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Human papillomavirus (HPV) is involved in virtually all cases of cervical cancer. However, HPV alone is not sufficient to cause malignant development. The effects of chronic inflammation and the interaction of immune components with the microenvironment infected with the high-risk HPV type (HR) may contribute to cancer development. Transforming growth factor β (TGFB) appears to play an important role in cervical carcinogenesis. Protein and mRNA levels of this cytokine gradually increase as normal tissue develops into malignant tissue and are closely related to the severity of HPV infection. At the onset of infection, TGFB can inhibit the proliferation of infected cells and viral amplification by inhibiting cell growth and downregulating the transcriptional activity of the long control region (LCR) of HPV, thereby reducing the expression of early genes. When infected cells progress to a malignant phenotype, the response to the cell growth inhibitory effect of TGFB1 is lost and the suppression of E6 and E7 expression decreases. Subsequently, TGFB1 expression is upregulated by high levels of E6 and E7 oncoproteins, leading to an increase in TGFB1 in the tumor microenvironment, where this molecule promotes epithelial-to-mesenchymal transition (EMT), cell motility, angiogenesis, and immunosuppression. This interaction between HPV oncoproteins and TGFB1 is an important mechanism promoting the development and progression of cervical cancer., 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 © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Celiac disease (CD) and type 1 diabetes (T1D) often co-occur and share genetic components in the human leukocyte antigen (HLA) class II region. We aimed to study the usefulness of HLA genotyping in predicting the risk of developing T1D in patients with CD and the temporal relationship between these diseases., Methods: A cohort of 1,886 Sardinian patients, including 822 with CD, 1,064 with T1D, and 627 controls, underwent HLA class II typing. Seventy-six of 822 patients with CD were also affected by T1D (CD-T1D), and their HLA genotypes were analyzed for specific HLA associations with CD, T1D, and controls., Results: High-risk HLA-DQ genotypes, including HLA-DQ2.5/DQ8, -DQ2.5/DQ2.5, and -DQ2.5/DQ2.3, were strongly associated with CD-T1D with frequencies of 34.5%, 15.9%, and 18.8%, respectively. Conversely, certain HLA genotypes associated with CD seemed to confer protection against T1D development. Therefore, HLA genotyping allows for the identification of those patients with CD who might develop T1D. The frequency of patients with CD preceding T1D is higher in younger children than older ones, with implications for the early childhood approach to diabetes prevention., Discussion: CD is a condition for future T1D development, and specific HLA genotypes can predict this risk. Early screening for celiac autoimmunity and subsequent HLA typing in CD children could help identify those at high risk of T1D, allowing for proactive interventions and immunotherapies to preserve β-cell function. These findings may support the re-evaluation of HLA typing in children with CD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Aims: The primary objectives were to investigate the incidence rate (IR) of type 1 diabetes (T1D) in Sardinian children aged 0-14 years in 2019-2022 and to examine the temporal trend from 1989-1999., Methods: Data from new-onset T1D patients aged 0-14 years who were residents of Sardinia were collected from all pediatric diabetology clinics. The overall, sex- and age specific (groups 0-4, 5-9, and 10-14 years), and calendar year IRs were calculated. The standardized IR (SIR) was also calculated using the direct method. Poisson regression was used to estimate the temporal trend in the SIRs from 1989-1999 to 2019-2022., Results: In 2019-2022, 512 patients aged 0-14 years were diagnosed with T1D in Sardinia. The overall IR was 73.9 per 100,000 person-years (95 % CI 67.6-80.0). Since 1989, the SIR has increased by 2.3 % per year (CI 1.7-2.8, p < 0.0001). The frequency of ketoacidosis at onset was 26.4 %, with no significant differences among the four years., Conclusions: The incidence of T1D in Sardinia, unlike in other countries such as Finland, has almost doubled in the last 20 years, and currently, it appears to be the highest in the world., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that they have no potential conflicts of interest related to this article. In the last 36 months, the authors reported the following conflicts of interest not specific to this work. C.R. received a speaker honorarium from Eli-Lilly and Sanofi and received support for attending meetings and travel from Medtronic, Theras, MOVI, and Roche. M.RC. received support for attending meetings and travel from Medtronic, Theras, and Roche. G.P. received support for attending meetings and travel from Medtronic, Theras, MOVI, and Roche. A.O. received support for attending meetings and travel from Medtronic, MOVI, and Theras. M.M.O., G.L.C., and A.C. received support for attending meetings and travel from Medtronic and MOVI. R.M. and M.P.S. received support for attending meetings and travel from Medtronic. M.R.A., G.M., A.P., G.P., V.C., P.B., L.C., and O.A. have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic Lymphocytic Leukemia (CLL) is an indolent malignancy characterized by the accumulation of quiescent mature B cells. However, these cells are transcriptionally and translationally active, implicating an active metabolism. The recent literature suggests that CLL cells have an oxidative-type phenotype. Given the role of cell metabolism, which is able to influence the outcome of treatments, in other neoplasms, we aimed to assess its prognostic role in CLL patients by determining the ex vivo bioenergetic metabolic profile of CLL cells, evaluating the correlation with the patient clinical/biological characteristics and the in vivo response to BTK inhibitor treatment. Clustering analysis of primary samples identified two groups, characterized by low (CLL low) or high (CLL high) bioenergetic metabolic rates. Compared to the CLL high, CLL with lower bioenergetic metabolic rates belonged to patients characterized by a statistically significant higher white blood cell count and by unfavorable molecular genetics. More importantly, patients in the CLL low cluster displayed a better and more durable response to the BTK inhibitor ibrutinib, thus defining a bioenergetic metabolic subgroup that can benefit the most from this therapy.

The primary objectives of the study were (a) to confirm that glucose 6-phosphate dehydrogenase (G6PD) deficiency affects HbA1c values in a sample of children and adolescents with type 1 diabetes (T1D) and (b) to quantify this effect so that a correction can be applied to the HbA1c values found in current clinical practice. The following data were collected: age, sex, G6PD, number of daily capillary blood glucose measurements, 90-day average blood glucose levels prior to the study, HbA1c, and glycated hemoglobin estimated (eA1c) obtained from blood glucose levels. Patients were divided into three groups based on G6PD values: deficient, intermediate, and nondeficient. In each group, a comparison between the average eA1C and HbA1c values was performed. Then, the difference between the eA1c and HbA1c values of each patient and the mean of the differences (MD) of all patients was calculated within the three groups. Finally, a comparison of the MD values between groups was performed. Seventy-four subjects with T1D were studied. Based on the G6PD value, 33 subjects were deficient, 8 were intermediate, and 33 subjects were nondeficient. In deficient patients, the eA1c values were significantly higher than the HbA1c values. In the other two groups, however, there were no differences. The MD values between the three groups were significantly different. In deficient patients, MD values were higher than those in intermediate and in nondeficient patients. No difference was found between intermediate and nondeficient subjects. Our study confirms that G6PD deficiency affects HbA1c values in children and adolescents with T1D, both in deficient subjects and, to a much lesser extent, in intermediate subjects. In deficient subjects, there is an average reduction in HbA1c attributable to enzyme deficiency of 1.3% (14 mmol/mol) and in intermediate subjects of 0.3% (3 mmol/mol)., (© 2024. The Author(s).)

Oxidative stress and impaired mitophagy are the hallmarks of cardiomyocyte senescence. Specifically, a decrease in mitophagic flux leads to the accumulation of damaged mitochondria and the development of senescence through increased ROS and other mediators. In this study, we describe the preventive role of A5 + , a mix of polyphenols and other micronutrients, in doxorubicin (DOXO)-induced senescence of H9C2 cells. Specifically, H9C2 cells exposed to DOXO showed an increase in the protein expression proteins of senescence-associated genes, p21 and p16, and a decrease in the telomere binding factors TRF1 and TRF2, indicative of senescence induction. Nevertheless, A5 + pre-treatment attenuated the senescent-like cell phenotype, as evidenced by inhibition of all senescent markers and a decrease in SA-β-gal staining in DOXO-treated H9C2 cells. Importantly, A5 + restored the LC3 II/LC3 I ratio, Parkin and BNIP3 expression, therefore rescuing mitophagy, and decreased ROS production. Further, A5 + pre-treatment determined a ripolarization of the mitochondrial membrane and improved basal respiration. A5 + -mediated protective effects might be related to its ability to activate mitochondrial SIRT3 in synergy with other micronutrients, but in contrast with SIRT4 activation. Accordingly, SIRT4 knockdown in H9C2 cells further increased MnSOD activity, enhanced mitophagy, and reduced ROS generation following A5 + pre-treatment and DOXO exposure compared to WT cells. Indeed, we demonstrated that A5 + protects H9C2 cells from DOXO-induced senescence, establishing a new specific role for A5 + in controlling mitochondrial quality control by restoring SIRT3 activity and mitophagy, which provided a molecular basis for the development of therapeutic strategies against cardiomyocyte senescence.

In this study we analyzed the expression of Yin and Yang 1 protein (YY1), a member of the noncanonical PcG complexes, in AML patient samples and AML cell lines and the effect of YY1 downregulation on the AML differentiation block. Our results show that YY1 is significantly overexpressed in AML patient samples and AML cell lines and that YY1 knockdown relieves the differentiation block. YY1 downregulation in two AML cell lines (HL-60 and OCI-AML3) and one AML patient sample restored the expression of members of the CEBP protein family, increased the expression of extrinsic growth factors/receptors and surface antigenic markers, induced morphological cell characteristics typical of myeloid differentiation, and sensitized cells to retinoic acid treatment and to apoptosis. Overall, our data show that YY1 is not a secondary regulator of myeloid differentiation but that, if overexpressed, it can play a predominant role in myeloid differentiation block.

Introduction: T cell reactivity against pancreatic autoantigens is considered one of the main contributors to the destruction of insulin-producing cells in type 1 diabetes (T1D). Over the years, peptide epitopes derived from these autoantigens have been described in NOD mice and in both HLA class II transgenic mice and humans. However, which ones are involved in the early onset or in the progressive phases of the disease is still unclear., Methods: In this work we have investigated, in early-onset T1D pediatric patients and HLA-matched controls from Sardinia, the potential of preproinsulin (PPI) and glutamate decarboxylase 65 (GAD65)-derived peptides to induce spontaneous T cell proliferation responses of peripheral blood mononuclear cells (PBMCs)., Results: Significant T cell responses against PPI1-18, PPI7-19 and PPI31-49, the first two belonging to the leader sequence of PPI, and GAD65271-285 and GAD65431-450, were found in HLA-DR4, -DQ8 and -DR3, -DQ2 T1D children., Conclusions: These data show that cryptic epitopes from the leader sequence of the PPI and GAD65271-285 and GAD65431-450 peptides might be among the critical antigenic epitopes eliciting the primary autoreactive responses in the early phases of the disease. These results may have implications in the design of immunogenic PPI and GAD65 peptides for peptide-based immunotherapy., Competing Interests: The 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 © 2023 Jores, Baldera, Schirru, Muntoni, Rossino, Manchinu, Marongiu, Caria, Ripoli, Ricciardi, Cucca and Congia.)

Additive Manufacturing (AM) techniques have recently attracted the attention of scientists for the development of prototypes with complex or particular geometry in a fast and cheap way. Among the different AM processes, the Fused Deposition Modelling process (FDM) offers several advantages in terms of costs, implementation features and design freedom. Recently, it has been adopted to realise auxetic structures, which are characterised by negative Poisson ratio, enhanced mechanical properties, and a higher compression resistance than conventional structures. This review outlines the use of AM processes, in particular FDM, to design and obtain auxetic structures, with the final aim to exploit their applications in different fields. The first part of this work presents a brief classification of auxetic structures and materials. Subsequently, a summary of additive manufacturing processes is presented, focusing on the use of FDM and its limitations. Finally, the studies on the use of additive manufacturing to produce auxetic structures are shown, evidencing the potential of the concurrent combination of a fast prototyping technique such as FDM and the characteristics of polymer- and/or composite-based auxetic structures. Indeed, this new technological field opens the possibility of realising novel structures with integrated smart behaviour, multifunctional properties, compression resistance, and a tailored microstructure and shape.

Disordered eating behaviors (DEB) are more common in adolescents with type 1 diabetes (T1D) than in peers without diabetes. Emotional eating is a risk factor for binge eating in children and adolescents in the general population and is associated with increased intake of high energy-dense foods rich in sugars and fats. The primary objective is to evaluate whether emotional eating is associated with the metabolic control (glycated hemoglobin, plasma lipids and uric acid) in children and adolescents with type 1 diabetes and whether subjects with DEB (DEPS-R ≥ 20) have higher emotional eating than those without DEB. The secondary objective is to evaluate whether emotional eating is associated with the different symptoms of DEB. Emotional eating is positively correlated with HbA1c, total and LDL cholesterol values in children and adolescents with T1D. Subjects with DEB have a higher emotional eating score than subjects without DEB. Disinhibition is the most common disordered eating behavior in children and adolescents with T1D and is associated with a higher emotional eating score. Early identification and treatment of emotional eating could be tools for preventing DEB in people with type 1 diabetes. A total of 212 adolescents with T1D completed two self-administered questionnaires: the Diabetes Eating Problem Survey-Revised (DEPS-R) and the Emotional Eating Scale for Children and Adolescents (EES-C). Demographic (age, sex, duration of the disease), anthropometric (weight, height, BMI, BMI-SDS), therapeutic (type of insulin therapy, daily insulin dose) and metabolic (HbA1c, total cholesterol, HDL, LDL, triglycerides, uric acid) data were taken from the patients' medical records. The presence of other autoimmune diseases was also recorded., (© 2022. The Author(s).)

[This corrects the article .]., (Copyright © 2022 Cherubini, Marino, Scaramuzza, Tiberi, Bobbio, Delvecchio, Piccinno, Ortolani, Innaurato, Felappi, Gallo, Ripoli, Ricciardi, Pascarella, Stamati, Citriniti, Arnaldi, Monti, Graziani, De Berardinis, Giannini, Chiarelli, Zampolli, De Marco, Bracciolini, Grosso, De Donno, Piccini, Toni, Coccioli, Cardinale, Bassi, Minuto, D’Annunzio, Maffeis, Marigliano, Zanfardino, Iafusco, Rollato, Piscopo, Curto, Lombardo, Bombaci, Sordelli, Mameli, Macedoni, Rigamonti, Bonfanti, Frontino, Predieri, Bruzzi, Mozzillo, Rosanio, Franzese, Piredda, Cardella, Iovane, Calcaterra, Berioli, Lasagni, Pampanini, Patera, Schiaffini, Rutigliano, Meloni, De Sanctis, Tinti, Trada, Guerraggio, Franceschi, Cauvin, Tornese, Franco, Musolino, Maltoni, Talarico, Iannilli, Lenzi, Matteoli, Pozzi, Moretti, Zucchini, Rabbone and Gesuita.)

The aim of this study was to investigate the association between uric acid (UA) and cardiometabolic risk factors (CMRFs) by sex in youth with type 1 diabetes (T1D). Retrospective data collected from 1323 children and adolescents (5-18 years; 716 boys) with T1D recruited in 9 Italian Pediatric Diabetes Centers were analyzed. CMRFs included UA, HbA 1c , blood pressure (BP), cholesterol (TC), HDL, triglycerides (TG), neutrophils (N) and lymphocytes (L) count, glomerular filtration rate (eGFR) (calculated using Schwartz-Lyon equation). In boys, we found a higher age, daily insulin dose, TG, TG/HDL ratio, TC/HDL ratio, systolic BP, N/L ratio and lower HDL, and eGFR across UA tertiles (p = 0.01-0.0001). Similar results were found in girls but not for TG and systolic BP. In boys, the odds ratio (OR) of high levels of TG/HDL ratio, TC/HDL ratio, BP and mildly reduced eGFR (MRGFR) increased for 0.5 mg/dL of UA. Instead, in girls an increased levels of 0.5 mg/dL of UA were associated with high OR of TC/HDL ratio, N/L ratio and MRGFR. Uric acid may represent a useful marker for identifying youth with T1D at high cardiometabolic risk, and this association appears to vary by sex., (© 2022. The Author(s).)

Aim/hypothesis: To compare the frequency of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in Italy during the COVID-19 pandemic in 2020 with the frequency of DKA during 2017-2019., Methods: Forty-seven pediatric diabetes centers caring for >90% of young people with diabetes in Italy recruited 4,237 newly diagnosed children with type 1 diabetes between 2017 and 2020 in a longitudinal study. Four subperiods in 2020 were defined based on government-imposed containment measures for COVID-19, and the frequencies of DKA and severe DKA compared with the same periods in 2017-2019., Results: Overall, the frequency of DKA increased from 35.7% (95%CI, 33.5-36.9) in 2017-2019 to 39.6% (95%CI, 36.7-42.4) in 2020 (p=0.008), while the frequency of severe DKA increased from 10.4% in 2017-2019 (95%CI, 9.4-11.5) to 14.2% in 2020 (95%CI, 12.3-16.4, p<0.001). DKA and severe DKA increased during the early pandemic period by 10.4% (p=0.004) and 8% (p=0.002), respectively, and the increase continued throughout 2020. Immigrant background increased and high household income decreased the probability of presenting with DKA (OR: 1.55; 95%CI, 1.24-1.94; p<0.001 and OR: 0.60; 95 CI, 0.41-0.88; p=0.010, respectively)., Conclusions/interpretation: There was an increase in the frequency of DKA and severe DKA in children newly diagnosed with type 1 diabetes during the COVID-19 pandemic in 2020, with no apparent association with the severity of COVID-19 infection severity or containment measures. There has been a silent outbreak of DKA in children during the pandemic, and preventive action is required to prevent this phenomenon in the event of further generalized lockdowns or future outbreaks., Competing Interests: No author reported any conflict of interest as regards this study. The following conflicts of interest pointed out are referred to a period from January 2020 to the submission of this manuscript. VCh’s institution has received research grants from AstraZeneca, Novonordisk, Eli Lilly, Movi, Dompè, and Menarini, and VCh received honoraria from Eli Lilly, Tandem, and Insulet for participating on speakers’ bureaus and scientific advisory boards. CR, DT, IRa, BPr, BPi, SZ, ST, and AR has received support Eli Lilly. In addition, SZ’s institution has received support from Pfeizer, ST, BPi, and DT have received support from Abbott and Theras. MM and AR have received support from Menarini. BPr and PB received honoraria for participating on speakers’ bureaus and scientific advisory boards for Sandoz. Lastly, RS has received research grants by Sanofi and received honoraria for participating on speakers’ bureaus and scientific advisory boards for Movi. 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 Cherubini, Marino, Scaramuzza, Tiberi, Bobbio, Delvecchio, Piccinno, Ortolani, Innaurato, Felappi, Gallo, Ripoli, Ricciardi, Pascarella, Stamati, Citriniti, Arnaldi, Monti, Graziani, De Berardinis, Giannini, Chiarelli, Zampolli, De Marco, Bracciolini, Grosso, De Donno, Piccini, Toni, Coccioli, Cardinale, Bassi, Minuto, D’Annunzio, Maffeis, Marigliano, Zanfardino, Iafusco, Rollato, Piscopo, Curto, Lombardo, Bombaci, Sordelli, Mameli, Macedoni, Rigamonti, Bonfanti, Frontino, Predieri, Bruzzi, Mozzillo, Rosanio, Franzese, Piredda, Cardella, Iovane, Calcaterra, Berioli, Lasagni, Pampanini, Patera, Schiaffini, Rutigliano, Meloni, De Sanctis, Tinti, Trada, Guerraggio, Franceschi, Cauvin, Tornese, Franco, Musolino, Maltoni, Talarico, Iannilli, Lenzi, Matteoli, Pozzi, Moretti, Zucchini, Rabbone and Gesuita.)

Aim: To evaluate the impact of a virtual educational camp (vEC) on glucose control in children and adolescents with type 1 diabetes using a closed-loop control (CLC) system., Materials and Methods: This was a prospective multicentre study of children and adolescents with type 1 diabetes using the Tandem Basal-IQ system. Insulin pumps were upgraded to Control-IQ, and children and their parents participated in a 3-day multidisciplinary vEC. Clinical data, glucose metrics and HbA1c were evaluated over the 12 weeks prior to the Control-IQ update and over the 12 weeks after the vEC., Results: Forty-three children and adolescents (aged 7-16 years) with type 1 diabetes and their families participated in the vEC. The median percentage of time in target range (70-180 mg/dL; TIR) increased from 64% (interquartile range [IQR] 56%-73%) with Basal-IQ to 76% (IQR 71%-81%) with Control-IQ (P < .001). After the vEC, more than 75% of participants achieved a TIR of more than 70%. The percentage of time between 180 and 250 mg/dL and above 250 mg/dL decreased by 5% (P < .01) and 6% (P < .01), respectively, while the time between 70 and 54 mg/dL and below 54 mg/dL remained low and unaltered. HbA1c decreased by 0.5% (P < .01). There were no episodes of diabetic ketoacidosis or severe hypoglycaemia., Conclusions: In this study of children managing their diabetes in a real-world setting, more than 75% of children who participated in a vEC after starting a CLC system could obtain and maintain a TIR of more than 70%. The vEC was feasible and resulted in a significant and persistent improvement in TIR in children and adolescents with type 1 diabetes., (© 2021 John Wiley & Sons Ltd.)