The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets

Cannabidiol (CBD), the major nonpsychoactive Cannabis constituent, has been proposed for the treatment of a wide panel of neurological and neuropsychiatric disorders, including anxiety, schizophrenia, epilepsy and drug addiction due to the ability of its versatile scaffold to interact with diverse molecular targets that are not restricted to the endocannabinoid system. Albeit the molecular mechanisms responsible for the therapeutic effects of CBD have yet to be fully elucidated, many efforts have been devoted in the last decades to shed light on its complex pharmacological profile. In particular, an ever-increasing number of molecular targets linked to those disorders have been identified for this phytocannabinoid, along with the modulatory effects of CBD on their cascade signaling. In this view, here we will try to provide a comprehensive and up-to-date overview of the molecular basis underlying the therapeutic effects of CBD involved in the treatment of neurological and neuropsychiatric disorders.     

Vaginal-sigmoid fistula caused by diverticular disease

A case of a 66 years old patient suffering from a sigmoido-vaginal fistula and diverticulosis, previously treated with a total laparohysterectomy, is reported. Retrograde studies demonstrated the presence of fistula, whereas colonoscopy and barium enema failed. After laparotomy and an appropriate bowel preparation, surgery was restricted to the bowel resection and anastomosis, whereas the vaginal defect was not closed.     

Rare association of human herpesvirus 6 DNA with human papillomavirus DNA in cervical smears of women with normal and abnormal cytologies

We investigated by nested PCR the possible association of human herpesvirus 6 (HHV-6) and human papillomavirus (HPV) genomes in the cervixes of 109 women with normal and abnormal cytological smears. HPV DNA was detected in 8.33% of 24 women with normal cytologies and in 41.1% of 85 women with abnormal cytologies; the proportion of HPV DNA was directly related to the severity of the lesions. HHV-6 DNA was found in only one patient, who had a cytological pattern of koilocytosis. The HHV-6 genome was classified by restriction enzyme analysis as variant B. The study indicates that detection of the HHV-6 genome in the cervixes of women with a wide spectrum of gynecological complaints is a rare event and rules out the possible association between HHV-6 and HPV genomes in cervical cancer lesions.     

BRAF Gene and Melanoma: Back to the Future

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.     

Syndecan-1 Depletion Has a Differential Impact on Hyaluronic Acid Metabolism and Tumor Cell Behavior in Luminal and Triple-Negative Breast Cancer Cells

Glycosaminoglycans (GAGs) and proteoglycans (PGs) are major components of the glycocalyx. The secreted GAG and CD44 ligand hyaluronic acid (HA), and the cell surface PG syndecan-1 (Sdc-1) modulate the expression and activity of cytokines, chemokines, growth factors, and adhesion molecules, acting as critical regulators of tumor cell behavior. Here, we studied the effect of Sdc-1 siRNA depletion and HA treatment on hallmark processes of cancer in breast cancer cell lines of different levels of aggressiveness. We analyzed HA synthesis, and parameters relevant to tumor progression, including the stem cell phenotype, Wnt signaling constituents, cell cycle progression and apoptosis, and angiogenic markers in luminal MCF-7 and triple-negative MDA-MB-231 cells. Sdc-1 knockdown enhanced HAS-2 synthesis and HA binding in MCF-7, but not in MDA-MB-231 cells. Sdc-1-depleted MDA-MB-231 cells showed a reduced CD24-/CD44+ population. Furthermore, Sdc-1 depletion was associated with survival signals in both cell lines, affecting cell cycle progression and apoptosis evasion. These changes were linked to the altered expression of KLF4, MSI2, and miR-10b and differential changes in Erk, Akt, and PTEN signaling. We conclude that Sdc-1 knockdown differentially affects HA metabolism in luminal and triple-negative breast cancer model cell lines and impacts the stem phenotype, cell survival, and angiogenic factors.     

Risk factors for noncompliance with glaucoma follow-up visits in a residents' eye clinic

OBJECTIVE: This study aimed to identify factors associated with compliance with glaucoma follow-up visits. DESIGN: Computer records of a university residents' eye clinic were reviewed to identify a random sample of all persons who had an examination with International Classification of Disease (ICD) 9 coding (ICD9) for glaucoma suspect or glaucoma during a 2-year period (1991-1993) to undergo telephone interview. PARTICIPANTS: Those who were seen at least every 6 months regardless of earlier return instructions were defined as compliant with follow-up (controls, n = 362). Those who had any lapse between visits of longer than 6 months were defined as noncompliant (cases, n = 362). RESULTS: Interviews were completed for 196 cases and 242 controls. Noncompliant persons were significantly more likely to be suspects for glaucoma rather than to have definite glaucoma and to be dissatisfied with waiting time in the clinic (29.1% vs. 17.8%, P < 0.005) and to state that they did not take their glaucoma medications as prescribed (25.4% vs. 13.4%, P < 0.004). They also were less likely to have been prescribed eyedrop medication. A high percentage of both patients and controls knew that glaucoma can lead to blindness (85.2% and 88.4%, respectively). The most common reasons patients gave for not keeping follow-up visits were the perception that their eye problem was "not serious enough," the cost of examinations, and that the doctor did not tell them to come back. CONCLUSION: Compliance with follow-up visits for glaucoma is associated with markers for early disease. Attempts to improve compliance might focus on improved communication of the seriousness of the disease and improvements in clinic waiting time.     

Synthesis and characterization of coprecipitation-derived ferrimagnetic glass-ceramic

Ferrimagnetic glass-ceramics could be used for magnetic induction hyperthermia. This technique is utilised for the destruction of solid neoplastic diseases by application of an alternating magnetic field. Biocompatible ferrimagnetic materials could be easily incorporated into a tumour and could generate heat mainly by hysteresis loss. A ferrimagnetic glass-ceramic in the system SiO₂–Na₂O–CaO–P₂O₅–FeO–Fe₂O₃ has been prepared by melting of the coprecipitation-derived raw materials. This glass-ceramic contains a unique crystalline phase, magnetite, embedded in an amorphous matrix. Magnetite crystals precipitate during cooling from melting temperature. This glass-ceramic would no longer require any nucleation and growth thermal treatment, since the maximal quantity of magnetite crystals was produced during cooling. The average unit-cell parameter, crystallite size of magnetite, and the quantitative ratio of the crystallographic phases in the glass-ceramic samples were evaluated using two different methods. Similar results were obtained with both methods. The magnetite crystals are about 50 nm in dimensions. The samples contain 45 wt% of magnetite, homogeneously distributed in the amorphous residual matrix. The as prepared glass-ceramic has a saturation magnetisation of 34 A·m²/kg and a coercive force of 6.7 kA/m. The estimated magnetic loss/cycle under the magnetic field up to 796 kA/m is around 1.45 mJ/g. The specific power loss of this glass-ceramic under a magnetic field of 40 kA/m and a frequency of 440 kHz is 25 W/g. This material showed a bioactive behaviour, as after 2 weeks of soaking in a simulated body fluid the formation of a hydroxylapatite layer on their surface was observed. This feature makes it also suitable for bone cancer.