Long-Term Safety and Effectiveness of Rituximab Biosimilar RTXM83: A Retrospective Extension Study in Brazilian Patients with Diffuse Large B-Cell Lymphoma.

INTRODUCTION: RTXM83, a biosimilar of rituximab, was approved after physicochemical, functional, non-clinical, and clinical studies demonstrated their similarity; these studies included RTXM83-AC-01-11, a multicentric double-blind international prospective pivotal study. Long-term data on biosimilars can potentially elucidate their clinical robustness and facilitate their broader adoption. METHODS: In this retrospective observational study, we analyzed a dataset from a Brazilian cohort previously randomized in the RTXM83-AC-01-11 study followed by the assessment of long-term outcomes in an observational extension phase from randomization in the RTXM83-AC-01-11 study to the last recorded evaluation. Patients with diffuse large B cell lymphoma (DLBCL) received either reference rituximab (R) or RTXM83 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as adjuvant treatment. RESULTS: The median follow-up period was 77.0 months. Patients with initial DLBCL stages III and IV comprised 50% of the R-CHOP group and 40% of the biosimilar group. Five (18.5%) patients, including two RTXM83-CHOP-treated and three R-CHOP-treated individuals, experienced late adverse events (AEs) of interest. No new safety signs were established. At the final assessment, the progression-free survival (PFS) rates were 93.3% and 50.0% in the RTXM83-CHOP and R-CHOP groups, respectively. Median PFS was not achieved in the RTXM83-CHOP group, which was 40.5 months in the R-CHOP group. The overall survival (OS) rates were 100% and 66.7% in the RTXM83-CHOP and R-CHOP groups, respectively. The median OS was not reached in any group. CONCLUSION: This study demonstrated the long-term safety and effectiveness of RTXM83 in treating DLBCL; outcomes comparable to those of the reference product and potentially improved access to treatment have been indicated. However, further research with more diverse patient groups can validate these findings and advocate the broader adoption of biosimilars in cancer care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04928573. June 16, 2021, "retrospectively registered".

Real-World Study of Adjuvant Biosimilar Trastuzumab-dkst for HER2-Positive Breast Cancer Treatment in a Brazilian Population.

INTRODUCTION: Biological monoclonal antibodies play a pivotal role in cancer treatment, with biosimilars significantly enhancing their accessibility. In Brazil's ethnically diverse setting, real-world evidence is crucial for assessing the effectiveness and applicability of these therapies in routine clinical practice. METHODS: We performed a multicentric, observational, prospective real-world study on biosimilar trastuzumab-dkst for adjuvant treatment of early HER2-positive breast cancer in Brazilian patients. Data were collected using a case-report form. RESULTS: Of the 176 recruited, we present data from the first 59 patients (mean age 51.7 ± 12.9 years) who had completed treatment with trastuzumab-dkst. The mean time from diagnosis to the first adjuvant treatment with trastuzumab-dkst was 5.5 ± 2.7 months. Of the patients, 59% of patients achieved at least a 30-month follow-up. The 31.7-month invasive disease-free survival rate (IDFS) was 94.5% (95% CI 83.9-98.2%) and median IDFS was not achieved, since only three patients had invasive disease recurrence. The overall survival rate was 100% until the last assessment. The observed adverse events were similar to those presented by other studies using biosimilar or reference trastuzumab. Four serious adverse events (8.5%) were observed. A reduction in left ventricular ejection fraction of at least 10% was observed in 16.9% of participants. There was no treatment interruption, and three participants (5.1%) had their trastuzumab-dkst dose reduced. CONCLUSION: Our study reinforces the existing pivotal data, underscoring the real-world efficacy and safety of biosimilar trastuzumab-dkst in the adjuvant treatment for early HER2-positive breast cancer. The preliminary long-term effectiveness and safety data we present further validate trastuzumab-dkst's role as a cost-saving alternative in oncological care. These findings have important implications for improving patient access to crucial treatments and for the more efficient use of healthcare resources. GOV REGISTRATION: NCT03892655.

Functional and structural basis of human parainfluenza virus type 3 neutralization with human monoclonal antibodies.

Human parainfluenza virus type 3 (hPIV3) is a respiratory pathogen that can cause severe disease in older people and infants. Currently, vaccines against hPIV3 are in clinical trials but none have been approved yet. The haemagglutinin-neuraminidase (HN) and fusion (F) surface glycoproteins of hPIV3 are major antigenic determinants. Here we describe naturally occurring potently neutralizing human antibodies directed against both surface glycoproteins of hPIV3. We isolated seven neutralizing HN-reactive antibodies and a pre-fusion conformation F-reactive antibody from human memory B cells. One HN-binding monoclonal antibody (mAb), designated PIV3-23, exhibited functional attributes including haemagglutination and neuraminidase inhibition. We also delineated the structural basis of neutralization for two HN and one F mAbs. MAbs that neutralized hPIV3 in vitro protected against infection and disease in vivo in a cotton rat model of hPIV3 infection, suggesting correlates of protection for hPIV3 and the potential clinical utility of these mAbs.

Advanced renal cell carcinoma management: the Latin American Cooperative Oncology Group (LACOG) and the Latin American Renal Cancer Group (LARCG) consensus update.

PURPOSE: Renal cell carcinoma is an aggressive disease with a high mortality rate. Management has drastically changed with the new era of immunotherapy, and novel strategies are being developed; however, identifying systemic treatments is still challenging. This paper presents an update of the expert panel consensus from the Latin American Cooperative Oncology Group and the Latin American Renal Cancer Group on advanced renal cell carcinoma management in Brazil. METHODS: A panel of 34 oncologists and experts in renal cell carcinoma discussed and voted on the best options for managing advanced disease in Brazil, including systemic treatment of early and metastatic renal cell carcinoma as well as nonclear cell tumours. The results were compared with the literature and graded according to the level of evidence. RESULTS: Adjuvant treatments benefit patients with a high risk of recurrence after surgery, and the agents used are pembrolizumab and sunitinib, with a preference for pembrolizumab. Neoadjuvant treatment is exceptional, even in initially unresectable cases. First-line treatment is mainly based on tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs); the choice of treatment is based on the International Metastatic Database Consortium (IMCD) risk score. Patients at favourable risk receive ICIs in combination with TKIs. Patients classified as intermediate or poor risk receive ICIs, without preference for ICI + ICIs or ICI + TKIs. Data on nonclear cell renal cancer treatment are limited. Active surveillance has a place in treating favourable-risk patients. Either denosumab or zoledronic acid can be used for treating metastatic bone disease. CONCLUSION: Immunotherapy and targeted therapy are the standards of care for advanced disease. The utilization and sequencing of these therapeutic agents hinge upon individual risk scores and responses to previous treatments. This consensus reflects a commitment to informed decision-making, drawn from professional expertise and evidence in the medical literature.

Anti-Acanthamoeba metallopharmaceuticals: Amoebicidal activity and synergistic effect of copper(II) coordination compound.

Acanthamoeba spp. emerged as a clinically important pathogen related to amoebic keratitis. It is among the main causes of corneal transplantation and vision loss in ophthalmology. The treatment protocols have a low cure rate, high toxicity, and need for drug combination. Transition metal compounds have shown promising antiprotozoal effects. This study evaluates the amoebicidal activity of copper(II) coordination compounds in combination with chlorhexidine and the cytotoxicity to topical ocular application. These copper(II) coordination compounds were screened against Acanthamoeba castellanii trophozoites (ATCC 50492). The cytotoxicity on rabbit corneal cell line (ATCC-CCL 60) was performed. The compounds showed high amoebicidal potential, with inhibition of trophozoite viability above 80%. The Cp12 and Cp13 compounds showed Minimal Inhibitory Amoebicidal Concentration (MIAC) at 200 µM and mean inhibitory concentration (IC50) values lower than 10 µM. Against the cysts, Cp12 showed a reduction in viability (48%) in the longest incubation period. A synergistic effect for Cp12 with chlorhexidine was observed. The compounds have a dose-dependent effect against rabbit corneal cells. Compound Cp12 has potential for future application in developing ophthalmic formulations against Acanthamoeba keratitis and its use in multipurpose solutions is highlighted.

Vitamin D regulates microbiome-dependent cancer immunity.

A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.

Early Intensive Neurorehabilitation in Traumatic Peripheral Nerve Injury-State of the Art.

Traumatic nerve injuries are common lesions that affect several hundred thousand humans, as well as dogs and cats. The assessment of nerve regeneration through animal models may provide information for translational research and future therapeutic options that can be applied mutually in veterinary and human medicine, from a One Health perspective. This review offers a hands-on vision of the non-invasive and conservative approaches to peripheral nerve injury, focusing on the role of neurorehabilitation in nerve repair and regeneration. The peripheral nerve injury may lead to hypersensitivity, allodynia and hyperalgesia, with the possibility of joint contractures, decreasing functionality and impairing the quality of life. The question remains regarding how to improve nerve repair with surgical possibilities, but also considering electrical stimulation modalities by modulating sensory feedback, upregulation of BDNF, GFNF, TrKB and adenosine monophosphate, maintaining muscle mass and modulating fatigue. This could be improved by the positive synergetic effect of exercises and physical activity with locomotor training, and other physical modalities (low-level laser therapy, ultrasounds, pulsed electromagnetic fields, electroacupuncture and others). In addition, the use of cell-based therapies is an innovative treatment tool in this field. These strategies may help avoid situations of permanent monoplegic limbs that could lead to amputation.

Chronic arsenic exposure suppresses proteasomal and autophagic protein degradation.

Ubiquitin Proteasomal System (UPS) and autophagy dysregulation initiate cancer. These pathways are regulated by zinc finger proteins. Trivalent inorganic arsenic (iAs) displaces zinc from zinc finger proteins disrupting functions of important cellular proteins. The effect of chronic environmental iAs exposure (100 nM) on UPS has not been studied. We tested the hypothesis that environmental iAs exposure suppresses UPS, activating autophagy as a compensatory mechanism. We exposed skin (HaCaT and Ker-CT; independent quadruplicates) and lung (BEAS-2B; independent triplicates) cell cultures to 0 or 100 nM iAs for 7 or 8 weeks. We quantified ER stress (XBP1 splicing employing Reverse Transcriptase -Polymerase Chain Reaction), proteasomal degradation (immunoblots), and initiation and completion of autophagy (immunoblots). We demonstrate that chronic iAs exposure suppresses UPS, initiates autophagy, but suppresses autophagic protein degradation in skin and lung cell lines. Our data suggest that chronic iAs exposure inhibits autophagy which subsequently suppresses UPS.

Percepção de cuidadores de pré-escolares com TEA sobre seu comportamento e desempenho ocupacional durante a pandemia da COVID-19 / Perception of caregivers of preschool children with ASD on their behavior and occupational performance during the COVID-19 pandemic

Resumo Introdução Crianças com Transtorno do Espectro Autista (TEA) podem apresentar questões comportamentais, no processamento sensorial, na cognição e na linguagem, que afetam seu desempenho ocupacional, necessitando de acesso a serviços escolares, terapêuticos e de saúde. O acesso a esses serviços esteve restrito durante a pandemia de COVID-19, tornando essa população particularmente ainda mais vulnerável às restrições sociais impostas à época. Objetivo Descrever a percepção dos pais cuidadores de pré-escolares com TEA acerca do comportamento e desempenho ocupacional de seus filhos durante a pandemia da COVID-19. Método Estudo transversal, descritivo, quantitativo e qualitativo baseado em entrevistas com 60 cuidadores de pré-escolares com TEA. Os participantes responderam à seguinte pergunta: Você está notando alguma diferença no comportamento e desempenho da criança durante a pandemia? Para caracterização das crianças, foram utilizados o Sistema de Classificação de Funcionalidade no Autismo: Comunicação Social (ACSF:SC), o Inventário de Avaliação Pediátrica de Incapacidade - Teste Adaptativo de Computador (PEDI-CAT) e o Perfil Sensorial 2 (SP-2). Todas as entrevistas foram anotadas e 15 delas foram gravadas e transcritas. O material foi submetido à análise temática de conteúdo. Resultados Foram entrevistadas 43 mães, 15 casais e dois pais de crianças com TEA. Das 60 crianças, 46 (76,7%) eram meninos, com idade de 3 a 5 anos (53,6 ±10,18 meses). Os cuidadores perceberam mudanças no comportamento e desempenho ocupacional, com prevalência de relatos de piora. Houve aumento nas estereotipias, rigidez e hiperfoco, bem como menor engajamento nas atividades cotidianas. A presença dos cuidadores beneficiou algumas crianças, mas há relato de estresse, especialmente por parte das mães. Conclusão Houve variação nos relatos, com maior tendência à piora no comportamento e desempenho ocupacional das crianças com TEA.

Abstract Introduction Children with Autism Spectrum Disorder (ASD) face behavioral, sensory processing, cognitive, and language challenges that affect their ability to perform activities of daily living (ADL) and necessitate access to educational, therapeutic, and health services. The COVID-19 pandemic limited access to these essential services, exacerbating the challenges faced by this vulnerable population due to imposed social distancing measures. Objective To explore the perceptions of parent caregivers of preschoolers with ASD regarding their children's behavior and performance in ADL during the COVID-19 pandemic. Method This cross-sectional, descriptive study utilized both quantitative and qualitative approaches, interviewing 60 caregivers of preschoolers with ASD. Participants were asked about any observed changes in their child's behavior and ability to engage in ADL during the pandemic. Child characterization involved the Autism Classification System of Functioning: Social Communication (ACSF:SC), the Pediatric Evaluation of Disability Inventory - Computer Adaptive Test (PEDI-CAT), and the Sensory Profile 2 (SP-2). Interviews were documented, with 15 recorded and transcribed for thematic content analysis. Results Participants included 43 mothers, 15 couples, and two fathers, totaling 60 children, of whom 46 (76.7%) were boys aged between 3 and 5 years (mean age 53.6 ±10.18 months). Caregivers reported changes in behavior and performance in ADL, predominantly noting deterioration. Increases in stereotypic behaviors, rigidity, and hyperfocus were observed, along with decreased participation in ADL. While the presence of caregivers benefited some children, it also led to reported stress, particularly among mothers. Conclusion The study found a predominant trend of deteriorating behavior and performance in ADL among children with ASD during the pandemic, based on caregiver reports.

Religiosidade/espiritualidade entre a população brasileira diante da pandemia Covid-19 e a correlação com a qualidade de vida / Religiosity/spirituality among the brazilian population in the face of the Covid-19 pandemic and the correlation with quality of life / Religiosidad/espiritualidad en la población brasileña frente a la pandemia de Covid-19 y la correlación con la calidad de vida

A pandemia causada pelo SARS-CoV-2 (COVID-19) trouxe inúmeros impactos na vida cotidiana, tanto nos aspectos econômicos, como nos emocionais, psicológicos e sociais. Em situações difíceis, as pessoas, muitas vezes, recorrem à espiritualidade ou à religiosidade. O objetivo deste estudo foi investigar a presença da religiosidade/espiritualidade entre a população brasileira diante da pandemia da COVID- 19, correlacionado com a qualidade de vida. É um estudo quantitativo, descritivo e transversal, realizado nos últimos meses de 2020. Os dados foram coletados por meio de respostas aos instrumentos WHOQOL-Bref e o WHOQOL-SRPB, de forma online, por meio do Google Forms®. Utilizou-se o método de amostragem não probabilístico do tipo snowball sampling, totalizando 948 respostas. Os dados foram tabulados por meio do software Microsoft Excel (2019) e analisados estatisticamente, considerando significativo p<0,05. Os dados apresentados mostram de forma enfática como os participantes que pertencem a alguma religião, apresentaram melhor relação nos domínios saúde psicológica, independência, meio ambiente e espiritualidade/religião/crenças pessoais em comparação àqueles que declaram não pertencer a uma religião. No entanto, não houve diferença estatisticamente significativa para os domínios saúde física e relações sociais. Conclui-se que o pertencimento a uma religião pode contribuir para a melhoria da qualidade de vida e auxiliar o enfrentamento das situações desfavoráveis durante a pandemia COVID-19. Diante disso, destaca-se a importância do desenvolvimento de novos estudos sobre o tema, para compreender com mais veemência e detalhamento, a relação dessas variáveis em contextos de crise que possam alterar a rotina de vida das pessoas.

The pandemic caused by SARS-CoV-2 (COVID-19) has brought numerous impacts on daily life, both in economic, emotional, psychological, and social aspects. In difficult situations, people often turn to spirituality or religiosity. The objective of this study was to investigate the presence of religiosity/spirituality among the Brazilian population facing the pandemic of COVID-19, correlated with quality of life. Quantitative, descriptive, cross-sectional study conducted in the last months of 2020. Data were collected by means of responses to the WHOQOL-Bref and the WHOQOL-SRPB instruments, online, through Google Forms®. The non-probabilistic snowball sampling method was used, totaling 948 answers. Data were tabulated using Microsoft Excel software (2019) and statistically analyzed, considering p<0.05 significant. The data presented emphatically show how the participants, who belong to some religion, presented a better relationship in the domains psychological health, independence, and environment and spirituality/religion/personal beliefs compared to those who do not have a religion. However, there was no statistically significant difference for the physical health and social relationships domains. It is concluded that belonging to a religion can contribute to improved quality of life and assist in coping with unfavorable situations during the COVID-19 pandemic. Therefore, the importance of developing new studies on the subject is highlighted, in order to understand more vehemently the relationship of these variables in crisis contexts that can change the routine of people's lives.

La pandemia causada por el SARS-CoV-2 (COVID-19) ha traído numerosos impactos en la vida cotidiana, tanto en los aspectos económicos, emocionales, psicológicos y sociales. En situaciones difíciles, las personas suelen recurrir a la espiritualidad o la religiosidad. El objetivo de este estudio fue investigar la presencia de religiosidad/espiritualidad en la población brasileña que enfrenta la pandemia de COVID- 19, correlacionada con la calidad de vida. Estudio cuantitativo, descriptivo, transversal, realizado en los últimos meses de 2020. Los datos fueron recolectados por medio de respuestas a los instrumentos WHOQOL-Bref y WHOQOL-SRPB, en línea, a través de Google Forms®. Se utilizó el método de muestreo no probabilístico de bola de nieve, totalizando 948 respuestas. Los datos fueron tabulados utilizando el software Microsoft Excel (2019) y analizados estadísticamente, considerando p<0,05 significativa. Los datos presentados muestran enfáticamente cómo los participantes, que pertenecen a alguna religión, presentaron una mejor relación en los dominios salud psicológica, independencia y entorno y espiritualidad/religión/creencias personales en comparación con aquellos que no tienen religión. Sin embargo, no hubo diferencias estadísticamente significativas para los dominios salud física y relaciones sociales. Se concluye que la pertenencia a una religión puede contribuir a mejorar la calidad de vida y ayudar a afrontar situaciones desfavorables durante la pandemia de COVID-19. Por lo tanto, se destaca la importancia de desarrollar nuevos estudios sobre el tema, para comprender con más vehemencia la relación de estas variables en contextos de crisis que pueden cambiar la rutina de vida de las personas.

Assessing Mode-Switching Strategies for Assistive Robotic Manipulators Using a Preliminary Version of the Novel Non-invasive Tongue-Computer Interface.

The inductive tongue-computer interface allows individuals with tetraplegia to control assistive devices. However, controlling assistive robotic arms often requires more than 14 different commands, which cannot always fit into a single control layout. Previous studies have separated the commands into modes, but few have investigated strategies to switch between them. In this feasibility study, we compare the efficiency of switching modes using buttons, swipe gestures and double taps using a preliminary version of a new non-invasive mouthpiece unit (nMPU), which includes an integrated activation unit and a single sensor board. Three participants controlled a JACO assistive robot to pick up a bottle using different mode-switching strategies. Compared with switching modes with buttons, switching modes with swipes and double taps increased the task completion time by 21% and 58% respectively. Therefore, we recommend that configurations with multiple modes for the non-invasive tongue-computer interface include buttons for mode-switching.Clinical relevance- Cumbersome mode-switching strategies can lower a control interface's responsiveness and contribute to end-user abandonment of assistive technologies. This study showed that using buttons to switch modes is more reliable. Moreover, this study will inform the development of future control layouts with improved usability.

The Effect of Upper Eyelid Blepharoplasty on Corneal Tomography and Epithelial Profile.

Introduction: Upper tarsal mechanical forces influence corneal epithelial thickness profile, which could modulate corneal astigmatism. Upper eyelid blepharoplasty reduces upper tarsal strength and may have an impact on ocular surface. The aim of this study is to evaluate the effect of upper eyelid blepharoplasty on corneal epithelial thickness profile, astigmatism and aberrations. Methods: Patients with dermatochalasis underwent bilateral upper eyelid blepharoplasty. Anterior segment optical coherence tomography (AS-OCT) (Zeiss Cirrus 5000 HD-OCT) and Pentacam (Oculus, Wetzlar Germany) were performed before surgery and in the 8th postoperative week. Corneal epithelial thickness, keratometry, aberrations and asphericity were considered for statistical purposes. Only right eyes were considered. A p-value lower than 0.05 was considered significant. Results: Thirty eyes of 30 patients were included. The degree of astigmatism did not change after surgery (0.95D vs 0.83D, p=0.23). The difference between preoperative and postoperative steepest axis was 3.1° (p=0.04) with a tendency to change toward the vertical meridian. Mean epithelial thickness was higher in the inferior region both pre- and postoperatively and did not change. ET in the superior octant was lower (42 µm vs 45 µm, p<0.01) and the difference between inferior and superior octants (I-S) was higher (7 µm vs 3 µm, p<0.001) before surgery. There were no statistically significant changes in corneal aberrations (p=0.52) and asphericity (p=0.41) after surgery. Conclusion: Our results support that upper tarsus pressure influences epithelial thickness profile and, consequently, the corneal steepest keratometry. These results lead us to postulate that upper eyelid blepharoplasty may influence biometric and keratometric measurements.

SYK ubiquitination by CBL E3 ligases restrains cross-presentation of dead cell-associated antigens by type 1 dendritic cells.

Cross-presentation of dead cell-associated antigens by conventional dendritic cells type 1 (cDC1s) is critical for CD8+ T cells response against many tumors and viral infections. It is facilitated by DNGR-1 (CLEC9A), an SYK-coupled cDC1 receptor that detects dead cell debris. Here, we report that DNGR-1 engagement leads to rapid activation of CBL and CBL-B E3 ligases to cause K63-linked ubiquitination of SYK and terminate signaling. Genetic deletion of CBL E3 ligases or charge-conserved mutation of target lysines within SYK abolishes SYK ubiquitination and results in enhanced DNGR-1-dependent antigen cross-presentation. We also find that cDC1 deficient in CBL E3 ligases are more efficient at cross-priming CD8+ T cells to dead cell-associated antigens and promoting host resistance to tumors. Our findings reveal a role for CBL-dependent ubiquitination in limiting cross-presentation of dead cell-associated antigens and highlight an axis of negative regulation of cDC1 activity that could be exploited to increase anti-tumor immunity.

Clonal variability in chromosomal instability as a potential driver in the acquisition of tumorigenic phenotype in chronic arsenic-exposed and hsa-miR-186 overexpressing human keratinocytes.

Chronic arsenic exposure through drinking water is a global health issue, affecting >200 million people. Arsenic is a group I human carcinogen and causes chromosomal instability (CIN). Arsenic exposure is the second most common cause of skin cancer after UV radiation. hsa-miR-186 is overexpressed in arsenic-induced squamous cell carcinoma relative to premalignant hyperkeratosis. Among predicted targets of hsa-miR-186 are cell cycle regulators including regulators of mitotic progression. Disruption of mitotic progression can contribute to CIN. Thus, we hypothesized that hsa-miR-186 overexpression contributes to malignant transformation of arsenic exposed HaCaT cells by induction of CIN. Stable clones of HaCaT cells transfected with pEP-hsa-miR-186 expression vector or empty vector were maintained under puromycin selection and exposed to 0 or 100 nM NaAsO2 and cultured for 29 weeks. HaCaT clones overexpressing hsa-miR-186 and exposed to NaAsO2 showed increased CIN and anchorage independent growth at 29 weeks in a stochastic manner, in contrast to unexposed empty vector transfected clones. These results suggest that clonal variability mediates arsenic-induced carcinogenesis in hsa-miR-186 overexpressing human keratinocytes.

Meaning of Life Therapy: A Pilot Study of a Novel Psycho-Existential Intervention for Palliative Care in Cancer.

Intervention in Palliative Care aims to provide physical, psychosocial, and spiritual relief for patients and family members. Brief interventions with a psycho-existential approach have shown positive responses; however, cultural adaptations are needed. This pilot study aimed to develop the Meaning of Life Therapy (MLT), a novel psycho-existential intervention, rooted in the Dignity Therapy, Life Review, and Meaning-Centered Psychotherapy. MLT was culturally adapted to the Portuguese context to include questions about forgiveness, apology, reconciliation, farewell, and a legacy document, i.e., the Life Letter. Nine PC cancer patients answered a 14-question MLT protocol, intended to help patients find purpose and meaning in life. Eight themes emerged: Family, Preservation of Identity, Life Retrospective, Clinical Situation, Achievements, Socio-Professional Valorization, Forgiveness/Apology/Reconciliation, and Saying Goodbye. MLT has proved its ability to respond to the psycho-existential needs of PC patients. Further studies should be conducted to gain extensive knowledge of the effectiveness of culturally responsive interventions.

Novel Foscan®-derived ring-fused chlorins for photodynamic therapy of cancer.

Photodynamic therapy (PDT) is an established anticancer treatment that combines the use of a photosensitiser (PS) and a light source of a specific wavelength for the generation of reactive oxygen species (ROS) that are toxic to the tumour cells. Foscan® (mTHPC) is a clinically-approved chlorin used for the PDT treatment of advanced head and neck, prostate and pancreatic cancers but is characterized by being photochemically unstable and associated with prolonged skin photosensitivity. Herein, we report the synthesis of new 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, having the meso-tetra(3-hydroxyphenyl)macrocycle core of mTHPC, by exploring the [8π + 2π] cycloaddition of a meso-tetra(3-hydroxyphenyl)porphyrin derivative with diazafulvenium methides. These chlorins have photochemical properties similar to Foscan® but are much more photostable. Among the novel compounds, two chlorins with a hydroxymethyl group and its azide derivative present in the 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused system, are promising photodynamic agents with activity in the 100 nM range against triple-negative breast cancer cells and, in the case of azidomethyl chlorin, a safer phototherapeutic index compared to Foscan®.

Interplay between CXCR4 and CCR2 regulates bone marrow exit of dendritic cell progenitors.

Conventional dendritic cells (cDCs) are found in most tissues and play a key role in initiation of immunity. cDCs require constant replenishment from progenitors called pre-cDCs that develop in the bone marrow (BM) and enter the blood circulation to seed all tissues. This process can be markedly accelerated in response to inflammation (emergency cDCpoiesis). Here, we identify two populations of BM pre-cDC marked by differential expression of CXCR4. We show that CXCR4lo cells constitute the migratory pool of BM pre-cDCs, which exits the BM and can be rapidly mobilized during challenge. We further show that exit of CXCR4lo pre-cDCs from BM at steady state is partially dependent on CCR2 and that CCR2 upregulation in response to type I IFN receptor signaling markedly increases efflux during infection with influenza A virus. Our results highlight a fine balance between retention and efflux chemokine cues that regulates steady-state and emergency cDCpoiesis.

Food Knowledge for Better Nutrition and Health: A Study among University Students in Portugal.

When students enter university, they suffer adaptations, including, usually, greater autonomy and responsibility for the choices they make. Therefore, it is crucial that they are well informed so as to make healthier food choices. The aim of this study was to determine whether sociodemographic characteristics, academic performance and lifestyle (tobacco and alcohol consumption) interfere with food literacy in university students. A quantitative, analytical, descriptive, transversal and correlational study was carried out, using quantitative data obtained through a questionnaire survey applied to a sample of 924 university students in Portugal. Food literacy was assessed through a scale of 27 items, distributed in three dimensions: D1-Literacy about food nutritional value and composition, D2-Literacy about labelling and food choice and D3-Literacy about healthy eating practices. Results showed no differences in food literacy according to sex or age. However, food literacy varied significantly with nationality, either globally (p = 0.006) or in the different dimensions evaluated (p-values of 0.005, 0.027 and 0.012 for D1, D2 and D3, respectively). In terms of academic achievement, the results showed no significant differences according to self-reported academic performance or even to the average classification obtained in the course. Regarding lifestyle variables, it was observed that alcohol consumption or smoking are not associated with food literacy, that is, food literacy does not vary significantly with these two lifestyle variables. In conclusion, food literacy in general and the dimensions evaluated are essentially constant among university students in Portugal, only varying for students from abroad. These results help to better perceive the food literacy levels for the population under study, university students, and that can be a valuable tool to better increase food literacy at these institutions as a way to better prepare for a healthier life and proper food habits that can enhance health in the long term.

Iron metabolism in colorectal cancer: a balancing act.

BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second deadliest malignancy worldwide. Current dietary habits are associated with increased levels of iron and heme, both of which increase the risk of developing CRC. The harmful effects of iron overload are related to the induction of iron-mediated pro-tumorigenic pathways, including carcinogenesis and hyperproliferation. On the other hand, iron deficiency may also promote CRC development and progression by contributing to genome instability, therapy resistance, and diminished immune responses. In addition to the relevance of systemic iron levels, iron-regulatory mechanisms in the tumor microenvironment are also believed to play a significant role in CRC and to influence disease outcome. Furthermore, CRC cells are more prone to escape iron-dependent cell death (ferroptosis) than non-malignant cells due to the constitutive activation of antioxidant genes expression. There is wide evidence that inhibition of ferroptosis may contribute to the resistance of CRC to established chemotherapeutic regimens. As such, ferroptosis inducers represent promising therapeutic drugs for CRC. CONCLUSIONS AND PERSPECTIVES: This review addresses the complex role of iron in CRC, particularly in what concerns the consequences of iron excess or deprivation in tumor development and progression. We also dissect the regulation of cellular iron metabolism in the CRC microenvironment and emphasize the role of hypoxia and of oxidative stress (e.g. ferroptosis) in CRC. Finally, we underline some iron-related players as potential therapeutic targets against CRC malignancy.