Invasive growth associated with cold-inducible RNA-binding protein expression drives recurrence of surgically resected brain metastases.

BACKGROUND: Sixty percent of surgically resected brain metastases (BrM) recur within 1 year. These recurrences have long been thought to result from the dispersion of cancer cells during surgery. We tested the alternative hypothesis that invasion of cancer cells into the adjacent brain plays a significant role in local recurrence and shortened overall survival. METHODS: We determined the invasion pattern of 164 surgically resected BrM and correlated with local recurrence and overall survival. We performed single-cell RNA sequencing (scRNAseq) of >15,000 cells from BrM and adjacent brain tissue. Validation of targets was performed with a novel cohort of BrM patient-derived xenografts (PDX) and patient tissues. RESULTS: We demonstrate that invasion of metastatic cancer cells into the adjacent brain is associated with local recurrence and shortened overall survival. scRNAseq of paired tumor and adjacent brain samples confirmed the existence of invasive cancer cells in the tumor-adjacent brain. Analysis of these cells identified cold-inducible RNA-binding protein (CIRBP) overexpression in invasive cancer cells compared to cancer cells located within the metastases. Applying PDX models that recapitulate the invasion pattern observed in patients, we show that CIRBP is overexpressed in highly invasive BrM and is required for efficient invasive growth in the brain. CONCLUSIONS: These data demonstrate peritumoral invasion as a driver of treatment failure in BrM that is functionally mediated by CIRBP. These findings improve our understanding of the biology underlying postoperative treatment failure and lay the groundwork for rational clinical trial development based upon invasion pattern in surgically resected BrM.

Localization of Hand and Wrist Anatomic Structures Among Physical Medicine and Rehabilitation Residents: Implication of Ultrasonography in Palpation Skill Verification.

Objective: The objective of this cross-sectional study is to evaluate the accuracy of physical medicine and rehabilitation (PM&R) resident palpation skills of hand and wrist joint and soft tissue structures using ultrasonography (US) verification. Methods: PM&R residents palpated hand and wrist anatomic structures in an outpatient musculoskeletal (MSK) clinic. Once the presumed structures were localized, residents marked a one centimeter size circle on the overlying skin with an ink marker. The accuracy of the circle over the joint line and soft tissue structures was verified using US. Results: Overall palpation accuracy for 16 joint line and soft tissue structures was 40.6%. There was no significant difference in palpation accuracy with advanced educational level (37.5% in PGY-2, 33.8% in PGY-3, 50% in PGY-4, p = 0.12). The percentage of combined accurate palpation and less than one centimeter error in accurate palpation revealed a significant improvement along the advancement of PGY training (50%, 61.3%, 69.8% in PGY-2, 3, 4 respectively, p = 0.01). Conclusions: This study demonstrated an overall suboptimal accuracy of hand and wrist palpation skills by PM&R residents and a need to improve palpation skills among PM&R residents.

Inhibition of glioblastoma cell proliferation, invasion, and mechanism of action of a novel hydroxamic acid hybrid molecule.

Glioblastoma multiforme is one of the most aggressive brain tumors and current therapies with temozolomide or suberoylanilide hydroxamic acid (SAHA, vorinostat) show considerable limitations. SAHA is a histone deacetylase (HDAC) inhibitor that can cause undesirable side effects due to the lack of selectivity. We show here properties of a novel hybrid molecule, sahaquine, which selectively inhibits cytoplasmic HDAC6 at nanomolar concentrations without markedly suppressing class I HDACs. Inhibition of HDAC6 leads to significant α-tubulin acetylation, thereby impairing cytoskeletal organization in glioblastoma cells. The primaquine moiety of sahaquine reduced the activity of P-glycoprotein, which contributes to glioblastoma multiforme drug resistance. We propose the mechanism of action of sahaquine to implicate HDAC6 inhibition together with suppression of epidermal growth factor receptor and downstream kinase activity, which are prominent therapeutic targets in glioblastoma multiforme. Sahaquine significantly reduces the viability and invasiveness of glioblastoma tumoroids, as well as brain tumor stem cells, which are key to tumor survival and recurrence. These effects are augmented with the combination of sahaquine with temozolomide, the natural compound quercetin or buthionine sulfoximine, an inhibitor of glutathione biosynthesis. Thus, a combination of agents disrupting glioblastoma and brain tumor stem cell homeostasis provides an effective anti-cancer intervention.

Spirulina maxima peptides suppress mast cell degranulation via inactivating Akt and MAPKs phosphorylation in RBL-2H3 cells.

In this study, the suppressive effects of peptides P1 (LDAVNR) and P2 (MMLDF) from enzymatic hydrolysate of Spirulina maxima on mast cell degranulation was elucidated. It was revealed that P1 and P2 exhibited significant inhibition on cell degranulation via decreasing ß-hexosaminidase release at concentration of 200 µM. Moreover, the inhibitory effects of P1 and P2 on expression and production of interleukin (IL)-13 were evidenced. Furthermore, peptide treatment caused a remarkable inhibition on the phosphorylation of Akt and mitogen-activated protein kinases (MAPKs) including ERK, p38, and JNK. Notably, the inhibitory activity of P1 on cell degranulation was found due to blockade of FcεRI receptor. Meanwhile, the inhibitory activity of P2 was involved in alleviation of intracellular reactive oxygen species (ROS) production. Collectively, peptides P1 and P2 from S. maxima were suggested to be promising inhibitors of mast cell degranulation, contributing to the development of bioactive ingredients for amelioration of allergic diseases.

The Role of Pelvic Floor Muscle Training in the Conservative and Surgical Management of Female Stress Urinary Incontinence: Does the Strength of the Pelvic Floor Muscles Matter?

The purpose of this review is to provide an in-depth overview of the role of pelvic floor muscle (PFM) training in the management of stress urinary incontinence (SUI). The definition, epidemiology, and pathogenesis of SUI are described. We review the anatomy of the PFM and the importance of PFM strength in maintaining urinary continence and establishing normal voiding function. A brief description of the surgical options currently available for SUI and the existing data regarding the role of perioperative PFM training for SUI are included. Critical research questions to better evaluate and assess PFM training during the perioperative period are proposed. Promising novel approaches in the treatment of SUI are also presented. This review is useful for physiatrists, urogynecologists, female urologists, and nurse practitioners who specialize in the management and treatment of women with SUI. LEVEL OF EVIDENCE: IV.

Inhibition of carbonic anhydrase IX in glioblastoma multiforme.

Carbonic anhydrase IX (CAIX) is a transmembrane enzyme upregulated in several types of tumors including glioblastoma multiforme (GBM). GBM is among the most aggressive tumors among gliomas. Temozolomide (TMZ) therapy combined with surgical or radiation approaches is the standard treatment but not effective in long term. In this study we tested the treatment with acetazolamide (ATZ), an inhibitor of CAIX, alone or combined with TMZ. The experiments were performed in 2D and 3D cultures (spheroids) using glioblastoma U251N and human brain tumor stem cells (BTSCs). Several proteins implicated in tumor cell death were also investigated. The key results from these studies suggest the following: (1) Cell death of human glioblastoma spheroids and BTSC is significantly increased with combined treatment after 7 days, and (2) the effectiveness of ATZ is significantly enhanced against BTSC and U251N when incorporated into nano-carriers. Collectively, these results point toward the usefulness of nano-delivery of CAIX inhibitors and their combination with chemotherapeutics for glioblastoma treatment.

Is Genicular Nerve Radiofrequency Ablation Safe? A Literature Review and Anatomical Study.

Genicular nerve radiofrequency ablation (RFA) has recently gained popularity as an intervention for chronic knee pain in patients who have failed other conservative or surgical treatments. Long-term efficacy and adverse events are still largely unknown. Under fluoroscopic guidance, thermal RFA targets the lateral superior, medial superior, and medial inferior genicular nerves, which run in close proximity to the genicular arteries that play a crucial role in supplying the distal femur, knee joint, meniscus, and patella. RFA targets nerves by relying on bony landmarks, but fails to provide visualization of vascular structures. Although vascular injuries after genicular nerve RFA have not been reported, genicular vascular complications are well documented in the surgical literature. This article describes the anatomy, including detailed cadaveric dissections and schematic drawings, of the genicular neurovascular bundle. The present investigation also included a comprehensive literature review of genicular vascular injuries involving those arteries which lie near the targets of genicular nerve RFA. These adverse vascular events are documented in the literature as case reports. Of the 27 cases analyzed, 25.9% (7/27) involved the lateral superior genicular artery, 40.7% (11/27) involved the medial superior genicular artery, and 33.3% (9/27) involved the medial inferior genicular artery. Most often, these vascular injuries result in the formation of pseudoaneurysm, arteriovenous fistula (AVF), hemarthrosis, and/or osteonecrosis of the patella. Although rare, these complications carry significant morbidities. Based on the detailed dissections and review of the literature, our investigation suggests that vascular injury is a possible risk of genicular RFA. Lastly, recommendations are offered to minimize potential iatrogenic complications.

Arabinonucleic acids: 2'-stereoisomeric modulators of siRNA activity.

We have investigated, for the first time, short interfering duplexes containing arabinonucleotides (ANA; the 2'-stereoisomer of RNA), as well as combinations of ANA with RNA, and their 2'-fluorinated derivatives 2F-ANA and/or 2'F-RNA. The results show that ANA is especially well accommodated in the sense strand of small interfering RNA (siRNA) duplexes, which can be extensively modified with little effect on potency. Furthermore, combining ANA with RNA and 2'F-ANA in siRNA passenger strands, particularly in patterns that bias duplex thermal stability, produces duplexes with similar (and sometimes enhanced) potency compared with native siRNA. Effective patterns of modification were identified against firefly luciferase screens in HeLa cells and then applied to knockdown of down-regulated in renal cell carcinoma (DRR), a novel and clinically tractable target for the treatment of glioblastoma.