Anticancer Activity of the Marine Triterpene Glycoside Cucumarioside A2-2 in Human Prostate Cancer Cells.

Despite recent advances in the treatment of metastatic castration-resistant prostate cancer (CRPC), treatment is inevitably hampered by the development of drug resistance. Thus, new drugs are urgently needed. We investigated the efficacy, toxicity, and mechanism of action of the marine triterpene glycoside cucumarioside A2-2 (CA2-2) using an in vitro CRPC model. CA2-2 induced a G2/M-phase cell cycle arrest in human prostate cancer PC-3 cells and caspase-dependent apoptosis executed via an intrinsic pathway. Additionally, the drug inhibited the formation and growth of CRPC cell colonies at low micromolar concentrations. A global proteome analysis performed using the 2D-PAGE technique, followed by MALDI-MS and bioinformatical evaluation, revealed alterations in the proteins involved in cellular processes such as metastatic potential, invasion, and apoptosis. Among others, the regulation of keratin 81, CrkII, IL-1ß, and cathepsin B could be identified by our proteomics approach. The effects were validated on the protein level by a 2D Western blotting analysis. Our results demonstrate the promising anticancer activity of CA2-2 in a prostate cancer model and provide insights on the underlying mode of action.

Activity of nintedanib in germ cell tumors.

Germ cell tumors (GCTs) are the most frequent malignancy in male patients between 15 and 45 years of age. Cisplatin-based chemotherapy shows excellent cure rates, but patients with cisplatin-resistant GCTs have a poor prognosis. Nintedanib (BIBF 1120, Vargatef) inhibits the receptor classes vascular endothelial growth factor receptor, platelet derived growth factor receptor, and fibroblast growth factor receptor, and has shown activity against many tumors, as well as in idiopathic lung fibrosis and bleomycin-induced lung injury. Here, we investigated the antineoplastic and antiangiogenic properties of nintedanib in cisplatin-resistant and cisplatin-sensitive GCT cells, both alone and in combination with classical cytotoxic agents such as cisplatin, etoposide, and bleomycin. The half-maximal inhibitory concentration (IC50) of nintedanib was 4.5 ± 0.43 µmol/l, 3.1 ± 0.45 µmol/l, and 3.6 ± 0.33 µmol/l in cisplatin-sensitive NTERA2, 2102Ep, and NCCIT cells, whereas the IC50 doses of the cisplatin-resistant counterparts were 6.6 ± 0.37 µmol/l (NTERA2-R), 4.5 ± 0.83 µmol/l (2102Ep-R), and 6.1 ± 0.41 µmol/l (NCCIT-R), respectively. Single treatment with nintedanib induced apoptosis and resulted in a sustained reduction in the capacity of colony formation in both cisplatin-sensitive and cisplatin-resistant GCT cells. Cell cycle analysis showed that nintedanib induced a strong G0/G1-phase arrest in all investigated cell lines. Combination treatment with cisplatin did not result in additive, synergistic, or antagonistic effects. The in-vivo activity was studied using the chorioallantoic membrane assay and indicated the antiangiogenic potency of nintedanib with markedly reduced microvessel density. Topical treatment of inoculated tumor plaques resulted in a significant reduction of the tumor size. This indicates that nintedanib might be a promising substance in the treatment of GCT.

Cone beam computed tomography for diagnosis of bisphosphonate-related osteonecrosis of the jaw: evaluation of quantitative and qualitative image parameters.

OBJECTIVE: To assess the diagnostic performance of quantitative and qualitative image parameters in cone-beam computed tomography (CBCT) for diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). MATERIALS AND METHODS: A BRONJ (22 patients, mean age 70.0 years) group was age and gender matched to a healthy control group (22 patients, mean age 68.0 years). On CBCT images two independent readers performed quantitative bone density value (BDV) measurements with region and volume-of-interest (ROI and VOI) based approaches and qualitative scoring of BRONJ-associated necrosis, sclerosis and periosteal thickening (1 = not present to 5 = definitely present). Intraoperative and clinical findings served as standard of reference. Interreader agreements and diagnostic performance were assessed by intraclass correlation coefficients (ICC), kappa-statistics and receiver-operating characteristic (ROC) analysis. RESULTS: Twenty-three regions in 22 patients were affected by BRONJ. ICC values for mean BDV VOI and mean BDV ROI were 0.864 and 0.968, respectively (p < 0.001). The area under the curve (AUC) for mean BDV VOI and mean BDV ROI was 0.58/0.83 with a sensitivity of 57/83% and specificity of 61/77% for diagnosis of BRONJ, respectively. Kappa values for presence of necrosis, sclerosis and periosteal thickening were 0.575, 0.617 and 0.885, respectively. AUC values for qualitative parameters ranged between 0.90-0.96 with sensitivity of 96% and specificities between 79-96% at respective cutoff scores. CONCLUSIONS: BRONJ can be effectively diagnosed with CBCT. Qualitative image parameters yield a higher diagnostic performance than quantitative parameters, and ROI-based attenuation measurements were more accurate than VOI-based measurements.

Osteopathology induced by bisphosphonates and dental implants: clinical observations.

OBJECTIVES: Although there are many reports about risk factors for the development of BP-associated osteonecrosis of the jaws, the role of dental implants as a local risk factor is still discussed, especially in patients with oral BP treatment. Until now, a few case reports and surveys display a possible minor risk in patients with oral BP therapy, whereas the avoidance of implant placement is generally accepted in patients with intravenous BP therapy. PATIENT AND METHODS: In this study, the cases of 14 patients with osteonecrosis of the jaws in association with BP therapy and dental implant placement were analyzed carefully with a detailed literature review. RESULTS: Of 14 patients, nine had underlying malignant disease and five patients had osteoporosis. In ten patients, implants were placed either in the posterior mandible or maxilla; the mean interval between implant insertion and disease onset was 20.9 months. Pain (n12) and signs of infection (n10) were the most common symptoms. Histologically, signs of infection were found in nine of 11 analyzed patients with presence of Actinomyces in six patients. Two patients turned out to have infiltration of underlying malignant disease. CONCLUSIONS: Posteriorly placed implants seem to be of higher risk of development of osteonecrosis of the jaws. Not only the implant placement but also the inserted implant itself seems to be a continuous risk factor. CLINICAL RELEVANCE: The herein elaborated risk factors help dentists plan dental rehabilitation with implants in this high-risk group of patients and indicate careful and regular dental recall.

Postoperative cranial vault growth in premature sagittal craniosynostosis.

Various techniques for the correction of sagittal craniosynostosis have been described in the literature. Nevertheless, there is a lack of consensus regarding surgical procedure and timing, although a long-term anthropometric analysis may shed light on this controversy. The aim of the current study was to collect serial anthropometric data of children before and after total cranial vault remodeling and to evaluate cranial vault growth pattern. Twenty-nine Swiss children with a surgical age between 8 and 10 months were included in this 5-year follow-up. Anthropologic data of sex- and age-matched healthy Swiss children served as a control. A standardized time protocol (before, after, 6 wk after surgery, 6 mo after surgery, and then annually until the age of six) for anthropometric skull measurements (head circumference, cranial length, breadth, and cephalic index) was used. Data were converted into the z score for standardized intercenter comparison. Postoperatively, all patients showed a marked benefit in cranial vault shape. Significant differences in long-term cranial growth pattern could be seen and a relapse into a dolichocephal skull growth. Both observations were rated as clinically irrelevant.

Cranial vault growth in multiple-suture nonsyndromic and syndromic craniosynostosis: a postoperative long-term anthropometric follow-up.

Long-term anthropometric follow-up of cranial vault growth may considerably add valuable information to current literature focusing on treatment strategies for premature multiple-suture craniosynostosis. The aim of this paper was to compare postoperative growth patterns of nonsyndromic and syndromic multiple-suture craniosynostotic children with sex-matched and age-matched children from the typically developing population. Forty-one multiple-suture craniosynostotic patients (19 nonsyndromic and 22 syndromic) were included in this 5-year follow-up. Anthropological data of sex-matched and age-matched normal Swiss children served as a control. A standardized time protocol for anthropometric skull measurements (head circumference and cephalic index) was used. Data were converted into Z-scores for standardized intercenter comparison. All patients showed a marked benefit in cranial vault shape after open skull remodeling. Significant differences in long-term cranial vault growth pattern could be seen between the nonsyndromic and the syndromic groups compared to the control group.

[Risk assessment in patients undergoing osseous antiresorptive therapy in dentistry. An update]. / Risikobeurteilung von Patienten mit ossärer, antiresorptiver Therapie in der zahnärztlichen Praxis. Ein Update.

Antiresorptive therapy is prescribed in particular for the treatment of osteoporosis as well as for the treatment of tumor-induced hypercalcemia and metastatic bone disease. As a consequence, osteopathologies such as bisphosphonate-related osteonecrosis of the jaws (BRONJ) may occur. In 2008, our department reported on BRONJ in a paper that provided dental clinicians with information on diagnostics, therapy, and prevention (Dannemann et al., Schweizer Monatsschrift für Zahnmedizin, Vol. 118, 2/2008). During the last 8 years, new findings have emerged concerning potential etiologies, modes of therapy, and the use of additional antiresorptive therapies. For example, an important point for colleagues in dental practice is the now common intravenous administration of bisphosphonates in osteoporosis patients, which may lead to uncertainty when assessing risk in these patients. For this reason, this article provides an update of the above mentioned publication and gives dental clinicians an updated guideline concerning risk assessment in patients undergoing antiresorptive therapy. In this context, a risk assessment algorithm is presented. The pathogenesis, diagnosis, therapy, and prevention of BRONJ and oral implantation in patients receiving antiresorptive therapy are addressed with regard to the current literature. Finally, we present two example cases.

A prospective, multi-site, cohort study to estimate incidence of infection and disease due to Lassa fever virus in West African countries (the Enable Lassa research programme)-Study protocol.

BACKGROUND: Lassa fever (LF), a haemorrhagic illness caused by the Lassa fever virus (LASV), is endemic in West Africa and causes 5000 fatalities every year. The true prevalence and incidence rates of LF are unknown as infections are often asymptomatic, clinical presentations are varied, and surveillance systems are not robust. The aim of the Enable Lassa research programme is to estimate the incidences of LASV infection and LF disease in five West African countries. The core protocol described here harmonises key study components, such as eligibility criteria, case definitions, outcome measures, and laboratory tests, which will maximise the comparability of data for between-country analyses. METHOD: We are conducting a prospective cohort study in Benin, Guinea, Liberia, Nigeria (three sites), and Sierra Leone from 2020 to 2023, with 24 months of follow-up. Each site will assess the incidence of LASV infection, LF disease, or both. When both incidences are assessed the LASV cohort (nmin = 1000 per site) will be drawn from the LF cohort (nmin = 5000 per site). During recruitment participants will complete questionnaires on household composition, socioeconomic status, demographic characteristics, and LF history, and blood samples will be collected to determine IgG LASV serostatus. LF disease cohort participants will be contacted biweekly to identify acute febrile cases, from whom blood samples will be drawn to test for active LASV infection using RT-PCR. Symptom and treatment data will be abstracted from medical records of LF cases. LF survivors will be followed up after four months to assess sequelae, specifically sensorineural hearing loss. LASV infection cohort participants will be asked for a blood sample every six months to assess LASV serostatus (IgG and IgM). DISCUSSION: Data on LASV infection and LF disease incidence in West Africa from this research programme will determine the feasibility of future Phase IIb or III clinical trials for LF vaccine candidates.

Proteomic profiling of germ cell cancer cells treated with aaptamine, a marine alkaloid with antiproliferative activity.

Aaptamine is a marine compound isolated from the sponge Aaptos aaptos showing antiproliferative properties via an undefined mode of action. We analyzed the effects of aaptamine treatment on the proliferation and protein expression of the pluripotent human embryonal carcinoma cell line NT2. Effects on proliferation, cell cycle distribution, and induction of apoptosis were analyzed. At lower concentrations, including the IC50 of 50 µM, aaptamine treatment resulted in a G2/M phase cell cycle arrest, whereas at higher concentrations, induction of apoptosis was seen. Differentially expressed proteins were assessed by 2D-PAGE and mass spectrometry, followed by verification and analysis of protein modifications of the most significantly up- and down-regulated proteins. Aaptamine treatment at the IC50 for 48 h resulted in alteration of 10 proteins, of which five each showed up- and down-regulation. Changes in the 2D map were frequently noticed as a result of post-transcriptional modifications, e.g., of the hypusine modification of the eukaryotic initiation factor 5A (eIF5A). Observed alterations such as increased expression of CRABP2 and hypusination of eIF5A have previously been identified during differentiation of pluripotent cells. For the first time, we describe changes in protein expression caused by aaptamine, providing valuable information regarding the mode of action of this compound.

Segmental distraction osteogenesis of the anterior alveolar process using tooth-borne devices: is it skeletal movement or mainly dental tipping?

PURPOSE: Segmental distraction osteogenesis of the anterior alveolar process has been introduced as a technique designed to avoid extractions in patients with severe dental crowding. The aim of this study was to quantify the degree of dental tipping within the alveolar segment after distraction osteogenesis. PATIENTS AND METHODS: Patients treated for dental crowding, retruded anterior alveolar process, or flat curves of Spee using segmental distraction osteogenesis of the anterior alveolar process were included in the study. Dental-borne distraction devices were used while measuring points, and angles were defined to analyze the amount of dental tipping of the lower incisors after distraction. The measurements were performed using cone-beam computed tomographic scans. Periodontal health (eg, gingival recession, tooth mobility, and dental socket depths) was evaluated after distraction. A descriptive statistical analysis was performed. RESULTS: Fifteen patients were included in the study. The amount of dental tipping within the total movement of the alveolar process showed a mean of 24% after distraction osteogenesis, whereas the skeletal movement was 76%. Dental socket depths and tooth mobility remained at the same levels as those before distraction osteogenesis. In one third of patients, gingival recession was observed around the canines. CONCLUSIONS: Segmental distraction osteogenesis of the anterior process is a powerful technique that can prevent extractions in patients with dental crowding. The technique can also compensate for retruded anterior alveolar process and accelerate or decelerate the curve of Spee. Patients with constricted periodontal health and those with a thin mandibular symphysis, however, cannot be treated with this technique because of the increased risk of dental tipping. Severe gingival recession must also be considered a possible side effect associated with this technique.

Anterior alveolar segmental osteodistraction with a bone-borne device: clinical and radiographic evaluation.

PURPOSE: Anterior alveolar osteodistraction is a common method for enlargement of the dentoalveolar process, and bone-borne distraction devices are hypothesized to avoid the risk of dental tipping and periodontal impairment during distraction. The aim of this study was to objectify this thesis and to determine the reliability of bone-borne osteodistraction of the anterior alveolar process. PATIENTS AND METHODS: The study group consisted of 18 consecutive patients who underwent anterior alveolar segmental distraction with a bone-borne distraction device for the treatment of dental crowding or alveolar retrusion from 2008 through 2011. Clinical and radiologic changes within the apical base and dentoalveolar process were analyzed after bone-borne distraction osteogenesis. All measurements were carried out using cone-beam computed tomography. RESULTS: Surgery and the postoperative period were uneventful in all patients. Mean alveolar movement was 8.2° ± 2.4°. Skeletal movement was 97.6% and absolute dental tipping was 2.4%. A mean change in the occlusal plane of 1.9° ± 1.1° was verified. The apical base enlargement showed a mean of 7.9 ± 1.4 mm, and the dentoalveolar arch a mean increase of 12.7 ± 2.1 mm. Within the distraction zone, a mean vertical bone loss of 3.5 ± 0.7 mm and a mean horizontal bone loss of 3.9 ± 0.8 mm were seen. After orthodontic gap closure, both were clinically irrelevant, with no need for additional bone grafts. Periodontal impairment (gingival recessions of 1 mm) was observed in 7 patients but affected only the teeth bordering the vertical osteotomy line. CONCLUSIONS: Bone-borne anterior alveolar osteodistraction is sufficient for enlargement of the apical base and the dentoalveolar arch of the mandible. Skeletal movement of the alveolar segment was predictable and dental tipping was clinically irrelevant. This technique presents further indications and approaches in orthognathic surgery.

Hybrid distraction: a novel method for distraction osteogenesis of the alveolar process.

Segmental distraction osteogenesis of the anterior alveolar process is a sufficient method to enlarge the alveolar arch. Indications for this method are dental crowding, retroalveolism, and leveling of the curve of Spee. However, after the distraction period, the anterior alveolar segment often shows an unfavorable inclination resulting in nonphysiologic load on the lower incisors.The aim of this paper was to introduce a new approach in segmental distraction osteogenesis of the anterior alveolar process. This new method combines 2 different surgical techniques: a segmental osteotomy for the alveolar ridge with instant fixation in the desired position and a distraction procedure for the alveolar segment. This hybrid distraction avoids an unfavorable inclination of the lower incisors after front-block distraction procedures.

Growing skull fractures after craniosynostosis repair: risk factors and treatment algorithm.

Growing skull fractures (GSFs) are rare complications after severe head injuries in the early childhood and rarely occur after craniosynostosis repair. The aim of this study was to define an algorithm for sufficient treatment for GSF after craniofacial procedures. Literature research was performed to clarify risk factors for GSFs after cranial vault reshaping. Conclusions of the literature and experiences of the authors based on a case of GSF after craniofacial surgery were matched to establish guidelines for successful therapy.

Needle breakage during local anesthesia in the oral cavity--a retrospective of the last 50 years with guidelines for treatment and prevention.

Needle breakage in the oral cavity after local anesthesia is a common complication with possible serious complications of injuring vital structures. There are different possible reasons for needle breakage, with a main focus on preventable mistakes in treatment. In this study, an analysis of literature of the last 50 years as well as own cases has been performed to renew knowledge and prevention and therapy strategies for this serious complication. A systematic, multilingual review of medical literature from 1900 until today was conducted and information was evaluated systematically. In the majority of cases needle fracture happened during inferior alveolar nerve block. It is mainly a problem due to inadequate technique or the use of too thin needles for the performance of inferior alveolar nerve block. Different arguments about possible therapy strategies and methods exist. Basically, if a hypodermic needle fractures, it should be removed surgically under general anesthesia. To localize the fragment, use of either multi-plane X-rays or fluoroscopy with at least two reference needles in place or, if possible, of three-dimensional CT scans is recommended. This article shows, that despite progression in material, needle fracture is still an existing, preventable problem, if some basic rules are followed.

Histological evaluation of microsurgical revascularized bone in the intraoral cavity: does it remain alive?

INTRODUCTION: Microsurgical revascularized fibula graft is a standard for the reconstruction of mandible or maxilla after major resection. Usually, screwed implants are inserted as a second procedure for dental rehabilitation. A lot has been published about the advantages of vascularized bone grafts, but until now there is only little information about long-term viability of inserted bone grafts. MATERIAL AND METHODS: In this study, previously inserted vascularized fibula bone grafts were examined histologically. Bone biopsies were taken during dental implant insertion procedure in average of 19 months after insertion of bone grafts from 10 patients. RESULTS: All bone biopsies showed partially or totally necrotic bone, although clinical examination and postoperative monitoring of the revascularized bone remained unremarkable. CONCLUSION: The results of histological examination are surprising, due to the fact of previous insertion of a vascularized bone graft and pretended osseointegration of inserted dental implants with satisfying primary stability. Therefore, one would expect vital bone. For better understanding how much viability is really necessary for sufficient remodeling of inserted bone grafts for adequate functional load, further studies should be performed.

Microvascular tissue transfer in cleft palate patients: advocacy of the prelaminated radial free forearm flap.

The closure of wide palatal clefts and recurrent oronasal fistulae may be challenging. After repeated failure of conventional techniques, microvascular tissue transfer may be indicated in the closure of such fistulae. Depending on the location and the size of the palatal fistula, different tissues are required to sufficiently close the palatal gaps. A subdivision of common flaps into mucosa, muscular, bony, skin, and fascia flaps was carried out to analyze their suitability for alveolar, hard, and soft palate reconstruction. Furthermore, the bulk of flaps and the length of the vascular pedicle were analyzed to rate the suitability of different flaps for palatal closure. Based on a new classification of oronasal fistulae, all these factors were taken into consideration to introduce a decision guidance of what microvascular flap fits a particular clinical situation. The radial free forearm flap was found to be sufficient in the closure of all classes of oronasal fistulae.

Clinical reliability of radial forearm free-flap procedure in reconstructive head and neck surgery.

OBJECTIVE: The purpose of the study was to evaluate the indications, reliability, and complications of the radial forearm fasciocutaneous flap (RFFF) procedure in reconstructive head and neck surgery. METHODS: The records of 81 patients who were treated with an RFFF between 1998 and 2009 were systematically reviewed. Data of recipient localization, previous T status, and postoperative complications were analyzed. RESULTS: From the 50 male and 31 female patients, 4 patients (3 men and 1 woman) experienced flap failure during the first 36 hours: in 1 patient because of arterial and in 3 patients because of venous complications. None of the 4 patients had preoperative radiotherapy. A dehiscence was observed in 2 patients without a need for further surgery. CONCLUSIONS: With a success rate of more than 95%, the RFFF is a reliable flap and a workhorse, particularly in defects where thinness is needed to substitute for the oral mucosa, such as on the floor of the mouth or the tongue.

Clinical and Personality Disorders in a Danish Treatment-Seeking Sample of Intimate Partner Violence Perpetrators.

Intimate partner violence (IPV) is a global public health concern with profound psychological consequences. Perpetrators often have a history of childhood trauma and a range of co-occurring psychiatric problems, which may have implications for treatment. This study examines the prevalence of psychiatric and personality disorders (PD) among perpetrators and the association between a range of demographic, childhood trauma, and adult criminality variables for the most prominent disorders. Data were collected from IPV perpetrators ( n = 529) engaging in a treatment program, ' Dialogue Against Violence'. High rates of childhood trauma were observed. There was significant variation in the prevalence of clinical disorders and PDs, with Antisocial PD and Anxiety Disorder being the most common. A clinical disorder was the strongest predictor of PDs, likewise a PD was the strongest predictor of clinical disorders. Findings demonstrated that IPV perpetrators have a number of personality and clinical disorders and traumatic histories that need to be considered within a treatment perspective.

Inferior alveolar nerve function after open reduction and internal fixation of mandibular fractures.

PURPOSE: Mandibular fractures are amongst the most common facial fractures and are usually treated by open reduction and internal fixation (ORIF). Inferior alveolar nerve (IAN) injuries are seen frequently in mandibular fractures as well as after ORIF of these fractures due to the exposition and the close proximity of the nerve during fracture reduction. Therefore the continuity of the IAN can be disrupted. Permanent injury to the IAN can result in diminished quality of life. This retrospective study was designed to objectively analyse the incidence and the outcome of pre- and postoperative mental nerve hypoesthesia after ORIF of mandibular fractures. MATERIAL AND METHODS: Patients who were consecutively treated at the Department of Cranio-Maxillofacial and Oral Surgery of the University Hospital Zurich between 2004 and 2010 with mandibular fractures who underwent ORIF were included. Follow-up period was 12 months. Demographic, pre-, peri- and postsurgical data were tabulated and statistically evaluated using the χ(2) test and the Kruskall-Wallis-Test. RESULTS: 340 patients met the inclusion criteria. 27% of the study population presented with postinjury (preoperative) mental nerve hypoesthesia, 46% suffered from purely postoperative hypoesthesia and 27% showed no nerve damage. Complete recovery was seen in 70% of all cases, partial recovery in 20% of the cases and less than 10% suffered from a permanent (>12 months) IAN damage. Mandibular angle fractures were accompanied with significantly higher rates of hypoesthesia (79% vs. 68%). Recovery rate was significantly worse in older patients, when preoperative hypoesthesia was present (66% vs. 73%) and in patients with multiple fractures in proximity to the IAN (36% vs. 52%). Mandibular body fractures showed worse recovery rates than fractures that did not affect the body (44% vs. 52%). CONCLUSION: The present study shows that IAN injury is seen frequently in mandibular fractures. Mental nerve hypoesthesia may influence quality of life. Nerve continuity may not be preserved due to the initial trauma or may result as a postoperative complication. Nevertheless the results of this study show a high potential for full recovery.