Examining the relationship of concurrent obesity and tobacco use disorder on the development of substance use disorders and psychiatric conditions: Findings from the NESARC-III.

Background: Multimorbidity is linked to worse health outcomes than single health conditions. However, recent studies show that obesity may reduce the risk of developing substance use disorders (SUDs), particularly in vulnerable populations. We investigated how comorbid obesity and tobacco use disorder (TUD) relate to the risk of SUDs and psychiatric conditions. Methods: Data was used from 36,309 individuals who completed the National Epidemiological Survey on Alcohol and Related Conditions - Wave III. Individuals who met the DSM-5 criteria for TUD in the last year were defined as the TUD group. Obesity was defined as having a body mass index (BMI) greater than 30 kg/m2. Using this information, individuals were grouped into categories, with people being identified as either having obesity, TUD, both obesity and TUD, or not having either obesity or TUD (comparison). Groups were compared against their comorbid diagnoses of either an additional SUD or psychiatric conditions. Results: Controlling for demographic characteristics, we found that individuals with obesity including those individuals with TUD, had lower rates of comorbid SUD diagnosis than individuals with TUD alone. Additionally, individuals with combined TUD and obesity, and those with TUD alone, had the highest rates of comorbid psychiatric disorder diagnosis. Conclusions: The current study aligns with previous research suggesting that obesity may reduce risk of substance use disorders, even in individuals who have other risk factors promoting harmful substance use (e.g., tobacco use). These findings may inform targeted intervention strategies for this clinically relevant subpopulation.

Integrating skeletal anchorage into fixed and aligner biomechanics.

Routine alignment with fixed appliances and aligners is indeterminate mechanics because equilibrium equations are only applicable to two abutments: teeth, segments, or arches. Orthodontists must depend on compliance and resilience of materials (archwires and aligners) for initial alignment. However, stabilized segments and arches are "large multirooted teeth" that can be moved with determinate mechanics using temporary skeletal anchorage devices. Temporary skeletal anchorage devices have advanced from retromolar implants and inter-radicular miniscrews to extra-alveolar bone screws placed in the basilar bone buccal to the first molars: mandibular buccal shelf and infrazygomatic crest. Extra-alveolar anchorage is determinate mechanics to move teeth, segments, and arches. Retraction and rotation of the lower arch reverses the etiology of Class III open bite malocclusion to correct severe skeletal dysplasia with no extractions or orthognathic surgery.

SFPQ promotes an oncogenic transcriptomic state in melanoma.

The multifunctional protein, splicing factor, proline- and glutamine-rich (SFPQ) has been implicated in numerous cancers often due to interaction with coding and non-coding RNAs, however, its role in melanoma remains unclear. We report that knockdown of SFPQ expression in melanoma cells decelerates several cancer-associated cell phenotypes, including cell growth, migration, epithelial to mesenchymal transition, apoptosis, and glycolysis. RIP-seq analysis revealed that the SFPQ-RNA interactome is reprogrammed in melanoma cells and specifically enriched with key melanoma-associated coding and long non-coding transcripts, including SOX10, AMIGO2 and LINC00511 and in most cases SFPQ is required for the efficient expression of these genes. Functional analysis of two SFPQ-enriched lncRNA, LINC00511 and LINC01234, demonstrated that these genes independently contribute to the melanoma phenotype and a more detailed analysis of LINC00511 indicated that this occurs in part via modulation of the miR-625-5p/PKM2 axis. Importantly, analysis of a large clinical cohort revealed that elevated expression of SFPQ in primary melanoma tumours may have utility as a prognostic biomarker. Together, these data suggest that SFPQ is an important driver of melanoma, likely due to SFPQ-RNA interactions promoting the expression of numerous oncogenic transcripts.

The role of CAF derived exosomal microRNAs in the tumour microenvironment of melanoma.

Exosomes play a crucial role in the crosstalk between cancer associated fibroblasts (CAFs) and cancer cells, contributing to carcinogenesis and the tumour microenvironment. Recent studies have revealed that CAFs, normal fibroblasts and cancer cells all secrete exosomes that contain miRNA, establishing a cell-cell communication network within the tumour microenvironment. For example, miRNA dysregulation in melanoma has been shown to promote CAF activation via induction of epithelial-mesenchymal transition (EMT), which in turn alters the secretory phenotype of CAFs in the stroma. This review assesses the roles of melanoma exosomal miRNAs in CAF formation and how CAF exosome-mediated feedback signalling to melanoma lead to tumour progression and metastasis. Moreover, efforts to exploit exosomal miRNA-mediated network communication between tumour cells and their microenvironment, and their potential as prognostic biomarkers or novel therapeutic targets in melanoma will also be considered.

Does the Stomatognathic System Adapt to Changes in Occlusion? Best Evidence Consensus Statement.

PURPOSE: The purpose of this Best Evidence Consensus Statement was to evaluate the existing literature on the stomatognathic system's ability to adapt to occlusal changes. MATERIALS AND METHODS: The search term stomatognathic system was not useful as it resulted in over 400,000 results nor was the search term temporomandibular joint adaptation with 738 results due to the large number of references not related to the topic. The terms stomatognathic system adaptation to occlusal changes (186 results), teeth flexion (139 results), muscle adaptation to dental occlusion (278 results), and occlusal changes and neuroplasticity (11 results) provided the best selection of articles related to the topic. Limiting the above searches to systematic reviews and randomized controlled clinical trials resulted in multiple publications that were related to the question.9-13 Other literature reviews, data-based publications, and expert opinion resources have been included due to their relationship to the question. RESULTS: From the extensive list of search results, 242 articles were determined to be potentially related to the focus question and were evaluated with 56 being included in this paper. It was determined that the stomatognathic system adapts to occlusal changes through the temporomandibular joint, muscles, teeth and bone. The dynamically modified periosteum on the articulator surfaces of the condyle and fossa has a unique load-bearing morphology with 3 subarticular layers of fibrocartilage that absorb and dissipate both peak (impact) and sustained loads. Adaptability of the TMJs and muscles can be documented through studies where artificially produced occlusal interferences were placed in patients and those study participants with normal temporomandibular joints (TMJs) adapted fairly well whereas those with a previous history of temporomandibular disorders (TMD) did not adapt as well. CONCLUSIONS: Available evidence indicates patients generally adapt to the occlusal change inherent in orthodontic treatment, mandibular advancement surgery, and the use of mandibular advancement devices. The head and neck muscles also adapt to occlusal changes in patients without a history of TMD. The dentition adapts to changes through the bone and periodontal ligaments as well as the ability of teeth to undergo slight flexion under masticatory loading. This article is protected by copyright. All rights reserved.

Non-specific rheumatic manifestations in patients with Hashimoto's thyroiditis: a pilot cross-sectional study.

PURPOSE: Hashimoto's thyroiditis (HT) is often associated with rheumatic disorders (arthritis, etc.), but many HT patients report non-specific rheumatic signs and symptoms in the absence of clinically evident rheumatic diseases. Aim of this study was to evaluate the prevalence of non-specific rheumatic manifestations (RMs) in HT subjects without classified autoimmune comorbidities. METHODS: 500 HT patients (467 F, 33 M; median age 41 years, range 14-69) and 310 age- and sex-matched controls, consecutively referred to the Endocrine Unit of Messina University Hospital, were evaluated for non-specific RMs. None took L-thyroxine. EXCLUSION CRITERIA: autoimmune comorbidities, infectious, and/or inflammatory diseases, history of neoplasia, BMI > 30 kg/m2. RESULTS: In our HT cohort, 100 patients (20%) complained of one or more RMs, vs 21 controls (6.8%; P < 0.001). There were minimal differences between the manifestations recorded in the two groups, the most common being polyarthralgias and myalgias/fibromyalgia, but non-specific RMs occurred threefold more in HT patients. Comparing HT patients with RMs (96 F and 4 M) with those affected by HT alone, female sex was prevalent (F:M ratio 24:1 vs 5:1) with higher age at diagnosis (median 43 vs 37 years; P < 0.001). HT patients with RMs (62%) were mostly euthyroid (median TSH 2.0 µIU/L) and only 7% overtly hypothyroid, discouraging a possible causal relationship between thyroid dysfunction per se and RMs. CONCLUSIONS: A significant percentage of HT patients complains of non-specific rheumatic signs and symptoms, in the absence of other diagnosed systemic comorbidities and regardless of thyroid functional status, deserving careful evaluation and prolonged follow-up.

Failure rates for stainless steel versus titanium alloy infrazygomatic crest bone screws: A single-center, randomized double-blind clinical trial.

OBJECTIVES: To compare failure rates for stainless steel (SS) and titanium alloy (TiA) bone screws (BSs) placed in the infrazygomatic crest (IZC). MATERIALS AND METHODS: A total of 386 consecutive patients (76 male, 310 female; mean age 24.3 years, range 10.3-59.4 years) received IZC BSs (SS or TiA) via a double-blind, split-mouth design. BSs penetrated attached gingiva (AG) or moveable mucosa (MM) with 5 mm of soft tissue clearance. All BSs were immediately loaded and reactivated monthly with ≤14 oz (397 g or 389 cN) applied directly to the upper archwire bilaterally for 6 months to retract the maxilla to correct Class II or bimaxillary protrusion. RESULTS: Of the 772 devices, there were 49 (6.3%) failures: 27 SS (7.0%) and 22 TiA (5.7%). The 1.3% difference was not statistically significant ( P = .07). There was no significant relationship between SS or TiA failures relative to (1) right vs left side, (2) unilateral vs bilateral, or (3) age at failure. Significantly ( P < .05) increased failure rates were noted for SS screws in only two subgroups: AG site (7.4%) and right side (7.8%). Unilateral failure occurred in 21 patients (5.4%), and bilateral failures occurred in 14 of the total 772 patients (1.8%). CONCLUSIONS: The overall success rate of 93.7% indicates that both SS and TiA are clinically acceptable for IZC BSs.

Diagnosis and conservative treatment of skeletal Class III malocclusion with anterior crossbite and asymmetric maxillary crowding.

A man, aged 28 years 9 months, came for an orthodontic consultation for a skeletal Class III malocclusion (ANB angle, -3°) with a modest asymmetric Class II and Class III molar relationship, complicated by an anterior crossbite, a deepbite, and 12 mm of asymmetric maxillary crowding. Despite the severity of the malocclusion (Discrepancy Index, 37), the patient desired noninvasive camouflage treatment. The 3-Ring diagnosis showed that treatment without extractions or orthognathic surgery was a viable approach. Arch length analysis indicated that differential interproximal enamel reduction could resolve the crowding and midline discrepancy, but a miniscrew in the infrazygomatic crest was needed to retract the right buccal segment. The patient accepted the complex, staged treatment plan with the understanding that it would require about 3.5 years. Fixed appliance treatment with passive self-ligating brackets, early light short elastics, bite turbos, interproximal enamel reduction, and infrazygomatic crest retraction opened the vertical dimension of the occlusion, improved the ANB angle by 2°, and achieved excellent alignment, as evidenced by a Cast Radiograph Evaluation score of 28 and a Pink and White dental esthetic score of 3.

A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors.

OBJECTIVE: VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies. METHODS: Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state. RESULTS: Forty-six patients were treated across nine dose levels (12.5-750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d. CONCLUSIONS: VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.

Long-Term Safety With Axitinib in Previously Treated Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND: Axitinib is an approved treatment for advanced renal cell carcinoma (RCC) after failure of 1 systemic therapy. PATIENTS AND METHODS: Long-term safety with single-agent axitinib was analyzed using pooled data from clinical trials in 672 previously treated patients with metastatic RCC (mRCC) and in 1304 patients with different advanced solid tumors. In all studies, except the phase I first-in-human, dose-finding study, the starting dose of oral axitinib was 5 mg twice daily continuously. Common long-term treatment-emergent adverse events (AEs) were identified in patients who received axitinib for ≥ 2 years, then evaluated in all patients, and assessed using interval, cumulative, and latency analyses. RESULTS: In all, 108 (16%) previously treated patients with mRCC received axitinib for ≥ 2 years. In interval analysis, most AEs occurred during the first 6 months of treatment, with rates stable or decreased over time; rates increased for proteinuria, peripheral edema, and increased blood creatinine. Common Grade ≥ 3 AE rates declined or plateaued over time, except for increased amylase and myocardial infarction. Results were similar in cumulative analysis in this population, and in interval and cumulative analyses in all patients with mRCC and those with advanced solid tumors. CONCLUSION: Declining or stable rates of most AEs support an acceptable long-term safety profile for axitinib in patients with mRCC. However, increases in the rates of some AEs warrant monitoring. This analysis is limited in that it was retrospective and included a relatively small patient population.

The Role of Maternal Gestational Diabetes in Inducing Fetal Endothelial Dysfunction.

Gestational diabetes mellitus (GDM) is known to be associated with fetal endothelial dysfunction, however, the mechanisms are not fully understood. This study examines the effect of maternal diabetes on fetal endothelial function and gene expression under physiological glucose conditions (5 mM). Human umbilical vein endothelial cell (HUVEC) isolated from diabetic mothers (d.HUVEC) grew more slowly than HUVEC isolated from healthy mothers (c.HUVEC) and had delayed doubling time despite increased levels of total vascular endothelial growth factor (VEGF) expression and protein production as determined by real-time PCR and ELISA respectively. Using western blot, the levels of antiproliferative VEGF165b isoform were increased in d.HUVEC relative to c.HUVEC. Successful VEGF165b knockdown by small interfering RNA (siRNA) resulted in increased proliferation of d.HUVEC measured by MTT, compared with negative siRNA control, to similar levels measured in c.HUVEC. In addition, d.HUVEC generated excess levels of ROS as revealed by 2',7' Dichlorodihydrofluorescein Diacetate (DCFH-DA) and Nitrotetrazolium blue (NBT). Using microarray, 102 genes were differentially overexpressed between d.HUVEC versus c.HUVEC (>1.5-fold change; P < 0.05). Functional clustering analysis of these differentially expressed genes revealed participation in inflammatory responses (including adhesion) which may be related to pathological outcomes. Of these genes, ICAM-1 was validated as upregulated, confirming microarray results. Additional confirmatory immunofluorescence staining revealed increased protein expression of ICAM-1 compared with c.HUVEC which was reduced by vitamin C treatment (100 µM). Thus, maternal diabetes induces persistent alterations in fetal endothelial function and gene expression following glucose normalization and antioxidant treatment could help reverse endothelium dysfunction.

Hypertension among patients with renal cell carcinoma receiving axitinib or sorafenib: analysis from the randomized phase III AXIS trial.

Inhibitors of the vascular endothelial growth factor (VEGF) pathway frequently induce hypertension when used to treat patients with advanced renal cell carcinoma (RCC). This analysis characterizes hypertension and hypertension-related events in patients treated with the VEGF pathway inhibitors axitinib or sorafenib in the AXIS trial. AXIS was a randomized phase III study of axitinib versus sorafenib in patients with metastatic RCC following failure of one prior systemic regimen. Patients with uncontrolled hypertension were excluded, but patients with hypertension controlled with antihypertensive medication were allowed to participate. Guidelines for hypertension management included adjustment or addition of antihypertensive medications and/or axitinib or sorafenib dose reductions, interruptions, or discontinuations. Treatment-emergent all-causality hypertension occurred in 145 (40.4 %) axitinib-treated patients (N = 359) and 103 (29.0 %) sorafenib-treated patients (N = 355), with grade 3 hypertension reported in 55 (15.3 %) and 38 (10.7 %) patients, respectively, and grade 4 hypertension reported in one (0.3 %) patient in each arm. Hypertension-related events led to axitinib dose interruptions (n = 46; 12.8 %), dose reductions (n = 16; 4.5 %), or discontinuations (n = 1; 0.3 %). Approximately 50 % of axitinib-treated patients with grade 3 or 4 hypertension continued treatment for ≥ 9 months. Hypertension-related sequelae occurred in <1 % of axitinib-treated patients. Hypertension was more frequently observed during treatment with axitinib than sorafenib in patients with RCC, but axitinib-induced hypertension rarely led to treatment discontinuation or cardiovascular sequelae. Recommendations for monitoring blood pressure and managing hypertension during axitinib therapy are presented.

Safety, pharmacokinetic, and pharmacodynamic phase I dose-escalation trial of PF-00562271, an inhibitor of focal adhesion kinase, in advanced solid tumors.

PURPOSE: PF-00562271 is a novel inhibitor of focal adhesion kinase (FAK). The objectives of this study were to identify the recommended phase II dose (RP2D) and assess safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of PF-00562271. PATIENTS AND METHODS: Part 1 was a dose escalation without and with food. Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF-00562271 on single-dose midazolam PK in a subgroup of patients. RESULTS: Ninety-nine patients (median age, 60 years; 98% with Eastern Cooperative Oncology Group performance status of 0 or 1) were treated in 12 fasting and three fed cohorts. The 125-mg twice-per-day fed dose was deemed the maximum-tolerated dose (MTD) and RP2D. Grade 3 dose-limiting toxicities included headache, nausea/vomiting, dehydration, and edema. Nausea was the most frequently observed toxicity (60% of patients, all grades 1 or 2 at RP2D). PF-00562271 exposure increased with increasing dose; serum concentration-time profiles showed characteristic nonlinear disposition. Steady-state exposures were reached within 1 week. On coadministration, geometric mean values of midazolam maximal observed serum concentration and area under the serum concentration-time curve increased by 60% and more than two-fold, respectively. Of 14 patients evaluable by [(18)F]fluorodeoxyglucose positron emission tomography in the expansion cohorts, seven metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans, and 15 of these remained stable for six or more cycles. CONCLUSION: The MTD and RP2D of PF-00562271 is 125 mg twice per day with food. PF-00562271 displayed time- and dose-dependent nonlinear PK and is likely a potent CYP 3A inhibitor. This first-in-class study supports further investigation of FAK as a promising therapeutic target.

8q24 allelic imbalance and MYC gene copy number in primary prostate cancer.

Four independent regions within 8q24 near the MYC gene are associated with risk for prostate cancer (Pca). Here, we investigated allelic imbalance (AI) at 8q24 risk variants and MYC gene DNA copy number (CN) in 27 primary Pcas. Heterozygotes were observed in 24 of 27 patients at one or more 8q24 markers and 27% of the loci exhibited AI in tumor DNA. The 8q24 risk alleles were preferentially favored in the tumors. Increased MYC gene CN was observed in 33% of tumors, and the co-existence of increased MYC gene CN with AI at risk loci was observed in 86% (P<0.004 exact binomial test) of the informative tumors. No AI was observed in tumors, which did not reveal increased MYC gene CN. Higher Gleason score was associated with tumors exhibiting AI (P=0.04) and also with increased MYC gene CN (P=0.02). Our results suggest that AI at 8q24 and increased MYC gene CN may both be related to high Gleason score in Pca. Our findings also suggest that these two somatic alterations may be due to the same preferential chromosomal duplication event during prostate tumorigenesis.

Nitric oxide specifically inhibits integrin-mediated platelet adhesion and spreading on collagen.

BACKGROUND: Nitric oxide (NO) inhibits platelet adhesion to collagen, although the precise molecular mechanisms underlying this process are unclear. OBJECTIVES: Collagen-mediated adhesion is a multifaceted event requiring multiple receptors and platelet-derived soluble agonists. We investigated the influence of NO on these processes. RESULTS: S-nitrosoglutathione (GSNO) induced a concentration-dependent inhibition of platelet adhesion to immobilized collagen. Maximal adhesion to collagen required platelet-derived ADP and TxA(2). GSNO-mediated inhibition was lost in the presence of apyrase and indomethacin, suggesting that NO reduced the availability of, or signaling by, ADP and TxA(2). Exogenous ADP, but not the TxA(2) analogue U46619, reversed the inhibitory actions of GSNO on adhesion. Under adhesive conditions NO inhibited dense granule secretion but did not influence TxA(2) generation. These data indicated that NO may block signaling by TxA(2) required for dense granule secretion, thereby reducing the availability of ADP. Indeed, we found TxA(2)-mediated activation of PKC was required to drive dense granule secretion, a pathway that was inhibited by NO. Because our data demonstrated that NO only inhibited the activation-dependent component of adhesion, we investigated the effects of NO on individual collagen receptors. GSNO inhibited platelet adhesion and spreading on alpha(2)beta(1) specific peptide ligand GFOGER. In contrast, GSNO did not inhibit GPVI-mediated adhesion to collagen, or adhesion to the GPVI specific ligand, collagen related peptide (CRP). CONCLUSIONS: NO targets activation-dependent adhesion mediated by alpha(2)beta(1), possibly by reducing bioavailability of platelet-derived ADP, but has no effect on activation-independent adhesion mediated by GPVI. Thus, NO regulates platelet spreading and stable adhesion to collagen.

Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention.

The tumor microenvironment plays a central role in cancer progression and metastasis. Within this environment, cancer cells respond to a host of signals including growth factors and chemotactic factors, as well as signals from adjacent cells, cells in the surrounding stroma, and signals from the extracellular matrix. Targeting the pathways that mediate many of these signals has been a major goal in the effort to develop therapeutics.

Integrating evidence into clinical information systems for nursing decision support.

PURPOSE: To illustrate approaches for providing decision support for evidence-based nursing practice through integration of evidence into clinical information systems (CISs) with examples from our experience at Columbia University Medical Center. ORGANIZING CONSTRUCT: Examples are organized according to three types of decision support functions: information management, focusing attention, and patient-specific consultation. METHODS: Three decision support tools that are integrated into three types of CISs are discussed: (1) infobuttons that provide context-specific access to digital sources of evidence; (2) automated Fall-Injury Risk Assessment; and (3) personal digital assistant-based screening reminders, screening assessments, and tailored documentation templates for the identification and management of obesity, depression, and tobacco cessation. The informatics infrastructure for implementing these decision support tools is described from the perspective of components identified in the published literature. CONCLUSIONS: Efforts to facilitate application of evidence into nursing practice are unlikely to be successful unless the approaches used are integrated into the clinical workflow. Our approaches use a variety of informatics methods to integrate evidence into CISs as a mechanism for providing decision support for evidence-based practice in a manner consistent with nursing workflow.

PDA-based informatics strategies for tobacco use screening and smoking cessation management: a case study.

The purpose of this case study is to describe three incremental personal digital PDA-based informatics strategies aimed at improving screening for tobacco use and guideline-based tobacco cessation management: 1) PDA clinical log with tobacco cessation diagnoses and plan of care options, 2) PDA decision support system, and 3) PDA decision support system with infobuttons--context-specific links to the National Cancer Institute's Cancer Information Services tobacco cessation information. These strategies were implemented within the context of an evidence-based advanced practice nurse curriculum at the Columbia University School of Nursing.