CBD reduced breast cancer metastasis in advanced stages of the disease as the direct . CBD increases survival in a syngeneic mouse model of breast cancer. Meanwhile, in vivo study results revealed major increase in survival when . Syngeneic mouse models were created by subcutaneously (s.c.) Remarkably, 5 µg of CBD was found to achieve greater tumor cell killing than 4 Gy of RT. .. death in breast cancer cells by coordinating the cross-talk between. Many studies investigating the effects of cannabinoids on tumor progression . Colitisis induced colon cancer model (Azoxymethane, AOM+dextran sulfate .. that CBD inhibited tumor growth and increased the survival of animals .. and triple negative breast cancer (TNBC), a type of breast cancer which is.
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Here we demonstrate the use of complementary approaches, 3D bioprinting and scaffold-free 3D tissue culture, to examine the invasion of glioma cells into neural-like tissue with 3D confocal microscopy.
We found that, while both approaches were successful, the use of 3D tissue culture for organoid development offers the advantage of broad accessibility. As a proof-of-concept of our approach, we developed a system in which we could model the invasion of human glioma cells into mouse neural progenitor cell-derived spheroids. We show that we can follow invasion of human tumour cells using cell-tracking dyes and 3D laser scanning confocal microscopy, both in real time and in fixed samples.
We validated these results using conventional cryosectioning. Our scaffold-free 3D approach has broad applicability, as we were easily able to examine invasion using different neural progenitor cell lines, thus mimicking differences that might be observed in patient brain tissue. These results, once applied to iPSC-derived cerebral organoids that incorporate the somatic genetic variability of patients, offer the promise of truly personalized treatments for brain cancer.
Murine model of long-term obstructive jaundice. With the recent emergence of conjugated bile acids as signaling molecules in cancer, a murine model of obstructive jaundice by cholestasis with long-term survival is in need. Here, we investigated the characteristics of three murine models of obstructive jaundice. The LHML group developed portal hypertension and severe fibrosis by day 14 in addition to prolonged jaundice. The standard tCL model is too unstable with high mortality for long-term studies.
Patient specific actual size 3D printed models for patient education in glioma treatment: Cancer patients need high quality information about the disease stage, treatment options and side effects. High quality information can also improve health literacy, shared decision-making and satisfaction. We created patient-specific 3D models of tumours including surrounding functional areas, and assessed what patients with glioma actually value or fear about these models when they are used to educate them about the relation between their tumour and specific brain parts, the surgical procedure, and risks.
We carried out an explorative study with adult glioma patients, who underwent functional MRI and DTi as part of the pre-operative work-up. Semi-structured interviews were held to identify facilitators and barriers for using the model , and perceived effects. A model was successfully created for all 11 participants.
A total of 18 facilitators and 8 barriers were identified. The model improved patients' understanding about their situation, that it was easier to ask questions to their neurosurgeon based on their model and that it supported their decision about the preferred treatment. A perceived barrier for using the 3D model was that it could be emotionally confronting, particularly in an early phase of the disease process. Positive effects were related to psychological domains including coping, learning effects and communication.
Patient-specific 3D models are promising and simple tools that could help patients with glioma to better understand their situation, treatment options and risks. They have the potential to improve shared decision-making. Tumor-associated macrophages are predominant carriers of cyclodextrin-based nanoparticles into gliomas. The goal of this study was to evaluate the mechanism of cyclodextrin-based nanoparticle CDP-NP uptake into a murine glioma model. Fluorescent microscopy and flow cytometry analysis of intracranial GL gliomas confirmed these findings and demonstrated a predominant CDP-NP uptake by macrophages MPs and MG within and around the tumor site.
In conclusion, these studies better characterize the cellular distribution of CDP-NPs in intracranial tumors and demonstrate that MPs and MG could potentially be used as nanoparticle drug carriers into malignant brain tumors. Macrophages and MG could potentially be used as nanoparticle drug carriers into malignant brain tumors.
Copyright Elsevier Inc. Electrocautery effect on intestinal vascularisation in a murine model. The use of electrocautery devices is associated with complications such as perforation or fistulisation when used near intestinal structures. This is likely due to its effect on vascularisation of the bowel wall. To test this hypothesis we established a murine model to quantify the effect of electrocautery injury on the intestinal microvascularisation.
The segments were analysed to measure the fluorescence of injured bowel compared to adjacent unharmed tissue. Unsurprisingly, the decrease in microvascularisation is greater with higher intensity and duration of electrocautery and is associated with more perforations in the experimental model.
The jejunum seems more vulnerable to electrocautery injury than the ileum. These observations support caution when using electrocautery devices near intestinal structures.
Clindamycin in a murine model of toxoplasmic encephalitis. We investigated the efficacy of clindamycin in a murine model of toxoplasmic encephalitis using direct intracerebral inoculation. Although we were unable to document appreciable levels of clindamycin in the brains of infected mice, the histological features of cerebral infection were markedly altered.
The formation of large numbers of cysts and the intense inflammatory response seen in the brains of normal mice and the unchecked infection and tissue necrosis in the brains of cortisone-treated mice were absent in the brains of clindamycin-treated mice. Enumeration of cysts in the brains of mice 10 weeks after infection revealed a significantly lower number in the clindamycin-treated mice.
Spread of infection to other organs was also decreased during clindamycin administration. These observations suggest that clindamycin may have a role in the therapy of toxoplasmic encephalitis. Reactivation of Latent Tuberculosis: Variations on the Cornell Murine Model. Mycobacterium tuberculosis causes active tuberculosis in only a small percentage of infected persons.
In most cases, the infection is clinically latent, although immunosuppression can cause reactivation of a latent M. Surprisingly little is known about the biology of the bacterium or the host during latency, and experimental studies on latent tuberculosis suffer from a lack of appropriate animal models. The Cornell model is a historical murine model of latent tuberculosis, in which mice infected with M.
Reactivation of infection during this culture-negative state occurred spontaneously and following immunosuppression. In the present study, three variants of the Cornell model were evaluated for their utility in studies of latent and reactivated tuberculosis.
The antibiotic regimen, inoculating dose, and antibiotic-free rest period prior to immunosuppression were varied. A variety of immunosuppressive agents, based on immunologic factors known to be important to control of acute infection, were used in attempts to reactivate the infection. Although reactivation of latent infection was observed in all three variants, these models were associated with characteristics that limit their experimental utility, including spontaneous reactivation, difficulties in inducing reactivation, and the generation of altered bacilli.
The results from these studies demonstrate that the outcome of Cornell model -based studies depends critically upon the parameters used to establish the model. A fluorescence model of the murine lung for optical detection of pathogenic bacteria. We present a computer model of intravital excitation and external fluorescence detection in the murine lungs validated with a three-dimensional lung tissue phantom.
The model is applied to optical detection of pulmonary tuberculosis infection. A translational model system for convection-enhanced delivery. Canine spontaneous intracranial tumors bear striking similarities to their human tumor counterparts and have the potential to provide a large animal model system for more realistic validation of novel therapies typically developed in small rodent models.
We used spontaneously occurring canine gliomas to investigate the use of convection-enhanced delivery CED of liposomal nanoparticles, containing topoisomerase inhibitor CPT To facilitate visualization of intratumoral infusions by real-time magnetic resonance imaging MRI , we included identically formulated liposomes loaded with Gadoteridol. Real-time MRI defined distribution of infusate within both tumor and normal brain tissues. The most important limiting factor for volume of distribution within tumor tissue was the leakage of infusate into ventricular or subarachnoid spaces.
Decreased tumor volume, tumor necrosis, and modulation of tumor phenotype correlated with volume of distribution of infusate Vd , infusion location, and leakage as determined by real-time MRI and histopathology. This study demonstrates the potential for canine spontaneous gliomas as a model system for the validation and development of novel therapeutic strategies for human brain tumors.
Data obtained from infusions monitored in real time in a large, spontaneous tumor may provide information, allowing more accurate prediction and optimization of infusion parameters. Variability in Vd between tumors strongly suggests that real-time imaging should be an essential component of CED therapeutic trials to allow minimization of inappropriate infusions and accurate assessment of clinical outcomes.
Quantitative multiparametric MRI assessment of glioma response to radiotherapy in a rat model. The inability of structural MRI to accurately measure tumor response to therapy complicates care management for patients with gliomas. The purpose of this study was to assess the potential of several noninvasive functional and molecular MRI biomarkers for the assessment of glioma response to radiotherapy.
Fourteen U87 tumor-bearing rats were irradiated using a small-animal radiation research platform 40 or 20 Gy , and 6 rats were used as controls. MRI was performed on a 4. Image features of the tumors, as well as tumor volumes and animal survival, were quantitatively compared. Structural MRI showed that all irradiated tumors still grew in size during the initial days postradiation. The apparent diffusion coefficient ADC values of tumors increased significantly postradiation 40 and 20 Gy , except at day 3 postradiation, compared with preradiation.
The tumor blood flow decreased significantly postradiation 40 and 20 Gy , but the relative blood flow tumor vs contralateral did not show a significant change at most time points postradiation. The amide proton transfer weighted APTw signals of the tumor decreased significantly at all time points postradiation 40 Gy , and also at day 9 postradiation 20 Gy. The blood flow and APTw maps demonstrated tumor features that were similar to those seen on gadolinium-enhanced T1-weighted images.
Tumor ADC, blood flow, and APTw were all useful imaging biomarkers by which to predict glioma response to radiotherapy. The APTw signal was most promising for early response assessment in this model. Current advances of murine models for food allergy. Food allergy affects an increasing population in Western world but also developing countries. Researchers have been taking great efforts in identifying and characterising food allergens using molecular tools.
However, there are still many mechanistic hypotheses that need to be tested using an appropriate in vivo experimental platform. To date, a number of mouse models for food allergy have been established and provided valuable insights into food allergenicity, development of therapies and allergic inflammation mechanisms. Nevertheless, a large diversity of protocols have been developed for the establishment of relevant mouse models.
As a result, comparisons of outcomes between different models are very difficult to be conducted. The phenotypes of mouse models are greatly influenced by genetic background, gender, route of allergen exposure, the nature and concentration of food allergens, as well as the usage of adjuvants. This review focuses on IgE-mediated food allergy, compares the differential approaches in developing appropriate murine models for food allergy and details specific findings for three major food allergens, peanut, milk and shellfish.
Published by Elsevier Ltd. An in vitro model of murine middle ear epithelium. Otitis media OM , or middle ear inflammation, is the most common paediatric disease and leads to significant morbidity. Although understanding of underlying disease mechanisms is hampered by complex pathophysiology it is clear that epithelial abnormalities underpin the disease.
There is currently a lack of a well-characterised in vitro model of the middle ear ME epithelium that replicates the complex cellular composition of the middle ear. Here, we report the development of a novel in vitro model of mouse middle ear epithelial cells mMECs at an air-liquid interface ALI that recapitulates the characteristics of the native murine ME epithelium.
We demonstrate that mMECs undergo differentiation into the varied cell populations seen within the native middle ear. Proteomic analysis confirmed that the cultures secrete a multitude of innate defence proteins from their apical surface. We showed that the mMECs supported the growth of the otopathogen, nontypeable Haemophilus influenzae NTHi , suggesting that the model can be successfully utilised to study host-pathogen interactions in the middle ear.
Overall, our mMEC culture system can help to better understand the cell biology of the middle ear and improve our understanding of the pathophysiology of OM. The model also has the potential to serve as a platform for validation of treatments designed to reverse aspects of epithelial remodelling that underpin OM development. Published by The Company of Biologists Ltd. Therapeutic protocols in immunotherapy are usually proposed following the intuition and experience of the therapist.
In order to deduce such protocols mathematical modeling , optimal control and simulations are used instead of the therapist's experience. Clinical efficacy of dendritic cell DC vaccines to cancer treatment is still unclear, since dendritic cells face several obstacles in the host environment, such as immunosuppression and poor transference to the lymph nodes reducing the vaccine effect.
In view of that, we have created a mathematical murine model to measure the effects of dendritic cell injections admitting such obstacles. In addition, the model considers a therapy given by bolus injections of small duration as opposed to a continual dose. Doses timing defines the therapeutic protocols, which in turn are improved to minimize the tumor mass by an optimal control algorithm.
We intend to supplement therapist's experience and intuition in the protocol's implementation. Experimental results made on mice infected with melanoma with and without therapy agree with the model.
It is shown that the dendritic cells' percentage that manages to reach the lymph nodes has a crucial impact on the therapy outcome. This suggests that efforts in finding better methods to deliver DC vaccines should be pursued. A murine model of targeted infusion for intracranial tumors.
Historically, intra-arterial IA drug administration for malignant brain tumors including glioblastoma multiforme GBM was performed as an attempt to improve drug delivery. With the advent of percutaneous neuorovascular techniques and modern microcatheters, intracranial drug delivery is readily feasible; however, the question remains whether IA administration is safe and more effective compared to other delivery modalities such as intravenous IV or oral administrations.
Preclinical large animal models allow for comparisons between treatment routes and to test novel agents, but can be expensive and difficult to generate large numbers and rapid results. Accordingly, we developed a murine model of IA drug delivery for GBM that is reproducible with clear readouts of tumor response and neurotoxicities. Herein, we describe a novel mouse model of IA drug delivery accessing the internal carotid artery to treat ipsilateral implanted GBM tumors that is consistent and reproducible with minimal experience.
The intent of establishing this unique platform is to efficiently interrogate targeted anti-tumor agents that may be designed to take advantage of a directed, regional therapy approach for brain tumors. Arthritis is a frequent complication of infection in humans with Borrelia burgdorferi. Weeks to months following the onset of Lyme borreliosis, a histopathological reaction characteristic of synovitis including bone, joint, muscle, or tendon pain may occur. A subpopulation of patients may progress to a chronic, debilitating arthritis months to years after infection which has been classified as severe destructive Lyme arthritis.
This arthritis involves focal bone erosion and destruction of articular cartilage. Hamsters and mice are animal models that have been utilized to study articular manifestations of Lyme borreliosis. The hamster model of severe destructive Lyme arthritis facilitates easy assessment of Lyme borreliosis vaccine preparations for deleterious effects while murine models of severe destructive Lyme arthritis allow for investigation of mechanisms of immunopathology.
Murine models of atrophy, cachexia, and sarcopenia in skeletal muscle. With the extension of life span over the past several decades, the age-related loss of muscle mass and strength that characterizes sarcopenia is becoming more evident and thus, has a more significant impact on society.
To determine ways to intervene and delay, or even arrest the physical frailty and dependence that accompany sarcopenia, it is necessary to identify those biochemical pathways that define this process. Animal models that mimic one or more of the physiological pathways involved with this phenomenon are very beneficial in providing an understanding of the cellular processes at work in sarcopenia.
The ability to influence pathways through genetic manipulation gives insight into cellular responses and their impact on the physical expression of sarcopenia.
This review evaluates several murine models that have the potential to elucidate biochemical processes integral to sarcopenia. Identifying animal models that reflect sarcopenia or its component pathways will enable researchers to better understand those pathways that contribute to age-related skeletal muscle mass loss, and in turn, develop interventions that will prevent, retard, arrest, or reverse this phenomenon.
Pharmacokinetic modeling of dynamic contrast enhanced DCE -MRI data provides measures of the extracellular volume fraction ve and the volume transfer constant Ktrans in a given tissue. These parameter estimates may be biased, however, by confounding issues such as contrast agent and tissue water dynamics, or assumptions of vascularization and perfusion made by the commonly used model.
Pharmacological doses of daily ascorbate protect tumors from radiation damage after a single dose of radiation in an intracranial mouse glioma model. Pharmacological ascorbate is currently used as an anti-cancer treatment, potentially in combination with radiation therapy, by integrative medicine practitioners. In the acidic, metal-rich tumor environment, ascorbate acts as a pro-oxidant, with a mode of action similar to that of ionizing radiation; both treatments kill cells predominantly by free radical-mediated DNA damage.
In addition, we report the effect of a single fraction 4. While radiation delayed tumor progression, intraperitoneal ascorbate alone had no effect on tumor progression. Tumor progression was faster in tumor-bearing mice treated with radiation and daily ascorbate than in those treated with radiation alone. Histological analysis showed less necrosis in tumors treated with both radiation and ascorbate, consistent with a radio-protective effect of ascorbate in vivo.
Discrepancies between our in vitro and in vivo results may be explained by differences in the tumor microenvironment, which determines whether ascorbate remains outside the cell, acting as a pro-oxidant, or whether it enters the cells and acts as an anti-oxidant.
A functional murine model of hindlimb demand ischemia. To date, murine models of treadmill exercise have been used to study general exercise physiology and angiogenesis in ischemic hindlimbs. The purpose of these experiments was to develop a murine model of demand ischemia in an ischemic limb to mimic claudication in humans. The primary goal was to determine whether treadmill exercise reflected a hemodynamic picture which might be consistent with the hyperemic response observed in humans.
Peripheral perfusion of the hindlimbs at rest was determined by serial evaluation using laser Doppler imaging LDI on days 0, 7, and 14 following FAL. During the experiments, mice were also assessed on an established five-point clinical ischemic score, which assessed the degree of digital amputation, necrosis, and cyanosis compared to the nonischemic contralateral limb.
An evaluation of preexercise and postexercise perfusion using LDI was performed on two separate occasions following the onset of daily exercise. During the immediate 15 min postexercise evaluation, LDI scanning was obtained in quadruplicate, to allow identification of peak flux ratios. Statistical analysis included unpaired t-tests and analysis of variance.
After FAL, the LDI flux ratio reached a nadir between days 1 and 2, then stabilized by day 14 and remained stable through day The clinical ischemic score stabilized at day 7 and remained stable throughout the rest of the experiment. Based on stabilization of both the clinical ischemic score and LDI ratio, exercise training began on day Effects of anticancer drugs on glia- glioma brain tumor model characterized by acoustic impedance microscopy.
An ultrasonic microscope is a useful tool for observing living tissue without chemical fixation or histochemical processing. Two-dimensional 2D acoustic impedance microscopy developed in our previous study for living cell observation was employed to visualize intracellular changes. We proposed a brain tumor model by cocultivating rat glial cells and C6 gliomas to quantitatively analyze the effects of two types of anticancer drugs, cytochalasin B CyB and temozolomide TMZ , when they were applied.
As CyB targets the actin filament polymerization of the cells, we have concluded that the decrease in acoustic impedance was in fact due to actin filament depolymerization and the data can be quantitatively assessed for future studies in novel drug development.
Perspective on translating biomaterials into glioma therapy: Lessons from in vitro models. Glioblastoma GBM is the most common and malignant form of brain cancer. Even with aggressive standard of care, GBM almost always recurs because its diffuse, infiltrative nature makes these tumors difficult to treat.
The use of biomaterials is one strategy that has been, and is being, employed to study and overcome recurrence. Biomaterials have been used in GBM in two ways: In vitro systems are a useful platform for studying the effects of drugs and tissue-level effectors on tumor cells in a physiologically relevant context. These systems have aided examination of how glioma cells respond to a variety of natural, synthetic, and semi-synthetic biomaterials with varying substrate properties, biochemical factor presentations, and non-malignant parenchymal cell compositions in both 2D and 3D environments.
The current in vivo paradigm is completely different, however. Polymeric implants are simply used to line the post-surgical resection cavities and deliver secondary therapies, offering moderate impacts on survival. Instead, perhaps we can use the data generated from in vitro systems to design novel biomaterial-based treatments for GBM akin to a tissue engineering approach. Here we offer our perspective on the topic, summarizing how biomaterials have been used to identify facets of glioma biology in vitro and discussing the elements that show promise for translating these systems in vivo as new therapies for GBM.
Modeling of Chronic Myeloid Leukemia: Over the past years, a wide variety of in vivo mouse models have been generated in order to unravel the molecular pathology of Chronic Myeloid Leukemia CML and to develop and improve therapeutic approaches. These models range from conditional transgenic models , knock-in models , and murine bone marrow retroviral transduction models followed by transplantation. These models not only mimic CML but also have been instrumental in uncovering various fundamental mechanisms of CML disease progression and tyrosine kinase inhibitor TKI resistance.
With the availability of iPSC technology, it has become feasible to derive, maintain, and expand CML subclones that are at least genetically identical to those in patients.
The following review provides an overview of all murine as well as human xenograft models for CML established till date. A true orthotopic gastric cancer murine model using electrocoagulation. Currently, orthotopic mouse models of gastric cancer require an operative procedure involving either injection or implantation of tumor cells in stomach layers. The resultant tumor does not grow from the stomach's mucosal surface, so it does not mimic the human disease process.
A low-dose gastric mucosal coagulation was done transorally in the body of stomach using a specially designed polyethylene catheter in 16 female severe combined immunodeficient mice.
Five mice each were euthanized at 1 and 2 months, and 6 mice were euthanized at 3 months. Three control mice underwent electrocoagulation alone and 3 mice underwent cell line instillation alone. Tumors were detected in 11 of 16 experimental mice, but not in the control mice.
Tumors were noted in mice at 1 month. Over time, there was an increase in tumor growth and metastasis to lymph nodes and surrounding organs.
Histopathologic evaluation showed that the tumors grew from the gastric mucosa. Our model is easy to create and overcomes the limitations of the existing models , as the tumor arises from the stomach's mucosal layer and mimics the human disease in terms of morphology and biologic behavior.
This is the first report of a true orthotopic gastric cancer murine model. This model opens new doors for additional studies that were not possible earlier. Development of a novel mouse glioma model using lentiviral vectors. We report the development of a new method to induce glioblastoma multiforme in adult immunocompetent mice by injecting Cre-loxP—controlled lentiviral vectors expressing oncogenes.
Cell type- or region-specific expression of activated forms of the oncoproteins Harvey-Ras and AKT in fewer than 60 glial fibrillary acidic protein—positive cells in the hippocampus, subventricular zone or cortex of mice heterozygous for the gene encoding the tumor suppressor Tp53 were tested.
Mice developed glioblastoma multiforme when transduced either in the subventricular zone or the hippocampus. However, tumors were rarely detected when the mice were transduced in the cortex.
We suggest that the use of Cre-loxP—controlled lentiviral vectors is a novel way to generate a mouse glioblastoma multiforme model in a region- and cell type-specific manner in adult mice.
Diagnosing hypoxia in murine models of rheumatoid arthritis from reflectance multispectral images. Spectra computed from multispectral images of murine models of Rheumatoid Arthritis show a characteristic decrease in reflectance within the nm region which is indicative of the reduction in blood oxygenation and is consistent with hypoxia.
Enterocin CRL35 inhibits Listeria monocytogenes in a murine model. Listeria monocytogenes is a foodborne pathogen causative of opportunistic infections. Listeriosis is associated with severe infections in pregnant women causing abortion or neonatal listeriosis.
An alternative to antibiotics are safe novel bacteriocins peptides such as enterocin CRL35 with strong antilisterial activity produced by Enterococcus mundtii CRL In the present paper, our goal is to study the effectiveness of this peptide and the producer strain in a murine model of pregnancy-associated listeriosis.
The maximum level of Listeria was observed on day 3 postinfection. Interestingly, the intragastric administration of enterocin CRL35 significantly reduced the translocation of the pathogen to vital organs.
On the other hand, the preadministration of E. Listeria infection caused a significant increase in polymorphonuclear leukocytes at day 3 postinfection compared to the noninfected group. This value was reduced after the administration of enterocin CRL No significant changes were observed in either white blood cells or lymphocytes counts. Based on the data presented in the present work enterocin CRL35 would be a promising alternative for the prevention of Listeria infections.
A murine model was developed that recapitulates key features of clinical hypersensitivity to Escherichia coli asparaginase. Sensitized mice developed high levels of anti-asparaginase IgG antibodies and had immediate hypersensitivity reactions to asparaginase upon challenge.
We investigated the influence of pretreatment with triprolidine, cimetidine, the platelet activating factor PAF receptor antagonist CV [2- 2-acetylmethoxy-3,9-dioxo-4,8-dioxa-2,diazaoctacosyl ethyl-pyridinium chloride], or dexamethasone on the severity of asparaginase-induced allergies. To rescue asparaginase activity in sensitized mice without requiring dexamethasone, a 5-fold greater dose of asparaginase was needed to restore enzyme activity to a similar concentration as in nonsensitized mice.
Our results suggest a role of histamine and PAF in asparaginase-induced allergies and indicate that mast cell—derived proteases released during asparaginase allergy may be a useful marker of clinical hypersensitivity. Fluorescent microscopy and flow cytometry analysis of intracranial i. Interestingly, in mice bearing bilateral i. Development of a murine model of blunt hepatic trauma. Despite the prevalence of blunt hepatic trauma in humans, there are few rodent models of blunt trauma that can be used to study the associated inflammatory responses.
We present a mouse model of blunt hepatic trauma that was created by using a cortical contusion device. Male mice were anesthetized with ketamine-xylazine-buprenorphine and placed in left lateral recumbency.
A position of 2 mm ventral to the posterior axillary line and 5 mm caudal to the costal margin on the right side was targeted for impact. All mice that recovered from anesthesia survived without complication for the length of the study. Some mice were reanesthetized for serial monitoring of hepatic lesions via MRI.
At 2 h after trauma, mice consistently displayed laceration, hematoma, and discoloration of the right lateral and caudate liver lobes, with intraabdominal hemorrhage but no other gross injuries. Blood and peritoneal lavage fluid were collected from all mice for cytokine analysis. At 7 d after trauma, the mice had regained body weight, and the hepatic lesions, which initially had increased in size during the first 48 h, had returned to their original size.
In summary, this technique produced a reliable, low mortality, murine model that recreates features of blunt abdominal liver injury in human subjects with similar acute inflammatory response. A Murine Hypertrophic Cardiomyopathy Model: Familial hypertrophic cardiomyopathy HCM is attributed to mutations in genes that encode for the sarcomere proteins, especially Mybpc3 and Myh7. Genotype-phenotype correlation studies show significant variability in HCM phenotypes among affected individuals with identical causal mutations.
Morphological changes and clinical expression of HCM are the result of interactions with modifier genes. With the exceptions of angiotensin converting enzyme, these modifiers have not been identified.
Although mouse models have been used to investigate the genetics of many complex diseases, natural murine models for HCM are still lacking. Of great interest, blood pressure and cardiac function are within the normal range in the D2 strain, demonstrating that cardiac hypertrophy and fibrosis are not secondary to hypertension, myocardial infarction, or heart failure.
Because D2 and B6 strains have been used to generate a large family of recombinant inbred strains, the BXD cohort, the D2 model can be effectively exploited for in-depth genetic analysis of HCM susceptibility and modifier screens. Murine model for congenital CMV infection and hearing impairment. But the pathogenic mechanism remains unknown, and there is no ideal CMV intrauterine infection animal model to study the mechanisms by which SNHL develops.
Phytocannabinoids are terpenophenolic secondary metabolites predominantly produced in Cannabissativa L. More recently, these molecules have gained special attention for their role in cancer cell proliferation and death.
Natural Products and Cancer Drug Discovery. Cannabaceae is one of the first plants cultivated by man and one of the oldest plant sources of fibre, food and remedies. It has a long history of medical use in the Middle East and Asia, dating back to the sixth century BC. During a period of colonial expansion in the early nineteenth century, cannabis found a way to Western Europe as a medicine to alleviate a variety of conditions, such as pain, spasms, dysentery, depression, sleep disturbance and loss of appetite.
In the beginning of the twentieth century, due to the availability of substitute drugs, absence of quality control and the risk of abuse and intoxication, cannabis medication fell into disuse. Moreover, following the UN Single Convention on Narcotic Drugs in , cannabis and its products were classified as narcotics. Many natural products besides cannabinoids have been isolated from cannabis, including terpenes, flavonoids, steroids and nitrogenous compounds.
The therapeutic properties of cannabis have been much debated from scientific and regulatory points of view over the years. The medical use of cannabis is still controversial and strongly limited by unavoidable psychotropic effects.
Nowadays, many countries legalised cannabis for medical purposes. To avoid abuse, numerous centres for cannabis therapy are founded worldwide and usually organised as clinics where cannabis can be prescribed in various forms, including dried plant material and cannabis extract.
In this chapter, we will focus on phytochemistry and pharmacology of cannabinoids as well as their current and potential roles in symptom management and cancer therapy. Other previously described species, including C. Staminate male plants are usually taller but less robust than pistillate female plants. The leaves are petiolate, palmately compound, with an odd number 3—13 of coarsely serrate, lanceolate leaflets. The male inflorescence is a lax panicle or compound cyme composed of many individual, yellowish green, pedicellate flowers containing five pendulous anthers.
The pistillate flowers are green, sometimes purple to red, sessile, grouped in apical leaf axils or terminals of branches. Each flower has a small green bract enclosing the ovary with two long, slender pistils projecting well above the bract. The male plants commence flowering slightly before the females. When mature, the sepals on the male flowers are open to enable passing air currents to transfer the released pollens to the pistillate flowers.
Soon after pollination, the male plants wither and die in order to secure more space, nutrients and water to the females so that they could produce a healthy crop of viable seeds. Following fertilisation, the ovary develops into an achene, a fruit containing a single seed with a hard shell [ 11 — 13 ].
The surface of aerial plant parts is covered in trichomes. Three morphologically distinct types of glandular trichomes have been identified: These are mainly associated with the female inflorescences, but they can also be found on the underside of the leaves and occasionally on the stems of young plants.
Besides cannabinoids, these trichomes produce terpenes, which are responsible for the typical plant aroma. The extreme variations in cannabinoid contents of the different tissues are due to markedly different distributions of glandular trichomes on the surface of the plant [ 14 , 15 ]. Phytocannabinoids represent a group of terpenophenolic compounds predominantly produced in the cannabis plant.
These secondary metabolites are biosynthesised as prenylated aromatic carboxylic acids, and while almost no neutral forms can be found in fresh plants. However, cannabinoid acids may convert to their neutral homologues by spontaneous decarboxylation under the influence of light, heat or prolonged storage.
The precursors of phytocannabinoids originate from two distinct biosynthetic pathways: Biosynthesis and degradation of the major phytocannabinoids. The structural diversity of naturally occurring cannabinoids is the result of differences in the nature of their isoprenyl residue, resorcinyl core and side chain.
The Cannabigerol type compounds are one of the most structurally diversified classes of phytocannabinoids. A linear isoprenyl residue is their main feature, as exemplified by CBG, which was the first structurally elucidated and also the first natural cannabinoid to be synthesised. The isoprenyl residue is oxidatively fused to the resorcinyl ring in the cannabichromene type. Cannabichromene CBC is the simplest natural cannabinoid to obtain by synthesis and the only major phytocannabinoid that shows a bluish fluorescence under UV light.
CBD, as the main representative of the cannabidiol type compounds, was isolated in , but the correct structure elucidation was reported more than two decades later. CBN and its derivatives and analogues cannabinol type are considered artefacts derived from oxidative aromatisation of the corresponding THC type compounds.
Their concentration in cannabis products depends on age and storage condition. CBN is highly stable towards oxidative degradation and so has been used as a marker for the identification of narcotic cannabis in archaeological findings. CBD receptors are not located in the brainstem areas which control respiration and, therefore, lethal overdoses from CBDs are not common 8 , Nevertheless, there are CBD receptors in other tissues throughout the body, which may lead to toxicities or adverse effects such as tachycardia, hypotension, conjunctival injection, bronchodilation, and decreased gastrointestinal motility.
Site-targeted delivery via SRBs could minimize such adverse effects as well as the psychoactive effects that have limited clinical translation efforts. Ongoing work is focusing on demonstrating this expected toxicity advantage in a large cohort study. A limitation of the current study is the short-term investigation on the survival.
This is partly due to an initial focus to explore and demonstrate feasibility to inform further studies. With view to clinical translation, further investigations will build on the current work for longer term survival studies employing CBD-loaded smart biomaterials with and without RT.
This will also include investigations of other CBDs besides CBD that have demonstrated potential as anticancer agents but have not been rigorously tested, or have been limited by off-target toxicities, which may be minimized with the use of SRBs. The multifunctional SRBs will be able to ensure geometric accuracy but also sustainably deliver potent CBD payloads directly to the tumor with the anticipated benefits of greater therapeutic efficacy and minimal toxicities.
In the previous clinical trial on brain tumors 3 , CBDs had to be repeatedly administered. Our approach could allow for sustained delivery, which will obviate the need for repeated administration and be more convenient for patients. Illustration of innovative approach with potential to significantly enhance therapeutic efficacy using cannabinoids CBDs.
A Currently used commercially available inert radiotherapy RT biomaterials, e. Such replacement would come at no additional inconvenience to cancer patients. Once in place the SRB can be activated to sustainably release its payload as the polymer coating degrades for greater effective tumor cell kill working in synergy with RT as highlighted by our study results. The use of smart RT biomaterials for sustained delivery could also integrate the use of NP drones 12 loaded with CBDs that can bind specifically to tumor cells to deliver their potent payloads, enhancing tumor cell kill with minimal off-target distribution.
The drone technology could also be designed to target CBDs to CB1-type receptors expressed on the peripheral terminals of nociceptors around the RT planning target volume for CBD-induced analgesia. It has been shown 29 that CBDs mediate analgesia largely via peripheral type 1 CBD receptors in nociceptors, so such an approach with sustained delivery could also help in pain management for cancer patients. In the US, an increasing number of states have now legalized the use of medical cannabis.
This trend has also spread internationally, with more countries recognizing the medicinal components of cannabis and legalizing medical use. Unfortunately, medical cannabis research has been lagging in animal or human placebo-controlled studies addressing barriers to clinical translation.
Viable pathways to clinical translation for cancer treatment should include combination approaches or smart CBD cancer therapy that leverages the antitumor effects of CBDs with high therapeutic efficacy and minimal side effects. Altogether, our results offer an approach for leveraging the antineoplastic activity of CBDs to achieve enhanced therapeutic efficacy during cancer treatment with the possibility of addressing toxicity concerns that have hampered clinical translation efforts.
The potential for using smart RT biomaterials, which integrate enhanced tumor cell killing when combining CBDs with RT, and delivery with smart biomaterials, provide a promising pathway for clinical translation. To this end, ongoing work is investigating such SRBs loaded with CBDs, which could simply replace currently used inert RT biomaterials during image-guided RT, all at no additional inconvenience to cancer patients. SY-K designed the work, acquired and analyzed data, and participated in writing the manuscript; MM acquired and analyzed data and revised the manuscript; RM and NS analyzed the CT image data and contributed in revision of the manuscript; RD and AH contributed to the concept and design of the work, reviewed and revised the manuscript; and WN contributed to the concept of the work, reviewed and revised the manuscript.
All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U. Journal List Front Oncol v. Published online Apr Raymond Dabney 6 Cannabis Science, Inc.
Allen Herman 6 Cannabis Science, Inc. Author information Article notes Copyright and License information Disclaimer. This article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology. Received Jan 16; Accepted Mar The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract Over the years, many in vitro and in vivo studies have shown the antineoplastic effects of cannabinoids CBDs , with reports advocating for investigations of combination therapy approaches that could better leverage these effects in clinical translation.
Introduction Many in vitro and in vivo studies have reported on the antitumorigenic effects of plant-derived cannabinoids CBDs and their synthetic analogs, including effects in inducing apoptosis and inhibiting tumor cell growth and metastasis 1 , 2. Clonogenic Cell Survival Assay A cells from an actively growing monolayer were trypsinized and cells per well were seeded in well plates Corning.
Open in a separate window. Statistical Analysis Log-rank Mantel—Cox test and Gehan—Breslow—Wilcoxon test were performed to analyze statistical significance of the survival assay for in vivo lung cancer model with GraphPad prism software. Author Contributions SY-K designed the work, acquired and analyzed data, and participated in writing the manuscript; MM acquired and analyzed data and revised the manuscript; RM and NS analyzed the CT image data and contributed in revision of the manuscript; RD and AH contributed to the concept and design of the work, reviewed and revised the manuscript; and WN contributed to the concept of the work, reviewed and revised the manuscript.
Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer 12 6: Critical appraisal of the potential use of cannabinoids in cancer management. Cancer Manag Res 5: A pilot clinical study of delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme.
Br J Cancer 95 2: Nat Rev Clin Oncol 11 2: Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression.
Cancer Res 68 6: Cannabinoids increase lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM Biochem Pharmacol 92 2: Delta9-tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo.
Orthotopic and i.v. mouse models of breast cancer metastasis were used to test the activity of .. CBD increases survival in a syngeneic mouse. The endogenous cannabinoid anandamide inhibits human breast cancer cell Using a mouse model, we previously determined that metastatic breast cancer cells became Here, we report that cannabidiol (CBD), a cannabinoid with a low -toxicity .. Id1. However, this was associated with moderate increases in survival . Previously, it was showed that cannabinoids inhibit tumor growth and to the blockade of the G2 to mitosis transition and increased the number of cells in G2 that cannabidiol was the most potent inhibitor of breast cancer cell growth. .. (22 ) and (d) reduce bone pain in various preclinical models (22,23).