Unilateral Stereotactic Radiofrequency Lesioning as a Surgical Treatment Option for Meige Syndrome.

Background Meige syndrome is a segmental dystonia affecting the head and neck, with bilateral blepharospasm as the primary symptom. First-line treatment typically involves Botox injections. For cases resistant to this treatment, bilateral deep brain stimulation of the globus pallidus internus (GPi) is considered. This study explores the efficacy of unilateral radiofrequency (RF) lesioning as an alternative surgical treatment for Meige syndrome. Methods We investigated six cases of medically refractory Meige syndrome treated with unilateral RF lesioning between October 2022 and August 2023. The procedures utilized the Leksell Stereotactic System (Elekta, Stockholm, Sweden) and the StealthStation S8 system (Medtronic, Dublin, Ireland). Target coordinates were initially set at 8-9 mm lateral and 1-2 mm inferior to the mid-commissure point (MCP) for the pallidothalamic tract (PTT), and 20 mm lateral, 2 mm anterior, and 3.0-4.5 mm inferior to the MCP for GPi, with fine adjustments based on MRI findings. Results The mean age of patients was 53. 3 ±16.5 years. Five patients underwent PTT RF lesioning, while one received GPi RF lesioning (pallidotomy). No surgical complications were reported. The Burke-Fahn-Marsden Dystonia Rating Scale scores were 32.9 ± 19.4 preoperatively and 17.7 ± 13.9 three months postoperatively, reflecting an average improvement of 42.7%. The Jankovic Rating Scale scores were 7.17 ± 0.76 preoperatively, 2.33 ± 2.34 the day after surgery (average improvement of 67%), and 3.50 ± 1.64 three months postoperatively (average improvement of 51%). Bilateral facial symptoms improved in four patients (67%). Conclusion Unilateral RF lesioning for Meige syndrome demonstrated the potential to improve bilateral symptoms and may be considered a viable treatment option for patients with refractory cases.

TACI deficiency impairs sustained Blimp-1 expression in B cells decreasing long-lived plasma cells in the bone marrow.

Deficiencies in transmembrane activator and CAML interactor (TACI) result in common variable immune deficiency, a syndrome marked by recurrent infections with encapsulated microorganisms, impaired production of antibodies, and lymphoproliferation. How TACI promotes antibody production and inhibits lymphoproliferation is not understood. To answer this question, we studied the generation of immunity to protein antigens in both TACI-deficient and TACI-proficient mice. We show that TACI promotes sustained Blimp-1 expression by B cells responding to antigen, which in turn limits B-cell clonal expansion and facilitates differentiation of long-lived antibody-secreting cells. Short-term IgG secretion occurs independently of TACI as DNA double-strand breaks associated with isotype class switching induce Blimp-1 transiently, independently of TACI. Our results showing that TACI induces and maintains Blimp-1 provide, for the first time, a unified molecular and cellular mechanism explaining the primary features of common variable immune deficiency, exquisite vulnerability to infection with encapsulated organisms, lymphoproliferation, and hypogammaglobulinemia.

A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth.

SP/KLF (Specificity protein/Krüppel-like factor) transcription factors comprise an emerging group of proteins that may behave as tumour suppressors. Incidentally, many cancers that display alterations in certain KLF proteins are also associated with a high incidence of KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue) mutations. Therefore in the present paper we investigate whether SP/KLF proteins suppress KRAS-mediated cell growth, and more importantly, the potential mechanisms underlying these effects. Using a comprehensive family-wide screening of the 24 SP/KLF members, we discovered that SP5, SP8, KLF2, KLF3, KLF4, KLF11, KLF13, KLF14, KLF15 and KLF16 inhibit cellular growth and suppress transformation mediated by oncogenic KRAS. Each protein in this subset of SP/KLF members individually inhibits BrdU (5-bromo-2-deoxyuridine) incorporation in KRAS oncogenic-mutant cancer cells. SP5, KLF3, KLF11, KLF13, KLF14 and KLF16 also increase apoptosis in these cells. Using KLF11 as a representative model for mechanistic studies, we demonstrate that this protein inhibits the ability of cancer cells to form both colonies in soft agar and tumour growth in vivo. Molecular studies demonstrate that these effects of KLF11 are mediated, at least in part, through silencing cyclin A via binding to its promoter and leading to cell-cycle arrest in S-phase. Interestingly, similar to KLF11, KLF14 and KLF16 mechanistically share the ability to modulate the expression of cyclin A. Collectively, the present study stringently defines a distinct subset of SP/KLF proteins that impairs KRAS-mediated cell growth, and that mechanistically some members of this subset accomplish this, at least in part, through regulation of the cyclin A promoter.

Novel functions of B cells in transplantation.

PURPOSE OF REVIEW: This manuscript reviews current knowledge and recent findings regarding antibody-independent functions of B cells in transplantation. RECENT FINDINGS: Until recently the functions of B cells in transplantation have been attributed almost entirely to the antibodies they produce. However, the results of recent trials of B-cell-depleting agents for treatment of antibody-mediated rejection as well as auto-immune disease raised awareness that B cells mediate functions independent of antibody synthesis. SUMMARY: These 'nonclassical' functions place B cells at the center of immune regulation with the power to enhance or inhibit immunity.

Microsurgical resection of unruptured cerebellar arteriovenous malformation presenting with trigeminal neuralgia.

Cerebellar arteriovenous malformations (AVMs) represent 10%-15% of all intracranial AVMs and are associated with a greater risk for hemorrhagic presentation compared with supratentorial AVMs. When they reach the cerebellopontine angle cistern, neurovascular compression syndromes, including trigeminal neuralgia and hemifacial spasm, can occur. Due to the aggressive natural history of cerebellar AVM, an effective treatment strategy is required. In this video, the authors demonstrate the technical nuances of microsurgical resection of an unruptured cerebellar AVM in a 24-year-old female presenting with trigeminal neuralgia. The patient underwent right retrosigmoid craniotomy and complete resection of the AVM with resolution of trigeminal neuralgia. The video can be found here: https://youtu.be/6GmNjgFQwx8.

Management of an Uncommon Complication: Anterior Choroidal Artery Occlusion by Posterior Clinoid Process Detected Through Intraoperative Monitoring After Clipping of Paraclinoid Aneurysm: 2-Dimensional Operative Video.

Despite technological advances in endovascular therapy, surgical clipping of paraclinoid aneurysms remains an indispensable treatment option and has an acceptable profile risk. Intraoperative monitoring of motor and somatosensory evoked potentials has proven to be an effective tool in predicting and preventing postoperative motor deficits during aneurysm clipping.1,2 We describe the case of a 61-yr-old Japanese woman with a history of hypertension and smoking. During follow-up for bilateral aneurysms of ophthalmic segment of the internal carotid artery (ICA), left-sided aneurysm growth was detected. A standard pterional approach with extradural clinoidectomy was used to approach the aneurysm. After clipping, a significant intraprocedural change in motor evoked potential (MEP) amplitude was observed despite native vessel patency was confirmed through micro-Doppler and indocyanine green video angiography.3-5 After extensive dissection of the sylvian fissure and exposure of the communicating segment of ICA, the anterior choroidal artery was found to be compressed and occluded by the posterior clinoid because of an inadvertent shift of the ICA after clip application and removal of brain retractors. Posterior clinoidectomy was performed intradurally with microrongeur and MEP amplitude returned readily to baseline values. Computed tomography (CT) angiogram demonstrated complete exclusion of the aneurysm, and magnetic resonance imaging (MRI) was negative for postoperative ischemic lesions on diffusion weighted images. The patient tolerated the procedure well and was discharged home on postoperative day 3 with modified Rankin Scale (mRS) 0. The patient signed the Institutional Consent Form to undergo the surgical procedure and to allow the use of her images and videos for any type of medical publications.

All-trans retinoic acid induces differentiation of ducts and endocrine cells by mesenchymal/epithelial interactions in embryonic pancreas.

Retinoids during the embryonic period act as a mesenchymal inducer in many organs, including kidney, lung, central nervous system, and gut. Retinoic acid (RA) demonstrates insulinotropic effects in adult pancreas, but only a limited study has elucidated its role in pancreatic organogenesis. In this study, we have analyzed the existence of RA-signaling machinery in embryonic pancreas and evaluated its role using in vitro tissue culture experiments. Here we show the presence of endogenous retinaldehyde dehydrogenase 2 (RALDH2), the most effective RA-synthesizing enzyme, RA-binding proteins, and RA receptors (RARs) in embryonic pancreatic tissue. RALDH2 is expressed exclusively in the mesenchyme. Exogenously added all-trans-retinoic acid (atRA) in tissue culture experiments stimulated differentiation of endocrine and duct cells and promoted apoptotic cell death of acinar tissue. Furthermore, we demonstrate that atRA upregulates the PDX-1 expression. Taken together, our data suggest that atRA-mediated mesenchymal/epithelial interactions play an important role in determining the cell fate of epithelial cells via regulation of the PDX-1 gene, leading to the proper formation of the endocrine versus exocrine component during pancreatic organogenesis.

RECK expression in pancreatic cancer: its correlation with lower invasiveness and better prognosis.

BACKGROUND: The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene was initially isolated as a transformation suppressor gene. The RECK gene is expressed widely in normal organs but is undetectable in many tumor-derived cell lines. When artificially expressed in such cell lines, RECK negatively regulates at least matrix metalloprotease (MMP)-9, MMP-2, and MT1-MMP activation and suppresses the invasive and metastatic potentials of these cells. Clinical relevance of these observations, however, is yet to be established. The aim of this study was to examine RECK expression in pancreatic cancer, where intensive invasiveness and metastasis are frequently observed, and investigate its clinical significance. We also analyzed the correlation between RECK expression and MMP activation. METHODS: (a) RECK expression in surgically resected tissue samples of invasive ductal carcinomas of the pancreas (n = 50) was examined immunohistochemically, and its correlation with clinicopathological factors was analyzed; and (b) gelatin zymography was used for the detection of latent and activated forms of MMP-2 and MMP-9 in some of the tissue samples (n = 33). The gelatinase activity was quantified by densitometory, and the ratio of intensity of the active MMP-2 band to the total intensity of the pro- and active MMP-2 bands was evaluated as an indicator of MMP-2 activation. The MMP-9 activation was also studied. RESULTS: Among the 50 ductal carcinoma samples, 26 (52%) were stained positive for RECK. In the normal pancreas, both acinar and beta cells were stained positive, but ductal cells did not. Tumors with positive RECK staining were significantly less invasive as compared with RECK-negative tumors (P = 0.0438). Importantly, patients who had tumors with high RECK expression showed significantly better prognosis than those who had RECK-negative tumors (P = 0.0463, by Log-rank test). Zymographic analysis indicated significant inverse correlation between the level of RECK expression and extent of MMP-2 activation (P = 0.0374). CONCLUSIONS: Our findings support the hypothesis that the RECK protein has negative effects on the invasiveness of pancreatic cancer by inhibiting MMP-2 activation and suggest the potential value of RECK as a prognostic molecular marker for pancreatic cancer.

N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma.

PURPOSE: Loss of intercellular adhesion and increased cell motility promote tumor cell invasion. In the present study, E- and N-cadherin, members of the classical cadherin family, are investigated as inducers of epithelial-to-mesenchymal transition (EMT) that is thought to play a fundamental role during the early steps of invasion and metastasis of carcinomas. Cell growth factors are known to regulate cell adhesion molecules. The purpose of the study presented here was to investigate whether a gain in N-cadherin in pancreatic cancer is involved in the process of metastasis via EMT and whether its expression is affected by growth factors. EXPERIMENTAL DESIGN: We immunohistochemically examined the expression of N- and E-cadherins and vimentin, a mesenchymal marker, in pancreatic primary and metastatic tumors. Correlations among the expressions of N-cadherin, transforming growth factor (TGF)beta, and fibroblast growth factor 2 was evaluated in both tumors, and the induction of cadherin and vimentin by growth factors was examined in cultured cell lines. RESULTS: N-cadherin expression was observed in 13 of 30 primary tumors and in 8 of 15 metastatic tumors. N-cadherin expression correlated with neural invasion (P = 0.008), histological type (P = 0.043), fibroblast growth factor expression in primary tumors (P = 0.007), and TGF expression (P = 0.004) and vimentin (P = 0.01) in metastatic tumors. Vimentin, a mesenchymal marker, was observed in a few cancer cells of primary tumor but was substantially expressed in liver metastasis. TGF stimulated N-cadherin and vimentin protein expression and decreased E-cadherin expression of Panc-1 cells with morphological change. CONCLUSION: This study provided the morphological evidence of EMT in pancreatic carcinoma and revealed that overexpression of N-cadherin is involved in EMT and is affected by growth factors.

Expression of IL-6 receptor in pancreatic cancer: involvement in VEGF induction.

BACKGROUND: Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic growth factors and its expression is correlated with MVD (microvascular density) in malignant tumors, including pancreatic adenocarcinoma. On the other hand, serum interleukin-6 (IL-6) is elevated in many patients with pancreatic cancer in accordance with their disease progression. In this study, we examined whether IL-6 and its receptors have any involvement in the induction of VEGF in pancreatic cancer. MATERIALS AND METHODS: Two human pancreatic cancer cell lines were examined for the induction of VEGF after treatment with IL-6. Thirty-two pancreatic cancer surgical specimens were stained immunohistochemically with VEGF, IL-6 and IL-6 receptor antibodies. RESULTS: CFPAC-1 cells expressed IL-6 receptor whereas AsPC-1 cells rarely expressed it. IL-6 treatment induced VEGF expression significantly and dose-dependently in CFPAC-1 cells, while it did not change in AsPC-1 cells. The intensity of VEGF expression in CFPAC-1 also increased time-dependently with IL-6 treatment. In 32 surgical pancreatic cancer tissues, 19 (59%) stained positive for VEGF and 26 (87%) positive for IL-6 receptor beta subunit. The correlation between IL-6 receptors and VEGF was significant (p = 0.0002 and p = 0.0019) while less correlation was seen between IL-6 and VEGF (p = 0.1937). CONCLUSION: Our results suggest that IL-6 is likely to take part in VEGF expression in both paracrine and autocrine fashion in pancreatic cancer. Induction of VEGF seems to be regulated by the extent of the IL-6 receptor expression on cancer cells.

TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen.

The transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) controls differentiation of long-lived plasma cells, and almost 10% of individuals with common variable immunodeficiency (CVID) express either the C104R or A181E variants of TACI. These variants impair TACI function, and TACI-deficient mice exhibit a CVID-like disease. However, 1%-2% of normal individuals harbor the C140R or A181E TACI variants and have no outward signs of CVID, and it is not clear why TACI deficiency in this group does not cause disease. Here, we determined that TACI-deficient mice have low baseline levels of Ig in the blood but retain the ability to mutate Ig-associated genes that encode antigen-specific antibodies. The antigen-specific antibodies in TACI-deficient mice were produced in bursts and had higher avidity than those of WT animals. Moreover, mice lacking TACI were able to clear Citrobacter rodentium, a model pathogen for severe human enteritis, more rapidly than did WT mice. These findings suggest that the high prevalence of TACI deficiency in humans might reflect enhanced host defense against enteritis, which is more severe in those with acquired or inherited immunodeficiencies.

Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma.

Many cancers are resistant to Fas-mediated apoptosis despite the expression of Fas. To investigate the mechanisms by which Fas signals are attenuated, we focused on decoy receptor 3 (DcR3). DcR3 is a soluble receptor against Fas ligand belonging to the tumor necrosis factor receptor superfamily and overexpresses in some forms of cancers. Exogenous DcR3 inhibits Fas-mediated apoptosis in Fas-sensitive Jurkat cells. In our study, we examined the expression and function of DcR3 in pancreatic cancers. TaqMan RT-PCR showed that DcR3 mRNA was highly expressed in pancreatic cancer cell lines (71%) and tissues (67%). Its expression significantly correlated with cancer invasion to veins. Western blotting showed that the DcR3 protein was produced and secreted in 4 of 6 cell lines. The protein expressions were compatible with the mRNA expression. Five of 7 pancreatic cancer cell lines became sensitive to agonistic anti-Fas antibody (CH-11) to various extents, without Fas upregulation, when exposed to CH-11 for 48 hr after pretreatment with IFNgamma. Four of 7 pancreatic cancer cell lines were inhibited from growing, compared to control cells, when cocultured with membrane-bounded Fas ligand (mFasL) transfected lymphomas for 48 hr after pretreatment with IFNgamma. DcR3 reduced this growth inhibition when added exogenously. Regression analysis showed that the DcR3 expression significantly correlated with the sensitivity to mFasL, and not to CH-11. These results suggest that DcR3 is highly expressed in many pancreatic cancers and endogenous DcR3 blocks the growth inhibition signals mediated by mFasL. DcR3 can be a candidate target molecule for the therapeutic intervention.