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Abstract Background Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-related death worldwide. This heterogeneous disease has been historically considered a non-immunogenic type of cancer. However, recent advances in immunotherapy have increased the interest in knowing the role of the immune checkpoints (IC) and other immune regulation pathways in this neoplasia. Methods In this retrospective study, we evaluated the correlation of mRNA expression of CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), CD276 (B7-H3), JAK2, and FOXO1 with clinicopathological factors and BC patient’s outcome by real-time quantitative polymerase chain reaction (qPCR). Results Our results showed that immunoregulatory gene expression depends on BC immunophenotype being CTLA-4 and PDCD1 (PD1) overexpressed on triple-negative/basal-like (TN/BL) and luminal B/HER2-positive phenotypes, respectively, and CD276 (B7-H3), JAK2 and FOXO1 associated with both luminal A and luminal B/HER2-negative tumors. In addition, we found that these genes can also be related to aggressive and non-aggressive clinicopathological characteristics in BC. Finally, survival analysis showed that CTLA-4 expression levels emerge as a significant independent factor of good prognosis in BC patients, especially in the HER2-enriched subtype. Conclusion Considering all these data, we can conclude that the expression of immunoregulatory genes depends on tumor phenotype and has potential clinical implications in BC patients.

Abstract Background Carboplatin and paclitaxel (CP) have been the standard of care for advanced/recurrent endometrial cancer (EC) for many years. However, this chemotherapy combination shows limited efficacy and recurrences often occur in less than 12 months. ABTL0812 is a novel drug that selectively kill cancer cells by cytotoxic autophagy and has shown anticancer efficacy in preclinical models of EC in combination with CP. Methods ENDOLUNG was an open-label, phase 1/2 clinical trial designed to determine the safety and efficacy of Ibrilatazar (ABTL0812) with CP in patients with advanced/recurrent EC and non-irradiable stage III and IV squamous non-small cell lung cancer (sq-NSCLC). The phase 1 part consisted of a 3 + 3 de-escalation design followed by an expansion cohort with 12 patients. The primary endpoint was safety. ABTL0812 starting dose was 1300 mg tid combined with carboplatin at area under the curve (AUC) 5 and paclitaxel at 175 mg/m2 both administered every 21 days for up to 8 cycles. The phase 2 part included a total of 51 patients. The primary endpoint was overall response rate (ORR) and the secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results During the phase 1 only one dose limiting toxicity (DLT), a grade 4 neutropenia, was observed in 1 out of 6 patients, thus no de-escalation was applied. One additional DLT, a grade 3 febrile neutropenia, was observed in the expansion cohort, thus the recommended phase 2 dose (RP2D) for ABTL0812 was established at 1300 mg tid. Most frequent hematological adverse events (AE) of the combination were neutropenia (52.9%), anemia (37.3%) and thrombocytopenia (19.6%). Nausea (66.7%), asthenia (66.7%), diarrhea (54.9%) and vomiting (54.9%) were the most frequent non-hematological adverse events (AEs). The combination of ABTL0812 plus CP showed an ORR of 65.8% (13.2% complete response and 52.6% partial response) with a median DOR of 7.4 months (95% CI: 6.3–10.8 months). Median PFS was 9.8 months (95% CI: 6.6–10.6) and median OS 23.6 months (95% CI 6.4-ND). Pharmacokinetic parameters were compatible with target engagement observed in preclinical studies, and blood pharmacodynamic biomarkers indicated sustained target regulation during, at least, 28 days after starting the treatment. Conclusions This study suggests that the combination of ABTL0812 with CP is safe and feasible with an encouraging activity in patients with advanced/recurrent EC. Our data warrant further confirmation in prospective randomized trials. Trial registration EU Clinical Trial Register, EudraCT number 2016-001352-21 and National Clinical Trials Number, NCT03366480. Registration on 19 September 2016.

Question Mindfulness-based programmes (MBPs) and practices have demonstrated effects in mental health and well-being, yet questions regarding the target mechanisms that drive change across the population remain unresolved.Study selection and analysis Five databases were searched for randomised controlled trials that evaluate the indirect effects (IEs) of an MBP or mindfulness practice in relation to mental health and well-being outcomes through psychological mechanisms.Findings 27 eligible studies were identified, with only four exploring mechanisms in the context of specific mindfulness practices. Significant IEs were reported for mindfulness skills, decentering and attitudes of mindfulness (eg, self-compassion) across different outcomes, population samples, mental health strategies and active comparators. Evidence gap maps and requirements for testing and reporting IEs are provided to help guide future work.Conclusions Mindfulness skills, decentering and attitudes of mindfulness may be key intervention targets for addressing the mental health of whole populations. However, future work needs to address significant knowledge gaps regarding the evidence for alternative mechanisms (eg, attention and awareness) in relation to unique outcomes (eg, well-being), mental health strategies (ie, promotion) and active comparators. High-quality trials, with powered multivariate mediation analyses that meet key requirements, will be needed to advance this area of work.Trial registration number 10.17605/OSF.IO/NY2AH.

Abstract Oxidative stress has been linked to the onset and progression of different neoplasia. Antioxidants might help prevent it by modulating biochemical processes involved in cell proliferation. Here, the aim was to evaluate the in vitro cytotoxic effect of Haloferax mediterranei bacterioruberin-rich carotenoid extracts (BRCE) (0–100 µg/ml) in six BC cell lines, representative of the intrinsic phenotypes and a healthy mammary epithelium cell line. Cell index values were obtained using xCELLigence RTCA System. Furthermore, cell diameter, viability, and concentration were measured at 12 h, 24 h, and 30 h. We found that BC cells were selectively affected by BRCE (SI > 1, p

Abstract Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor‐negative, ER−) from four independent cohorts. RANK protein expression was more frequent in ER− tumors, where it associated with poor outcome and poor response to chemotherapy. In ER− breast cancer patient‐derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER− breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK+ ER− tumors after menopause.

Topical imiquimod has been used off-label as monotherapy or adjuvant treatment for lentigo maligna. Our aim is to describe treatment modalities, clinical outcomes, and management of recurrence in patients receiving imiquimod for lentigo maligna.Patients from our unit with lentigo maligna or lentigo maligna melanoma treated with imiquimod 5% as monotherapy or in combination with surgery were included in this study.Fourteen cases were recruited (85.7% lentigo maligna and 14.3% lentigo maligna melanoma). Eight patients (57.1%) received imiquimod without surgery, and six (42.9%) underwent narrow excision before beginning treatment. During the follow-up period, pigmentation reappeared in 6 patients (4 postinflammatory hyperpigmentation and 2 relapses). Relapses were managed with very narrow excision (1 mm margin) and retreatment with imiquimod 5%.All imiquimod modalities showed well-tolerated side effects and low recurrence rates, with long periods of follow-up. Imiquimod appears to be a versatile option for treating LM in suitable candidates. Resumen: Imiquimod tópico ha sido utilizado como monoterapia o tratamiento adyuvante fuera de indicación para el lentigo maligno (LM). Nuestro objetivo es describir las modalidades de tratamiento, los resultados clínicos y el manejo de la recidiva en los pacientes que reciben imiquimod para lentigo maligno.Se incluyó en este estudio a los pacientes de nuestra unidad con lentigo maligno o lentigo maligno melanoma tratados con imiquimod 5% en régimen de monoterapia o junto con cirugía.Se seleccionaron 14 casos (el 85,7% de lentigo maligno y el 14,3% de lentigo maligno melanoma). Ocho pacientes (57,1%) recibieron imiquimod sin cirugía, y seis (42,9%) fueron sometidos a resección antes de iniciar el tratamiento. Durante el periodo de seguimiento, reapareció la pigmentación en seis pacientes (cuatro con hiperpigmentación postinflamatoria y dos recidivas). Las recidivas fueron tratadas con un margen de resección muy estrecho (1 mm) y retratamiento con imiquimod 5%.Todas las modalidades de imiquimod reflejaron buena tolerancia de efectos secundarios y bajas tasas de recidiva. Imiquimod parece ser una opción muy versátil para tratar LM en candidatos idóneos.

This study measured the level of self-confidence in English of 36 first-year English majors of Kabankalan Catholic College who were officially enrolled for the Academic Year 2022-2023. The participants' self-confidence in English was classified into five macro skills namely reading, writing, listening, speaking, and viewing skills. Their selfconfidence in the five skills was correlated to their performance in Purposive Communication course. Descriptivecorrelational design was used to determine the association between the two variables. An adopted and compiled standardized questionnaires from different sources were administered. Mean, standard deviation, t-test, and Pearson correlation coefficient were utilized for data analyses. The results revealed that males garnered higher mean results in the level of self confidence in English in terms of listening, reading, writing, and speaking skills while females excelled in viewing skills. This finding implies that males are more confident in English compared to females. In terms of school of origin when taken as a whole, viewing skills got the highest mean while writing skills got the lowest mean for both private and public schools which implies that viewing skill is dominant due to digitalization and wide impact of media. Significant differences also vary in the five macro skills. A significant relationship was found between the students' self-confidence in English in terms of reading skills and their performance in Purposive Communication. Thus, the study suggests that language programs may be implemented to help enhance the students' English skills so they can fully excel in their academics and in the use of English language. [ABSTRACT FROM AUTHOR]

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Abstract Background Pre-exposure prophylaxis (PrEP) is recommended by the WHO for HIV prevention among female sex workers (FSWs). A study conducted in 2016–2017 in Côte d’Ivoire showed that if PrEP is acceptable, FSWs also have many uncovered sexual health needs. Based on this evidence, the ANRS 12381 PRINCESSE project was developed in collaboration with a community-based organization. The main objective is to develop, document, and analyze a comprehensive sexual and reproductive healthcare package among FSWs in Côte d’Ivoire. Methods PRINCESSE is an open, single-arm interventional cohort of 500 FSWs in San Pedro (Côte d’Ivoire) and its surroundings. Recruitment started on November 26th, 2019 and is ongoing; the cohort is planned to last at least 30 months. The healthcare package (including HIV, hepatitis B, and sexually transmitted infection management, pregnancy screening, and contraception) is available both at mobile clinics organized for a quarterly follow-up (10 intervention sites, each site being visited every two weeks) and at a fixed clinic. Four waves of data collection were implemented: (i) clinical and safety data; (ii) socio-behavioral questionnaires; (iii) biological data; and (iv) in-depth interviews with female participants. Four additional waves of data collection are scheduled outside the cohort itself: (i) the medical and activity records of Aprosam for the PRINCESSE participants; (ii) the medical records of HIV+ FSW patients not participating in the PRINCESSE cohort, and routinely examined by Aprosam; (iii) in-depth interviews with key informants in the FSW community; and (iv) in-depth interviews with PRINCESSE follow-up actors. Discussion The PRINCESSE project is one of the first interventions offering HIV oral PrEP as part of a more global sexual healthcare package targeting both HIV- and HIV+ women. Second, STIs and viral hepatitis B care were offered to all participants, regardless of their willingness to use PrEP. Another innovation is the implementation of mobile clinics for chronic/quarterly care. In terms of research, PRINCESSE is a comprehensive, interdisciplinary project combining clinical, biological, epidemiological, and social specific objectives and outcomes to document the operational challenges of a multidisease program in real-life conditions. Trial registration The PRINCESSE project was registered on the Clinicaltrial.gov website ( NCT03985085 ) on June 13, 2019.

BackgroundGlioblastoma multiforme (GBM) is the most malignant adult brain tumor. Current standard of care treatments have very limited efficacy, being the patients´ overall survival 14 months and the 2-year survival rate less than 10%. Therefore, the treatment of GBM is an urgent unmet clinical need.MethodsThe aim of this study was to investigate in vitro and in vivo the potential of ABTL0812, an oral anticancer compound currently in phase II clinical stage, as a novel therapy for GBM.ResultsWe showed that ABTL0812 inhibits cell proliferation in a wide panel of GBM cell lines and patient-derived glioblastoma stem cells (GSCs) with half maximal inhibitory concentrations (IC50s) ranging from 15.2 µM to 46.9 µM. Additionally, ABTL0812 decreased GSCs neurosphere formation. GBM cells aggressiveness is associated with a trans-differentiation process towards a less differentiated phenotype known as proneural to mesenchymal transition (PMT). ABTL0812 was shown to revert PMT and induce cell differentiation to a less malignant phenotype in GBM cell lines and GSCs, and consequently reduced cell invasion. As previously shown in other cancer types, we demonstrated that the molecular mechanism of action of ABTL0812 in glioblastoma involves the inhibition of Akt/mTORC1 axis by overexpression of TRIB3, and the activation of endoplasmic reticulum (ER) stress/unfolded protein response (UPR). Both actions converge to induce autophagy-mediated cell death. ABTL0812 anticancer efficacy was studied in vivo using subcutaneous and orthotopic intra-brain xenograft tumor models. We demonstrated that ABTL0812 impairs tumor growth and increases disease-free survival and overall survival of mice. Furthermore, the histological analysis of tumors indicated that ABTL0812 decreases angiogenesis. Finally, we investigated the combination of ABTL0812 with the standard of care treatments for GBM radiotherapy and temozolomide in an orthotopic model, detecting that ABTL0812 potentiates the efficacy of both treatments and that the strongest effect is obtained with the triple combination of ABTL0812+radiotherapy+temozolomide.ConclusionsOverall, the present study demonstrated the anticancer efficacy of ABTL0812 as single agent and in combination with the GBM standard of care treatments in models of glioblastoma and supports the clinical investigation of ABTL0812 as a potential novel therapy for this aggressive brain tumor type.

Resumen: Imiquimod tópico ha sido utilizado como monoterapia o tratamiento adyuvante fuera de indicación para el lentigo maligno (LM). Nuestro objetivo es describir las modalidades de tratamiento, los resultados clínicos y el manejo de la recidiva en los pacientes que reciben imiquimod para lentigo maligno.Se incluyó en este estudio a los pacientes de nuestra unidad con lentigo maligno o lentigo maligno melanoma tratados con imiquimod 5% en régimen de monoterapia o junto con cirugía.Se seleccionaron 14 casos (el 85,7% de lentigo maligno y el 14,3% de lentigo maligno melanoma). Ocho pacientes (57,1%) recibieron imiquimod sin cirugía, y seis (42,9%) fueron sometidos a resección antes de iniciar el tratamiento. Durante el periodo de seguimiento, reapareció la pigmentación en seis pacientes (cuatro con hiperpigmentación postinflamatoria y dos recidivas). Las recidivas fueron tratadas con un margen de resección muy estrecho (1 mm) y retratamiento con imiquimod 5%.Todas las modalidades de imiquimod reflejaron buena tolerancia de efectos secundarios y bajas tasas de recidiva. Imiquimod parece ser una opción muy versátil para tratar LM en candidatos idóneos. Abstract: Topical imiquimod has been used off-label as monotherapy or adjuvant treatment for lentigo maligna. Our aim is to describe treatment modalities, clinical outcomes, and management of recurrence in patients receiving imiquimod for lentigo maligna.Patients from our unit with lentigo maligna or lentigo maligna melanoma treated with imiquimod 5% as monotherapy or in combination with surgery were included in this study.Fourteen cases were recruited (85.7% lentigo maligna and 14.3% lentigo maligna melanoma). Eight patients (57.1%) received imiquimod without surgery, and six (42.9%) underwent narrow excision before beginning treatment. During the follow-up period, pigmentation reappeared in 6 patients (4 postinflammatory hyperpigmentation and 2 relapses). Relapses were managed with very narrow excision (1 mm margin) and retreatment with imiquimod 5%.All imiquimod modalities showed well-tolerated side effects and low recurrence rates, with long periods of follow-up. Imiquimod appears to be a versatile option for treating LM in suitable candidates.