Preserved White Matter Integrity and Recovery After Brain Tumor Surgery: A Prospective Pilot Study on the Frontal Aslant Tract.

Introduction: Damage to white matter tracts can cause severe neurological deficits, which are often hardly predictable before brain tumor surgery. To explore the possibility of assessing white matter integrity and its preservation, we chose the frontal aslant tract (FAT) due to its involvement in multiple neurological functions such as speech and movement initiation. Methods: Right-handed patients with left hemispheric intracerebral tumors underwent FAT tractography within 7 days before and 3 days after surgery. Neurological performance score and aphasia score were assessed within 7 days before and after surgery, as well as at follow-up 3 months postoperatively. Results: Fifteen patients were prospectively analyzed. After multivariate analysis and receiver operating characteristic analysis, we found that preoperative fractional anisotropy (FA) of the left FAT indicated the preoperative aphasia score (cutoff 0.40, p = 0.015). Aphasia scores 3 months postoperatively were predicted by both postoperative FA of the left FAT (cutoff 0.35, p = 0.005) and postoperatively preserved FA of the left FAT (cutoff 95.8%, p = 0.017). Postoperatively preserved right FAT FA inversely predicted postoperative aphasia score (cutoff 95.1%, p = 0.016). Discussion: Assessment of white matter integrity preservation is possible and correlates with outcome after brain tumor surgery. It may be useful for patient counseling and assessment of rehabilitation potential, as well as to investigate relevant brain networks in the future. Clinical Trial Registration: The trial was prospectively registered at ClinicalTrials.gov (NCT04302857).

Assessment of a Reliable Fractional Anisotropy Cutoff in Tractography of the Corticospinal Tract for Neurosurgical Patients.

BACKGROUND: Tractography has become a standard technique for planning neurosurgical operations in the past decades. This technique relies on diffusion magnetic resonance imaging. The cutoff value for the fractional anisotropy (FA) has an important role in avoiding false-positive and false-negative results. However, there is a wide variation in FA cutoff values. METHODS: We analyzed a prospective cohort of 14 patients (six males and eight females, 50.1 ± 4.0 years old) with intracerebral tumors that were mostly gliomas. Magnetic resonance imaging (MRI) was obtained within 7 days before and within 7 days after surgery with T1 and diffusion tensor image (DTI) sequences. We, then, reconstructed the corticospinal tract (CST) in all patients and extracted the FA values within the resulting volume. RESULTS: The mean FA in all CSTs was 0.4406 ± 0.0003 with the fifth percentile at 0.1454. FA values in right-hemispheric CSTs were lower (p < 0.0001). Postoperatively, the FA values were more condensed around their mean (p < 0.0001). The analysis of infiltrated or compressed CSTs revealed a lower fifth percentile (0.1407 ± 0.0109 versus 0.1763 ± 0.0040, p = 0.0036). CONCLUSION: An FA cutoff value of 0.15 appears to be reasonable for neurosurgical patients and may shorten the tractography workflow. However, infiltrated fiber bundles must trigger vigilance and may require lower cutoffs.

A late systemic and brain metastasis from subcutaneous leiomyosarcoma of the right forearm: a case report and review of the literature.

BACKGROUND: Leiomyosarcomas are rare malignant tumors which originate from smooth muscle cells and very seldom give rise to intracerebral metastases. Nearly all cases of intracranial metastases stem from leiomyosarcomas of the uterus. We present a 61-year-old Caucasian man who developed multiple intracranial and extracranial metastases from leiomyosarcoma of the right forearm, diagnosed and treated 9 years before the current presentation. CASE PRESENTATION: The Caucasian patient presented to the emergency department due to a progressive hemiparesis on the left side. Magnetic resonance imaging scans of the neurocranium showed multiple intracerebral masses with perifocal edema. One of these was located in the right parietal lobe, corresponding to the hemiparesis. The patient underwent microsurgical complete resection of the parietal mass and was subsequently subjected to further radiotherapy. Histopathological studies revealed metastasis of the former leiomyosarcoma. CONCLUSIONS: Leiomyosarcomas represent a rare entity of mesenchymal tumors. Intracerebral metastasis of these tumors is even less frequent. This case shows the importance of long-term follow-up in patients with leiomyosarcoma.

PTPIP51 crosslinks the NFκB signaling and the MAPK pathway in SKBR3 cells.

AIM: PTPIP51 interacts with NFκB signaling at the RelA and IκB level. NFκB signaling is linked to the initiation, progression and metastasis of breast cancer. Her2-amplified breast cancer cells frequently display activation of the NFκB signaling. We aimed to clarify the effects of NFκB inhibition on the NFκB- and MAPK-related interactome of PTPIP51 and cell viability in HaCat cells and SKBR3 cells. RESULTS: IKK-16 selectively reduced cell viability in SKBR3 cells. PDTC induced a formation of the Raf1/14-3-3/PTPIP51 complex in SKBR3 cells, indicating a shift of PTPIP51 into MAPK signaling. CONCLUSION: IKK-16 selectively inhibits cell viability of SKBR3 cells. In addition, PTPIP51 might serve as the mediator between NFκB signaling and the MAPK pathway in SKBR3.

Crosstalks of the PTPIP51 interactome revealed in Her2 amplified breast cancer cells by the novel small molecule LDC3/Dynarrestin.

LDC3/Dynarrestin, an aminothiazole derivative, is a recently developed small molecule, which binds protein tyrosine phosphatase interacting protein 51 (PTPIP51). PTPIP51 interacts with various proteins regulating different signaling pathways leading to proliferation and migration. Her2 positive breast cancer cells (SKBR3) express high levels of PTPIP51. Therefore, we investigated the effects of LDC3/Dynarrestin on PTPIP51 and its interactome with 12 different proteins of various signal pathways including the interaction with dynein in SKBR3 cells. The localization and semi-quantification of PTPIP51 protein and the Tyr176 phosphorylated PTPIP51 protein were evaluated. Protein-protein-interactions were assessed by Duolink proximity ligation assays. Interactions and the activation of signal transduction hubs were examined with immunoblots. LDC3/Dynarrestin led to an increased PTPIP51 tyrosine 176 phosphorylation status while the overall amount of PTPIP51 remained unaffected. These findings are paralleled by an enhanced interaction of PTPIP51 with its crucial kinase c-Src and a reduced interaction with the counteracting phosphatase PTP1B. Furthermore, the treatment results in a significantly augmented interaction of PTPIP51/14-3-3ß and PTPIP51/Raf1, the link to the MAPK pathway. Under the influence of LDC3/Dynarrestin, the activity of the MAPK pathway rose in a concentration-dependent manner as indicated by RTK assays and immunoblots. The novel small molecule stabilizes the RelA/IκB/PTPIP51 interactome and can abolish the effects caused by TNFα stimulation. Moreover, LDC3/Dynarrestin completely blocked the Akt signaling, which is essential for tumor growth. The data were compared to the recently described interactome of PTPIP51 in LDC3/Dynarrestin treated non-cancerous keratinocyte cells (HaCaT). Differences were identified exclusively for the mitochondrial-associated ER-membranes (MAM) interactions and phospho-regulation related interactome of PTPIP51.LDC3/Dynarrestin gives the opportunity/possibility to influence the MAPK signaling, NFkB signaling and probably calcium homeostasis in breast cancer cells by affecting the PTPIP51 interactome.

The Importance of the Right Framework: Mitogen-Activated Protein Kinase Pathway and the Scaffolding Protein PTPIP51.

The protein tyrosine phosphatase interacting protein 51 (PTPIP51) regulates and interconnects signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway and an abundance of different others, e.g., Akt signaling, NF-κB signaling, and the communication between different cell organelles. PTPIP51 acts as a scaffold protein for signaling proteins, e.g., Raf-1, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (Her2), as well as for other scaffold proteins, e.g., 14-3-3 proteins. These interactions are governed by the phosphorylation of serine and tyrosine residues of PTPIP51. The phosphorylation status is finely tuned by receptor tyrosine kinases (EGFR, Her2), non-receptor tyrosine kinases (c-Src) and the phosphatase protein tyrosine phosphatase 1B (PTP1B). This review addresses various diseases which display at least one alteration in these enzymes regulating PTPIP51-interactions. The objective of this review is to summarize the knowledge of the MAPK-related interactome of PTPIP51 for several tumor entities and metabolic disorders.

Effectiveness of EGFR/HER2-targeted drugs is influenced by the downstream interaction shifts of PTPIP51 in HER2-amplified breast cancer cells.

Breast cancer is the most common female cancerous disease and the second most cause of cancer death in women. About 20-30% of these tumors exhibit an amplification of the HER2/ErbB2 receptor, which is coupled to a more aggressive and invasive growth of the cancer cells. Recently developed tyrosine kinase inhibitors and therapeutic antibodies targeting the HER2 receptor improved the overall survival time compared with sole radio- and chemotherapy. Upcoming resistances against the HER2-targeted therapy make a better understanding of the receptor associated downstream pathways an absolute need. In earlier studies, we showed the involvement of Protein Tyrosine Phosphatase Interacting Protein 51 (PTPIP51) in the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is one of the most frequently overactivated pathways in HER2-amplified breast cancer cells. This study is aimed to elucidate the effects of four different TKIs on the interactome of PTPIP51, namely with the receptors EGFR and HER2, 14-3-3/Raf1 (MAPK pathway), its regulating enzymes, and the mitochondria-associated interaction partners in HER2 breast cancer cell lines (SK-BR3 and BT474) by using the Duolink proximity ligation assay, immunoblotting and knockdown of PTPIP51. Inhibition of both EGFR and HER2/ErbB2R shifted PTPIP51 into the MAPK pathway, but left the mitochondria-associated interactome of PTPIP51 unattended. Exclusively inhibiting HER2/ErbB2 by Mubritinib did not affect the interaction of PTPIP51 with the MAPK signaling. Selective inhibition of HER2 induced great alterations of mitochondria-associated interactions of PTPIP51, which ultimately led to the most-effective reduction of cell viability of SK-BR3 cells of all tested TKIs. The results clearly reveal the importance of knowing the exact mechanisms of the inhibitors affecting receptor tyrosine kinases in order to develop more efficient anti-HER2-targeted therapies.

Altered Protein Interactions of the Endogenous Interactome of PTPIP51 towards MAPK Signaling.

Protein-protein interactions play a pivotal role in normal cellular functions as well as in carcinogenesis. The protein-protein interactions form functional clusters during signal transduction. To elucidate the fine calibration of the protein-protein interactions of protein tyrosine phosphatase interacting protein 51 (PTPIP51) a small molecule drug, namely LDC-3, directly targeting PTPIP51 is now available. Therefore, LDC-3 allows for the studying of the regulation of the endogenous interactome by modulating PTPIP51 binding capacity. Small interfering ribonucleic acid (siRNA) experiments show that the modification in PTPIP51 binding capacity is induced by LDC-3. Application of LDC-3 annuls the known regulatory phosphorylation mechanisms for PTPIP51 and consequently, significantly alters the assembly of the PTPIP51 associated protein complexes. The treatment of human keratinocytes (HaCaT cells) with LDC-3 induces an altered protein-protein interaction profile of the endogenous interactome of PTPIP51. In addition, LDC-3 stabilizes PTPIP51 within a mitogen activated protein kinase (MAPK) complex composed of Raf-1 and the scaffold protein 14-3-3, independent of the phosphorylation status of PTPIP51. Of note, under LDC-3 treatment the regulatory function of the PTP1B on PTPIP51 fails to impact the PTPIP51 interaction characteristics, as reported for the HaCaT cell line. In summary, LDC-3 gives the unique opportunity to directly modulate PTPIP51 in malignant cells, thus targeting potential dysregulated signal transduction pathways such as the MAPK cascade. The provided data give critical insights in the therapeutic potential of PTPIP51 protein interactions and thus are basic for possible targeted therapy regimens.