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OBJECTIVE Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) has been shown to be an effective therapeutic option for select patients with limbic epilepsy. However, the optimal target and electrode position for this indication remains undefined. Therefore, the objective of this systematic review and meta-analysis is to quantify the association between active contact location and outcomes across all published series of ANT DBS. METHODS A literature search using PRISMA criteria was performed to identify all studies that reported both active contact locations and outcomes of DBS in the ANT for epilepsy. Patient, disease, treatment, and outcome data were extracted for statistical analysis. Contact locations of responders (defined as ≥ 50% seizure reduction at last follow-up) versus nonresponders to DBS were analyzed on a common reference frame. Centers of mass, weighted by clinical response, were computed for the contacts in each cohort. RESULTS From 555 studies that were screened for review, a total of 7 studies comprising 162 patients met criteria for inclusion and were analyzed. Across the cohort, the mean duration of epilepsy was 23 years and the mean pre-DBS seizure frequency was 56 seizures per month. DBS electrodes were implanted using direct targeting in 5 studies (n = 62, 38% of patient cohort) via a transventricular electrode trajectory in 4 studies (n = 123, 76%). At the mean follow-up duration of 2.3 years, 56% of patients were considered responders. Active contacts of responders were 1.6 mm anterior (95% CI 1.5–1.6 mm, p < 0.001) compared to those of nonresponders and were adjacent to the mammillothalamic tract (MTT). CONCLUSIONS Accurate targeting of the ANT is crucial to successful DBS outcomes in epilepsy. These findings suggest that stimulation within the ANT subregions adjacent to the MTT improves outcomes.

Bacterial infections are increasingly epitomizing major global health concerns, with rising death rates. Since the most complete assessment of the worldwide impact of antimicrobial resistance to date, with over 1.2 million people dead in 2019 as a direct result of antibiotic-resistant bacterial infections. The majority of antimicrobial drugs have been associated with a multitude of adverse effects including financial costs as well. Pyrrolidine derivatives have sparked the interest of researchers to create novel synthetic molecules with minimal side effect and drawbacks. To close the research gap, the current review discusses the synthetic compounds with active pyrrolidine scaffolds, critical findings and most crucially the structure–activity relationship that affects the activity of the ring over the last one and half decade.

Abstract: SARS-CoV-2 infection is the most contagious among the three coronavirus infections the world has witnessed to date, which has affected almost all parts of the world in millions of population since its outbreak in China in December 2019. Moreover, it has severely hit the world economy and therefore there is a dire need to develop the treatment of this deadly disease. A number of potential vaccines are in the early or advanced stage of clinical trials. But the development of a vaccine is a very tedious and time-consuming task. Therefore, various groups are working on repurposing of drugs with already known safety and efficacy profiles to shorten the time of development of the potential treatment. The main aim of this review article is to summarize the clinical outcomes of Interleukin receptor antagonists and Janus kinase inhibitors based drugs which have been repurposed for the treatment of COVID-19 associated with SARS-CoV-2.

Abstract: A novel magnetite silica-coated nanoparticle-supported molybdate nanocatalyst has been prepared successfully by a simple co-precipitation method. Prepared nanocatalyst has been characterized by different techniques like Fourier Transmission Infrared Spectroscopy (FT-IR), X-ray diffraction (XRD), Field Emission Scanning Electron Microscope (FE-SEM), and Energy Dispersive X-ray Spectroscopy (EDX). Further, the catalytic activity of the nanocatalyst was explored for N-formylation reactions under solvent-free conditions. Interestingly, the catalyst could be reused for 10 cycles, and only 2 mol % of the catalyst was sufficient to catalyze the N-formylation reaction at 700C under solvent-free conditions.

Background Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit. Methods The international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected. Results We collected 1,008 patients with newly diagnosed IDHwt glioblastoma. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC-26981/22981 (TMZ/RT→TMZ) following surgery. Among these homogenously treated patients, lower absolute residual tumor volumes (in cm3) were favorably associated with outcome: patients with “maximal CE resection” (class 2) had superior outcome compared to patients with “submaximal CE resection” (class 3) or “biopsy” (class 4). Extensive resection of non-CE tumor (≤5 cm3 residual non-CE tumor) was associated with better survival among patients with complete CE resection, thus defining class 1 (“supramaximal CE resection”). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers. Conclusions The proposed “RANO categories for extent of resection in glioblastoma” are highly prognostic and may serve for stratification within clinical trials. Removal of non-CE tumor beyond the CE tumor borders may translate into additional survival benefit, providing a rationale to explicitly denominate such “supramaximal CE resection.”

Reading a sentence entails integrating the meanings of individual words to infer more complex, higher-order meaning. This highly rapid and complex human behavior is known to engage the inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) in the language-dominant hemisphere, yet whether there are distinct contributions of these regions to sentence reading is still unclear. To probe these neural spatiotemporal dynamics, we used direct intracranial recordings to measure neural activity while reading sentences, meaning-deficient Jabberwocky sentences, and lists of words or pseudowords. We isolated two functionally and spatiotemporally distinct frontotemporal networks, each sensitive to distinct aspects of word and sentence composition. The first distributed network engages the IFG and MTG, with IFG activity preceding MTG. Activity in this network ramps up over the duration of a sentence and is reduced or absent during Jabberwocky and word lists, implying its role in the derivation of sentence-level meaning. The second network engages the superior temporal gyrus and the IFG, with temporal responses leading those in frontal lobe, and shows greater activation for each word in a list than those in sentences, suggesting that sentential context enables greater efficiency in the lexical and/or phonological processing of individual words. These adjacent, yet spatiotemporally dissociable neural mechanisms for word- and sentence-level processes shed light on the richly layered semantic networks that enable us to fluently read. These results imply distributed, dynamic computation across the frontotemporal language network rather than a clear dichotomy between the contributions of frontal and temporal structures.

Speech production is known to engage a distributed network. The brain regions responsible for the initiation of articulation are unclear, and they would be expected to coordinate a distributed network. Using direct intracranial recordings in a large cohort, during stereotyped speech production to eliminate confounds of phonological and semantic complexity, we performed a comprehensive analysis of cortical sites engaged in speech initiation. We found that the supplementary motor area (SMA) was the earliest speech motor region to be active prior to speech onset and was active almost exclusively prior to articulation. Broadband gamma activity in the SMA was predictive of the response time of word production, predicting response time from 250 ms after stimulus onset. Neural activity in SMA began at a highly predictable time after stimulus onset and extended until speech onset. SMA activityoffsetcoincided with ventral premotor cortex and primary motor activityonset. This suggests that the SMA may coordinate the concerted activation of motor execution cortex. Our results support the idea that SMA is a key node in the speech initiation network.Significance statementProducing speech requires coordination across multiple brain regions. One cortical region - the supplementary motor area (SMA) - has long been a candidate region to coordinate across other regions to initiate speech production. In this study, we used human intracranial recordings from patients with epilepsy to investigate the role of the SMA in initiating speech. In a picture-naming task, subjects repeated the word “scrambled” scores of times; using this condition to eliminate any linguistic confounds, we found that the SMA was consistently one of the earliest regions to activate during word production. We also uncovered the SMA’s temporally precise tuning to speech onset at the single-trial level.

OBJECTIVE: Lexical retrieval deficits are characteristic of a variety of different neurological disorders. However, the exact substrates responsible for this are not known. We studied a large cohort of patients undergoing surgery in the dominant temporal lobe for medically intractable epilepsy (n = 95) to localize brain regions that were associated with anomia. METHODS: We performed a multivariate voxel-based lesion–symptom mapping analysis to correlate surgical lesions within the temporal lobe with changes in naming ability. Additionally, we used a surface-based mixed-effects multilevel analysis to estimate group-level broadband gamma activity during naming across a subset of patients with electrocorticographic recordings and integrated these results with lesion–deficit findings. RESULTS: We observed that ventral temporal regions, centered around the middle fusiform gyrus, were significantly associated with a decline in naming. Furthermore, we found that the ventral aspect of temporal lobectomies was linearly correlated to a decline in naming, with a clinically significant decline occurring once the resection extended 6 cm from the anterior tip of the temporal lobe on the ventral surface. On electrocorticography, the majority of these cortical regions were functionally active following visual processing. These loci coincide with the sites of susceptibility artifacts during echoplanar imaging, which may explain why this region has been previously underappreciated as the locus responsible for postoperative naming deficits. SIGNIFICANCE: Taken together, these data highlight the crucial contribution of the ventral temporal cortex in naming and its important role in the pathophysiology of anomia following temporal lobe resections. As such, surgical strategies should attempt to preserve this region to mitigate postoperative language deficits.

Leveraging firsthand experience, BRAIN-funded investigators conducting intracranial human neuroscience research propose two fundamental ethical commitments: (1) maintaining the integrity of clinical care and (2) ensuring voluntariness. Principles, practices, and uncertainties related to these commitments are offered for future investigation.

Nanotheranostics is a young but rapidly expanding science that incorporates elements of therapy and diagnostics in a unique and miniscule area of research. The potential to combine diagnostic and therapeutic abilities inside a complete unit opens up interesting possibilities for innovative biomedical research. Silver-based nanoparticles, for instance, are widely utilized as pharmacological and biomedical imaging molecules, and hence offer a lot of potential for the development of versatile targeted therapy compositions. These nanoparticles have been used for cancer diagnosis and cancer treatments recently. We evaluate major innovations based on silver nanotheranostics technologies in this review paper, with an emphasis on cancer treatment implications. The present review covers papers, from 2010 to 2020.

The blood-brain barrier (BBB) controls the movement of molecules into and out of the central nervous system (CNS). Since a functional BBB forms by mouse embryonic day E15.5, we reasoned that gene cohorts expressed in CNS endothelial cells (EC) at E13.5 contribute to BBB formation, whereas adult gene signatures reflect BBB maintenance mechanisms. Supporting this hypothesis, transcriptomic analysis revealed distinct cohorts of EC genes during BBB formation and maintenance. Here we demonstrate that epigenetic regulator’s histone deacetylase 2 (HDAC2) and polycomb repressive complex 2 (PRC2) control EC gene expression for BBB development and prevented Wnt/β-catenin (Wnt) target genes from being expressed in adult CNS ECs. Low Wnt activity during development modifies BBB genes epigenetically for the formation of functional BBB. As a Class-I HDAC inhibitor induces adult CNS ECs to regain Wnt activity and BBB genetic signatures that support BBB formation, our results inform strategies to promote BBB repair.

Meningioangiomatosis (MA) is a rare process at the intersection of cerebral developmental and neoplastic disorders that often results in epilepsy. We evaluated molecular alterations in MA to characterize its biology and pathogenesis. We searched a comprehensive institutional database for patients with MA treated between 2004 and 2019. Demographic, clinical, surgical, and radiographical data were collected. MA and associated meningioma tissues were evaluated using a next-generation sequencing assay interrogating 1425 cancer-related genes. We studied 5 cases: 3 with MA and 2 with MA associated with a meningioma. Of the MAs associated with a meningioma, 1 had deletions in the NF2 gene in both the MA and the meningioma components, whereas the other had an NF2 deletion in only the MA component. Additional mutations were identified in the MA components, suggesting that MA arises from the meningioma rather than the meningioma resulting from a transformation of the MA. The 3 cases of pure MA showed variants of unknown significance with no alterations in known oncogenic drivers. Our findings provide a starting point to a better understanding of the pathogenesis of this rare lesion. Our study indicates that MA-meningiomas have a neoplastic nature that differs from the hamartomatous/developmental nature of pure MA.

Pyrrolidine molecules are a significant class of synthetic and natural plant metabolites, which show the diversity of pharmacological activities. An extensive variety of synthetic pyrrolidine compounds with numerous derivatization like spirooxindole, thiazole, metal complexes, coumarin, etc have revealed significant anticancer activity. Pyrrolidine molecules are found not only as potential anticancer candidates but also retain the lowest side effects. Depending upon the diverse substitution patterns of the derivatives, these molecules have demonstrated an incredible ability to regulate the various targets to give excellent anti-proliferative activities. Taking these into consideration, efforts have been taken by the scientific fraternity to design and develop a potent anticancer scaffold with negligible side effects. In the present review, we cover the latest advancements in the synthesis of pyrrolidine molecules which have promising anticancer activity toward numerous cancer cell lines. Additionally, it also highlights the effectiveness of derivatives via elucidation of Structural-Activity-Relationship (SAR) which is discussed in detail.

The degree of synchronized fluctuations in neocortical network activity can vary widely during alertness. One influential idea that has emerged over the past few decades is that perceptual decisions are more accurate when the state of population activity is desynchronized. This suggests that optimal task performance may occur during a particular cortical state – the desynchronized state. Here we show that, contrary to this view, cortical state can both facilitate and suppress perceptual performance in a task-dependent manner. We performed electrical recordings from surface-implanted grid electrodes in the temporal lobe while human subjects completed two perceptual tasks. We found that when local population activity is in a synchronized state, network and perceptual performance are enhanced in a detection task and impaired in a discrimination task, but these modulatory effects are reversed when population activity is desynchronized. These findings indicate that the brain has adapted to take advantage of endogenous fluctuations in cortical state to selectively enhance different modes of sensory processing during perception in a state-dependent manner.

Language depends critically on the integration of lexical information to derive semantic concepts. The neurobiology of this fundamental aspect of human cognition remains mostly unknown. Limitations of spatiotemporal resolution have previously rendered it difficult to disentangle processes involved in semantic integration from independent computations such as tracking word meaning and establishing referents. We utilized intracranial recordings (n = 58) during the presentation of orthographic descriptions that were either referential or non-referential to a common object. Referential contexts enabled high frequency broadband gamma activation (70–150 Hz) of a distributed network including the inferior frontal sulcus (IFS), medial parietal cortex (MPC) and medial temporal lobe (MTL) in the left, language-dominant hemisphere. Components of this network (IFS, MPC), alongside posterior superior temporal sulcus, showed greater engagement for trials that did not progressively isolate a limited set of referents, relative to trials that did. IFS and posterior middle temporal gyrus activity was modulated by semantic coherence, regardless of whether the sentence picked out a common object. Centered around IFS and spreading out dorsally towards middle frontal gyrus and ventrally towards anterior/posterior inferior frontal gyrus, we uncovered a cortical mosaic of functional specialization for reference, coherence and semantic narrowing. Early processing windows implicated IFS in all aspects of semantics, and in later windows sub-portions of IFS exposed a clearer functional tessellation with some remaining overlap. This work unveils how lateral fronto-temporal regions make distinctly rich semantic contributions and are involved jointly in semantic integration and conflict resolution, depending on the sub-region and processing stage.

INTRODUCTION: Optimal treatment for recurrent glioblastoma isocitrate dehydrogenase 1 and 2 wild-type (rGBM IDH-WT) is not standardized, resulting in multiple therapeutic approaches. A phase III clinical trial showed that tumor treating fields (TTFields) monotherapy provided comparable survival benefits to physician’s chemotherapy choice in rGBM. However, patients did not equally benefit from TTFields, highlighting the importance of identifying predictive biomarkers of TTFields efficacy. METHODS: A retrospective review of an institutional database with 530 patients with infiltrating gliomas was performed. Patients with IDH-WT rGBM receiving TTFields at first recurrence were included. Tumors were evaluated by next-generation sequencing for mutations in 205 cancer-related genes. Post-progression survival (PPS) was examined using the log-rank test and multivariate Cox-regression analysis. RESULTS: 149 rGBM patients were identified of which 29 (19%) were treated with TTFields. No significant difference in median PPS was observed between rGBM patients who received versus did not receive TTFields (13.9 versus 10.9 months, p = 0.068). However, within the TTFields-treated group (n = 29), PPS was improved in PTEN-mutant (n = 14) versus PTEN-WT (n = 15) rGBM, (22.2 versus 11.6 months, p = 0.017). Within the PTEN-mutant group (n = 70, 47%), patients treated with TTFields (n = 14) had longer median PPS (22.2 versus 9.3 months, p = 0.005). No PPS benefit was observed in PTEN-WT patients receiving TTFields (n = 79, 53%). CONCLUSIONS: TTFields therapy conferred a significant PPS benefit in PTEN-mutant rGBM. Understanding the molecular mechanisms underpinning the differences in response to TTFields therapy could help elucidate the mechanism of action of TTFields and identify the rGBM patients most likely to benefit from this therapeutic option.

HER2-enriched breast cancer and triple-negative breast cancer (TNBC) have the highest propensity to metastasize to the brain; patients with breast cancer brain metastasis (BCBM) survive only 6-18 months after diagnosis. Mechanisms that drive brain metastasis remain unclear, contributing to limited effective treatments and poor prognoses for HER2-enriched breast cancer and TNBC patients. Our lab recently reported that breast cancer with truncated glioma-associated oncogene homolog 1, a BCBM-promoting transcription factor, secretes high levels of extracellular vesicle (EV)-derived miR-1290 (Cancer Letters 540:215726, 2022). EV-miR-1290 activates astrocytes in the brain microenvironment. Using mammosphere assays, which enrich breast cancer stem cells (BCSCs), we found conditioned media from miR-1290-activated astrocytes promotes mammosphere formation of breast cancer cells. Furthermore, miR-1290-activated astrocytes secrete high levels of ciliary neurotrophic factor (CNTF) to promote the progression of brain metastases through the novel EV-miR-1290-FOXA2-CNTF signaling axis. However, it remains unknown whether intratumoral miR-1290 promotes BCSCs and BCBM. To help fill this knowledge gap, we first examined whether a miR-1290 mimic enhanced expression of known BCSC markers in SKBR3, HER2-enriched breast cancer, and CN34, TNBC, cells. Our results showed that overexpression of miR-1290 significantly increased the expression of stemness genes, CD44, Nanog, and OCT4, in both cell lines. Furthermore, we determined whether miR-1290 promotes formation of mammospheres that are enriched with BCSCs, and the results indicated that ectopic miR-1290 expression significantly enriched BCSCs in SKBR3 and CN34 cells. Conversely, inhibition of miR-1290 suppressed mammosphere-forming ability of SKBRM and CN34-BRM cells, two brain metastatic breast cancer cell lines derived from SKBR3 and CN34 cells, respectively. We further observed that miR-1290 overexpression in SKBR3 cells significantly increased the percentage of CD44+/CD24− cells, indicative of the BCSCs. Analysis of Gene Expression Omnibus breast cancer patient datasets revealed that miR-1290 expression is significantly increased in HER2-positive and basal subtypes of breast cancer patient tumors. Using the publicly available miR-1290 gene signature, we performed Gene Set Enrichment Analysis and found that high miR-1290 gene activation signature is positively enriched with multiple pathway gene signatures that are known to be upregulated in breast cancer, such as EGFR, MAPK, PI3K, and STAT3 pathways. Furthermore, the miR-1290 gene signature is upregulated in HER2-positive breast cancer and TNBC tumors, and is correlated with worse metastasis-free survival (MFS) and brain-MFS in breast cancer patients. In summary, our study suggests an important role for intratumoral miR-1290 in BCSCs and BCBM. Citation Format: Grace L. Wong, Mariana Najjar, Yoshua Esquenazi, Nitin Tandon, Angelina T. Regua, Hui-Wen Lo. Intracellular miR-1290 promotes breast cancer stemness in HER2-enriched and triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3769.