Cancer management during COVID-19 pandemic: is immune checkpoint inhibitors-based immunotherapy harmful or beneficial?

The coronavirus disease 2019 (COVID-19) is currently representing a global health threat especially for fragile individuals, such as cancer patients. It was demonstrated that cancer patients have an increased risk of developing a worse symptomatology upon severe acute respiratory syndrome associated coronavirus-2 (SARS-CoV-2) infection, often leading to hospitalization and intensive care. The consequences of this pandemic for oncology are really heavy, as the entire healthcare system got reorganized. Both oncologists and cancer patients are experiencing rescheduling of treatments and disruptions of appointments with a concurrent surge of fear and stress. In this review all the up-to-date findings, concerning the association between COVID-19 and cancer, are reported. A remaining very debated question regards the use of an innovative class of anti-cancer molecules, the immune checkpoint inhibitors (ICIs), given their modulating effects on the immune system. For that reason, administration of ICIs to cancer patients represents a question mark during this pandemic, as its correlation with COVID-19-associated risks is still under investigation. Based on the mechanisms of action of ICIs and the current evidence, we suggest that ICIs not only can be safely administered to cancer patients, but they might even be beneficial in COVID-19-positive cancer patients, by exerting an immune-stimulating action

Measurement of the production of a W boson in association with a charm quark in pp collisions at √s = 7 TeV with the ATLAS detector

The production of a W boson in association with a single charm quark is studied using 4.6 fb−1 of pp collision data at s√ = 7 TeV collected with the ATLAS detector at the Large Hadron Collider. In events in which a W boson decays to an electron or muon, the charm quark is tagged either by its semileptonic decay to a muon or by the presence of a charmed meson. The integrated and differential cross sections as a function of the pseudorapidity of the lepton from the W-boson decay are measured. Results are compared to the predictions of next-to-leading-order QCD calculations obtained from various parton distribution function parameterisations. The ratio of the strange-to-down sea-quark distributions is determined to be 0.96+0.26−0.30 at Q 2 = 1.9 GeV2, which supports the hypothesis of an SU(3)-symmetric composition of the light-quark sea. Additionally, the cross-section ratio σ(W + +c¯¯)/σ(W − + c) is compared to the predictions obtained using parton distribution function parameterisations with different assumptions about the s−s¯¯¯ quark asymmetry

Association of arterial stiffness with a prothrombotic state in uncomplicated nondiabetic hypertensive patients

Background and aims: Past studies reported a significant contribution of a prothrombotic state to the development and progression of target organ damage in hypertensive patients. Stiffening of arterial vessels is associated with aging and hypertension, and additional factors could contribute to this process. This study was designed to examine the relationships between arterial stiffening and the hemostatic and fibrinolytic system. Methods: In 128 middle-aged, nondiabetic, essential hypertensive patients without major cardiovascular and renal complications, we measured coagulation markers that express the spontaneous activation of the hemostatic and fibrinolytic system and assessed stiffness of the arterial tree by measurement of the carotid/femoral pulse wave velocity (cfPWV) and pulse wave analysis with calculation of the brachial augmentation index (AIx). Results: Levels of fibrinogen (FBG), D-dimer (D-d), and plasminogen activator-inhibitor 1 (PAI-1) were significantly higher in patients with PWV and AIx above the median of the distribution. FBG, D-d, and PAI-1 were significantly and directly related with both cfPWV and AIx, and multivariate regression analysis indicated that the relationships of D-d and PAI-1 with both cfPWV and AIx and of FBG with AIx, were independent of age, body mass index, severity and duration of hypertension, use of antihypertensive drugs, blood glucose, and plasma lipids. Conclusion: In middle-aged, uncomplicated, nondiabetic patients with essential hypertension, spontaneous activation of plasma hemostatic cascade and impaired fibrinolysis is significantly and independently associated with stiffening of the arterial tree

The 68 kDa subunit of mammalian cleavage factor I interacts with the U7 small nuclear ribonucleoprotein and participates in 3′-end processing of animal histone mRNAs

Metazoan replication-dependent histone pre-mRNAs undergo a unique 3′-cleavage reaction which does not result in mRNA polyadenylation. Although the cleavage site is defined by histone-specific factors (hairpin binding protein, a 100-kDa zinc-finger protein and the U7 snRNP), a large complex consisting of cleavage/polyadenylation specificity factor, two subunits of cleavage stimulation factor and symplekin acts as the effector of RNA cleavage. Here, we report that yet another protein involved in cleavage/polyadenylation, mammalian cleavage factor I 68-kDa subunit (CF Im68), participates in histone RNA 3′-end processing. CF Im68 was found in a highly purified U7 snRNP preparation. Its interaction with the U7 snRNP depends on the N-terminus of the U7 snRNP protein Lsm11, known to be important for histone RNA processing. In vivo, both depletion and overexpression of CF Im68 cause significant decreases in processing efficiency. In vitro 3′-end processing is slightly stimulated by the addition of low amounts of CF Im68, but inhibited by high amounts or by anti-CF Im68 antibody. Finally, immunoprecipitation of CF Im68 results in a strong enrichment of histone pre-mRNAs. In contrast, the small CF Im subunit, CF Im25, does not appear to be involved in histone RNA processin

Explant-derived human dental pulp stem cells enhance differentiation and proliferation potentials

Numerous stem cell niches are present in the different tissues and organs of the adult human body. Among these tissues, dental pulp, entrapped within the 'sealed niche' of the pulp chamber, is an extremely rich site for collecting stem cells. In this study, we demonstrate that the isolation of human dental pulp stem cells by the explants culture method (hD-DPSCs) allows the recovery of a population of dental mesenchymal stem cells that exhibit an elevated proliferation potential. Moreover, we highlight that hD-DPSCs are not only capable of differentiating into osteoblasts and chondrocytes but are also able to switch their genetic programme when co-cultured with murine myoblasts. High levels of MyoD expression were detected, indicating that muscle-specific genes in dental pulp cells can be turned on through myogenic fusion, confirming thus their multipotency. A perivascular niche may be the potential source of hD-DPSCs, as suggested by the consistent Ca(2+) release from these cells in response to endothelin-1 (ET-1) treatment, which is also able to significantly increase cell proliferation. Moreover, response to ET-1 has been found to be superior in hD-DPSCs than in DPSCs, probably due to the isolation method that promotes release of stem/progenitor cells from perivascular structures. The ability to isolate, expand and direct the differentiation of hD-DPSCs into several lineages, mainly towards myogenesis, offers an opportunity for the study of events associated with cell commitment and differentiation. Therefore, hD-DPSCs display enhanced differentiation abilities when compared to DPSCs, and this might be of relevance for their use in therapy

The 68 kDa subunit of mammalian cleavage factor I interacts with the U7 small nuclear ribonucleoprotein and participates in 3′-end processing of animal histone mRNAs

Metazoan replication-dependent histone pre-mRNAs undergo a unique 3′-cleavage reaction which does not result in mRNA polyadenylation. Although the cleavage site is defined by histone-specific factors (hairpin binding protein, a 100-kDa zinc-finger protein and the U7 snRNP), a large complex consisting of cleavage/polyadenylation specificity factor, two subunits of cleavage stimulation factor and symplekin acts as the effector of RNA cleavage. Here, we report that yet another protein involved in cleavage/polyadenylation, mammalian cleavage factor I 68-kDa subunit (CF Im68), participates in histone RNA 3′-end processing. CF Im68 was found in a highly purified U7 snRNP preparation. Its interaction with the U7 snRNP depends on the N-terminus of the U7 snRNP protein Lsm11, known to be important for histone RNA processing. In vivo, both depletion and overexpression of CF Im68 cause significant decreases in processing efficiency. In vitro 3′-end processing is slightly stimulated by the addition of low amounts of CF Im68, but inhibited by high amounts or by anti-CF Im68 antibody. Finally, immunoprecipitation of CF Im68 results in a strong enrichment of histone pre-mRNAs. In contrast, the small CF Im subunit, CF Im25, does not appear to be involved in histone RNA processing

Comparison of a fast track protocol and standard care after hip arthroplasty in the reduction of the length of stay and the early weight-bearing resumption: study protocol for a randomized controlled trial

Background: To date, hip arthroplasty is one of the most commonly performed surgical procedures, with growing worldwide demand. In recent decades, major progress made in terms of surgical technique, biomechanics, and tribology knowledge has contributed to improve the medical and functional management of the patient. This study aims to assess if the application of a fast track protocol, consisting of a preoperative educational intervention, adequate postoperative pain control, and intensive rehabilitation intervention, reduces the length of stay (LOS) and allows the early functional recovery compared to standard clinical practice for patients undergoing hip arthroplasty. Methods: The study population consists of 90 patients with primary arthrosis of the hip with an anterior indication of hip arthroplasty. The exclusion criteria are older than 70 years, a contraindication to performing spinal anesthesia, and bone mass index (BMI) greater than 32. Participants, 45 for each group, are randomly allocated to one of two arms: fast track clinical pathway or standard care protocol. During allocation, baseline parameters such as Harris Hip Score (HHS) and Western Ontario and McMaster Universities (WOMAC) index are collected. On the third postoperative day, the functional autonomy for each patient is assessed by the Iowa Level of Assistance (ILOA) scale, and it is expected the discharge for patients in the fast track group (primary outcome). On the other hand, standard care patient discharge is expected after 5–7 days after surgery. During follow-up fixed at 6 weeks and 3, 6, and 12 months, HHS and WOMAC scores are collected for each patient (secondary outcomes). Discussion: Although total hip replacement has become a widespread standardized procedure, to the authors’ knowledge, only few randomized controlled trials were performed to evaluate the effectiveness of fast track pathway vs. standard care procedure in the reduction of the LOS after hip arthroplasty. It is expected that our results collected by the application of minimally invasive surgical interventions with concomitant management of perioperative pain and bleeding and early functional rehabilitation will contribute to enriching the understanding of clinical and organizational aspects linked to fast track arthroplasty. Trial registration: ClinicalTrials.gov NCT03875976. Registered on 15 March 2019—“retrospectively registered”

Immune-checkpoint inhibitors from cancer to COVID‑19: A promising avenue for the treatment of patients with COVID‑19

The severe acute respiratory syndrome associated coronavirus‑2 (SARS‑CoV‑2) poses a threat to human life worldwide. Since early March, 2020, coronavirus disease 2019 (COVID‑19), characterized by an acute and often severe form of pneumonia, has been declared a pandemic. This has led to a boom in biomedical research studies at all stages of the pipeline, from the in vitro to the clinical phase. In line with this global effort, known drugs, currently used for the treatment of other pathologies, including antivirals, immunomodulating compounds and antibodies, are currently used off‑label for the treatment of COVID‑19, in association with the supportive standard care. Yet, no effective treatments have been identified. A new hope stems from medical oncology and relies on the use of immune‑checkpoint inhibitors (ICIs). In particular, amongst the ICIs, antibodies able to block the programmed death‑1 (PD‑1)/PD ligand-1 (PD‑L1) pathway have revealed a hidden potential. In fact, patients with severe and critical COVID‑19, even prior to the appearance of acute respiratory distress syndrome, exhibit lymphocytopenia and suffer from T‑cell exhaustion, which may lead to viral sepsis and an increased mortality rate. It has been observed that cancer patients, who usually are immunocompromised, may restore their anti‑tumoral immune response when treated with ICIs. Moreover, viral-infected mice and humans, exhibit a T‑cell exhaustion, which is also observed following SARS‑CoV‑2 infection. Importantly, when treated with anti‑PD‑1 and anti‑PD‑L1 antibodies, they restore their T‑cell competence and efficiently counteract the viral infection. Based on these observations, four clinical trials are currently open, to examine the efficacy of anti‑PD‑1 antibody administration to both cancer and non‑cancer individuals affected by COVID‑19. The results may prove the hypothesis that restoring exhausted T‑cells may be a winning strategy to beat SARS‑CoV‑2 infection

Development of FTK architecture: a fast hardware track trigger for the ATLAS detector

The Fast Tracker (FTK) is a proposed upgrade to the ATLAS trigger system that will operate at full Level-1 output rates and provide high quality tracks reconstructed over the entire detector by the start of processing in Level-2. FTK solves the combinatorial challenge inherent to tracking by exploiting the massive parallelism of Associative Memories (AM) that can compare inner detector hits to millions of pre-calculated patterns simultaneously. The tracking problem within matched patterns is further simplified by using pre-computed linearized fitting constants and leveraging fast DSP's in modern commercial FPGA's. Overall, FTK is able to compute the helix parameters for all tracks in an event and apply quality cuts in approximately one millisecond. By employing a pipelined architecture, FTK is able to continuously operate at Level-1 rates without deadtime. The system design is defined and studied using ATLAS full simulation. Reconstruction quality is evaluated for single muon events with zero pileup, as well as WH events at the LHC design luminosity. FTK results are compared with the tracking capability of an offline algorithm.Comment: To be published in the proceedings of DPF-2009, Detroit, MI, July 2009, eConf C09072