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Potassium is necessary for the mechanical-electrical transduction needed for hearing. Here the authors study mice lacking the potassium channel KCNK5 and show that these channels are mostly expressed in the outer sulcus and are required for hearing, pointing to their essential role in potassium recycling.

Results from the randomized ProfiLER-02 trial, which compared two gene panels in guiding molecular-based treatment in patients with solid tumors, show that a broader gene panel led to more molecular-based recommended therapies compared to a more limited gene panel.

In the randomized phase 1b/2 Morpheus-Melanoma trial evaluating various neoadjuvant immune checkpoint inhibitor regimens in patients with resectable stage III melanoma, tobemstomig, an anti-PD-1/anti-LAG-3 bispecific antibody, showed the highest pathologic response rate with a better safety profile than the standard treatment approach of ipilimumab plus nivolumab.

In this single-arm phase 2 trial in patients with HR⁺HER2⁻ advanced breast cancer, treatment with the HER3-targeting antibody–drug conjugate paritumab deruxtecan led to encouraging objective response rates, and comprehensive exploratory analyses indicate potential biomarkers of response.

Single-agent maintenance PARP inhibition may represent an effective strategy for advanced/metastatic endometrial cancer treatment. Here this randomized phase IIb UTOLA trial evaluates the efficacy and safety of orally administered olaparib in female patients (n = 145) without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer.

Borcoman and colleagues present the efficacy and safety results of the phase 2 PEVOsq basket trial investigating the combination of pembrolizumab with the epidrug vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma.

Guppy colouration is a very diverse trait under natural and sexual selection. Using a combination of high-resolution phenotyping and genomic analysis, the authors reveal the genetic architecture of this complex trait.

A comprehensive analysis of models of brain metastasis and multiple cohorts of patient samples identifies a targetable molecular mechanism underlying the resistance to whole-brain radiotherapy that can inform patient selection for personalized radiotherapy.

In the final analysis of all cohorts in the phase 2 ROAR basket trial, dabrafenib plus trametinib exhibited tumor-agnostic clinical activity in patients with rare BRAFV800E-mutated cancers, including anaplastic thyroid carcinoma, biliary tract cancer, low-grade glioma and hairy cell leukemia.

The antitumour activity of bispecific antibodies in immunocompromised hosts can be potentiated via allogeneic T cells engineered with a T-cell receptor that decouples antigen-mediated T-cell activation from T-cell cytotoxicity.

Vaccines induce beneficial immunity for COVID-19, but immune waning prompts boosting vaccination. Here, the authors show that a third, boosting dose of COVID-19 mRNA vaccine induces transient CD8 + T effector cell response while conserving the CD8 memory T cell pool, thereby permitting reactivation of spike-specific CD8 + T cells upon breakthrough infection or 4th vaccination.

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Targeted therapies matched to genomics improved progression-free survival when genomic alterations were classified as level I/II (according to ESCAT), and genomics should thus be driven by target actionability in patients with metastatic breast cancer.

The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.

Immune checkpoint blockade could improve the complete cytoreduction rate with standard-of-care neoadjuvant chemotherapy (NACT) in patients with ovarian cancer. Here the authors report the results of a randomized phase II trial of NACT alone or in combination with pembrolizumab (anti-PD1) in patients with advanced high-grade serous carcinoma.

Microbial rhodopsins can be used to control action potentials, while animal opsins can be used to control intracellular signaling pathways. The authors identify Opn7b as constitutively active G_i/o coupled receptor that can be deactivated by light and used to modulate neuronal activity.

Prognosis for patients diagnosed with advanced stage ovarian cancer remains poor. Here the authors report the results of a phase 2 study of a triple combination of the PARP inhibitor olaparib in combination with durvalumab (anti-PD1) and bevacizumab (antiVEGF) in advanced ovarian cancer.

The mechanism by which adenosine monophosphate modulates dynein ATPase-mediated ciliary and flagellar beating remains obscure. Here the authors identify an axonemal module including cilia and flagella associated protein 45 that supports adenine nucleotide homeostasis and underlies a human ciliopathy

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

We describe netrin-1 upregulation in a majority of human endometrial carcinomas and demonstrate that netrin-1 blockade, using the anti-netrin-1 antibody NP137, is effective both in a mouse model and in patients with endometrial carcinomas.

Trastuzumab deruxtecan, an anti-HER2–drug conjugate, exhibits the highest objective response rate in patients with HER2-overexpressing metastatic breast cancer, but clinical activity is also observed in patients with HER2-low or non-expressing tumors, potentially pointing to additional determinants of drug efficacy.

Heymut Omran, Mary Porter and colleagues identify the nexin link–dynein regulatory complex subunit DRC1 from Chlamydomonas and show that mutations in the human DRC1 homolog CCDC164 cause primary ciliary dyskinesia. Their analyses show that loss of DRC1 results in distinct axonemal defects and altered ciliary beat patterns.

SnRK2 kinase activity is rapidly activated in response to ABA. Here the authors show that initial activation of SnRK2s is achieved by B2 and B3 RAF kinase-mediated phosphorylation of the activation loop and that transphosphorylation between SnRK2s then amplifies the response.

Differences in a non-coding enhancer region of the HOXDB locus underlie the differences between stickleback species in dorsal spine length and number. These differences include single-nucleotide polymorphisms, deletions and transposable element insertions.

Oligodendroglial tumours are characterized into three different molecular subtypes. Here, the authors use genomic data to identify a further three subgroups of 1p/19q co-deleted tumours and demonstrate an association with an aggressive phenotype.

Anaplastic oligodendrogliomas are rare and incurable primary brain tumours with few treatment options. Here Labrecheet al. perform whole-exome sequencing and identify recurring mutations in transcription factor TCF12, which are associated with aggressive tumours.

Anthracyclines can induce a type 1 interferon response in tumor cells that may predict clinical response to these drugs.

Exploratory analyses from the phase 2 randomized SAFIR02-IMMUNO trial identify biomarkers associated with improved outcomes to durvalumab as compared to maintenance chemotherapy in patients with triple-negative breast cancer.

Radiotherapy is used in >50% of patients with cancer but may be associated with short-term toxicity and long-term consequences. This Primer summarizes the mechanisms by which normal tissues are affected by irradiation, the techniques to mitigate such damage and how to treat the symptoms of radiotherapy toxicity.