Wnt canonical signaling is critical for normal development as well as homeostasis of several epithelial tissues, and constitutive activation of this pathway is commonly observed in carcinomas. We ...show here that 50% of human sarcomas (n = 45) and 65% of sarcoma cell lines (n = 23) of diverse histological subtypes exhibit upregulated autocrine canonical Wnt signaling. Furthermore, in Wnt autocrine cell lines, we identify alterations including overexpression or gene amplification of Wnt ligands and/or
LRP5/6 coreceptors and epigenetic silencing of different cell surface Wnt antagonists. Mutations in adenomatous polyposis coli (
APC) gene were observed in two nonautocrine Wnt-positive sarcoma cell lines. Finally, downregulation of the activated Wnt pathway inhibited sarcoma cell proliferation both in vitro and in vivo by a mechanism involving the downregulation of CDC25A.
► Upregulated canonical Wnt signaling in human sarcomas ► Autocrine activation of the Wnt canonical pathway in sarcomas ► Wnt-induced sarcoma cell proliferation is mediated through CDC25A ► CDC25A is a TCF/β-catenin target gene in hMSCs and sarcoma cells
The protein tyrosine phosphatase PTP1B is a major regulator of glucose homeostasis and energy metabolism, and a validated target for therapeutic intervention in diabetes and obesity. Nevertheless, it ...is a challenging target for inhibitor development. Previously, we generated a recombinant antibody (scFv45) that recognizes selectively the oxidized, inactive conformation of PTP1B. Here, we provide a molecular basis for its interaction with reversibly oxidized PTP1B. Furthermore, we have identified a small molecule inhibitor that mimics the effects of scFv45. Our data provide proof-of-concept that stabilization of PTP1B in an inactive, oxidized conformation by small molecules can promote insulin and leptin signaling. This work illustrates a novel paradigm for inhibiting the signaling function of PTP1B that may be exploited for therapeutic intervention in diabetes and obesity.
Development of advanced and minimally invasive surgical procedures is providing treatment opportunities to older and higher risk patients. This has also led to highly specialized physicians and a ...need for better communication and planning with the patients and within the care team.
In the field of cardiac surgery, the heart team model has been advocated and implemented as a vehicle to optimize decision making prior to procedure, care during the procedure and in the recovery process. The goal is to provide a treatment path that prioritizes the patient's goals and to anticipate and minimize complications.
In this review, we discuss the concepts of shared decision making (SDM) and implementation science in the context of the complex cardiac patient. We also review the most recent evidence for their use in cardiac surgery. We argue that a team model not only bridges knowledge gaps but provides a multidisciplinary environment for the practice of SDM and implementation of evidence-based practices. Be believe this will provide patients with a better experience as they navigate their care and improve their medical outcomes as well.
Abstract Objectives To explore the literature for the definitions of informal payments in healthcare and critically analyze the proposed definitions. This will serve in the process of getting to a ...coherent definition of informal payments, which will further support acknowledging and addressing them globally. Methods A search strategy was developed to identify papers addressing informal payments on PubMed, ScienceDirect, Econlit, EconPapers and Google Scholar. Results 2225 papers were identified after a first search. 61 papers were included in the systematic review. Out of all definitions provided, we selected three definitions as being original. All other definitions either cite these definitions or do not provide new insight into the topic of informal payments. Although informal payments have been nominated by various terms over the years, there is a tendency in recent years towards an agreement to use this singular term. Definitions differ in terms of the relation of informal payments with other informal activities, their legality and the motivation behind them. Conclusions The variety of forms which informal payments may take makes it difficult to define them in a comprehensive manner. However, we identified a definition that could serve as a beginning in this process. More effort is needed to build on it and get to a commonly accepted and shared definition of informal payments.
Allogeneic SCT for older patients remains challenging at least in part due to graft-versus-host disease (GVHD) and higher non-relapse mortality (NRM). We conducted a prospective pilot study primarily ...for older patients undergoing matched unrelated donor (MUD) SCT using a reduced-intensity (RIC) melphalan-based conditioning and post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis with tacrolimus and mycophenolate mofetil. Twenty-two patients (median age 64, IQR 58, 66) underwent RIC MUD SCT for high-risk hematological malignancies including AML/MDS (73%), CML/MPD (18%), and other (10%). Two (9%) patients had early death; the rest (100%) engrafted. After a median follow-up of 17 months, 11 patients were alive and disease-free with an estimated 2-year progression-free (PFS) and overall (OS) survival of 48%. The cumulative incidences of grades 2-4 and 3-4 acute GVHD (aGVHD) at day + 100 and 2-years were 32 and 4%, and 59 and 24%, respectively. No cases of chronic GVHD (cGVHD) were noted. However, late acute GVHD was observed in 6 (27%) patients. In conclusion, RIC MUD SCT with melphalan-based conditioning and PTCy-based GVHD-based prophylaxis for older patients appears effective in controlling relapse. While cGVHD was not seen and early aGVHD appears controllable, a significant proportion developed late aGVHD responsible for higher NRM seen in these patients.
Basophils are white blood cells that play an important role in the human immune system. These cells physiologically increase in number in immune response to certain allergies, chronic inflammation, ...and parasitic infections. Basophils are also a significant indicator for the presence of certain malignancies such as chronic myeloproliferative neoplasms and acute myeloid leukemia. In the current manuscript we present a statistically significant correlation between persistent basophilia in primary myelofibrosis (PMF) and the risk for the subsequent development of acute myeloid leukemia. We have retrospectively identified in the files of the Department of Hematology, Ion Chiricuta Clinical Cancer Center in Cluj Napoca, Romania 623 consecutive patients diagnosed with AML over a period spanning from 2008 to 2018. We afterwards identified 32 patients with AML diagnosis following a previous diagnosis of myelofibrosis (either post-PV, post-ET, or post-PMF). All the patients were diagnosed according to the WHO criteria. We subsequently established a control group consisting of 32 patients with underlying BCR–ABL-negative MPN who did not develop AML (AML-negative group). Following this, we assessed whether the AML-negative patients from our control group also had a persistent (>3 months) absolute basophilia. When comparing both groups of patients with myelofibrosis, the group with subsequent AML development and the one without AML, the follow-up did not present statistically significant differences between the two groups. In the univariate analysis, patients who progressed to AML had more frequently basophilia, longer basophilia duration, higher pre-therapy absolute, and relative basophil count and presented more frequently calreticulin (CALR) mutations. In the current study, we emphasize the need for a closer clinical monitoring for chronic MPNs with marked basophilia, with an important potential clinical impact.
This research comes to empirical investigate whether the country's levels of corruption may be explained by some behavioral factors such as culture, tax moral, trust, religion or happiness. For this ...purpose, a cross-country survey of 148 countries is used. The findings document that power distance, trust in legal system, happiness and religion are the most important behavioral determinants of corruption, explaining by 50% from the level of corruption around the world. A higher power distance, a lower level of trust in legal system, a lower level of happiness (measure by subjective well-being) and a higher level of religiosity conduct to a higher level of corruption. The findings are important for the policy makers in order to include the non-economic factors in the analysis of corruption behavior of the people belong to a county, and thus to adopt the most appropriate decisions to fight this phenomenon.
Introduction: Acute myeloid leukaemia (AML) is a haematological disease associated with a dismal prognosis, despite major progress made in recent years in terms of antileukemic agents and supportive ...care. Methods: We investigated the results of the intensive treatment of 133 fit AML patients (de novo and secondary) from a referral cancer centre in Romania, treated between January 2015 and December 2021. Results: We included 79 male and 54 female patients with a median age of 53 years (range 18-70). Molecular biology analysis was available for 82.7% of patients, whereas karyotype analysis was only available for 33% of patients. The median overall survival (OS) was 8.7 months, and the disease-free survival rate was 26.3% at a median follow-up of 33.7 months. The complete remission (CR) rate after induction was 48.9% for all patients and 61.9% for patients who were assessable (excluding patients who died before being assessed for response). Twelve patients underwent allogeneic bone marrow transplantation (BMT), with the median OS not reached. Early mortality (EM), defined as death during the first 30 days after admission, was 17.3%, with the main cause of death being septic shock (78.3%). Elderly patients (≥60 years of age) had a lower OS, more primary refractory disease, and higher rates of early mortality. Conclusion: Complete remission rates and OS in our cohort were lower than in other reports. Early mortality was unexpectedly high, mainly due to infections, which were the main causes of death in our cohort.
Hemophagocytic lymphohistiocytosis (HLH) is a rare, elusive, and life-threatening condition that is characterized by the pathologic and uncontrolled secondary activation of the cytotoxic T-cells, ...natural killer cells (NK-cells), and macrophages of the innate immune system. This condition can develop in sporadic or familial contexts associated with hematological malignancies, as a paraneoplastic syndrome, or linked to an infection related to immune system deficiency. This leads to the systemic inflammation responsible for the overall clinical manifestations. Diagnosis should be thorough, and treatment should be initiated as soon as possible. In the current manuscript, we focus on classifying the HLH spectrum, describing the pathophysiology and the tools needed to search for and correctly identify HLH, and the current therapeutic opportunities. We also present the first case of a multiple myeloma patient that developed HLH following therapy with the ixazomib-lenalidomide-dexamethasone protocol.
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