Neurosurgical neuromodulation therapy for psychiatric disorders.

Psychiatric disorders are among the leading contributors to global disease burden and disability. A significant portion of patients with psychiatric disorders remain treatment-refractory to best available therapy. With insights from the neurocircuitry of psychiatric disorders and extensive experience of neuromodulation with deep brain stimulation (DBS) in movement disorders, DBS is increasingly being considered to modulate the neural network in psychiatric disorders. Currently, obsessive-compulsive disorder (OCD) is the only U.S. FDA (United States Food and Drug Administration) approved DBS indication for psychiatric disorders. Medically refractory depression, addiction, and other psychiatric disorders are being explored for DBS neuromodulation. Studies evaluating DBS for psychiatric disorders are promising but lack larger, controlled studies. This paper presents a brief review and the current state of DBS and other neurosurgical neuromodulation therapies for OCD and other psychiatric disorders. We also present a brief review of MR-guided Focused Ultrasound (MRgFUS), a novel form of neurosurgical neuromodulation, which can target deep subcortical structures similar to DBS, but in a noninvasive fashion. Early experiences of neurosurgical neuromodulation therapies, including MRgFUS neuromodulation are encouraging in psychiatric disorders; however, they remain investigational. Currently, DBS and VNS are the only FDA approved neurosurgical neuromodulation options in properly selected cases of OCD and depression, respectively.

Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease.

Antiamyloid antibodies have been used to reduce cerebral amyloid-beta (Aß) load in patients with Alzheimer's disease. We applied focused ultrasound with each of six monthly aducanumab infusions to temporarily open the blood-brain barrier with the goal of enhancing amyloid removal in selected brain regions in three participants over a period of 6 months. The reduction in the level of Aß was numerically greater in regions treated with focused ultrasound than in the homologous regions in the contralateral hemisphere that were not treated with focused ultrasound, as measured by fluorine-18 florbetaben positron-emission tomography. Cognitive tests and safety evaluations were conducted over a period of 30 to 180 days after treatment. (Funded by the Harry T. Mangurian, Jr. Foundation and the West Virginia University Rockefeller Neuroscience Institute.).

Safety and feasibility clinical trial of nucleus accumbens deep brain stimulation for treatment-refractory opioid use disorder.

OBJECTIVE: There were more than 107,000 drug overdose deaths in the US in 2021, the most ever recorded. Despite advances in behavioral and pharmacological treatments, over 50% of those receiving treatment for opioid use disorder (OUD) experience drug use recurrence (relapse). Given the prevalence of OUD and other substance use disorders (SUDs), the high rate of drug use recurrence, and the number of drug overdose deaths, novel treatment strategies are desperately needed. The objective of this study was to evaluate the safety and feasibility of deep brain stimulation (DBS) targeting the nucleus accumbens (NAc)/ventral capsule (VC) and potential impact on outcomes in individuals with treatment-refractory OUD. METHODS: A prospective, open-label, single-arm study was conducted among participants with longstanding treatment-refractory OUD (along with other co-occurring SUDs) who underwent DBS in the NAc/VC. The primary study endpoint was safety; secondary/exploratory outcomes included opioid and other substance use, substance craving, and emotional symptoms throughout follow-up and 18FDG-PET neuroimaging. RESULTS: Four male participants were enrolled and all tolerated DBS surgery well with no serious adverse events (AEs) and no device- or stimulation-related AEs. Two participants sustained complete substance abstinence for > 1150 and > 520 days, respectively, with significant post-DBS reductions in substance craving, anxiety, and depression. One participant experienced post-DBS drug use recurrences with reduced frequency and severity. The DBS system was explanted in one participant due to noncompliance with treatment requirements and the study protocol. 18FDG-PET neuroimaging revealed increased glucose metabolism in the frontal regions for the participants with sustained abstinence only. CONCLUSIONS: DBS of the NAc/VC was safe, feasible, and can potentially reduce substance use, craving, and emotional symptoms in those with treatment-refractory OUD. A randomized, sham-controlled trial in a larger cohort of patients is being initiated.

Low-intensity focused ultrasound targeting the nucleus accumbens as a potential treatment for substance use disorder: safety and feasibility clinical trial.

Introduction: While current treatments for substance use disorder (SUD) are beneficial, success rates remain low and treatment outcomes are complicated by co-occurring SUDs, many of which are without available medication treatments. Research involving neuromodulation for SUD has recently gained momentum. This study evaluated two doses (60 and 90 W) of Low Intensity Focused Ultrasound (LIFU), targeting the bilateral nucleus accumbens (NAc), in individuals with SUD. Methods: Four participants (three male), who were receiving comprehensive outpatient treatment for opioid use disorder at the time of enrollment and who also had a history of excessive non-opioid substance use, completed this pilot study. After confirming eligibility, these participants received 10 min sham LIFU followed by 20 min active LIFU (10 min to left then right NAc). Outcomes were the safety, tolerability, and feasibility during the LIFU procedure and throughout the 90-day follow-up. Outcomes also included the impact of LIFU on cue-induced substance craving, assessed via Visual Analog Scale (VAS), both acutely (pre-, during and post-procedure) and during the 90-day follow-up. Daily craving ratings (without cues) were also obtained for one-week prior to and one-week following LIFU. Results: Both LIFU doses were safe and well-tolerated based on reported adverse events and MRI scans revealed no structural changes (0 min, 24 h, and 1-week post-procedure). For the two participants receiving "enhanced" (90 W) LIFU, VAS craving ratings revealed active LIFU attenuated craving for participants' primary substances of choice relative to sham sonication. For these participants, reductions were also noted in daily VAS craving ratings (0 = no craving; 10 = most craving ever) across the week following LIFU relative to pre-LIFU; Participant #3 pre- vs. post-LIFU: opioids (3.6 ± 0.6 vs. 1.9 ± 0.4), heroin (4.2 ± 0.8 vs. 1.9 ± 0.4), methamphetamine (3.2 ± 0.4 vs. 0.0 ± 0.0), cocaine (2.4 ± 0.6 vs. 0.0 ± 0.0), benzodiazepines (2.8 ± 0.5 vs. 0.0 ± 0.0), alcohol (6.0 ± 0.7 vs. 2.7 ± 0.8), and nicotine (5.6 ± 1.5 vs. 3.1 ± 0.7); Participant #4: alcohol (3.5 ± 1.3 vs. 0.0 ± 0.0) and nicotine (5.0 ± 1.8 vs. 1.2 ± 0.8) (all p's < 0.05). Furthermore, relative to screening, longitudinal reductions in cue-induced craving for several substances persisted during the 90-day post-LIFU follow-up evaluation for all participants. Discussion: In conclusion, LIFU targeting the NAc was safe and acutely reduced substance craving during the LIFU procedure, and potentially had longer-term impact on craving reductions. While early observations are promising, NAc LIFU requires further investigation in a controlled trial to assess the impact on substance craving and ultimately substance use and relapse.

A cross-sectional study on the nasopharyngeal microbiota of individuals with SARS-CoV-2 infection across three COVID-19 waves in India.

Background: Multiple variants of the SARS-CoV-2 virus have plagued the world through successive waves of infection over the past three years. Independent research groups across geographies have shown that the microbiome composition in COVID-19 positive patients (CP) differs from that of COVID-19 negative individuals (CN). However, these observations were based on limited-sized sample-sets collected primarily from the early days of the pandemic. Here, we study the nasopharyngeal microbiota in COVID-19 patients, wherein the samples have been collected across the three COVID-19 waves witnessed in India, which were driven by different variants of concern. Methods: The nasopharyngeal swabs were collected from 589 subjects providing samples for diagnostics purposes at the Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India and subjected to 16s rRNA gene amplicon - based sequencing. Findings: We found variations in the microbiota of symptomatic vs. asymptomatic COVID-19 patients. CP showed a marked shift in the microbial diversity and composition compared to CN, in a wave-dependent manner. Rickettsiaceae was the only family that was noted to be consistently depleted in CP samples across the waves. The genera Staphylococcus, Anhydrobacter, Thermus, and Aerococcus were observed to be highly abundant in the symptomatic CP patients when compared to the asymptomatic group. In general, we observed a decrease in the burden of opportunistic pathogens in the host microbiota during the later waves of infection. Interpretation: To our knowledge, this is the first analytical cross-sectional study of this scale, which was designed to understand the relation between the evolving nature of the virus and the changes in the human nasopharyngeal microbiota. Although no clear signatures were observed, this study shall pave the way for a better understanding of the disease pathophysiology and help gather preliminary evidence on whether interventions to the host microbiota can help in better protection or faster recovery.

Identifying biomarkers of drug use recurrence using wearable device technologies and phone applications.

BACKGROUND: Identifying predictors of drug use recurrence (DUR) is critical to combat the addiction epidemic. Wearable devices and phone-based applications for obtaining self-reported assessments in the patient's natural environment (e.g., ecological momentary assessment; EMA) have been used in various healthcare settings. However, the utility of combining these technologies to predict DUR in substance use disorder (SUD) has not yet been explored. This study investigates the combined use of wearable technologies and EMA as a potential mechanism for identifying physiological/behavioral biomarkers of DUR. METHODS: Participants, recruited from an SUD treatment program, were provided with a commercially available wearable device that continuously monitors biometric signals (e.g., heart rate/variability [HR/HRV], sleep characteristics). They were also prompted daily to complete an EMA via phone-based application (EMA-APP) that included questionnaires regarding mood, pain, and craving. RESULTS: Seventy-seven participants are included in this pilot study (34 participants experienced a DUR during enrollment). Wearable technologies revealed that physiological markers were significantly elevated in the week prior to DUR relative to periods of sustained abstinence (p<0.001). Results from the EMA-APP revealed that those who experienced a DUR reported greater difficulty concentrating, exposure to triggers associated with substance use, and increased isolation the day prior to DUR (p<0.001). Compliance with study procedures during the DUR week was lower than any other period of measurement (p<0.001). CONCLUSIONS: These results suggest that data acquired via wearable technologies and the EMA-APP may serve as a method of predicting near-term DUR, thereby potentially prompting intervention before drug use occurs.

Ultrasound-mediated blood-brain barrier opening uncovers an intracerebral perivenous fluid network in persons with Alzheimer's disease.

BACKGROUND: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is under investigation as a therapeutic modality for neurodegeneration, yet its effects in humans are incompletely understood. Here, we assessed physiologic responses to FUS administered in multifocal brain sites of persons with Alzheimer's disease (AD). METHODS: At a tertiary neuroscience institute, eight participants with AD (mean age 65, 38% F) enrolled in a phase 2 clinical trial underwent three successive targeted BBB opening procedures at 2 week intervals using a 220 kHz FUS transducer in combination with systemically administered microbubbles. In all, 77 treatment sites were evaluated and encompassed hippocampal, frontal, and parietal brain regions. Post-FUS imaging changes, including susceptibility effects and spatiotemporal gadolinium-based contrast agent enhancement patterns, were analyzed using serial 3.0-Tesla MRI. RESULTS: Post-FUS MRI revealed expected intraparenchymal contrast extravasation due to BBB opening at all targeted brain sites. Immediately upon BBB opening, hyperconcentration of intravenously-administered contrast tracer was consistently observed around intracerebral veins. Following BBB closure, within 24-48 h of FUS intervention, permeabilization of intraparenchymal veins was observed and persisted for up to one week. Notably, extraparenchymal meningeal venous permeabilization and associated CSF effusions were also elicited and persisted up to 11 days post FUS treatment, prior to complete spontaneous resolution in all participants. Mild susceptibility effects were detected, however no overt intracranial hemorrhage or other serious adverse effects occurred in any participant. CONCLUSIONS: FUS-mediated BBB opening is safely and reproducibly achieved in multifocal brain regions of persons with AD. Post-FUS tracer enhancement phenomena suggest the existence of a brain-wide perivenous fluid efflux pathway in humans and demonstrate reactive physiological changes involving these conduit spaces in the delayed, subacute phase following BBB disruption. The delayed reactive venous and perivenous changes are consistent with a dynamic, zonal exudative response to upstream capillary manipulation. Further preclinical and clinical investigations of these FUS-related imaging phenomena and of intracerebral perivenous compartment changes are needed to elucidate physiology of this pathway as well as biological effects of FUS administered with and without adjuvant neurotherapeutics. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03671889, registered 9/14/2018.

Outcomes of a hypertension care program based on task-sharing with private pharmacies: a retrospective study from two blocks in rural India.

Low density of formal care providers in rural India results in restricted and delayed access to standardized management of hypertension. Task-sharing with pharmacies, typically the first point of contact for rural populations, can bridge the gap in access to formal care and improve health outcomes. In this study, we implemented a hypertension care program involving task-sharing with twenty private pharmacies between November 2020 and April 2021 in two blocks of Bihar, India. Pharmacists conducted free hypertension screening, and a trained physician offered free consultations at the pharmacy. We calculated the number of subjects screened, initiated on treatment (enrolled) and the change in blood pressure using the data collected through the program application. Of the 3403 subjects screened at pharmacies, 1415 either reported having a history of hypertension or had elevated blood pressure during screening. Of these, 371 (26.22%) were enrolled in the program. Of these, 129 (34.8%) made at least one follow-up visit. For these subjects, the adjusted average difference in systolic and diastolic blood pressure between the screening and follow-up visits was -11.53 (-16.95 to -6.11, 95% CI) and -4.68 (-8.53 to -0.82, 95% CI) mmHg, respectively. The adjusted odds of blood pressure being under control in this group during follow-up visits compared to screening visit was 7.07 (1.29 to 12.85, 95% CI). Task-sharing with private pharmacies can lead to early detection and improved control of blood pressure in a resource-constrained setting. Additional strategies to increase patient screening and retention rates are needed to ensure sustained health benefits.

Trends in Stereotactic Radiosurgery for Intracranial and Spinal Pathologies: Analysis of the Top 100 Most Cited Articles.

There is a plethora of papers on the role of stereotactic radiosurgery (SRS) in various benign and malignant intracranial tumors, and it is possible to overlook the most important and landmark studies. Thus, the necessity of citation analysis arises, which reviews the most cited articles and recognizes the impact made by these articles. Utilizing the 100 most cited articles describing the use of SRS for intracranial and spinal pathologies, this article aims to provide meaningful information regarding the historical trends and recent directions in which this field is headed. We performed a search of the Web of Science database using the keywords "stereotactic radiosurgery," "gamma knife," "GKRS," "gamma knife radiosurgery," "LINAC," and "Cyberknife" on May 14, 2022. Our search retrieved a total of 30,652 articles published between the years 1968 and 2017. The top 100 cited articles were arranged in descending order based on citation count (CC) and citation per year (CY). The journal with the largest number of publications as well as citation count was the International Journal of Radiation Oncology Biology Physics (n = 33), followed by Journal of Neurosurgery (n = 25). The most cited article was authored by Andrews, which was published in 2004 in The Lancet (1699 CC, 89.42 CY). Flickinger, with 25 papers and 7635 total citations, was the author with the highest impact. Lunsford, with 25 publications and total citations of 7615, was a close second. The USA was the leading country with the maximum number of total citations (n = 23,054). Ninety-two articles described the use of SRS for intracranial pathologies (metastases, n = 38; AVM, n = 16; vestibular schwannoma, n = 9; meningioma, n = 8; trigeminal neuralgia, n = 6; sellar lesion, n = 2; glioma, n = 2; functional, n = 1; and procedure related, n = 10). Eight studies describing spinal radiosurgery were included, out of which four were on spinal metastases. Citation analyses of the top 100 articles revealed that the focus of research in the field of SRS started with functional neurosurgery and progressed to benign intracranial tumors and AVMs. More recently, central nervous system (CNS) metastases have received the maximum attention with 38 articles, including 14 randomized controlled trials finding a place in the top 100 cited articles. Presently, the use of SRS is concentrated in developed countries. Efforts need to be made for more widespread use in developing nations to bring the maximum possible benefits of this focused noninvasive treatment to a wider population.

Comparative transcriptome analysis reveals the phosphate starvation alleviation mechanism of phosphate accumulating Pseudomonas putida in Arabidopsis thaliana.

Phosphate starvation is one of the major factors limiting plant productivity globally. Soil microflora with an inherent trait of phosphate accumulation directly influences soil phosphorus level by regulating its labile form in soil solution. However, the detailed mechanism involved during their interaction with plants under phosphate deficient conditions is still unexplored. Hence, to dissect these complex gene regulatory networks, transcriptome analysis of A. thaliana roots grown under phosphate starved conditions in presence of phosphate accumulating bacteria (Pseudomonas putida; RAR) was performed. Plants grown under phosphate starved conditions showed upregulation of phosphate starvation responsive genes associated with cell biogenesis, stress, photosynthesis, senescence, and cellular transport. Inoculation of RAR upregulated genes linked to defense, cell wall remodeling, and hormone metabolism in stressed plants. Gene ontology analysis indicated the induction of S-glycoside, glucosinolate, and glycosinolate metabolic processes in RAR inoculated plants under phosphate stressed conditions. Further, protein-protein interaction analysis revealed upregulation of root development, cation transport, anion transport, sulfur compound metabolic process, secondary metabolic process, cellular amino metabolic process, and response to salicylic acid in RAR inoculated plants under phosphate starved conditions. These results indicate the potential role of phosphate accumulating bacteria in alleviating phosphate starvation in plants by involving multiple pathways.

Focused ultrasound-mediated blood-brain barrier opening in Alzheimer's disease: long-term safety, imaging, and cognitive outcomes.

OBJECTIVE: MRI-guided low-intensity focused ultrasound (FUS) has been shown to reversibly open the blood-brain barrier (BBB), with the potential to deliver therapeutic agents noninvasively to target brain regions in patients with Alzheimer's disease (AD) and other neurodegenerative conditions. Previously, the authors reported the short-term safety and feasibility of FUS BBB opening of the hippocampus and entorhinal cortex (EC) in patients with AD. Given the need to treat larger brain regions beyond the hippocampus and EC, brain volumes and locations treated with FUS have now expanded. To evaluate any potential adverse consequences of BBB opening on disease progression, the authors report safety, imaging, and clinical outcomes among participants with mild AD at 6-12 months after FUS treatment targeted to the hippocampus, frontal lobe, and parietal lobe. METHODS: In this open-label trial, participants with mild AD underwent MRI-guided FUS sonication to open the BBB in ß-amyloid positive regions of the hippocampus, EC, frontal lobe, and parietal lobe. Participants underwent 3 separate FUS treatment sessions performed 2 weeks apart. Outcome assessments included safety, imaging, neurological, cognitive, and florbetaben ß-amyloid PET. RESULTS: Ten participants (range 55-76 years old) completed 30 separate FUS treatments at 2 participating institutions, with 6-12 months of follow-up. All participants had immediate BBB opening after FUS and BBB closure within 24-48 hours. All FUS treatments were well tolerated, with no serious adverse events related to the procedure. All 10 participants had a minimum of 6 months of follow-up, and 7 participants had a follow-up out to 1 year. Changes in the Alzheimer's Disease Assessment Scale-cognitive and Mini-Mental State Examination scores were comparable to those in controls from the Alzheimer's Disease Neuroimaging Initiative. PET scans demonstrated an average ß-amyloid plaque of 14% in the Centiloid scale in the FUS-treated regions. CONCLUSIONS: This study is the largest cohort of participants with mild AD who received FUS treatment, and has the longest follow-up to date. Safety was demonstrated in conjunction with reversible and repeated BBB opening in multiple cortical and deep brain locations, with a concomitant reduction of ß-amyloid. There was no apparent cognitive worsening beyond expectations up to 1 year after FUS treatment, suggesting that the BBB opening treatment in multiple brain regions did not adversely influence AD progression. Further studies are needed to determine the clinical significance of these findings. FUS offers a unique opportunity to decrease amyloid plaque burden as well as the potential to deliver targeted therapeutics to multiple brain regions in patients with neurodegenerative disorders.

MR-guided focused ultrasound thalamotomy for lithium-induced tremor: a case report and literature review.

Drug-induced tremor is a common side effect of lithium with an occurrence of approximately 25% of patients. Cessation of the offending drug can be difficult, and many medical treatments for drug-induced tremor are ineffective. Deep brain stimulation (DBS) has been shown in a limited number of case reports to effectively reduce drug-induced tremor, however, which remains an invasive therapeutic option. MR-guided focused ultrasound (MRgFUS) thalamotomy is an FDA-approved non-invasive treatment for essential tremor (ET). To the best of our knowledge, MRgFUS thalamotomy has never been reported to treat drug-induced tremor. Here, we present a case of a left-handed 55-year-old man with a progressive, medically refractory lithium-induced tremor of the bilateral upper extremities. The patient underwent MRgFUS thalamotomy targeting the right ventral intermediate nucleus (VIM) of the thalamus to treat the left hand. There was almost complete resolution of his left-hand tremor immediately following MRgFUS. There were no side effects. The patient continues to show excellent tremor control at 90-day follow-up and remains free from side effects. This case demonstrates MRgFUS thalamotomy as a possible novel treatment option to treat drug-induced tremor.

Characterization of passive permeability after low intensity focused ultrasound mediated blood-brain barrier disruption in a preclinical model.

BACKGROUND: Systemic drug delivery to the central nervous system is limited by presence of the blood-brain barrier (BBB). Low intensity focused ultrasound (LiFUS) is a non-invasive technique to disrupt the BBB, though there is a lack of understanding of the relationship between LiFUS parameters, such as cavitation dose, time of sonication, microbubble dose, and the time course and magnitude of BBB disruption. Discrepancies in these data arise from experimentation with modified, clinically untranslatable transducers and inconsistent parameters for sonication. In this report, we characterize microbubble and cavitation doses as LiFUS variables as they pertain to the time course and size of BBB opening with a clinical Insightec FUS system. METHODS: Female Nu/Nu athymic mice were exposed to LiFUS using the ExAblate Neuro system (v7.4, Insightec, Haifa, Israel) following target verification with magnetic resonance imaging (MRI). Microbubble and cavitation doses ranged from 4-400 µL/kg, and 0.1-1.5 cavitation dose, respectively. The time course and magnitude of BBB opening was evaluated using fluorescent tracers, ranging in size from 105-10,000 Da, administered intravenously at different times pre- or post-LiFUS. Quantitative autoradiography and fluorescence microscopy were used to quantify tracer accumulation in brain. RESULTS: We observed a microbubble and cavitation dose dependent increase in tracer uptake within brain after LiFUS. Tracer accumulation was size dependent, with 14C-AIB (100 Da) accumulating to a greater degree than larger markers (~ 625 Da-10 kDa). Our data suggest opening of the BBB via LiFUS is time dependent and biphasic. Accumulation of solutes was highest when administered prior to LiFUS mediated disruption (2-fivefold increases), but was also significantly elevated at 6 h post treatment for both 14C-AIB and Texas Red. CONCLUSION: The magnitude of LiFUS mediated BBB opening correlates with concentration of microbubbles, cavitation dose as well as time of tracer administration post-sonication. These data help define the window of maximal BBB opening and applicable sonication parameters on a clinically translatable and commercially available FUS system that can be used to improve passive permeability and accumulation of therapeutics targeting the brain.

A scientometric analysis of the 100 most cited articles on magnetic resonance guided focused ultrasound.

Background: Diagnostic ultrasound has long been a part of a physician's armamentarium, but transcranial focused ultrasound (FUS) is an emerging treatment of neurological disorders. Consequently, the literature in this field is increasing at a rapid pace. Objective: This analysis was aimed to identify the top-cited articles on FUS to discern their origin, spread, current trends highlighting future impact of this novel neurosurgical intervention. Methods: We searched the Web of Science database on 28th May 2021 and identified the top 100 cited articles. These articles were analyzed with various scientometric parameters like the authors, corresponding authors, country of corresponding author, journal of publication, year of publication. Citation based parameters including total citations, mean citations per article and mean citations, citation count, and the citation per year, citations per year and co-authors per document were studied as well in addition to Hirsch h-index, g-index, m-index, Bradford's Law, Lotka's law and Collaboration index. Results: The 100 top-cited articles were published between 1998 and 2019 in 45 different journals. The average citations per document and citations per document per year were 97.78 and 12.47, respectively. The most prolific authors were Hynynen K (Medical Biophysics-Toronto), Elias WJ (Neurosurgery-Virginia), Zadicario (InSightec). The Journal of Neurosurgery published the most top-cited articles (n = 11), and most articles originated from the United States, followed by Canada. Among individual institutions, the University of Toronto was the most productive. Conclusion: FUS is an emerging treatment of neurological disorders. With its increasing application, the FUS literature is increasing rapidly. Eleven countries contributed to the top 100 cited articles, with the top 2 countries (the United States and Canada) contributing to more than half of these articles.

Patient-Derived Xenograft Models for Studying Vascular Mimicry in Melanoma In Vivo.

Tumor growth needs supply of nutrients, oxygen, and blood like the rest of the tissue, but it has been observed that tumor tissue may develop its own neovascular vessels lined with tumor cells instead of the endothelial cells. This phenomenon is referred to as vascular mimicry. Understanding vascular mimicry in melanoma is necessary for the progress of targeted therapeutic research. Patient-derived melanoma xenograft models replicate the tumor microenvironment in vivo and are more reliable in predicting patient response to therapy compared to tissue culture-based methods. This book chapter describes the patient-derived xenograft (PDX) models for studying vascular mimicry in melanoma in vivo. The chapter discusses methods for tissue collection, preimplantation processing, implantation, harvest, storage, and postharvest. Detection of vasculogenic mimicry has been described using immunohistochemical expression of markers.

Lipid exposure activates gene expression changes associated with estrogen receptor negative breast cancer.

Improved understanding of local breast biology that favors the development of estrogen receptor negative (ER-) breast cancer (BC) would foster better prevention strategies. We have previously shown that overexpression of specific lipid metabolism genes is associated with the development of ER- BC. We now report results of exposure of MCF-10A and MCF-12A cells, and mammary organoids to representative medium- and long-chain polyunsaturated fatty acids. This exposure caused a dynamic and profound change in gene expression, accompanied by changes in chromatin packing density, chromatin accessibility, and histone posttranslational modifications (PTMs). We identified 38 metabolic reactions that showed significantly increased activity, including reactions related to one-carbon metabolism. Among these reactions are those that produce S-adenosyl-L-methionine for histone PTMs. Utilizing both an in-vitro model and samples from women at high risk for ER- BC, we show that lipid exposure engenders gene expression, signaling pathway activation, and histone marks associated with the development of ER- BC.

Functional Genetic Diversity and Plant Growth Promoting Potential of Polyphosphate Accumulating Bacteria in Soil.

Polyphosphate (polyP) accumulation is an important trait of microorganisms. Implication of polyP accumulating bacteria (PAB) in enhanced biological phosphate removal, heavy metal sequestration, and dissolution of dental enamel is well studied. Phosphorous (P) accumulated within microbial biomass also regulates labile P in soil; however, abundance and diversity of the PAB in soil is still unexplored. Present study investigated the genetic and functional diversity of PAB in rhizosphere soil. Here, we report the abundance of Pseudomonas spp. as high PAB in soil, suggesting their contribution to global P cycling. Additional subset analysis of functional genes i.e., polyphosphate kinase (ppk) and exopolyphosphatase (ppx) in all PAB, indicates their significance in bacterial growth and metabolism. Distribution of functional genes in phylogenetic tree represent a more biologically realistic discrimination for the two genes. Distribution of ppx gene disclosed its phylogenetic conservation at species level, however, clustering of ppk gene of similar species in different clades illustrated its environmental condition mediated modifications. Selected PAB showed tolerance to abiotic stress and strong correlation with plant growth promotary (PGP) traits viz. phosphate solubilization, auxin and siderophore production. Interaction of PAB with A. thaliana enhanced the growth and phosphate status of the plant under salinity stress, suggestive of their importance in P cycling and stress alleviation. IMPORTANCE Study discovered the abundance of Pseudomonas genera as a high phosphate accumulator in soil. The presence of functional genes (polyphosphate kinase [ppk] and exopolyphosphatase [ppx]) in all PAB depicts their importance in polyphosphate metabolism in bacteria. Genetic and functional diversity reveals conservation of the ppx gene at species level. Furthermore, we found a positive correlation between PAB and plant growth promotary traits, stress tolerance, and salinity stress alleviation in A. thaliana.

The Antimicrobial Effect of Pomegranate Peel Extract versus Chlorhexidine in High Caries Risk Individuals Using Quantitative Real-Time Polymerase Chain Reaction: A Randomized Triple-Blind Controlled Clinical Trial.

The aim of the present study was to compare the antibacterial effectiveness of chlorhexidine and PPE oral rinse on S. mutans, Lactobacilli, and Veillonella, in clinical salivary samples of patients with advanced stages of dental caries at baseline and two and four weeks with PCR technique. This triple-blind randomized clinical trial involved 60 high caries risk adult patients, 19-59 years of age, randomly allocated into two groups of 30 subjects each. The intervention group received pomegranate peel extract mouthwash, whereas the control group received chlorhexidine mouthwash. Unstimulated pooled saliva was collected from the floor of the mouth before and after the intervention. The quantitative real-time polymerase chain reaction was employed to analyze the bacterial copies of each salivary sample at baseline and two and four weeks. The significance level was fixed at 5% (α = 0.05). Overall comparison of antimicrobial effectiveness across both groups revealed insignificant outcomes. The control group evinced a significant reduction in S. mutans between a specific time, i.e., baseline and 4 weeks (p=0.043). PPE oral rinse as a natural product or ecological alternative was effective in disrupting activity across all microorganisms tested in this triple-blind RCT; however, the nutraceutical, when compared to chlorhexidine, was not as effective against S. mutans.