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Tania Mariastella Caputo,1,* Giovannina Barisciano,2,* Chiara Mulè,1 Angela Maria Cusano,3 Anna Aliberti,1 Livio Muccillo,2 Vittorio Colantuoni,2 Lina Sabatino,2 Andrea Cusano1,3 1Optoelectronics Group, Department of Engineering, University of Sannio, Benevento, Italy; 2Department of Sciences and Technologies, University of Sannio, Benevento, Italy; 3CeRICTscrl Regional Center Information Communication Technology, Benevento, Italy*These authors contributed equally to this workCorrespondence: Anna Aliberti; Lina Sabatino, Email anna.aliberti@unisannio.it; sabatino@unisannio.itBackground: Trastuzumab, a therapeutic monoclonal antibody directed against HER2, is routinely used to treat HER2-positive breast cancer with a good response rate. However, concerns have arisen in the clinical practice due to adverse side effects. One way to overcome these limitations is to encapsulate trastuzumab in nanoparticles to improve cytotoxic activity, increase intracellular drug concentrations, escape the immune system and avoid systemic degradation of the drug in vivo.Methods: A double emulsion method was used to encapsulate trastuzumab into poly(lactic-co-glycolic) nanoparticles, effective for their biocompatibility and biodegradability. These nanocarriers, hereafter referred to as TZPs, were characterised in terms of size, homogeneity, zeta potential and tested for their stability and drug release kinetics. Finally, the TZPs cytotoxicity was assessed in vitro on the HER2 positive SKBR3 breast cancer cell line and compared to free trastuzumab.Results: The TZPs were stable, homogeneous in size, with a reduced zeta potential. They showed higher encapsulation efficiency and drug loading, a prolonged trastuzumab release kinetics that retained its physicochemical properties and functionality. TZPs showed a stronger cytotoxicity and increased apoptosis than similar doses of free trastuzumab in the cell line analysed. Confocal microscopy and flow cytometry assessed TZPs and trastuzumab cellular uptake while Western blot evaluated downstream signalling, overall HER2 content and shedding.Conclusion: TZPs exert more robust effects than free trastuzumab via a dual mode of action: TZPs are taken up by cells through an endocytosis mechanism and release the drug intracellularly for longer time. Additionally, the TZPs that remain in the extracellular space release trastuzumab which binds to the cognate receptor and impairs downstream signalling. This is the sole modality used by free trastuzumab. Remarkably, half dose of TZPs is as efficacious as the highest dose of free drug supporting their possible use for drug delivery in vivo. Keywords: PLGA nanoparticles, double-emulsion method, trastuzumab, breast cancer, signaling transduction

Tania Mariastella Caputo,1,* Angela Maria Cusano,2,* Sofia Principe,1 Paola Cicatiello,1 Giorgia Celetti,1 Anna Aliberti,1 Alberto Micco,2 Menotti Ruvo,3 Maria Tagliamonte,4 Concetta Ragone,4 Michele Minopoli,5 Maria Vincenza Carriero,5 Luigi Buonaguro,4 Andrea Cusano1,2 1Optoelectronics Group, Department of Engineering, University of Sannio, Palazzo Dell’ Aquila Bosco Lucarelli, Benevento, Italy; 2CeRICTscrl Regional Center Information Communication Technology, Palazzo Ex Poste, Benevento, Italy; 3Institute of Biostructure and Bioimaging, National Research Council, Naples, Italy; 4Innovative Immunological Models Unit, Istituto Nazionale Tumori - IRCCS - “Fond G. Pascale”, Naples, Italy; 5Neoplastic Progression Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, Italy*These authors contributed equally to this workCorrespondence: Andrea Cusano; Anna Aliberti, Palazzo Dell’Aquila Bosco Lucarelli, Corso Garibaldi 107, Benevento, I-82100, Italy, Email a.cusano@unisannio.it; anna.aliberti@unisannio.itIntroduction: Currently, conventional treatments of hepatocellular carcinoma (HCC) are not selective enough for tumor tissue and lead to multidrug resistance and drug toxicity. Although sorafenib (SOR) is the standard first-line systemic therapy approved for the clinical treatment of HCC, its poor aqueous solubility and rapid clearance result in low absorption efficiency and severely limit its use for local treatment.Methods: Herein, we present the synthesis of biodegradable polymeric Poly (D, L-Lactide-co-glycolide) (PLGA) particles loaded with SOR (PS) by emulsion-solvent evaporation process. The particles are carefully characterized focusing on particle size, surface charge, morphology, drug loading content, encapsulation efficiency, in vitro stability, drug release behaviour and tested on HepG2 cells. Additionally, PLGA particles have been coupled on side emitting optical fibers (seOF) integrated in a microfluidic device for light-triggered local release.Results: PS have a size of 248 nm, tunable surface charge and a uniform and spherical shape without aggregation. PS shows encapsulation efficiency of 89.7% and the highest drug loading (8.9%) between the SOR-loaded PLGA formulations. Treating HepG2 cells with PS containing SOR at 7.5 μM their viability is dampened to 40%, 30% and 17% after 48, 129 and 168 hours of incubation, respectively.Conclusion: The high PS stability, their sustained release profile and the rapid cellular uptake corroborate the enhanced cytotoxicity effect on HepG2. With the prospect of developing biomedical tools to control the spatial and temporal release of drugs, we successfully demonstrated the potentiality of seOF for light-triggered local release of the carriers. Our prototypical system paves the way to new devices integrating microfluidics, optical fibers, and advanced carriers capable to deliver minimally invasive locoregional cancer treatments.Graphical Abstract: Keywords: poly(lactic-co-glycolic acid), sorafenib, emulsion solvent evaporation technique, hepatocellular carcinoma, optical fiber, microfluidics

This paper reports the results of a content analysis of the business/strategic plans of 23 Canadian police services that provide service to 48% of the country's population. The results indicate that these plans vary considerably with respect to environmental scans; statements of values, vision and mission; descriptions of goals; resources to be applied to goal achievement; and indicators to be used to assess success and inform ameliorate action. The findings also indicate that the plans pay limited attention to statements of strategic purpose and the competitive environments within which these police services operate. These results are considered in light of the potential that well-done strategic planning processes may have for police leaders and oversight bodies as well as for helping police services better meet accountability requirements and stakeholder expectations. [ABSTRACT FROM AUTHOR]

Objective: To describe the clinical outcomes of histologically confirmed adenocarcinoma in situ (AIS) of the cervix treated with cervical conization. Materials and Methods: A retrospective chart review of patients with histologically confirmed AIS from July 1998 to February 2011 included 52 patients. The rates of residual disease in subsequent excisions, the clinical recurrence rate, the average disease- free interval, and risk of progression to adenocarcinoma were described. The clinical outcomes of patients treated with cold knife cone (CKC) and loop electrosurgical excisional procedure (LEEP) were compared. Results: Fifteen LEEPs and 37 CKC procedures were performed as initial treatment and 26 patients (50%) had positive margins. There was no significant difference in rate of positive margins between LEEP and CKC (40% vs. 54%, respectively. p = 0.55). LEEPs and CKCs resulted in similar volumes of cervical tissue resected (4.98 cm3 vs. 5.04 cm³, p = 0.40). Of patients with positive margins, ten underwent immediate hysterectomy, six underwent a second cone biopsy, seven were managed expectantly, and four were lost to follow up. Residual AIS was found in 47% (eight of 17) of repeat cone biopsy and hysterectomy specimens performed for positive cone margins. Of the 26 patients with negative cone margins, no residual or recurrent disease was found after an average follow-up of 32 months. Conclusions:A positive surgical margin was associated with residual disease in 47% of patients with AIS treated with conization. No patient with negative cone margins had recurrent or progressive disease. Cervical conization with negative margins appears to be a safe treatment option for patients with AIS but requires further investigation. CKC and LEEP were equally efficacious treatments in our study population. [ABSTRACT FROM AUTHOR]