Engineered nanomedicine for myeloma and bone microenvironment targeting

Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of poly(d,l-lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and bisphosphonate (or alendronate, a targeting ligand). The engineered NPs were formulated by blending varying ratios of the synthesized polymers: PLGA-b-PEG and alendronate-conjugated polymer PLGA-b-PEG-Ald, which ensured long circulation and targeting capabilities, respectively. The bone-binding ability of Ald-PEG-PLGA NPs was investigated by hydroxyapatite binding assays and ex vivo imaging of adherence to bone fragments. In vivo biodistribution of fluorescently labeled NPs showed higher retention, accumulation, and bone homing of targeted Ald-PEG-PLGA NPs, compared with nontargeted PEG-PLGA NPs. A library of bortezomib-loaded NPs (bone-targeted Ald-Bort-NPs and nontargeted Bort-NPs) were developed and screened for optimal physiochemical properties, drug loading, and release profiles. Ald-Bort-NPs were tested for efficacy in mouse models of multiple myeloma (MM). Results demonstrated significantly enhanced survival and decreased tumor burden in mice pretreated with Ald-Bort-NPs versus Ald-Empty-NPs (no drug) or the free drug. We also observed that bortezomib, as a pretreatment regimen, modified the bone microenvironment and enhanced bone strength and volume. Our findings suggest that NP-based anticancer therapies with bone-targeting specificity comprise a clinically relevant method of drug delivery that can inhibit tumor progression in MM.The incidence of bone metastasis is common in 60–80% of cancer patients (1). During bone metastasis, cancer cells induce a sequence of changes in the microenvironment such as secreting cytokines to increase the activity of osteoclasts via the parathyroid hormone-related protein (PTHrP), receptor activator of nuclear factor-κB ligand (RANKL), and interleukin-6 (IL-6), resulting in increased bone resorption and secretion of growth factors from the bone matrix (2). This creates a “vicious cycle” of bone metastasis, where bone marrow becomes packed with cancer cells that develop resistance to conventional chemotherapy, and leads to devastating consequences of bone fractures, pain, hypercalcaemia, and spinal cord and nerve compression syndromes (2, 3). Multiple myeloma (MM) is a plasma cell cancer that proliferates primarily in bone marrow and causes osteolytic lesions (1). Antiresorption agents, such as bisphosphonates, may alleviate bone pain, but they are ineffective at inducing bone healing or osteogenesis in MM patients (4).Bortezomib is a proteasome inhibitor that has shown marked antitumor effects in patients with MM. Proteasome inhibitors, such as bortezomib, are also effective at increasing bone formation, both preclinically and clinically (5–9). However, the major drawback of bortezomib use in early stages of MM development is its toxicity, specifically, peripheral neuropathy (5). Therefore, we aimed to develop a method to deliver bortezomib with decreased off-target side effects by using bone-specific, bortezomib-loaded nanoparticles (NPs). The NP system was based on biodegradable, biocompatible, and Food and Drug Administration (FDA)-approved components, which are both clinically and translationally relevant. NPs derived from poly(d,l-lactic-co-glycolic acid) (PLGA), a controlled release polymer system, are an excellent choice because their safety in the clinic is well established (10, 11). Polyethylene glycol (PEG)-functionalized PLGA NPs are especially desirable as PEGylated polymeric NPs have significantly reduced systemic clearance compared with similar particles without PEG (12, 13). A number of FDA-approved drugs in clinical practice use PEG for improved pharmaceutical properties such as enhanced circulation in vivo (12, 13). To target NPs to bone [rich in the mineral hydroxyapatite (HA)], the calcium ion-chelating molecules of bisphosphonates represent a promising class of ligands (14). Bisphosphonates, upon systemic administration, are found to deposit in bone tissue, preferentially at the high bone turnover sites, such as the metastatic bone lesions, with minimal nonspecific accumulation (14) and were used herein to deliver NPs to the bone.A few systems explored for MM treatment have been tested in vitro including the following: (i) snake venom and silica NPs (15); (ii) thymoquinone and PLGA-based particles (16); (iii) curcumin and poly(oxyethylene) cholesteryl ether (PEG-Chol) NPs (17), polyethylenimine-based NPs for RNAi in MM (18), paclitaxel-Fe₃O₄ NPs (19), and liposomes (20). However, none of the above-mentioned systems have aimed to manipulate the bone marrow microenvironment rather than the myeloma cells directly (21). To date, there are no reports of using bone-targeted, controlled release, polymeric NPs with stealth properties for MM therapy. In this study, we designed NPs bearing three main components: (i) a targeting element that can selectively bind to bone mineral; (ii) a layer of stealth (PEG) to minimize immune recognition and enhance circulation; and (iii) a biodegradable polymeric material, forming an inner core, that can deliver therapeutics and/or diagnostics in a controlled manner. In this study, the physicochemical properties of a range of NPs was investigated (including NP size, charge, targeting ligand density, drug loading, and drug release kinetics) and an optimal formulation with ideal properties and maximal drug encapsulation was used for in vivo efficacy studies. We fine-tuned the NP targeting ligand density to optimize its bone-binding ability and further investigated its application for targeting myeloma in the bone microenvironment. We believe our NP system has the potential to increase drug availability by improving pharmacokinetics and biodistribution that can provide bone microenvironment specificity, which may increase the therapeutic window and most certainly decrease the off-target effects (12, 13).     

Using virtual reality to maintain surgical skills during periods of robotic surgery inactivity

Periodic practice is needed for newly trained robotic surgeons to maintain skills during periods of robotic inactivity. The current study was performed to determine whether virtual robotic skill maintenance can serve as an adequate substitute for practice on a surgical robot. Eleven surgical residents with no prior robotic training were trained to a level of robotic proficiency with inanimate models, including a needle driving pad, a running suture pad, and ring placement on a rocking peg board. After reaching proficiency, each resident was tested on a complex tissue closure task. For the next 8 weeks, the only robotic activity was biweekly virtual robotic skills maintenance. After 8 weeks, the residents performed the tissue closure task twice with the robot, followed by evaluation on the inanimate models used to reach proficiency. Repeated-measures statistical analyses were used to compare between the three tissue closure trials and between the final test at week 0 and the evaluation at week 8 for the other inanimate models. Time to complete the tissue closure task was more than 20 % lower for the second evaluation at 8 weeks than for the other two trials (p < 0.05). Residents maintained their skills for needle driving, but times for suture running and rocking peg board increased by more than 20 % at 8 weeks (p < 0.01). Virtual practice shows promise for maintaining robotic skills. Following a warm-up period, some skills may actually improve with biweekly virtual practice, but skill retention is selective, so further improvements are needed.     

Long-term follow-up evaluation of endoscopic sclerotherapy for dilated gastrojejunostomy after gastric bypass

Background

Endoscopic sclerotherapy using sodium morrhuate has been used to treat patients with weight regain after Roux-en-Y gastric bypass whose presumed etiology is loss of restriction due to gastrojejunostomy dilation. Weight loss and stability have been demonstrated in several studies with short-term follow-up evaluation.

Methods

This retrospective review evaluated all the patients who underwent sclerotherapy for a dilated gastrojejunostomy between 2007 and 2012.

Results

The study identified 48 patients with a mean follow-up period of 22 months (range 12–60 months). The mean age of these patients was 47.5 ± 10.5 years, and 92 % were women. The average weight loss from the primary procedure was 132.5 ± 54.82 lb, and the average weight regain from the lowest weight to the maximum weight before sclerotherapy was 46 ± 40.32 lb. The median number of sclerotherapy sessions was two (range 1–4). The pre-procedure mean gastrojejunostomy diameter was 20 ± 3.6 mm, and the mean volume of sodium morrhuate injected per session was 12.8 ± 3.7 ml. The average weight loss from sclerotherapy to the final documented weight was 3.17 ± 19.70 lb, which was not statistically significant. The following variables in the multivariate analysis were not associated with statistically significant weight loss: volume of sodium morrhuate, patient age, gastrojejunostomy diameter, number of sclerotherapy sessions, decrease in gastrojejunostomy diameter between the first and second sessions, and number of follow-up years. Weight stabilization or loss was achieved by 58 % of our cohort, with a mean weight loss of 15.9 ± 14.6 lb in this subgroup.

Conclusion

The long-term follow-up evaluation of patients undergoing sclerotherapy of the gastrojejunostomy for weight regain after gastric bypass showed only a marginal weight loss, which was not statistically significant in our study population, although more than 50 % of the patients achieved weight loss or stabilization.     

Decreased white matter integrity in fronto-occipital fasciculus bundles: Relation to visual information processing in alcohol-dependent subjects

Chronic alcohol abuse is characterized by impaired cognitive abilities with a more severe deficit in visual than in verbal functions. Neuropathologically, it is associated with widespread brain structural compromise marked by gray matter shrinkage, ventricular enlargement, and white matter degradation. The present study sought to increase current understanding of the impairment of visual processing abilities in alcohol-dependent subjects, and its correlation with white matter microstructural alterations, using diffusion tensor imaging (DTI). To that end, a DTI study was carried out on 35 alcohol-dependent subjects and 30 healthy male control subjects. Neuropsychological tests were assessed for visual processing skills and deficits were reported as raw dysfunction scores (rDyS). Reduced FA (fractional anisotropy) and increased MD (mean diffusivity) were observed bilaterally in inferior and superior fronto-occipital fasciculus (FOF) fiber bundles. A significant inverse correlation in rDyS and FA values was observed in these fiber tracts whereas a positive correlation of these scores was found with the MD values. Our results suggest that FOF fiber bundles linking the frontal lobe to occipital lobe might be related to visual processing skills. This is the first report of an alteration of the white matter microstructure of FOF fiber bundles that might have functional consequences for visual processing in alcohol-dependent subjects who exhibit no neurological complications.     

Advances in the molecular classification of pediatric brain tumors: a guide to the galaxy

Central nervous system (CNS) tumors are the most common solid tumor in pediatrics, accounting for approximately 25% of all childhood cancers, and the second most common pediatric malignancy after leukemia. CNS tumors can be associated with significant morbidity, even those classified as low grade. Mortality from CNS tumors is disproportionately high compared to other childhood malignancies, although surgery, radiation, and chemotherapy have improved outcomes in these patients over the last few decades. Current therapeutic strategies lead to a high risk of side effects, especially in young children. Pediatric brain tumor survivors have unique sequelae compared to age-matched patients who survived other malignancies. They are at greater risk of significant impairment in cognitive, neurological, endocrine, social, and emotional domains, depending on the location and type of the CNS tumor. Next-generation genomics have shed light on the broad molecular heterogeneity of pediatric brain tumors and have identified important genes and signaling pathways that serve to drive tumor proliferation. This insight has impacted the research field by providing potential therapeutic targets for these diseases. In this review, we highlight recent progress in understanding the molecular basis of common pediatric brain tumors, specifically low-grade glioma, high-grade glioma, ependymoma, embryonal tumors, and atypical teratoid/rhabdoid tumor (ATRT). © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Complex airway reconstruction in children with tracheobronchial injuries: a case series

Paediatric airway surgery in the setting of complex tracheobronchial defects is challenging. This report describes the surgical management and outcomes of pericardial flap repair in three children. The first patient was a 4-month-old boy with a history of tracheoesophageal fistula repair who presented after out-of-hospital cardiac arrest. He was treated by re-do tracheobronchial reconstruction of the carina using a pedicled pericardial flap. The second patient was an 11-month-old boy who presented following aspiration of a button battery. Bronchoscopy showed erosion of the battery through both main bronchi and the oesophagus. The patient underwent emergency reconstruction of the extensive tracheobronchial defect with pedicled right and left pericardial patches. The third patient was a 5-year-old girl who fell from a swing, resulting in avulsion of the right main bronchus. Pedicled pericardium was used to reconstruct the damaged posterior tracheal wall and the right and left main bronchi. All three patients underwent successful repair of complex tracheobronchial defects with good outcomes in terms of survival and quality of life during 6 to 21 months of follow-up. Pedicled pericardial flap repair may be a viable option for achieving improved results in children with severe tracheobronchial defects.     

Awareness,Beliefs and Perspectives Regarding Weight Retention and Weight Gain among Postpartum Women in India: A Thematic Analysis of Focus Group Discussions and In-Depth Interviews

Background and AimsThe pregnancy weight is usually retained in the form of abdominal fat during the postpartum period. The willingness to lose weight is influenced by knowledge, attitude, beliefs and practices. This study aims to comprehend the awareness, beliefs and perspectives of postpartum women regarding their perceived factors, barriers and facilitators associated with post-pregnancy weight status.MethodsOverweight and obese postpartum women aged between 20 and 40 years and had delivered an infant in the last 2 years were recruited via convenience and purposive sampling techniques. The final sample comprised 27 participants with a mean age of 29.96 ± 4.50 years. Four focus group discussions and eight in-depth interviews carried out were audio-recorded and transcribed verbatim. Codes, sub-themes and themes were generated using Atlas.ti 9 software.ResultsMajor themes identified were perceived factors causing postpartum weight retention/weight gain including social and cultural beliefs related to diet and exercise specifically associated with this period, perceived motivators and deterrents of weight loss including eagerness to lose weight and perceived facilitators and barriers to weight loss including intrinsic and extrinsic factors such as time, energy, evidence-based knowledge about diet and physical activity, family support and obligation to family’s advice.ConclusionThe unique challenges and barriers associated with postpartum weight loss efforts should be taken into consideration by healthcare professionals and public health policy-makers to design strategies specific to postpartum women.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13224-022-01644-9.     

Association of cerebral small vessel disease burden with brain structure and cognitive and vascular risk trajectories in mid-to-late life

We characterize the associations of total cerebral small vessel disease (SVD) burden with brain structure, trajectories of vascular risk factors, and cognitive functions in mid-to-late life. Participants were 623 community-dwelling adults from the Whitehall II Imaging Sub-study with multi-modal MRI (mean age 69.96, SD = 5.18, 79% men). We used linear mixed-effects models to investigate associations of SVD burden with up to 25-year retrospective trajectories of vascular risk and cognitive performance. General linear modelling was used to investigate concurrent associations with grey matter (GM) density and white matter (WM) microstructure, and whether these associations were modified by cognitive status (Montreal Cognitive Asessment [MoCA] scores of < 26 vs. ≥ 26). Severe SVD burden in older age was associated with higher mean arterial pressure throughout midlife (β = 3.36, 95% CI [0.42-6.30]), and faster cognitive decline in letter fluency (β = −0.07, 95% CI [−0.13–−0.01]), and verbal reasoning (β = −0.05, 95% CI [−0.11–−0.001]). Moreover, SVD burden was related to lower GM volumes in 9.7% of total GM, and widespread WM microstructural decline (FWE-corrected p < 0.05). The latter association was most pronounced in individuals who demonstrated cognitive impairments on MoCA (MoCA < 26; F_3,608 = 2.14, p = 0.007). These findings highlight the importance of managing midlife vascular health to preserve brain structure and cognitive function in old age.     

A prospective study on TT virus infection in transfusion-dependent patients with beta-thalassemia

A novel DNA virus designated TT virus (TTV) has been reported to be involved in the development of posttransfusion non-A-C hepatitis. We evaluated the frequency and natural course of TTV infection in a cohort of transfusion-dependent thalassemic patients in a 3-year follow-up study. Ninety-three serum hepatitis C virus (HCV) antibody-negative patients (median age of 8 years; range, 0 to 25) from eight centers were studied. Of them, 34 (37%) had an abnormal alanine-aminotransferase (ALT) baseline pattern, and the other 12 (13%) showed ALT flare-ups during the follow-up. TTV DNA in patient sera collected at the time of enrollment and at the end of follow-up was determined by polymerase chain reaction (PCR). In parallel, serum samples from 100 healthy blood donors were also tested. At baseline, 87 patient sera (93.5%) tested positive for the TTV DNA. Of these TTV DNA-positive patients, 84 (96.5%) remained viremic at the end of the study period. Of the 6 TTV DNA-negative patients, 3 acquired TTV infection during follow-up. However, no definite relation was observed between the results of TTV DNA determination and ALT patterns. TTV viremia was also detectable in 22% of blood donors. In conclusion, TTV infection is frequent and persistent among Italian transfusion-dependent patients. The high rate of viremia observed in healthy donors indicates that the parenteral route is not the only mode of TTV spread.