An evaluation of periodontal assessment procedures among Indiana dental hygienists.

Using a descriptive correlational design, this study surveyed periodontal assessment procedures currently performed by Indiana dental hygienists in general dentistry practices to reveal if deficiencies in assessment exist. Members (n = 354) of the Indiana Dental Hygienists' Association (IDHA) were invited to participate in the survey. A 22 multiple choice question survey, using Likert scales for responses, was open to participants for three weeks. Descriptive and non-parametric inferential statistics analyzed questions related to demographics and assessment procedures practiced. In addition, an evaluation of the awareness of periodontal assessment procedures recommended by the American Academy of Periodontology (AAP) was examined. Of the 354 Indiana dental hygienists surveyed, a 31.9% response rate was achieved. Participants were asked to identify the recommended AAP periodontal assessment procedures they perform. The majority of respondents indicated either frequently or always performing the listed assessment procedures. Additionally, significant relationships were found between demographic factors and participants' awareness and performance of recommended AAP assessment procedures. While information gathered from this study is valuable to the body of literature regarding periodontal disease assessment, continued research with larger survey studies should be conducted to obtain a more accurate national representation of what is being practiced by dental hygienists.

BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma.

Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with other agents, as a novel strategy for acute leukemias and MM.

Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition.

Mammalian target of rapamycin (mTOR) regulates cellular processes important for progression of human cancer. RAD001 (everolimus), an mTORC1 (mTOR/raptor) inhibitor, has broad antitumor activity in preclinical models and cancer patients. Although most tumor lines are RAD001 sensitive, some are not. Selective mTORC1 inhibition can elicit increased AKT S473 phosphorylation, involving insulin receptor substrate 1, which is suggested to potentially attenuate effects on tumor cell proliferation and viability. Rictor may also play a role because rictor kinase complexes (including mTOR/rictor) regulate AKT S473 phosphorylation. The role of raptor and rictor in the in vitro response of human cancer cells to RAD001 was investigated. Using a large panel of cell lines representing different tumor histotypes, the basal phosphorylation of AKT S473 and some AKT substrates was found to correlate with the antiproliferative response to RAD001. In contrast, increased AKT S473 phosphorylation induced by RAD001 did not correlate. Similar increases in AKT phosphorylation occurred following raptor depletion using siRNA. Strikingly, rictor down-regulation attenuated AKT S473 phosphorylation induced by mTORC1 inhibition. Further analyses showed no relationship between modulation of AKT phosphorylation on S473 and T308 and AKT substrate phosphorylation patterns. Using a dual pan-class I phosphatidylinositol 3-kinase/mTOR catalytic inhibitor (NVP-BEZ235), currently in phase I trials, concomitant targeting of these kinases inhibited AKT S473 phosphorylation, eliciting more profound cellular responses than mTORC1 inhibition alone. However, reduced cell viability could not be predicted from biochemical or cellular responses to mTORC1 inhibitors. These data could have implications for the clinical application of phosphatidylinositol 3-kinase/mTOR inhibitors.

Experiencing social connection: A qualitative study of mothers of nonspeaking autistic children.

Autistic children do not consistently show conventional signs of social engagement, which some have interpreted to mean that they are not interested in connecting with other people. If someone does not act like they are interested in connecting with you, it may make it difficult to feel connected to them. And yet, some parents report feeling strongly connected to their autistic children. We conducted phenomenological interviews with 13 mothers to understand how they experienced connection with their 5- to 14-year-old nonspeaking autistic children. Mothers of nonspeaking autistic children represent a unique group in which to study connection because their children both may not seem interested in connecting with them and have limited ability to communicate effectively using speech, a common way people connect with each other. The mothers in this study interpreted a range of child behaviors-some unconventional, but many conventional-as signs that their children were interested in connecting with them, (re)framed child behaviors that could undermine connection as caused by factors unrelated to the relationship, and expressed several convictions that may help build and sustain connection in the face of uncertainty about the meaning of their children's behavior. Even though their autistic children may not consistently act in conventional socially oriented ways, these mothers reported perceiving their children's behavior as embedded within an emotionally reciprocal relationship.

The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells.

The RET kinase has emerged as a promising target for the therapy of medullary thyroid cancers (MTC) and of a subset of papillary thyroid cancers. NVP-AST487, a N,N'-diphenyl urea with an IC(50) of 0.88 mumol/L on RET kinase, inhibited RET autophosphorylation and activation of downstream effectors, and potently inhibited the growth of human thyroid cancer cell lines with activating mutations of RET but not of lines without RET mutations. NVP-AST487 induced a dose-dependent growth inhibition of xenografts of NIH3T3 cells expressing oncogenic RET, and of the MTC cell line TT in nude mice. MTCs secrete calcitonin, a useful indicator of tumor burden. Human plasma calcitonin levels derived from the TT cell xenografts were inhibited shortly after treatment, when tumor volume was still unchanged, indicating that the effects of RET kinase inhibition on calcitonin secretion were temporally dissociated from its tumor-inhibitory properties. Accordingly, NVP-AST487 inhibited calcitonin gene expression in vitro in TT cells, in part, through decreased gene transcription. These data point to a previously unknown physiologic role of RET signaling on calcitonin gene expression. Indeed, the RET ligands persephin and GDNF robustly stimulated calcitonin mRNA, which was blocked by pretreatment with NVP-AST487. Antagonists of RET kinase activity in patients with MTC may result in effects on plasma calcitonin that are either disproportionate or dissociated from the effects on tumor burden, because RET kinase mediates a physiologic pathway controlling calcitonin secretion. The role of traditional tumor biomarkers may need to be reassessed as targeted therapies designed against oncoproteins with key roles in pathogenesis are implemented.

[Acute flexor tendon surgery]. / Die primäre Naht der Fingerbeugesehnen.

OBJECTIVE: Flexor tendon repair by direct suture, providing tendon function and mechanical properties and allowing postoperative active extension and flexion. INDICATIONS: Flexor tendon laceration in all zones, when primary healing and a good functional outcome can be expected. CONTRAINDICATIONS: Florid and chronic infection. Lack of skill, instruments, or manpower. Tension-free suture is not feasible. Severe soft-tissue problems. Mantero suture in case of coexistent artery injury. SURGICAL TECHNIQUE: Hand surgical incisions and approach to the tendon. Opening of the tendon sheath in the region of oblique pulley. A four-strand core suture consisting of two locked two-strand sutures and a circumferential epitendon cross-stitch suture are performed. Lacerations in zone I with a tendon stump shorter than 1 cm require a Mantero suture and avulsions require a pull-out suture technique. POSTOPERATIVE MANAGEMENT: Active flexion and active extension in a dorsal wrist cast. RESULTS: The clinical outcome studies after repair of zone II flexor tendon injuries using a multiple-strand suture technique describe 69-96% excellent and good results.

Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells.

The orally bioavailable rapamycin derivative RAD001 (everolimus) targets the mammalian target of rapamycin pathway and possesses potent immunosuppressive and anticancer activities. Here, the antitumor activity of RAD001 was evaluated in the CA20948 syngeneic rat pancreatic tumor model. RAD001 demonstrated dose-dependent antitumor activity with daily and weekly administration schedules; statistically significant antitumor effects were observed with 2.5 and 0.5 mg/kg RAD001 administered daily [treated tumor versus control tumor size (T/C), 23% and 23-30%, respectively], with 3-5 mg/kg RAD001 administered once weekly (T/C, 14-36%), or with 5 mg/kg RAD001 administered twice weekly (T/C, 36%). These schedules were well tolerated and exhibited antitumor potency similar to that of the cytotoxic agent 5-fluorouracil (T/C, 23%). Moreover, the efficacy of intermittent treatment schedules suggests a therapeutic window allowing differentiation of antitumor activity from the immunosuppressive properties of this agent. Detailed biochemical profiling of mammalian target of rapamycin signaling in tumors, skin, and peripheral blood mononuclear cells (PBMCs), after a single administration of 5 mg/kg RAD001, indicated that RAD001 treatment blocked phosphorylation of the translational repressor eukaryotic initiation factor 4E-binding protein 1 and inactivated the translational activator ribosomal protein S6 kinase 1 (S6K1). The efficacy of intermittent treatment schedules was associated with prolonged inactivation of S6K1 in tumors and surrogate tissues (> or =72 h). Furthermore, detailed analysis of the dose dependency of weekly treatment schedules demonstrated a correlation between antitumor efficacy and prolonged effects (> or =7 days) on PBMC-derived S6K1 activity. Analysis of human PBMCs revealed that S6K1 also underwent a concentration-dependent inactivation after RAD001 treatment ex vivo (>95% inactivation with 20 nM RAD001). In contrast, human PBMC-derived eukaryotic initiation factor 4E-binding protein 1 was present predominantly in the hypophosphorylated form and was unaffected by RAD001 treatment. Taken together, these results demonstrate a correlation between the antitumor efficacy of intermittent RAD001 treatment schedules and prolonged S6K1 inactivation in PBMCs and suggest that long-term monitoring of PBMC-derived S6K1 activity levels could be used for assessing RAD001 treatment schedules in cancer patients.

[Dorsal capsulodesis for the treatment of scapholunate instability]. / Die dorsale Kapsulodese zur Behandlung der skapholunären Instabilität.

OBJECTIVE: To regain stability of the proximal carpal row after scapholunate ligament rupture in order to avoid osteoarthritis and carpal collapse. INDICATIONS: As additional therapy in scapholunate ligament repair especially in patients with static, but reducible scapholunate malalignment. CONTRAINDICATIONS: Fixed scapholunate malalignment. Osteoarthritis of the radiocarpal or the midcarpal joint. SURGICAL TECHNIQUE: Dorsal approach to the carpal joint with release of the second, third and fourth extensor compartment and resection of the dorsal interosseous nerve. Opening of the radiocarpal joint for inspection of the chondral surfaces and the scapholunate ligament for possible repair. If needed, reduction of scaphoid and lunate. Repair of the scapholunate ligament. If a reduction of scaphoid and lunate is necessary, temporary Kirschner wire fixation of the scaphoid to the capitate and the lunate. The dorsal intercarpal ligament is identified and its middle third is dissected and elevated from the triquetrum remaining attached to the distal scaphoid pole. The ulnar end of the elevated part of the dorsal intercarpal ligament is pulled through a split in the dorsal radiotriquetral ligament and fixed to itself. Closure of the proximal and distal third of the dorsal intercarpal ligament. POSTOPERATIVE MANAGEMENT: Management Immobilization in a below-elbow cast including the metacarpophalangeal joint of the thumb for 6 weeks. Removal of the Kirschner wires, if used, 8 weeks postoperatively. Physiotherapy to improve wrist motion. RESULTS: Most of the reports in the literature show an improvement of pain. The effect on radiologic parameters and the development of osteoarthritis remains uncertain.

The Ret receptor tyrosine kinase pathway functionally interacts with the ERalpha pathway in breast cancer.

A limited number of receptor tyrosine kinases (e.g., ErbB and fibroblast growth factor receptor families) have been genetically linked to breast cancer development. Here, we investigated the contribution of the Ret receptor tyrosine kinase to breast tumor biology. Ret was expressed in primary breast tumors and cell lines. In estrogen receptor (ER)alpha-positive MCF7 and T47D lines, the ligand (glial-derived neurotrophic factor) activated signaling pathways and increased anchorage-independent proliferation in a Ret-dependent manner, showing that Ret signaling is functional in breast tumor cells. Ret expression was induced by estrogens and Ret signaling enhanced estrogen-driven proliferation, highlighting the functional interaction of Ret and ER pathways. Furthermore, Ret was detected in primary cancers, and there were higher Ret levels in ERalpha-positive tumors. In summary, we showed that Ret is a novel proliferative pathway interacting with ER signaling in vitro. Expression of Ret in primary breast tumors suggests that Ret might be a novel therapeutic target in breast cancer.

Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data.

PURPOSE: To use preclinical and clinical pharmacokinetic (PK)/pharmacodynamic (PD) modeling to predict optimal clinical regimens of everolimus, a novel oral mammalian target of rapamycin (mTOR) inhibitor, to carry forward to expanded phase I with tumor biopsy studies in cancer patients. PATIENTS AND METHODS: Inhibition of S6 kinase 1 (S6K1), a molecular marker of mTOR signaling, was selected for PD analysis in peripheral blood mononuclear cells (PBMCs) in a phase I clinical trial. PK and PD were measured up to 11 days after the fourth weekly dose. A PK/PD model was used to describe the relationship between everolimus concentrations and S6K1 inhibition in PBMCs of cancer patients and in PBMCs and tumors of everolimus-treated CA20948 pancreatic tumor-bearing rats. RESULTS: Time- and dose-dependent S6K1 inhibition was demonstrated in human PBMCs. In the rat model, a relationship was shown between S6K1 inhibition in tumors or PBMCs and antitumor effect. This allowed development of a direct-link PK/PD model that predicted PBMC S6K1 inhibition-time profiles in patients. Comparison of rat and human profiles simulated by the model suggested that a weekly 20- to 30-mg dose of everolimus would be associated with an antitumor effect in an everolimus-sensitive tumor and that daily administration would exert a greater effect than weekly administration at higher doses. CONCLUSION: A direct-link PK/PD model predicting the time course of S6K1 inhibition during weekly and daily everolimus administration allowed extrapolation from preclinical studies and first clinical results to select optimal doses and regimens of everolimus to explore in future clinical trials.