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This editorial is being published simultaneously in multiple journals. It highlights now as the time to treat the climate and nature crisis as one indivisible global health emergency. [ABSTRACT FROM AUTHOR]

Over 200 health journals have issued a joint statement calling on the United Nations, political leaders, and health professionals to recognize that climate change and biodiversity loss are interconnected crises that must be addressed together. The statement emphasizes that the current approach of treating these issues separately is a dangerous mistake. The impacts of these crises on human health are significant and include disruptions to social and economic systems, shortages of land, shelter, food, and water, and the spread of infectious diseases. The health community must advocate for the restoration of biodiversity and the mitigation of climate change, and political leaders must recognize the threats to health and the potential benefits of addressing these crises. The statement concludes by urging the World Health Organization to declare the climate and nature crisis as a global health emergency. [Extracted from the article]

The 2022 report of the Intergovernmental Panel on Climate Change (IPCC) paints a dark picture of the future of life on earth, characterized by ecosystem collapse, species extinction, and climate hazards such as heatwaves and floods (1). These are all linked to physical and mental health problems, with direct and indirect consequences of increased morbidity and mortality. To avoid these catastrophic health effects across all regions of the globe, there is broad agreement—as 231 health journals argued together in 2021—that the rise in global temperature must be limited to less than 1.5oC compared with pre-industrial levels. While the Paris Agreement of 2015 outlines a global action framework that incorporates providing climate finance to developing countries, this support has yet to materialize (2). COP27 is the fifth Conference of the Parties (COP) to be organized in Africa since its inception in 1995. Ahead of this meeting, we—as health journal editors from across the continent—call for urgent action to ensure it is the COP that finally delivers climate justice for Africa and vulnerable countries. This is essential not just for the health of those countries, but for the health of the whole world.

Since the largest and most fatal Ebola virus epidemic during 2014-2016, there have been several consecutive filoviral outbreaks in recent years, including those in 2021, 2022, and 2023. Ongoing outbreak prevalence and limited FDA-approved filoviral therapeutics emphasize the need for novel small molecule treatments. Here, we showcase the structure-activity relationship development of N-substituted pyrrole-based heterocycles and their potent, submicromolar entry inhibition against diverse filoviruses in a target-based pseudovirus assay. Inhibitor antiviral activity was validated using replication-competent Ebola, Sudan, and Marburg viruses. Mutational analysis was used to map the targeted region within the Ebola virus glycoprotein. Antiviral counter-screen and phospholipidosis assays were performed to demonstrate the reduced off-target activity of these filoviral entry inhibitors. Favorable antiviral potency, selectivity, and drug-like properties of the N-substituted pyrrole-based heterocycles support their potential as broad-spectrum antifiloviral treatments.

Human tumor samples hold a plethora of information about their microenvironment and immune repertoire. Effective dissociation of human tissue samples into viable cell suspensions is a required input for the single-cell RNA sequencing (scRNAseq) pipeline. Unlike bulk RNA sequencing approaches, scRNAseq enables us to infer the transcriptional heterogeneity in tumor specimens at the single-cell level. Incorporating this approach in recent years has led to many discoveries, such as identifying immune and tumor cellular states and programs associated with clinical responses to immunotherapies and other types of treatments. Moreover, single-cell technologies applied to dissociated tissues can be used to identify accessible chromatin regions T and B cell receptor repertoire, and the expression of proteins, using DNA barcoded antibodies (CITEseq). The viability and quality of the dissociated sample are critical variables when using these technologies, as these can dramatically affect the cross-contamination of single cells with ambient RNA, the quality of the data, and interpretation. Moreover, long dissociation protocols can lead to the elimination of sensitive cell populations and the upregulation of a stress response gene signature. To overcome these limitations, we devised a rapid universal dissociation protocol, which has been validated on multiple types of human and murine tumors. The process begins with mechanical and enzymatic dissociation, followed by filtration, red blood lysis, and live dead enrichment, suitable for samples with a low input of cells (e.g., needle core biopsies). This protocol ensures a clean and viable single-cell suspension paramount to the successful generation of Gel Bead-In Emulsions (GEMs), barcoding, and sequencing.

Background: Perceptual and speech production abilities of children with cochlear implants (CIs) are usually tested by word and sentence repetition or naming tests. However, these tests are quite far apart from daily life linguistic contexts., Aim: Here, we describe a way of investigating the link between language comprehension and anticipatory verbal behaviour promoting the use of more complex listening situations., Methods and Procedure: The setup consists in watching the audio-visual dialogue of two actors. Children's gaze switches from one speaker to the other serve as a proxy of their prediction abilities. Moreover, to better understand the basis and the impact of anticipatory behaviour, we also measured children's ability to understand the dialogue content, their speech perception and memory skills as well as their rhythmic skills, that also require temporal predictions. Importantly, we compared children with CI performances with those of an age-matched group of children with normal hearing (NH)., Outcomes and Results: While children with CI revealed poorer speech perception and verbal working memory abilities than NH children, there was no difference in gaze anticipatory behaviour. Interestingly, in children with CI only, we found a significant correlation between dialogue comprehension, perceptual skills and gaze anticipatory behaviour., Conclusion: Our results extend to a dialogue context of previous findings showing an absence of predictive deficits in children with CI. The current design seems an interesting avenue to provide an accurate and objective estimate of anticipatory language behaviour in a more ecological linguistic context also with young children., What This Paper Adds: What is already known on the subject Children with cochlear implants seem to have difficulties extracting structure from and learning sequential input patterns, possibly due to signal degradation and auditory deprivation in the first years of life. They also seem to have a reduced use of contextual information and slow language processing among children with hearing loss. What this paper adds to existing knowledge Here we show that when adopting a rather complex linguistic context such as watching a dialogue of two individuals, children with cochlear implants are able to use the speech and language structure to anticipate gaze switches to the upcoming speaker. What are the clinical implications of this work? The present design seems an interesting avenue to provide an accurate and objective estimate of anticipatory behaviour in a more ecological and dynamic linguistic context. Importantly, this measure is implicit and it has been previously used with very young (normal-hearing) children, showing that they spontaneously make anticipatory gaze switches by age two. Thus, this approach may be of interest to refine the speech comprehension assessment at a rather early age after cochlear implantation where explicit behavioural tests are not always reliable and sensitive., (© 2024 The Author(s). International Journal of Language & Communication Disorders published by John Wiley & Sons Ltd on behalf of Royal College of Speech and Language Therapists.)

Cetuximab every 2 weeks (Q2W) dosing schedule is approved by the US FDA and by the Japanese Pharmaceuticals and Medical Devices Agency in patients with metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Phase II trials have found comparable efficacy and safety for the weekly (Q1W) and Q2W schedules, and real-world studies have shown noninferiority of the Q2W compared with the Q1W schedule. Several guidelines recommend cetuximab Q2W administration as an alternative to the Q1W dosing schedule. Cetuximab Q2W can be administered with a Q2W dose of chemotherapy, making it a more convenient option to the Q1W schedule, potentially resulting in reduced costs for administration, increased flexibility for clinical staff and improved patient adherence.

Competing Interests: The authors declare that they do not have any conflicts of interest.

Purpose: Prognostic and predictive biomarkers to cyclin-dependent kinases 4 and 6 inhibitors are lacking. Circulating tumor DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy., Experimental Design: Correlative blood samples were collected at baseline [cycle 1-day 1 (C1D1)] and prior to treatment [cycle 1-day 15 (C1D15)]. Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A prespecified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model., Results: 201 patients were profiled at baseline, with ctDNA detection associated with worse progression-free survival (PFS)/overall survival (OS). Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n = 120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms., Conclusions: We show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with hormone receptor-positive/HER2-negative metastatic breast cancer harboring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: The European Society for Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS) has been accepted as a robust tool to evaluate the magnitude of clinical benefit reported in trials for oncological therapies. However, the ESMO-MCBS hitherto has only been validated for solid tumours. With the rapid development of novel therapies for haematological malignancies, we aimed to develop an ESMO-MCBS version that is specifically designed and validated for haematological malignancies., Methods: ESMO and the European Hematology Association (EHA) initiated a collaboration to develop a version for haematological malignancies (ESMO-MCBS:H). The process incorporated five landmarks: field testing of the ESMO-MCBS version 1.1 (v1.1) to identify shortcomings specific to haematological diseases, drafting of the ESMO-MCBS:H forms, peer review and revision of the draft based on re-scoring (resulting in a second draft), assessment of reasonableness of the scores generated, final review and approval by ESMO and EHA including executive boards., Results: Based on the field testing results of 80 haematological trials and extensive review for feasibility and reasonableness, five amendments to ESMO-MCBS were incorporated in the ESMO-MCBS:H addressing the identified shortcomings. These concerned mainly clinical trial endpoints that differ in haematology versus solid oncology and the very indolent nature of nevertheless incurable diseases such as follicular lymphoma, which hampers presentation of mature data. In addition, general changes incorporated in the draft version of the ESMO-MCBS v2 were included, and specific forms for haematological malignancies generated. Here we present the final approved forms of the ESMO-MCBS:H, including instructions., Conclusion: The haematology-specific version ESMO-MCBS:H allows now full applicability of the scale for evaluating the magnitude of clinical benefit derived from clinical studies in haematological malignancies., (Copyright © 2023. Published by Elsevier Ltd.)

(1) Objective: Late-line chemotherapy rechallenge in recurrent cervical cancer is associated with modest therapy response but significant side effects. As mTOR pathways modulate cellular growth via estrogen receptor (ER) signaling and combined mTOR and ER inhibition previously demonstrated survival benefits in breast cancer, this exploratory study evaluates mTOR pathway and ER expression interactions in a preclinical cervical cancer model. (2) Methods: Immunostaining of a 126-tumor core tissue microarray was performed to assess phosphorylated-mTOR and ER expression. To identify tumor subsets with different clinical behavior, expression results were matched with clinicopathologic patient characteristics, and both univariate and multivariable survival statistics were performed. (3) Results: phosphorylated-mTOR correlates with ER (r = 0.309, p < 0.001) and loss of PTEN expression (r = -2.09, p = 0.022) in tumor samples across stages but not in matched negative controls. Positive ER expression is observed significantly more often in phosphorylated-mTOR positive samples (30.0% vs. 6.3%, p = 0.001). In the subgroup of phosphorylated-mTOR positive tumors (n = 60), ER expression is associated with improved survival ( p = 0.040). (4) Conclusion: ER expression appears closely intertwined with EGFR/PTEN/mTOR-pathway activation and seems to define a subgroup with clinically distinct behavior. Considering limited therapeutic options in recurrent cervical cancer, further validation of combined mTOR and ER inhibition in selected patients could appear promising.

Purpose: In hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC), it is imperative to identify patients who respond poorly to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting, but further validation is needed., Experimental Design: We performed mRNA gene expression profiling and correlation with progression-free survival (PFS) on 455 tumor samples included in the phase III PEARL study, which assigned patients with HR+/HER2- MBC to receive palbociclib+endocrine therapy (ET) versus capecitabine. Estrogen receptor-positive (ER+)/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET., Results: Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4 months with palbociclib+ET and 9.3 months with capecitabine; HR 4.16, adjusted P value < 0.0001. Tumors with high CCNE1 expression (above median) also had worse median PFS with palbociclib+ET (6.2 months) than with capecitabine (9.3 months); HR 1.55, adjusted P value = 0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile), we found higher levels of Polo-like kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2- cell line models, we show that PLK1 inhibition reverses resistance to palbociclib+ET., Conclusions: We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i., (©2023 The Authors; Published by the American Association for Cancer Research.)

The Immunotherapy of Cancer conference (ITOC) is an European meeting providing a global platform for discussions where all those dedicated to the immunotherapy of cancer can exchange their knowledge and the latest findings about immuno-oncology. The 9th ITOC was held in Munich in September 2022. Major highlights of the 2022 edition included the key note address and life time achievement to Laurence Zitvogel on her contributions on the understanding of the role of microbiota in cancer development and therapy resistance. Her research has paved the way for therapeutic exploitation of the microbiome.