Mineral Crystal Thickness in Calcified Cartilage and Subchondral Bone in Healthy and Osteoarthritic Human Knees.

Osteoarthritis (OA) is the most common joint disease, where articular cartilage degradation is often accompanied with sclerosis of the subchondral bone. However, the association between OA and tissue mineralization at the nanostructural level is currently not understood. In particular, it is technically challenging to study calcified cartilage, where relevant but poorly understood pathological processes such as tidemark multiplication and advancement occur. Here, we used state-of-the-art microfocus small-angle X-ray scattering with a 5-µm spatial resolution to determine the size and organization of the mineral crystals at the nanostructural level in human subchondral bone and calcified cartilage. Specimens with a wide spectrum of OA severities were acquired from both medial and lateral compartments of medial compartment knee OA patients (n = 15) and cadaver knees (n = 10). Opposing the common notion, we found that calcified cartilage has thicker and more mutually aligned mineral crystals than adjoining bone. In addition, we, for the first time, identified a well-defined layer of calcified cartilage associated with pathological tidemark multiplication, containing 0.32 nm thicker crystals compared to the rest of calcified cartilage. Finally, we found 0.2 nm thicker mineral crystals in both tissues of the lateral compartment in OA compared with healthy knees, indicating a loading-related disease process because the lateral compartment is typically less loaded in medial compartment knee OA. In summary, we report novel changes in mineral crystal thickness during OA. Our data suggest that unloading in the knee might be involved with the growth of mineral crystals, which is especially evident in the calcified cartilage. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Anti-tobacco policy in schools: upcoming preventive strategy or prevention myth? A review of 31 studies.

OBJECTIVE: To summarise the evidence on effectiveness of school anti-tobacco policies (exposure) in preventing tobacco use (outcome) among high school students. DATA SOURCES: The search was conducted between 1 September and 30 November 2011 on six electronic databases with keywords: 'policy', 'ban', 'restriction' and 'environment' in combination with 'adolescent' or 'student', 'school' and 'smoking' in titles, abstracts or keywords. Restrictions were made to articles published in English. STUDY SELECTION: Studies were included if they targeted the relevant grades/age; reported at least one outcome measure of students' ever or current tobacco use; reported on the effects of exposure to policy separately from other interventions. Inclusion criteria were assessed independently by two of the coauthors. Of 2723 articles initially identified, 31 articles met the inclusion criteria (1.1%). DATA EXTRACTION: Independent multiple observers extracted the data following the GRADE system guidelines to classify the level of evidence in relation to the review objective. DATA SYNTHESIS: Studies were very heterogeneous in the definitions of exposure to school anti-tobacco policy and of tobacco use, adjustment for potential confounders and reporting of results, therefore summary quantitative measures of effect were not calculated. Qualitative summary statements were derived by reviewing the results reported in text and tables for distinct policy constructs. Evidence could be classified as low or very low, resting on cross-sectional studies with high risk of bias. Studies were rather consistent in indicating that comprehensive smoking bans, clear rules, strict policy enforcement, availability of education and prevention were associated with decreased smoking prevalence. Formally adopted and written policies, surveillance of students' behaviour and presence/severity of sanctions were not consistently associated to students' tobacco use. CONCLUSIONS: The evidence concerning the effectiveness of a school policy alone in preventing youth tobacco use is weak and inconclusive. Experimental studies or observational studies with longitudinal design are warranted, employing clear definitions of policy components and careful control for confounding.

A Phase I study of CHS 828 in patients with solid tumor malignancy.

CHS 828 is a cyanoguanidine, which has demonstrated potent antitumor activity in preclinical tumor models. The activity of CHS 828 in vitro showed only low to moderate correlation to other antineoplastic agents suggesting a unique mechanism of action. Ten females and 6 males (median age 58 years) with solid tumors refractory to standard therapy were included in this Phase I study. The study drug was administered to fasting patients as a single oral dose on days 1-5 of each treatment cycle. Patients received one to six cycles of treatment. The doses ranged from 30 mg to 200 mg (total dose within a cycle). Hematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Nonhematological toxicity most frequently consisted of nausea, vomiting, diarrhea, fatigue, and localized genital mucositis. The dose-limiting toxicities were thrombocytopenia, thrombosis, esophagitis, diarrhea, and constipation. The recommended Phase II dose of CHS 828 was 20 mg once daily for 5 days in cycles of 28 days duration. The extent of systemic exposure of CHS 828 across patients was approximately dose proportional. The time at which the highest drug concentration occurs was 2.2 +/- 1.3 h and half-life was 2.1 +/- 0.52 h (mean +/- SD). Large intra- and interindividual variation in dose level-adjusted maximum plasma concentration and the area under the curve from time 0 h to infinity were observed. There was an apparent inverse relationship between systemic exposure of CHS 828, and thrombocyte and lymphocyte nadir levels. No objective tumor responses were observed, and 7 patients showed stable disease after two courses of therapy.

In vitro evaluation of the efficacy of idarubicin in human tumour cells from patients with low-grade non-Hodgkin's lymphoma.

Evaluating the potential benefit of the new anthracycline, idarubicin (Ida), in lymphoma, 58 tumour samples from patients suffering from low-grade non-Hodgkin's lymphoma (L-NHL), were analysed in vitro for their sensitivity to 0.5 microg/ml Ida. This was compared with the sensitivity to other anthracyclines (0.5 microg/ml), using the fluorometric microculture cytotoxicity assay. A total of 132 samples from patients with acute leukaemia and a cell-line panel representing different resistance mechanisms was included for comparison. The median cell survival of L-NHL cells did not differ after exposing the cells to Ida or daunorubicin (Dnr), whereas epirubicin, doxorubicin (Dox) and mitoxantrone (Mitox) were significantly less cytotoxic than Ida (P < 0.001). The median cell survival in L-NHL cells did not differ from that of acute leukaemia cells after exposure to 0.5 microg/ml Ida, Dnr, Dox and Mitox. Cells from previously treated patients with L-NHL had a higher median survival than cells from untreated patients after exposure to all drugs, except for Ida. In samples from previously untreated patients, Spearman rank correlations were high (Rho = 0.81-0.90) between cell survival after exposure to Ida and the other anthracyclines. The same pattern was observed in the cell-line panel (Rho = 0.78-0.91) (P < 0.05). In contrast, low correlations (Rho = 0.24-0.42) were observed among samples from previously treated patients. Our results indicate a potential benefit of Ida in previously drug-treated patients with L-NHL.

CHS 828 inhibits neuroblastoma growth in mice alone and in combination with antiangiogenic drugs.

CHS 828 is a new chemotherapeutic drug, a pyridyl cyanoguanidine. CHS 828 has low toxicity and lacks known patterns of multidrug resistance. Here we report that oral, daily treatment with CHS 828 reduced the growth of SH-SY5Y human neuroblastoma tumors in male NMRI nu/nu mice by 82% without apparent toxicity. CHS 828 induced complete tumor regression for at least 5 weeks in four of nine animals (44%). Combination therapy with CHS 828 and the antiangiogenic drugs TNP-470 or SU5416 decreased neuroblastoma growth by a further 10 and 3%, respectively. Combination therapy induced tumor regression at d 4 with CHS plus TNP and d 6 with CHS plus SU5416, compared with d 14 with CHS 828 alone (p < 0.05), and complete tumor regression was seen in nine of 19 animals (47%). Combination treatment of CHS 828 and TNP-470 decreased the total viable tumor volume by 71% compared with treatment with CHS 828 alone. Our findings support CHS 828 as a promising new drug in treatment of childhood cancers. Furthermore, they imply efficiency of daily administration of nontoxic doses of chemotherapy, and a possible additive effect when chemotherapy is combined with angiogenesis inhibitors.