The bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease.

Multiple myeloma (MM) is an osteolytic malignancy that is incurable due to the emergence of treatment resistant disease. Defining how, when and where myeloma cell intrinsic and extrinsic bone microenvironmental mechanisms cause relapse is challenging with current biological approaches. Here, we report a biology-driven spatiotemporal hybrid agent-based model of the MM-bone microenvironment. Results indicate MM intrinsic mechanisms drive the evolution of treatment resistant disease but that the protective effects of bone microenvironment mediated drug resistance (EMDR) significantly enhances the probability and heterogeneity of resistant clones arising under treatment. Further, the model predicts that targeting of EMDR deepens therapy response by eliminating sensitive clones proximal to stroma and bone, a finding supported by in vivo studies. Altogether, our model allows for the study of MM clonal evolution over time in the bone microenvironment and will be beneficial for optimizing treatment efficacy so as to significantly delay disease relapse.

The impact of interaction between verteporfin and yes-associated protein 1/transcriptional coactivator with PDZ-binding motif-TEA domain pathway on the progression of isocitrate dehydrogenase wild-type glioblastoma.

Verteporfin and 5-ALA are used for visualizing malignant tissue components in different body tumors and as photodynamic therapy in treating isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM). Additionally, verteporfin interferes with Yes-associated protein 1 (YAP)/Transcriptional coactivator with PDZ-binding motif - TEA domain (TAZ-TEAD) pathway, thus inhibiting the downstream effect of these oncogenes and reducing the malignant properties of GBM. Animal studies have shown verteporfin to be successful in increasing survival rates, which have led to the conduction of phase 1 and 2 clinical trials to further investigate its efficacy in treating GBM. In this article, we aimed to review the novel mechanism of verteporfin's action, the impact of its interaction with YAP/TAZ-TEAD, its effect on glioblastoma stem cells, and its role in inducing ferroptosis.

How circulating tumor cluster biology contributes to the metastatic cascade: from invasion to dissemination and dormancy.

Circulating tumor cells (CTCs) are known to be prognostic for metastatic relapse and are detected in patients as solitary cells or cell clusters. Circulating tumor cell clusters (CTC clusters) have been observed clinically for decades and are of significantly higher metastatic potential compared to solitary CTCs. Recent studies suggest distinct differences in CTC cluster biology regarding invasion and survival in circulation. However, differences regarding dissemination, dormancy, and reawakening require more investigations compared to solitary CTCs. Here, we review the current state of CTC cluster research and consider their clinical significance. In addition, we discuss the concept of collective invasion by CTC clusters and molecular evidence as to how cluster survival in circulation compares to that of solitary CTCs. Molecular differences between solitary and clustered CTCs during dormancy and reawakening programs will also be discussed. We also highlight future directions to advance our current understanding of CTC cluster biology.

Comparing The Effects of Botulinum toxin-A and multiple surgical parasympathectomy on treatment of allergic rhinitis.

OBJECTIVE: Allergic rhinitis (AR) is a common disease with a recent increasing in prevalence. Traditional treatment strategies of AR, sometimes, show limited effectiveness and side effects. Intranasal injection of Botulinum toxin type A (BTX-A) and multiple postganglionic parasympathectomy of pterygopalatine ganglion (PPG) are among the increasingly used alternative treatment options of AR. In this study, we compared the early efficacy of BTX-A and multiple surgical parasympathectomy (MSP) on treatment of uncontrolled AR. METHODS: Sixty patients who were diagnosed with uncontrolled AR, were recruited to the study. Participants randomly underwent either intranasal injection of BTX-A (45 IU in each nostril) (Group A) or bilateral MSP (Group B). All patients were evaluated in terms of nasal hypersecretions, congestion and sneezing with visual analogue scale prior to treatment and at weeks 1, 2, 4, 8, 12 and 6 months during the follow-up period. RESULTS: A significant difference in the degree of nasal hypersecretions and sneezing could be identified in both groups before and after the interventions. Although the significant efficacy on sneezing was documented in group A and B only in the first 4 and 8 weeks, respectively, such efficacy on nasal hypersecretions extended for 12 weeks in group A and throughout the follow-up period in group B. Nasal congestion did not differ significantly in both groups. CONCLUSION: Both BTX-A and MSP, in patients with uncontrolled AR, may be a long-lasting therapeutic option for the treatment of nasal hypersecretions, but not as effective as for sneezing and nasal congestion.

Evaluation of Retention and Attachment Wear of CAD/CAM Versus Conventional Implant-Assisted Overdenture Frameworks.

Previous studies have demonstrated problems with implant-supported overdenture attachments, such as denture base fracture and retention loss of the attachment's nylon insert. In this study, three implants were surgically inserted at the anterior mandibular region of 16 completely edentulous men (mean age: 50 years), divided into two groups depending on the received mandibular complete overdenture: a conventional metal-reinforced framework with prefabricated metal housing (Group I) or a CAD/CAM metal-reinforced framework with custom metal housing (Group II). At 3 months (prostheses loading), 6 months, and 12 months after implant placement, the retention of the mandibular dentures and wear of O-ring attachments were evaluated. Data were collected, tabulated, and statistically analyzed using Student t test. Statistically significant differences were found between the two groups and within the same groups during the evaluation period (P < .05). Attachment housing incorporated within a CAD/CAM implant overdenture can be a better alternative to the manufacturer's metal housing, as it diminishes retention loss and attachment wear over time, thus increasing patient satisfaction and chewing efficiency.

A role for Rad5 in ribonucleoside monophosphate (rNMP) tolerance.

Ribonucleoside monophosphate (rNMP) incorporation in genomic DNA poses a significant threat to genomic integrity. In addition to repair, DNA damage tolerance mechanisms ensure replication progression upon encountering unrepaired lesions. One player in the tolerance mechanism is Rad5, which is an E3 ubiquitin ligase and helicase. Here, we report a new role for yeast Rad5 in tolerating rNMP incorporation, in the absence of the bona fide ribonucleotide excision repair pathway via RNase H2. This role of Rad5 is further highlighted after replication stress induced by hydroxyurea or by increasing rNMP genomic burden using a mutant DNA polymerase (Pol ε - Pol2-M644G). We further demonstrate the importance of the ATPase and ubiquitin ligase domains of Rad5 in rNMP tolerance. These findings suggest a similar role for the human Rad5 homologues helicase-like transcription factor (HLTF) and SNF2 Histone Linker PHD RING Helicase (SHPRH) in rNMP tolerance, which may impact the response of cancer cells to replication stress-inducing therapeutics.

Between an ugly truth and a perfect lie: Wiping off fearful memories using beta-adrenergic receptors antagonists.

Psychiatric disorders such as anxiety, phobias, and post-traumatic stress disorder are considered of high global prevalence. Currently, a therapeutic approach to treat these disorders using beta-blockers, which antagonize the beta-adrenergic receptors (B1, B2, and B3) is being studied. This approach claims that beta-blockers, such as propranolol, inhibit fear memory reconsolidation. However, there are several studies refuting such claims by discrediting their experimental design and pointing out both the drugs pharmacokinetic properties and confounding factors. In this review, we explore the different effects of central beta-adrenergic agonists and antagonists on the fear memory consolidation providing mixed-evidence, limitations, and future directions.

Resistance of primary breast cancer cells with enhanced pluripotency and stem cell activity to sex hormonal stimulation and suppression.

Female sex steroid hormones have a fundamental role in breast cancer. Meanwhile, current evidence supports the contribution of breast cancer stem cells in carcinogenesis, metastasis, and resistance to cytotoxic chemotherapy. Nevertheless, the interaction between breast cancer stem cells with sex hormones or key hormonal antagonists remains elusive. OBJECTIVE: To investigate the effect of diverse sex hormonal stimulation and suppression regimens on the proliferation of a primary human breast cancer cells with stem cell activity. METHODS: Cells were exposed to estradiol, progesterone, letrozole, ulipristal acetate, or a combination of ulipristal acetate-letrozole, continually for 6 months. Additionally, nanoparticle-linked letrozole and ulipristal acetate formulations were included in a subsequent short-term exposure study. Phenotypic, pathologic, and functional characteristics of unexposed cells were investigated. RESULTS: The proliferation of breast cancer cells was comparable among all hormonal stimulation and suppression groups (P= 0.8). In addition, the nanoparticle encapsulated hormonal antagonists were not able to overcome the observed resistance of cells. Cell characterization showed a mesenchymal-like phenotype overexpressing three master pluripotency markers (Oct 4, SOX2, and Nanog), and 92% of cells were expressing ALDH1A1. Notably, the CD44 high/CD24 low cell population presented only 0.97%-5.4% over repeat analyses. Most cells lacked the expression of mesenchymal markers; however, they showed differentiation into osteogenic and adipogenic lineages. Upon transfer to serum-free culture, the long-term maintained mesenchymal-like cancer cells showed remarkable morphologic plasticity as they switched promptly into an epithelial-like phenotype with significant mammosphere formation capacity (P= 0.008). CONCLUSION: Breast cancer cells can develop a pluripotent program with enhanced stemness activity that may together contribute to universal resistance to sex hormonal stimulation or deprivation. Isolation and characterization of patient-derived breast cancer stem cells in large clinical studies is therefore crucial to identify new targets for endocrine therapies, potentially directed towards stemness and pluripotency markers. Such direction may help overcoming endocrine resistance and draw attention to breast cancer stem cells' behaviour under endogenous and exogenous sex hormones throughout a woman's reproductive life.

Recent advances in stem cells therapy: A focus on cancer, Parkinson's and Alzheimer's.

Stem cells serve as potential therapeutics due to their high proliferative capacity, low immunogenic reactivity and their differentiating capabilities. Several pre-clinical and early-stage clinical studies are carried out to treat genetic diseases, cancers and neurodegenerative disorders with promising preliminary results. However, there are still many challenges that scientists are trying to overcome such as the unclear expression profile of stem cells in vivo, the homing of stem cells to the site of injury and their potential immune-reactivity. Prospective research lies in gene editing of autologous stem cells in vitro and safe injection of these modified cells back into patients. Here, we review the clinical trials executed using stem cell therapy in an attempt to cure challenging diseases like cancer, Parkinson's and Alzheimer's diseases.