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A contemporary serious lack of scientific knowledge by the general public and many decision-makers is now quite perceptible, both globally and in Portugal. Living in a science-driven technological world filled with scientific illiteracy is dangerous and a path toward disaster. Recent years brought a fairly strong global movement promoting the so-called "alternative therapy" that also affected Portugal. I propose an evidence-based ethics reflection and argumentation, both encompassing the global and the specific Portuguese reality. I debate the specific arguments used in favour of alternative therapies, demonstrating the inherent fallacies of thought, deliberate manipulation of words and concepts, and the dire consequences for global and local health politics by following this line of biased reasoning., (© 2022. The Author(s).)

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric cancer. Amongst the wide array of driver mutations, 10% of T-ALL patients display gain-of-function mutations in the IL-7 receptor α chain (IL-7Rα, encoded by IL7R), which occur in different molecular subtypes of this disease. However, it is still unclear whether IL-7R mutational activation is sufficient to transform T-cell precursors. Also, which genes cooperate with IL7R to drive leukemogenesis remain poorly defined. Here, we demonstrate that mutant IL7R alone is capable of inducing T-ALL with long-latency in stable transgenic zebrafish and transformation is associated with MYC transcriptional activation. Additionally, we find that mutant IL7R collaborates with Myc to induce early onset T-ALL in transgenic zebrafish, supporting a model where these pathways collaborate to drive leukemogenesis. T-ALLs co-expressing mutant IL7R and Myc activate STAT5 and AKT pathways, harbor reduced numbers of apoptotic cells and remake tumors in transplanted zebrafish faster than T-ALLs expressing Myc alone. Moreover, limiting-dilution cell transplantation experiments reveal that activated IL-7R signaling increases the overall frequency of leukemia propagating cells. Our work highlights a synergy between mutant IL7R and Myc in inducing T-ALL and demonstrates that mutant IL7R enriches for leukemia propagating potential., (© 2022. The Author(s).)

Pachydermodactyly is a rare and benign superficial fibromatosis characterized by painless and progressive swelling of periarticular soft tissues of the proximal interphalangeal (PIP) joints, most commonly of both hands. There is no tenderness, warmth, morning stiffness, or reduced range of motion associated. Our purpose is to highlight the diagnostic utility of ultrasonography, superb microvascular imaging (SMI), and elastography in pachydermodactyly. We report the case of a 15-year-old adolescent white boy, with a 6-month history of insidious and progressive, asymptomatic swelling of the lateral and dorsal regions of the metacarpophalangeal (MCP), and PIP joints of both hands. Articular ultrasonography showed thickening of the skin around the lateral regions of the PIP and MCP joints, with no synovitis, hydrarthrosis, or muscle, tendon, or bone changes. Strain elastography revealed lower elasticity in the aforementioned skin regions, corresponding to increased tissue hardness due to hyperkeratosis. No SMI or Doppler signals were detected in epidermal or dermal tissues, as well as in tendons, joints, and bone. This case report shows that ultrasonography, SMI, and elastography may play a significant role in the accurate diagnosis of pachydermodactyly and exclusion of alternative conditions. These imaging modalities have no ionizing radiation; they are fast, inexpensive, and performed on site. They do not require usage of contrast agents and thus can eliminate the need of invasive procedures such as skin biopsy. They also contribute to reduce health care costs with unnecessary complementary tests and inappropriate treatment., (© 2021. ISS.)

Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy., (© 2021. The Author(s).)

Purpose: To determine prognostic factors for stage IIA colon cancer (CC) recurrence in patients undergoing curative intent surgery without adjuvant treatment., Methods: Single-centre cohort study. All patients with stage IIA CC discussed in a multidisciplinary colorectal cancer clinic from January 2010 to December 2012 were evaluated. Clinical data, laboratory data and tumour features, including expression of DNA repair proteins (EDRP), were analysed. Assessment of overall and disease free survival, recurrence, recurrence site and recurrence's method of diagnosis was performed. The associations between variables were tested through the Fisher's exact test (SPSS 23)., Results: Fifty-five patients were included (55% male gender; mean age at diagnosis was 70.3 years (42-88)). CC was in the left colon in 62%, high grade in 7% and had lymphovascular invasion in 7% of the cases. Only one patient was submitted to emergent surgery for obstructive symptoms. In 55% of cases ≥ 12 lymph nodes were collected. There was EDRP loss in nine patients (MLH1/PMS2: six; MSH2/MSH6: three)-only two fulfilled revised Bethesda criteria. Recurrence occurred in five patients (8.9%), and it was diagnosed through surveillance in all of them. No variable showed a statistically significant association with recurrence; however, there were no recurrences in patients with EPRD loss (p = 0.209). Mean follow-up time was 43 months (2-70). In those with recurrence, mean disease-free survival was 23.4 months., Conclusions: The overall good prognosis and absence of recurrence predictive factors were confirmed, validating the decision of not to submit stage IIA CC patients to chemotherapy risks.

The cytokine IL-7 and its receptor, IL-7R, are critical for T cell and, in the mouse, B cell development, as well as differentiation and survival of naive T cells, and generation and maintenance of memory T cells. They are also required for innate lymphoid cell (ILC) development and maintenance, and consequently for generation of lymphoid structures and barrier defense. Here we discuss the central role of IL-7 and IL-7R in the lymphoid system and highlight the impact of their deregulation, placing a particular emphasis on their 'dark side' as promoters of cancer development. We also explore therapeutic implications and opportunities associated with either positive or negative modulation of the IL-7-IL-7R signaling axis.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer for which treatment options often result in incomplete therapeutic efficacy and long-term side-effects. Interleukin 7 (IL-7) and its receptor IL-7Rα promote T-ALL development and mutational activation of IL-7Rα associates with very high risk in relapsed disease. Using combinatorial phage-display libraries and antibody reformatting, we generated a fully human IgG1 monoclonal antibody (named B12) against both wild-type and mutant human IL-7Rα, predicted to form a stable complex with IL-7Rα at a different site from IL-7. B12 impairs IL-7/IL-7R-mediated signaling, sensitizes T-ALL cells to treatment with dexamethasone and can induce cell death per se. The antibody also promotes antibody-dependent natural killer-mediated leukemia cytotoxicity in vitro and delays T-cell leukemia development in vivo, reducing tumor burden and promoting mouse survival. B12 is rapidly internalized and traffics to the lysosome, rendering it an attractive vehicle for targeted intracellular delivery of cytotoxic cargo. Consequently, we engineered a B12-MMAE antibody-drug conjugate and provide proof-of-concept evidence that it has increased leukemia cell killing abilities as compared with the naked antibody. Our studies serve as a stepping stone for the development of novel targeted therapies in T-ALL and other diseases where IL-7Rα has a pathological role.

Interleukin-7 and interleukin-7 receptor are essential for normal T-cell development and homeostasis, whereas excessive interleukin-7/interleukin-7 receptor-mediated signaling promotes leukemogenesis. The protein kinase, casein kinase 2, is overexpressed and hyperactivated in cancer, including T-cell acute lymphoblastic leukemia. Herein, we show that while interleukin-7 had a minor but significant positive effect on casein kinase 2 activity in leukemia T-cells, casein kinase 2 activity was mandatory for optimal interleukin-7/interleukin-7 receptor-mediated signaling. Casein kinase 2 pharmacological inhibition impaired signal transducer and activator of transcription 5 and phosphoinositide 3-kinase/v-Akt murine thymoma viral oncogene homolog 1 pathway activation triggered by interleukin-7 or by mutational activation of interleukin-7 receptor. By contrast, forced expression of casein kinase 2 augmented interleukin-7 signaling in human embryonic kidney 293T cells reconstituted with the interleukin-7 receptor machinery. Casein kinase 2 inactivation prevented interleukin-7-induced B-cell lymphoma 2 upregulation, maintenance of mitochondrial homeostasis and viability of T-cell acute lymphoblastic leukemia cell lines and primary leukemia cells collected from patients at diagnosis. Casein kinase 2 inhibition further abrogated interleukin-7-mediated cell growth and upregulation of the transferrin receptor, and blocked cyclin A and E upregulation and cell cycle progression. Notably, casein kinase 2 was also required for the viability of mutant interleukin-7 receptor expressing leukemia T-cells. Overall, our study identifies casein kinase 2 as a major player in the effects of interleukin-7 and interleukin-7 receptor in T-cell acute lymphoblastic leukemia. This further highlights the potential relevance of targeting casein kinase 2 in this malignancy., (Copyright© Ferrata Storti Foundation.)

Adult B-cell acute lymphoblastic leukemia remains a major therapeutic challenge, requiring a better characterization of the molecular determinants underlying disease progression and resistance to treatment. Here, using a phospho-flow cytometry approach we show that adult diagnostic B-cell acute lymphoblastic leukemia specimens display PI3K/Akt pathway hyperactivation, irrespective of their BCR-ABL status and despite paradoxically high basal expression of PTEN, the major negative regulator of the pathway. Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation. In agreement, we found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls. Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells. Our studies indicate that CK2-mediated PTEN posttranslational inactivation, associated with PI3K/Akt pathway hyperactivation, are a common event in adult B-cell acute lymphoblastic leukemia and suggest that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy., (Copyright© Ferrata Storti Foundation.)

Purpose: Septic arthritis can be disabling and life-threatening, requiring prompt diagnosis and treatment. The infectious agent is not always identified in these patients. We revaluate septic arthritis cases discharged from our department, describing the affected population, causative microorganisms and antibiotic therapy used, and characterised differences between patients with and without isolated pathogenic agents., Methods: Sixty-eight septic arthritis patients were included in this study. Diagnosis was based on clinical findings, and/or the presence of joint purulent material, and/or bacterial pathogen isolation from joint fluid/synovial membrane/blood cultures and response to antibiotics. Data analysis was performed using SPSS 20., Results: Patients had a mean age of 61.1 ± 18.8 years, without sex predominance. 26.5 % had an infection ≤ 15 days before septic arthritis diagnosis. Besides previous infection, 57.4 % had ≥ 1 risk factors for septic arthritis, most commonly pharmacological immunosuppression (20.6 %), diabetes mellitus type 2 (19.1 %) and rheumatoid arthritis (17.6 %). The knee was the most often affected (54.3 %). Only 39.7 % presented fever from clinical onset until hospital admission (mean 13.4 ± 18.9 days). Leucocytosis was present in 45.6 % of patients, elevated erythrocyte sedimentation rate (ESR) in 75 % and elevated C-reactive protein (CRP) in 97.1 %. 5.9 % had articular damage attributable to septic arthritis. An infectious agent was isolated in 41.2 % of patients, with Staphylococcus aureus being the most frequent. 38.7 % of synovial fluid and 23.5 % of synovial membrane cultures were positive. Patients with an identified infectious agent have no significant differences other than more days of hospitalisation (p = 0.003) and in-hospital antibiotic treatment (p = 0.017)., Conclusion: Synovial fluid and synovial membrane cultures more often identified pathogens compared to blood or urine cultures. Patients with and without an identified infectious agent have similar demographic, clinical, laboratory and radiographic characteristics.

Objective: This study examined demographic and clinical characteristics of frequent users of a psychiatric inpatient unit in Portugal., Methods: Data (2004-2008) for 1,348 consecutive psychiatric inpatients were reviewed. Frequent users (N=137), who had at least three admissions in the study period, were compared with nonfrequent users (N=1,211) on age, gender, race-ethnicity, diagnosis, and compulsory admissions. Data were analyzed with chi square and Student's t tests., Results: Frequent users accounted for 29% of admissions. They were significantly younger than nonfrequent users (39±14 versus 44±17, p<.001), and a larger proportion had compulsory admissions (28% versus 14%, p<.001). The frequent user group also had significantly higher rates of bipolar disorder (61% versus 46%, p<.001) and schizophrenia (29% versus 18%, p<.003)., Conclusions: Understanding characteristics of frequent users can inform development of appropriate services. Research should address other variables related to frequent admissions, including socioeconomic factors, general medical and psychiatric comorbidities, and treatment compliance.

Pachydermodactyly is a superficial benign fibromatosis of unknown etiology; it is rare, more frequent in adolescent males, and characterized by painless swelling of the proximal interphalangeal joints(PIP) of the hands. Histologic examination of the skin shows epidermal hyperplasia and increased number of dermal fibroblasts and collagen fibers.We report the case of a 16-year-old adolescent boy who presented swelling of the lateral and dorsal regions of all the metacarpophalangeal and PIP joints of the left hand and PIP and metacarpophalangeal joints of the second and fifth fingers of the right hand, with 3 years of evolution and no arthritis or functional impairment. Results of complementary diagnostic examinations were normal, with the exception of hand ultra sound that showed skin thickening, without synovial proliferation or joint effusion. Skin biopsy confirmed pachydermodactyly. The patient under went aesthetic surgery with good outcome, without recurrence.This rare condition should be distinguished from idiopathic juvenile arthritis and other entities such as knuckle pads syndrome.

Gene alterations affecting elements of PI3K signaling pathway do not appear to be sufficient to explain the extremely high frequency of PI3K signaling hyperactivation in leukemia. It has been known for long that PTEN phosphorylation at the C-terminal tail, in particular by CK2, contributes to the stabilization and simultaneous inhibition of this critical tumor suppressor. However, direct evidence of the involvement of this mechanism in cancer has been gathered only recently. It is now known that CK2-mediated posttranslational, non-deleting, inactivation of PTEN occurs in T-ALL, CLL and probably other leukemias and solid tumors. To explore this knowledge for therapeutic purposes remains one of the challenges ahead.

Although interleukin-7 (IL-7) is essential for human and murine lymphopoiesis and homeostasis, clear disparities between these species regarding the role of IL-7 during B-cell development suggest that other, subtler differences may exist. One basic unsolved issue of IL-7 biology concerns cross-species activity, because in contrast to the human ortholog, the ability of murine (m)IL-7 to stimulate human cells remains unresolved. Establishing whether two-way cross-species reactivity occurs is fundamental for evaluating the role of IL-7 in chimeric human-mouse models, which are the most versatile tools for studying human lymphoid development and disease in vivo. Here, we show that mIL-7 triggers the same signaling pathways as human (h)IL-7 in human T cells, promoting similar changes in viability, proliferation, size, and immunophenotype, even at low concentrations. This ability is not confined to T cells, because mIL-7 mediates cell growth and protects human B-cell precursors from dexamethasone-induced apoptosis. Importantly, endogenous mIL-7 produced in the mouse thymic microenvironment stimulates human T cells, because their expansion in chimeric fetal thymic organ cultures is inhibited by a mIL-7-specific neutralizing antibody. Our results demonstrate that mIL-7 affects human lymphocytes and indicate that mouse models of human lymphoid development and disease must integrate the biological effects of endogenous IL-7 on human cells.

The malignant transformation and expansion of tumor cells involve both cell-autonomous mechanisms and microenvironment signals that regulate viability, nutrient utilization, metabolic activity and cell growth. In T-cell acute lymphoblastic leukemia (T-ALL), the co-culture of leukemic cells with stroma or the addition of particular cytokines prevents ex vivo spontaneous apoptosis. Interleukin-7 (IL-7), a cytokine produced by thymic and bone marrow stroma, increases the viability and proliferation of T-ALL cells. IL-7 induces the activation of Jak/STAT, MEK/Erk and PI3K/Akt signaling pathways in T-ALL cells. PI3K/Akt is the dominant pathway that mediates the effects of IL-7 on T-ALL. PI3K signaling is required for the induction of Bcl-2, the down-regulation of p27(kip1) and cell cycle progression. PI3K signaling is also required for the expression of the glucose transporter Glut1, uptake of glucose, activation of the metabolic machinery, increase in cell size, and maintenance of mitochondrial integrity. These observations suggest that substrates of molecular pathways activated by microenvironmental factors represent attractive molecular targets for the regulation of the viability and proliferation of T-ALL cells and provide the means for the development of novel treatment strategies.