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Cancer cells-derived extracellular vesicles can trigger the transformation of adipose-derived mesenchymal stem cells (ADMSC) into a pro-inflammatory, cancer-associated adipocyte (CAA) phenotype. Such secretome-mediated crosstalk between the adipose tissue and the tumor microenvironment (TME) therefore impacts tumor progression and metastatic processes. In addition, emerging roles of diet-derived phytochemicals, especially epigallocatechin-3-gallate (EGCG) among other polyphenols, in modulating exosome-mediated metabolic and inflammatory signaling pathways have been highlighted. Here, we discuss how selected diet-derived phytochemicals could alter the secretome signature as well as the crosstalk dynamics between the adipose tissue and the TME, with a focus on breast cancer. Their broader implication in the chemoprevention of obesity-related cancers is also discussed.

Background: Percutaneous intradiscal hydrogel injection has been used to treat low-back pain (LBP) due to degenerative disc disease with or without mild radicular pain. Complications from these procedures are underreported. In this case lesson, the authors present a rare case of a patient with herniated intradiscal hydrogel following a minor trauma leading to neurological injury., Observations: A 36-year-old female who had been previously treated with L4-5 and L5-S1 intradiscal hydrogel injections for LBP presented with painful, progressive right-sided lower-extremity weakness after experiencing a twisting trauma. Cross-sectional imaging results revealed a herniated hydrogel-based disc implant in the spinal canal. She underwent an urgent L4-5 laminectomy for decompression and removal of the herniated implant. A large annular defect was noted. Postoperatively, she had resolution of her right leg pain but experienced persistent right foot drop requiring an ankle-foot orthosis., Lessons: Herniated intradiscal hydrogel implants can lead to permanent neurological injury. While the risk factors for hydrogel herniation have not been elucidated, they can be related to pre-existing disruptions to the annulus and/or posterior longitudinal ligament, excess volume of hydrogel injection, and insufficient fixation time. Further research is needed to determine the safety and efficacy of this technology. https://thejns.org/doi/10.3171/CASE24394.

The origin of primates has long been associated with an increased emphasis on manual grasping and touch. Precision touch, facilitated by specialized mechanoreceptors in glabrous skin, provides critical sensory feedback for grasping-related tasks and perception of ecologically-relevant stimuli. Despite its importance, studies of mechanoreceptors in primate hands are limited, in part due to challenges of sample availability and histological methods. Dermatoglyphs have been proposed as alternative proxies of mechanoreceptor density. We investigated the relationships between mechanoreceptors (Meissner and Pacinian corpuscles), dermatoglyphs, and demography in the apical finger pads of 15 juvenile to adult rhesus macaques (Macaca mulatta) from a free-ranging population at Cayo Santiago Primate Field Station (Puerto Rico). Our results indicate substantial interindividual variation in mechanoreceptor density (Meissner corpuscles: 11.9-43.3 corpuscles/mm 2 ; Pacinian corpuscles: 0-4.5 corpuscles/mm 2 ). While sex and digit were generally not associated with variation, there was strong evidence of a developmental effect. Specifically, apical pad length, Meissner corpuscle size, and Pacinian corpuscle depth increased while mechanoreceptor densities decreased throughout juvenescence, suggesting that primate mechanoreceptors change as fingers grow during adolescence and then stabilize at physical maturity. We also found Meissner corpuscle density was significantly associated with dermatoglyph ridge width and spacing, such that density predicted by a dermatoglyph model was strongly correlated with observed values. Dermatoglyphs thus offer a useful proxy of relative Meissner corpuscle density in primates, which opens exciting avenues of noninvasive research. Finally, our results underscore the importance of considering demographic factors and methodology in comparative studies of primate touch., (© 2024 American Association for Anatomy.)

Mesenchymal stromal/stem cells (MSC) play a crucial role in promoting neovascularization, which is essential for wound healing. They are commonly utilized as an autologous source of progenitor cells in various stem cell-based therapies. However, incomplete MSC differentiation towards a vascular endothelial cell phenotype questions their involvement in an alternative process to angiogenesis, namely vasculogenic mimicry (VM), and the signal transducing events that regulate their in vitro priming into capillary-like structures. Here, human MSC were primed on top of Cultrex matrix to recapitulate an in vitro phenotype of VM. Total RNA was extracted, and differential gene expression assessed through RNA-Seq analysis and RT-qPCR. Transient gene silencing was achieved using specific siRNA. AG490, Tofacitinib, and PP2 pharmacological effects on VM structures were analyzed using the Wimasis software. In vitro VM occurred within 4 h and was prevented by the JAK/STAT3 inhibitors AG490 and Tofacitinib, as well as by the Src inhibitor PP2. RNA-Seq highlighted STAT3 as a signaling hub contributing to VM when transcripts from capillary-like structures were compared to those from cell monolayers. Concomitant increases in IL6, IL1b, CSF1, CSF2, STAT3, FOXC2, RPSA, FN1, and SNAI1 transcript levels suggest the acquisition of a combined angiogenic, inflammatory and epithelial-to-mesenchymal transition phenotype in VM cultures. Increases in STAT3, FOXC2, RPSA, Fibronectin, and Snail protein expression were confirmed during VM. STAT3 and RPSA gene silencing abrogated in vitro VM. In conclusion, in vitro priming of MSC into VM structures requires Src/JAK/STAT3 signaling. This molecular evidence indicates that a clinically viable MSC-mediated pseudo-vasculature process could temporarily support grafts through VM, allowing time for the host vasculature to infiltrate and remodel the injured tissues., (© 2024. The Author(s).)

Glioblastoma (GBM) is a highly angiogenic malignancy of the central nervous system that resists standard antiangiogenic therapy, in part because of an alternative process to angiogenesis termed vasculogenic mimicry. Intricately linked to GBM, dysregulation of the Hippo signaling pathway leads to overexpression of YAP/TEAD and several downstream effectors involved in therapy resistance. Little is known about whether vasculogenic mimicry and the Hippo pathway intersect in the GBM chemoresistance phenotype. This study seeks to investigate the expression patterns of Hippo pathway regulators within clinically annotated GBM samples, examining their involvement in vitro regarding vasculogenic mimicry. In addition, it aims to assess the potential for pharmacological targeting of this pathway. In-silico analysis of the Hippo signaling members YAP1 , TEAD1 , AXL , NF2 , CTGF , and CYR61 transcript levels in low-grade GBM and GBM tumor tissues was done by Gene Expression Profiling Interactive Analysis. Gene expression was analyzed by real-time quantitative PCR from human U87, U118, U138, and U251 brain cancer cell lines and in clinically annotated brain tumor cDNA arrays. Transient gene silencing was performed with specific small interfering RNA. Vasculogenic mimicry was assessed using a Cultrex matrix, and three-dimensional capillary-like structures were analyzed with Wimasis. CYR61 and CTGF transcript levels were elevated in GBM tissues and were further induced when in-vitro vasculogenic mimicry was assessed. Silencing of CYR61 and CTGF , or treatment with a small-molecule TEAD inhibitor LM98 derived from flufenamic acid, inhibited vasculogenic mimicry. Silencing of SNAI1 and FOXC2 also altered vasculogenic mimicry and reduced CYR61 / CTGF levels. Pharmacological targeting of the Hippo pathway inhibits in-vitro vasculogenic mimicry. Unraveling the connections between the Hippo pathway and vasculogenic mimicry may pave the way for innovative therapeutic strategies., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Trigeminal autonomic cephalalgias (TACs) are a group of highly disabling primary headache disorders. Although pharmacological treatments exist, they are not always effective or well tolerated. Occipital nerve stimulation (ONS) is a potentially effective surgical treatment., Objective: To perform a systematic review of the efficacy of ONS in treating TACs., Methods: A systematic review was performed using Medline, Embase, and Cochrane databases. Primary outcomes were reduction in headache intensity, duration, and frequency. Secondary outcomes included adverse event rate and reduction in medication use. Because of large differences in outcome measures, data for patients suffering from short-lasting, unilateral, and neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and cranial autonomic symptoms (SUNA) were reported separately. Risk of bias was assessed using the NIH Quality Assessment Tools., Results: A total of 417 patients from 14 published papers were included in the analysis, of which 15 patients were in the SUNCT/SUNA cohort. The mean reduction in headache intensity and duration was 26.2% and 31.4%, respectively. There was a mean reduction in headache frequency of 50%, as well as a 61.2% reduction in the use of abortive medications and a 31.1% reduction in the use of prophylactic medications. In the SUNCT/SUNA cohort, the mean decrease in headache intensity and duration was 56.8% and 42.8%. The overall responder rate, defined as a >50% reduction in attack frequency, was 60.8% for the non-SUNCT/non-SUNA cohort and 66.7% for the SUNCT/SUNA cohort. Adverse events requiring repeat surgery were reported in 33% of cases. Risk of bias assessment suggests that articles included in this review had reasonable internal validity., Conclusion: ONS may be an effective surgical treatment for approximately two thirds of patients with medically refractory TACs., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Background: Since the emergence of neurosurgery as a distinct specialty ∼100 years ago in Canada, it took >40 years for Canadian women to enter the field in the province of Quebec, and longer in the other provinces., Methods: We provide a historical overview of Canadian women in neurosurgery, from the early pioneers to the modern-day leaders and innovators in the field. We also define the current participation of women in Canadian neurosurgery. Chain-referral sampling, historical books, interviews, personal communications, and online resources were used as data sources., Results: Our historical review highlights the exceptional journey and unique experiences of female neurosurgeons, describes their achievements, and identifies career obstacles and enabling factors. We also incorporate comments from Canadian female neurosurgeons, both retired and in active practice, addressing gender inequities in the field, and provide advice and encouragement to the new generations to come. Despite the achievements of these female trailblazers, women represent a small proportion of the Canadian neurosurgery trainees and the active workforce, in stark contrast to the increasing number of women in medical school., Conclusions: To the best of our knowledge, this study represents the first historical overview of female women neurosurgeons in Canada. Providing a historical context will help us to better understand the important role of women in modern neurosurgery, identify persistent gender issues in the field, and provide a vision for aspiring female neurosurgeons., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Zika virus (ZIKV) has become an epidemic in several countries and was declared a major public health issue by the WHO. Although ZIKV infection is asymptomatic or shows mild fever-related symptoms in most people, the virus can be transmitted from a pregnant mother to the fetus, resulting in severe brain developmental abnormalities, including microcephaly. Multiple groups have identified developmental neuronal and neuronal progenitor compromise during ZIKV infection within the fetal brain, but little is known about whether ZIKV could infect human astrocytes and its effect on the developing brain. Thus, our objective was to determine astrocyte ZiKV infection in a developmental-dependent manner., Methods: We analyze infection of pure cultures of astrocytes and mixed cultures of neurons and astrocytes in response to ZIKV using plaque assays, confocal, and electron microscopy to identify infectivity, ZIKV accumulation and intracellular distribution as well as apoptosis and interorganelle dysfunction., Results: Here, we demonstrated that ZIKV enters, infects, replicates, and accumulates in large quantities in human fetal astrocytes in a developmental-dependent manner. Astrocyte infection and intracellular viral accumulation resulted in neuronal apoptosis, and we propose astrocytes are a ZIKV reservoir during brain development., Conclusions: Our data identify astrocytes in different stages of development as major contributors to the devastating effects of ZIKV in the developing brain., Competing Interests: Competing interests: None., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

We report on an ytterbium-free, erbium-doped single-mode all-fiber laser reaching a record output power of 107 W at 1598 nm, with a slope efficiency of 38.6% according to the absorbed pump power at 981 nm. The erbium-doped gain fiber, co-doped with cerium, aluminum, and phosphorus, was fabricated in-house with adjusted doping concentrations to reduce erbium ions clustering, thereby increasing efficiency while keeping the numerical aperture low to ensure a single-mode laser operation. The addition of cerium co-dopant in the core glass of an erbium system is used for the first time, to the best of our knowledge, in order to adjust the fiber's numerical aperture without increasing the erbium concentration. Numerical modeling, validated by the experimental results, demonstrates that adding aluminum and phosphorus at high concentration mitigates erbium ions clustering, with an estimated erbium paired ions of only 5.0% in the reported gain fiber.

A 24-year-old woman was referred to us for an intracranial haemorrhage in the left temporal lobe caused by a ruptured cavernous malformation; the bleeding extended over the left Heschl's gyrus and Wernicke area. On admission, the patient had global aphasia. A few days later, she spontaneously improved but remained with mild residual comprehensive dysphasia. She reported hearing, in her right ear, recently heard words, which is consistent with palinacousis. Auditory acuity testing was normal. EEG showed focal slowing in the left temporal region with no epileptiform activity. During awake surgery for resection of the cavernous malformation, stimulation of the superior temporal gyrus did not provoke palinacousis. The patient made good recovery with complete resolution of the aphasia and no recurrence of palinacousis. We aimed to review this phenomenon and to provide a systematic review of the current literature., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Although the past decades have seen a steady increase of women in medicine in general, women continue to represent a minority of the physician-training staff and workforce in neurosurgery in Canada and worldwide. As such, the aim of this study was to analyze the experiences of women faculty practicing neurosurgery across Canada to better understand and address the factors contributing to this disparity., Methods: A historical, cross-sectional, and mixed-method analysis of survey responses was performed using survey results obtained from women attending neurosurgeons across Canada. A web-based survey platform was utilized to collect responses. Quantitative analyses were performed on the responses from the study questionnaire, including summary and comparative statistics. Qualitative analyses of free-text responses were performed using axial and open coding., Results: A total of 19 of 31 respondents (61.3%) completed the survey. Positive enabling factors for career success included supportive colleagues and work environment (52.6%); academic accomplishments, including publications and advanced degrees (36.8%); and advanced fellowship training (47.4%). Perceived barriers reported included inequalities with regard to career advancement opportunities (57.8%), conflicting professional and personal interests (57.8%), and lack of mentorship (36.8%). Quantitative analyses demonstrated emerging themes of an increased need for women mentors as well as support and recognition of the contributions to career advancement of personal and family-related factors., Conclusions: This study represents, to the authors' knowledge, the first analysis of factors influencing career success and satisfaction in women neurosurgeons across Canada. This study highlights several key factors contributing to the low representation of women in neurosurgery and identifies specific actionable items that can be addressed by training programs and institutions. In particular, female mentorship, opportunities for career advancement, and increased recognition and integration of personal and professional roles were highlighted as areas for future intervention. These findings will provide a framework for addressing these factors and improving the recruitment and retention of females in this specialty.

Competing Interests: No potential conflict of interest was reported by the authors.

The search for compounds with biological activity for many diseases is turning increasingly to drug repurposing. In this study, we have focused on the European Union-approved antimalarial pyronaridine which was found to have in vitro activity against Mycobacterium tuberculosis (MIC 5 μg/mL). In macromolecular synthesis assays, pyronaridine resulted in a severe decrease in incorporation of 14 C-uracil and 14 C-leucine similar to the effect of rifampicin, a known inhibitor of M. tuberculosis RNA polymerase. Surprisingly, the co-administration of pyronaridine (2.5 μg/ml) and rifampicin resulted in in vitro synergy with an MIC 0.0019-0.0009 μg/mL. This was mirrored in a THP-1 macrophage infection model, with a 16-fold MIC reduction for rifampicin when the two compounds were co-administered versus rifampicin alone. Docking pyronaridine in M. tuberculosis RNA polymerase suggested the potential for it to bind outside of the RNA polymerase rifampicin binding pocket. Pyronaridine was also found to have activity against a M. tuberculosis clinical isolate resistant to rifampicin, and when combined with rifampicin (10% MIC) was able to inhibit M. tuberculosis RNA polymerase in vitro. All these findings, and in particular the synergistic behavior with the antitubercular rifampicin, inhibition of RNA polymerase in combination in vitro and its current use as a treatment for malaria, may suggest that pyronaridine could also be used as an adjunct for treatment against M. tuberculosis infection. Future studies will test potential for in vivo synergy, clinical utility and attempt to develop pyronaridine analogs with improved potency against M. tuberculosis RNA polymerase when combined with rifampicin., (Copyright © 2018 Elsevier Ltd. All rights reserved.)