Lessons for the Next Generation of Scientists from the Second Annual Arthur and Sandra Irving Cancer Immunology Symposium.

The Arthur and Sandra Irving Cancer Immunology Symposium has been created as a platform for established cancer immunologists to mentor trainees and young investigators as they launch their research career in the field. By sharing their different paths to success, the senior faculty mentors provide an invaluable resource to support the development of the next generation of leaders in the cancer immunology community. This Commentary describes some of the key topics that were discussed during the 2022 symposium: scientific and career trajectory, leadership, mentoring, collaborations, and publishing. For each of these topics, established investigators discussed the elements that facilitate success in these areas as well as mistakes that can hinder progress. Herein, we outline the critical points raised in these discussions for establishing a successful independent research career. These points are highly relevant for the broader scientific community.

Skin pigmentation as landmark for arteriovenous fistula cannulation in hemodialysis.

BACKGROUND: The cannulation of the arteriovenous fistula (AVF) for hemodialysis (HD) has traditionally depended on the nurse's tactile sensation, which has been associated with suboptimal needle placement and detrimental effects on vascular access (VA) longevity. While the introduction of ultrasound (US) has proven beneficial in mapping the AVF outflow vein and assisting in cannulation planning, aneurysmal deformations remain a common occurrence resulting from various factors, including inadequate cannulation techniques. Within this context, the utilization of skin pigmentation as a clinical landmark has emerged as a potential approach to enhance cannulation planning in HD. METHODS: A prospective longitudinal study was undertaken to investigate the correlation between the occurrence of venous morphological deformations and the cannulation technique guided by skin pigmentation after a 2-month period of implementation. RESULTS: Thirty patients were enrolled in the study with 433 cannulations being described within the first 2 months of AVF use. The overall rate of cannulation-related adverse events was 21.9%. Comparative analysis demonstrated a statistically significant relationship (p < 0.001) between aneurysmal deformation and non-compliance with the proposed cannulation technique, resulting in cannulation outside the designated points. Non-compliance was primarily attributed to nurse's decision (57.1%). CONCLUSION: The integration of US mapping of the AVF outflow vein and the utilization of skin pigmentation as a guiding tool have shown promising results in enhancing cannulation planning over time. Consistent adherence to a cannulation technique other than the area technique has been found to reduce the risk of AVF morphological deformation. These findings underscore the potential benefits of incorporating skin pigmentation as a clinical landmark in cannulation practices, highlighting its ability to impact positively cannulation outcomes.

N-acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer.

A genome-wide PiggyBac transposon-mediated screen and a resistance screen in a PIK3CAH1047R-mutated murine tumor model reveal NF1 loss in mammary tumors resistant to the phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor alpelisib. Depletion of NF1 in PIK3CAH1047R breast cancer cell lines and a patient-derived organoid model shows that NF1 loss reduces sensitivity to PI3Kα inhibition and correlates with enhanced glycolysis and lower levels of reactive oxygen species (ROS). Unexpectedly, the antioxidant N-acetylcysteine (NAC) sensitizes NF1 knockout cells to PI3Kα inhibition and reverts their glycolytic phenotype. Global phospho-proteomics indicates that combination with NAC enhances the inhibitory effect of alpelisib on mTOR signaling. In public datasets of human breast cancer, we find that NF1 is frequently mutated and that such mutations are enriched in metastases, an indication for which use of PI3Kα inhibitors has been approved. Our results raise the attractive possibility of combining PI3Kα inhibition with NAC supplementation, especially in patients with drug-resistant metastases associated with NF1 loss.

Hypothalamic hamartoma: a cause of precocious puberty.

Hypothalamic hamartomas are uncommon congenital malformations that present as precocious puberty, gelastic seizures and/or psychiatric disorders. Characteristic changes in MRI scans lead to a diagnosis. Treatment may include surgery or gonadotropin-releasing hormone agonists (GnRHa) depending on clinical manifestations.Here, we describe a case of hypothalamic hamartoma diagnosed in a girl in middle childhood, who presented with early development of secondary sexual characteristics. Physical examination, hormonal study, bone age and pelvic ultrasound findings were consistent with those of precocious puberty. The investigation also included a brain MRI scan, which revealed a small nodule with regular limits in the left hypothalamic region/tuber cinereum. GnRHa treatment and neurosurgical follow-ups were initiated promptly. The patient showed a reversal of secondary sexual characteristics and stable hamartoma size. This case illustrates the importance of brain MRI scans as part of the assessment of suspected precocious puberty because clinical features do not identify patients with an underlying pathology.

Locally sourced: site-specific immune barriers to metastasis.

Tumour cells migrate very early from primary sites to distant sites, and yet metastases often take years to manifest themselves clinically or never even surface within a patient's lifetime. This pause in cancer progression emphasizes the existence of barriers that constrain the growth of disseminated tumour cells (DTCs) at distant sites. Although the nature of these barriers to metastasis might include DTC-intrinsic traits, recent studies have established that the local microenvironment also controls the formation of metastases. In this Perspective, I discuss how site-specific differences of the immune system might be a major selective growth restraint on DTCs, and argue that harnessing tissue immunity will be essential for the next stage in immunotherapy development that reliably prevents the establishment of metastases.

A Challenging Case: Botulism in a Toddler.

Botulism is a life-threatening, rapidly progressive neuroparalytic disease caused by one of the most potent toxins known, botulinum toxin. It manifests as flaccid and symmetrical descending paralysis that can affect both cranial and peripheral nerves. The only specific treatment available is the administration of botulinum antitoxin. We present the case of a three-year-old boy who had gastrointestinal symptoms and had ingested garden soil/dust at a construction site before the onset of cranial nerve palsy, which manifested as dysphagia in swallowing liquid and solid food and bilateral progressive ptosis. Early suspicion of botulism and treatment with botulinum antitoxin resulted in complete neurologic recovery. This case highlights the importance of a careful history and neurologic examination to avoid misdiagnosis. Administration of botulinum antitoxin should not be delayed until the diagnosis is confirmed and clinicians should be aware that this approach can be life-saving.

The Impact of Different Pedagogical Models on Moderate-to-Vigorous Physical Activity in Physical Education Classes.

The aims of this study were twofold: (i) to examine differences in physical activity (PA) variables regarding the length of Physical Education (PE) lessons (45 vs. 90 min) and teaching methodology (Teaching Games for Understanding (TGfU) or hybrid TGfU-sports education (SE)); and (ii) to estimate the percentage of time spent in moderate-to-vigorous (MV) PA assessed via an accelerometer based on total step count, BMI, age, and sex, considering the pedagogical models and the class length. This study was carried out in three classes of invasion games in PE. Two classes were taught based on TGfU (44 students, 18 males, 12.6 ± 0.55), and one was taught based on a hybrid TGfU-SE (17 students, 9 males, 13.7 ± 0.90). The same students were assessed twice, first in a 45 min class and then in a 90 min class. The students' MVPA was assessed using the Actigraph GT3X Activity Monitor. The results revealed significant differences in PA intensity regarding the length of the PE lesson (45 vs. 90 min) and the teaching methodology. The 45 min classes using TGfU were more intense and had less sedentary time than the 90 min classes. When using a hybrid TGfU-SE, the 90 min classes had higher intensities than the 45 min classes. Generally, when comparing the two types of pedagogical intervention, the TGfU model provided more active lessons and less sedentary time in class than a hybrid TGfU-SE. The TGfU model is more profitable for increasing MVPA in class. Due to the issues related to the organization and management of sports practice in class, several recommendations for maximizing MVPA in a hybrid TGfU-SE class must be considered.

Association between the Duration of the Active Commuting to and from School, and Cognitive Performance in Urban Portuguese Adolescents.

This study aimed to analyze the differences between active commuting to school (ACS) and non-ACS in cognitive performance (CP), and the association of ACS duration with CP. This cross-sectional study included 370 adolescents (males n = 170), with a mean age of 15.28 ± 2.25 years. CP was assessed through an interview, and ACS, extracurricular physical activity, and socioeconomic status was assessed by self-report. Body composition was assessed using the FitnessGram test battery. One in two adolescents did ACS (51.6%). ACS was associated with boys (53.9%), younger adolescents (14.91 ± 2.15 vs. 15.69 ± 2.29), those having school social support (55.0%), and those doing one or more extracurricular physical activities (53.6%), compared to non-ACS participants (p < 0.05). The analysis of covariance, after controlling for age, sex, school social support, and participation in extracurricular physical activity, showed an effect of ACS on the total cognitive score (F(2,362) = 3.304, p < 0.05). The CP was higher in adolescents with more than 30 min of ACS than non-ACS (p < 0.05). The influence of ACS duration can be seen in the dimensions of inductive reasoning (ß = 0.134, t = 2.587, p < 0.05) and working memory (ß = 0.130, t = 2.525, p < 0.05). The role of ACS for CP, as well as guidelines for future research, are discussed.

A high-throughput drug screen reveals means to differentiate triple-negative breast cancer.

Plasticity delineates cancer subtypes with more or less favourable outcomes. In breast cancer, the subtype triple-negative lacks expression of major differentiation markers, e.g., estrogen receptor α (ERα), and its high cellular plasticity results in greater aggressiveness and poorer prognosis than other subtypes. Whether plasticity itself represents a potential vulnerability of cancer cells is not clear. However, we show here that cancer cell plasticity can be exploited to differentiate triple-negative breast cancer (TNBC). Using a high-throughput imaging-based reporter drug screen with 9 501 compounds, we have identified three polo-like kinase 1 (PLK1) inhibitors as major inducers of ERα protein expression and downstream activity in TNBC cells. PLK1 inhibition upregulates a cell differentiation program characterized by increased DNA damage, mitotic arrest, and ultimately cell death. Furthermore, cells surviving PLK1 inhibition have decreased tumorigenic potential, and targeting PLK1 in already established tumours reduces tumour growth both in cell line- and patient-derived xenograft models. In addition, the upregulation of genes upon PLK1 inhibition correlates with their expression in normal breast tissue and with better overall survival in breast cancer patients. Our results indicate that differentiation therapy based on PLK1 inhibition is a potential alternative strategy to treat TNBC.

Metastasis.

Metastasis, the major cause of cancer death, represents one of the major challenges in oncology. Scientists are still trying to understand the biological basis underlying the dissemination and outgrowth of tumor cells, why these cells can remain dormant for years, how they become resistant to the immune system or cytotoxic effects of systemic therapy, and how they interact with their new microenvironment. We asked experts to discuss some of the unknowns, advances, and areas of opportunity related to cancer metastasis.

A Less Common Cause of Acute Hepatitis in Kidney Transplant Recipients: A Case Series.

BACKGROUND: Hepatitis E virus (HEV) is a cause of significant morbidity and mortality, representing an important global public health problem. Immunocompetent patients with acute hepatitis E can clear the infection spontaneously; however, in approximately two thirds of cases, immunosuppressed patients, such as kidney transplant (KT) recipients, fail to clear the HEV infection and develop chronic hepatitis. PATIENTS AND METHODS: We report 3 cases of HEV infection in KT patients. Two presented only with laboratory abnormalities and elevated liver enzymes, and 1 presented with symptomatic disease motivating hospital admission. None was able to clear the infection spontaneously, and they were all treated with ribavirin, accompanied with reduction of immunosuppressive drugs. Adverse effects of the treatment were reported in 2 patients, and in 1 case, a dose reduction was necessary. All patients responded to the treatment and have no current evidence of active disease. No alterations of basal kidney function during or related to the treatment were registered. DISCUSSION: HEV screening in KT patients presenting with abnormal liver function of undetermined cause is fundamental, as it might have poorer outcomes in this specific population. The treatment with ribavirin seems to be safe and effective, although we must always be alert to potential side effects, maintaining a close follow-up of these patients.

Long-Term Complications After Nephrectomy for Living Donor Transplant.

BACKGROUND: Living donor kidney transplant represents the best treatment option for patients with end-stage kidney disease; however, it has been associated with possible risks to the donor. Our aim was to evaluate the impact of kidney donation in the donor's estimated glomerular filtration rate (eGFR), blood pressure, and proteinuria and related risk factors. PATIENTS AND METHODS: A single-center, retrospective study, including all living donors who underwent nephrectomy between January 2000 and December 2019, was performed. Demographic, clinical, and laboratory data were collected. Risk factors for a decrease in eGFR >30 mL/min/1.73 m2 one year after donation were assessed. RESULTS: Eighty-six donors were included with a mean age of 46.7 ± 9.07 years. The mean follow-up was 105.6 ± 65.4 months, and 35 patients (41%) had more than 10 years of follow-up. No significant difference was found in proteinuria or body mass index (P > .1) before and after the donation. The prevalence of hypertension was higher after kidney donation (9.3% vs 22.1%; P < .001). A mean reduction in the eGFR in the first year of 37 ± 12 mL/min/1.73 m2, followed by stabilization in the following years, was observed. The only variable that was significantly associated with a decline in GFR >30 mL/min/1.73 m2 was a lower predonation eGFR, with a cutoff value established at 100 mL/min/1.73 m2 for our sample. DISCUSSION: Living donor nephrectomy appears to be an acceptably safe intervention. Predonation eGFR influences the adaptative response after nephrectomy; however, other variables did not have an impact on long-term outcome in our population.

The type of SARS-CoV-2 vaccine influences serological response in kidney transplant recipients.

Vaccination is a promising strategy to control the ongoing pandemic; however, solid organ recipients tend to develop a weaker immune response to vaccination. Anti-spike SARS-CoV-2 antibodies titers were measured 2-4 weeks post-vaccination completion in 131 KT patients without previous infection. Demographic, clinical, and laboratorial parameters were analyzed to identify which factors contributed to seroconversion. Factors that influenced seroconversion, that occurred in 76 patients (58%), were longer time post-transplant, immunosuppression without an antiproliferative drug and vaccination with mRNA vaccines. Patients who received mRNA vaccines had significantly higher rates of seroconversion compared with adenovirus vector vaccines (67% vs 33%, P < .001) and higher anti-spike IgG titers. These findings reinforce the need to discuss the vaccination strategy in this population, including a third dose with a mRNA vaccine.

Digital home-based multidisciplinary cardiac rehabilitation: How to counteract physical inactivity during the COVID-19 pandemic.

Introduction and Objectives: Center-based cardiac rehabilitation (CR) programs have been forced to close due to COVID-19. Alternative delivery models to maintain access to CR programs and to avoid physical inactivity should be considered. The aim of this study was to assess physical activity (PA) levels after completing a home-based digital CR program. Methods: A total of 116 cardiovascular disease (CVD) patients (62.6±8.9 years, 95 male) who had been attending a face-to-face CR program were recruited and assessed (baseline and at three months) on the following parameters: PA, sedentary behavior, adherence, cardiovascular and non-cardiovascular symptoms, feelings toward the pandemic, dietary habits, risk factor control, safety and adverse events. The intervention consisted of a multidisciplinary digital CR program, including regular patient assessment, and exercise, educational and psychological group sessions. Results: Ninety-eight CVD patients successfully completed all the online assessments (15.5% drop-out rate). A favorable main effect of time was an increase in moderate to vigorous PA and a decrease in sedentary time at three months. Almost half of the participants completed at least one online exercise training session per week and attended at least one of the online educational sessions. No major adverse events were reported and only one minor event occurred. Conclusion: During the pandemic, levels of moderate to vigorous PA improved after three months of home-based CR in CVD patients with previous experience in a face-to-face CR model. Diversified CR programs with a greater variety of content tailored to individual preferences are needed to meet the motivational and clinical requirements of CVD patients.

Introdução e objetivos: Os programas convencionais de reabilitação cardíaca (RC) foram forçados a encerrar devido à Covid-19. Modelos alternativos para que os doentes tenham acesso a um programa de RC evitando a inatividade física devem ser considerados. O objetivo deste estudo foi avaliar os níveis de atividade física (AF) de um programa digital de RC em casa. Métodos: Foram recrutados e avaliados (inicialmente e aos três meses) 116 doentes cardiovasculares (CV) (62,6±8,9 anos, 95 homens) que frequentavam um programa presencial de RC, nos seguintes parâmetros: AF, comportamento sedentário, adesão, sintomas CV e não CV, sentimentos face à pandemia, hábitos alimentares, fatores de risco, segurança e eventos adversos. A intervenção consistiu num programa digital multidisciplinar de RC, inclusive acompanhamento regular, sessões de exercício, de ensino e de psicologia em grupo. Resultados: Completaram com sucesso todas as avaliações online (15,5% drop-out) 98 pessoas com doença CV. Houve um efeito favorável no aumento da AF moderada a vigorosa e diminuição do tempo sedentário aos três meses. Quase metade da amostra fez, pelo menos, mais de uma sessão de exercício físico online por semana e assistiu a pelo menos uma das sessões educacionais online. Não se verificaram eventos major e registou-se apenas um minor. Conclusão: Em tempo de pandemia, os níveis de AF moderada a vigorosa melhoraram após três meses em doentes CV que frequentavam previamente um modelo presencial de RC. São necessários mais programas de RC com maior variedade de conteúdos adaptados à preferência individual para dar resposta às necessidades motivacionais e clínicas dos doentes CV.