Digital image analysis workflows for evaluation of cell behavior and tumor microenvironment to aid therapeutic assessment in high-risk neuroblastoma.

Digital pathology and artificial intelligence are promising emerging tools in precision oncology as they provide more robust and reproducible analysis of histologic, morphologic and topologic characteristics of tumor cells and the surrounding microenvironment. This study aims to develop digital image analysis workflows for therapeutic assessment in preclinical in vivo models. For this purpose, we generated pipelines that enable automatic detection and quantification of vitronectin and αvß3 in heterotopic high-risk neuroblastoma xenografts, demonstrating that digital analysis workflows can be used to provide robust detection of vitronectin secretion and αvß3 expression by malignant neuroblasts and to evaluate the possibility of combining traditional chemotherapy (etoposide) with extracellular matrix-targeted therapies (cilengitide). Digital image analysis added evidence for the relevance of territorial vitronectin as a therapeutic target in neuroblastoma, since its expression is modified after treatment, with a mean percentage of 60.44% in combined therapy tumors vs 45.08% in control ones. In addition, the present study revealed the efficacy of cilengitide for reducing αvß3 expression, with a mean αvß3 positivity of 34.17% in cilengitide treated material vs 66.14% in control and with less tumor growth when combined with etoposide, with a final mean volume of 0.04 cm3 in combined therapy vs 1.45 cm3 in control. The results of this work highlight the importance of extracellular matrix-focused therapies in preclinical studies to improve therapeutic assessment for high-risk neuroblastoma patients.

The complexity of cancer immunotherapy illustrated through skin tumors.

Skin tumours are among the cancer types most sensitive to immunotherapy, due to their unique immunogenic features including skin-associated lymphoid tissue, high mutational load, overexpression of tumour antigens, and high frequency of viral antigens. Despite this high immunotherapy response rate, however, ultimately most skin tumours develop similar treatment resistance to most other malignant tumours, which highlights the need for in-depth study of mechanisms of response and resistance to immunotherapy. A bibliographic review of the most recent publications regarding currently in use and emerging biomarkers on skin tumors has been done. Predictive biomarkers of treatment response, biomarkers that warn of possible resistance, and emerging markers, the majority of a systemic nature, are described. Including factors affecting not only genomics, but also the immune system, nervous system, microbiota, tumour microenvironment, metabolism and stress. For accurate diagnosis of tumour type, knowledge of its functional mechanisms and selection of a comprehensive therapeutic protocol, this inclusive view of biology, health and disease is fundamental. This field of study could also become a valuable source of practical information applicable to other areas of oncology and immunotherapy.

Magnesium sensing via LFA-1 regulates CD8+ T cell effector function.

The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8+ T cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T cells, enhanced effectiveness of bi-specific T cell engaging antibodies, and improved CAR T cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.

The golden jackal (Canis aureus): A new host for Echinococcus multilocularis and Trichinella britovi in Switzerland.

INTRODUCTION: The golden jackal (Canis aureus) is a wild canid new to Switzerland. It is an officially monitored species and all deceased individuals are submitted for post-mortem examination to collect baseline health data. This includes parasitological examinations, with an emphasis on zoonotic, reportable infections, such as those caused by Trichinella spp. or Echinococcus spp. From 2016 to 2021, five golden jackals originating from four Swiss cantons were submitted for full post-mortem examination. In one case only organ samples were available, and therefore parasitological examination was not possible. Parasite stages recovered during necropsy, as well as by routine coproscopical techniques, were morphologically identified. Taeniid eggs and adult tapeworms were processed for molecular species identification. Additionally, tongue and diaphragm were analysed for Trichinella spp. by the artificial digestion technique followed by multiplex-PCR in positive cases. Of the four jackals investigated for parasites, hookworm eggs were detected in one animal, both adult worms and eggs of Echinococcus multilocularis were present in another case, and one animal was free of parasites. Eggs of E. multilocularis as well as eggs of Toxocara canis and sporocysts of Sarcocystis sp. were detected in the intestinal content, and Trichinella britovi larvae were found in the muscle samples of the last case. The health monitoring programme in place for protected carnivores in Switzerland allowed us to add the golden jackal to the list of hosts for the endemic zoonotic parasites E. multilocularis and T. britovi in this country. Hunters, farmers, and other persons who could come in contact with golden jackals should be aware of the associated health risk and handle faeces and carcasses with caution.

INTRODUCTION: Le chacal doré (Canis aureus) est un canidé sauvage nouvellement présent en Suisse. Il s'agit d'une espèce officiellement surveillée et tous les individus morts sont soumis à un examen post-mortem afin de recueillir des données sanitaires de base. Cela inclut un examen parasitologique mettant l'accent sur les infections zoonotiques à déclaration obligatoire, telles que celles causées par Trichinella spp. ou Echinococcus spp. De 2016 à 2021, cinq chacals dorés originaires de quatre cantons suisses ont été soumis à un examen post-mortem complet. Dans un cas, seuls des échantillons d'organes ont été envoyés, l'examen parasitologique n'a pas été possible pour cet animal. Les stades parasitaires trouvés lors de l'examen pathologique et de la coprologie de routine ont été identifiés morphologiquement. Les espèces de ténias (œufs et stades adultes) ont été déterminées par des techniques de biologie moléculaire. En outre, la recherche de Trichinella spp. a été effectuée sur du tissu musculaire lingual et diaphragmatique par la technique de digestion artificielle suivie d'une PCR multiplex dans les cas positifs. Sur les quatre chacals ayant fait l'objet d'une recherche de parasites, des œufs d'ankylostomes ont été détectés chez un animal, des vers adultes et des œufs d'Echinococcus multilocularis étaient présents chez un autre animal, et aucun parasite n'a été trouvé dans un autre cas. Chez le dernier cas, des œufs d'E. multilocularis ainsi que des œufs de Toxocara canis et des sporocystes de Sarcocystis sp. ont été détectés dans le contenu intestinal, et des larves de Trichinella britovi ont été trouvées dans les échantillons de muscle. Le programme de surveillance sanitaire mis en place pour les carnivores protégés en Suisse a donc permis d'ajouter le chacal doré à la liste des hôtes des parasites zoonotiques endémiques E. multilocularis et T. britovi. Les chasseurs, agriculteurs et autres personnes susceptibles d'entrer en contact avec le chacal doré doivent être conscients du risque sanitaire associé et manipuler les fèces et les carcasses avec précaution.

Usefulness of high-frequency ultrasonography in the evaluation and monitoring of sclerosing dermatoses: a cohort study.

BACKGROUND: Monitoring of disease activity in sclerosing dermatoses (SD) can be challenging and tools to support clinical decision-making are lacking. AIM: To analyse the impact of high-frequency ultrasonography (HFUS) on the clinical management of SD and to describe the US characteristics of disease activity. METHODS: This was a cohort study of patients with various SD [morphoea, systemic sclerosis (SS) and chronic graft-versus-host disease (cGvHD)] who underwent HFUS between January 2017 and August 2019. HFUS criteria for diagnosing active SD were increased Doppler vascularity and/or meeting all B-mode greyscale US signs of activity. Discordance in SD activity between HFUS and clinical examination was evaluated at the time of the first US assessment. Changes in patient management were instituted after HFUS were recorded. RESULTS: In total, 72 patients (31 with morphoea, 19 with SS and 22 with cGvHD), who underwent 163 HFUS sessions in total, were included. All HFUS-active morphoea lesions exhibited increased vascularity, and all HFUS-active SS exhibited dermal thickening and dermal hypoechogenicity. HFUS-active cGvHD displayed increased dermal thickness and loss of definition of the dermal-hypodermal junction, and there were signs of panniculitis in 80% of cases and of increased vascularity in 70%. Discordance in disease activity between clinical and HFUS evaluation was found in 17 (23.6%) patients. Changes in clinical management after HFUS were made for 14 (19.4%) patients: treatment discontinuation for 6 patients (42.9%), treatment initiation for 5 (35.7%), medication change for 2 (14.3%) and skin biopsy taken for 1 (7.1%). CONCLUSION: HFUS seems an efficacious support tool in the monitoring of SD activity with a notable impact on clinical management. Further studies are warranted to evaluate the impact of HFUS-supported management changes on SD outcomes.

Arginine-dependent immune responses.

A growing body of evidence indicates that, over the course of evolution of the immune system, arginine has been selected as a node for the regulation of immune responses. An appropriate supply of arginine has long been associated with the improvement of immune responses. In addition to being a building block for protein synthesis, arginine serves as a substrate for distinct metabolic pathways that profoundly affect immune cell biology; especially macrophage, dendritic cell and T cell immunobiology. Arginine availability, synthesis, and catabolism are highly interrelated aspects of immune responses and their fine-tuning can dictate divergent pro-inflammatory or anti-inflammatory immune outcomes. Here, we review the organismal pathways of arginine metabolism in humans and rodents, as essential modulators of the availability of this semi-essential amino acid for immune cells. We subsequently review well-established and novel findings on the functional impact of arginine biosynthetic and catabolic pathways on the main immune cell lineages. Finally, as arginine has emerged as a molecule impacting on a plethora of immune functions, we integrate key notions on how the disruption or perversion of arginine metabolism is implicated in pathologies ranging from infectious diseases to autoimmunity and cancer.

Psychotic symptoms in COVID-19 patients. A retrospective descriptive study.

Psychotic symptoms have been related to other coronavirus infections. We conducted a single-centre retrospective and observational study to describe new-onset psychotic episodes in COVID-19 patients. Ten patients infected by the novel coronavirus with psychotic symptoms and no previous history of psychosis were identified by the emergency and liaison psychiatry departments. Nine of the cases presented with psychotic symptoms at least two weeks after the first somatic manifestations attributed to COVID-19 and receiving pharmacological treatment. Structured delusions mixed with confusional features were the most frequent clinical presentations. Hence, COVID-19 patients can develop psychotic symptoms as a consequence of multiple concurrent factors.

Mitochondrial arginase-2 is a cell­autonomous regulator of CD8+ T cell function and antitumor efficacy.

As sufficient extracellular arginine is crucial for T cell function, depletion of extracellular arginine by elevated arginase 1 (Arg1) activity has emerged as a hallmark immunosuppressive mechanism. However, the potential cell-autonomous roles of arginases in T cells have remained unexplored. Here, we show that the arginase isoform expressed by T cells, the mitochondrial Arg2, is a cell-intrinsic regulator of CD8+ T cell activity. Both germline Arg2 deletion and adoptive transfer of Arg2-/- CD8+ T cells significantly reduced tumor growth in preclinical cancer models by enhancing CD8+ T cell activation, effector function, and persistence. Transcriptomic, proteomic, and high-dimensional flow cytometry characterization revealed a CD8+ T cell-intrinsic role of Arg2 in modulating T cell activation, antitumor cytoxicity, and memory formation, independently of extracellular arginine availability. Furthermore, specific deletion of Arg2 in CD8+ T cells strongly synergized with PD-1 blockade for the control of tumor growth and animal survival. These observations, coupled with the finding that pharmacologic arginase inhibition accelerates activation of ex vivo human T cells, unveil Arg2 as a potentially new therapeutic target for T cell-based cancer immunotherapies.

Hematoma hepático espontáneo en gestante a término durante el trabajo de parto / Spontaneous hepatic haematoma in a pregnant woman during labour

La aparición de una ruptura hepática en el transcurso de un embarazo normal es algo excepcional. A veces el diagnóstico de ruptura hepática puede ser difícil, lo que condiciona una elevada tasa de mortalidad. Aunque la ruptura hepática es más frecuente que se asocie en gestantes con síndrome de HELLP, también puede ocurrir en pacientes afectas de otras patologías hepáticas, incluso en pacientes sanas. Se debe mantener el estado de vigilancia ante cuadros clínicos sospechosos aun sin evidencia analítica de alteración hepática ni hemodinámica de hipertensión del embarazo, ya que un diagnóstico temprano facilitará el trabajo multidisciplinar que precisa el manejo de esta patología y disminuirá la morbilidad y mortalidad tanto materna como fetal (AU)

Spontaneous hepatic rupture during labour is a rare condition. Because of the difficulty in diagnosing hepatic rupture in pregnant women, it is often associated with a high mortality rate. Although pregnant women with HELLP syndrome are more prone to hepatic rupture, it can also occur with other liver pathologies and even in healthy women. We should be vigilant in case of suspicious clinical signs even if we have no evidence of preeclampsia. An early diagnosis will be the key to reducing the mortality and morbidity rate (AU)

[Spontaneous hepatic haematoma in a pregnant woman during labour]. / Hematoma hepático espontáneo en gestante a término durante el trabajo de parto.

Spontaneous hepatic rupture during labour is a rare condition. Because of the difficulty in diagnosing hepatic rupture in pregnant women, it is often associated with a high mortality rate. Although pregnant women with HELLP syndrome are more prone to hepatic rupture, it can also occur with other liver pathologies and even in healthy women. We should be vigilant in case of suspicious clinical signs even if we have no evidence of preeclampsia. An early diagnosis will be the key to reducing the mortality and morbidity rate.