Host genetic variability and determinants of severe COVID-19.

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, convergent studies have provided evidence that host genetic background may contribute to the development of severe coronavirus disease (COVID-19). Here, we summarize how some genetic variations, such as in SARS-CoV-2 receptor angiotensin-converting enzyme 2 or interferon signaling pathway, may help to understand why some individuals can develop severe COVID-19.

Pivotal role of NAMPT in the switch of melanoma cells toward an invasive and drug-resistant phenotype.

In BRAFV600E melanoma cells, a global metabolomic analysis discloses a decrease in nicotinamide adenine dinucleotide (NAD+) levels upon PLX4032 treatment that is conveyed by a STAT5 inhibition and a transcriptional regulation of the nicotinamide phosphoribosyltransferase (NAMPT) gene. NAMPT inhibition decreases melanoma cell proliferation both in vitro and in vivo, while forced NAMPT expression renders melanoma cells resistant to PLX4032. NAMPT expression induces transcriptomic and epigenetic reshufflings that steer melanoma cells toward an invasive phenotype associated with resistance to targeted therapies and immunotherapies. Therefore, NAMPT, the key enzyme in the NAD+ salvage pathway, appears as a rational target in targeted therapy-resistant melanoma cells and a key player in phenotypic plasticity of melanoma cells.

Using Genetics To Dissect SARS-CoV-2 Infection.

To uncover the key cellular pathways associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity, Daniloski and coworkers used CRISPR-based whole-genome screening. Their results could propose new or repositioned drugs for the ongoing fight against COVID-19.

New technologies for improved relevance in miRNA research.

After a number of years of research in the field of miRNA, the robustness and biological relevance of many published articles is increasingly being questioned. We propose the use of new RNA-seq approaches, genome editing technologies, and updated public databases to improve the quality, reliability, and relevance of published data.

Host Polymorphisms May Impact SARS-CoV-2 Infectivity.

Based on a broad public database compilation, we support the hypothesis that germinal polymorphisms may regulate the expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular target itself and proteases controlling the process of its shedding or, conversely, its internalization. Consequently, a genetic influence on individual susceptibility to coronavirus disease 2019 (COVID-19) infection is strongly suspected.

Checkpoint inhibitors and anti-angiogenic agents: a winning combination.

The combination of immune checkpoint inhibitors and anti-angiogenic agents is a promising new approach in cancer treatment. Immune checkpoint inhibitors block the signals that help cancer cells evade the immune system, while anti-angiogenic agents target the blood vessels that supply the tumour with nutrients and oxygen, limiting its growth. Importantly, this combination triggers synergistic effects based on molecular and cellular mechanisms, leading to better response rates and longer progression-free survival than treatment alone. However, these combinations can also lead to increased side effects and require close monitoring.

Assessment of Different Circulating Tumor Cell Platforms for Uveal Melanoma: Potential Impact for Future Routine Clinical Practice.

Liquid biopsy and circulating tumor cell (CTC) screening has gained interest over the last two decades for detecting almost all solid malignancies. To date, the major limitation in terms of the applicability of CTC screening in daily clinical practice is the lack of reproducibility due to the high number of platforms available that use various technologies (e.g., label-dependent versus label-free detection). Only a few studies have compared different CTC platforms. The aim of this study was to compare the efficiency of four commercially available CTC platforms (Vortex (VTX-1), ClearCell FX, ISET, and Cellsearch) for the detection and identification of uveal melanoma cells (OMM 2.3 cell line). Tumor cells were seeded in RPMI medium and venous blood from healthy donors, and then processed similarly using these four platforms. Melan-A immunochemistry was performed to identify tumor cells, except when the Cellsearch device was used (automated identification). The mean overall recovery rates (with mean recovered cells) were 39.2% (19.92), 22.2% (11.31), 8.9% (4.85), and 1.1% (0.20) for the ISET, Vortex (VTX-1), ClearCell FX, and CellSearch platforms, respectively. Although paramount, the recovery rate is not sufficient to assess a CTC platform. Other parameters, such as the purpose for using a platform (diagnosis, genetics, drug sensitivity, or patient-derived xenograft models), reproducibility, purity, user-friendliness, cost-effectiveness, and ergonomics, should also be considered before they can be used in daily clinical practice and are discussed in this article.

COVID-19 vaccination and cancer immunotherapy: should they stick together?

The combination of COVID-19 vaccination with immunotherapy by checkpoint inhibitors in cancer patients could intensify immunological stimulation with potential reciprocal benefits. Here, we examine more closely the possible adverse events that can arise in each treatment modality. Our conclusion is that caution should be exercised when combining both treatments.

Checkpoint inhibitors in a marriage: consented or arranged?

There is currently a strong development of therapeutic combinations with checkpoint inhibitors (CPIs). The most promising combinations with CPIs concern anti-angiogenic agents and BRAF/MEK inhibitors. The timing of the initiation of the combination should be particularly well investigated for chemotherapy. Combinations between CPIs raise questions about risk/benefit ratio and overall clinical activity.

More light on cancer and COVID-19 reciprocal interaction.

Cancer patients are vulnerable to COVID-19 with consequences on treatment delays and on mortality rate. This Comment explores the interaction between COVID-19 and cancer with attention paid to the modulation by cancer treatments of both ADAM17 and TMPRSS2, the proteases which control ACE2 processing, the SARS-CoV-2 target.

Rapid decay of engulfed extracellular miRNA by XRN1 exonuclease promotes transient epithelial-mesenchymal transition.

Extracellular vesicles (EVs) have been shown to play an important role in intercellular communication as carriers of DNA, RNA and proteins. While the intercellular transfer of miRNA through EVs has been extensively studied, the stability of extracellular miRNA (ex-miRNA) once engulfed by a recipient cell remains to be determined. Here, we identify the ex-miRNA-directed phenotype to be transient due to the rapid decay of ex-miRNA. We demonstrate that the ex-miR-223-3p transferred from polymorphonuclear leukocytes to cancer cells were functional, as demonstrated by the decreased expression of its target FOXO1 and the occurrence of epithelial-mesenchymal transition reprogramming. We showed that the engulfed ex-miRNA, unlike endogenous miRNA, was unstable, enabling dynamic regulation and a return to a non-invasive phenotype within 8 h. This transient phenotype could be modulated by targeting XRN1/PACMAN exonuclease. Indeed, its silencing was associated with slower decay of ex-miR-223-3p and subsequently prolonged the invasive properties. In conclusion, we showed that the 'steady step' level of engulfed miRNA and its subsequent activity was dependent on the presence of a donor cell in the surroundings to constantly fuel the recipient cell with ex-miRNAs and of XRN1 exonuclease, which is involved in the decay of these imported miRNA.

Targeting eIF5A Hypusination Prevents Anoxic Cell Death through Mitochondrial Silencing and Improves Kidney Transplant Outcome.

The eukaryotic initiation factor 5A (eIF5A), which is highly conserved throughout evolution, has the unique characteristic of post-translational activation through hypusination. This modification is catalyzed by two enzymatic steps involving deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Notably, eIF5A may be involved in regulating the lifespan of Drosophila during long-term hypoxia. Therefore, we investigated the possibility of a link between eIF5A hypusination and cellular resistance to hypoxia/anoxia. Pharmacologic targeting of DHPS by N1-guanyl-1,7-diaminoheptane (GC7) or RNA interference-mediated inhibition of DHPS or DOHH induced tolerance to anoxia in immortalized mouse renal proximal cells. Furthermore, GC7 treatment of cells reversibly induced a metabolic shift toward glycolysis as well as mitochondrial remodeling and led to downregulated expression and activity of respiratory chain complexes, features characteristic of mitochondrial silencing. GC7 treatment also attenuated anoxia-induced generation of reactive oxygen species in these cells and in normoxic conditions, decreased the mitochondrial oxygen consumption rate of cultured cells and mice. In rats, intraperitoneal injection of GC7 substantially reduced renal levels of hypusinated eIF5A and protected against ischemia-reperfusion-induced renal injury. Finally, in the preclinical pig kidney transplant model, intravenous injection of GC7 before kidney removal significantly improved graft function recovery and late graft function and reduced interstitial fibrosis after transplant. This unconventional signaling pathway offers an innovative therapeutic target for treating hypoxic-ischemic human diseases and organ transplantation.

Artificial Intelligence and Anticancer Drug Development-Keep a Cool Head.

Artificial intelligence (AI) is progressively spreading through the world of health, particularly in the field of oncology. AI offers new, exciting perspectives in drug development as toxicity and efficacy can be predicted from computer-designed active molecular structures. AI-based in silico clinical trials are still at their inception in oncology but their wider use is eagerly awaited as they should markedly reduce durations and costs. Health authorities cannot neglect this new paradigm in drug development and should take the requisite measures to include AI as a new pillar in conducting clinical research in oncology.

Current challenges and practical aspects of molecular pathology for non-small cell lung cancers.

The continuing evolution of treatment options in thoracic oncology requires the pathologist to regularly update diagnostic algorithms for management of tumor samples. It is essential to decide on the best way to use tissue biopsies, cytological samples, as well as liquid biopsies to identify the different mandatory predictive biomarkers of lung cancers in a short turnaround time. However, biological resources and laboratory member workforce are limited and may be not sufficient for the increased complexity of molecular pathological analyses and for complementary translational research development. In this context, the surgical pathologist is the only one who makes the decisions whether or not to send specimens to immunohistochemical and molecular pathology platforms. Moreover, the pathologist can rapidly contact the oncologist to obtain a new tissue biopsy and/or a liquid biopsy if he/she considers that the biological material is not sufficient in quantity or quality for assessment of predictive biomarkers. Inadequate control of algorithms and sampling workflow may lead to false negative, inconclusive, and incomplete findings, resulting in inappropriate choice of therapeutic strategy and potentially poor outcome for patients. International guidelines for lung cancer treatment are based on the results of the expression of different proteins and on genomic alterations. These guidelines have been established taking into consideration the best practices to be set up in clinical and molecular pathology laboratories. This review addresses the current predictive biomarkers and algorithms for use in thoracic oncology molecular pathology as well as the central role of the pathologist, notably in the molecular tumor board and her/his participation in the treatment decision-making. The perspectives in this setting will be discussed.

Further knowledge and developments in resistance mechanisms to immune checkpoint inhibitors.

The past decade has witnessed a revolution in cancer treatment, shifting from conventional drugs (chemotherapies) towards targeted molecular therapies and immune-based therapies, in particular immune-checkpoint inhibitors (ICIs). These immunotherapies release the host's immune system against the tumor and have shown unprecedented durable remission for patients with cancers that were thought incurable, such as metastatic melanoma, metastatic renal cell carcinoma (RCC), microsatellite instability (MSI) high colorectal cancer and late stages of non-small cell lung cancer (NSCLC). However, about 80% of the patients fail to respond to these immunotherapies and are therefore left with other less effective and potentially toxic treatments. Identifying and understanding the mechanisms that enable cancerous cells to adapt to and eventually overcome therapy can help circumvent resistance and improve treatment. In this review, we describe the recent discoveries on the onco-immunological processes which govern the tumor microenvironment and their impact on the resistance to PD-1/PD-L1 checkpoint blockade.

CFTR is involved in the fine tuning of intracellular redox status: physiological implications in cystic fibrosis.

Adaptation to hypoxia is an essential physiological response to decrease in tissue oxygenation. This process is primarily under the control of transcriptional activator hypoxia-inducible factor (HIF1). A better understanding of the intracellular HIF1 stabilization pathway would help in management of various diseases characterized by anemia. Among human pathologies, cystic fibrosis disease is characterized by a chronic anemia that is inadequately compensated by the classical erythroid response mediated by the HIF pathway. Because the kidney expresses CFTR and is a master organ involved in the adaptation to hypoxia, we used renal cells to explore the relationship between CFTR and the HIF1-mediated pathway. To monitor the adaptive response to hypoxia, we engineered a hypoxia-induced fluorescent reporter system to determine whether CFTR modulates hypoxia-induced HIF1 stabilization. We show that CFTR is a regulator of HIF stabilization by controlling the intracellular reactive oxygen species (ROS) level through its ability to transport glutathione (a ROS scavenger) out of the cell. Moreover, we demonstrated in a mouse model that both the pharmacological inhibition and the ΔF508 mutation of CFTR lead to an impairment of the adaptive erythroid response to oxygen deprivation. We conclude that CFTR controls HIF stabilization through control of the level of intracellular ROS that act as signaling agents in the HIF-1 pathway.

Should evidence of an autolysosomal de-acidification defect in Alzheimer and Parkinson diseases call for caution in prescribing chronic PPI and DMARD?

Nearly fifty million older people suffer from neurodegenerative diseases, including Alzheimer (AD) and Parkinson (PD) disease, a global burden expected to triple by 2050. Such an imminent "neurological pandemic" urges the identification of environmental risk factors that are hopefully avoided to fight the disease. In 2022, strong evidence in mouse models incriminated defective lysosomal acidification and impairment of the autophagy pathway as modifiable risk factors for dementia. To date, the most prescribed lysosomotropic drugs are proton pump inhibitors (PPIs), chloroquine (CQ), and the related hydroxychloroquine (HCQ), which belong to the group of disease-modifying antirheumatic drugs (DMARDs). This commentary aims to open the discussion on the possible mechanisms connecting the long-term prescribing of these drugs to the elderly and the incidence of neurodegenerative diseases.Abbreviations: AD: Alzheimer disease; APP-ßCTF: amyloid beta precursor protein-C-terminal fragment; BACE1: beta-secretase 1; BBB: brain blood barrier; CHX: Ca2+/H+ exchanger; CMI: cognitive mild impairment; CQ: chloroquine; DMARD: disease-modifying antirheumatic drugs; GBA1: glucosylceramidase beta 1; HCQ: hydroxychloroquine; HPLC: high-performance liquid chromatography; LAMP: lysosomal associated membrane protein; MAPK/JNK: mitogen-activated protein kinase; MAPT: microtubule associated protein tau; MCOLN1/TRPML1: mucolipin TRP cation channel 1; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NRBF2: nuclear receptor binding factor 2; PANTHOS: poisonous flower; PD: Parkinson disease; PIK3C3: phosphatIdylinositol 3-kinase catalytic subunit type 3; PPI: proton pump inhibitor; PSEN1: presenilin 1, RUBCN: rubicon autophagy regulator; RUBCNL: rubicon like autophagy enhancer; SQSTM1: sequestosome 1; TMEM175: transmembrane protein 175; TPCN2: two pore segment channel 2; VATPase: vacuolar-type H+-translocating ATPase; VPS13C: vacuolar protein sorting ortholog 13 homolog C; VPS35: VPS35 retromer complex component; WDFY3: WD repeat and FYVE domain containing 3; ZFYVE1: zinc finger FYVE-type containing 1.

Manipulating the gut and tumor microbiota for immune checkpoint inhibitor therapy: from dream to reality.

The past decade has witnessed a revolution in cancer treatment by shifting from conventional therapies to immune checkpoint inhibitors (ICIs). These immunotherapies unleash the host immune system against the tumor and have achieved unprecedented durable remission. However, 80% of patients do not respond. This review discusses how bacteria are unexpected drivers that reprogram tumor immunity. Manipulating the microbiota impacts on tumor development and reprograms the tumor microenvironment (TME) of mice on immunotherapy. We anticipate that harnessing commensals and the tumor microbiome holds promise to identify patients who will benefit from immunotherapy and guide the choice of new ICI combinations to advance treatment efficacy.

Need for a Dedicated Ophthalmic Malignancy Clinico-Biological Biobank: The Nice Ocular MAlignancy (NOMA) Biobank.

Ophthalmic malignancies include various rare neoplasms involving the conjunctiva, the uvea, or the periocular area. These tumors are characterized by their scarcity as well as their histological, and sometimes genetic, diversity. Uveal melanoma (UM) is the most common primary intraocular malignancy. UM raises three main challenges highlighting the specificity of ophthalmic malignancies. First, UM is a very rare malignancy with an estimated incidence of 6 cases per million inhabitants. Second, tissue biopsy is not routinely recommended due to the risk of extraocular dissemination. Third, UM is an aggressive cancer because it is estimated that about 50% of patients will experience metastatic spread without any curative treatment available at this stage. These challenges better explain the two main objectives in the creation of a dedicated UM biobank. First, collecting UM samples is essential due to tissue scarcity. Second, large-scale translational research programs based on stored human samples will help to better determine UM pathogenesis with the aim of identifying new biomarkers, allowing for early diagnosis and new targeted treatment modalities. Other periocular malignancies, such as conjunctival melanomas or orbital malignancies, also raise specific concerns. In this context, the number of biobanks worldwide dedicated to ocular malignancies is very limited. The aims of this article were (i) to describe the specific challenges raised by a dedicated ocular malignancy biobank, (ii) to report our experience in setting up such a biobank, and (iii) to discuss future perspectives in this field.