incubating MSCs with a preconditioning stimulus, enhancing their therapeutic efficacy. We hypothesize that systemic administration of conditioned medium derived from preconditioned MSCs could reverse DPN and prevent foot ulcer formation in a mouse model of type II diabetes mellitus. Methods Diabetic BKS db/db mice were treated with systemic administration of conditioned medium derived from preconditioned human MSCs; conditioned medium derived from non-preconditioned MSCs or vehicle after behavioral signs of DPN was already present. Conditioned medium or vehicle administration was repeated every 2 weeks for a total of four administrations, and several functional and structural parameters characteristic of DPN were evaluated. Finally, a wound was made in the dorsal surface of both feet, and the kinetics of wound closure, re-epithelialization, angiogenesis, and cell proliferation were evaluated. Results Our molecular, electrophysiological, and histological analysis demonstrated that the administration of conditioned medium derived from non-preconditioned MSCs or from preconditioned MSCs to diabetic BKS db/db mice strongly reverts the established DPN, improving thermal and mechanical sensitivity, restoring intraepidermal nerve fiber density, reducing neuron and Schwann cell apoptosis, improving angiogenesis, and reducing chronic inflammation of peripheral nerves. Furthermore, DPN reversion induced by conditioned medium administration enhances the wound healing process by accelerating wound closure, improving the re-epithelialization of the injured skin and increasing blood vessels in the wound bed in a skin injury model that mimics a foot ulcer. Conclusions Studies conducted indicate that MSC-conditioned medium administration could be a novel cell-free therapeutic approach to reverse the initial stages of DPN, avoiding the risk of lower limb amputation triggered by foot ulcer formation and accelerating the wound healing process in case it occurs.

The aim of this study was to compare filter-aided sample preparation (FASP) and protein aggregation capture (PAC) starting from a three-species protein mix (Human, Soybean and Pisum sativum) and two different starting amounts (1 and 10 µg). Peptide mixtures were analyzed by data-independent acquisition (DIA) and raw files were processed by three commonly used software: Spectronaut, MaxDIA and DIA-NN. Overall, the highest number of proteins (mean value of 5491) were identified by PAC (10 µg), while the lowest number (4855) was identified by FASP (1 µg). The latter experiment displayed the worst performance in terms of both specificity (0.73) and precision (0.24). Other tested conditions showed better diagnostic accuracy, with specificity values of 0.95–0.99 and precision values between 0.61 and 0.86. In order to provide guidance on the data analysis pipeline, the accuracy diagnostic of three software was investigated: (i) the highest sensitivity was obtained with Spectronaut (median of 0.67) highlighting the ability of Spectronaut to quantify low-abundance proteins, (ii) the best precision value was obtained by MaxDIA (median of 0.84), but with a reduced number of identifications compared to Spectronaut and DIA-NN data, and (iii) the specificity values were similar (between 0.93 and 0.99). The data are available on ProteomeXchange with the identifier PXD044349.

The Kodjadermen-Gumelnița-Karonovo VI human group (KGK VI) reached its maximal extension around 4500 BC, covering a large area comprised between southern Ukraine and northern Greece. Afterward, its distribution gradually receded, before vanishing altogether at the end of the fifth – early fourth millenniums BC. This study seeks to investigate the role of individual mobility during this process by performing strontium isotopic analyses on the human remains found at Gumelnița, Romania. It provides 87 Sr/ 86 Sr values for 21 human tooth enamel samples from 17 different individuals, together with those of 60 plant samples from 20 different locations (15 in Romania and 5 in Bulgaria) that were used to create a bioavailable strontium (BASr) baseline of the region. To obtain reliable sex estimations, proteomic analysis of amelogenin of human tooth enamel were also performed on seven individuals. According to the results, four individuals, three females and one male, should be considered as non-local, and may have spent their childhood on the southern bank of the Danube River. These data suggest that individual mobility was particularly prevalent during the last centuries of the fifth millennium, when the KGK VI complex was undergoing a process of disintegration. Main Text.

Background The p97 complex participates in the degradation of muscle proteins during atrophy upon fasting or denervation interacting with different protein adaptors. We investigated whether and how it might also be involved in muscle wasting in cancer, where loss of appetite occurs, or amyotrophic lateral sclerosis (ALS), where motoneuron death causes muscle denervation and fatal paralysis. Methods As cancer cachexia models, we used mice bearing colon adenocarcinoma C26, human renal carcinoma RXF393, or Lewis lung carcinoma, with breast cancer 4T1‐injected mice as controls. As ALS models, we employed 129/SvHsd mice carrying the mutation G93A in human SOD1. The expression of p97 and its adaptors was analysed in their muscles by quantitative real‐time polymerase chain reaction (qPCR) and western blot. We electroporated plasmids into muscles or treated mice with disulfiram (DSF) to test the effects of inhibiting p97 and nuclear protein localization protein 4 (Nploc4), one of its adaptors, on atrophy. Results The mRNA levels of p97 were induced by 1.5‐fold to 2‐fold in tibialis anterior (TA) of all the cachectic models but not in the non‐cachectic 4T1 tumour‐bearing mice (P ≤ 0.05). Similarly, p97 was high both in mRNA and protein in TA from 17‐week‐old SOD1G93A mice (P ≤ 0.01). Electroporation of a shRNA for murine p97 into mouse muscle reduced the fibre atrophy caused by C26 (P = 0.0003) or ALS (P ≤ 0.01). When we interrogated a microarray, we had previously generated for the expression of p97 adaptors, we found Derl1, Herpud1, Nploc4, Rnf31, and Hsp90ab1 induced in cachectic TA from C26‐mice (Fold change > 1.2, adjusted P ≤ 0.05). By qPCR, we validated their inductions in TA of cachectic and ALS models and selected Nploc4 as the one also induced at the protein level by 1.5‐fold (P ≤ 0.01). Electroporation of a CRISPR/Cas9 vector against Nploc4 into muscle reduced the fibre atrophy caused by C26 (P = 0.01) or ALS (P ≤ 0.0001). Because DSF uncouples p97 from Nploc4, we treated atrophying myotubes with DSF, and found accumulated mono and polyubiquitinated proteins and reduced degradation of long‐lived proteins by 35% (P ≤ 0.0001), including actin (P ≤ 0.05). DSF halves Nploc4 in the soluble muscle fraction (P ≤ 0.001) and given to C26‐bearing mice limited the body and muscle weight loss (P ≤ 0.05), with no effect on tumour growth. Conclusions Overall, cancer cachexia and ALS seem to display similar mechanisms of muscle wasting at least at the catabolic level. The p97‐Nploc4 complex appears to have a crucial role in muscle atrophy during these disorders and disrupting this complex might serve as a novel drug strategy.

Background The addition of pertuzumab (P) to trastuzumab (H) and standard chemotherapy (CT) as neoadjuvant treatment (NaT) for patients with HER2 + breast cancer (BC), has shown to increase the pathological complete response (pCR) rate, without main safety concerns. The aim of NeoPowER trial is to evaluate safety and efficacy of P  + H + CT in a real–world population. Methods We retrospectively reviewed the medical records of stage II–III, HER2 + BC patients treated with NaT: who received P  + H + CT (neopower group) in 5 Emilia Romagna institutions were compared with an historical group who received H + CT (control group). The primary endpoint was the safety, secondary endpoints were pCR rate, DRFS and OS and their correlation to NaT and other potential variables. Results 260 patients were included, 48% received P  + H + CT, of whom 44% was given anthraciclynes as part of CT, compared to 83% in the control group. The toxicity profile was similar, excluding diarrhea more frequent in the neopower group (20% vs. 9%). Three patients experienced significant reductions in left ventricular ejection fraction (LVEF), all receiving anthracyclines. The pCR rate was 46% ( P  + H + CT) and 40% (H + CT) ( p  = 0.39). The addition of P had statistically correlation with pCR only in the patients receiving anthra-free regimens (OR = 3.05, p  = 0.047). Preoperative use of anthracyclines (OR = 1.81, p  = 0.03) and duration of NaT (OR = 1.18, p  = 0.02) were statistically related to pCR. 12/21 distant-relapse events and 14/17 deaths occurred in the control group. Patients who achieve pCR had a significant increase in DRFS (HR = 0.23, p  = 0.009). Conclusions Adding neoadjuvant P to H and CT is safe. With the exception of diarrhea, rate of adverse events of grade > 2 did not differ between the two groups. P did not increase the cardiotoxicity when added to H + CT, nevertheless in our population all cardiac events occurred in patients who received anthracycline-containing regimens. Not statistically significant, higher pCR rate is achievable in patients receiving neoadjuvant P  + H + CT. The study did not show a statistically significant correlation between the addition of P and long-term outcomes.

Multiple myeloma (MM) is tightly dependent on inflammatory bone marrow microenvironment. IL-17 producing CD4+ T cells (Th17) sustain MM cells growth and osteoclasts-dependent bone damage. In turn, Th17 differentiation relies on inflammatory stimuli. Here, we investigated the role of miR-21 in Th17-mediated MM tumor growth and bone disease. We found that early inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired Th17 differentiation in vitro and abrogated Th17-mediated MM cell proliferation and osteoclasts activity. We validated these findings in NOD/SCID-g-NULL mice, intratibially injected with miR-21i-T cells and MM cells. A Pairwise RNAseq and proteome/phosphoproteome analysis in Th17 cells demonstrated that miR-21 inhibition led to upregulation of STAT-1/-5a-5b, STAT-3 impairment and redirection of Th17 to Th1/Th2 like activated/polarized cells. Our findings disclose the role of miR-21 in pathogenic Th17 activity and open the avenue to the design of miR-21-targeting strategies to counteract microenvironment dependence of MM growth and bone disease.