Antisense oligonucleotides (ASOs) are used to selectively inhibit the translation of disease-associated genes via Ribonuclease H (RNaseH)-mediated cleavage or steric hindrance. They are being ...developed as a novel and promising class of drugs targeting a wide range of diseases. Despite the great potential and numerous ASO drugs in preclinical research and clinical trials, there are many limitations to this technology. In this review we will focus on the challenges of ASO delivery and the strategies adopted to improve their stability in the bloodstream, delivery to target sites, and cellular uptake. Focusing on liposomal delivery, we will specifically describe liposome-incorporated growth factor receptor-bound protein-2 (Grb2) antisense oligodeoxynucleotide BP1001. BP1001 is unique because it is uncharged and is essentially non-toxic, as demonstrated in preclinical and clinical studies. Additionally, its enhanced biodistribution makes it an attractive therapeutic modality for hematologic malignancies as well as solid tumors. A detailed understanding of the obstacles that ASOs face prior to reaching their targets and continued advances in methods to overcome them will allow us to harness ASOs' full potential in precision medicine.
The B-cell lymphoma 2 (Bcl-2) family, comprised of pro- and anti-apoptotic proteins, regulates the delicate balance between programmed cell death and cell survival. The Bcl-2 family is essential in ...the maintenance of tissue homeostasis, but also a key culprit in tumorigenesis. Anti-apoptotic Bcl-2, the founding member of this family, was discovered due to its dysregulated expression in non-Hodgkin's lymphoma. Bcl-2 is a central protagonist in a wide range of human cancers, promoting cell survival, angiogenesis and chemotherapy resistance; this has prompted the development of Bcl-2-targeting drugs. Antisense oligonucleotides (ASO) are highly specific nucleic acid polymers used to modulate target gene expression. Over the past 25 years several Bcl-2 ASO have been developed in preclinical studies and explored in clinical trials. This review will describe the history and development of Bcl-2-targeted ASO; from initial attempts, optimizations, clinical trials undertaken and the promising candidates at hand.
A more complete understanding of aberrant oncogenic signaling in neuroblastoma, a malignancy of the developing sympathetic nervous system, is paramount to improving patient outcomes. Recently, we ...identified LIN28B as an oncogenic driver in high-risk neuroblastoma. Here, we identify the oncogene RAN as a LIN28B target and show regional gain of chromosome 12q24 as an additional somatic alteration resulting in increased RAN expression. We show that LIN28B influences RAN expression by promoting RAN Binding Protein 2 expression and by directly binding RAN mRNA. Further, we demonstrate a convergence of LIN28B and RAN signaling on Aurora kinase A activity. Collectively, these findings demonstrate that LIN28B-RAN-AURKA signaling drives neuroblastoma oncogenesis, suggesting that this pathway may be amenable to therapeutic targeting.
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•LIN28B and regional gain of chromosome 12q24 mediate RAN oncogene overexpression•RAN promotes cell proliferation in neuroblastoma•LIN28B promotes RAN levels by binding RAN mRNA and via RAN binding protein 2•LIN28B promotes Aurora kinase A expression in a let-7-dependent manner
Extending from prior identification of LIN28B as an oncogenic driver in high-risk neuroblastoma, Schnepp et al. show that LIN28B regulates the RAN level directly by mRNA binding and indirectly via let-7-regulated RANBP2. LIN28B and RAN signaling converge on Aurora kinase A, suggesting therapeutic potential.
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are hepatotropic viruses that differ in their genomic content, life cycle and molecular prognosis. HBV and HCV establish chronic lifespan ...infections that can evolve to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). This malignant liver cancer affects more commonly male patients than females, with a male-to-female incidence ratio of 2:1 up to 7:1. Sex significantly contributes to shape the immune responses, contributing to differences in the pathogenesis of infectious diseases, in males and females patients. Females usually develop more intense innate, humoral and cellular immune responses to viral infections and to vaccination compared to male subjects. Sex hormones, in turn, differentially affect the immune responses to viruses, by specific binding to the hormone receptors expressed on the immune cells. In general, estrogens have immune-stimulating effect, while androgens are immune-suppressing. However, sex hormones, such as androgen, can also directly interact with HBV genome integrated into the cell nucleus and activate transcription of HBV oncoproteins. On the other side, estradiol and estrogen receptors protect liver cells from inflammatory damage, apoptosis and oxidative stress, which contribute to fibrosis and malignant transformation preceding HCC. In HCV-associated cirrhosis and HCC the decreased expression of estrogen receptor alfa (ERα) in male patients may explain the worse outcome of HCV infection in men than in women. The synergistic action of male and female sex hormones and of immune responses, together with viral factors contribute to the mechanism of sex/gender disparity in the outcome and progression of hepatitis viruses infection.
Wnt signaling is a key regulator of development that is often associated with cancer. Wingless, a Drosophila Wnt homolog, has been reported to be a survival factor in wing imaginal discs. However, we ...found that prospective wing cells survive in the absence of Wingless as long as they are not surrounded by Wingless-responding cells. Moreover, local autonomous overactivation of Wg signaling (as a result of a mutation in APC or axin) leads to the elimination of surrounding normal cells. Therefore, relative differences in Wingless signaling lead to competitive cell interactions. This process does not involve Myc, a well-established cell competition factor. It does, however, require Notum, a conserved secreted feedback inhibitor of Wnt signaling. We suggest that Notum could amplify local differences in Wingless signaling, thus serving as an early trigger of Wg signaling-dependent competition.
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► Wingless-blind cells survive within large groups but die as part of small clones ► Patches of APC or axin mutant cells trigger apoptosis in surrounding normal cells ► The competitive nature of axin mutant cells is not mediated by Myc ► Tissue takeover by axin cells requires Notum, a secreted inhibitor of Wg signaling
Introducción: La industria acuícola está en constante crecimiento, registrando una producción mundial de casi 88 millones de toneladas para el año 2020. Esta industria trae consigo problemas ...ambientales si sus efluentes no son debidamente tratados. En el 2020, se constituyó la primera empresa de base tecnológica del CONICET en la Patagonia Argentina cuyo propósito es la producción acuícola del erizo verde de mar, Arbacia dufresnii con la finalidad de elaborar una gama de productos nutracéuticos. Su sistema de cultivo conlleva un compromiso de sustentabilidad desde su creación, y sin embargo genera efluentes con niveles altos de nitratos y fosfatos. Objetivo: Ante este escenario, y valorizando la biorremediación como herramienta de tratamiento de aguas, se propone en este trabajo la utilización de las microalgas marinas como agentes fitorremediadores del efluente acuícola. Métodos: Se utilizaron las microalgas Chaetoceros gracilis, Navicula sp., Tetraselmis suecica., Rhodomona salina., Nanochloropsis galvana y Cylindrotheca closterium, las cuales son usadas como alimento de las larvas del erizo en el proceso productivo. Se diseñó un experimento que compara el crecimiento microalgal y la capacidad de remoción de los nutrientes en el efluente en contraste con el medio de cultivo artificial actualmente usado en el ciclo productivo. Resultados: Es posible remediar el efluente de la industria acuícola mediante las microalgas seleccionadas, con porcentaje de eficacia de remoción del 100 % del nitrato y un porcentaje de eficacia de remoción promedio de 50 % para todas las microalgas testeadas. Asimismo, se obtuvieron valores de biomasa microalgal significativamente mayores cuando el cultivo fue realizado en el efluente respecto del cultivo en el medio artificial. Conclusiones: Los avances en investigación proporcionados en este trabajo ponen de manifiesto que es posible el aprovechamiento de un descarte para cultivar las microalgas, incluso mejorando la productividad microalgal para su uso como alimento, disminuyendo los costos involucrados en el sector de producción microalgal cambiando el uso del tipo de medio de cultivo actual (F/2) por el proveniente de un descarte. Estos avances si son escalados y validados, pueden mejorar los estándares de sustentabilidad de la industria en el marco de una economía circular.
Background
The treatment of high‐risk neuroblastoma continues to present a formidable challenge to pediatric oncology. Previous studies have shown that Bromodomain and extraterminal (BET) inhibitors ...can inhibit MYCN expression and suppress MYCN‐amplified neuroblastoma in vivo. Furthermore, alterations within RAS‐MAPK (mitogen‐activated protein kinase) signaling play significant roles in neuroblastoma initiation, maintenance, and relapse, and mitogen‐activated extracellular signal‐regulated kinase (MEK) inhibitors demonstrate efficacy in subsets of neuroblastoma preclinical models. Finally, hyperactivation of RAS‐MAPK signaling has been shown to promote resistance to BET inhibitors. Therefore, we examined the antitumor efficacy of combined BET/MEK inhibition utilizing I‐BET726 or I‐BET762 and trametinib in high‐risk neuroblastoma.
Procedure
Utilizing a panel of genomically annotated neuroblastoma cell line models, we investigated the in vitro effects of combined BET/MEK inhibition on cell proliferation and apoptosis. Furthermore, we evaluated the effects of combined inhibition in neuroblastoma xenograft models.
Results
Combined BET and MEK inhibition demonstrated synergistic effects on the growth and survival of a large panel of neuroblastoma cell lines through augmentation of apoptosis. A combination therapy slowed tumor growth in a non‐MYCN–amplified, NRAS‐mutated neuroblastoma xenograft model, but had no efficacy in an MYCN‐amplified model harboring a loss‐of‐function mutation in NF1.
Conclusions
Combinatorial BET and MEK inhibition was synergistic in the vast majority of neuroblastoma cell lines in the in vitro setting but showed limited antitumor activity in vivo. Collectively, these data do not support clinical development of this combination in high‐risk neuroblastoma.
Neuroblastoma is treated with aggressive multimodal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to ...hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition.
We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse microscopy, and xenograft studies.
Sensitivity to binimetinib and ribociclib was inversely related (
= -0.58,
= 0.009).
amplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell-cycle progression that was reversible upon removal of drugs.
Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed high-risk neuroblastoma patients, with focus on cases with hyperactivated RAS-MAPK signaling.
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The growing population of failing single‐ventricle (SV) patients might benefit from ventricular assist device (VAD) support as a bridge to heart transplantation. However, the documented experience is ...limited to isolated case reports. Considering the complex and different physiopathology of Norwood, Glenn, and Fontan patients and the lack of established experience, the aim of this work is to realize and test a lumped parameter model of the cardiovascular system able to simulate SV hemodynamics and VAD implantation effects to support clinical decision. Hemodynamic and echocardiographic data of 30 SV patients (10 Norwood, 10 Glenn, and 10 Fontan) were retrospectively collected and used to simulate patients' baseline. Then, the effects of VAD implantation were simulated. Simulation results suggest that the implantation of VAD: (i) increases the cardiac output and the mean arterial systemic pressure in all the three palliation conditions (Norwood 77.2 and 19.7%, Glenn 38.6 and 32.2%, and Fontan 17.2 and 14.2%); (ii) decreases the SV external work (Norwood 55%, Glenn 35.6%, and Fontan 41%); (iii) decreases the pressure pulsatility index (Norwood 65.2%, Glenn 81.3%, and Fontan 64.8%); (iv) increases the pulmonary arterial pressure in particular in the Norwood circulation (Norwood 39.7%, Glenn 12.1% and Fontan 3%); and (v) decreases the atrial pressure (Norwood 2%, Glenn 10.6%, and Fontan 8.6%). Finally, the VAD work is lower in the Norwood circulation (30.4 mL·mm Hg) in comparison with Fontan (40.3 mL·mm Hg) and to Glenn (64.5 mL·mm Hg) circulations. The use of VAD in SV physiology could be helpful to bridge patients to heart transplantations by increasing the CO and unloading the SV with a decrement of the atrial pressure and the SV external work. The regulation of the pulmonary flow is challenging because the Pap is increased by the presence of VAD. The hemodynamic changes are different in the different SV palliation step. The use of numerical models could be helpful to support patient and VAD selection to optimize the clinical outcome.
To evaluate the efficacy of discoid resection for the treatment of deep infiltrating endometriosis and whether it could be considered to be a valid alternative to the rectosigmoid segmental ...resection.
Case-control study.
Departments of Obstetrics and Gynecology, Ospedale Sacro Cuore of Negrar, Verona, and Catholic University of the Sacred Heart, Rome, Italy.
Women with deep infiltrating and intestinal endometriosis divided into study group (48 patients) and control group (88 patients).
All patients underwent laparoscopic endometriosis excision plus discoid rectosigmoid resection (study group) or segmental resection (control group).
Short- and long-term outcomes.
In the study group, median operating time was 200 minutes, with a median estimated blood loss of 203 mL. Median ileus was 3 days with a median postoperative hospitalization of 7 days. Early complications were observed in six patients (12.5%), and in two of them (4.16%) a surgical management was necessary. Median follow-up period was 33 months, and five recurrences (10.4%) were registered. In the control group, no significant differences were noticed except for longer operative time, more temporary ileostomy, postoperative fever, and long-term bladder dysfunctions.
Laparoscopic mechanical discoid resection is feasible, markedly improved endometriosis related symptoms, and could be considered as a worthy alternative to classic segmental resection in selected patients.
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