PanDrugs2: prioritizing cancer therapies using integrated individual multi-omics data.

Genomics studies routinely confront researchers with long lists of tumor alterations detected in patients. Such lists are difficult to interpret since only a minority of the alterations are relevant biomarkers for diagnosis and for designing therapeutic strategies. PanDrugs is a methodology that facilitates the interpretation of tumor molecular alterations and guides the selection of personalized treatments. To do so, PanDrugs scores gene actionability and drug feasibility to provide a prioritized evidence-based list of drugs. Here, we introduce PanDrugs2, a major upgrade of PanDrugs that, in addition to somatic variant analysis, supports a new integrated multi-omics analysis which simultaneously combines somatic and germline variants, copy number variation and gene expression data. Moreover, PanDrugs2 now considers cancer genetic dependencies to extend tumor vulnerabilities providing therapeutic options for untargetable genes. Importantly, a novel intuitive report to support clinical decision-making is generated. PanDrugs database has been updated, integrating 23 primary sources that support >74K drug-gene associations obtained from 4642 genes and 14 659 unique compounds. The database has also been reimplemented to allow semi-automatic updates to facilitate maintenance and release of future versions. PanDrugs2 does not require login and is freely available at https://www.pandrugs.org/.

Dependence of corneal hysteresis on non-central corneal thickness in healthy subjects.

OBJECTIVE: To evaluate the dependence of corneal hysteresis (CH) on non-central corneal thickness. METHODS: Cross-sectional study of 1561 eyes of 1561 healthy volunteers with IOP less than 21mmHg, open angles on gonioscopy and no prior eye surgeries or local or systemic diseases. Pentacam-Scheimpflug technology was employed to segment the cornea into 6 circular zones centered on the apex (zones 1-6) and to determine the mean corneal thickness of these areas. CH was measured with ORA. Univariate and multivariate linear regression models adjusted for age and sex were created to model the dependence of CH on corneal thickness in zones 1 to 6. RESULTS: In the univariate linear regression models, we found that CH was dependent on mean corneal thickness of zone 1 (B=0,004; R2=0.95%; P<0.001), zone 2 (B=0,004; R2=0.57%; P=0.002), zone 4 (B=0,005; R2=1.50%; P<0.001) and zone 6 (B=0,003; R2=0.92%; P<0.001). Similar results were obtained in the multivariate model (R2=3.46%; P<0.001). CONCLUSION: This study suggests a significant dependence of CH on non-central corneal thickness. The model of corneal thickness segmentation into circular zones centered on the corneal apex is able to explain 3.47% of the variation in CH measurements.

RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer.

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.

Subfoveal choroidal thickness as a potential predictor of treatment response after intravitreal ranibizumab injections for polypoidal choroidal vasculopathy.

OBJECTIVE: To evaluate the impact of subfoveal choroidal thickness (SFCT) and other clinical biomarkers in intravitreal anti-vascular endothelial growth factor response in treatment-naive Caucasian patients diagnosed with polypoidal choroidal vasculopathy (PCV/AT1). DESIGN: Cross-sectional study. PARTICIPANTS: Treatment-naive patients diagnosed with PCV/AT1 recruited in a single centre from January 2013 to December 2020. METHODS: Eligibility was determined in treatment-naive PCV patients who received a loading dose of 3 injections of 0.5 mg ranibizumab. A diagnosis of PCV/AT1 was made based on the diagnostic criteria in the efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with sumptomatic macular polypoidal choroidal vasculopathy study. Choroidal thickness was manually measured by enhanced depth imaging technology in Spectralis spectral domain optical coherence tomography. RESULTS: Eighty-three eyes of 83 patients were included in this study, 47 patients diagnosed with PCV/AT1 with a good response to 3 intravitreal injections of ranibizumab and 36 with a poor response. The receiver operating characteristic curve of treatment effect against the SFCT revealed that the area under the curve was 0.85 (range, 0.74-0.96). Based on the Youden index, the optimal SFCT cut-off point for predicting a poor response to anti-vascular endothelial growth factor is 257 µm. In the multivariate analysis, the SFCT remained statistically significant (odds ratio 1.02 [range, 1.01-1.04]; P = 0.008). The combined effect of treatment effect against clinical biomarkers produced an area under the curve of 0.90 (range, 0.82-0.98). CONCLUSION: SFCT is a risk factor for a poor response to the 3 loading injections of ranibizumab in treatment-naive PCV/AT1 Caucasian patients. A cut-off point of 257 µm could be a valuable parameter for defining the population at risk for an inadequate response to ranibizumab.

Spontaneous resolution of inflammatory epiretinal membrane: Case series and review of the literature.

Epiretinal membrane (ERM) represents a common complication of uveitis that may contribute independently to vision loss in patients with uveitis. Although spontaneous idiopathic ERM separation has been previously reported, to the best of our knowledge there are only two case reports in the scientific literature that depicts spontaneous regression of an inflammation-associated ERM. Spontaneous ERM separation is a rare but possible event, which occurs most often subsequent to posterior vitreous detachment. We present a case series of three patients with uveitis that exhibit the formation and subsequent spontaneous resolution of an inflammatory ERM.

CALR-mutated cells are vulnerable to combined inhibition of the proteasome and the endoplasmic reticulum stress response.

Cancer is driven by somatic mutations that provide a fitness advantage. While targeted therapies often focus on the mutated gene or its direct downstream effectors, imbalances brought on by cell-state alterations may also confer unique vulnerabilities. In myeloproliferative neoplasms (MPN), somatic mutations in the calreticulin (CALR) gene are disease-initiating through aberrant binding of mutant CALR to the thrombopoietin receptor MPL and ligand-independent activation of JAK-STAT signaling. Despite these mechanistic insights into the pathogenesis of CALR-mutant MPN, there are currently no mutant CALR-selective therapies available. Here, we identified differential upregulation of unfolded proteins, the proteasome and the ER stress response in CALR-mutant hematopoietic stem cells (HSCs) and megakaryocyte progenitors. We further found that combined pharmacological inhibition of the proteasome and IRE1-XBP1 axis of the ER stress response preferentially targets Calr-mutated HSCs and megakaryocytic-lineage cells over wild-type cells in vivo, resulting in an amelioration of the MPN phenotype. In serial transplantation assays following combined proteasome/IRE1 inhibition for six weeks, we did not find preferential depletion of Calr-mutant long-term HSCs. Together, these findings leverage altered proteostasis in Calr-mutant MPN to identify combinatorial dependencies that may be targeted for therapeutic benefit and suggest that eradicating disease-propagating Calr-mutant LT-HSCs may require more sustained treatment.

Vieussens' ring fistula to pulmonary artery: embolization with grandmother-mother-child technique / Fístula del anillo de Vieussens a arteria pulmonar: embolización con técnica abuela-madre-hijo

Abstract A 53-year-old man with an asymptomatic fistula from the Vieussens ring to the pulmonary artery presented with progressive respiratory distress. Coil embolization of this type of fistula has been described by femoral access. The advanced transradial "grandmother-mother-son" technique for high active support safely allows successful embolization of this type of coronary fistulae.

Resumen Un hombre de 53 años con una fístula asintomática del anillo de Vieussens a la arteria pulmonar comenzó con dificultad respiratoria progresiva. La embolización con coils de este tipo de fístulas ha sido descrita por acceso femoral. La técnica transradial avanzada "abuela-madre-hijo" para un alto soporte activo permite de manera segura la embolización exitosa de este tipo fístulas coronarias.

Vieussens' ring fistula to pulmonary artery: embolization with grandmother-mother-child technique.

A 53-year-old man with an asymptomatic fistula from the Vieussens ring to the pulmonary artery presented with progressive respiratory distress. Coil embolization of this type of fistula has been described by femoral access. The advanced transradial "grandmother-mother-son" technique for high active support safely allows successful embolization of this type of coronary fistulae.

Un hombre de 53 años con una fístula asintomática del anillo de Vieussens a la arteria pulmonar comenzó con dificultad respiratoria progresiva. La embolización con coils de este tipo de fístulas ha sido descrita por acceso femoral. La técnica transradial avanzada "abuela-madre-hijo" para un alto soporte activo permite de manera segura la embolización exitosa de este tipo fístulas coronarias.

An Unusual Equatorial Constriction of the Ventricular Cone.

A 25-year-old woman with a recent diagnosis of congenital heart disease and probable endocarditis was referred to our institution. During our evaluation we observed an unusual deformation of both ventricles. We discuss its possible origin as revealed by printing of a three-dimensional model. (Level of Difficulty: Advanced.).

Bioinformatics roadmap for therapy selection in cancer genomics.

Tumour heterogeneity is one of the main characteristics of cancer and can be categorised into inter- or intratumour heterogeneity. This heterogeneity has been revealed as one of the key causes of treatment failure and relapse. Precision oncology is an emerging field that seeks to design tailored treatments for each cancer patient according to epidemiological, clinical and omics data. This discipline relies on bioinformatics tools designed to compute scores to prioritise available drugs, with the aim of helping clinicians in treatment selection. In this review, we describe the current approaches for therapy selection depending on which type of tumour heterogeneity is being targeted and the available next-generation sequencing data. We cover intertumour heterogeneity studies and individual treatment selection using genomics variants, expression data or multi-omics strategies. We also describe intratumour dissection through clonal inference and single-cell transcriptomics, in each case providing bioinformatics tools for tailored treatment selection. Finally, we discuss how these therapy selection workflows could be integrated into the clinical practice.

Whole-genome CRISPR screening identifies N-glycosylation as a genetic and therapeutic vulnerability in CALR-mutant MPNs.

Calreticulin (CALR) mutations are frequent, disease-initiating events in myeloproliferative neoplasms (MPNs). Although the biological mechanism by which CALR mutations cause MPNs has been elucidated, there currently are no clonally selective therapies for CALR-mutant MPNs. To identify unique genetic dependencies in CALR-mutant MPNs, we performed a whole-genome clustered regularly interspaced short palindromic repeats (CRISPR) knockout depletion screen in mutant CALR-transformed hematopoietic cells. We found that genes in the N-glycosylation pathway (among others) were differentially depleted in mutant CALR-transformed cells as compared with control cells. Using a focused pharmacological in vitro screen targeting unique vulnerabilities uncovered in the CRISPR screen, we found that chemical inhibition of N-glycosylation impaired the growth of mutant CALR-transformed cells, through a reduction in MPL cell surface expression. We treated Calr-mutant knockin mice with the N-glycosylation inhibitor 2-deoxy-glucose (2-DG) and found a preferential sensitivity of Calr-mutant cells to 2-DG as compared with wild-type cells and normalization of key MPNs disease features. To validate our findings in primary human cells, we performed megakaryocyte colony-forming unit (CFU-MK) assays. We found that N-glycosylation inhibition significantly reduced CFU-MK formation in patient-derived CALR-mutant bone marrow as compared with bone marrow derived from healthy donors. In aggregate, our findings advance the development of clonally selective treatments for CALR-mutant MPNs.

Assessment of the perception of healthcare barriers and the impact of intravitreal injections on neovascular age-related macular degeneration.

AIM: To evaluate the perception of barriers in healthcare and the impact of intravitreal injections in patients with neovascular age-related macular degeneration (nAMD). METHODS: Cross-sectional study including 108 patients with nAMD in treatment with intravitreal injections. The patients answered a questionnaire with 26 questions (score from 1 to 5) divided in three sections: 1) the disease and its treatment with injections, 2) healthcare barriers and 3) new technologies. RESULTS: The mean age was 80.4 ±â€¯7.0 years and visual acuity (VA) was 75.2 ±â€¯12.4 letters. The main barriers in healthcare were long waiting times (72%), followed by other comorbidities (10%). Some 63% of patients have to wait between 3 and 5 h to attend their clinical visit. Significant anxiety due to the injections (2.8 ±â€¯1.3) was observed, being present in 71% of the cases the day before. A great fear of blindness and losing independence was observed (4.4 ±â€¯0.9 and 4.3 ±â€¯1.1), with no differences in relation to VA, age or sex (p ≥ 0.135). Moreover, 28% of the patients reported that it was quite or very difficult for them to attend the clinical visit, with 69% of the total showing great interest in having a diagnostic device at home. CONCLUSION: The nAMD and its treatment represent a significant burden on patients, among whom there is a great fear of blindness and of losing their independence, the main barrier being the long waiting time for the clinical visit.

Evaluación de la percepción de las barreras en la asistencia sanitaria y del impacto de las inyecciones intravítreas en la degeneración macular asociada a la edad neovascular / AEvaluación de la percepción de las barreras en la asistencia sanitaria y del impacto de las inyecciones intravítreas en la degeneración macular asociada a la edad neovascular

Propósito Evaluar la percepción de las barreras en la asistencia sanitaria y del impacto de las inyecciones intravítreas en los pacientes con degeneración macular asociada a la edad neovascular (DMAEn). Métodos Estudio transversal de 108 pacientes con DMAEn en tratamiento con inyecciones intravítreas mediante un cuestionario de 26 preguntas (puntuación del 1 al 5) divididas en 3 bloques: 1)enfermedad y su tratamiento con inyecciones; 2)barreras en la asistencia sanitaria, y 3)nuevas tecnologías. Resultados La edad media fue 80,4±7,0 años y la agudeza visual (AV) de 75,2±12,4 letras. Las principales barreras en la asistencia sanitaria fueron los largos tiempos de espera en consulta (72%), seguida por otras comorbilidades (10%). El 63% de los pacientes dedican entre 3 y 5h para acudir a la consulta. Se apreció una ansiedad notable debida a las inyecciones (2,8±1,3), estando presente en el 71% el día antes. Se observó un gran miedo a la ceguera y a dejar de ser independientes (4,4±0,9 y 4,3±1,1), sin existir diferencias en relación con la AV, la edad o el sexo (p≥0,135). El 28% de los pacientes refieren que les cuesta bastante o mucho la asistencia a consulta, presentando el 69% del total un gran interés en tener un aparato diagnóstico en el domicilio. Conclusiones La DMAEn y su tratamiento suponen una importante carga asistencial para los pacientes, existiendo un gran miedo a la ceguera y a perder su independencia, siendo la principal barrera el largo tiempo de espera en consulta (AU)

Aim To evaluate the perception of barriers in healthcare and the impact of intravitreal injections in patients with neovascular age-related macular degeneration (nAMD). Methods Cross-sectional study including 108 patients with nAMD in treatment with intravitreal injections. The patients answered a questionnaire with 26 questions (score from 1 to 5) divided in three sections: 1)the disease and its treatment with injections; 2)healthcare barriers, and 3)new technologies. Result The mean age was 80.4±7.0 years and visual acuity (VA) was 75.2±12.4 letters. The main barriers in healthcare were long waiting times (72%), followed by other comorbidities (10%). Some 63% of patients have to wait between 3 and 5hours to attend their clinical visit. Significant anxiety due to the injections (2.8±1.3) was observed, being present in 71% of the cases the day before. A great fear of blindness and losing independence was observed (4.4±0.9 and 4.3±1.1), with no differences in relation to VA, age or sex (P≥.135). Moreover, 28% of the patients reported that it was quite or very difficult for them to attend the clinical visit, with 69% of the total showing great interest in having a diagnostic device at home.Conclusion The nAMD and its treatment represent a significant burden on patients, among whom there is a great fear of blindness and of losing their independence, the main barrier being the long waiting time for the clinical visit (AU)