The Renaissance of Cyclin Dependent Kinase Inhibitors

Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor entities. Their success is reflected in clinical approvals of specific CDK4/6 inhibitors for breast cancer. This review provides a detailed insight into the molecular mechanisms of CDKs as well as a general overview of CDK inhibition. It also summarizes the latest research approaches and current advances in the treatment of head and neck cancer with CDK inhibitors. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results in tumor therapy. Indeed, recent studies have shown a synergistic effect of CDK inhibition together with chemo- and radio- and immunotherapy in cancer treatment to overcome tumor evasion, which may lead to a renaissance of CDK inhibitors

Checkpoint Inhibitors in Cancer Therapy: Clinical Benefits for Head and Neck Cancers

Recently, considerable progress has been achieved in cancer immunotherapy. Targeted immune checkpoint therapies have been established for several forms of cancers, which resulted in a tremendous positive impact on patient survival, even in more advanced tumor stages. With a better understanding of cellular responses to immune checkpoint therapies, it will soon be feasible to find targeted compounds which will make personalized medicine practicable. This is a great opportunity, but it also sets tremendous challenges on both the scientific and clinical aspects. Head and neck tumors evade immune surveillance through various mechanisms. They contain fewer lymphocytes (natural killer cells) than normal tissue with an accumulation of immunosuppressive regulatory T cells. Standard therapies for HNSCC, such as surgery, radiation, and chemotherapy, are becoming more advantageous by targeting immune checkpoints and employing combination therapies. The purpose of this review is to provide an overview of the expanded therapeutic options, particularly the combination of immune checkpoint inhibition with various conventional and novel therapeutics for head and neck tumor patients. regulatory T cells. Standard therapies for HNSCC, such as surgery, radiation, and chemotherapy, are becoming more advantageous by targeting immune checkpoints and employing combination therapies. The purpose of this review is to provide an overview of the expanded therapeutic options, particularly the combination of immune checkpoint inhibition with various conventional and novel therapeutics for head and neck tumor patients

Recurrent osteomyelitis with proliferative periostitis after segmental resection and reconstruction of the mandible: a case report

A 50-year-old patient presented with a two-year history of chronic osteomyelitis of the left mandibular body. It was treated by wide segmental resection of the left hemimandible and reconstruction with a free vascularized fibular graft. Six months after surgery, the patient returned with pain, swelling, and moth-like lesions in the transplant in combination with appositional bone formation surrounding the ossified fibular bone. Radiographic and histological examination led to the diagnosis of a recurrent osteomyelitis with proliferative periostitis affecting the resected and reconstructed mandible. Application of ibandronate led to a significant symptom decrease

Treatment of extracapsular fractures of the mandibular condylar process: A retrospective evaluation of 377 cases

Background/Aim Mandibular condylar fractures represent 25%–35% of all mandibular fractures. Despite profound research, there is still a controverse debate about treating these fractures conservatively or by open reduction and internal fixation (ORIF). The aim of this study is to analyse the outcome after open and closed treatment of extracapsular mandibular condyle fractures regarding general characteristics, post-treatment malocclusion, facial nerve palsy (FNP), maximum mouth opening (MMO) and parotid complications. Methods A retrospective cohort of 377 fractures (350 open, 27 closed treatment) was reviewed by reference to clinical and radiological pre- and postoperative documentation. Follow-up period was 12 months. Pearsons' chi-square-test, correlations, Kruskal–Wallis test and t-test were carried out for statistical analysis. Results The dominant type of fracture was type II in Spiessl and Schroll classification (50.1%). In the open treated fractures, the most common approach was retromandibular transparotid (91.7%). Post-treatment malocclusion occurred in 18.0% and was significantly increased in bilateral fractures (p = .039), in luxation fractures (p = .016) and in patients with full dentition (p = .004). After open reduction and internal fixation (ORIF), temporary FNP was documented in 7.1% whereas a permanent paresis occurred in 1.7%. FNP was significantly associated with high fractures (p = .001), comminution (p = .028) and increased duration of surgery (p = .040). Parotid complications were significantly associated with revision surgery (p = .009). Post-treatment reduction of MMO mainly occurred in female patients (p < .001) as well as in patients with bilateral fractures (p < .001), high fractures (p = .030) and concomitant mandibular (p = .001) and midfacial fractures (p = .009). Conclusion Malocclusion seems to be the most frequent long-term complication after open reduction and osteosynthesis of extracapsular mandibular condyle fractures. We suggest ORIF by a transparotid approach to be an appropriate treatment with a low complication rate regarding especially FNP for extracapsular fractures of the mandibular condyle

Loss of MMP-27 Predicts Mandibular Bone Invasion in Oral Squamous Cell Carcinoma

Invasion of the mandibular bone is frequent in oral squamous cell carcinoma (OSCC), which often results in extensive ablative and reconstructive procedures for the patient. The purpose of this single-center, retrospective study was to identify and evaluate potential biomarkers and risk factors for bone invasion in OSCC. Initially, in silico gene expression analysis was performed for different HNSCC tumor T-stages to find factors associated with invasive (T4a) tumor growth. Afterwards, the protein expression of bone-metabolizing MMP-27, TNFRSF11B (Osteoprotegerin, OPG), and TNFSF11 (RANKL) was investigated via Tissue Microarrays (TMAs) for their impact on mandibular bone invasion. TMAs were assembled from the bone–tumor interface of primary OSCCs of the floor of the mouth and gingiva from 119 patients. Sixty-four carcinomas with patho-histological jaw invasion (pT4a) were compared to 55 carcinomas growing along the mandible without invasion (pT2, pT3). Tissue samples were additionally evaluated for patterns of invasion using the WPOI grading system. Statistical analysis of in silico data revealed decreased MMP-27 mRNA expression to be strongly associated with the pT4a-stage in OSCC, indicating invasive tumor growth with infiltration of adjacent anatomical structures. Our own clinico-pathological data on OSCCs presented a significant decrease of MMP-27 in tumors invading the nearby mandible (pT4a), compared to pT2 and pT3 tumors without bone invasion. Loss of MMP27 evolved as the strongest predictor of mandibular bone invasion in binary logistic regression analysis. To our knowledge, this is the first study investigating the role of MMP-27 expression in OSCC and demonstrating the importance of the loss of MMP-27 in mandibular bone invasion

Elective Tracheotomy in Patients Receiving Mandibular Reconstructions: Reduced Postoperative Ventilation Time and Lower Incidence of Hospital-Acquired Pneumonia

Elective tracheotomy (ET) secures the airway and prevents adverse airway-related events as unplanned secondary tracheotomy (UT), prolonged ventilation (PPV) or nosocomial infection. The primary objective of this study was to identify factors predisposing for airway complications after reconstructive lower ja surgery. We reviewed records of patients undergoing mandibulectomy and microvascular bone reconstruction (N = 123). Epidemiological factors, modus of tracheotomy regarding ET and UT, postoperative ventilation time and occurrence of hospital-acquired pneumonia HAP were recorded. Predictors for PPV and HAP, ET and UT were identified. A total of 82 (66.7%) patients underwent tracheotomy of which 12 (14.6%) were performed as UT. A total of 52 (42.3%) patients presented PPV, while 19 (15.4%) developed HAP. Increased operation time (OR 1.004, p = 0.005) and a difficult airway (OR 2.869, p = 0.02) were predictors, while ET reduced incidence of PPV (OR 0.054, p = 0.006). A difficult airway (OR 4.711, p = 0.03) and postoperative delirium (OR 6.761, p = 0.01) increased UT performance. HAP increased with anesthesia induction time (OR 1.268, p = 0.001) and length in ICU (OR 1.039, p = 0.009) while decreasing in ET group (HR 0.32, p = 0.02). OR for ET increased with mounting CCI (OR 1.462, p = 0.002) and preoperative radiotherapy (OR 2.8, p = 0.018). ET should be strongly considered in patients with increased CCI, preoperative radiotherapy and prolonged operation time. ET shortened postoperative ventilation time and reduced HAP

Rate Control System for Sounding Rockets

DLR/Moraba has a long history in the development of Rate Control Systems (RCS) which have been flown for several programs for research in weightlessness in Europe and Brazil. They had been used in various European μG programs such as MAXUS, MASER and TEXUS. Moraba has now developed a RCS for 14 inch payloads. This RCS uses a standard interface and can be easily joined to a REXUS service module. This combination (RCS and REXUS service system) came into operation for the MAPHEUS maiden flight. MAPHEUS (Materialphysikalisches Experiment unter Schwerelosigkeit) is an internal project of the DLR. The payload for this project, including the service systems and 4 experiments, flew on a Nike/improved Orion two stage motor which took the payload to an altitude of about 140.8 km, providing a period of weightlessness of more than 187 seconds. To achieve conditions of weightlessness above the atmosphere a RCS system is indispensable. The aim of the RCS is to reduce the angular rates of the payload significantly above the atmosphere in order to minimize the centrifugal accelerations to a level lower than 10 μg. This article describes the principle of a rate control system. It provides an insight into the interaction between the control loop, payload and actuators

SHEFEX II Precession Control

The SHEFEX II sounding rocket vehicle comprised a two stage VS40 motor combination, whereby the first stage was passively aerodynamically stabilized by canted fins but the spinning second stage motor and payload, was repointed before ignition and controlled during its burn phase by a two axis, cold gas, precession attitude control system. The result was a suppressed trajectory with greatly reduced dispersion, which provided a significant increase in the time available for the re-entry thermal protection and canard guidance experiments and improved the possibility for down range tracking and data retrieval as well as sea recovery of the payload

SHEFEX-2 - Development Status of the Vehicle and Sub-Systems for a Hypersonic Re-Entry Flight Experiment

The SHarp Edge Flight EXperiment (SHEFEX) is a DLR program to investigate aerodynamic behaviour and thermal protection problems of re-entry vehicles at hypersonic velocities, using unconventional shapes comprising multi-facetted surfaces with sharp edges. SHEFEX 1 was launched on a parabolic trajectory from Andøya Rocket Range in 2005 to provide a re-entry velocity in the order of Mach 7. To obtain greater velocities in the order of Mach 10, without reducing the experiment time, a larger vehicle and a flatter re-entry trajectory are required. A Brazilian VS40 motor system will be used, whereby the S40 first stage will provide a conventional spin stabilized unguided flight, but a pitch down precession manoeuvre of the S44 second stage will be performed prior to its ignition above the atmosphere. This will result in a suppressed trajectory and a re-entry angle of the order of 40 degrees. In addition to the thermal protection experiments, a canard system will provide data on the aerodynamic control parameters at hypersonic velocities. A further experiment comprises a separate inertial navigation system with a star reference update and GPS, which should determine the instantaneous flight vector and provide fine corrections to the main payload attitude control system to reduce any angle of attack inaccuracy

New Techniques and Instrumentation – TEXUS Service Module (TSM)

Until the TEXUS-42 (EML-1) project, successfully launched in Dec. 2005, the payload of the TEXUS and the MAXUS were equipped with the former Kayser-Threde 12 bit based PCM data acquisition system. To fulfill experimental requirements for higher data resolution and the intention to reduce weight and also to improve the performance of the service module, ESA has taken initiative to contract industry for the development and built up of a new data acquisition system and the new TEXUS Service Module (TSM) in 2004. For the design, manufacturing and qualification task sharing, a cooperation of DLR Moraba and the Kayser-Threde GmbH has been initialized. With respect to the compatibility of already existing experiment modules, Kayser-Threde has developed, manufactured and qualified the decentralized 16 bit CTS 3000 (Compact Telemetry System) data acquisition system and together with DLR Moraba the TSM. In order to improve existing systems and to comply with new requirements the DLR/Moraba has designed a new power distribution and a GPS system. The TSM is incorporating all known standard features, modern technologies and is capable of serving actual and future experiment requirements. The TSM provides flexibility for future implementation of up to two digital TV respectively TM down links besides the three standard analog TV down links. The design implies economic technical concepts consuming a minimum of service module mass and length. The service module acquires and transmits all experimental and service system housekeeping data via telemetry transmitter to ground. Commands to the service system and for experiment control are received with a dedicated diversity system from the ground station and distributed onboard. Furthermore three TV down links, 3-axis micro-g and acceleration measurement as well as a rate control (RCS) and a GPS system are incorporated. The TSM is integrated within a standard TEXUS cylindrical structure with Radax flanges on both ends. Most of the components are assembled on the instrumentation deck, which is fixated via shock mounts to the outer structure. All electronic boards for TM/TC, RCS, power switching, sequencing, μ-g measurement and housekeeping are integrated and wired within one