Understanding the Roles of the Hedgehog Signaling Pathway during T-Cell Lymphopoiesis and in T-Cell Acute Lymphoblastic Leukemia (T-ALL)

The Hedgehog (HH) signaling network is one of the main regulators of invertebrate and vertebrate embryonic development. Along with other networks, such as NOTCH and WNT, HH signaling specifies both the early patterning and the polarity events as well as the subsequent organ formation via the temporal and spatial regulation of cell proliferation and differentiation. However, aberrant activation of HH signaling has been identified in a broad range of malignant disorders, where it positively influences proliferation, survival, and therapeutic resistance of neoplastic cells. Inhibitors targeting the HH pathway have been tested in preclinical cancer models. The HH pathway is also overactive in other blood malignancies, including T-cell acute lymphoblastic leukemia (T-ALL). This review is intended to summarize our knowledge of the biological roles and pathophysiology of the HH pathway during normal T-cell lymphopoiesis and in T-ALL. In addition, we will discuss potential therapeutic strategies that might expand the clinical usefulness of drugs targeting the HH pathway in T-ALL

Postsynthetic Metalated MOFs as Atomically Dispersed Catalysts for Hydroformylation Reactions

A manganese-based metal-organic framework with dipyrazole ligands has been metalated with atomically dispersed Rh and Co species and used as a catalyst for the hydroformylation of styrene. The Rh-based materials exhibited excellent conversion at 80 °C with complete chemoselectivity, high selectivity for the branched aldehyde, high recyclability, and negligible metal leaching

Correlations between chest-CT and laboratory parameters in SARS-CoV-2 pneumonia: A single-center study from Italy

To investigate the relationship between damaged lung assessed by chest computed tomography (CT) scan and laboratory biochemical parameters with the aim of finding other diagnostic tools. Patients who underwent chest CT for suspected Corona Virus Disease-2019 (COVID-19) pneumonia at the emergency department admission in the first phase of COVID-19 epidemic in Italy were retrospectively analyzed. Patients with both negative chest CT and absence of the novel coronavirus in nasopharyngeal or oropharyngeal real-time reverse transcriptase polymerase chain reaction (RT-PCR) swabs were excluded from the study. A total of 462 patients with positive CT scans for interstitial pneumonia were included in the study (250 males and 212 females, mean age 57 ± 17 years, range 18–89). Of these, 344 were positive to RT-PCR test, 118 were negative to double RT-PCR tests. CTs were analyzed for quantification of affected lung volume visually and by dedicated software. Statistical analysis to evaluate the relationship between laboratory analyses and CT patterns and amount of damaged lung related with COVID-19 pneumonia was performed in 2 groups of patients: positive RT-PCR COVID-19 group and negative RT-PCR COVID-19 group, but both with positive CT scans for interstitial pneumonia. Lymphocytopenia, C-reactive protein (CRP), lactate dehydrogenase (LDH), d-dimer, and fibrinogen increased levels occurred in most patients without statistically significant differences between the 2 groups with CT scans suggestive for COVID-19. In fact, in both groups the volume of lung damage was strongly associated with altered laboratory test results, even for patients with negative RT-PCR test. The decreased number of lymphocytes, and the increased levels of CRP, LDH, d-dimer, and fibrinogen levels are associated with SARS-CoV 2 related pneumonia. This may be useful as an additional diagnostic tool in patients with double negative RT-PCR assay and with highly suspected clinic and chest CT features for COVID-19 to isolate patients in a pandemic period.publishedVersio

Correlation between Chest Computed Tomography Score and Laboratory Biomarkers in the Risk Stratification of COVID-19 Patients Admitted to the Emergency Department

background: it has been reported that mid-regional proadrenomedullin (MR-proADM) could be considered a useful tool to stratify the mortality risk in COVID-19 patients upon admission to the emergency department (ED). during the COVID-19 outbreak, computed tomography (CT) scans were widely used for their excellent sensitivity in diagnosing pneumonia associated with SARS-CoV-2 infection. however, the possible role of CT score in the risk stratification of COVID-19 patients upon admission to the ED is still unclear. aim: the main objective of this study was to assess if the association of the CT findings alone or together with MR-proADM results could ameliorate the prediction of in-hospital mortality of COVID-19 patients at the triage. moreover, the hypothesis that CT score and MR-proADM levels together could play a key role in predicting the correct clinical setting for these patients was also evaluated. methods: epidemiological, demographic, clinical, laboratory, and outcome data were assessed and analyzed from 265 consecutive patients admitted to the triage of the ED with a SARS-CoV-2 infection. results and conclusions: the accuracy results by AUROC analysis and statistical analysis demonstrated that CT score is particularly effective, when utilized together with the MR-proADM level, in the risk stratification of COVID-19 patients admitted to the ED, thus helping the decision-making process of emergency physicians and optimizing the hospital resources

Fibrosis-4 (FIB-4) Index and mortality in COVID-19 patients admitted to the emergency department

Liver damage worsens the prognosis of coronavirus 19 disease (COVID-19). However, the best strategy to stratify mortality risk according to liver damage has not been established. The aim of this study is to test the predictive value of the validated Fibrosis-4 (FIB-4) Index and compared it to liver transaminases and to the AST-to-Platelet ratio index (APRI). Multicenter cohort study including 992 consecutive COVID-19 patients admitted to the Emergency Department. FIB-4 > 3.25 and APRI > 0.7 were used to define liver damage. Multivariable Cox regression and ROC curve analysis for mortality were performed. Secondary endpoints were (1) need for high-flow oxygen and (2) mechanical ventilation. 240 (24.2%) patients had a FIB-4 > 3.25. FIB-4 > 3.25 associated with an increased mortality (n = 119, log-rank test p  3.25 was also superior to APRI > 0.7 (AUC 0.58, 95% CI 0.553-0.615, p = 0.0008). Using an optimized cut-off > 2.76 (AUC 0.689, 95% CI 0.659-0.718, p  3.25 (p = 0.0302), APRI > 0.7 (p  51 (p = 0.0119) and ALT > 42 (p < 0.0001). FIB-4 was also associated with high-flow oxygen use (n = 255, HR 1.69, 95% CI 1.25-2.28, p = 0.001) and mechanical ventilation (n = 39, HR 2.07, 95% CI 1.03-4.19, p = 0.043). FIB-4 score predicts mortality better than liver transaminases and APRI score. FIB-4 score may be an easy tool to identify COVID-19 patients at worse prognosis in the emergency department

Minimally Invasive Autopsy Practice in COVID-19 Cases: Biosafety and Findings

Postmortem studies are crucial for providing insight into emergent diseases. However, a complete autopsy is frequently not feasible in highly transmissible diseases due to biohazard challenges. Minimally invasive autopsy (MIA) is a needle-based approach aimed at collecting samples of key organs without opening the body, which may be a valid alternative in these cases. We aimed to: (a) provide biosafety guidelines for conducting MIAs in COVID-19 cases, (b) compare the performance of MIA versus complete autopsy, and (c) evaluate the safety of the procedure. Between October and December 2020, MIAs were conducted in six deceased patients with PCR-confirmed COVID-19, in a basic autopsy room, with reinforced personal protective equipment. Samples from the lungs and key organs were successfully obtained in all cases. A complete autopsy was performed on the same body immediately after the MIA. The diagnoses of the MIA matched those of the complete autopsy. In four patients, COVID-19 was the main cause of death, being responsible for the different stages of diffuse alveolar damage. No COVID-19 infection was detected in the personnel performing the MIAs or complete autopsies. In conclusion, MIA might be a feasible, adequate and safe alternative for cause of death investigation in COVID-19 cases

Fibrosis-4 (FIB-4) index and mortality in COVID-19 patients admitted to the emergency department

: Liver damage worsens the prognosis of coronavirus 19 disease (COVID-19). However, the best strategy to stratify mortality risk according to liver damage has not been established. The aim of this study is to test the predictive value of the validated Fibrosis-4 (FIB-4) Index and compared it to liver transaminases and to the AST-to-Platelet ratio index (APRI). Multicenter cohort study including 992 consecutive COVID-19 patients admitted to the Emergency Department. FIB-4 &gt; 3.25 and APRI &gt; 0.7 were used to define liver damage. Multivariable Cox regression and ROC curve analysis for mortality were performed. Secondary endpoints were (1) need for high-flow oxygen and (2) mechanical ventilation. 240 (24.2%) patients had a FIB-4 &gt; 3.25. FIB-4 &gt; 3.25 associated with an increased mortality (n = 119, log-rank test p &lt; 0.001 and adjusted hazard ratio (HR) 1.72 (95% confidence interval [95%CI] 1.14-2.59, p = 0.010). ROC analysis for mortality showed that FIB-4 (AUC 0.734, 95% CI 0.705-0.761) had a higher predictive value than AST (p = 0.0018) and ALT (p &lt; 0.0001). FIB-4 &gt; 3.25 was also superior to APRI &gt; 0.7 (AUC 0.58, 95% CI 0.553-0.615, p = 0.0008). Using an optimized cut-off &gt; 2.76 (AUC 0.689, 95% CI 0.659-0.718, p &lt; 0.0001), FIB-4 was superior to FIB-4 &gt; 3.25 (p = 0.0302), APRI &gt; 0.7 (p &lt; 0.0001), AST &gt; 51 (p = 0.0119) and ALT &gt; 42 (p &lt; 0.0001). FIB-4 was also associated with high-flow oxygen use (n = 255, HR 1.69, 95% CI 1.25-2.28, p = 0.001) and mechanical ventilation (n = 39, HR 2.07, 95% CI 1.03-4.19, p = 0.043). FIB-4 score predicts mortality better than liver transaminases and APRI score. FIB-4 score may be an easy tool to identify COVID-19 patients at worse prognosis in the emergency department

Multiple contemporary arterial dissection in Ehlers-Danlos syndrome type IV

We report a case of multiple spontaneous arteries dissection in a 52-year-old female; the patient had a relevant family history of vascular complications and typical features so we hypothesized vascular Ehlers-Danlos syndrome (EDS) that was confirmed by genetic analysis of COL3A1 gene. We adopted a conservative approach: the patient was treated with heparin in the acute phase followed by aspirin and then celiprolol was started on the basis of a recent trial that demonstrates a reduction in arterial events in EDS patient treated. A careful follow-up was done with Doppler ultrasound and computed tomography scan, as non-invasive diagnostic techniques are preferred in these patients, and no other vascular symptomatic events have occurred. We tested all living relatives: half of them had COL3A1 mutation, they were referred to another center specialized in rare diseases and EDS for long-term follow-up and genetic counseling. This case demonstrates as a careful evaluation of clinical signs, clinical history of the patient and his family has allowed a definitive diagnosis, proper management of the patient during the acute event and in terms of prophylaxis of recurrence

Production and Quality Control of [¹⁷⁷Lu]Lu-PSMA-I&T: Development of an Investigational Medicinal Product Dossier for Clinical Trials

Since prostate cancer is the most commonly diagnosed malignancy in men, the theranostic approach has become very attractive since the discovery of urea-based PSMA inhibitors. Different molecules have been synthesized starting from the Glu-urea-Lys scaffold as the pharmacophore and then optimizing the linker and the chelate to improve functional characteristics. This article aimed to highlight the quality aspects, which could have an impact on clinical practice, describing the development of an Investigational Medicinal Product Dossier (IMPD) for clinical trials with [177Lu]Lu-PSMA-I&T in prostate cancer and other solid tumors expressing PSMA. The results highlighted some important quality issues of the final preparation: radiolabeling of PSMA-I&T with lutetium-177 needs a considerably longer time compared with the radiolabeling of the well-known [177Lu]Lu-PSMA-617. When the final product was formulated in saline, the stability of [177Lu]Lu-PSMA-I&T was reduced by radiolysis, showing a decrease in radiochemical purity (<95% in 24 h). Different formulations of the final product with increasing concentrations of ascorbic acid have been tested to counteract radiolysis and extend stability. A solution of 20 mg/mL of ascorbic acid in saline prevents radiolysis and ensures stability over 30 h