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Domestic animals can serve as consequential conveyors of zoonotic pathogens across wildlife-human interfaces. Still, there has been little study on how different domestic species and their behaviors influence the zoonotic risk to humans. In this study, we examined patterns of bat encounters with domestic animals that resulted in submission for testing at the rabies laboratories of the Canadian Food Inspection Agency (CFIA) during 2014-2020. Our goals were specifically to examine how the number of bats submitted and the number of rabies positive bats varied by the type of domestic animal exposure and whether domestic cats were indoor or free-roaming. The CFIA reported 6258 bat submissions for rabies testing, of which 41.5% and 8.7% had encounter histories with cats and dogs, respectively. A much smaller fraction of bat submissions (0.3%) had exposure to other domestic animals, and 49.5% had no domestic animal exposure. For the bat submissions related to cats, and where lifestyle was noted, 91.1% were associated with free-roaming cats and 8.9% with indoor cats. Model results indicated the probability of a rabies-positive bat was the highest with a history of dog association (20.2%), followed by bats with no animal exposure (16.7%), free-roaming cats (6.9%), cats with unspecified histories (6.0%) and the lowest probability associated with non-free-roaming (indoor) cats (3.8%). Although there was lower rabies prevalence in bats associated with cats compared to dogs, the 4.8 fold higher number of cat-bat interactions cumulatively leads to a greater overall rabies exposure risk to humans from any free-roaming outdoor cats. This study suggests that free-roaming owned cats may have an underappreciated role in cryptic rabies exposures in humans and as a significant predator of bats. Preventing free-roaming in cats is a cost-effective and underutilized public health recommendation for rabies prevention that also synergistically reduces the health burden of other feline-associated zoonotic diseases and promotes feline welfare and wildlife conservation.

Introduction: Suśruta, Caraka and other ācāryas advocate the collection of medicinal plants keeping in view the part used, season, soil in which the herb grows and the desired pharmacological actions or therapeutic benefits. The logic behind such recommendations is being validated by modern scientific research. Aim: To assess the effect of seasonal variations on the phytoconstituents of Aśvagandhā (Withania somnifera L. Dunal) w.s.r. to lunar cycles. Material and Methods: The plant specimens were collected from Jamnagar identified pharmacognostically and cultivated under a defined habitat in a herbal garden of IPGT and RA on 7 Oct 2013. The root samples were collected on every paurṃimā (full moon) and amāvāsyā (new moon) days in śiśira and grīşṃa ṃṛtu (as per classics) of the year 2013-14. The physicochemical parameters such as pH, ash values, extractive value, total alkaloid content, total flavonoids content (UV spectrometer with AlCl3 reagent), total phenolic content (Singleton and Rossi method), total carbohydrate content (UV spectroscopy with glucose as standard), UV-VIS-NIR and HPTLC were determined. Result: The results of the analytical studies clearly validate the logic of the recommendations of Suśruta and Cakrapāṃi. According to these recommendations, uşṃa vīrya drugs must be collected during āgneya ṃṛtu i.e. grīşṃa ṃṛtu. In present study, total phenolic, flavonide and carbohydrate content were found more in pournima samples. GAP samples showed maximum differentiation from rest of the samples with regards to TCA, TCW, TFW, MEx, WEX, pH etc. parameters. The Grīşṃa Jyeşṃha Paurṃimā (GJP) and Āşāḍha Paurṃimā (GAP) samples were found to be superior than amāvāsyā samples w.r.t. functional groups and withanoloid content respectively on HPTLC. Conclusion: The observations of experimental studies validate the concept of seasonal as well as lunar collection of herb Ashwagandha to yield a drug of superior quality of active principles.

Background/Objective: Transcatheter aortic valve replacement (TAVR) is indicated for severe aortic stenosis patients with a prohibitive surgical risk. However, its use has been expanding in recent years to include intermediate- and low-risk patients. Thus, registry data describing changes in patient characteristics and outcomes are needed. The aim of this study was to analyse the temporal changes in patient profiles and clinical outcomes of all-comer TAVR. Methods: Baseline characteristics and VARC-3 outcomes of 1632 consecutive patients undergoing TAVR between 2008 and 2021 were analysed. Results: The annual rate of TAVR increased from 30 procedures in 2008-2009 to 398 in 2020-2021. Over the follow-up period, patient age decreased from 85 ± 4 to 80 ± 6.8 ( p < 0.001) and the STS score decreased from 5.9% to 2.8% ( p < 0.001). Procedural characteristics significantly changed, representing a shift into a minimally invasive approach: adoption of local anaesthesia (none to 48%, p < 0.001) and preference of transfemoral access (74% in 2011-2012 vs. 94.5% in 2020-2021, p < 0.001). The rates of almost all procedural complications decreased, including major vascular and bleeding complications, acute kidney injury (AKI) and in-hospital heart failure. There was a striking decline in rates of complete atrioventricular block (CAVB) and the need for a permanent pacemaker (PPM). PPM rates, however, remain high (17.8%). Thirty-day and one-year mortality significantly declined to 1.8% and 8.3%, respectively. Multivariable analysis shows that AKI, bleeding and stroke are strong predictors of one-year mortality ( p < 0.001). Conclusions: The TAVR procedure has changed dramatically during the last 14 years in terms of patient characteristics, procedural aspects and device maturity. These shifts have led to improved procedural safety, contributing to improved short- and long-term patient outcomes.

Rheumatoid vasculitis (RV) constitutes a rare but serious complication of rheumatoid arthritis (RA), characterized by the inflammation of small and medium-sized blood vessels. We present a case of a 34-year-old male with chronic alcoholism who presented with epigastric pain, hematemesis, purpuric rashes, and multiple joint swelling and pain, without prior RA diagnosis. Abdominal angiography was unremarkable, ruling out Polyarteritis Nodosa (PAN) and Mallory Weiss tear. Upper GI endoscopy revealed erosive gastroduodenitis, and biopsies confirmed small vessel leukocytoclastic vasculitis with fibrinoid necrosis, initially raising suspicion of Henoch-Schonlein Purpura (HSP). However, positive rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibody, elevated inflammatory markers (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)), and negative immunoassay tests led to the diagnosis of RV. Treatment with intravenous hydrocortisone led to rapid improvement, and the patient is now being monitored on an outpatient basis with progressive recovery. This case underscores the unusual presentation of gastrointestinal involvement in RV. It highlights the importance of considering RV as a primary diagnosis, even in the absence of a prior RA diagnosis. Early recognition and intervention are critical for managing complications, emphasizing the need for a high index of suspicion in rheumatic diseases' unusual presentations., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Karra et al.)

Background: Scleroderma, also referred to as systemic sclerosis, is a multifaceted autoimmune condition characterized by abnormal fibrosis and impaired vascular function. Pathologically, it encompasses the persistent presence of inflammation, abnormal collagen buildup, and restructuring of blood vessels in various organs, resulting in a wide range of clinical symptoms. This review incorporates the most recent scientific literature on scleroderma, with a particular emphasis on its pathophysiology, clinical manifestations, diagnostic approaches, and treatment options., Methodology: A comprehensive investigation was carried out on numerous databases, such as PubMed, MEDLINE, Scopus, Web of Science, and Google Scholar, to collect pertinent studies covering diverse facets of scleroderma research., Results: Scleroderma presents with a range of systemic manifestations, such as interstitial lung disease, gastrointestinal dysmotility, Raynaud's phenomenon, pulmonary arterial hypertension, renal complications, neurological symptoms, and cardiac abnormalities. Serological markers, such as antinuclear antibodies, anti-centromere antibodies, and anti-topoisomerase antibodies, are important for classifying diseases and predicting their outcomes., Discussion: The precise identification of scleroderma is crucial for promptly and correctly implementing effective treatment plans. Treatment approaches aim to improve symptoms, reduce complications, and slow down the progression of the disease. An integrated approach that combines pharmacological agents, including immunosuppressants, endothelin receptor antagonists, and prostanoids, with nonpharmacological interventions such as physical and occupational therapy is essential for maximizing patient care., Conclusion: Through the clarification of existing gaps in knowledge and identification of emerging trends, our goal is to improve the accuracy of diagnosis, enhance the effectiveness of therapeutic interventions, and ultimately enhance the overall quality of life for individuals suffering from scleroderma. Ongoing cooperation and creative research are necessary to advance the field and achieve improved patient outcomes and new therapeutic discoveries., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Objectives: Gender equality in the healthcare workforce has been a topic of discourse for many decades. In dental academia, women's representation of enrolled students and faculty has risen consistently since the 1980s. However, women in faculty leadership positions may still be lagging when compared to men. The purpose of this study was to evaluate the number of women who occupy the upper echelons of academic rank and title by analyzing cross-referenced data from the American Dental Association and the American Dental Education Association on women dental school graduates in relation to academic appointments., Methods: Gender distribution in rank, title, and appointments in the decade from 2011 to 2019, as well as percentage of women graduates over the same period, were collected for descriptive statistics. Multiple linear regression analysis, Cochran Armitage, and chi-square tests were conducted to examine trends over the years and to determine significant differences in overall percentages (p < 0.05)., Results: The total women faculty percentages ranged from 36% to 40%. While the lower-level rank of instructor retained a higher representation of women (56%-65%), the higher rank of professor had disproportionately lower women percentages (18%-26%). Graduates, full-time faculty, lower-level academic ranks, and higher-level academic ranks for women followed similar upward trends that were statistically significant (p < 0.05). When comparing the different groups against each other, the annual increase in women DMD/DDS graduate percentage was higher than women full-time faculty (0.28%), instructor rank (0.92%), professor rank (0.50%), and department chair appointments (0.49%)., Conclusions: Our data show that women are still underrepresented at higher academic ranks. However, the upward trends for professors, assistant deans, and program chairs suggest that in recent years, more women faculty may have been encouraged, mentored, or offered higher administrative positions in academic institutions., (© 2023 American Dental Education Association.)

A droplet generator has been developed that interfaces with a barrier-on-chip platform for temporal analyte compartmentalisation and analysis. Droplets are generated every 20 minutes in 8 separate parallel microchannels, with an average droplet volume of 9.47 ± 0.6 μL, allowing simultaneous analysis of 8 different experiments. The device was tested using an epithelial barrier model by monitoring the diffusion of a fluorescent high molecular weight dextran molecule. The epithelial barrier was perturbed using detergent leading to a peak at 3-4 hours, correlating with simulations. For the untreated (control) a constant, very low level of dextran diffusion was observed. The epithelial cell barrier properties were also continuously measured using electrical impedance spectroscopy to extract an equivalent trans epithelial resistance., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Organ on a chip or microphysiological systems (MPSs) aim to resolve current challenges surrounding drug discovery and development resulting from an unrepresentative static cell culture or animal models that are traditionally used by generating a more physiologically relevant environment. Many different airway MPSs have been developed that mimic alveolar or bronchial interfaces, but few methods for aerosol drug delivery at the air-liquid interface exist. This work demonstrates a compact Surface Acoustic Wave (SAW) drug delivery device that generates an aerosol of respirable size for delivery of compounds directly onto polarized or differentiated epithelial cell cultures within an airway barrier MPS and conventional static inserts. As proof of principle, the SAW drug delivery device was used to nebulize viral dsRNA analog poly I:C and steroids fluticasone and dexamethasone without disrupting their biological function., (© 2022 Author(s).)

Breast milk is essential for facilitating the growth and development of infants and for providing immune protection against viral infections in the infant's airways. Yet, regulation of inflammation by milk components may be needed to reduce immune pathology. While milk-derived extracellular vesicles (EVs) are bestowed with immunomodulatory capacities, their role in bronchial epithelial barrier function and inflammation has not yet been examined. We hypothesised that during feeding, milk is not only ingested, but aerosols containing milk EVs are inhaled and locally delivered to the infant's airways to suppress aberrant inflammation. A bronchial epithelial model of viral infection was used to explore the direct effect of milk EVs on cellular barrier function and cytokine release during stimulation with a viral dsRNA analogue (Poly I:C). We demonstrate that milk EVs improved the dsRNA-mediated decrease in ionic barrier integrity, limited tight junction reorganisation and reduced inflammatory cytokine production (IL-6, IL-8 and TNF-α). This protective response was EV-mediated, could be successfully titrated and exhibited a time-dependent response. The results indicate that if EV-containing milk aerosols are inhaled during feeding, this may lead to protection of the airway integrity from adverse inflammatory effects., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Journal of Extracellular Biology published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

A multichannel microfluidic platform for real-time monitoring of epithelial barrier integrity by electrical impedance has been developed. Growth and polarization of human epithelial cells from the airway or gastrointestinal tract was continuously monitored over 5 days in 8 parallel, individually perfused microfluidic chips. Electrical impedance data were continuously recorded to monitor cell barrier formation using a low-cost bespoke impedance analyser. Data was analysed using an electric circuit model to extract the equivalent transepithelial electrical resistance and epithelial cell layer capacitance. The cell barrier integrity steadily increased overtime, achieving an average resistance of 418 ± 121 Ω cm 2 (airway cells) or 207 ± 59 Ω cm 2 (gastrointestinal cells) by day 5. The utility of the polarized airway epithelial barrier was demonstrated using a 24 hour challenge with double stranded RNA to mimic viral infection. This caused a rapid decrease in barrier integrity in association with disruption of tight junctions, whereas simultaneous treatment with a corticosteroid reduced this effect. The platform is able to measure barrier integrity in real-time and is scalable, thus has the potential to be used for drug development and testing.

Background: During a global crisis like the current COVID-19 pandemic, delayed admission to hospital in cases of emergent medical illness may lead to serious adverse consequences. We aimed to determine whether such delayed admission affected the severity of an inflammatory process regarding acute appendicitis, and its convalescence., Methods: In a retrospective observational cohort case-control study, we analyzed the medical data of 60 patients who were emergently and consecutively admitted to our hospital due to acute appendicitis as established by clinical presentation and imaging modalities, during the period of the COVID-19 pandemic (our study group). We matched a statistically control group consisting of 97 patients who were admitted during a previous 12-month period for the same etiology. All underwent laparoscopic appendectomy. The main study parameters included intraoperative findings (validated by histopathology), duration of abdominal pain prior to admission, hospital stay and postoperative convalescence (reflecting the consequences of delay in diagnosis and surgery)., Results: The mean duration of abdominal pain until surgery was significantly longer in the study group. The rate of advanced appendicitis (suppurative and gangrenous appendicitis as well as peri-appendicular abscess) was greater in the study than in the control group (38.3 vs. 21.6%, 23.3 vs. 16.5%, and 5 vs. 1% respectively), as well as mean hospital stay., Conclusions: A global crisis like the current viral pandemic may significantly affect emergent admissions to hospital (as in case of acute appendicitis), leading to delayed surgical interventions and its consequences., (© 2021. The Author(s).)

Objective: The objective of this study was to evaluate the efficacy and safety of lymphaticovenular anastomosis (LVA) in patients with lymphedema., Methods: A retrospective analysis was conducted of 70 patients suffering from primary or secondary lymphedema who underwent LVA surgery with indocyanine green fluorescence lymphangiography. Postoperative evaluation included qualitative and quantitative volumetric assessment and analysis. Limb volume was measured by circumferential tape measurement volumetric method, in which the limb is subdivided into five segments and each segment's circumference is measured., Results: LVA was performed in 70 patients, 22 with primary lymphedema and 48 with secondary lymphedema. The difference in preoperative upper limb volume was 35% with mean postoperative follow-up of 9 months. The mean number of lymphovenous bypasses was 3.9. The reduction in limb volume at 3, 6, and 12 months was 40.4%, 41%, and 45%, respectively. Patients with early-stage lymphedema had significantly higher volume reductions than patients with late-stage lymphedema at 3, 6, and 12 months (48% vs 18%, 49% vs 22%, and 65% vs 31%; P < .001). For lower extremity lymphedema, the preoperative volume differential was 25.5%. The mean postoperative follow-up was 9 months. The reduction in limb volume at 3, 6, and 12 months was 28%, 37%, and 39%, respectively., Conclusions: LVA surgery is a safe and effective method of reducing lymphedema severity, especially in upper extremity lymphedema at an earlier disease stage., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Sleep disorders have a comparatively high prevalence worldwide and create a burden on the health system. Pharmacological agents used for insomnia are associated with considerable side effects. Therefore, searching for safe and effective agents from plant-based natural sources is a worthy effort. Jatamansi ( Nardostachys jatamansi DC.) rhizome has been recommended for insomnia and mental conditions in the Indian system of medicine., Aim: This study aimed to determine central nervous system (CNS) depressant activity of Jatamansi ( N . jatamansi) rhizome on experimental animals., Materials and Methods: Gross behavior study and open field test (locomotor activity) were performed by using Charle's foster albino rats whereas rota-rod test and pentobarbital-induced sleep test in Swiss albino mice. Animals were divided into 3 groups (per model) having six animals in each group. The control group was treated with water, the standard group with diazepam and the test drug with powder of N . Jatamansi rhizome. Results were calculated by one-way ANOVA and post hoc test with P < 0.05 as significant., Results: Data suggested that Jatamansi did not produce a significant effect on the behavior of animals. It reduced the horizontal activity significantly ( P < 0.001) in the open field apparatus. The test drug did not show a significant decrease in latency of fall-off time in rota-rod performance in mice. Still, it exerted a significant effect by a reduction in latency of onset of sleep ( P < 0.01) and also extended the total duration of sleep ( P < 0.05) in albino mice in comparison to the control group., Conclusion: This study shows that Jatamansi rhizome powder possesses CNS depressant activity without affecting gross behavior and muscle coordination in rats., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 AYU (An International Quarterly Journal of Research in Ayurveda).)

Background: One anastomosis gastric bypass- minigastric bypass (OAGB-MGB) is an emerging bariatric surgery that is being endorsed by surgeons worldwide. Internal herniation is a rare and dreaded complication after malabsorptive bariatric procedures, which necessitates early diagnosis and intervention., Case Presentation: We describe a 29-year-old male with chylous ascites caused by an internal hernia 8 months following laparoscopic one anastomosis gastric bypass. An abdominal CT showed enlargement of lymph nodes at the mesentery, with a moderate amount of liquid in the abdomen and pelvis. An emergent exploratory laparoscopic surgery demonstrated an internal hernia at the Petersen's space with a moderate quantity of chylous ascites. The patient made an uneventful recovery after surgery., Conclusions: Internal herniation can occur after OAGB-MGB and in extremely rare cases lead to chylous ascites. To our knowledge, this is the first reported case of chylous ascites following one anastomosis gastric bypass.

[This corrects the article DOI: 10.1371/journal.pone.0197196.].

Background: Current knowledge regarding chronic use of psychotropic medications during breastfeeding is limited. The objective of this study was to evaluate the long-term effects of psychotropic monotherapy use during lactation on the breastfed infant., Materials and Methods: In this prospective study, we followed 280 infants whose mothers contacted the Drug Consultation Center (DCC) at Assaf Harofeh Medical Center between January 2011 and December 2015, seeking information regarding the chronic use of psychotropic medications during lactation. This group was compared with a group of 152 callers, who inquired evidence regarding the use of antibiotics compatible with breastfeeding. Information on adverse effects, physical measures and gross motor developmental milestone achievements of the breastfed infants was obtained during a follow-up telephone interview. At follow up, the median age of the infants in the Psychotropic-drug group was 20 (11-33) months versus 36 (20-48) months in the Antibiotic group (p < 0.001). The outcomes were compared between the groups followed by a propensity score matching to control for difference in baseline characteristics., Results: At follow-up, no significant differences between infants in the two groups were observed with regard to height, weight, head circumference and weight-length ratio percentile (p = 0.339, p = 0.223, p = 0.738, p = 0.926, respectively). Children in both groups were, according to their parents, within the normal developmental range for all milestones, according to the Denver Developmental Scale. Use of psychotropic medications during breastfeeding was not significantly associated with adverse reactions. After propensity score matching (n = 120 pairs) to control for differences in baseline characteristics and the length of lactation, only one significant difference was reported, sleepiness in infants in the study group (7/120) and none in the comparison group (p = 0.008)., Conclusions: Chronic use of psychotropic monotherapy during lactation is associated with normal growth and gross motor developmental as by milestone achievements reported by parents. Sleepiness was reported, it seemed self-limited with no developmental effect., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Mebendazole is an effective drug widely used in the treatment of parasitic infections. Although theoretically considered as safe during lactation, no studies have evaluated its potential adverse effects in infants of breastfeeding mothers., Objectives: We aimed to evaluate the safety of mebendazole in infants of lactating women treated with the drug., Methods: Women referred for consultation regarding mebendazole use were invited to participate in the study. Overall 45 lactating women treated with various protocols of mebendazole were recruited in this case series study., Results: Regardless of the treatment protocol used (single or repeated doses) mebendazole was well tolerated and was not associated with any adverse effects in infants of lactating mothers. There was mild GI irritability in two treated women., Conclusion: This study provides first evidence in humans as to the safety of mebendazole in breastfeeding., Competing Interests: N. Karra, R. Cohen, M. Berlin, N. Dinavitser, G. Koren and M. Berkovitch declare that they have no conflict of interest. Funding No funding was received for this study. Ethical approval The study was approved by the local ethics committee of Assaf Harofeh Medical Center and is in accordance with the 1964 Helsinki declaration and its later amendments. Informed consent Informed consent was obtained from all individual participants to use the collected data.

Purpose: The aim of the present study was to assess patients' quality of life (QOL) after mandibular resection and reconstruction with the free fibula flap (FFF)., Materials and Methods: We performed a retrospective study of all patients who underwent segmental mandibular resection and FFF reconstruction at the Division of Oral and Maxillofacial Surgery, McGill University Health Center. The patients were contacted and asked to complete a QOL assessment at least 1 year after surgery. The patients' photographs were taken and evaluated for the esthetic outcomes after surgery by 2 dental health professionals using a visual analog scale and compared with the patients' self-evaluations. A descriptive analysis was used for data analysis., Results: Seventeen patients underwent segmental mandibular resection and reconstruction with a FFF, and 11 completed the QOL questionnaire. Two patients were deceased at the start of the study, 1 refused to complete the QOL questionnaire, and 3 had developed disease recurrence and were not asked to complete the QOL questionnaire. Of the 11 patients who completed the QOL assessment, 8 rated their overall QOL as outstanding, very good, or good and 3 reported it to be fair. No significant correlation was found between the patients' self-reported esthetic evaluation and the third-party evaluations., Conclusions: Most patients who underwent mandibular resection and FFF reconstruction reported satisfaction with their overall QOL. We did not find a correlation between the patients' perceived esthetic outcome and the dental healthcare professionals' assessment., (Copyright © 2014 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Aberrant signaling of the epidermal growth factor receptor (EGFR) is common to a variety of human cancers and is also found to be over-expressed in most cases of non-small cell lung cancer. For the development of a molecularly targeted therapy, cetuximab-conjugated nanoparticles (immunonanoparticles, INPs) are designed and loaded with the lipophilic paclitaxel palmitate (pcpl) prodrug. Oleyl cysteineamide (OCA) is synthesized whereby its amphiphilic nature enables interfacial anchoring and thiol surface functionalization of PLGA NPs, facilitating bioconjugation to cetuximab by thioether bonds. It is demonstrated that the in vitro targeting efficiency and improved cellular internalization and cytotoxicity of this targeted delivery system in lung cancer cells over-expressing EGFR. A quantitative measure of the high binding affinity of INPs to EGFR is demonstrated using surface plasmon resonance. In vivo tolerability and enhanced efficacy of cetuximab pcpl INPs in a metastatic lung cancer model are reported. Its therapeutic efficacy in A549-luc-C8 lung tumors is shown using non-invasive bioluminescent imaging. Intravenous administration of cetuximab pcpl INPs to mice results in significantly higher inhibition of tumor growth and increased survival rates as compared to the non-targeted drug solution, drug-loaded nanoparticles or blank INPs. Pharmacokinetics and organ biodistribution of the prodrug and parent drug are evaluated by LC-MS/MS in lung tumor bearing mice. No enhanced total accumulation of nanoparticles or INPs is found at the tumor tissue. However, persistent pcpl levels with sustained conversion and release of paclitaxel are observed for the encapsulated prodrug possibly suggesting the formation of a drug reservoir. The overall results indicate the potential of this promising targeted platform for the improved treatment of lung cancer and other EGFR positive tumors., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An original oral formulation of docetaxel nanocapsules (NCs) embedded in microparticles elicited in rats a higher bioavailability compared with the i.v. administration of the commercial docetaxel solution, Taxotere. In the present study, various animal studies were designed to elucidate the absorption process of docetaxel from such a delivery system. Again, the docetaxel NC formulation elicited a marked enhanced absorption compared with oral Taxotere in minipigs, resulting in relative bioavailability and Cmax values 10- and 8.4-fold higher, respectively, confirming the previous rat study results. It was revealed that orally absorbed NCs altered the elimination and distribution of docetaxel, as shown in the organ biodistribution rat study, due to their reinforced coating, while transiting through the enterocytes by surface adsorption of apoproteins and phospholipids. These findings were demonstrated by the cryogenic-temperature transmission electron microscopy results and confirmed by the use of a chylomicron flow blocker, cycloheximide, that prevented the oral absorption of docetaxel from the NC formulation in an independent pharmacokinetic study. The lipoproteinated NCs reduced the docetaxel release in plasma and its distribution among the organs. The improved anticancer activity compared with i.v. Taxotere, observed in the metastatic lung cancer model in Severe Combined Immune Deficiency-beige (SCID-bg) mice, should be attributed to the extravasation effect, leading to the lipoproteinated NC accumulation in lung tumors, where they exert a significant therapeutic action. To the best of our knowledge, no study has reported that the absorption of NCs was mediated by a lymphatic process and reinforced during their transit.

Pulmonary delivery of drug-loaded nanoparticles is a novel approach for lung cancer treatment and the conjugation of nanoparticles to a targeting ligand further promotes specificity of the carrier cargo to cancer cells. Notably, the epithelial cell adhesion molecule (EpCAM, CD326) is over expressed in lung cancer. Here, we report the safety and proof-of-concept efficacy of drug-loaded nanoparticles and EpCAM immunonanoparticles in a c-Raf transgenic lung cancer model. PEG-PLA nanoparticles and immunonanoparticles were prepared whereby paclitaxel palmitate (Pcpl) was incorporated as a medication for its common use in lung cancer treatment. Four doses of aerosolized nanoparticle formulations or vehicle were endotracheally administered to mice by consecutive or alternate regimes. Pulmonary delivery of drug loaded nano- and/or immunonanoparticle formulations elicited mild inflammation as evidenced by the slightly increased neutrophil and activated macrophage counts in bronchoalveolar lavage. No evidence for pulmonary toxicity following treatment with either blank or drug-loaded nano- and/or immunonanoparticles was observed. Proof-of-concept efficacy was determined by serial CT scanning and histopathology. Animals treated with either EpCAM antibody or Pcpl solution or drug loaded nano- or immunonanoparticles inhibited disease progression. Conversely, disease progression was noted with vehicle treated animals with nearly 30% loss of their aerated lung volume. Importantly, treatment of mice with either Pcpl or EpCAM antibody solution caused 80% mortality and/or haemorrhage, respectively, thus causing unacceptable toxicity. In contrast, the survival of animals treated with either nano- or immunonanoparticles was 60 and 70%, respectively. Taken collectively, pulmonary delivered drug-loaded nano- and EpCAM immunonanoparticles were well tolerated and can be considered a promising strategy for improving lung cancer treatment.

Cancer therapy often requires frequent and high drug dosing. Yet, despite the significant progress in cancer research and the wide versatility of potent available drugs, treatment efficacy is still hurdled and often failed by the lack of pharmaco-selectivity to diseased cells, indiscriminate drug toxicities and poor patient compliance. Thus, innovative pharmaceutical solutions are needed to effectively deliver the cytotoxic drugs specifically to the tumor site while minimizing systemic exposure to frequent and high drug doses. Polymeric nanocarriers, particularly nanoparticles, have been extensively studied for improved oncological use. Such nanocarriers hold great potential in cancer treatment as they can be biocompatible, adapted to specific needs, tolerated and deliver high drug payloads while targeting tumors. Active targeting, as opposed to passive targeting, should add value to selective and site specific treatment. Active targeting of nanosized drug delivery systems is firmly rooted in the Magic Bullet Concept as was envisioned by Paul Ehrlich over 100 years ago. This targeting strategy is based on the molecular recognition of tumor biomarkers which are over-expressed on cancer cells, via specific vector molecules conjugated to the surface of the drug carrier. These vector molecules dictate the carrier's biodistribution and its biological affinity to the desired site of action. Many recent publications have shown encouraging results suggesting that targeting nanocarriers represent a highly-promising strategy for improved cancer treatment. This chapter will focus mainly on polymeric nanoparticles as the main drug carriers to be conjugated to various ligands able to deliver the drug to the specific desired pathological tissue.