Central Nervous System Activity Research Articles

Cerebrospinal Fluid Biomarkers of Myeloid and Glial Cell Activation Are Correlated With Multiple Sclerosis Lesional Inflammatory Activity.

Multiple sclerosis (MS)-related inflammation can be divided into lesional activity, mediated by immune cells migrating from the periphery to the central nervous system (CNS) and non-lesional activity, mediated by inflammation compartmentalized to CNS tissue. Lesional inflammatory activity, reflected by contrast-enhancing lesions (CELs) on the magnetic resonance imaging (MRI), is effectively inhibited by current disease modifying therapies (DMTs). While, the effect of DMTs on non-lesional inflammatory activity is currently unknown. Reliable and simultaneous measurements of both lesional and non-lesional MS activity is necessary to understand their contribution to CNS tissue destruction in individual patients. We previously demonstrated that CNS compartmentalized inflammation can be measured by combined quantification of cerebrospinal fluid (CSF) immune cells and cell-specific soluble markers. The goal of this study is to develop and validate a CSF-biomarker-based molecular surrogate of MS lesional activity. The training cohort was dichotomized into active (CELs > 1 or clinical relapse) and inactive lesional activity (no CELs or relapse) groups. Matched CSF and serum samples were analyzed for 20 inflammatory and axonal damage biomarkers in a blinded fashion. Only the findings from the training cohort with less than 0.1% probability of false positive (i.e., p < 0.001) were validated in an independent validation cohort. MS patients with lesional activity have elevated IL-12p40, CHI3L1, TNFα, TNFβ, and IL-10, with the first two having the strongest effects and validated statistically-significant association with lesional activity in an independent validation cohort. Marker of axonal damage, neurofilament light (NfL), measured in CSF (cNfL) was also significantly elevated in MS patients with active lesions. NfL measured in serum (sNfL) did not differentiate the two MS subgroups with pre-determined significance, (p = 0.0690) even though cCSF and sNfL correlated (Rho = 0.66, p < 0.0001). Finally, the additive model of IL12p40 and CHI3L1 outperforms any biomarker discretely. IL12p40 and CHI3L1, released predominantly by immune cells of myeloid lineage are reproducibly the best CSF biomarkers of MS lesional activity. The residuals from the IL12p40/CHI3L1-cNfL correlations may identify MS patients with more destructive inflammation or contributing neurodegeneration.

The features of temperament and levels of activation of central nervous system of female students with various condition of reproductive health

The article demonstrates the relationship between temperamental features and functional state of central nervous system in female students various regimen of reproductive system functioning. The sampling included 115 female students of Krasnoyarsk with different status of menstrual function, including 51 female students with normal gonadotropic and prolactin type of anovulation and 64 female students with ovulatory menstrual cycle. The questionnaire DOTS-R was applied to establish the temperament characteristics. The functional condition of the central nervous system was studied using method of simple and complex visual-motor reaction by means of device "Psychophysiologist". The results of the study demonstrated that girls with "calm" and "rigid" types of temperament have features of functional state of the central nervous system that can condition predisposition to menstrual cycle disorders. The particular features of functional state of the central nervous system in female students with anovulatory cycle were established: decreasing of level of activation of the central nervous system in individuals with "intense" and "unstable" types of temperament and workability of girls of "adequate" type. The application of complex reproductive health evaluation to female students to establish personalty temperamental features will input into forming of risk groups relating to development of menstrual cycle disorders in female students.

Endosomal escape cell-penetrating peptides significantly enhance pharmacological effectiveness and CNS activity of systemically administered antisense oligonucleotides

Antisense oligonucleotides (ASOs) are an emerging class of gene-specific therapeutics for diseases associated with the central nervous system (CNS). However, ASO delivery across the blood–brain barrier (BBB) to their CNS target cells remains a major challenge. Since ASOs are mainly taken up into the brain capillary endothelial cells interface through endosomal routes, entrapment in the endosomal compartment is a major obstacle for efficient CNS delivery of ASOs. Therefore, we evaluated the effectiveness of a panel of cell-penetrating peptides (CPPs) bearing several endosomal escape domains for the intracellular delivery, endosomal release and antisense activity of FDA-approved Spinraza (Nusinersen), an ASO used to treat spinal muscular atrophy (SMA). We identified a CPP, HA2-ApoE(131–150), which, when conjugated to Nusinersen, showed efficient endosomal escape capability and significantly increased the level of full-length functional mRNA of the survival motor neuron 2 (SMN2) gene in SMA patient-derived fibroblasts. Treatment of SMN2 transgenic adult mice with this CPP-PMO conjugate resulted in a significant increase in the level of full-length SMN2 in the brain and spinal cord. This work provides proof-of-principle that integration of endosomal escape domains with CPPs enables higher cytosolic delivery of ASOs, and more importantly enhances the efficiency of BBB-permeability and CNS activity of systemically administered ASOs.

CAPE and Neuroprotection: A Review.

Propolis, a product of the honey bee, has been used in traditional medicine for many years. A hydrophobic bioactive polyphenolic ester, caffeic acid phenethyl ester (CAPE), is one of the most extensively investigated active components of propolis. Several studies have indicated that CAPE has a broad spectrum of pharmacological activities as anti-oxidant, anti-inflammatory, anti-viral, anti-fungal, anti-proliferative, and anti-neoplastic properties. This review largely describes CAPE neuroprotective effects in many different conditions and summarizes its molecular mechanisms of action. CAPE was found to have a neuroprotective effect on different neurodegenerative disorders. At the basis of these effects, CAPE has the ability to protect neurons from several underlying causes of various human neurologic diseases, such as oxidative stress, apoptosis dysregulation, and brain inflammation. CAPE can also protect the nervous system from some diseases which negatively affect it, such as diabetes, septic shock, and hepatic encephalopathy, while numerous studies have demonstrated the neuroprotective effects of CAPE against adverse reactions induced by different neurotoxic substances. The potential role of CAPE in protecting the central nervous system (CNS) from secondary injury following various CNS ischemic conditions and CAPE anti-cancer activity in CNS is also reviewed. The structure–activity relationship of CAPE synthetic derivatives is discussed as well.

Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis

BackgroundFollicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear.MethodsTo determine the impact of dysregulated regulatory T cells (Tregs), TFR cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells.ResultsMice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased TFH-Ab responses, more IgE deposition in the CNS, and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE.ConclusionsBlimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity.

Toward a unified model of stress recovery and cognitive restoration in nature

There is abundant evidence for both cognitive and affective improvements stemming from spending time in nature; however, the mechanism underlying these effects are still under debate. Frameworks such as Attention Restoration Theory (ART; Kaplan 1995) and Stress Recovery Theory (SRT; Ulrich et al. 1991) have been helpful in understanding how restoration is achieved. Using the neurovisceral integration model (NIVM; Thayer and Lane 2000, 2002), we suggest that cognitive restoration and stress recovery co-occur and that they are bidirectional manifestations of activity in the vagus nerve, which links the peripheral nervous system (PNS) to the central nervous system (CNS). Future research should examine both PNS and CNS activity simultaneously to provide a better understanding of the changes in the body and brain associated with immersion in nature. This research program will provide the scientific evidence to help inform public policy related to human health, urban design, and environmental protection.

A Comparison Between First-, Second- and Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Non-Small-Cell Lung Cancer and Brain Metastases

Patients with non-small-cell lung cancer (NSCLC), harboring Epidermal Growth Factor Receptor (EGFR) mutations, are more susceptible to brain metastases (BM). Comparisons of the efficacy of different-generation EGFR-tyrosine kinase inhibitors (TKI) on BMs from NSCLC are currently limited. We identified studies comparing different EGFR-TKIs for NSCLC through Pubmed literature search and selected those with neurological outcome data. By two retrospective analyses, Erlotinib showed longer neurological time-to-progression (30 months vs. 15.8 months, P = 0.024) and reduced the risk of central nervous system (CNS) progression (Hazard Ratio (HR) 0.25; 95% CI, 0.08–0.81; P = 0.021) compared to Gefitinib. In a phase 2b randomized trial, 16% of patients with BMs had a similar Progression Free Survival (PFS) (HR 0.76, 95% CI 0.41–1.44) or Overall Survival (OS) (HR 1.16, 95% CI 0.61–2.21) with Afatinib versus Gefitinib; a lower risk of developing subsequent BMs with Afatinib than Gefitinib (HR 0.49; 95% CI 0.34–0.71; P &lt; 0.001) was reported by a retrospective study. A randomized phase 3 trial proved that patients with BMs treated with Osimertinib had longer PFS (HR 0.47, 95% CI 0.30–0.74) and OS (HR 0.79, 95% CI 0.61–1.01) than with Gefitinib, and lower incidence of CNS progression (6% vs. 15%, respectively). Although there is limited evidence, differences in CNS activity may exist between EGFR-TKIs.

Skutki hamowania funkcji PCSK9 w obrębie wybranych tkanek*

Streszczenie Konwertazy probiałkowe (PCs, proprotein convertases) to rodzina 9 proteaz serynowych (PC1/3, PC2, furyna, PC4, PC5/6, PACE4, PC7, SKI-1), której przedstawicielem jest również konwertaza probiałkowa typu 9 o aktywności subtylizyny/keksyny (PCSK9). Poszczególni członkowie tej rodziny, są głównym elementem w potranslacyjnej obróbce białek prekursorowych, prowadzącej do powstania biologicznie czynnych cząsteczek, takich jak hormony, enzymy, czynniki transkrypcyjne oraz czynniki wzrostu. W związku ze zdolnością aktywacji dużej liczby substratów, PCs odgrywają znaczącą rolę w przebiegu procesów fizjologicznych, takich jak embriogeneza, aktywność ośrodkowego układu nerwowego, metabolizm lipidów, a także w stanach patofizjologicznych m.in. infekcjach wirusowych i bakteryjnych, osteoporozie, hiperglikemii, chorobach sercowo-naczyniowych, neurodegeneracyjnych oraz nowotworowych. Zahamowanie funkcji konwertazy proproteiny typu 9 o aktywności subtylizyny/keksyny (PCSK9, proprotein convertase subtilisin/kexin 9) przez przeciwciała, takie jak alirokumab czy ewolokumab zmniejsza tempo degradacji receptora LDL (lipoproteina o małej gęstości). Wiąże się to z redukcją stężenia cholesterolu LDL w osoczu, którego normalizacja jest jednym z głównych celów służących ograniczeniu ryzyka sercowo-naczyniowego. Inhibitory PCSK9 (alirokumab, ewolokumab, bococizumab) zostały stworzone m.in. z myślą o pacjentach, u których mimo stosowania optymalnych dawek dostępnych leków hipolipemizujących (statyn, ezetymibu) nie udało się uzyskać pożądanych wartości stężeń cholesterolu LDL we krwi. Wydaje się, że ze względu na dużą skuteczność, przyszłe zastosowanie inhibitorów PCSK9 (PCSK9i) w codziennej praktyce klinicznej będzie bardziej powszechne. Uwzględniając działania plejotropowe substancji dotychczas stosowanych w hiperlipidemii, takich jak statyny, omówiono piśmiennictwo pod kątem innych, poza hipolipemizującymi, możliwych skutków działania inhibitorów PCSK9 oraz oceniono ich potencjalne zalety lub wady.

A Phase II study of nab-Paclitaxel (nab-P) in patients with advanced non-small cell lung cancer with EGFR mutations after frontline tyrosine kinase inhibitor therapy

BackgroundPatients with metastatic non-small cell lung cancer (NSCLC) harboring a sensitizing EGFR mutation have effective targeted therapy options initially but most patients eventually progress and receive cytotoxic chemotherapy. In this single-institution phase II study, we evaluated the role of nab-paclitaxel monotherapy in this patient population. Patients and MethodsPatients with metastatic NSCLC with an activating EGFR mutation whose disease progressed after frontline tyrosine kinase inhibitor therapy and who were chemotherapy naïve received nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint was response rate per RECIST 1.1 and secondary endpoints were duration of response, progression free survival, toxicity and overall survival. ResultsA total of 27 patients were enrolled and 21 patients were evaluable for response. Median age was 65 (range 52–81), 69% of patients were women, 42% of patients did not having a smoking history. 31% of patients had central nervous system (CNS) metastatic disease at baseline. Confirmed partial response was documented in 9 of 26 patients (35%, 95% CI 17–56) and disease control rate was 58% (95% CI 35–73). CNS was a common first site of progression. Median progression free survival was 4.0 months (95% CI 1.8–5.2). No new safety signals were observed. ConclusionSingle agent nab-paclitaxel showed modest antitumor activity in patients with EGFR mutation positive NSCLC and may be an option in patients who are platinum ineligible. Patients often progressed in the CNS and the results underscores the importance of CNS activity of systemic therapies in this patient population.

Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery

Allopregnanolone, a positive modulator of GABAA receptors with antiseizure activity, has potential in the treatment of seizure emergencies. Instillation of allopregnanolone in 40% sulfobutylether-β-cyclodextrin into the nose in mice rapidly elevated the seizure threshold in the timed intravenous pentylenetetrazol (ED50, 5.6 mg/kg), picrotoxin (ED50, 5.9 mg/kg), and bicuculline seizure tests. The effect peaked at 15 min, decayed over 1 h, and was still evident in some experiments at 6 h. Intranasal allopregnanolone also delayed the onset of seizures in the maximal PTZ test. At an allopregnanolone dose (16 mg/kg) that conferred comparable effects on seizure threshold as the benzodiazepines midazolam and diazepam (both at doses of 1 mg/kg), allopregnanolone caused minimal sedation or motor toxicity in the horizontal screen test whereas both benzodiazepines produced marked behavioral impairment. In addition, intranasal allopregnanolone failed to cause loss-of-righting reflex in most animals, but when the same dose was administered intramuscularly, all animals became impaired. Intranasal allopregnanolone (10 mg/kg) caused a rapid increase in brain allopregnanolone with a Tmax of ~5 min after initiation of the intranasal delivery. High levels of allopregnanolone were recovered in the olfactory bulb (Cmax, 16,000 ng/mg) whereas much lower levels (Cmax, 670 ng/mg) were present in the remainder of the brain. We conclude that the unique ability of intranasal allopregnanolone to protect against seizures without inducing behavioral adverse effects is due in part to direct nose-to-brain delivery, with preferential transport to brain regions relevant to seizures. Benzodiazepines are commonly administered intranasally for acute seizure therapy, including for the treatment of acute repetitive seizures, but are not transported from nose-to-brain. Intranasal allopregnanolone acts with greater speed, has less propensity for adverse effects, and has the ability to overcome benzodiazepine refractoriness. This is the first study demonstrating rapid functional central nervous system activity of a nose-to-brain-delivered steroid. Intranasal delivery circumvents the poor oral bioavailability of allopregnanolone providing a route of administration permitting its evaluation as a treatment for diverse neuropsychiatric indications.

Analgesia in the intensive care unit

Background. Sedation is a technique of using drugs to put a patient in a condition in which he can tolerate unpleasant procedures, while maintaining cardiorespiratory function. The main problems associated with analgesia and sedation (AS) are associated with the development of hypoxia, vomiting and aspiration, hypotension and hemodynamic instability, apnea.&#x0D; Objective. To describe the features of the modern AS.&#x0D; Materials and methods. Analysis of literature data on this issue.&#x0D; Results and discussion. AS can be performed with the help of different drugs. Benzodiazepines (preferably midazolam) and/or propofol in combination with low doses of opioids should be used in patients with concomitant cardiac abnormalities. The use of propofol in this category of patients is carried out by fractional administration (on average, 50 mg) with an interval of 30-40 seconds until an adequate sedative effect is achieved. Dexmedetomidine has been suggested as an adjuvant. It should be kept in mind that benzodiazepines are not suitable for creating a long-lasting sedative effect, and can cause paradoxical agitation in the elderly. Features of sedation in patients at risk of obstructive sleep apnea syndrome are represented with the use of a minimum dose of hypnotics without the use of opioids. Dexmedetomidine is considered as an alternative. It is advisable to use continuous positive airways pressure by inhalation of oxygen through the nasal cannula. Patients with morbid obesity should avoid lying on their back. For the effective control of airway patency, it is advisable to use endotracheal intubation. It is recommended to avoid long-acting drugs and drugs that cause respiratory depression. The use of propofol in this group is often associated with respiratory complications, so the use of remifentanil and dexmedetomidine is recommended as an alternative. For patients with chronic renal failure, midazolam and/or fentanyl should be preferred, however, the cardiovascular and pulmonary side effects of any of these drugs are exacerbated when they are used concomitantly. In patients with hepatic dysfunction, midazolam may exacerbate symptoms, so propofol should be preferred. If the latter is used, the doctor should be near the patient throughout the procedure and monitor him exclusively. As for dexmedetomidine, this drug selectively binds and activates presynaptic α2-adrenoreceptors, inhibiting the release of norepinephrine. As a result, postsynaptic activation of adrenoceptors is inhibited, sympathetic activity is suppressed, leading to analgesia, sedation and decrease of anxiety. Under conditions of mild or moderate sedation caused by dexmedetomidine, patients respond to verbal stimulation and are able to communicate and cooperate with medical staff, and after awakening show high results in tests of central nervous system activity. Dexmedetomidine is less likely to cause postoperative delirium than midazolam (54 % vs. 76.6 %) and does not adversely affect sleep quality, unlike propofol. Dexmedetomidine can be used together with paracetamol. Intravenous paracetamol significantly reduces postoperative pain and the need for opioids.&#x0D; Conclusions. 1. AS can be performed with the use of benzodiazepines, propofol, dexmedetomidine. 2. Benzodiazepines are not suitable for creating a long-lasting sedative effect, and can cause paradoxical agitation in the elderly. 3. Patients with different comorbid conditions are characterized by different features of required AS. 4. Dexmedetomidine gives the patient the opportunity to communicate and cooperate with medical staff, rarely causes postoperative delirium and does not adversely affect the sleep quality. 5. Intravenous paracetamol significantly reduces postoperative pain and the need for opioids.

Surface Electromyography Meets Biomechanics: Correct Interpretation of sEMG-Signals in Neuro-Rehabilitation Needs Biomechanical Input.

Coordinated activation of muscles is the basis for human locomotion. Impaired muscular activation is related to poor movement performance and disability. To restore movement performance, information about the subject's individual muscular activation is of high relevance. Surface electromyography (sEMG) allows the pain-free assessment of muscular activation and many ready-to-use technologies are available. They enable the usage of sEMG measurements in several applications. However, due to the fact that in most rehabilitation applications dynamic conditions are analyzed, the correct interpretation of sEMG signals remains difficult which hinders the spread of sEMG in clinical applications. From biomechanics it is well-known that the sEMG signal depends on muscle fiber length, contraction velocity, contraction type and on the muscle's biomechanical moment. In non-isometric conditions these biomechanical factors have to be considered when analyzing sEMG signals. Additionally, the central nervous system control strategies used to activate synergistic and antagonistic muscles have to be taken into consideration. These central nervous system activation strategies are rarely known in physiology and are hard to manage in pathology. In this perspective report we discuss how the consideration of biomechanical factors leads to more reliable information extraction from sEMG signals and how the limitations of sEMG can be overcome in dynamic conditions. This is a prerequisite if the use of sEMG in rehabilitation applications is to extend. Examples will be given showing how the integration of biomechanical knowledge into the interpretation of sEMG helps to identify the central nervous system activation strategies involved and leads to relevant clinical information.

Normative data and correlation between dynamic knee valgus and neuromuscular response among healthy active males: a cross-sectional study

The dynamic knee valgus (DKV) during different sport maneuvers has been widely described as risk factor to develop an anterior cruciate ligament injury. Hip and knee muscles seem to have a crucial role to prevent the dynamic knee valgus. This study aimed to give normative and correlational data about DKV and hip and knee neuromuscular response (NMR) among healthy active males. The hypothesis is that DKV could be correlated with hip NMR. A cross-sectional correlational study. Research Anatomy Laboratory. The study was carried out among 50 active, non-injured males. Dynamic Knee-Valgus angle and lower limb posterior chain muscles Neuromuscular Response. DKV was measured using Kinovea software during a Single-Legged Drop Jump test and NMR was measured using tensiomyography and myotonometry for gluteus maximum, biceps femoris, semitendinosus, lateral and medial gastrocnemius. Right and left limbs were both performed and analyzed independently. No significant correlation was observed between DKV and hip and knee muscles NMR. This study shows normative and correlational data about dynamic knee valgus, tensiomyography and myotonometry for healthy and active males. The DKV control seems to be non-correlated with isolated hip and knee muscles NMR so this suggests it is more about Central Nervous System activity than about isolated muscles NMR.

A systematic review of caregiver-child physiological synchrony across systems: Associations with behavior and child functioning.

Extensive research has established a positive association between caregiver-child behavioral synchrony and child developmental functioning. Burgeoning research examining physiological synchrony has yet to elucidate its impact for children's developing self-regulation. The objectives of this systematic review were to: 1) determine whether there is evidence that caregiver-child physiological synchrony promotes positive child development, 2) examine developmental differences in physiological synchrony and its correlates, and 3) explore whether context, risk, and/or stress influence patterns of synchrony. Sixty-nine studies met the following criteria on PubMed and PsycINFO: 1) peer-reviewed empirical articles in English that 2) examine autonomic, hypothalamic-pituitary-adrenocortical, and/or central nervous system activity 3) for caregivers and children 4) in response to a task and 5) directly examine the association between caregiver and child physiology. Findings varied based on developmental period and current behavioral context. Functional differences may exist across physiological systems and contexts. Synchrony may have different developmental consequences for dyads with and without certain risk factors. Few studies examine physiological synchrony across multiple systems or contexts, nor do they measure child characteristics associated with synchrony. Statistical and methodological challenges impede interpretation. Findings generally support the idea that physiological synchrony may support children's developing self-regulation. Longitudinal research is needed to examine child developmental outcomes over time.

Intranasal Delivery: Effects on the Neuroimmune Axes and Treatment of Neuroinflammation.

This review highlights the pre-clinical and clinical work performed to use intranasal delivery of various compounds from growth factors to stem cells to reduce neuroimmune interactions. We introduce the concept of intranasal (IN) delivery and the variations of this delivery method based on the model used (i.e., rodents, non-human primates, and humans). We summarize the literature available on IN delivery of growth factors, vitamins and metabolites, cytokines, immunosuppressants, exosomes, and lastly stem cells. We focus on the improvement of neuroimmune interactions, such as the activation of resident central nervous system (CNS) immune cells, expression or release of cytokines, and detrimental effects of signaling processes. We highlight common diseases that are linked to dysregulations in neuroimmune interactions, such as Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis, and traumatic brain injury.

Central Nervous System (CNS) Involvement in Adult Acute Lymphoblastic Leukemia (ALL) Assessed Solely By Flow Cytometry Has an Adverse Impact on Survival

Introduction: Several studies published in recent years dealing with the detection of Central Nervous System (CNS) disease in Acute Lymphoblastic Leukemia (ALL) have demonstrated superiority in terms of sensitivity of Flow Cytometry (FCM) over standard cytology (Tawfik et al, 2018). However, whether CNS activity detected by FCM has an impact on the clinical outcome of ALL adult patients, is still a matter of debate. (Del Principe et al, 2019) Methodology: We analyzed a retrospective cohort of newly diagnosed ALL adult patients in an oncologic center in Mexico, who had a CNS analysis by FCM and conventional cytology, diagnosed between 2017 and 2019. The primary endpoint was to assess the impact on the survival of patients with CNS disease detected by FCM. We defined positive FCM (FCM+) when the patient had &amp;gt;10 phenotypically pathologic events and positive cytology (Cyt+) when the patent had confirmed CNS-2 or CNS-3 activity as defined by NCCN and ESMO; double-negative (DN) patients were considered when neither FCM nor cytology demonstrated disease as described above. Baseline characteristics were grouped in tables and summarized as medians and ranges for quantitative variables or frequencies in qualitative variables. Basal characteristics and different outcomes were compared by the chi-square test for binary variables, and the Mann-Whitney U test for quantitative variables. Overall Survival (OS) and Disease-Free Survival (DFS) analysis were made by Kaplan-Meier curves. A comparison between groups was performed using the log-rank test, with a significant P value less than 0.05 and a 95% confidence interval (CI). We performed a Cox regression model to obtain an HR with a 95% confidence interval for survival to identify risk associations. Results: Of the 92 evaluable patients, the median age was 28 years. 88% of all ALL were ALL-B. The median count of leucocytes was 11.65 x109/L (range 4.71-38.24 x109/L); median LDH was 758 UI/L (range 314-1242 UI/L). 63% of patients had an unfavorable karyotype (hypodiploidy, complex karyotype, or KMT2A). At diagnosis, 27 (28%) were positive by FCM and negative by cytology. The median of the analyzed events was 14,733 (5,025-50,000) with a viability of 38.5% (22-61.75). Only 6 patients were positive by both techniques. 45% of patients with CNS involvement had neurological symptoms (mainly headache). The most used treatment was BFM in 56.7% of patients, followed by HyperCVAD in 37.8%. Patients with documented CNS infiltration by FCM or cytology were treated with triple intrathecal chemotherapy two times per week. Three patients had no response after two weeks of treatment, one received radiotherapy without any response and the other two were dead for chemotherapy toxicity. We found gender as the only statistically significant variable associated with a higher FCM+ (77% males vs 23% females, p&amp;lt;0.01). For the entire cohort, the complete remission (CR) after induction was 84% and 63% had a negative minimal residual disease (MRD) by FCM in the bone marrow. 15% of the patients were refractory. There were no differences between CR (73% versus 88%, p= 0.16), MRD negativity (46% versus 69%, p=0.11), refractory disease (26% versus 10%, p=0.13) or relapsed disease (50% versus 43%, p=0.65) between FCM(+) and ND groups. The OS for the entire cohort was 11.3 months. Patients with FCM+ had a lower survival of 5.6 months [CI95% (0.72-10.67)] compared with 11.8 months [CI95% (0.47-11.95)] in the DN group. The median DFS for the FCM+ patients was 4.6 months [CI95% (3.42-5.92)] versus 16.4 months [CI95% (6.21-26.75)] for DN group. In the Cox regression model, the HR for survival in patients with FCM+ was 1.85 (CI95% 1.004-3.421; p=0.04). Conclusions: Despite the retrospective nature of this study, the detection of CNS involvement was increased from 6% to 28% employing FCM compared with cytology. As mentioned previously, in other studies, FCM has greater sensitivity than cytology (Ranta et al. 2014). According to our results, the presence of CNS disease, detected by FCM has an adverse impact on OS in adult patients with newly diagnosed ALL. These results dictate consideration of FCM as a routine study in the diagnosis of ALL. Prospective studies are needed to evaluate more intensive treatment in these patients. Figure Disclosures No relevant conflicts of interest to declare.

Review of the Chemical Properties, Pharmacological Properties, and Development Studies of Cymbopogon sp.

Cymbopogon is a genus of aromatic plants that famed because of the essential oil production that has many benefit in industrial, daily life, or even for disease treatment. The Cymbopogon genus consists of about 180 plants, including different species, subspecies, varieties, and subvarieties. The aim of this review is to present chemical properties, pharmacological, and development of the Cymbopogon genus from books and research studies. There were many types of research that have been done to prove the benefits of the Cymbopogon genus, including studies about the extract, essential oil, the chemical compound biological activity, and development studies. Some pharmacological studies that have been confirmed are regarding the pharmacological effects of Cymbopogon in the central nervous system, anti-inflammatory, antimicrobial, antioxidant, and anticancer activity. In addition, there have been studied to improve Cymbopogon benefits.

Ensartinib as Treatment for ALK-Rearranged NSCLC

Ensartinib as Treatment for ALK-Rearranged NSCLC

Somatic embryogenesis and in vitro plant regeneration of Bacopa monnieri (Linn.) Wettst., a potential medicinal water hyssop plant.

Bacopa monnieri (Linn.) Wettst. commonly known as waterhyssop, Brahmi plant, traditionally used for memory enhancement, nerve tonic, epilepsy, central nervous system (CNS), antidepressant, anxiety, blood pressure and antioxidant activities. Due to pharmaceutical demands its lost natural habitat. At this juncture we describe a resourceful protocol for micropropagation of water hyssop plant. Surface sterilized leaf and nodal explants were inoculated on basal MS semi-solid medium added with PGRs; auxins, cytokinins. Highest calli formation from leaf explants was obtained on NAA (2.5 mg−1) and showed (94.22%) accompanied via 2,4-D showed (2.5 mg−1; 82.43%), maximum calli formation in nodal explants was obtained on 2,4-D showed (2.5 mg−1; 71.14%) followed by NAA (2.5 mg−1) showed (62.15%), in internodes explants uppermost calli formation was obtained from 2,4-D showed (2.5 mg−1; 65.21%) followed by NAA (2.5 mg−1) showed (52.14%). The maximum somatic embryogenic callus, calli induction and formation (84%) was observed on 2,4-D + KIN (2.0 + 1.5 mg−1) amended solid medium. Uppermost shoot formation was observed in combination of IAA + BAP (1.0 + 1.0 mg−1) showed (78.54%) shoot formation followed by IBA (2.0 mg−1) alone showed (75.37%). The maximum shoot elongation was noticed from NAA + BAP (3.0 + 3.0 mg−1) with 21.21 cm followed by NAA (2.0 mg−1) showed (15.22 cm) although, chief root formation was obtained from IBA (2.0 mg−1) with 83.75% root formation along higher number of roots (47.43%) per shoot. Followed by IAA (2.0 mg−1) showed root induction (73.43%) and no of roots (38.54%) per shoot. In hardening under pot condition plants survivability (100%) was observed under glass house conditions, the present in vitro PTC techniques is extremely significant to gratifying its natural conservation.

Synthesis and biological evaluation of imidazoline derivatives as potential CNS and CVS agents

A series of substituted imidazoline derivatives were synthesized and characterized. Compounds were tested in-vivo for their antihypertensive, analgesic, antiaggressive, depressant, antidepressant, and ALD50 activities. The compounds 3a, 3c, 4c, 5a, and 6c showed cardiovascular as well as central nervous system activities and are potential candidate as drug among all fifteen compounds tested. All these compounds have shown better activity for antihypertensive, analgesic, antiaggressive, and depressant-antidepressant, properties than reference compounds clonidine, morphine, diazepam, and imipramine respectively. Most of the compounds have shown ALD50 > 500 mg/kg with maximum in 4a and 5a (>1000 mg/kg).