Local Lung Targeting of Tumor Associated Macrophages Combined with Cytoreductive Therapy Decrease Tumor Burden in a Secondary Lung Cancer Model

Backgrounds. The efficacy of a locally administered small molecule colony stimulating factor 1 receptor inhibitor (CSF-1Ri), PLX3397, alone or in combination with cytoreductive therapy (paclitaxel) in reducing the tumor burden of an in vivo model of secondary lung cancer was investigated in this work. Local administration of immunotherapy to the lungs may enhance lung biodistribution of such therapies and reduce potential unwanted off-target toxicity. In addition, combination of such therapy with low dose standard of care chemotherapy may offer improved anti-tumor effects. Methods. Murine breast cancer cells (4T1, known to be highly metastasized to the lungs) were transduced to express the genes luciferase and tdTomato, and cells were injected to female Balb/c mice before being treated with PLX (intratracheally administered), paclitaxel (intravenously given), or the combination therapy. Both ex vivo bioluminescent imaging and lung weights were used to evaluate tumor burden. Western blot was performed using lung tumors to assess the effect of PLX3397 on its molecular target (phosphorylated CSF-1R). Immunofluorescence and Flowcytometry were utilized to examine the impact of treatment on tumorigenic tumor associated macrophages (M2 TAM). Results. Single-agent treatment partially decreased tumor burden, while combination therapy led to a significant reduction in tumor burden. PLX3397 significantly inhibited the expression of phosphorylated CSF-1R and reduced the number of M2 TAM without affecting the total macrophage population, thereby increasing the anti-tumorigenic (M1)/M2 ratio. Conclusion. Tumor burden reduction upon local administration of PLX3397 to the lungs correlates with the marked inhibition of the molecular target and the decrease in M2 TAM.https://scholarscompass.vcu.edu/gradposters/1065/thumbnail.jp

Dendrimer Conjugation Enhances Tumor Penetration and Cell Kill of Doxorubicin in 3D Coculture Lung Cancer Models

Background: Doxorubicin (DOX) is a potent chemotherapeutic widely used for solid tumors (1). Despite high efficacy in 2D cell culture, DOX efficacy does not translate to in vivo lung cancer models (2). Major side effects such as cardiotoxicity may be alleviated with nano-based drug delivery systems (nanoDDS). However, tumor penetration of DOX and DOX-nanoDDS is largely unknown and is an additional barrier to effective clinical therapy (3). Here we describe a nanoDDS capable of enhancing the penetration of DOX. Methods: DOX was conjugated to generation 4 poly(amido-amine) dendrimers through (GFLG) tumor- liable bond. G4SA-GFLG-DOX was synthesized/characterized. spheroids were formed of (A549) lung adenocarcinoma cells and (3T3) fibroblasts. Spheroids were characterized for ECM components with immunohistochemistry. Confocal microscopy was used to evaluate the penetration, internalization, and colocalization of DOX and G4SA-GFLG-DOX. MTT assay and Caspase 3/7 to assess 2D and 3D cytotoxicity. Flow cytometry to determine cells uptake. Results: DOX conjugation to dendrimer resulted in G4SA-GFLG-DOX with ~5.5 DOX, 10±1 nm hydrodynamic diameter, and a -17±3 mV zeta-potential. Spheroids of (A549:3T3) were ECM- rich, developed ECM containing collagen-I, hyaluronan, laminin, and fibronectin. While DOX and G4SA-GFLG-DOX had similar toxicities in 2D model, G4SA-GFLG-DOX demonstrated a 3.1-fold greater penetration into spheroids compared to DOX and correlated to a greater efficacy as measured by caspase 3/7 activity. Also, flow cytometry showed higher uptake of G4SA- GFLG-DOX in cancer cells compared to fibroblasts. Conclusion: The work demonstrates enhanced penetration of DOX, via dendrimer conjugation, into an ECM- rich 3D lung cancer model. The enhanced penetration of G4SA-GFLG-DOX correlated with greater antitumor efficacy. Acknowledgements: We acknowledge partial financial support from the Center for Pharmaceutical Engineering and Sciences - School of Pharmacy at VCU. This study was supported by VCU Quest for Distinction and NSF (DRM #1508363). Microscopy was performed at the VCU Microscopy Facility, supported, in part, by funding from NIH-NCI Cancer Center Support Grant P30 CA016059. RA would like to acknowledge King Faisal University (KFU) and Saudi Arabian Cultural Mission (SACM) for a scholarship.https://scholarscompass.vcu.edu/gradposters/1091/thumbnail.jp

The impact of law enforcement on the dispensing antibiotics without prescription in Saudi Arabia : findings and implications

Background: Dispensing of antibiotics without a prescription (DAwP) has been widely practised in Saudi Arabia despite being illegal. This is a concern increasing AMR. In May 2018, the law and regulations were enforced including fines up to 100,000 SR (equivalent to US$26,666) and cancellation of licences. Consequently, we wanted to evaluate the impact. Methods: Mixed method study among 116 community pharmacies in two phases. Pre-law enforcement phase between December 2017 and March 2018 and post-law enforcement phase one year later. Each phase consisted of a cross-sectional questionnaire-based survey and a simulated client method (SCM). In the SCM, clients presented with either pharyngitis or urinary tract infections (UTI) with 3 levels: level 1 – SC asked for something to relieve the symptoms, level 2 – SC asked for something stronger if an antibiotic was not dispensed, level 3 – SC requested an antibiotic. In SCM for each phase, all 116 pharmacies were visited with at least one of the scenarios. Results: Before the law enforcement, 70.7% of community pharmacists reported DAwP was common. 96.6% and 87.7% of participating pharmacies dispensed antibiotics without a prescription for pharyngitis and UTI respectively. After law enforcement, only 12.9% of community pharmacists indicated that DAwP was common, with only 12.1% and 5.2% dispensing antibiotics without prescriptions for pharyngitis and UTI respectively and mostly after level 3. Conclusion: Law enforcement was effective. However, there is still further scope for improvement as community pharmacists are worried patients may go elsewhere if no antibiotic dispensed on request. This could include educational activities

Quantitative Analysis of 99mTc-MDP SPECT-CT Data in Diagnosing Bone Metastases in Breast Cancer Patients

Background: In patients with advanced breast cancer (BC), distant metastases happen mainly in the skeleton. This study aimed to investigate the role of 99mTc-MDP SPECT/CT in the differential diagnosis of malignant bone lesions from degenerative benign bone diseases in female BC patients. Methods and Results: The study included 39 female BC patients who underwent a baseline 99mTc-MDP SPECT/CT bone scans. After lesion detection, a quantitative radiotracer uptake analysis was conducted, and the standardized uptake value (SUVmax) was identified in each patient, and the data were then statistically analyzed. SUVmax values were significantly higher in BC patients with malignant metastasis than in patients with degenerative changes (33.04±15.3 vs. 13.25±5.46 g/mL, P<0.05). The SUVmax cut-off value of 22.75 g/mL (25th percentile) obtained through box plot analysis can help to discriminate metastatic from degenerative lesions. The logistic regression analysis indicated that the SUVmax was a significant predictor of metastatic BL (P<0.001, OR = 159.90, B=5.07). Conclusion: Our results suggested that quantitative analysis of the 99mTc-MDP SPECT-CT data can improve diagnostic accuracy in differentiating malignant metastatic bone lesions from degenerative bone lesions in high-risk BC patients

Satisfaction of adult and pediatric neurologists and neurosurgeons using telehealth during the COVID-19 pandemic in Saudi Arabia: a cross-sectional study

ObjectivesTelehealth has become increasingly important in achieving universal health coverage. It offers doctors and their patients' convenience, including providing quality care at reduced costs. During the coronavirus disease (COVID)-19 pandemic, telehealth has been a vital tool for remote healthcare services. This study aimed to assess the satisfaction of adult and pediatric neurologists and neurosurgeons using telehealth, during the COVID-19 pandemic in Saudi Arabia.MethodsThis study had 348 participants. It was conducted among adult and pediatric neurologists and neurosurgeons using telehealth technology at their clinics between February and June 2021. The self-administered questionnaire included sociodemographic data, behavior in using telehealth, and an assessment of satisfaction with telehealth; the SPSS Windows software version 26 was used to analyze the data.ResultsThe most common age group was 25–34 years (42.8%), with men dominating (68.4%). The mean satisfaction score was 25.9 (SD 3.91) out of 33 points, with 90.2% of respondents satisfied with telehealth and 9.8% dissatisfied. Working in an academic center or private hospital, being a first-time telehealth user, using messages as a telehealth method, and using telehealth daily were associated with increased satisfaction with telehealth use.ConclusionThe satisfaction of adult and pediatric neurologists and neurosurgeons with telehealth was high. Although physicians still preferred face-to-face interviews, they recognized the benefits of telehealth in strengthening the patient–provider relationship, improving productivity, and integrating into daily workflows. The satisfaction levels align with past studies, but physical examination needs should be considered. Telehealth is suitable for follow-up visits and varies across subspecialties

The impact of law enforcement on dispensing antibiotics without prescription: a multi-methods study from Saudi Arabia

Background: Dispensing of antibiotics without a prescription (DAwP) has been widely practised among community pharmacies in Saudi Arabia despite being illegal. However, in May 2018, the law and regulations were enforced alongside fines. Consequently, we wanted to evaluate the impact of these changes. Methods: A study was conducted among 116 community pharmacies in two phases. A pre-law enforcement phase between December 2017 and March 2018 and a post-law enforcement phase one year later. Each phase consisted of a cross-sectional questionnaire-based survey and a simulated client method (SCM) approach. In the SCM, clients presented with either pharyngitis or urinary tract infections (UTI). In SCM, for each phase, all 116 pharmacies were visited with one of the scenarios. Results: Before the law enforcement, 70.7% of community pharmacists reported that DAwP was common with 96.6% and 87.7% of participating pharmacies dispensed antibiotics without a prescription for pharyngitis and UTI respectively. After the law enforcement, only 12.9% reported that DAwP is still a common practice, with only 12.1% and 5.2% dispensing antibiotics without prescriptions for pharyngitis and UTI respectively. Conclusion: law enforcement was effective. However, there is still further scope for improvement. This could include further educational activities with pharmacists, physicians and the public

Nephroprotective potential of Polyalthia longifolia roots against vancomycin-induced renal toxicity in experimental animals

This study was done to investigate the possible nephroprotective effect of an ethanolic root extract of Polyalthia Longifolia (PL) on vancomycin-induced nephrotoxicity using curative and protective models. Vancomycin (150 mg/kg, intravenous) was given to healthy Wistar albino rats in the curative model before the start of treatment, whereas the protective group received vancomycin at the conclusion of the 10-day treatment procedure. Animals were divided into six groups for both models; group I served as the normal control, while groups II, III, IV, V, and VI were kept as toxic control, standard (selenium, 6 mg/kg), LDPL (low dose of PL 200 mg/kg), HDPL (high dose of PL 400 mg/kg), and HDPL + selenium (interactive) groups, respectively. Renal biomarkers [(uric acid, creatinine, blood urea nitrogen (BUN), serum proteins], and blood electrolyte levels were measured for all tested groups. When compared to the vancomycin group, the HDPL significantly (p &lt; 0.01) showed greater effectiveness in lowering the BUN, potassium, and calcium levels. Additionally, in the curative model, there was a significant (p &lt; 0.05) decrease in the blood levels of uric acid, creatinine, BUN, potassium, and calcium in the animals who received the combination of selenium and HDPL. Both LDPL and HDPL did not provide any distinguishable effect in the protective model, but groups that received HDPL with selenium did provide detectable protection by significantly lowering their levels of uric acid, BUN, serum potassium, and total serum protein in comparison to the vancomycin control group. These findings indicate that, whether administered before or after renal damage is induced, the Polyalthia longifolia root extract provided only modest protection to nephrons, which require selenium support to prevent vancomycin-induced kidney damage

Prevalence of neurometabolic diseases in Saudi Arabia

Neurometabolic disorders are most often seen in newborns and infants and have come to be recognized as an important group of disorders. Understanding diagnostic and therapeutic developments in neurometabolic disorders requires a concrete understanding of the classical principles of inborn errors of metabolism in order to provide key constructs for a fundamental understanding of this interesting category of disorders. The Saudi Arabian population has a comparatively high incidence of neurometabolic disorders, primarily due to consanguinity (with a high inbreeding coefficient factor) and large family sizes. The most frequently occurring group of disorders are lysosomal storage diseases, followed by organic acidemias; intellectual disability and cerebral palsy are the most commonly presented neurological features among Saudi Arabian children. This review summarizes the reports and studies of neurometabolic disorders prevalent in Saudi Arabia. It presents an overview of the types of disorders, current screening and diagnostic strategies, and prevalence of disease conditions in Saudi Arabia. [JBCGenetics 2020; 3(1.000): 14-21

Overcoming Mechanisms of Acquired and Innate Doxorubicin Resistance Using Nanomedicine and Tumor-Associated Macrophage Immunotherapy

ABSTRACT Overcoming Mechanisms of Acquired and Innate Doxorubicin Resistance Using Nanomedicine and Tumor-Associated Macrophage Immunotherapy By Rashed M. Almuqbil, Pharm.D. Director: Sandro R.P. da Rocha, PhD Cancer is a leading cause of death worldwide. The available treatment for solid tumors may include surgery, radiotherapy, immunotherapy, and chemotherapy or a combination of all those regimens. Chemotherapy is widely used in the treatment of both lung cancers and breast cancer, including metastases, irrespective of type and stage. The poor rates of survival can be attributed to late diagnosis, and due to the development of acquired and innate chemoresistance. Lung tumors are intrinsically resistant to chemotherapy, thus requiring the development of predictive biomarkers to personalize chemotherapeutic agents. In breast cancer patients, continuous exposure to a single chemotherapeutic agent can lead to (acquired resistance) such as multidrug resistance. Here, we formed a realistic in vitro model for the screening of chemotherapy, as the tumor stroma is composed of extracellular matrix, fibroblast, as well as how it is able to grow in a 3D manner. We described the formulation of a 4th generation PAMAM dendrimer and evaluated its efficacy and penetration through a 3D model of single and coculture spheroids, as a strategy to overcome doxorubicin’s resistance. Also, the efficacy of DOX in vivo as a single and in combination with the immunotherapy PLX3397 was evaluated, to modulate the tumor microenvironment in a syngeneic orthotopic Balb/c mice model by repolarizing M2 macrophages toward more M1 like macrophages, a potential strategy to enhance the innate immunity to fight cancer cells and overcome resistance and diminish distant metastasis