Correlation between compositional and mechanical properties of human mesenchymal stem cell-collagen microspheres during chondrogenic differentiation

Mesenchymal stem cell (MSC)-based engineering is promising for cartilage repair. However, the compositional mechanical relationship of the engineered structures has not been extensively studied, given the importance of such relationship in native cartilage tissues. In this study, a novel human MSC-collagen microsphere system was used to study the compositional mechanical relationship during in vitro chondrogenic differentiation using histological and biochemical methods and a microplate compression assay. The mechanical property was found positively correlating with newly deposited cartilage-relevant matrices, glycosaminoglycan, and type II collagen, and with the collagen crosslinker density, in agreement with the presence of thick collagen bundles upon structural characterization. On the other hand, the mechanical property negatively correlates with type I collagen and total collagen, suggesting that the initial collagen matrix scaffold of the microsphere system was being remodeled by the differentiating human MSCs. This study also demonstrated the application of a simple, sensitive, and nondestructive tool for monitoring the progression of chondrogenic differentiation of MSCs in tissue-engineered constructs and therefore contributes to future development of novel cartilage repair strategies. © Mary Ann Liebert, Inc. 2011.published_or_final_versio

Mechanical oscillations enhance gene delivery into suspended cells

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Integrated human papillomavirus analysis as an adjunct for triage of atypical cervical cytology

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Skeletal growth in class II malocclusion from childhood to adolescence: does the profile straighten?

BACKGROUND There is relatively little appreciation of the changes in maxillary-mandibular relationships occurring during adolescence among subjects with normal and increased overjet. The aim of this study was to assess differences in changes in maxillo-mandibular relationships during the adolescent growth period based on the presence of a normal ( 4 mm) overjet in childhood. Our hypothesis was that there is no difference in the change of the A point, nasion, B point (ANB) angle during growth between these two overjet groups. Lateral cephalograms were obtained from 65 subjects taken from the American Association of Orthodontists Foundation (AAOF) Craniofacial Growth Legacy Collections Project. Cephalograms were obtained at ages 7-10 (T0) and 14-17 (T1) with allocation into two groups based on baseline overjet (> 4 mm: group 1, 2-4 mm: group 2). Random effects linear regression was used to account for multiple within -patient measurements with dependent variables including antero-posterior skeletal pattern (based on sella, nasion, A point (SNA); sella, nasion, B point (SNB); and ANB angles). RESULTS We included a similar number of males (n = 34; 52.3%) and females (n = 31; 47.7%). The mean ANB was higher at baseline in group 1 (5.42, SD 2.16°) than in group 2 (3.08, SD 1.91°). The hypothesis was rejected as the ANB angle reduced by 1.92° more in the larger overjet group with the association being statistically significant after accounting for age and gender (P  4 mm overjet group compared to the 2-4 mm group (0.857°, P = 0.271; 95% CI - 0.669 to 2.383). The SNB angle increased by 1.15° more in the higher overjet group but there was only weak evidence of an association (P = 0.086; 95% CI - 2.464 to 0.164). CONCLUSIONS A slight straightening of the facial profile was observed in both groups with a statistically significant greater reduction in ANB arising in the group with larger baseline overjet. This translated into a marginal reduction in the overjet in this group

GRO-α and IL-8 enhance ovarian cancer metastatic potential via the CXCR2-mediated TAK1/NFκB signaling cascade

Intraperitoneal metastasis is a common occurrence and is usually involved in the poor prognosis of ovarian cancer. Its specific metastatic pattern implies that certain indispensable microenvironmental factors secreted in the peritoneal cavity can direct metastatic ovarian cancer cells to permissive niches for secondary lesion formation. However, the underlying molecular mechanisms are ill defined. Herein, we report that GRO-α and IL-8 are predominately upregulated in culture media derived from either normal or cancerous omenta and are associated with increased ovarian cancer aggressiveness. Methods: OCM was established from culture medium of fresh human omental tissues. Primary and metastatic ovarian cancer cell lines were generated from human tumor tissues and verified by specific antibodies. The functional roles of GRO-α, IL-8, and their specific receptor CXCR2 were examined by neutralizing antibodies, shRNA gene knockdown, CRISPR/Cas9 gene knockout and pharmaceutical CXCR2 inhibitor SB225002. The oncogenic properties of ovarian cancer cells were examined by in vitro and in vivo mouse models. Results: Both GRO-α and IL-8 can activate TAK1/NFκB signaling via the CXCR2 receptor. Intriguingly, TAK1/NFκB signaling activity was higher in metastatic ovarian cancer cells; this higher activity makes them more susceptible to OCM-induced tumor aggressiveness. Treatment of ovarian cancer cells with GRO-α and IL-8 neutralizing antibodies or ablation of CXCR2 by shRNA gene knockdown, CRISPR/Cas9 gene knockout, or CXCR2 inhibitor SB225002 treatment significantly attenuated TAK1/NFκB signaling and decreased in vitro and in vivo oncogenic and metastatic potential, suggesting CXCR2 plays a key role in the GRO-α and IL-8-governed metastatic spreading of ovarian cancer cells in the intraperitoneal cavity. Conclusion: This study highlights the significance of GRO-α and IL-8 as the key chemokines in the peritoneal tumor microenvironment and suggests the utility of targeting their receptor CXCR2 as a potential target-based therapy for peritoneal metastases of ovarian cancer.published_or_final_versio

A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer

The purpose of the study was to determine the maximum-tolerated dose (MTD) of oral capecitabine, combined with concurrent, standard preoperative pelvic radiotherapy, when given twice daily, from Monday to Friday throughout the course of radiotherapy, for locally advanced potentially resectable rectal cancer. Maximum-tolerated dose was defined as the total (given in two equally divided doses) oral dose of capecitabine that caused treatment-related grade 3 or 4 toxicity in one-third or more of the patients treated. Radiotherapy involved 50.4 Gy given in 28 fractions in 5 weeks and 3 days. Eligible patients had a newly diagnosed clinical stage T3–4 N0–2 M0 rectal adenocarcinoma located within 12 cm of the anal verge suitable for curative resection. Surgery was performed 4–6 weeks from completion of preoperative chemoradiotherapy. In all, 28 patients were enrolled in the study at predefined dose levels: 850 mg m−2 day−1 (n=3), 1000 mg m−2 day−1 (n=6), 1250 mg m−2 day−1 (n=3), 1650 mg m−2 day−1 (n=3), 1800 mg m−2 day−1 (n=8) and 2000 mg m−2 day−1 (n=5). The mean age was 62.3 years (range: 33–80 years). Five patients were female and 23 male. The median distance of tumour from the anal verge was 6 cm (range: 1–11 cm). Endorectal ultrasound was performed in 93% of patients. A total of 26 patients (93%) had T3 disease and two patients had resectable T4 disease. Dose-limiting toxicity (DLT) developed in one patient at dose level 1000 mg m−2 day−1 (RTOG grade 3 cystitis). Two of the five patients at dose level 2000 mg m−2 day−1 had a total of three DLT (grade 3 perineal skin reaction, grade 3 diarrhoea and grade 3 dehydration). Dose escalation of capecitabine was ceased at 2000 mg m−2 day−1 after reaching MTD. None of the eight patients at dose level 1800 mg m−2 day−1 developed DLT. All except one patient underwent surgery. A total of 15 patients had the clinical T stage reduced by at least one stage in pathologic specimens. Five patients (19%) achieved a pathologic complete response. We conclude that the MTD of capecitabine was reached at a dose level of 2000 mg m−2 day−1, given as 1000 mg m−2 twice daily, from Monday to Friday throughout the course of preoperative pelvic irradiation of 50.4 Gy. For patients with resectable rectal cancer receiving concurrent, full dose radiotherapy, the recommended dose of capecitabine for further study is 1800 mg m−2 day−1 when given in this schedule

Asian Society of Gynecologic Oncology International Workshop 2014

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Vinflunine: a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy

To evaluate the single agent activity, pharmacokinetics and tolerability of the novel tubulin targeted agent vinflunine (VFL) (320 mg m−2 q 21 days) as second-line chemotherapy in patients with metastatic breast carcinoma (MBC). All patients had disease progression after anthracycline/taxane (A/T) therapy. They could have received a nonanthracycline adjuvant treatment and subsequently received a first-line A/T combination for advanced/metastatic disease; or relapsed >6 months after completion of adjuvant A/T therapy and were subsequently treated with the alternative agent; or relapsed within 6 months from an adjuvant A/T combination. Objective response was documented in 18 of 60 patients enrolled (RR: 30% (95% confidence interval (CI): 18.9–43.2%)). Among the responders, seven patients had relapsed during a period of <3 months from taxane-based regimen yielding a RR of 33.3%. The median duration of response was 4.8 months (95% CI: 4.2–7.2), median progression-free survival was 3.7 months (95% CI: 2.8–4.2) and median overall survival was 14.3 months (95% CI: 9.2–19.6). The most frequent adverse event was neutropenia (grade 3 in 28.3% and grade 4 in 36.7% of patients). No febrile neutropenia was observed. Fatigue (grade 3 in 16.7% of patients) and constipation (grade 3 in 11.7% of patients) were also common; these were non-cumulative and manageable permitting achievement of a good relative dose intensity of 93.5%. Vinflunine is an active agent with acceptable tolerance in the management of MBC patients previously treated with (A/T)-based regimens. These encouraging phase II results warrant further investigation of this novel agent in combination with other active agents in this setting or in earlier stages of disease

Measurement of cosmic-ray muons and muon-induced neutrons in the Aberdeen Tunnel Underground Laboratory

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