Killing SCLC: insights into how to target a shapeshifting tumor.

Small cell lung cancer (SCLC) is a rapidly growing, highly metastatic, and relatively immune-cold lung cancer subtype. Historically viewed in the laboratory and clinic as a single disease, new discoveries suggest that SCLC comprises multiple molecular subsets. Expression of MYC family members and lineage-related transcription factors ASCL1, NEUROD1, and POU2F3 (and, in some studies, YAP1) define unique molecular states that have been associated with distinct responses to a variety of therapies. However, SCLC tumors exhibit a high degree of intratumoral heterogeneity, with recent studies suggesting the existence of tumor cell plasticity and phenotypic switching between subtype states. While SCLC plasticity is correlated with, and likely drives, therapeutic resistance, the mechanisms underlying this plasticity are still largely unknown. Subtype states are also associated with immune-related gene expression, which likely impacts response to immune checkpoint blockade and may reveal novel targets for alternative immunotherapeutic approaches. In this review, we synthesize recent discoveries on the mechanisms of SCLC plasticity and how these processes may impinge on antitumor immunity.

Effect of mandibular advancement splint therapy on cardiac autonomic function in obstructive sleep apnoea.

PURPOSE: This study aimed to evaluate the effect of mandibular advancement splint (MAS) therapy on cardiac autonomic function in patients with obstructive sleep apnoea (OSA) using heart rate variability (HRV) analysis. METHODS: Electrocardiograms (ECG) derived from polysomnograms (PSG) of three prospective studies were used to study HRV of patients with OSA before and after MAS treatment. HRV parameters were averaged across the entire ECG signal during N2 sleep using 2-min epochs shifted by 30 s. Paired t-tests were used to compare PSG and HRV measures before and after treatment, and the percent change in HRV measures was regressed on the percent change in apnoea-hypopnea index (AHI). RESULTS: In 101 patients with OSA, 72% were Caucasian, 54% men, the mean age was 56 ± 11 years, BMI 29.8 ± 5.3 kg/m2, and treatment duration was 4.0 ± 3.2 months. After MAS therapy, there was a significant reduction in OSA severity (AHI, - 18 ± 16 events per hour, p < 0.001) and trends towards increased low-frequency to high-frequency ratio, low-frequency power, and reduced high-frequency power (LF:HF, - 0.4 ± 1.5, p = 0.01; LF, - 3 ± 16 nu, p = 0.02, HF, 3.5 ± 13.7 nu, p = 0.01). Change in NN intervals correlated with the change in AHI (ß(SE) = - 2.21 (0.01), t = - 2.85, p = 0.005). No significant changes were observed in the time-domain HRV markers with MAS treatment. CONCLUSION: The study findings suggest that successful MAS treatment correlates with changes in HRV, specifically the lengthening of NN intervals, a marker for improved cardiac autonomic adaptability.

Upper airway morphology in adults with positional obstructive sleep apnea.

PURPOSE: To compare the anatomical balance and shape of the upper airway in the supine position between adults with positional obstructive sleep apnea (POSA) and adults with non-positional OSA (NPOSA). METHODS: Adults diagnosed with OSA (apnea-hypopnea index (AHI) > 10 events/h) were assessed for eligibility. POSA was defined as the supine AHI more than twice the AHI in non-supine positions; otherwise, patients were classified as NPOSA. Cone beam computed tomography (CBCT) imaging was performed for every participant while awake in the supine position. The anatomical balance was calculated as the ratio of the tongue size to the maxillomandibular enclosure size. The upper airway shape was calculated as the ratio of the anteroposterior dimension to the lateral dimension at the location of the minimal cross-sectional area of the upper airway (CSAmin-shape). RESULTS: Of 47 participants (28 males, median age [interquartile range] 56 [46 to 63] years, median AHI 27.8 [15.0 to 33.8]), 34 participants were classified as having POSA (72%). The POSA group tended to have a higher proportion of males and a lower AHI than the NPOSA group (P = 0.07 and 0.07, respectively). After controlling for both sex and AHI, the anatomical balance and CSAmin-shape were not significantly different between both groups (P = 0.18 and 0.73, respectively). CONCLUSION: Adults with POSA and adults with NPOSA have similar anatomical balance and shape of their upper airway in the supine position. TRIAL REGISTRATION: This study was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR Trial ACTRN12611000409976).

Cardiac autonomic function in REM-related obstructive sleep apnoea: insights from nocturnal heart rate variability profiles.

PURPOSE: In light of the reported association between REM-related obstructive sleep apnoea (OSA) and heightened cardiovascular risk, this study aims to compare cardiac autonomic function in patients with REM-OSA and OSA independent of sleep stage. We hypothesized that REM-OSA patients would exhibit higher sympathetic cardiac modulation based on heart rate variability (HRV) profiles. METHODS: HRV was compared between the OSA group (AHI ≥ 5 events/h, n = 252) and the REM-OSA group (AHI ≥ 5 events/h, AHIREM:AHINREM ≥ 2, n = 137). Time- and frequency-domain measures of HRV were analysed during N2 and REM sleep. RESULTS: Clinical characteristics between the two test groups differed significantly, 45% of REM-OSA patients were female, with mild OSA (median, interquartile range (IQR)) AHI of 10 (7) events/h. Only 26% of the OSA cohort were female with moderate OSA (AHI = 17 (20) events/h, p < 0.001). Compared with the OSA group, the low frequency to high frequency ratio (LF:HF) and LF power were lower and HF power was higher in the REM-OSA group during N2 (LF:HF, p = 0.012; LF; p = 0.013; HF, p = 0.007) and in REM sleep (LF:HF, p = 0.002; LF, p = 0.004; HF, p < 0.001). Patient sex and OSA severity had a significant combined effect on average N to N interval, LF power, and LF:HF ratio during N2 and REM sleep (all p < 0.001). CONCLUSION: Contrary to our hypothesis, REM-OSA patients demonstrated consistently higher cardiac vagal modulation, reflecting better cardiac autonomic adaptation. These results were attributed to differences in OSA severity and sex in these two groups, both independently affecting HRV. This study emphasises the need for future research into the underlying pathophysiology of REM-OSA and the potential implications of sex and OSA severity on cardiovascular risk.

Phenotypic Characterisation of Obstructive Sleep Apnoea in Acute Coronary Syndrome.

BACKGROUND: Recent neutral randomised clinical trials have created clinical equipoise for treating obstructive sleep apnoea (OSA) for managing cardiovascular risk. The importance of defining the links between OSA and cardiovascular disease is needed with the aim of advancing the robustness of future clinical trials. We aimed to define the clinical correlates and characterise surrogate cardiovascular markers in patients with acute coronary syndrome (ACS) and OSA. METHOD: Overall, 66 patients diagnosed with ACS were studied. Patients underwent an unattended polysomnogram after hospital discharge (median [interquartile range] 62 [37-132] days). The Epworth Sleepiness Scale, Berlin, and STOP-BANG questionnaires were administered. Surrogate measures of vascular structure and function, and cardiovascular autonomic function were conducted. Pulse wave amplitude drop was derived from the pulse oximetry signals of the overnight polysomnogram. RESULTS: OSA (apnoea-hypopnea index [AHI] ≥5) was diagnosed in 94% of patients. Moderate-to-severe OSA (AHI≥15) was observed in 68% of patients. Daytime sleepiness (Epworth Sleepiness Scale ≥10) was reported in 17% of patients. OSA screening questionnaires were inadequate to identify moderate-to-severe OSA, with an area under the receiver operating characteristic curve of approximately 0.64. Arterial stiffness (carotid-femoral pulse wave velocity, 6.1 [5.2-6.8] vs 7.4 [6.6-8.6] m/s, p=0.002) and carotid intima-media thickness (0.8 [0.7-1.0] vs 0.9 [0.8-1.0] mm, p=0.027) was elevated in patients with moderate-to-severe OSA. After adjusting for age, sex and body mass index, these relationships were not statistically significant. No relationships were observed in other surrogate cardiovascular markers. CONCLUSIONS: A high prevalence of OSA in a mostly non-sleepy population with ACS was identified, highlighting a gross underdiagnosis of OSA among cardiovascular patients. The limitations of OSA screening questionnaires highlight the need for new models of OSA screening as part of cardiovascular risk management. A range of inconsistent abnormalities were observed in measures of vascular structure and function, and these appear to be largely explained by confounding factors. Further research is required to elucidate biomarkers for the presence and impact of OSA in ACS patients.

Influence of social jetlag on daytime sleepiness in obstructive sleep apnea.

Social jetlag is the discrepancy between socially determined sleep timing on workdays and biologically determined sleep timing on days free of social obligation. Poor circadian timing of sleep may worsen sleep quality and increase daytime sleepiness in obstructive sleep apnea (OSA). We analysed de-identified data from 2,061 participants (75.2% male, mean [SD] age 48.6 [13.4] years) who completed Sleep Apnea Global Interdisciplinary Consortium (SAGIC) research questionnaires and underwent polysomnography at 11 international sleep clinic sites. Social jetlag was calculated as the absolute difference in the midpoints of sleep between weekdays and weekends. Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS). Linear regression analyses were performed to estimate the association between social jetlag and daytime sleepiness, with consideration of age, sex, body mass index, ethnicity, insomnia, alcohol consumption, and habitual sleep duration as confounders. Of the participants, 61.5% had <1 h of social jetlag, 27.5% had 1 to <2 h, and 11.1% had ≥2 h. Compared to those with <1 h of social jetlag, those with ≥2 h of social jetlag had 2.07 points higher ESS (95% confidence interval [CI] 0.77-3.38, p = 0.002), and those with 1 to <2 h of social jetlag had 0.80 points higher ESS (95% CI 0.04-1.55, p = 0.04) after adjustment for potential confounding. Interaction with OSA severity was observed; social jetlag appeared to have the greatest effect on daytime sleepiness in mild OSA. As social jetlag exacerbates daytime sleepiness in OSA, improving sleep timing may be a simple but novel therapeutic target for reducing the impact of OSA.

The effect of surgical weight loss on upper airway fat in obstructive sleep apnoea.

PURPOSE: Obesity is a reversible risk factor for obstructive sleep apnoea (OSA). Weight loss can potentially improve OSA by reducing fat around and within tissues surrounding the upper airway, but imaging studies are limited. Our aim was to study the effects of large amounts of weight loss on the upper airway and volume and fat content of multiple surrounding soft tissues. METHODS: Participants undergoing bariatric surgery were recruited. Magnetic resonance imaging (MRI) was performed at baseline and six-months after surgery. Volumetric analysis of the airway space, tongue, pharyngeal lateral walls, and soft palate were performed as well as calculation of intra-tissue fat content from Dixon imaging sequences. RESULTS: Among 18 participants (89% women), the group experienced 27.4 ± 4.7% reduction in body weight. Velopharyngeal airway volume increased (large effect; Cohen's d [95% CI], 0.8 [0.1, 1.4]) and tongue (large effect; Cohen's d [95% CI], - 1.4 [- 2.1, - 0.7]) and pharyngeal lateral wall (Cohen's d [95% CI], - 0.7 [- 1.2, - 0.1]) volumes decreased. Intra-tissue fat decreased following weight loss in the tongue, tongue base, lateral walls, and soft palate. There was a greater effect of weight loss on intra-tissue fat than parapharyngeal fat pad volume (medium effect; Cohen's d [95% CI], - 0.5 [- 1.2, 0.1], p = 0.083). CONCLUSION: The study showed an increase in velopharyngeal volume, reduction in tongue volume, and reduced intra-tissue fat in multiple upper airway soft tissues following weight loss in OSA. Further studies are needed to assess the effect of these anatomical changes on upper airway function and its relationship to OSA improvement.

Paracrine signaling between tumor subclones of mouse SCLC: a critical role of ETS transcription factor Pea3 in facilitating metastasis.

Tumor heterogeneity can create a unique symbiotic tumor microenvironment. Earlier, we showed that clonal evolution in mouse small cell lung cancer (SCLC) can result in subclones that, upon cografting, endow the neuroendocrine tumor cells with metastatic potential. We now show that paracrine signaling between SCLC subclones is a critical requirement in the early steps of the metastatic process, such as local invasion and intravasation. We further show evidence that paracrine signaling via fibroblast growth factor 2 (Fgf2) and Mapk between these diverged tumor subclones causes enhanced expression of the Pea3 (polyomavirus enhancer activator 3) transcription factor, resulting in metastatic dissemination of the neuroendocrine tumor subclones. Our data reveal for the first time paracrine signaling between tumor cell subclones in SCLC that results in metastatic spread of SCLC.

Mandibular Advancement Splint Therapy.

Mandibular advancement splint (MAS) therapy is the leading alternative to continuous positive airway pressure (CPAP) therapy for the treatment of obstructive sleep apnoea. A MAS is an oral appliance which advances the mandible in relation to the maxilla, thus increasing airway calibre and reducing collapsibility. Although it is less effective than CPAP in reducing the apnoea-hypopnoea index (AHI), it has demonstrated equivalence to CPAP in a number of key neurobehavioural and cardiovascular health outcomes, perhaps due to increased tolerability and patient adherence when compared to CPAP. However, response to MAS is variable, and reliable prediction tools for patients who respond best to MAS therapy have thus far been elusive; this is one of the key clinical barriers to wider uptake of MAS therapy. In addition, the most effective MAS devices are custom-made by a dentist specialising in the treatment of sleep disorders, which may present financial or accessibility barriers for some patients. MAS devices are generally well tolerated but may have side effects including temporomandibular joint (TMJ) dysfunction, hypersalivation, tooth pain and migration as well as occlusal changes. A patient-centred approach to treatment from a multidisciplinary team perspective is recommended. Evidence-based clinical practice points and areas of future research are summarised at the conclusion of the chapter.

Delineating the roles of Grhl2 in craniofacial development through tissue-specific conditional deletion and epistasis approaches in mouse.

BACKGROUND: The highly conserved Grainyhead-like (Grhl) family of transcription factors play critical roles in the development of the neural tube and craniofacial skeleton. In particular, deletion of family member Grainyhead-like 2 (Grhl2) leads to mid-gestational embryonic lethality, maxillary clefting, abdominoschisis, and both cranial and caudal neural tube closure defects. These highly pleiotropic and systemic defects suggest that Grhl2 plays numerous critical developmental roles to ensure correct morphogenesis and patterning. RESULTS: Here, using four separate Cre-lox conditional deletion models, as well as one genetic epistasis approach (Grhl2+/- ;Edn1+/- double heterozygous mice) we have investigated tissue-specific roles of Grhl2 in embryonic development, with a particular focus on the craniofacial skeleton. We find that loss of Grhl2 in the pharyngeal epithelium (using the ShhCre driver) leads to low-penetrance micrognathia, whereas deletion of Grhl2 within the ectoderm of the pharynx (NestinCre ) leads to small, albeit significant, differences in the proximal-distal elongation of both the maxilla and mandible. Loss of Grhl2 in endoderm (Sox17-2aiCre ) resulted in noticeable lung defects and a single instance of secondary palatal clefting, although formation of other endoderm-derived organs such as the stomach, bladder and intestines was not affected. Lastly, deletion of Grhl2 in cells of the neural crest (Wnt1Cre ) did not lead to any discernible defects in craniofacial development, and similarly, our epistasis approach did not detect any phenotypic consequences of loss of a single allele of both Grhl2 and Edn1. CONCLUSION: Taken together, our study identifies a pharyngeal-epithelium intrinsic, non-cell-autonomous role for Grhl2 in the patterning and formation of the craniofacial skeleton, as well as an endoderm-specific role for Grhl2 in the formation and establishment of the mammalian lung.

Critical cancer vulnerabilities identified by unbiased CRISPR/Cas9 screens inform on efficient cancer Immunotherapy.

The mutational landscape of human cancers is highly complex. While next generation sequencing aims to comprehensively catalogue somatic alterations in tumor cells, it fails to delineate driver from passenger mutations. Functional genomic approaches, particularly CRISPR/Cas9, enable both gene discovery, and annotation of gene function. Indeed, recent CRISPR/Cas9 technologies have flourished with the development of more sophisticated and versatile platforms capable of gene knockouts to high throughput genome wide editing of a single nucleotide base. With new platforms constantly emerging, it can be challenging to navigate what CRISPR tools are available and how they can be effectively applied to understand cancer biology. This review provides an overview of current and emerging CRISPR technologies and their power to model cancer and identify novel treatments. Specifically, how CRISPR screening approaches have been exploited to enhance immunotherapies through the identification of tumor intrinsic and extrinsic mechanisms to escape immune recognition will be discussed.

Heart rate variability and obstructive sleep apnea: Current perspectives and novel technologies.

Obstructive sleep apnea (OSA) is a highly prevalent condition, resulting in recurrent hypoxic events, sleep arousal, and daytime sleepiness. Patients with OSA are at an increased risk of cardiovascular morbidity and mortality. The mechanisms underlying the development of cardiovascular disease in OSA are multifactorial and cause a cascade of events. The primary contributing factor is sympathetic overactivity. Heart rate variability (HRV) can be used to evaluate shifts in the autonomic nervous system, during sleep and in response to treatment in patients with OSA. Newer technologies are aimed at improving HRV analysis to accelerate processing time, improve the diagnosis of OSA, and detection of cardiovascular risk. The present review will present contemporary understandings and uses for HRV, specifically in the realms of physiology, technology, and clinical management.

Development and validation of a model for diagnosis of obstructive sleep apnoea in primary care.

BACKGROUND AND OBJECTIVE: Use of in-laboratory polysomnography (PSG) to diagnose obstructive sleep apnoea (OSA) is cost and resource intensive. Questionnaires, physical measurements and home monitors have been studied as potential simpler alternatives. This study aimed to develop a diagnostic model for OSA for use in primary care. METHODS: Primary care practitioners were trained to recognize symptoms of sleep apnoea and recruited patients based on the clinical need to investigate OSA. Assessment was by symptom questionnaires, anthropomorphic measurements, digital facial photography, and a single-channel nasal flow monitor (Flow Wizard©, DiagnoseIT, Sydney, Australia) worn at home for 3 nights. The in-laboratory PSG was the reference test, with OSA defined as apnoea-hypopnoea index (AHI) ≥10 events/h. RESULTS: In the model development phase, 25 primary care practitioners studied 315 patients in whom they suspected OSA, of which 57% had AHI≥10 and 22% had AHI≥30. Published OSA questionnaires provided low to moderate prediction of OSA (area under the curve [AUC] 0.53-0.73). The nasal flow monitor alone yielded high accuracy for predicting OSA with AUC of 0.87. Sensitivity was 0.87 and specificity 0.77 at a threshold respiratory event index (REI) of 18 events/h. A model adding age, gender, symptoms and BMI to the nasal flow monitor REI only modestly improved OSA prediction (AUC 0.89), with similar AUC (0.88) confirmed in the validation population of 114 patients. CONCLUSION: Sleep apnoea can be diagnosed in the primary care setting with a combination of clinical judgement and portable monitor test outcomes.

Lung Basal Stem Cells Rapidly Repair DNA Damage Using the Error-Prone Nonhomologous End-Joining Pathway.

Lung squamous cell carcinoma (SqCC), the second most common subtype of lung cancer, is strongly associated with tobacco smoking and exhibits genomic instability. The cellular origins and molecular processes that contribute to SqCC formation are largely unexplored. Here we show that human basal stem cells (BSCs) isolated from heavy smokers proliferate extensively, whereas their alveolar progenitor cell counterparts have limited colony-forming capacity. We demonstrate that this difference arises in part because of the ability of BSCs to repair their DNA more efficiently than alveolar cells following ionizing radiation or chemical-induced DNA damage. Analysis of mice harbouring a mutation in the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key enzyme in DNA damage repair by nonhomologous end joining (NHEJ), indicated that BSCs preferentially repair their DNA by this error-prone process. Interestingly, polyploidy, a phenomenon associated with genetically unstable cells, was only observed in the human BSC subset. Expression signature analysis indicated that BSCs are the likely cells of origin of human SqCC and that high levels of NHEJ genes in SqCC are correlated with increasing genomic instability. Hence, our results favour a model in which heavy smoking promotes proliferation of BSCs, and their predilection for error-prone NHEJ could lead to the high mutagenic burden that culminates in SqCC. Targeting DNA repair processes may therefore have a role in the prevention and therapy of SqCC.

Advanced polysomnographic analysis for OSA: A pathway to personalized management?

Obstructive sleep apnea (OSA) is a highly heterogeneous disorder, with diverse pathways to disease, expression of disease, susceptibility to co-morbidities and response to therapy, and is ideally suited to precision medicine approaches. Clinically, the content of the information-rich polysomnogram (PSG) is not currently fully utilized in determining patient management. Novel PSG parameters such as hypoxic burden, pulse transit time, cardiopulmonary coupling and the frequency representations of PSG sensor signals could predict a variety of cardiovascular disease, cancer and neurodegeneration co-morbidities. The PSG can also be used to identify key pathophysiological parameters such as loop gain, arousal threshold and muscle compensation which can enhance understanding of the causes of OSA in an individual, and thereby guide choices on therapy. Machine learning methods performing their own parameter extraction coupled with large PSG data sets offer an exciting opportunity for discovering new links between the PSG variables and disease outcomes. By exploiting existing and emerging analytical methods, the PSG may offer a pathway to personalized management for OSA.

Dose-dependent effects of mandibular advancement on optimal positive airway pressure requirements in obstructive sleep apnoea.

BACKGROUND: Implementation of mandibular advancement splint (MAS) therapy as first-line treatment for obstructive sleep apnoea (OSA) is hindered by inter-individual variability of treatment outcomes and lack of robust patient selection methods. Optimal continuous positive airway pressure (CPAP) requirement provides an estimate of airway collapsibility severity, and high CPAP requirements predict MAS therapy failure in retrospective studies. Thus, understanding the effects of mandibular advancement on optimal CPAP requirements may enhance optimisation of patient selection for MAS therapy. OBJECTIVE: This study aims to determine dose-dependent effects of mandibular advancement on optimal CPAP requirements in OSA. METHODS: Prior to MAS therapy initiation, participants with OSA (apnoea-hypopnea index (AHI) > 10 events/h) underwent a research polysomnogram in which a remotely controlled mandibular positioner (RCMP) was used to determine dose-response effects of varying mandibular advancement positions (0% 'habitual bite' and 25, 50, 75 and 100% of maximum mandibular advancement, in random order) on optimal CPAP requirements. A separate polysomnography determined treatment outcome. Data are presented as mean ± SD or median (1st-3rd quartiles). RESULTS: Seventeen participants (age = 47 ± 9 years, body mass index = 26 kg/m2 (23-27), apnoea-hypopnea index = 18 events/h (14-44) and minimal oxygen saturation = 84 ± 7%) were studied. Optimal CPAP requirements were reduced with mandibular advancement in a dose-dependent manner (8.9 ± 2.4 vs. 7.9 ± 2.8, 6.4 ± 1.8, 5.7 ± 1.9 and 4.9 ± 1.8 cmH2O; respectively, p < 0.0001). Compared with non-responders, responders to MAS therapy had lower AHI, lower arousal index and greater MinSaO2 at baseline. Optimal CPAP requirements at 0% mandibular advancement (or other positions) were not different between groups. CONCLUSIONS: Increasing mandibular advancement lowers optimal CPAP requirements in a dose-dependent manner. This supports prior work indicating a beneficial effect of MAS on upper airway collapsibility.

Craniofacial photography and association with sleep-disordered breathing severity in children.

PURPOSE: Sleep-disordered breathing (SDB) in children has been associated with craniofacial characteristics. Facial photography provides a radiation-free means of estimating facial morphology through facial landmark analysis. Our objective was to determine whether facial analysis provides information about SDB severity. Specifically, we aimed to determine whether facial photographic measurements differ with SDB status, or were associated with SDB severity. METHODS: Single-center cohort of children undergoing overnight polysomnography for assessment of SDB; non-snoring controls were recruited from the community to undergo polysomnography. Standardized front and lateral facial photographs were analyzed according to previously published protocols. Multivariate analysis of variance was used to determine if facial measurements differed between SDB groups and controls. Linear regression was performed to determine if facial measurements were associated with SDB severity. RESULTS: Seventy-eight children (9 controls, 17 primary snoring, 23 mild SDB, 27 moderate-severe SDB) were included. Facial angles and upper-to-lower face height ratio showed variation between SDB groups (p = 0.038). Facial measurements related to SDB severity, specifically an increased cervicomental angle (p = 0.001), and increased lower-to-upper face height (p = 0.006). CONCLUSION: Evaluation of craniofacial features using clinical photography is feasible. Preliminary investigation shows some relationship with SBD severity. Further work is needed to determine if craniofacial photography is useful for stratifying SDB risk in children.

Lung morphogenesis is orchestrated through Grainyhead-like 2 (Grhl2) transcriptional programs.

The highly conserved transcription factor Grainyhead-like 2 (Grhl2) exhibits a dynamic expression pattern in lung epithelium throughout embryonic development. Using a conditional gene targeting approach to delete Grhl2 in the developing lung epithelium, our results demonstrate that Grhl2 plays multiple roles in lung morphogenesis that are essential for respiratory function. Loss of Grhl2 leads to impaired ciliated cell differentiation and perturbed formation of terminal saccules. Critically, a substantial increase in Sox9-positive distal tip progenitor cells was observed following loss of Grhl2, suggesting that Grhl2 plays an important role in branching morphogenesis. Gene transcription profiling of Grhl2-deficient lung epithelial cells revealed a significant down regulation of Elf5, a member of the Ets family of transcription factors. Furthermore, ChIP and comparative genomic analyzes confirmed that Elf5 is a direct transcriptional target of Grhl2. Taken together, these results support the hypothesis that Grhl2 controls normal lung morphogenesis by tightly regulating the activity of distal tip progenitor cells.

Parsing the craniofacial phenotype: effect of weight change in an obstructive sleep apnoea population.

PURPOSE: Craniofacial structure is an important risk factor in the development of obstructive sleep apnoea. Most craniofacial imaging methods are not feasible for large-scale studies or the clinic. Craniofacial photography is a high-throughput technique for facial phenotyping; however, derived measurements are a composite of skeletal and soft tissue craniofacial information. Weight change is a paradigm to help determine which facial measurements most relate to regional soft tissue (i.e. change with weight) versus skeletal structure (i.e. stable with weight changes). We aimed to assess the association between weight change and changes in key facial measurements from facial photography. METHODS: Calibrated frontal and profile photographs were taken of participants in weight loss studies (N = 106). Univariate linear regression was used to assess whether weight change explained changes in facial dimensions. RESULTS: Patients lost 11.7 ± 10.8 kg body weight and 2.0 ± 2.0 cm of neck circumference. Weight changes influenced face width (r = 0.3, p < 0.001), mandibular width (r = 0.4, p < 0.001) and cervicomental angle (r = 0.3, p = 0.001). Facial angles, facial heights and mandibular length were not influenced by weight change. CONCLUSIONS: A weight loss paradigm suggests that face and mandibular width and cervicomental angle most strongly reflect regional adiposity. Facial angles and heights are insensitive to weight change and could be more representative of craniofacial skeletal structure. This study informs the interpretation of facial phenotype assessed by this craniofacial photographic method which can be applied to future studies of craniofacial phenotype in OSA.

Phenotyping obstructive sleep apnoea-Bringing precision to oral appliance therapy.

Obstructive Sleep Apnoea (OSA) is a highly prevalent disorder across the world and is characterised by repeated obstruction of the pharyngeal airway during sleep, resulting in oxygen desaturation (intermittent hypoxia) and sleep fragmentation. As awareness of the disorder has risen over the last few decades, there is growing recognition that OSA is a highly heterogeneous disorder, and that application of a precision medicine framework to its treatment could significantly enhance patient outcomes by allowing prediction of who has OSA, who needs it treated, who is susceptible to symptoms and comorbidities, which treatment should be used and who will respond to therapy. To achieve this, there is a need to develop an understanding of intermediate OSA phenotypes in terms of their contribution to disease pathogenesis, clinical and physiological expression and treatment responses. Recently, there have been an increasing number of studies using unsupervised (cluster) analytical approaches that have generated new insights, demonstrating the viability of a precision medicine approach in sleep medicine. These advances will undoubtedly influence the emerging field of dental sleep medicine, and dentists need to be aware of these developments.