Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy ...represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4
T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM.
Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3–5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously ...believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.
In the last two decades, Fiber Reinforced Polymer (FRP) composites were effectively used for increasing the load-carrying capacity of masonry arches and for improving their mechanical response ...against the most critical arch failure mechanisms.
More recently, Fabric Reinforced Cementitious Matrix (FRCM) composites are appearing significantly promising for the strengthening of masonry arches, providing an alternative to the FRP composites, but only few experimental contributions are available to date.
In the present paper, the structural performance of masonry arches strengthened both at intrados and at extrados by using a polybenzoxazole (PBO) fabric reinforced cementitious mortar composite was experimentally investigated. Results, in terms of load-carrying capacity, post peak behavior and failure mechanism, were compared with those determined by using a Carbon Fiber Reinforced Polymer (CFRP) composite. The present experimental study contributes to improve the knowledge of the innovative PBO-FRCM composites and it provides mechanical data useful for defining masonry strengthening design guidelines.
In this research, our primary objective was to explore the correlation between basal ganglia dopaminergic neurotransmission, assessed using 123I-FP-CIT (DAT-SPECT), and finger movements abnormalities ...in patients with essential tremor (ET) and Parkinson's disease (PD).
We enrolled 16 patients with ET, 17 with PD, and 18 healthy controls (HC). Each participant underwent comprehensive clinical evaluations, kinematic assessments of finger tapping. ET and PD patients underwent DAT-SPECT imaging. The DAT-SPECT scans were subjected to both visual and semi-quantitative analysis using DaTQUANT®. We then investigated the correlations between the clinical, kinematic, and DAT-SPECT data, in patients.
Our findings confirm that individuals with ET exhibited slower finger tapping than HC. Visual evaluation of radiotracer uptake in both striata demonstrated normal levels within the ET patient cohort, while PD patients displayed reduced uptake. However, there was notable heterogeneity in the quantification of uptake within the striata among ET patients. Additionally, we found a correlation between the amount of radiotracer uptake in the striatum and movement velocity during finger tapping in patients. Specifically, lower radioligand uptake corresponded to decreased movement velocity (ET: coef. = 0.53, p-adj = 0.03; PD: coef. = 0.59, p-adj = 0.01).
The study's findings suggest a potential link between subtle changes in central dopaminergic tone and altered voluntary movement execution, in ET. These results provide further insights into the pathophysiology of ET. However, longitudinal studies are essential to determine whether the slight reduction in dopaminergic tone observed in ET patients represents a distinct subtype of the disease or could serve as a predictor for the clinical progression into PD.
Introduction: The term theragnostic refers to the combination of a predictive imaging biomarker with a therapeutic agent. The promising application of prostate-specific membrane antigen (PSMA)-based ...radiopharmaceuticals in the imaging and treatment of prostate cancer (PCa) patients opens the way to investigate a possible role of PSMA-based radiopharmaceuticals in cancers beyond the prostate. Therefore, the aim of this review was to evaluate the role of 177Lu-PSMA radioligand therapy (RLT) in malignancies other than prostate cancer by evaluating preclinical, clinical studies, and ongoing clinical trials. Methods: An extensive literature search was performed in three different databases using different combinations of the following terms: “Lu-PSMA”, “177Lu-PSMA”, “preclinical”, “mouse”, “salivary gland cancer”, “breast cancer”, “glioblastoma”, “solid tumour”, “renal cell carcinoma”, “HCC”, “thyroid”, “salivary”, “radioligand therapy”, and “lutetium-177”. The search had no beginning date limit and was updated to April 2024. Only articles written in English were included in this review. Results: A total of four preclinical studies were selected (breast cancer model n = 3/4). PSMA-RLT significantly reduced cell viability and had anti-angiogenic effects, especially under hypoxic conditions, which increase PSMA binding and uptake. Considering the clinical studies (n = 8), the complexity of evaluating PSMA-RLT in cancers other than prostate cancer was clearly revealed, since in most of the presented cases a sufficient tumour radiation dose was not achieved. However, encouraging results can be found in some types of diseases, such as thyroid cancer. Some clinical trials are still ongoing, and results from prospective larger cohorts of patients are awaited. Conclusions: The need for larger patient cohorts and more RLT cycles administered underscores the need for further comprehensive studies. Given the very preliminary results of both preclinical and clinical studies, ongoing clinical trials in the near future may provide stronger evidence of both the safety and therapeutic efficacy of PSMA-RLT in malignancies other than prostate cancer.
Aging accounts for increased risk and dismal outcome of ischemic stroke. Here, we investigated the impact of age-related changes in the immune system on stroke. Upon experimental stroke, compared ...with young mice, aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes. Aged mice showed an enhanced granulopoietic response to stroke that led to the accumulation of CD101
CD62L
mature and CD177
CD101
CD62L
and CD177
CD101
CD62L
immature atypical neutrophils in the blood, endowed with increased oxidative stress, phagocytosis and procoagulant features. Production of CXCL3 by CD62L
neutrophils of the aged had a key role in the development and pathogenicity of aging-associated neutrophils. Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome. In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62L
neutrophil subsets associated with worse reperfusion and outcome. Our results unveil how stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome.
Positron emission tomography (PET) is an instrumental diagnostic modality developed around the positron-emitting radioisotopes of biologically important elements such as carbon, oxygen and nitrogen ...(11C, 15O, 13N). Among longer-lived PET radionuclides, 18F is by far the most commonly used radiotracer, extensively used for tumour imaging with FDG (18F-fluorodeoxyglucose) and also frequently investigated in the development of novel radiopharmaceuticals. Many other positron- emitting radionuclides with higher atomic numbers and longer half-lives have been investigated for both imaging and therapeutic purposes, including the halogens (124I, 120I, 76Br) and a number of metal radionuclides. The radio-copper has attracted considerable attention, because they include isotopes which, due to their emission properties, offer themselves as agents of both diagnostic imaging (60Cu, 61Cu, 62Cu, 64Cu) and in vivo targeted radiation therapy (64Cu and 67Cu).
Although the use of this radionuclide has grown exponentially over the last decade, academic institutions have largely been responsible for its production and for the development of the vast majority of radiopharmaceutical based on these nuclides. A number of compounds labelled with Cuisotopes have been proposed, not only for imaging purposes but also for therapy. The aim of the present paper is to provide an overview on the clinical results obtained in human beings with copper radionuclides.
Several preliminary studies and clinical trials evaluated the potential clinical role of copper radioisotopes for diagnostic and therapeutic purposes. 64Cu seems to be the most suitable radioisotope for future clinical applications due to its longer half-life (12.7 h) and its commercial availability. Future clinical applications of copper radioisotopes could be enhanced by the possibility of radioligand therapy with the beta-emitting 67Cu, creating a new "theranostics pair".
Background
Hypertension management in older patients represents a challenge, particularly when hospitalized.
Objective
The objective of this study is to investigate the determinants and related ...outcomes of antihypertensive drug prescription in a cohort of older hospitalized patients.
Methods
A total of 5671 patients from REPOSI (a prospective multicentre observational register of older Italian in‐patients from internal medicine or geriatric wards) were considered; 4377 (77.2%) were hypertensive. Minimum treatment (MT) for hypertension was defined according to the 2018 ESC guidelines an angiotensin‐converting‐enzyme‐inhibitor (ACE‐I) or an angiotensin‐receptor‐blocker (ARB) with a calcium‐channel‐blocker (CCB) and/or a thiazide diuretic; if >80 years old, an ACE‐I or ARB or CCB or thiazide diuretic. Determinants of MT discontinuation at discharge were assessed. Study outcomes were any cause rehospitalization/all cause death, all‐cause death, cardiovascular (CV) hospitalization/death, CV death, non‐CV death, evaluated according to the presence of MT at discharge.
Results
Hypertensive patients were older than normotensives, with a more impaired functional status, higher burden of comorbidity and polypharmacy. A total of 2233 patients were on MT at admission, 1766 were on MT at discharge. Discontinuation of MT was associated with the presence of comorbidities (lower odds for diabetes, higher odds for chronic kidney disease and dementia). An adjusted multivariable logistic regression analysis showed that MT for hypertension at discharge was associated with lower risk of all‐cause death, all‐cause death/hospitalization, CV death, CV death/hospitalization and non‐CV death.
Conclusions
Guidelines‐suggested MT for hypertension at discharge is associated with a lower risk of adverse clinical outcomes. Nevertheless, changes in antihypertensive treatment still occur in a significant proportion of older hospitalized patients.
In this observational cohort study, we investigated the impact of hospitalization on changes in antihypertensive therapy in 5671 hypertensive older inpatients from the REPOSI register. Fifty‐one percent of patients were on minimum treatment (MT, defined according to the 2018 ESC guidelines) at admission. This percentage reduced to 40% at discharge, mostly due to specific clinical impairment and comorbidities such as chronic kidney disease and dementia. Maintaining a MT at discharge was associated with a lower risk of major clinical outcomes.
Chronic kidney disease remains an important risk factor for morbidity and mortality among LT recipients, but its exact incidence and risk factors are still unclear.
We carried out a retrospective ...cohort study of consecutive adults who underwent liver transplant (January 2009–December 2018) and were followed (at least 6 months) at our institution. CKD was defined following the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines. Long-term kidney function was classified into 4 groups: no CKD (eGFR, ≥60mL/min/1.73m2), mild CKD (eGFR, 30–59mL/min/1.73m2), severe CKD (eGFR, 15–29mL/min/1.73m2), and end-stage renal disease (ESRD).
We enrolled 410 patients followed for 53.2±32.6 months. 39 had CKD at baseline, and 95 developed de novo CKD over the observation period. There were 184 (44.9%) anti-HCV positive, 47 (11.5%) HBsAg positive, and 33 (8.1%) HBV/HDV positive recipients. Recipient risk factors for baseline CKD were advanced age (P=0.044), raised levels of serum uric acid (P<0.0001), and insulin dependent DM (P=0.0034). Early post-transplant AKI was common (n=95); logistic regression analysis found that baseline serum creatinine was an independent predictor of early post-LT AKI (P=0.0154). According to our Cox proportional hazards model, recipient risk factors for de novo CKD included aging (P<0.0001), early post-transplant AKI (P=0.007), and baseline serum creatinine (P=0.0002). At the end of follow-up, there were 116 LT recipients with CKD – 109 (93.9%) and 7 (6.1%) had stage 3 and advanced CKD, respectively. Only two of them are undergoing long-term dialysis.
The incidence of CKD was high in our cohort of LT recipients, but only a slight decline in kidney function over time was recorded. Prevention of post-transplant AKI will improve kidney function in the long run. We need more studies to analyze the function of kidneys among LT recipients over extended follow-ups and their impact on mortality.
La enfermedad renal crónica (ERC) sigue siendo un importante factor de riesgo de morbimortalidad entre los receptores de un trasplante hepático (TH), su incidencia exacta y sus factores de riesgo aún no están claros.
Llevamos a cabo un estudio de cohortes retrospectivo de adultos incluidos de forma consecutiva que habían recibido un TH (de enero de 2009 a diciembre de 2018) e hicimos el seguimiento (mínimo 6 meses) en nuestra institución. La ERC se definió siguiendo las guías de práctica clínica Kidney Disease: Improving Global Outcomes (KDIGO) de 2012. La función renal a largo plazo se clasificó en 4 grupos: sin ERC (filtración glomerular estimada FGe>60ml/min/1,73m2), ERC leve (FGe: 30-59ml/min/1,73m2), ERC grave (FGe: 15-29ml/min/1,73m2) y enfermedad renal terminal (ERT).
Incluimos a 410 pacientes a los que se hizo un seguimiento durante 53,2±32,6 meses: 39 tenían ERC al inicio y 95 desarrollaron ERC de novo durante el periodo de observación. Había 184 (44,9%) receptores con anticuerpos contra el VHC, 47 (11,5%) con positividad para el HBsAg y 33 (8,1%) portadores del virus de la hepatitis B (VHB) o el virus de la hepatitis D (VHD). Los factores de riesgo de los receptores para presentar ERC al inicio fueron la edad avanzada (p=0,044), unos niveles elevados de ácido úrico en suero (p<0,0001) y la presencia de diabetes mellitus (DM) insulinodependiente (p=0,0034). La aparición temprana de lesión renal aguda (LRA) postrasplante fue frecuente (n=95); un análisis de regresión logística reveló que la creatinina sérica al inicio era un factor predictivo independiente de LRA temprana después del TH (p=0,0154). Según nuestro modelo de riesgos proporcionales de Cox, los factores de riesgo de los receptores para presentar ERC de novo incluyeron la edad avanzada (p<0,0001), una LRA temprana postrasplante (p=0,007) y la creatinina sérica al inicio (p=0,0002). Al final del seguimiento, había 116 receptores de TH con ERC, 109 (93,9%) y 7 (6,1%) tenían ERC en estadio 3 y avanzada, respectivamente. Solo 2 de ellos estaban recibiendo diálisis a largo plazo.
La incidencia de ERC fue alta en nuestra cohorte de receptores de TH, pero solo se registró una ligera disminución de la función renal a lo largo del tiempo. La prevención de la LRA postrasplante mejorará la función renal a largo plazo. Necesitamos más estudios para analizar la función de los riñones entre los receptores de TH durante seguimientos prolongados, así como su efecto sobre la mortalidad.
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