Decreasing the Impact of Treatment Resistance in Schizophrenia: Identifying Novel Molecular Targets/ Pathways to Increase Treatment Efficacy

Abstract Background After the golden age of antibiotic discovery, bacterial infections still represent a major challenge for public health worldwide. The biofilm mode of growth is mostly responsible for chronic infections that current therapeutics fail to cure and it is well-established that novel strategies must be investigated. Particulate drug delivery systems are considered as a promising strategy to face issues related to antibiotic treatments in a biofilm context. Particularly, poly-lactic acid (PLA) nanoparticles present a great interest due to their ability to migrate into biofilms thanks to their submicronic size. However, questions still remain unresolved about their mode of action in biofilms depending on their surface properties. In the current study, we have investigated the impact of their surface charge, firstly on their behavior within a bacterial biofilm, and secondly on the antibiotic delivery and the treatment efficacy. Results Rifampicin-loaded PLA nanoparticles were synthetized by nanoprecipitation and characterized. A high and superficial loading of rifampicin, confirmed by an in silico simulation, enabled to deliver effective antibiotic doses with a two-phase release, appropriate for biofilm-associated treatments. These nanoparticles were functionalized with poly-l-lysine, a cationic peptide, by surface coating inducing charge reversal without altering the other physicochemical properties of these particles. Positively charged nanoparticles were able to interact stronger than negative ones with Staphylococcus aureus, under planktonic and biofilm modes of growth, leading to a slowed particle migration in the biofilm thickness and to an improved retention of these cationic particles in biofilms. While rifampicin was totally ineffective in biofilms after washing, the increased retention capacity of poly-l-lysine-coated rifampicin-loaded PLA nanoparticles has been associated with a better antibiotic efficacy than uncoated negatively charged ones. Conclusions Correlating the carrier retention capacity in biofilms with the treatment efficacy, positively charged rifampicin-loaded PLA nanoparticles are therefore proposed as an adapted and promising approach to improve antibiotic delivery in S. aureus biofilms.

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The impact of mitochondria on cancer treatment resistance

Cellular Oncology ◽

10.1007/s13402-021-00623-y ◽

2021 ◽

Author(s):

Michelle van der Merwe ◽

Gustav van Niekerk ◽

Carla Fourie ◽

Manisha du Plessis ◽

Anna-Mart Engelbrecht

Keyword(s):

Cancer Treatment ◽

Treatment Resistance ◽

The Impact

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Temporal Quantitative Proteomics Analysis of Neuroblastoma Cells Treated with Bovine Milk-Derived Extracellular Vesicles Highlights the Anti-Proliferative Properties of Milk-Derived Extracellular Vesicles

Cells ◽

10.3390/cells10040750 ◽

2021 ◽

Vol 10 (4) ◽

pp. 750

Author(s):

Pamali Fonseka ◽

Taeyoung Kang ◽

Sing Chee ◽

Sai V. Chitti ◽

Rahul Sanwlani ◽

...

Keyword(s):

High Risk ◽

Extracellular Vesicles ◽

Quantitative Proteomics ◽

Cell Metabolism ◽

Bovine Milk ◽

Neuroblastoma Cells ◽

Treatment Strategies ◽

Treatment Resistance ◽

Label Free ◽

The Impact

Neuroblastoma (NBL) is a pediatric cancer that accounts for 15% of childhood cancer mortality. Amplification of the oncogene N-Myc occurs in 20% of NBL patients and is considered high risk as it correlates with aggressiveness, treatment resistance and poor prognosis. Even though the treatment strategies have improved in the recent years, the survival rate of high-risk NBL patients remain poor. Hence, it is crucial to explore new therapeutic avenues to sensitise NBL. Recently, bovine milk-derived extracellular vesicles (MEVs) have been proposed to contain anti-cancer properties. However, the impact of MEVs on NBL cells is not understood. In this study, we characterised MEVs using Western blotting, NTA and TEM. Importantly, treatment of NBL cells with MEVs decreased the proliferation and increased the sensitivity of NBL cells to doxorubicin. Temporal label-free quantitative proteomics of NBL cells highlighted the depletion of proteins involved in cell metabolism, cell growth and Wnt signalling upon treatment with MEVs. Furthermore, proteins implicated in cellular senescence and apoptosis were enriched in NBL cells treated with MEVs. For the first time, this study highlights the temporal proteomic profile that occurs in cancer cells upon MEVs treatment.

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Clinical significance of prostatic-urethral angulation on the treatment outcome of patients with symptomatic benign prostatic hyperplasia treated with tamsulosin hydrochloride

Archivio Italiano di Urologia e Andrologia ◽

10.4081/aiua.2015.3.238 ◽

2015 ◽

Vol 87 (3) ◽

pp. 238

Author(s):

Hassan El-Tatawy ◽

Tarek Gameel ◽

Mohammed Abo El-enen ◽

Ayman Hagras ◽

Ayman Mousa ◽

...

Keyword(s):

Benign Prostatic Hyperplasia ◽

Clinical Significance ◽

Treatment Efficacy ◽

Specific Antigen ◽

Prostatic Hyperplasia ◽

Final Conclusion ◽

P Value ◽

Significant Difference ◽

Group A ◽

The Impact

Objectives: To evaluate the impact of the prostatic-urethral angulation (PUA) on the treatment efficacy of selective alpha-1A receptor blocker in male patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). Materials and methods: A total of 80 patients with LUTS/BPH and with mean age 53.3 ± 6.3 (range 47-70) were included in our prospective comparative study. The patients were classified into 2 groups as a consecutive cases 40 in each one depending on the PUA either ≤ 35° (group A) or > 35° (group B). PUA and different prostatic parameters were measured using transrectal ultrasound. Prostate-specific antigen (PSA), the International Prostate Symptom Score and quality of life score (IPSS/QoL score), maximum flow rate (Q<sub>max</sub>), and postvoid residual (PVR) volume were compared between the groups. The clinical significance of PUA was evaluated after 8 weeks of medical treatment with tamsulosin hydrochloride 0.4 mg daily. Results: Baseline evaluation (pre-treatment) for both groups were comparable to each other with no clinically significant difference regarding age, PSA, IPSS/QoL score, Qmax and PVR volume (P-value > 0.05). Comparison of parameters after 8 weeks showed that tamsulosin hydrochloride improved the total IPSS and all subscores (P < 0.001), QoL (P = 0.001), Q<sub>max</sub> (P = 0.002), and PVR (P = 0.04) in group A (Table 1). Conclusion: Tamsulosin hydrochloride appears to be less effective in improving IPSS/Qol score, Qmax and PVR in patients with lager PUA. The PUA might be a predictor for the treatment efficacy of α-blockers and more studies are warranted in the future before the final conclusion.

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P078 Oral Appliance Fabrication Settings Impact Treatment Efficacy

SLEEP Advances ◽

10.1093/sleepadvances/zpab014.122 ◽

2021 ◽

Vol 2 (Supplement_1) ◽

pp. A46-A46

Author(s):

D Levendowski ◽

E Sall ◽

W Odom ◽

B Beine ◽

D Cruz Arista ◽

...

Keyword(s):

Body Mass Index ◽

Sleep Apnea ◽

Treatment Outcomes ◽

Body Mass ◽

Treatment Efficacy ◽

Oral Appliance ◽

Chi Squared ◽

Pre Treatment ◽

The Impact

Abstract Purpose Assess the impact of custom oral appliance (CA) fabrication settings on treatment outcomes. Methods CPAP-intolerant patients completed a two-night home-sleep-apnea study (HSAT); Night1=baseline, Night2=Apnea Guard® trial appliance (AG). The AG vertical-dimension-of-occlusion (VDO) selection was based on tongue-scallop (women=5.5/6.5 mm, men= 6.5/8.0 mm), with a target protrusion of 70% from neutral-maximum while in situ. Study1 CA VDO was dependent on sex (women=2.5 mm, men=5 mm), with protrusion set using a George-Gauge measured 70% from maximum retrusion-protrusion with dentist-directed titration. Study2 CA was fabricated to the AG VDO and target protrusion bite-registration. Efficacy HSATs were conducted after completion of Study1 CA titration with vertical-elastics optional, and at the AG target protrusion with vertical-elastics mandatory in Study2. Statistics included Mann-Whitney, Chi-squared, and Bland-Altman analyses. Results The Study1 (n=84) and Study2 (n=46) distributions were equivalent for tongue-scallop (64/63%) and sex (women=45/41%), however, noted differences in age (53.8±11.9 vs. 58.4±12.2; P=0.052), body-mass-index (29.4±5.7 vs. 27.8±4.0; P=0.128) and pre-treatment AHI severities (24.6±14.4 vs. 29.2±17.4 events/h; P=0.155) were observed. The Bland-Altman biases were significant different (Study1=4.2±7.8 vs. Study2=1.3±7.0 events/h, P=0.035). The significant Study1 differences between the CA vs. AG AHIs (12.3±9.2 vs. 8.2±5.9 events/h, P<0.0002) were not apparent in Study2 (11.7±8.0 vs. 10.4±6.7 events/h, P=0.362), however, the Study2 AG AHI values were higher (P=0.055). Discussion Despite the trend toward greater Study2 pre-treatment and AG AHI severities, CA treatment efficacy was equivalent to the AG once VMO was controlled and fabricated using the AG VDO and protrusion bite-registration. These findings confirmed CA fabrication settings impact treatment outcomes.

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Molecular and Clinical Insights into the Invasive Capacity of Glioblastoma Cells

Journal of Oncology ◽

10.1155/2019/1740763 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 11

Author(s):

Carlos Velásquez ◽

Sheila Mansouri ◽

Carla Mora ◽

Farshad Nassiri ◽

Suganth Suppiah ◽

...

Keyword(s):

Treatment Resistance ◽

Host Cells ◽

Cellular Mechanisms ◽

Poor Overall Survival ◽

Cellular Processes ◽

New Therapeutic Approaches ◽

Invasive Capacity ◽

Molecular Machinery ◽

The Impact ◽

Infiltrative Tumor

The invasive capacity of GBM is one of the key tumoral features associated with treatment resistance, recurrence, and poor overall survival. The molecular machinery underlying GBM invasiveness comprises an intricate network of signaling pathways and interactions with the extracellular matrix and host cells. Among them, PI3k/Akt, Wnt, Hedgehog, and NFkB play a crucial role in the cellular processes related to invasion. A better understanding of these pathways could potentially help in developing new therapeutic approaches with better outcomes. Nevertheless, despite significant advances made over the last decade on these molecular and cellular mechanisms, they have not been translated into the clinical practice. Moreover, targeting the infiltrative tumor and its significance regarding outcome is still a major clinical challenge. For instance, the pre- and intraoperative methods used to identify the infiltrative tumor are limited when trying to accurately define the tumor boundaries and the burden of tumor cells in the infiltrated parenchyma. Besides, the impact of treating the infiltrative tumor remains unclear. Here we aim to highlight the molecular and clinical hallmarks of invasion in GBM.

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TMIC-15. HYPERACTIVATING THE HIPPO PATHWAY EFFECTOR TAZ DIFFERENTIALLY DISTORTS THE TUMOR MICROENVIRONMENT, PROMOTES TUMOR-ASSOCIATED NEUTROPHIL INFILTRATION, AND PHENOCOPIES MESENCHYMAL-GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.1049 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi250-vi250

Author(s):

Patricia Yee ◽

Yiju Wei ◽

Zhijun Liu ◽

Hui Guo ◽

Umeshkumar Manjibhai Vekariya ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Myeloid Cells ◽

Treatment Resistance ◽

Neutrophil Infiltration ◽

Adult Brain ◽

Tumor Evolution ◽

Binding Motif ◽

Mesenchymal Transition ◽

The Impact

Abstract Glioblastoma (GBM), the deadliest and most common adult brain malignancy, is molecularly and clinically heterogeneous. The most common subtype (both primary and recurrent), mesenchymal (MES)-GBM, has the worst prognosis and highest treatment resistance. MES-GBM exhibits hyperactive transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo tumor suppressive pathway effector whose expression in GBMs predicts short survival. Yet, how Hippo-TAZ dysregulation might drive GBM MES transition remains elusive, precluding subtype-specific treatments. Tumor evolution requires signaling dysregulation and co-opting the tumor microenvironment (TME). Understanding GBM heterogeneity was recently complicated by the notion that subtypes vary in TME immune composition. The MES-GBM TME is differentially-distorted in silico, with more tumor-associated macrophages/microglia (TAMs) and neutrophils (TANs). Yet, how TAZ hyperactivity, MES transition, and GBM TME distortion interrelate and impact tumor progression remains unknown. We suspected that TME distortion facilitates immune evasion, MES transition, and tumor progression, worsening treatment responses. To test this, we devised an orthotopic xenograft mouse model phenotypically and histopathologically recapitulating human MES-GBM by expressing constitutively-active TAZ (TAZ4SA) in human GBM cells lacking MES signatures (GBM4SA). GBM4SA mice lived significantly shorter compared to mice with GBM expressing vector (GBMvector) or mutant TAZ unable to bind its effector, TEAD (GBM4SA-S51A). Moreover, more myeloid cells infiltrate the GBM4SA TME than the GBMvector or GBM4SA-S51A TMEs. While most myeloid cells infiltrating the GBMvector and GBM4SA-S51A TMEs were TAMs, most infiltrating the GBM4SA TME were TANs, suggesting TAZ hyperactivation differentially distorts the TME. Next, to delineate the roles of TANs in GBM4SA tumor progression, mice were depleted of neutrophils by administering Ly6G antibody. Serial blood smears and flow cytometry revealed effective depletion was achieved. We are currently investigating the impact of systemic neutrophil depletion on GBM mesenchymal transition and tumor progression in hopes of informing future GBM clinical management and novel TME-targeted immunotherapies.

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