Cannabis and Cigarette Use Before and After Living Kidney Donation.

BACKGROUND: It is unclear whether kidney donation leads to lifestyle changes in terms of cannabis and cigarette use. OBJECTIVE: To describe cigarette and cannabis use before and after kidney donation and to determine their associations with lifestyle and clinical factors. DESIGN: Retrospective cohort study. SETTING: The Living Kidney Donor program in the Champlain Local Health Integration Network at The Ottawa Hospital in Ottawa, Canada. PATIENTS: The study included 178 living kidney donors who donated between January 2009 and December 2018. MEASUREMENTS: Donors were screened for cannabis and cigarette use by telephone interview. Their clinical characteristics and changes in kidney function before and after donation were recorded. METHODS: Cannabis and cigarette use before and after kidney donation were compared using chi-square test. Risk factors associated with their use was examined by univariate and multivariate logistic regression. Wilcoxon rank sum test was used to examine the association of cannabis and Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) estimated glomerular filtration rate (eGFR) at donation and at last follow-up. T-test was used to examine the association of cigarette smoking and CKD-EPI eGFR at donation and at last follow-up. RESULTS: Among 305 donors, 262 met inclusion criteria and 178 participated (mean of 4.7 ± 2.9 years from kidney donation). Cannabis and cigarette use were reported by 5% (9 of 178) and 13% (23 of 178) at donation. After donation, 8% (14 of 178) and 5% (9 of 178) started cannabis and cigarettes, respectively; 74% (17 of 23) of smokers remained smokers after donation and 88% (53 of 60) who quit smoking before donation did not restart after donation. In multivariate analysis, non-married/common-in-law status was associated with cannabis use (odds ratio, 2.73; 95% confidence interval, 1.05-7.11; P = .04). There was no difference in eGFR pre- or post-donation among cannabis or cigarette users. LIMITATIONS: The single-center study design limits generalizability. Social desirability bias may have affected survey responses and cigarette smoking was not quantified. CONCLUSIONS: Cannabis and cigarette use was uncommon in the studied population and was not associated with remaining kidney function. Cannabis use increased post-donation. Most smokers remained smokers after donation and most donors who quit smoking before donation did not restart after donation. This warrants education and support for potential donors who smoke, to quit smoking prior to donation to reduce risks of cardiovascular and end-stage kidney disease. TRIAL REGISTRATION: Not applicable as this is not a clinical trial.

CONTEXTE: On ignore si la perspective de faire don d'un rein conduit les donneurs potentiels à changer leurs habitudes de vie en matière de tabagisme et de consommation de cannabis. OBJECTIFS: Examiner la prévalence du tabagisme et de la consommation de cannabis avant et après le don d'un rein, puis déterminer leur association avec le mode de vie et les facteurs cliniques. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: Le program de don de rein vivant du Réseau local d'intégration des services de santé de Champlain de l'hôpital d'Ottawa (Canada). SUJETS: L'étude a inclus 178 individus ayant fait don d'un rein entre janvier 2009 et décembre 2018. MESURES: Les donneurs ont été questionnés par téléphone sur leur consommation de cigarettes et de cannabis. Les caractéristiques cliniques et les changements dans la fonction rénale ont été enregistrés pré- et post-don. MÉTHODOLOGIE: Le test du Chi2 a été employé pour comparer la consommation de cigarettes et de cannabis pré- et post-don, tandis que les facteurs de risque associés à leur utilization ont été examinés par régression logistique univariée et multivariée. L'association entre la consommation de cannabis/le tabagisme et le CKD-EPI eGFR (débit de filtration glomérulaire estimé [DFGe] par l'équation de la Chronic Kidney Disease Epidemiology [CKD-EPI] Collaboration) a été examinée au moment du don et lors du dernier suivi par le test Wilcoxon (cannabis) ou le test t (tabagisme), selon le cas. RÉSULTATS: Des 305 donneurs admissibles, 262 répondaient aux critères d'inclusion et 178 ont participé à l'étude (moyenne: 4,7 ± 2,9 ans depuis le don). Au moment du don, 5 % (9/178) des donneurs consommaient du cannabis et 13 % (23/178) fumaient la cigarette. Après le don, 8 % (14/178) des donneurs ont commencé à consommer du cannabis et 5 % (9/178) à fumer la cigarette. La majorité des donneurs qui fumaient avant le don ont continué après le don (74 % [17/23]). La grande majorité des donneurs qui avaient cessé de fumer avant le don n'ont pas repris après (88 % [53/60]). Dans l'analyze multivariée, le fait de ne pas être marié ou conjoint de fait a été associé à la consommation de cannabis (rapport de cotes: 2,73; IC à 95 %: 1,05-7,11; p=0,04). Aucune différence n'a été observée dans les taux de filtration glomérulaire estimé pré- et post-don chez les fumeurs et les consommateurs de cannabis. LIMITES: L'étude est monocentrique, ce qui limite la généralisabilité des résultats. Un biais de désirabilité sociale pourrait avoir influé sur les réponses à l'enquête. Le tabagisme n'a pas été quantifié. CONCLUSION: Le tabagisme et la consommation de cannabis étaient peu courants dans la population étudiée; ces habitudes de vie n'ont pas été associées à la fonction rénale résiduelle. La consommation de cannabis a augmenté après le don. La plupart des fumeurs le sont demeurés après le don et la majorité des donneurs qui avaient cessé de fumer avant le don n'ont pas repris après. Ces résultats justifient de sensibiliser les donneurs potentiels à l'importance de cesser de fumer avant le don, et de les appuyer dans cette démarche, afin de réduire les risques de maladies cardiovasculaires et d'insuffisance rénale terminale.

Sialyltransferase inhibition leads to inhibition of tumor cell interactions with E-selectin, VCAM1, and MADCAM1, and improves survival in a human multiple myeloma mouse model.

Aberrant glycosylation resulting from altered expression of sialyltransferases, such as ST3 ß-galactoside α2-3-sialyltransferase 6, plays an important role in disease progression in multiple myeloma (MM). Hypersialylation can lead to increased immune evasion, drug resistance, tumor invasiveness, and disseminated disease. In this study, we explore the in vitro and in vivo effects of global sialyltransferase inhibition on myeloma cells using the pan-sialyltransferase inhibitor 3Fax-Neu5Ac delivered as a per-acetylated methyl ester pro-drug. Specifically, we show in vivo that 3Fax-Neu5Ac improves survival by enhancing bortezomib sensitivity in an aggressive mouse model of MM. However, 3Fax-Neu5Ac treatment of MM cells in vitro did not reverse bortezomib resistance conferred by bone marrow (BM) stromal cells. Instead, 3Fax-Neu5Ac significantly reduced interactions of myeloma cells with E-selectin, MADCAM1 and VCAM1, suggesting that reduced sialylation impairs extravasation and retention of myeloma cells in the BM. Finally, we showed that 3Fax-Neu5Ac alters the post-translational modification of the α4 integrin, which may explain the reduced affinity of α4ß1/α4ß7 integrins for their counter-receptors. We propose that inhibiting sialylation may represent a valuable strategy to restrict myeloma cells from entering the protective BM microenvironment, a niche in which they are normally protected from chemotherapeutic agents such as bortezomib. Thus, our work demonstrates that targeting sialylation to increase the ratio of circulating to BM-resident MM cells represents a new avenue that could increase the efficacy of other anti-myeloma therapies and holds great promise for future clinical applications.

Development of medical-grade, discrete, multi-walled carbon nanotubes as drug delivery molecules to enhance the treatment of hematological malignancies.

Carbon nanotubes (CNTs) hold great potential as drug delivery transporters given their large drug-binding surface area. Herein, we designed novel, multi-walled, discrete CNTs (dMWCNTs), PEGylated dMWCNTs (PEG-dMWCNTs), and bone-targeting (BT), alendronate-conjugated PEG-dMWCNTs (BT-PEG-dMWCNTs). Using zeta potential, thermogravimetric analysis, TEM, SEM, and FTIR, dMWCNTs were characterized as individual, uniform, and stable. Drug binding and release assays validated dMWCNTs as effective doxorubicin (DOX) transporters. The mass ratio of DOX loading onto dMWCNTs was 35% wt/wt with a ~95% wt/wt efficiency. DOX release was ~51% w/w after 48 hours. Neoplastic transformation, chromosomal aberration, and cytotoxicity assays, confirmed biocompatibility for all dMWCNTs. PEG-dMWCNTs were well tolerated and modulated drug pharmacokinetics in mice. In mice with Burkitt's lymphoma, DOX-loaded PEG-dMWCNTs and BT-PEG-dMWCNTs reduced tumor burden and increased survival similarly to free drug. Importantly, DOX toxicity was abrogated when DOX was loaded onto PEG-dMWCNTs or BT-PEG-dMWCNTs. Overall, PEG-dMWCNTs and BT-PEG-dMWCNTs represent a promising new nanocarrier platform.

Neurovascular structures in human vastus lateralis muscle and the ideal biopsy site.

A density model of neurovascular structures was generated from 28 human vastus lateralis muscles isolated from embalmed cadavers. The intramuscular portion of arteries, veins, and nerves was dissected, traced on transparencies, and digitized before adjustment to an average muscle shape using Procrustes analysis to generate density distributions for the relative positions of these structures. The course of arteries, veins, and nerves was highly variable between individual muscles. Nevertheless, a zone of lower average neurovascular density was found between the tributaries from the lateral circumflex femoral and the deep femoral arteries. While the area with the lowest density was covered by the iliotibial tract and would therefore not be suitable for biopsies, another low-density area was located in the distal portion of vastus lateralis. This was just anterior to the iliotibial tract, in a zone that has been described as a good needle biopsy site. The reported complication rates of needle biopsies (0.1%-4%) are in the range of expectations when simulated based on this model. It is concluded that the optimal human vastus lateralis biopsy site is in the distal portion of the muscle, between ½ and ¾ of the length from the greater trochanter to the lateral epicondyle, just anterior to the iliotibial band.

Multicolour lineage tracing reveals clonal dynamics of squamous carcinoma evolution from initiation to metastasis.

Tumour cells are subjected to evolutionary selection pressures during progression from initiation to metastasis. We analysed the clonal evolution of squamous skin carcinomas induced by DMBA/TPA treatment using the K5CreER-Confetti mouse and stage-specific lineage tracing. We show that benign tumours are polyclonal, but only one population contains the Hras driver mutation. Thus, benign papillomas are monoclonal in origin but recruit neighbouring epithelial cells during growth. Papillomas that never progress to malignancy retain several distinct clones, whereas progression to carcinoma is associated with a clonal sweep. Newly generated clones within carcinomas demonstrate intratumoural invasion and clonal intermixing, often giving rise to metastases containing two or more distinct clones derived from the matched primary tumour. These data demonstrate that late-stage tumour progression and dissemination are governed by evolutionary selection pressures that operate at a multicellular level and, therefore, differ from the clonal events that drive initiation and the benign-malignant transition.