Absence of synergistic effects of CNS treatments on neuropsychologic test performance among children.

Three hypotheses are proposed to account for neurobehavioral impairments following treatment with cranial radiation therapy (CRT) and intrathecal (IT) chemotherapy: CNS treatments exert a synergistic effect (A x B), an additive effect (A + B), or a single-agent effect (A or B). Eighty-five long-term survivors of non-CNS cancers aged 6 to 16 years were classified into groups on the basis of CNS treatments: CRT-IT (n = 25), CRT-No IT (n = 11), No CRT-IT (n = 24), and No CRT-No IT (n = 25). Study I findings did not provide support for synergistic mechanisms; nonorthogonal analysis of variance showed interaction effects (CRT x IT) restricted to tactile-perceptual speed. However, main effects were significant for a single agent (CRT) across a wide range of measures. General intelligence, academic achievement, verbal knowledge and reasoning, and perceptual-motor abilities were found to be significantly lower among CRT-treated groups. Study II findings provided additional support for the role of CRT; Pearson correlations within the CRT-No IT group indicated significant negative associations between CRT dose estimates for cortical regions and perceptual-motor abilities.

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Anticancer effects of the combined Thai noni juice ethanolic extracts and 5-fluorouracil against cholangiocarcinoma cells in vitro and in vivo

Scientific Reports ◽

10.1038/s41598-021-94049-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jeerati Prompipak ◽

Thanaset Senawong ◽

Banchob Sripa ◽

Albert J. Ketterman ◽

Suppawit Utaiwat ◽

...

Keyword(s):

Nude Mice ◽

Combination Treatment ◽

Synergistic Effects ◽

Single Agent ◽

Xenograft Model ◽

Ethanolic Extract ◽

Model Combination ◽

Mouse Xenograft Model ◽

Ethanolic Extracts

AbstractApplication of 5-fluorouracil (5-FU) in cholangiocarcinoma (CCA) is limited by adverse side effects and chemoresistance. Therefore, the combination therapy of 5-FU with other substances, especially natural products may provide a new strategy for CCA treatment. The aim of this study was to evaluate the combination effects of 5-FU and two ethanolic extracts of Thai noni juice (TNJ) products on CCA cell lines and nude mice xenografts. The results of antiproliferative assay showed the combination treatment of 5-FU and each TNJ ethanolic extract exerted more cytotoxicity on CCA cells than either single agent treatment. Synergistic effects of drug combinations can enable the dose reduction of 5-FU. The mechanism underlying a combination treatment was apoptosis induction through an activation of p53 and Bax proteins. In the nude mouse xenograft model, combination treatments of 5-FU with each TNJ ethanolic extract suppressed the growth of CCA cells implanted mice more than single agent treatments with no effects on mouse body weight, kidney, and spleen. Moreover, low doses of TNJ ethanolic extracts reduced the hepatotoxicity of 5-FU in nude mice. Taken together, these data suggested that the ethanolic extracts of TNJ products can enhance the anti-CCA effect and reduce toxicity of 5-FU.

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Nanometals-Containing Polymeric Membranes for Purification Processes

Materials ◽

10.3390/ma14030513 ◽

2021 ◽

Vol 14 (3) ◽

pp. 513

Author(s):

Anna Rabajczyk ◽

Maria Zielecka ◽

Krzysztof Cygańczuk ◽

Łukasz Pastuszka ◽

Leszek Jurecki

Keyword(s):

Synergistic Effects ◽

Membrane Surface ◽

Antibacterial Properties ◽

Polymeric Membranes ◽

Treatment Processes ◽

Wide Range ◽

Different Types ◽

Type Size ◽

Titanium Zinc ◽

Membrane Surface Charge

A recent trend in the field of membrane research is the incorporation of nanoparticles into polymeric membranes, which could produce synergistic effects when using different types of materials. This paper discusses the effect of the introduction of different nanometals such as silver, iron, silica, aluminum, titanium, zinc, and copper and their oxides on the permeability, selectivity, hydrophilicity, conductivity, mechanical strength, thermal stability, and antiviral and antibacterial properties of polymeric membranes. The effects of nanoparticle physicochemical properties, type, size, and concentration on a membrane’s intrinsic properties such as pore morphology, porosity, pore size, hydrophilicity/hydrophobicity, membrane surface charge, and roughness are discussed, and the performance of nanocomposite membranes in terms of flux permeation, contaminant rejection, and antifouling capability are reviewed. The wide range of nanocomposite membrane applications including desalination and removal of various contaminants in water-treatment processes are discussed.

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Trans-Cinnamaldehyde Exhibits Synergy with Conventional Antibiotic against Methicillin-Resistant Staphylococcus aureus

International Journal of Molecular Sciences ◽

10.3390/ijms22052752 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2752

Author(s):

Shu Wang ◽

Ok-Hwa Kang ◽

Dong-Yeul Kwon

Keyword(s):

Staphylococcus Aureus ◽

Methicillin Resistant Staphylococcus Aureus ◽

Synergistic Effects ◽

Regulatory Gene ◽

Western Blot Assay ◽

Methicillin Resistant ◽

Wide Range ◽

Kill Curve ◽

Conventional Antibiotics ◽

Time Kill

Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen worldwide and has acquired multiple resistance to a wide range of antibiotics. Hence, there is a pressing need to explore novel strategies to overcome the increase in antimicrobial resistance. The present study aims to investigate the efficacy and mechanism of plant-derived antimicrobials, trans-cinnamaldehyde (TCA) in decreasing MRSA’s resistance to eight conventional antibiotics. A checkerboard dilution test and time–kill curve assay are used to determine the synergistic effects of TCA combined with the antibiotics. The results indicated that TCA increased the antibacterial activity of the antibiotics by 2-16-fold. To study the mechanism of the synergism, we analyzed the mecA transcription gene and the penicillin-binding protein 2a level of MRSA treated with TCA by quantitative RT-PCR or Western blot assay. The gene transcription and the protein level were significantly inhibited. Additionally, it was verified that TCA can significantly inhibit the biofilm, which is highly resistant to antibiotics. The expression of the biofilm regulatory gene hld of MRSA after TCA treatment was also significantly downregulated. These findings suggest that TCA maybe is an exceptionally potent modulator of antibiotics.

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Role of Physical Exercise and Nutraceuticals in Modulating Molecular Pathways of Osteoarthritis

International Journal of Molecular Sciences ◽

10.3390/ijms22115722 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5722

Author(s):

Alessandro de Sire ◽

Nicola Marotta ◽

Cinzia Marinaro ◽

Claudio Curci ◽

Marco Invernizzi ◽

...

Keyword(s):

Signaling Pathways ◽

Synergistic Effects ◽

Molecular Pathways ◽

Epigenetic Changes ◽

Pathological Features ◽

Oxidative Signaling ◽

Cartilage Extracellular Matrix ◽

Wide Range ◽

Comprehensive Picture

Osteoarthritis (OA) is a painful and disabling disease that affects millions of patients. Its etiology is largely unknown, but it is most likely multifactorial. OA pathogenesis involves the catabolism of the cartilage extracellular matrix and is supported by inflammatory and oxidative signaling pathways and marked epigenetic changes. To delay OA progression, a wide range of exercise programs and naturally derived compounds have been suggested. This literature review aims to analyze the main signaling pathways and the evidence about the synergistic effects of these two interventions to counter OA. The converging nutrigenomic and physiogenomic intervention could slow down and reduce the complex pathological features of OA. This review provides a comprehensive picture of a possible signaling approach for targeting OA molecular pathways, initiation, and progression.

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Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor

Cancers ◽

10.3390/cancers13153699 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3699

Author(s):

Marya Kozinova ◽

Shalina Joshi ◽

Shuai Ye ◽

Martin G. Belinsky ◽

Dinara Sharipova ◽

...

Keyword(s):

Cell Death ◽

Gastrointestinal Stromal Tumor ◽

Cell Lines ◽

Synergistic Effects ◽

Single Agent ◽

Xenograft Model ◽

Stromal Tumor ◽

In Vivo Studies ◽

Preclinical Model ◽

Kit Mutation

The majority of gastrointestinal stromal tumor (GIST) patients develop resistance to the first-line KIT inhibitor, imatinib mesylate (IM), through acquisition of secondary mutations in KIT or bypass signaling pathway activation. In addition to KIT, AKT is a relevant target for inhibition, since the PI3K/AKT pathway is crucial for IM-resistant GIST survival. We evaluated the activity of a novel pan-AKT inhibitor, MK-4440 (formerly ARQ 751), as monotherapy and in combination with IM in GIST cell lines and preclinical models with varying IM sensitivities. Dual inhibition of KIT and AKT demonstrated synergistic effects in IM-sensitive and -resistant GIST cell lines. Proteomic analyses revealed upregulation of the tumor suppressor, PDCD4, in combination treated cells. Enhanced PDCD4 expression correlated to increased cell death. In vivo studies revealed superior efficacy of MK-4440/IM combination in an IM-sensitive preclinical model of GIST compared with either single agent. The combination demonstrated limited efficacy in two IM-resistant models, including a GIST patient-derived xenograft model possessing an exon 9 KIT mutation. These studies provide strong rationale for further use of AKT inhibition in combination with IM in primary GIST; however, alternative agents will need to be tested in combination with AKT inhibition in the resistant setting.

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Separate Room Testing Accommodations for Students With and Without ADHD

Journal of Psychoeducational Assessment ◽

10.1177/0734282918801420 ◽

2018 ◽

Vol 37 (7) ◽

pp. 852-862 ◽

Cited By ~ 2

Author(s):

Benjamin J. Lovett ◽

Lawrence J. Lewandowski ◽

Lindsey Carter

Keyword(s):

Test Performance ◽

Significant Interaction ◽

Testing Accommodations ◽

Hyperactivity Disorder ◽

Level Data ◽

Parallel Forms ◽

Performance Patterns ◽

Students With Adhd ◽

Main Effects ◽

Separate Room

Students with attention-deficit/hyperactivity disorder (ADHD) are frequently provided a separate room in which to take exams, to reduce external distractions. However, little research has explored the efficacy of this accommodation. In the present study, college students with ( n = 27) and without ( n = 42) ADHD diagnoses were administered two parallel forms of a timed silent reading comprehension test, one in a classroom with other students, and one in a private, proctored setting. A two-way analysis of variance found no significant main effects for either ADHD status or test setting on performance, and no significant interaction between the factors either. However, inspection of student-level data and exploration of continuous relationships between self-reported ADHD symptoms and test performance patterns suggested that separate room accommodations may be beneficial for a subgroup of students with ADHD.

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Efficacy of Brentuximab Vedotin in Relapsed or Refractory High-CD30–Expressing Non-Hodgkin Lymphomas: Results of a Multicenter, Open-Labeled Phase II Trial

Cancer Research and Treatment ◽

10.4143/crt.2019.198 ◽

2020 ◽

Vol 52 (2) ◽

pp. 374-387 ◽

Cited By ~ 4

Author(s):

Seok Jin Kim ◽

Dok Hyun Yoon ◽

Jin Seok Kim ◽

Hye Jin Kang ◽

Hye Won Lee ◽

...

Keyword(s):

Treatment Outcome ◽

Disease Control ◽

Phase Ii ◽

Single Agent ◽

Survival Rates ◽

Sensory Neuropathy ◽

Large Cell ◽

Brentuximab Vedotin ◽

Disease Control Rate ◽

Wide Range

PurposeThe treatment outcome of brentuximab vedotin (BV) has not been related with CD30 expression in previous studies enrolling patients with a wide range of CD30 expression level. Thus, this study explored the efficacy of BV in high-CD30–expressing non-Hodgkin lymphoma (NHL) patients most likely to benefit.Materials and MethodsThis phase II study (Clinicaltrials.gov: NCT02280785) enrolled relapsed or refractory high-CD30–expressing NHL, with BV administered intravenously at 1.8 mg/kg every 3 weeks. The primary endpoint was > 40% disease control rate, consisting of complete response (CR), partial response (PR), or stable disease. We defined high CD30 expression as ≥ 30% tumor cells positive for CD30 by immunohistochemistry.ResultsHigh-CD30-expressing NHL patients (n=33) were enrolled except anaplastic large cell lymphoma. The disease control rate was 48.5% (16/33) including six CR and six PR; six patients (4CR, 2PR) maintained their response over 16 completed cycles. Response to BV and survival were not associated with CD30 expression levels. Over a median of 29.2 months of follow-up, the median progression-free and overall survival rates were 1.9 months and 6.1 months, respectively. The most common adverse events were fever (39%), neutropenia (30%), fatigue (24%), and peripheral sensory neuropathy (27%). In a <i>post-hoc</i> analysis for the association of multiple myeloma oncogene 1 (MUM1) on treatment outcome, MUM1- negative patients showed a higher response (55.6%, 5/9) than MUM1-positive patients (13.3%, 2/15).ConclusionBV performance as a single agent was acceptable in terms of disease control rates and toxicity profiles, especially MUM1-negative patients.

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Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL

Cancer Cell International ◽

10.1186/s12935-021-02330-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Simeng Zhang ◽

Zhongyan Hua ◽

Gen Ba ◽

Ning Xu ◽

Jianing Miao ◽

...

Keyword(s):

Cell Death ◽

Synergistic Effects ◽

Aerobic Glycolysis ◽

Single Agent ◽

Molecular Compound ◽

Dependent Manner ◽

Antitumor Effects ◽

Atp Production

Abstract Background Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. Methods We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. Results When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. Conclusions The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.

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Synaptic Signals from Glutamate-Treated Neurons Induce Aberrant Post-Synaptic Signals in Untreated Neuronal Networks

The Open Neurology Journal ◽

10.2174/1874205x02014010059 ◽

2020 ◽

Vol 14 (1) ◽

pp. 59-62

Author(s):

Mary Guaraldi ◽

Sangmook Lee ◽

Thomas B. Shea

Keyword(s):

Cortical Neurons ◽

Neuronal Networks ◽

Synaptic Function ◽

Glutamate Excitotoxicity ◽

Synaptic Connectivity ◽

Extracellular Glutamate ◽

Glutamate Neurotoxicity ◽

Wide Range ◽

Cortical Regions

Background and Objective: Glutamate neurotoxicity is associated with a wide range of disorders and can impair synaptic function. Failure to clear extracellular glutamate fosters additional cycles and spread of regional hyperexcitation. Methods and Results: Using cultured murine cortical neurons, herein it is demonstrated that synaptic signals generated by cultures undergoing glutamate-induced hyperactivity can invoke similar effects in other cultures not exposed to elevated glutamate. Conclusion: Since sequential synaptic connectivity can encompass extensive cortical regions, this study presents a potential additional contributor to the spread of damage resulting from glutamate excitotoxicity and should be considered in attempts to mitigate neurodegeneration.

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Efficacy and Toxicity of Treatments for Primary Central System Lymphoma: Review of the Recent Literature

University of Ottawa Journal of Medicine ◽

10.18192/uojm.v9i1.4184 ◽

2019 ◽

Vol 9 (1) ◽

pp. 61-67

Author(s):

Mohammad Jay ◽

David. A. MacDonald

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Survival Benefit ◽

Radiation Treatment ◽

Single Agent ◽

Central Nervous System Lymphoma ◽

Chemotherapeutic Agents ◽

High Dose ◽

Cell Transplant ◽

Wide Range

Primary Central Nervous system lymphoma (PCNSL) is an uncommon type of central nervous system lymphoma, most commonly presenting as hemiparesis and headache. Currently, there is a wide range of treatments for PCNSL, consisting of various permutations between chemotherapy, radiation and autologous stem cell transplant (ASCT). Although the backbone of PCNSL treatment consists of High-dose Methotrexate (HD-MTX), the role of combination versus single agent chemotherapy, combined modality (chemotherapy + radiation) versus chemotherapy or radiation alone, and the use of consolidative ASCT are contested. Surgery does not have a role in the treatment of PCNSL although stereotactic biopsies tend to help with symptomatic relief. Radiation monotherapy is generally reserved for patients with contraindications to chemotherapy or as a palliative measure. Combined chemotherapy and radiation treatment has been shown to have a great efficacy, although its increased neurotoxicity compared to chemotherapy alone is a major drawback. A growing body of research is focused on comparing the efficacy of various chemotherapeutic regimens. Currently, the MATRix regimen comprising of HD-MTX(3.5g/m2)-cytarabine/rituximab/thiotepa is widely used. The additional survival benefit of ASCT is contested although its role in the treatment of refractory or relapsed PCNSL is generally agreed upon. Finally, intrathecal HD-MTX has been shown to have added survival benefit when added to the standard therapies. Further retrospective and prospective studies are required to compare the efficacy and toxicity of various treatment options, with a focus on different chemotherapeutic agents and ASCT.

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