Molecular mechanisms behind BRACO19 and human telomeric G-quadruplex interaction.

Human telomeres (HTs) can form DNA G-quadruplex (G4), an attractive target for anticancer and antiviral drugs. HT-G4s exhibit inherent structural polymorphism, posing challenges for understanding their specific recognition by ligands. Here, we aim to explore the impact of different topologies within a small segment of the HT (Tel22) on its interaction with BRACO19, a rationally designed G4 ligand with high quadruplex affinity, already employed in in-vivo treatments. Our multi-technique approach is based on the combined use of a set of contactless spectroscopic tools. Circular dichroism and UV resonance Raman spectroscopy probe ligand-induced conformational changes in the G4 sequence, while UV-visible absorption, coupled with steady-state fluorescence spectroscopy, provides further insights into the electronic features of the complex, exploiting the photoresponsive properties of BRACO19. Overall, we find that modifying the topology of the unbound Tel22 through cations (K+ or Na+), serves as a critical determinant for ligand interactions and binding modes, thus influencing the HT-G4's assembly capabilities. Furthermore, we show how fluorescence serves as a valuable probe for recognizing cation-driven multimeric structures, which may be present in living organisms, giving rise to pathological forms.

Expression of the membrane tetraspanin claudin 18 on cancer cells promotes T lymphocyte infiltration and antitumor immunity in pancreatic cancer.

Tumors weakly infiltrated by T lymphocytes poorly respond to immunotherapy. We aimed to unveil malignancy-associated programs regulating T cell entrance, arrest, and activation in the tumor environment. Differential expression of cell adhesion and tissue architecture programs, particularly the presence of the membrane tetraspanin claudin (CLDN)18 as a signature gene, demarcated immune-infiltrated from immune-depleted mouse pancreatic tumors. In human pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer, CLDN18 expression positively correlated with more differentiated histology and favorable prognosis. CLDN18 on the cell surface promoted accrual of cytotoxic T lymphocytes (CTLs), facilitating direct CTL contacts with tumor cells by driving the mobilization of the adhesion protein ALCAM to the lipid rafts of the tumor cell membrane through actin. This process favored the formation of robust immunological synapses (ISs) between CTLs and CLDN18-positive cancer cells, resulting in increased T cell activation. Our data reveal an immune role for CLDN18 in orchestrating T cell infiltration and shaping the tumor immune contexture.

Extracellular vesicles from adipose mesenchymal stem cells target inflamed lymph nodes in experimental autoimmune encephalomyelitis.

BACKGROUND AIMS: Adipose mesenchymal stem cells (ASCs) represent a promising therapeutic approach in inflammatory neurological disorders, including multiple sclerosis (MS). Recent lines of evidence indicate that most biological activities of ASCs are mediated by the delivery of soluble factors enclosed in extracellular vesicles (EVs). Indeed, we have previously demonstrated that small EVs derived from ASCs (ASC-EVs) ameliorate experimental autoimmune encephalomyelitis (EAE), a murine model of MS. The precise mechanisms and molecular/cellular target of EVs during EAE are still unknown. METHODS: To investigate the homing of ASC-EVs, we intravenously injected small EVs loaded with ultra-small superparamagnetic iron oxide nanoparticles (USPIO) at disease onset in EAE-induced C57Bl/6J mice. Histochemical analysis and transmission electron microscopy were carried out 48 h after EV treatment. Moreover, to assess the cellular target of EVs, flow cytometry on cells extracted ex vivo from EAE mouse lymph nodes was performed. RESULTS: Histochemical and ultrastructural analysis showed the presence of labeled EVs in lymph nodes but not in lungs and spinal cord of EAE injected mice. Moreover, we identified the cellular target of EVs in EAE lymph nodes by flow cytometry: ASC-EVs were preferentially located in macrophages, with a consistent amount also noted in dendritic cells and CD4+ T lymphocytes. CONCLUSIONS: This represents the first direct evidence of the privileged localization of ASC-EVs in draining lymph nodes of EAE after systemic injection. These data provide prominent information on the distribution, uptake and retention of ASC-EVs, which may help in the development of EV-based therapy in MS.

A walnut shell biochar-nano zero-valent iron composite membrane for the degradation of carbamazepine via persulfate activation.

In this study, novel walnut shell biochar-nano zero-valent iron nanocomposites (WSBC-nZVI) were synthesized using a combined pyrolysis/reduction process. WSBC-nZVI displayed a high removal efficiency (86 %) for carbamazepine (CBZ) compared with walnut shell biochar (70 %) and nano zero-valent iron (76 %) in the presence of persulfate (PS) (0.5 g/L catalyst, 10 mg/L CBZ, 1 mM persulfate). Subsequently, WSBC-nZVI was applied for the fabrication of the membrane using a phase inversion method. The membrane demonstrated an excellent removal efficiency of 91 % for CBZ in a dead-end system (2 mg/L CBZ, 1 mM persulfate). In addition, the effect of various operating conditions on the degradation efficiency in the membrane/persulfate system was investigated. The optimum pH was close to neutral, and an increase in CBZ concentration from 1 mg/L to 10 mg/L led to a drop in removal efficiency from 100 % to 24 %. The degradation mechanisms indicated that oxidative species, including 1O2, OH, SO4-, and O2-, all contribute to the degradation of CBZ, while the role of 1O2 is highlighted. The CBZ degradation products were also investigated, and the possible pathways and the predicted toxicity of intermediates were proposed. Furthermore, the practical use of the membrane was validated by the treatment of real wastewater.

Quality of life and emotional distress in sarcoma patients diagnosed during COVID-19 pandemic: a supplementary analysis from the SarCorD study.

Background: The COVID-19 outbreak had a negative psychological impact on cancer patients. In this study, we analyzed emotional distress and quality of life in patients diagnosed with sarcoma during the first year of the pandemic compared to the previous year. Methods: We retrospectively enrolled patients with soft tissue, bone sarcoma, and aggressive benign musculoskeletal diseases diagnosed during the pandemic (COVID group) or the year before (control group) at the IRCCS Regina Elena National Cancer Institute in Rome. Patients who had undergone a psychological assessment with the EORTC QLQ-C30 and the Distress Thermometer at diagnosis were included in the final analysis. We analyzed whether there is a difference in the various domains of quality of life between the two groups and whether there are changes over time in each group. Results: We enrolled 114 patients (72 control group; 42 COVID group), affected by soft tissue (64%), bone sarcoma (29%), and aggressive benign musculoskeletal diseases (7%). We did not observe significant differences in the health-related quality of life domains in the control and COVID groups, except for the financial domain (p = 0.039), with 9.7% vs. 23.8% of patients with a score > 0 in the control and COVID groups, respectively. We observed emotional distress at diagnosis in 48.6% of patients in the control group vs. 69.0% in the COVID group (p = 0.034). In the control group, we observed an improvement in physical function (p = 0.043) and in QoL (p = 0.022), while in the COVID group, we observed a deterioration in role function (p = 0.044) during follow-up. In the COVID group, 22.2% of patients were concerned about COVID-19, 61.1% by tumor, 91.1% stated that the pandemic worsened their subjective perception of cancer, and 19.4% perceived that their quality of care had worsened. Conclusion: We observed a higher level of distress among patients diagnosed during the pandemic compared to the year before, probably due to the increased concern for both infection and cancer, the worsened perception of health status, and the perception of a poorer quality of health care.

The giant cell tumor during pregnancy: A review of literature.

BACKGROUND: Giant cell tumors (GTC) of bone are benign, locally aggressive tumors generally occurring in young people with a female predominance during reproductive age. Considering their worsening during pregnancy it has been suggested that pregnancy can accelerate GCT progression or favor recurrence but correlation between tumor growth and pregnancy has not yet been clarified. Aim of this study was to clarify clinical characteristics, timing and type of treatment through a literature review on GTCs occurring during pregnancy. PATIENTS AND METHODS: An electronic search was performed in December 2020 in PubMed, Scopus, Embase, Medline, Cochrane Register using the keywords "giant cell tumor" AND "pregnancy" looking for papers reporting cases of giant cell tumors of the bone onset or recurred during pregnancy. The electronic search identified 212 papers; sixteen studies were selected, for a total of 32 cases. RESULTS: The diagnosis was made during pregnancy in 24 cases and after the partum in 8 cases. 27 cases were new diagnoses while 5 cases were recurrences. Pulmonary metastases were reported in 3 patients. The treatment was performed during the pregnancy in 7 out of 32 cases; in the remaining 27 cases treatment was performed after delivery. The hormone receptor status was reported in 14 patients. Data regarding follow-up was reported for 26 out of 32 patients; three patients had local recurrences that were treated with wide resection and amputation in 2 and 1 case, respectively; at the last follow-up all patients were apparently without any evidence of disease except for three patients who had stable lung metastases. DISCUSSION: In case of GCT during pregnancy, a multidisciplinary approach is necessary to offer the patients the best treatment in terms of mother and child's health. A correct diagnosis is necessary and not confusing tumor symptoms with ones of pregnancy is mandatory in order not to delay the diagnosis and let the tumor progress. Actually, even though pregnancy would seem to promote GCT growth and aggressiveness, the relationship is not clear. More studies are necessary to clarify this interesting aspect. LEVEL OF EVIDENCE: IV, systematic review.

A multi-marker integrative analysis reveals benefits and risks of bariatric surgery.

Bariatric surgery (BS) is an effective intervention for severe obesity and associated comorbidities. Although several studies have addressed the clinical and metabolic effects of BS, an integrative analysis of the complex body response to surgery is still lacking. We conducted a longitudinal data study with 36 patients with severe obesity who were tested before, 6 and 12 months after restrictive BS for more than one hundred blood biomarkers, including clinical, oxidative stress and metabolic markers, peptide mediators and red blood cell membrane lipids. By using a synthetic data-driven modeling based on principal component and correlation analyses, we provided evidence that, besides the early, well-known glucose metabolism- and weight loss-associated beneficial effects of BS, a tardive, weight-independent increase of the hepatic cholesterol metabolism occurs that is associated with potentially detrimental inflammatory and metabolic effects. Canonical correlation analysis indicated that oxidative stress is the most predictive feature of the BS-induced changes of both glucose and lipids metabolism. Our results show the power of multi-level correlation analysis to uncover the network of biological pathways affected by BS. This approach highlighted potential health risks of restrictive BS that are disregarded with the current practice to use weight loss as surrogate of BS success.

The impact of the COVID-19 pandemic on diagnosis and treatment of patients with soft tissue and bone sarcomas or aggressive benign musculoskeletal diseases: A single-center retrospective study (SarCorD study).

Background: The COVID-19 pandemic led to a rapid reorganization of healthcare activities, leading to reduced access to clinics, interruption of screenings, and treatment schedule modifications in several cancer types. Few data are available on sarcomas. We analyzed COVID-19-related diagnostic delay in a sarcoma referral center in Italy. Methods: We retrospectively enrolled in this study patients with histological diagnosis of soft tissue or bone sarcoma and aggressive benign musculoskeletal diseases obtained during the first year of the pandemic (Covid group) or the year before (Control group) and followed at the Regina Elena National Cancer Institute in Rome. The primary endpoint was the time from the first symptom to histological diagnosis. Results: We evaluated 372 patients, 185 of whom were eligible for primary endpoint analysis (92 patients in the Control group and 93 patients in the Covid group). The patients were affected by soft tissue sarcoma in most cases (63.0% and 66.7% in Covid and Control groups, respectively). We observed a diagnostic delay in the Covid group with a median time from the first symptom to the definitive histological diagnosis of 103.00 days (95% CI 92.77-113.23) vs. 90.00 days (95% CI 69.49-110.51) in the Control group (p = 0.024), but not a delay in treatment beginning (151 days, 95% CI 132.9-169.1 vs. 144 days, 95% CI 120.3-167.7, respectively, p = 0.208). No differences in stage at diagnosis were observed (12% vs. 16.5% of patients with metastatic disease at diagnosis in the Covid and Control groups, respectively, p = 0.380). Progression-free survival (p = 0.897) and overall survival (p = 0.725) were comparable in the subgroup of patients affected by soft tissue sarcoma. Conclusions: A delay in sarcoma diagnosis but not in starting treatment has been observed during the first year of the COVID-19 pandemic. Nevertheless, no difference in stage at diagnosis or in terms of survival has been observed.

Is Pulmonary Artery Pulsatility Index (PAPi) a Predictor of Outcome after Pulmonary Endarterectomy?

Background: Pulmonary endarterectomy (PEA) is the gold standard therapy for chronic thromboembolic pulmonary hypertension (CTEPH). Traditionally, pulmonary vascular resistance (PVR) represents the main prognostic factor after surgery. The pulmonary artery pulsatility index (PAPi) has been proposed for the assessment of RV in advanced heart failure, but it has never been applied in CTEPH patients. The aim of the present study is to describe PAPi in patients who underwent PEA, before and after surgery, and to define its predictive impact on postoperative outcomes. Methods: We retrospectively reviewed 188 consecutive adult patients who underwent PEA, between December 2003 and December 2021. PAPi was calculated for 186 patients and reported. Patients were partitioned in two groups using median preoperative PAPi as cutoff value: Group 1 with PAPi ≤ 8.6 (n = 94) and Group 2 with PAPi > 8.6 (n = 92). The propensity-score-matched analysis identified 67 pairs: Early outcomes were compared between two groups. Results: Mean preoperative PAPi was 10.3 ± 7.2. Considering matched populations, no differences emerged in terms of postoperative hemodynamics; Group 1 demonstrated higher 90-day mortality significance (10.4% vs. 3.0%, p = 0.082); the need for mechanical circulatory support (MCS) was similar, but successful weaning was unlikely (25% vs. 85.7%, p = 0.032). Conclusions: Mean PAPi in the CTEPH population is higher than in other diseases. Low PAPi (≤8.6) seems to be associated with lower postoperative survival and successful weaning from MCS.

Amide Spectral Fingerprints are Hydrogen Bonding-Mediated.

The origin of the peculiar amide spectral features of proteins in aqueous solution is investigated, by exploiting a combined theoretical and experimental approach to study UV Resonance Raman (RR) spectra of peptide molecular models, namely N-acetylglycine-N-methylamide (NAGMA) and N-acetylalanine-N-methylamide (NALMA). UVRR spectra are recorded by tuning Synchrotron Radiation at several excitation wavelengths and modeled by using a recently developed multiscale protocol based on a polarizable QM/MM approach. Thanks to the unparalleled agreement between theory and experiment, we demonstrate that specific hydrogen bond interactions, which dominate hydration dynamics around these solutes, play a crucial role in the selective enhancement of amide signals. These results further argue the capability of vibrational spectroscopy methods as valuable tools for refined structural analysis of peptides and proteins in aqueous solution.

Therapeutic alternatives in chronic thromboembolic pulmonary hypertension: from pulmonary endarterectomy to balloon pulmonary angioplasty to medical therapy. State of the art from a multidisciplinary team.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease with a very complex pathophysiology differing from other causes of pulmonary hypertension (PH). It is an infrequent consequence of acute pulmonary embolism that is frequently misdiagnosed. Pathogenesis has been related to coagulation abnormalities, infection or inflammation, although these disturbances can be absent in many cases. The hallmarks of CTEPH are thrombotic occlusion of pulmonary vessels, variable degree of ventricular dysfunction and secondary microvascular arteriopathy. The definition of CTEPH also includes an increase in mean pulmonary arterial pressure of more than 25 mmHg with a normal pulmonary capillary wedge of less than 15 mmHg. It is classified as World Health Organization group 4 PH, and is the only type that can be surgically cured by pulmonary endarterectomy (PEA). This operation needs to be carried out by a team with strong expertise, from the diagnostic and decisional pathway to the operation itself. However, because the disease has a very heterogeneous phenotype in terms of anatomy, degree of PH and the lack of a standard patient profile, not all cases of CTEPH can be treated by PEA. As a result, PH-directed medical therapy traditionally used for the other types of PH has been proposed and is utilized in CTEPH patients. Since 2015, we have been witnessing the rebirth of balloon pulmonary angioplasty, a technique first performed in 2001 but has since fallen out fashion due to major complications. The refinement of such techniques has allowed its safe utilization as a salvage therapy in inoperable patients. In the present keynote lecture, we will describe these therapeutic approaches and results.

Comparative life cycle cost assessment of (lean) duplex stainless steel in wastewater treatment environments.

Some unit operations in wastewater treatment plants (WWTPs), such as settling tanks and pipes for aeration or sludge transfer, are composed of austenitic stainless steel (EN 1.4307 or EN 1.4404) instead of galvanised or painted carbon steel to reduce the maintenance costs. The sensitivity to pitting and crevice corrosion of austenitic grades in certain WWTP environments has also led to the use of duplex grades. The purpose of this study is to evaluate the maintenance of piping systems (WWTPs) and its effect on their life cycle environmental impacts and costs (LCC) for both austenitic and duplex stainless steel grades. The final objective is to aid grade selection for piping in a WWTP environment. The considered functional unit (FU) is a complete piping system. Conventional austenitic stainless steel grades (e.g., EN 1.4404) are studied alongside duplex ones (e.g., EN 1.4362 and EN 1.4462). The calculated environmental impacts are the Global Warming Potential (GWP) and Primary Energy Demand (PED). The production, manufacturing, transport, use including maintenance activities, and end-of-life (burdens and credits) phases are included in the life cycle assessment (LCA). The maintenance activities consist of the required replacements of stainless steel piping during the lifespan of the WWTP. Thus, the service lives of the pipes included in the considered WWTP environment are determined based on long-term corrosion prediction models (power law), which predict the evolution of pit or crevice depth as a function of time. The model parameters are estimated based on own experimental results, supplemented by the existing literature. The corrosion rates determine the number and frequency of replacements, i.e., define the different scenarios of maintenance. The LCA, LCC and corrosion prediction models are then combined into a user-friendly tool, which can be used in industry for an appropriate grade selection for pipes in a WWTP environment. The tool includes several degrees of freedom such as piping distribution, water pressure, chloride content, replacement criteria, etc. The results show that using duplex stainless steel grade EN 1.4462 leads to lower GWP and PED at the end of the WWTP's service life of 40 years. This is mainly due to multiple replacements of the system's parts in wastewater with high levels of chloride (>3000 ppm) if more conventional austenitic stainless steel alloys such as EN 1.4404 are used. Leaner duplex stainless steel grades were also included in this LCC assessment. The duplex grade EN 1.4062 showed the lowest total LCC, thanks to its leaner chemical composition (i.e., lower nickel content) combined with good localized corrosion resistance.

Operating procedures for electrochemotherapy in bone metastases: Results from a multicenter prospective study on 102 patients.

INTRODUCTION: Bone metastases are frequent in patients with cancer. Electrochemotherapy (ECT) is a minimally invasive treatment. Preclinical and clinical studies supported the use of ECT in patients with metastatic bone disease (MBD). The purposes of this multicentre study are to confirm the safety and efficacy of ECT, and to identify appropriate operating procedures in different MBD conditions. MATERIALS AND METHODS: 102 patients were treated in 11 Centres and recorded in the REINBONE registry (a shared database protected by security passwords): clinical and radiological information, ECT session, adverse events, response, quality of life indicators and duration of follow-up were registered. RESULTS: 105 ECT sessions were performed (one ECT session in 99 patients, two ECT sessions in 3 patients). 24 patients (23.5%) received a programmed intramedullary nail after ECT, during the same surgical procedure. Mean follow-up was 5.9 ± 5.1 months (range 1.5-52). The response to treatment by RECIST criteria was 40.4% objective responses, 50.6% stable disease and 9% progressive disease. According to PERCIST criteria the response was: 31.4% OR; 51.7% SD, 16.9% PD with no significant differences between the 2 criteria. Diagnosis of breast cancer and ECOG values 0-1 were significantly associated to objective response. A significant decrease in pain intensity and significant better quality of life was observed after ECT session at follow-up. CONCLUSION: The results are encouraging on pain and tumour local control. ECT proved to be an effective and safe treatment for MBD and it should be considered as an alternative treatment as well as in combination with radiation therapy.

Symptoms and their implications on quality of life and psychological distress in sarcoma patients.

The aim of this study was to investigate symptoms, their variation over time and their relationship with quality of life (QoL)/psychological distress in sarcoma patients, as few data regarding QoL and psychological distress in this set of patients are currently available. A total of 188 sarcoma patients from an Italian referral center were involved. Symptoms and financial difficulties were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire from the first treatment and over the follow-up period, up to 6 years. The authors found that patients with sarcoma experience several symptoms, especially fatigue and pain, which may dramatically worsen QoL and psychological distress. In conclusion, patients with sarcoma often experience fatigue, pain and financial difficulties, which negatively impacts QoL and psychological distress. To ameliorate overall QoL, proper control of symptoms is necessary.

Lifecycle cost assessment of high strength carbon and stainless steel girder bridges.

This paper addresses the lifecycle cost assessment of a steel girder bridge considering the material costs and maintenance activities along the bridge's lifecycle. A reference highway bridge case study is chosen. It was initially designed using carbon steel S355. Two more steel grades are included in the comparison: high strength carbon steel S460 and duplex stainless steel EN 1.4162. For each design option, fatigue appears to be the driving design criterion for the following critical welded details: transversal stiffeners, cope holes and full penetration butt welds in the flanges. In addition to ultimate limit state verifications, specific attention is therefore given to fatigue through the use of different verification methods: the well-known nominal stress method and the hot spot stress method. It is concluded that the net present value of the lifecycle cost of the stainless steel option is attractive compared to painted the carbon steel options.

Synchrotron Characterization of Hexagonal and Cubic Lipidic Phases Loaded with Azolate/Phosphane Gold(I) Compounds: A New Approach to the Uploading of Gold(I)-Based Drugs.

Gold(I) phosphane compounds have recently attracted a renewed interest as potential new protagonists in cancer therapy. A class of phosphane gold(I) complexes containing azolate ligands has been successfully tested against several cancer cell lines and, in particular, against basal-like breast (BLB) cancer, a form characterized by strongly severe diagnosis and short life lapse after classic chemotherapy. Even though the anticancer activity of gold(I) phosphane compounds is thoroughly ascertained, no study has been devoted to the possibility of their delivery in nanovectors. Herein, nonlamellar lyotropic liquid crystalline lipid nanosystems, a promising class of smart materials, have been used to encapsulate gold(I) azolate/phosphane complexes. In particular, ((triphenylphosphine)-gold(I)-(4,5-dichloroimidazolyl-1H-1yl)) (C-I) and ((triphenylphosphine)-gold(I)-(4,5-dicyanoimidazolyl-1H-1yl)) (C-II) have been encapsulated in three different lipid matrices: monoolein (GMO), phytantriol (PHYT) and dioleoyl-phosphatidylethanolamine (DOPE). An integrated experimental approach involving X-ray diffraction and UV resonant Raman (UVRR) spectroscopy, based on synchrotron light and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, has been employed to establish the effects of drug encapsulation on the structure and phase behavior of the host mesophases. The results indicate that gold(I) complexes C-I and C-II are successfully encapsulated in the three lipid matrices as evidenced by the drug-induced phase transitions or by the changes in the mesophase lattice parameters observed in X-ray diffraction experiments and by the spectral changes occurring in UV resonant Raman spectra upon loading the lipid matrices with C-I and C-II.

Nature-Identical Compounds and Organic Acids Ameliorate and Prevent the Damages Induced by an Inflammatory Challenge in Caco-2 Cell Culture.

Bioactive compounds, such as organic acids (OA) and nature-identical compounds (NIC), can exert a role in the protection of intestinal mucosa functionality due to their biological properties. The aim of this study was to understand the role of 2 OA (citric and sorbic acid) and 2 NIC (thymol and vanillin), alone or combined in a blend (OA + NIC), on intestinal barrier functionality, either during homeostatic condition or during an inflammatory challenge performed with pro-inflammatory cytokines and lipopolysaccharides (LPS). The study was performed on the human epithelial cell line Caco-2, a well-known model of the intestinal epithelial barrier. The results showed how OA and NIC alone can improve transepithelial electrical resistance (TEER) and mRNA levels of tight junction (TJ) components, but OA + NIC showed stronger efficacy compared to the single molecules. When an inflammatory challenge occurred, OA + NIC blend was able both to ameliorate, and prevent, damage caused by the pro-inflammatory stimulus, reducing or preventing the drop in TEER and improving the TJ mRNA expression. The data support the role of OA + NIC in modulating gut barrier functionality and reducing the negative effects of inflammation in intestinal epithelial cells, thereby supporting the gut barrier functionality.

The Real-Life Journey of Elderly Patients in Soft Tissue and Bone Sarcomas: A Retrospective Analysis from a Sarcoma Referral Center.

The high complexity of multimodality treatment frequently results in undertreatment of elderly sarcoma patients, and this may be one of the factors that influence their prognosis. We describe the real-life approach to a population of patients aged over 70 with both soft tissue (STS) and bone sarcomas (BS) followed by our Sarcoma Disease Management Team from 2012 to 2017. One-hundred and twenty-three patients with a median age of 77 years (range: 70-92) were identified. STS were the most common histological subtypes (94%) and the grade was high in 79/123 patients (64%). At diagnosis, 88% of patients had localized disease (LD) and 12% were metastatic (MD). Overall, 96% of patients with LD underwent surgery, 46/54 (85%) with high grade STS patients underwent complementary radiotherapy, and 10/54 (19%) received adjuvant treatments. Twelve out of 33 patients who relapsed (36%) underwent local therapies. Seventeen (52%) and eight (24%) patients were treated with first-line and second-line medical treatments, respectively. Tolerability to systemic treatments was fairly good. Overall, 21% of the patients with advanced disease were candidates for best supportive care alone. Our case series of elderly patients with both STS and BS shows that personalized multidisciplinary treatment can nevertheless be offered to this frail population in order to control the evolution of disease.

Thymol modulates the endocannabinoid system and gut chemosensing of weaning pigs.

BACKGROUND: The recent identification of the endocannabinoid system in the gastrointestinal tract suggests a role in controlling intestinal inflammation. In addition, the gut chemosensing system has therapeutic applications in the treatment of gastrointestinal diseases and inflammation due to the presence of a large variety of receptors. The purposes of this study were to investigate the presence of markers of the endocannabinoid system and the chemosensing system in the pig gut and, second, to determine if thymol modulates these markers. One hundred sixty 28-day-old piglets were allocated into one of 5 treatment groups (n = 32 per treatment): T1 (control), T2 (25.5 mg thymol/kg feed), T3 (51 mg thymol/kg feed), T4 (153 mg thymol/kg feed), and T5 (510 mg thymol/kg feed). After 14 days of treatment, piglets were sacrificed (n = 8), and then duodenal and ileal mucosal scrapings were collected. Gene expression of cannabinoid receptors (CB1 and CB2), transient receptor potential vanilloid 1 (TRPV1), the olfactory receptor OR1G1, diacylglycerol lipases (DGL-α and DGL-ß), fatty acid amine hydrolase (FAAH), and cytokines was measured, and ELISAs of pro-inflammatory cytokines levels were performed. RESULTS: mRNAs encoding all markers tested were detected. In the duodenum and ileum, the CB1, CB2, TRPV1, and OR1G1 mRNAs were expressed at higher levels in the T4 and T5 groups compared to the control group. The level of the FAAH mRNA was increased in the ileum of the T4 group compared to the control. Regarding the immune response, the level of the tumor necrosis factor (TNF-α) mRNA was significantly increased in the duodenum of the T5 group, but this increase was not consistent with the protein level. CONCLUSIONS: These results indicate the presence of endocannabinoid system and gut chemosensing markers in the piglet gut mucosa. Moreover, thymol modulated the expression of the CB1, CB2, TRPV1, and OR1G1 mRNAs in the duodenum and ileum. It also modulated the mRNA levels of enzymes involved in the biosynthesis and degradation of endocannabinoid molecules. Based on these findings, the effects of thymol on promoting gut health are potentially mediated by the activation of these receptors.

Reorganization Tips from a Sarcoma Unit at Time of the COVID-19 Pandemic in Italy: Early Experience from a Regional Referral Oncologic Center.

Since the World Health Organization declared the novel coronavirus outbreak a global health emergency, Italy's lockdown was declared on 9 March 2020. Elective orthopedic surgery was forced to stop to allow the healthcare system to face the emergency. However, many orthopedic oncology cases could not be postponed. The aim of this study was to report the experience in managing sarcoma patients and the reorganization of a cancer center in an attempt to maintain it free from COVID-19. A Coronavirus Crisis Unit was established by the health directorate coordination in order to adopt specific procedures. General rules of screening and social distancing were applied in different health settings (entrance check point, hospital inward, outpatient clinic, operative room). Regarding oncologic orthopedics, priority was given to bone and soft tissue sarcomas, metastases and aggressive benign tumors at risk of impending or pathologic fracture. Precise indications were followed to manage first outpatient visits, patients undergoing surgery and follow-up. Meticulous adherence to rules among patients and personnel and collaboration between leadership and medical staff in order to continue to perform multidisciplinary treatment protocols, maintain the availability of infrastructural spaces and source protective equipment, swabs and screening samples have been successful in the aim towards a safe cure for cancer patients.