Fragment-based approach to identify IDO1 inhibitor building blocks

Abstract Indoleamine 2,3-dioxygenase 1 (IDO1) is attracting a great deal of interest as drug target in immune-oncology being highly expressed in cancer cells and participating to the tumor immune-editing process. Although several classes of IDO1 inhibitors have been reported in literature and patent applications, only few compounds have proved optimal pharmacological profile in preclinical studies to be advanced in clinical trials. Accordingly, the quest for novel structural classes of IDO1 inhibitors is still open. In this paper, we report a fragment-based screening campaign that combines Water-LOGSY NMR experiments and microscale thermophoresis approach to identify fragments that may be helpful for the development of novel IDO1 inhibitors as therapeutic agents in immune-oncology disorders

The epidemiological analysis of maxillofacial fractures in Italy: The experience of a single tertiary center with 1720 patients

Maxillofacial fractures represent a serious public health problem. Their epidemiology is extremely variable, and its analysis is crucial to establish effective treatment and prevention of these injuries. However only two works have been published about maxillofacial fracture epidemiology in Italy

A Relay Pathway between Arginine and Tryptophan Metabolism Confers Immunosuppressive Properties on Dendritic Cells

Arginase 1 (Arg1) and indoleamine 2,3-dioxygenase 1\ua0(IDO1) are immunoregulatory enzymes catalyzing the degradation of L-arginine and L-tryptophan, respectively, resulting in local amino acid deprivation. In addition, unlike Arg1, IDO1 is also endowed with non-enzymatic signaling activity in dendritic cells (DCs). Despite considerable knowledge of their individual biology, no integrated functions of Arg1 and IDO1 have been reported yet. We found that IDO1 phosphorylation and consequent activation of IDO1 signaling in DCs was strictly dependent on prior expression of Arg1 and Arg1-dependent production of polyamines. Polyamines, either produced by DCs or released by bystander Arg1+ myeloid-derived suppressor cells, conditioned DCs toward an IDO1-dependent, immunosuppressive phenotype via activation of the Src kinase, which has IDO1-phosphorylating activity. Thus our data indicate that Arg1 and IDO1 are linked by an entwined pathway in immunometabolism and that their joint modulation could represent an important target for effective immunotherapy in several disease settings

Assessment of deep vein thrombosis using routine pre- and postoperative duplex Doppler ultrasound in patients with pelvic trauma : a prospective study

Aims: The aims of this study were to assess the pre- and postoperative incidence of deep vein thrombosis (DVT) using routine duplex Doppler ultrasound (DUS), to assess the incidence of pulmonary embolism (PE) using CT angiography, and to identify the factors that predict postoperative DVT in patients with a pelvic and/or acetabular fracture. Methods: All patients treated surgically for a pelvic and/or acetabular fracture between October 2016 and January 2020 were enrolled into this prospective single-centre study. The demographic, medical, and surgical details of the patients were recorded. DVT screening of the lower limbs was routinely performed using DUS before and at six to ten days after surgery. CT angiography was used in patients who were suspected of having PE. Age-adjusted univariate and stepwise multiple logistic regression analysis were used to determine the association between explanatory variables and postoperative DVT. Results: A total of 191 patients were included. A DVT was found preoperatively in 12 patients (6.3%), of which six were proximal. A postoperative DVT was found in 42 patients (22%), of which 27 were proximal. Eight patients (4.2%) had a PE, which was secondary to a DVT in three. None of the 12 patients in whom a vena cava filter was implanted prophylactically had a PE. Multivariate logistic regression analysis indicated that the association with the need for spinal surgery (odds ratio (OR) 19.78 (95% confidence interval (CI) 1.12 to 348.08); p = 0.041), intramedullary nailing of a long bone fracture (OR 4.44 (95% CI 1.05 to 18.86); p = 0.043), an operating time > two hours (OR 3.28 (95% CI 1.09 to 9.88); p = 0.035), and additional trauma surgery (OR 3.1 (95% CI 1.03 to 9.45); p = 0.045) were statistically the most relevant independent predictors of a postoperative DVT. Conclusion: The acknowledgement of the risk factors for the development of a DVT and their weight is crucial to set a threshold for the index of suspicion for this diagnosis by medical staff. We suggest the routine use of the DUS screening for DVT in patients with a pelvic and/or acetabular fracture before and six to ten days after surgery. Cite this article: Bone Joint J 2022;104-B(2):283-289

Head and neck cancer management in the Covid-19 era: Our experience

Introduction: In March 2020 a new viral pandemic was declared. As etiological factor a virus belonging to the coronavirus family was isolated. This virus was named SARS-CoV-2 or COVID-19. This virus can cause different clinical frames, variating from mild symptomatology to cases of ARDS or death. Although the pandemic outbroke in China, COVID-19 had one of first hotspots in Italy, where the Public Health System needed a re-arrangement to face the disease. The incidence of oncological disease doesn't suffer any variation in relation to pandemics or emergency period, but need to be managed as soon as possible in every situation. In our maxillo-facial surgery Unit we continued our regular activities to treat all oncological patient that needed surgery during the pandemic. Because of the absence of knowledge about the COVID-19, first periods were very difficult to manage, due to the risk of infection of patients and health professionals. We decided to share our experience. Materials and methods: Between March and June 2020, 34 patients affected by head and neck cancer were admitted at our Unit. All patients underwent surgical treatment and were hospitalized until their situation guaranteed a safe discharge. Results: All patients treated for head and neck cancer underwent surgery. All the medical and nurse post-operative management was performed by health operators by using all the personal protective equipment (PPE) to prevent any possible infection. All contacts between patients and their family were suspended.During phase 1, all patients were submitted to a short verbal triage, measurements of physiological parameters and qualitative COVID-19 test. They were also screened by imaging to guarantee there were not any bronchopulmonary diseases referable to viral infections. During phase 2, patients were also screened by serological tests. During phase 3, all patients practiced oropharyngeal swap before being hospitalized. Discussion: During lockdown a re-arrangement of the management of oncological patients was mandatory. The difficulties were caused by the restriction of several activities that guarantee a normal health care system function. To date there is not a standardized therapeutic protocol to face the infection. Main therapies are symptomatic and a lot of patients need to be treated in ICUs. To prevent any possible infections, surgical activities were reserved only for urgent disease that cannot be delayed. In our Unit we continued to manage oncological patients. Social distancing and confinement measures were necessary and mandatory, in order to manage our patients. During first phases we had not any valid instrument to totally exclude COVID-19 infection. During phase 3, when oropharyngeal swaps were introduced in the screening of our patients, we could start to work in a safer way. Conclusion: There are still a lot of difficulties in the management of patients during COVID 19 pandemic. Because of the important consequences deriving from the delay of oncological patients their management must to be clearly defined

The Role of Bacterial Colonization of the Suture Thread in Early Identification and Targeted Antibiotic Treatment of Surgical Site Infections: A Prospective Cohort Study

Background: The aim of the present study is to investigate the role of the colonization of suture thread to identify patients at risk of developing a surgical site infection (SSI) after clean surgical procedures. Methods: Patients who underwent elective clean surgery procedures at the Surgery Unit of the AOU-University of Campania Luigi Vanvitelli in a 21-month period were prospectively enrolled. For each patient, a synthetic absorbable thread in Lactomer 9-1 was inserted into the surgical site at the end of surgery and microbiologically evaluated after 48 h. Antibiotic prophylaxis was chosen according to international guidelines. Results: A total of 238 patients were enrolled; 208 (87.4%) of them were subjected to clean procedures without the placement of prosthesis, and 30 (12.6%) with prosthesis. Of the 238 patients, 117 (49.2%) underwent an antimicrobial prophylaxis. Overall, 79 (33.2%) patients showed a bacterial colonization of the thread: among the 208 without the implantation of prosthesis, 19 (21.8%) of the 87 with antibiotic prophylaxis and in 58 (47.9%) of the 121 without it; among the 30 patients with the implantation of prosthesis, only two patients showed a colonized thread. The patients with antibiotic prophylaxis developed a colonization of the thread less frequently than those without it (17.9% vs. 47.9%, p < 0.001). SSI was observed in six (2.5%) patients, all of them showing a colonized thread (7.6% vs. 0%, p < 0.001). The bacteria identified in colonized threads were the same as those found in SSIs. Conclusions: Our study presents a new method that is able to precociously assess patients who have undergone clean procedures who may develop SSI, and identify the microorganism involved

The epidemiological analysis of maxillofacial fractures in Italy: The experience of a single tertiary center with 1720 patients

Purpose Maxillofacial fractures represent a serious public health problem. Their epidemiology is extremely variable, and its analysis is crucial to establish effective treatment and prevention of these injuries. However only two works have been published about maxillofacial fracture epidemiology in Italy. Materials and methods The records of 1720 patients diagnosed with maxillofacial fractures in a 15-years period (2001â\u80\u932015) in our department were retrospectively reviewed. Results A total of 1108 male and 612 female patients were included in the study. The most frequent aetiology of fracture was road traffic injuries (57.1%), followed by assault (21.7%), falls (14.2%), work accidents (3.5%), sport accidents (3.3%) and other causes (0.2%). Significant variations of aetiology were detected between males and females and between Italians and individuals from other countries. The most frequently observed fracture involved the mandible (861 cases, 36%), followed by zygoma (489 cases, 20.4%), orbital walls (386 cases, 16.1%) and maxilla (282 cases, 11.8%). Conclusion Road traffic legislation enforcement and continuous public education regarding the use of security devices remain an ongoing problem in our region and should be encouraged. In the same way, as migration flows influence and change the epidemiology of facial traumas, it is crucial to establish social support programs that avoid these disadvantaged categories of victims of violence and crime