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The natural polyphenolic compound Rottlerin (RoT) showed anticancer properties in a variety of human cancers through the inhibition of several target molecules implicated in tumorigenesis, revealing its potential as an anticancer agent. Aquaporins (AQPs) are found overexpressed in different types of cancers and have recently emerged as promising pharmacological targets. Increasing evidence suggests that the water/glycerol channel aquaporin-3 (AQP3) plays a key role in cancer and metastasis. Here, we report the ability of RoT to inhibit human AQP3 activity with an IC50 in the micromolar range (22.8 ± 5.82 µM for water and 6.7 ± 2.97 µM for glycerol permeability inhibition). Moreover, we have used molecular docking and molecular dynamics simulations to understand the structural determinants of RoT that explain its ability to inhibit AQP3. Our results show that RoT blocks AQP3-glycerol permeation by establishing strong and stable interactions at the extracellular region of AQP3 pores interacting with residues essential for glycerol permeation. Altogether, our multidisciplinary approach unveiled RoT as an anticancer drug against tumors where AQP3 is highly expressed providing new information to aquaporin research that may boost future drug design.

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Currently, more than 2100 variants have been identified in the gene, with a large number being very rare. The approval of modulators that act on mutant CFTR protein, correcting its molecular defect and thus alleviating the burden of the disease, revolutionized the field of CF. However, these drugs do not apply to all patients with CF, especially those with rare mutations—for which there is a lack of knowledge on the molecular mechanisms of the disease and the response to modulators. In this work, we evaluated the impact of several rare putative class II mutations on the expression, processing, and response of CFTR to modulators. Novel cell models consisting of bronchial epithelial cell lines expressing CFTR with 14 rare variants were created. The variants studied are localized at Transmembrane Domain 1 (TMD1) or very close to the signature motif of Nucleotide Binding Domain 1 (NBD1). Our data show that all mutations analyzed significantly decrease CFTR processing and while TMD1 mutations respond to modulators, those localized in NBD1 do not. Molecular modeling calculations confirm that the mutations in NBD1 induce greater destabilization of CFTR structure than those in TMD1. Furthermore, the structural proximity of TMD1 mutants to the reported binding site of CFTR modulators such as VX-809 and VX-661, make them more efficient in stabilizing the CFTR mutants analyzed. Overall, our data suggest a pattern for mutation location and impact in response to modulators that correlates with the global effect of the mutations on CFTR structure.

Patritumab deruxtecan (HER3-DXd) is a novel antibody–drug conjugate targeting HER3, which is overexpressed in CNS metastases of advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the activity and safety of HER3-DXd in patients with advanced NSCLC and newly diagnosed brain metastases or brain metastases progressing after local therapy. TUXEDO-3 is a multicohort, multicentre, open-label, single-arm phase 2 trial. In this cohort (2 of 3), we enrolled adults (aged ≥18 years) with histologically documented squamous or non-squamous NSCLC, radiologically documented metastatic disease, newly diagnosed brain metastases or progressing brain metastases after local treatment, at least one brain lesion, no need for immediate local therapy, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients received HER3-DXd 5·6 mg/kg intravenously once every 3 weeks. The threshold to meet the primary endpoint was at least 15% of patients having an intracranial response according to Response Assessment in Neuro-Oncology Brain Metastases criteria. Activity and safety analyses were done in the full analysis set, which included all participants who received at least one dose of HER3-DXd. This trial (ClinicalTrials.govNCT05865990 and European Union Clinical Trials Register 2023-503251-10-00) is ongoing but no longer enrolling patients. Between Dec 27, 2023, and Sept 6, 2024, 20 patients were recruited; ten (50%) were female and ten (50%) were male. 16 (80%) of 20 patients were White; race was not reported in the remaining four patients. 13 (65%) of the 20 patients had brain metastases progressing after local therapy and seven (35%) had untreated brain metastases; five (25%) had activating driver mutations. Median follow-up was 5·3 months (IQR 2·0–8·5). The primary endpoint was met, with six (30%) of 20 patients having intracranial responses (objective response rate 30·0%, 95% CI 11·9–54·3). The six responders had non-squamous advanced NSCLC (two [33%] with untreated brain metastases and four [67%] with progressing brain metastases), of whom one (17%) had an activating driver mutation (KRAS G12C). Treatment-related adverse events occurred in 16 (80%) patients, the most common of which were nausea (seven [35%] patients), and diarrhoea and asthenia (each six [30%] patients). The most common grade 3 and 4 adverse events were neutropenia in three (15%) patients and febrile neutropenia in two (10%). There were no treatment-related deaths, and no new safety signals were identified. HER3-DXd showed promising clinical activity in patients with advanced NSCLC and active brain metastases, and could represent a novel treatment option in this setting. Daiichi-Sankyo and Merck Sharp & Dohme.

Patritumab deruxtecan (HER3-DXd) is a novel antibody–drug conjugate targeting HER3, which is overexpressed in CNS metastases of metastatic breast cancer. We aimed to evaluate the activity and safety of HER3-DXd in patients with metastatic breast cancer and brain metastases that are newly diagnosed or progressing after local therapy. TUXEDO-3 trial is a multicohort, multicentre, open-label, single-arm phase 2 trial, done in six sites in Spain and Austria. In this cohort (1 of 3), we enrolled adults (≥18 years) with histologically documented breast cancer and radiologically documented metastatic disease, newly diagnosed brain metastases or brain metastases progressing after local treatment, at least one measurable brain lesion of ≥10 mm, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients received HER3-DXd 5·6 mg/kg intravenously once every 3 weeks. The threshold for the primary endpoint was at least 15% of patients having intracranial response according to Response Assessment in Neuro-Oncology Brain Metastases criteria. Activity and safety analyses were done in the full analysis population (ie, all participants who received at least one dose of HER3-DXd). This trial (ClinicalTrials.govNCT05865990 and European Union Clinical Trials Register 2023-503251-10-00) is ongoing and is no longer enrolling patients. Between Dec 12, 2023, and July 8, 2024, 21 evaluable female patients (five with luminal breast cancer, nine with HER2-positive breast cancer, and seven with triple-negative breast cancer) were recruited. 15 (71%) were White; race was not reported in the remaining six patients. The median number of previous treatment lines for advanced disease was 4 (IQR 2–4). Median treatment duration was 3·0 months (IQR 0·7–7·7), and median follow-up was 4·9 months (IQR 3·6–8·5). The primary endpoint was met with five (24%) of 21 patients having intracranial responses irrespective of the breast cancer subtype (overall response rate 23·8%, 95% CI 8·2–47·1). The most common grade 3 or worse treatment-emergent adverse events were neutropenia in three (14%) patients, diarrhoea in two (10%) patients, and asthenia and vomiting in one (5%) patient each. Serious adverse events occurred in six (29%) patients, with one (5%) patient having grade 2 pneumonitis related to the study treatment. No treatment-related deaths were reported. HER3-DXd showed promising clinical activity in patients with metastatic breast cancer and active brain metastases, and could offer a novel therapeutic option in this setting. Daiichi-Sankyo and Merck Sharp & Dohme.

Ovarian cancer is one of the most common gynecological malignancies and has low survival rates. One of the main determinants of this unfavorable prognosis is the high rate of peritoneal metastasis at diagnosis, closely related to its morbidity and mortality. The mechanism underlying peritoneal carcinomatosis is not clearly defined, but a clear preference for omental spread has been described. Growing evidence suggests that adipose tissue plays a role in promoting cancer onset and progression. Moreover, obesity can lead to changes in the original functions of adipocytes, resulting in metabolic and inflammatory changes in the adipose tissue microenvironment, potentially increasing the risk of tumor growth. However, the specific roles of adipocytes in ovarian cancer have not yet been fully elucidated. Due to the undeniable link between obesity and cancer, the adipose tissue microenvironment could also present a promising therapeutic target that warrants further research. This review discusses the complex relationship between ovarian cancer and the adipose tissue microenvironment.

In a previous study we identified active Notch signaling in key cellular events occurring at adult spermatogenesis. In this study, we evaluated the function of Notch signaling in spermatogenesis through the effects of in vivo Notch blockade. Adult CD1 male mice were either submitted to a long term DAPT (?-secretase inhibitor) or vehicle treatment. Treatment duration was designed to attain one half the time (25 days) or the time (43 days) required to accomplish a complete cycle of spermatogenesis. Blockade of Notch signaling was depicted from decreased transcription of Notch effector genes. Notch signaling blockade disrupted the expression patterns of Notch components in the testis, induced male germ cell fate aberrations, and significantly increased germ cell apoptosis, mainly in the last stages of the spermatogenic cycle, and epididymis spermatozoa morphological defects. These effects were more pronounced following the 43 day than the 25 day DAPT treatment schedule. These results indicate a relevant regulatory role of Notch signaling in mammalian spermatogenesis.

The transcription and expression patterns of Notch pathway components (Notch 1–3, Delta1 and 4, Jagged1) and effectors (Hes1, Hes2, Hes5 and Nrarp) were evaluated (through RT-PCR and IHC) in the mouse testis at key moments of post-natal development, and along the adult spermatogenic cycle. Notch pathway components and effectors are transcribed in the testis and expressed in germ, Sertoli and Leydig cells, and each Notch component shows a specific cell-type and timewindow expression pattern. This expression at key testis developmental events prompt for a role of Notch signaling in prepubertal spermatogonia quiescence, onset of spermatogenesis, and regulation of the spermatogenic cycle.

The clinicopathological breast cancer subtypes are used in clinical practice to better anticipate biological behaviour and guide systemic treatment strategy. In the adjuvant setting, genomic assay recurrence scores became widely available for luminal-like disease. Recently, next-generation sequencing (NGS) platforms have been used, essentially, in more advanced disease setting, in situations refractory to conventional treatment, or even in rare cancers for which there are no established treatment guidelines. Moreover, subpopulations of cancer cells with unique genomes within the same patient may exist across different regions of a tumour or evolve over time, which is called intratumoural heterogeneity. We herein report a case of a 38-year-old woman with breast cancer whose primary and metastatic disease exhibited discordant expression of hormone receptors, with the former being positive and the latter negative. Furthermore, the NGS analysis revealed slight and dynamic changes of mutational profiles between different metastatic lesions, potentially impacting breast cancer management and prognosis. These alterations may reflect tissular and temporal changes in tumour subclones and may also be due to the selective pressure caused by antineoplastic treatment. The use of genomic analyses in order to improve cancer treatment has been studied prospectively with encouraging results. The widespread use of NGS tests in clinical practice also creates new challenges. The most relevant may be to know which genomic alterations detected should be valued and how they should be targeted.

Outdoor pig production (OPP) can be considered an intensive system in many areas of the Mediterranean region. The concentration of the rainfall in the winter season, the OPP’s topographic and soil properties, together with the continuous input of food and pigs’ excreta, contribute to a profound increase in the nutrients leaching and soil erosion. This work aimed to evaluate the accuracy of the DRASTIC-LU index and the Revised Universal Soil Loss Equation (RUSLE) to provide early information to improve the planning of this type of pig production through more adequate location and sustainable management practices. The two models were applied to an OPP with 2.24 ha, with a heavy animal charge (one adult per 1.120 m2). The results showed that 85% of the OPP area has a moderate risk to the vulnerability index to groundwater pollution and 15% high risk. The risk of soil erosion ranged from very severe to extremely severe in 96% of the area. The DRASTIC-LU indexes and the RUSLE model produce a multi-risk assessment that agreed with the observed field data. These two models showed accuracy to be used for early assessment when choosing the best location and improving management practices for OPP systems.

Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis. In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity. Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7–10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22–67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05–0·59). The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications. Mutua Madrileña Foundation; ISCIII–Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX.