An epigenetic increase in mitochondrial fission by MiD49 and MiD51 regulates the cell cycle in cancer: Diagnostic and therapeutic implications.

Excessive proliferation and apoptosis-resistance are hallmarks of cancer. Increased dynamin-related protein 1 (Drp1)-mediated mitochondrial fission is one of the mediators of this phenotype. Mitochondrial fission that accompanies the nuclear division is called mitotic fission and occurs when activated Drp1 binds partner proteins on the outer mitochondrial membrane. We examine the role of Drp1-binding partners, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51), as drivers of cell proliferation and apoptosis-resistance in non-small cell lung cancer (NSCLC) and invasive breast carcinoma (IBC). We also evaluate whether inhibiting MiDs can be therapeutically exploited to regress cancer. We show that MiD levels are pathologically elevated in NSCLC and IBC by an epigenetic mechanism (decreased microRNA-34a-3p expression). MiDs silencing causes cell cycle arrest through (a) increased expression of cell cycle inhibitors, p27Kip1 and p21Waf1 , (b) inhibition of Drp1, and (c) inhibition of the Akt-mTOR-p70S6K pathway. Silencing MiDs leads to mitochondrial fusion, cell cycle arrest, increased apoptosis, and tumor regression in a xenotransplant NSCLC model. There are positive correlations between MiD expression and tumor size and grade in breast cancer patients and inverse correlations with survival in NSCLC patients. The microRNA-34a-3p-MiDs axis is important to cancer pathogenesis and constitutes a new therapeutic target.

Ndufs2, a Core Subunit of Mitochondrial Complex I, Is Essential for Acute Oxygen-Sensing and Hypoxic Pulmonary Vasoconstriction.

RATIONALE: Hypoxic pulmonary vasoconstriction (HPV) optimizes systemic oxygen delivery by matching ventilation to perfusion. HPV is intrinsic to pulmonary artery smooth muscle cells (PASMCs). Hypoxia dilates systemic arteries, including renal arteries. Hypoxia is sensed by changes in mitochondrial-derived reactive oxygen species, notably hydrogen peroxide (H2O2) ([H2O2]mito). Decreases in [H2O2]mito elevate pulmonary vascular tone by increasing intracellular calcium ([Ca2+]i) through reduction-oxidation regulation of ion channels. Although HPV is mimicked by the Complex I inhibitor, rotenone, the molecular identity of the O2 sensor is unknown. OBJECTIVE: To determine the role of Ndufs2 (NADH [nicotinamide adenine dinucleotide] dehydrogenase [ubiquinone] iron-sulfur protein 2), Complex I's rotenone binding site, in pulmonary vascular oxygen-sensing. METHODS AND RESULTS: Mitochondria-conditioned media from pulmonary and renal mitochondria isolated from normoxic and chronically hypoxic rats were infused into an isolated lung bioassay. Mitochondria-conditioned media from normoxic lungs contained more H2O2 than mitochondria-conditioned media from chronic hypoxic lungs or kidneys and uniquely attenuated HPV via a catalase-dependent mechanism. In PASMC, acute hypoxia decreased H2O2 within 112±7 seconds, followed, within 205±34 seconds, by increased intracellular calcium concentration, [Ca2+]i. Hypoxia had no effects on [Ca2+]i in renal artery SMC. Hypoxia decreases both cytosolic and mitochondrial H2O2 in PASMC while increasing cytosolic H2O2 in renal artery SMC. Ndufs2 expression was greater in PASMC versus renal artery SMC. Lung Ndufs2 cysteine residues became reduced during acute hypoxia and both hypoxia and reducing agents caused functional inhibition of Complex I. In PASMC, siNdufs2 (cells/tissue treated with Ndufs2 siRNA) decreased normoxic H2O2, prevented hypoxic increases in [Ca2+]i, and mimicked aspects of chronic hypoxia, including decreasing Complex I activity, elevating the nicotinamide adenine dinucleotide (NADH/NAD+) ratio and decreasing expression of the O2-sensitive ion channel, Kv1.5. Knocking down another Fe-S center within Complex I (Ndufs1, NADH [nicotinamide adenine dinucleotide] dehydrogenase [ubiquinone] iron-sulfur protein 1) or other mitochondrial subunits proposed as putative oxygen sensors (Complex III's Rieske Fe-S center and COX4i2 [cytochrome c oxidase subunit 4 isoform 2] in Complex IV) had no effect on hypoxic increases in [Ca2+]i. In vivo, siNdufs2 significantly decreased hypoxia- and rotenone-induced constriction while enhancing phenylephrine-induced constriction. CONCLUSIONS: Ndufs2 is essential for oxygen-sensing and HPV.

Evaluating bowel enterotomy closures in simulated deep body cavities using the reversing half-hitch alternating post and square knots: a randomized controlled trial.

Background: Square knots can be difficult to construct in deep body cavities. The reversing half-hitch alternating post (RHAP) surgical knot has noninferior tensile strength and performance characteristics in deep body cavities. We compared the enterotomy repairs of novice learners in simulated deep body cavities using RHAP versus square knots after proficiency-based training. Methods: Undergraduate students were randomized to RHAP (n = 10) or square knot (n = 10) groups and trained to defined proficiency. They then performed hand-sewn enterotomy repairs of cadaveric porcine small bowels on flat surfaces and in simulated deep body cavities. We recorded time to knot-tying proficiency and to enterotomy repair, and burst pressures for the repair. Results: Mean time-to-proficiency in knot tying was equivalent between the RHAP and square knot groups (23 [standard deviation (SD) 3] v. 21 [SD 2] min, p = 0.33). Mean time for enterotomy repair in deep cavities was shorter for the RHAP group (16 [SD 2] min v. 21 [SD 1] min, p = 0.02). Mean burst pressures for enterotomy repair were equivalent on flat surfaces (128 [SD 41] v. 101 [SD 36] mm Hg, p = 0.31), and were significantly higher for the RHAP group in simulated deep body cavities (32 [SD 13] v. 105 [SD 37] mm Hg, p = 0.05). Conclusion: The RHAP knots appear to have superior performance versus square knots when tied in a deep body cavity by novice learners. Future work should focus on demonstrating the clinical relevance and broad utility of the RHAP knot in abdominal surgery. Both knot types should be taught to novice learners.

Contexte: L'exécution de noeuds plats peut être difficile dans les cavités corporelles profondes. Les noeuds de type demi-clé inversée alternée (RHAP, pour reversing halfhitch alternating post) ont une résistance à la traction et un rendement semblables à ceux des noeuds plats dans ces cavités. Nous avons comparé l'efficacité des noeuds plats et des noeuds de type RHAP réalisés par de nouveaux apprenants dans des cavités profondes simulées, après leur avoir enseigné les compétences nécessaires. Méthodes: Les étudiants de premier cycle ont été aléatoirement répartis en 2 groupes, soit le groupe RHAP (n = 10) et le groupe noeud plat (n = 10), et ont reçu une formation pour développer des compétences prédéfinies. Ils ont ensuite suturé à la main un intestin grêle provenant d'un cadavre de porc, sur une surface plane et à l'intérieur d'une cavité profonde simulée. Nous avons mesuré le temps nécessaire à l'exécution du noeud et à la suture complète de l'incision, de même que la pression que pouvait subir cette suture sans se rompre. Résultats: Le temps moyen d'exécution du noeud était semblable entre les groupes RHAP et noeud plat (23 min [écart type (E.T.) 3 min] c. 21 min [E.T. 2 min]; p = 0,33). Le temps moyen nécessaire à la suture de l'incision dans la cavité profonde était plus court dans le groupe RHAP (16 min [E.T. 2 min] c. 21 min [E.T. 1 min]; p = 0,02). La pression moyenne que pouvait subir la suture sans se rompre était comparable pour les sutures effectuées sur une surface plane (128 mm Hg [E.T. 41 mm Hg] c. 101 mm Hg [E.T. 36 mm Hg]; p = 0,31), mais était significativement plus élevée dans le groupe RHAP pour les sutures faites dans la cavité profonde (32 mm Hg [E.T. 13 mm Hg] c. 105 mm Hg [E.T. 37 mm Hg], p = 0,05). Conclusion: Les noeuds de type RHAP semblent avoir un rendement supérieur à celui des noeuds plats lorsqu'ils sont réalisés dans une cavité profonde par de nouveaux apprenants. Des études ultérieures devraient se pencher sur la pertinence clinique et l'utilité générale de ces noeuds en chirurgie abdominale. Les 2 types de noeuds devraient être enseignés aux nouveaux apprenants.

Pharyngitis: Approach to diagnosis and treatment.

OBJECTIVE: To provide family physicians with an updated approach to diagnosis and treatment of pharyngitis, detailing key symptoms, methods of investigation, and a summary of common causes. SOURCES OF INFORMATION: The approach described is based on the authors' clinical practice and peer-reviewed literature from 1989 to 2018. MAIN MESSAGE: Sore throat caused by pharyngitis is commonly seen in family medicine clinics and is caused by inflammation of the pharynx and surrounding tissues. Pharyngitis can be caused by viral, bacterial, or fungal infections. Viral causes are often self-limiting, while bacterial and fungal infections typically require antimicrobial therapy. Rapid antigen detection tests and throat cultures can be used with clinical findings to identify the inciting organism. Pharyngitis caused by Streptococcus pyogenes is among the most concerning owing to its associated severe complications such as acute rheumatic fever and glomerulonephritis. Hence, careful diagnosis of pharyngitis is necessary to provide targeted treatment. CONCLUSION: A thorough history is key to diagnosing pharyngitis. Rapid antigen detection tests should be reserved for concerns about antibiotic initiation. Physicians should exercise restraint in antibiotic initiation for pharyngitis, as restraint does not delay recovery or increase the risk of S pyogenes infections.

Tailoring nanoparticle designs to target cancer based on tumor pathophysiology.

Nanoparticles can provide significant improvements in the diagnosis and treatment of cancer. How nanoparticle size, shape, and surface chemistry can affect their accumulation, retention, and penetration in tumors remains heavily investigated, because such findings provide guiding principles for engineering optimal nanosystems for tumor targeting. Currently, the experimental focus has been on particle design and not the biological system. Here, we varied tumor volume to determine whether cancer pathophysiology can influence tumor accumulation and penetration of different sized nanoparticles. Monte Carlo simulations were also used to model the process of nanoparticle accumulation. We discovered that changes in pathophysiology associated with tumor volume can selectively change tumor uptake of nanoparticles of varying size. We further determine that nanoparticle retention within tumors depends on the frequency of interaction of particles with the perivascular extracellular matrix for smaller nanoparticles, whereas transport of larger nanomaterials is dominated by Brownian motion. These results reveal that nanoparticles can potentially be personalized according to a patient's disease state to achieve optimal diagnostic and therapeutic outcomes.

Approach to Ménière disease management.

OBJECTIVE: To provide family physicians with an updated approach to the diagnosis and management of Ménière disease (MD), detailing the natural course of MD and describing how to initiate medical therapy while awaiting consultation with otolaryngology-head and neck surgery. SOURCES OF INFORMATION: The approach is based on the authors' clinical practices and review articles from 1989 to 2018. Most of the cited studies provided level II or III evidence. MAIN MESSAGE: Ménière disease is an uncommon disorder of the inner ear causing vertigo attacks with associated unilateral hearing loss, tinnitus, and aural fullness. It has a degenerative course that often results in permanent sensorineural hearing loss. On average, MD stabilizes with no further vestibular attacks by about 8 years after the onset of symptoms; however, this is highly variable. Vertigo symptoms can be controlled through a combination of dietary salt restriction, stress reduction, and medical therapy (betahistine, diuretics, or both). These can be initiated by family physicians before consultation with otolaryngology-head and neck surgery. Symptoms refractory to such strategies can be treated using nonablative, and occasionally ablative, therapies. CONCLUSION: A thorough history is key to the approach to and management of MD and permits differentiating MD from other vestibular and nonvestibular conditions.

Comparison of knot-tying proficiency and knot characteristics for square and reversing half hitch alternating-post surgical knots in a simulated deep body cavity among notice medical students.

BACKGROUND: Proficiency-based knot-tying curricula have been developed for square knots for medical students, but, to our knowledge, no such curriculum exists for the reverse half hitch alternating-post (RHAP) knot. We aimed to compare medical students' knot-tying proficiency, knot-tying self-confidence and final knot characteristics for RHAP and square knots in a simulated deep body cavity. METHODS: We performed a within-subject prospective crossover study of novice medical students who received 30 minutes of training in tying both RHAP and square knots. Participant performance was assessed via a knot-tying checklist, and knot configuration, tensile strength, tightness (loop circumference) and mechanism of failure were also assessed. Participants' self-reported confidence in knot tying was captured. RESULTS: Twenty-one students participated in the study. Mean scores on the knot-tying checklist were significantly higher for RHAP knots than for square knots (6.9 [standard deviation (SD) 2.1] v. 5.2 [SD 2.3], p < 0.01), and RHAP knots were significantly tighter than square knots (46.8 mm [SD 0.4 mm] v. 49.3 mm [SD 0.7 mm], p < 0.05). There were no differences between RHAP and square knots in correct knot configuration, breaking strength or mechanism of failure. Reverse half hitch alternating-post knots were easier to tie within a deep-body cavity, whereas square knots were easier to learn. CONCLUSION: Novice medical students were more proficient in tying RHAP knots than square knots in a simulated deep body cavity. Students were able to construct RHAP knots more securely and reported increased confidence in tying RHAP knots at depth compared to square knots.

CONTEXTE: Des programmes d'enseignement fondés sur la compétence dans l'exécution de nœuds chirurgicaux par les étudiants en médecine ont été créés pour les nœuds plats, mais autant que nous sachions, un tel programme n'existe pas pour le nœud de type demi-clé inversée alternée. Nous avons comparé les aptitudes d'exécution de nœuds et la confiance des étudiants en médecine, ainsi que les caractéristiques des nœuds résultants, pour les nœuds de type demi-clé inversée alternée et les nœuds plats, dans une simulation de cavité profonde. MÉTHODES: Nous avons réalisé une étude croisée prospective intra-sujet portant sur des étudiants en médecine débutants, qui ont reçu une formation de 30 minutes sur l'exécution de nœuds de type demi-clé inversée alternée et de nœuds plats. Le travail des participants a été évalué à l'aide d'une liste de vérification d'exécution des nœuds; la configuration des nœuds, la résistance à la traction, le serrage (circonférence de la boucle) et le mécanisme de défaillance ont aussi été évalués. La confiance en soi rapportée par les participants quant à leurs aptitudes d'exécution de nœuds a aussi été examinée. RÉSULTATS: Vingt-et-un étudiants ont pris part à cette étude. Les scores moyens de la liste de vérification d'exécution des nœuds étaient significativement plus élevés pour les nœuds de type demi-clé inversée alternée que pour les nœuds plats (6,9 [écart-type (É.T.) : 2,1] contre 5,2 [É.T. : 2,3], p < 0,01), et les nœuds demi-clé inversée alternée étaient significativement plus serrés que les nœuds plats (46,8 mm [É.T. : 0,4 mm] contre 49,3 mm [É.T. : 0,7 mm], p < 0,05). Aucune différence n'a été observée entre les 2 types de nœuds quant à la configuration, à la résistance à la traction et au mécanisme de défaillance. Les nœuds de type demi-clé inversée alternée étaient plus faciles à nouer dans une cavité profonde, mais la technique des nœuds plats était plus simple à apprendre. CONCLUSION: Les aptitudes des étudiants en médecine débutants pour l'exécution de nœuds de type demi-clé inversée alternée étaient supérieures à leurs aptitudes pour l'exécution de nœuds plats, lors d'une simulation de cavité profonde. Les étudiants ont pu réaliser des nœuds de type demi-clé inversée alternée plus solides et ont rapporté une confiance plus grande quant à l'exécution de ce type de nœuds que pour l'exécution de nœuds plats en profondeur.

Mechanism of hard-nanomaterial clearance by the liver.

The liver and spleen are major biological barriers to translating nanomedicines because they sequester the majority of administered nanomaterials and prevent delivery to diseased tissue. Here we examined the blood clearance mechanism of administered hard nanomaterials in relation to blood flow dynamics, organ microarchitecture and cellular phenotype. We found that nanomaterial velocity reduces 1,000-fold as they enter and traverse the liver, leading to 7.5 times more nanomaterial interaction with hepatic cells relative to peripheral cells. In the liver, Kupffer cells (84.8 ± 6.4%), hepatic B cells (81.5 ± 9.3%) and liver sinusoidal endothelial cells (64.6 ± 13.7%) interacted with administered PEGylated quantum dots, but splenic macrophages took up less material (25.4 ± 10.1%) due to differences in phenotype. The uptake patterns were similar for two other nanomaterial types and five different surface chemistries. Potential new strategies to overcome off-target nanomaterial accumulation may involve manipulating intra-organ flow dynamics and modulating the cellular phenotype to alter hepatic cell interactions.

Comparing the tensile strength of square and reversing half-hitch alternating post knots.

BACKGROUND: Square knots are the gold standard in hand-tie wound closure, but are difficult to reproduce in deep cavities, inadvertently resulting in slipknots. The reversing half-hitch alternating post (RHAP) knot has been suggested as an alternative owing to its nonslip nature and reproducibility in limited spaces. We explored whether the RHAP knot is noninferior to the square knot by assessing tensile strength. METHODS: We conducted 10 trials for each baseline and knot configuration, using 3-0 silk and 3-0 polyglactin 910 sutures. We compared tensile strength between knot configurations at the point of knot failure between slippage and breakage. RESULTS: Maximal failure strength (mean ± SD) in square knots was reached with 4-throw in both silk (30 ± 1.5 N) and polyglactin 910 (39 ± 12 N). For RHAP knots, maximal failure strength was reached at 5-throw for both silk (31 ± 1.5 N) and polyglactin 910 (41 ± 13 N). In both sutures, there were no strength differences between 3-throw square and 4-throw RHAP, between 4-throw square and 5-throw RHAP, or between 5-throw square and 6-throw RHAP knots. Polyglactin 910 sutures, in all knot configurations, were more prone to slippage than silk sutures (p < 0.001). CONCLUSION: The difference in mean tensile strength could be attributed to the proportion of knot slippage versus breakage, which is material-dependent. Future studies can re-evaluate findings in monofilament sutures and objectively assess the reproducibility of square and RHAP knots in deep cavities. Our results indicate that RHAP knots composed of 1 extra throw provide equivalent strength to square knots and may be an alternative when performing hand-ties in limited cavities with either silk or polyglactin 910 sutures.

CONTEXTE: Les nœuds plats sont la norme en matière de points de suture manuels, mais ils sont difficiles à reproduire dans des cavités profondes et deviennent par inadvertance des nœuds coulants. Le nœud de type demi-clé inversée alternée a été proposé comme solution de rechange en raison de sa nature non glissante et de sa reproductibilité dans des espaces restreints. Nous avons voulu vérifier la non-infériorité de la demi-clé inversée alternée par rapport au nœud plat en évaluant sa résistance à la traction. MÉTHODES: Nous avons réalisé 10 essais de référence et autant d'essais pour chaque type de nœud, en utilisant des fils de soie de taille 3-0 et de polyglactine 910 de taille 3-0. Nous avons comparé la résistance à la traction des différentes configurations de nœuds, c'est-à-dire le point de défaillance entre le glissement du nœud et la rupture de celui-ci. RÉSULTATS: La résistance maximale à la traction (moyenne ± É.-T.) des nœuds plats a été atteinte avec 4 boucles, tant pour le fil de soie (30 ± 1,5 N) que le fil de polyglactine 910 (39 ± 12 N). Pour les demi-clés inversées alternées, la résistance maximale à la traction a été atteinte avec 5 boucles pour le fil de soie (31 ± 1,5 N) et de polyglactine 910 (41 ± 13 N). Dans les 2 types de sutures, on n'a noté aucune différence de résistance entre le nœud plat à 3 boucles et la demi-clé inversée alternée à 4 boucles, entre le nœud plat à 4 boucles et la demi-clé inversée alternée à 5 boucles, ni entre le nœud plat à 5 boucles et la demi-clé inversée alternée à 6 boucles. Dans tous les types de nœuds, les sutures de polyglactine 910 ont été plus sujettes au glissement que les sutures de soie (p < 0,001). CONCLUSION: La différence de résistance moyenne à la traction a pu être attribuée à la proportion de glissement c. la rupture des nœuds, qui dépend du matériau. D'autres études pourraient réévaluer les résultats obtenus avec des sutures monofilaments et mesurer objectivement la reproductibilité des nœuds plats et des demi-clés inversées alternées dans des cavités profondes. Selon nos résultats, les demi-clés inversées alternées comportant une boucle supplémentaire offrent une résistance équivalente à celle des nœuds plats et seraient une solution de rechange lors de sutures manuelles dans des cavités restreintes, avec la soie ou la polyglactine 910.

Pharyngite: Approche diagnostique et thérapeutique.

OBJECTIF: Offrir aux médecins de famille une approche diagnostique et thérapeutique actualisée de la pharyngite, en décrivant en détail les principaux symptômes, les méthodes d'investigation et un résumé des causes courantes. SOURCES D'INFORMATION: L'approche décrite est basée sur la pratique clinique des auteurs et sur les publications revues par les pairs de 1989 à 2018. MESSAGE PRINCIPAL: Le mal de gorge causé par la pharyngite est couramment observé dans les cliniques de médecine familiale; il est causé par l'inflammation du pharynx et des tissus environnants. La pharyngite est causée par une infection virale, bactérienne ou fongique. Les causes virales sont souvent spontanément résolutives, alors que les infections bactériennes et fongiques nécessitent habituellement l'antibiothérapie. Le test de détection rapide de l'antigène et la culture de gorge sont jumelés aux observations cliniques pour identifier l'organisme en cause. La pharyngite causée par streptococcus pyogenes fait partie des organismes les plus préoccupants en raison de ses complications graves, telles la fièvre rhumatismale aiguë et la glomérulonéphrite. Ainsi, il est nécessaire de poser un diagnostic attentif de pharyngite afin de pouvoir dispenser un traitement ciblé. CONCLUSION: L'anamnèse détaillée est la clé du diagnostic de pharyngite. Le test de détection rapide de l'antigène doit être réservé aux cas où l'instauration de l'antibiothérapie est préoccupante. Les médecins doivent user de retenue lorsqu'ils instaurent l'antibiothérapie contre la pharyngite, puisque la retenue ne retarde pas le rétablissement ni n'augmente le risque d'infection à s. pyogenes.

Approche à adopter pour la prise en charge de la maladie de Ménière.

OBJECTIF: Fournir aux médecins de famille une approche actualisée pour le diagnostic et la prise en charge de la maladie de Ménière, décrivant en détail l'évolution naturelle de la maladie de Ménière et la façon d'instaurer un traitement médical en attendant une consultation en otorhinolaryngologie­chirurgie cervico-faciale. SOURCES DE L'INFORMATION: L'approche se base sur les pratiques cliniques des auteurs et sur des articles de synthèse publiés entre 1989 et 2018. La plupart des études citées ont fourni des données probantes de niveau II ou III. MESSAGE PRINCIPAL: La maladie de Ménière est une affection peu fréquente de l'oreille interne, qui cause des crises de vertige et qui est associée à une perte auditive unilatérale, un acouphène et une sensation de plénitude auditive. La maladie est dégénérative et entraîne souvent une perte auditive neurosensorielle permanente. En moyenne, la maladie de Ménière se stabilise sans autre crise vestibulaire environ 8 ans après l'apparition des symptômes; cela est cependant très variable. Les symptômes de vertige peuvent être maîtrisés en combinant une alimentation hyposodée, une réduction du stress et un traitement médical (bétahistine, diurétiques ou les 2). Ces interventions peuvent être instaurées par le médecin de famille avant la consultation en otorhinolaryngologie­chirurgie cervico-faciale. Les symptômes réfractaires à ces interventions sont traités par l'entremise de traitements non ablatifs et, occasionnellement, ablatifs. CONCLUSION: Une anamnèse détaillée est la clé de l'approche à adopter pour la prise en charge de la maladie de Ménière et permet de différencier la maladie de Ménière des autres affections vestibulaires et non vestibulaires.

Methods, Detection Rates, and Survival Outcomes of Screening for Head and Neck Cancers: A Systematic Review.

Importance: Head and neck cancers (HNCs) are often diagnosed at advanced clinical stages during their symptomatic phase, leading to a reduced treatment window and poor survival. Screening programs have been suggested as a mitigation strategy. Objective: To examine the effectiveness of current HNC screening programs in improving diagnosis and survival in adults. Evidence Review: This Preferred Reporting Items for Systematic Reviews and Meta-analyses-guided systematic review involved use of peer-reviewed, English-language journal articles identified from MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials between January 1, 2001, and July 15, 2022. Snowballing was applied to retrieve more studies. Eligible articles were original clinical trials and observational studies presenting a universal or risk-targeted screening program of primary HNC in the adult population. Reporting quality was assessed using the JBI's critical appraisal tools. Findings: Database searches yielded 3646 unique citations with an additional 8 studies found via snowballing. Five reviewers assessed the full text of 106 studies. Sixteen articles were ultimately included in the review, involving 4.7 million adults (34.1%-100% male; median age, 30-59 years). Fifteen studies were based in Asia and 1 in Europe (Portugal). Five reported data from randomized clinical trials. An oral inspection conducted once or once every 2 to 3 years was described in 11 studies for screening oral cancer, while multistep screening involving Epstein-Barr virus serologic testing for nasopharyngeal carcinoma delivered every 1 to 4 years was presented in 5. In 4 trials and 6 observational studies, screening significantly increased the detection of localized (stage I/II) tumor or was associated with an increased proportion of diagnoses, respectively, regardless of the population and cancer subsites. Universal screening of asymptomatic adults improved 3- to 5-year overall survival but did not increase cancer-specific survival in 4 trials. Targeted screening improved overall and cancer-specific survival or was associated with improved survival outcomes in 2 trials and 2 observational studies, respectively. Studies had low to medium risks of bias. Conclusions and Relevance: Evidence from the existing literature suggests that a risk-targeted screening program for oral and nasopharyngeal cancers could improve diagnosis and patient survival. Screening adherence, societal cost-effectiveness, and optimal risk stratification of such a program warrant future research, especially in low-incidence settings outside Asia.

Dynamic interaction networks in a hierarchically organized tissue.

Intercellular (between cell) communication networks maintain homeostasis and coordinate regenerative and developmental cues in multicellular organisms. Despite the importance of intercellular networks in stem cell biology, their rules, structure and molecular components are poorly understood. Herein, we describe the structure and dynamics of intercellular and intracellular networks in a stem cell derived, hierarchically organized tissue using experimental and theoretical analyses of cultured human umbilical cord blood progenitors. By integrating high-throughput molecular profiling, database and literature mining, mechanistic modeling, and cell culture experiments, we show that secreted factor-mediated intercellular communication networks regulate blood stem cell fate decisions. In particular, self-renewal is modulated by a coupled positive-negative intercellular feedback circuit composed of megakaryocyte-derived stimulatory growth factors (VEGF, PDGF, EGF, and serotonin) versus monocyte-derived inhibitory factors (CCL3, CCL4, CXCL10, TGFB2, and TNFSF9). We reconstruct a stem cell intracellular network, and identify PI3K, Raf, Akt, and PLC as functionally distinct signal integration nodes, linking extracellular, and intracellular signaling. This represents the first systematic characterization of how stem cell fate decisions are regulated non-autonomously through lineage-specific interactions with differentiated progeny.

Cell-cell interaction networks regulate blood stem and progenitor cell fate.

Communication networks between cells and tissues are necessary for homeostasis in multicellular organisms. Intercellular (between cell) communication networks are particularly relevant in stem cell biology, as stem cell fate decisions (self-renewal, proliferation, lineage specification) are tightly regulated based on physiological demand. We have developed a novel mathematical model of blood stem cell development incorporating cell-level kinetic parameters as functions of secreted molecule-mediated intercellular networks. By relation to quantitative cellular assays, our model is capable of predictively simulating many disparate features of both normal and malignant hematopoiesis, relating internal parameters and microenvironmental variables to measurable cell fate outcomes. Through integrated in silico and experimental analyses, we show that blood stem and progenitor cell fate is regulated by cell-cell feedback, and can be controlled non-cell autonomously by dynamically perturbing intercellular signalling. We extend this concept by demonstrating that variability in the secretion rates of the intercellular regulators is sufficient to explain heterogeneity in culture outputs, and that loss of responsiveness to cell-cell feedback signalling is both necessary and sufficient to induce leukemic transformation in silico.

A digital microfluidic system for serological immunoassays in remote settings.

Serosurveys are useful for assessing population susceptibility to vaccine-preventable disease outbreaks. Although at-risk populations in remote areas could benefit from this type of information, they face several logistical barriers to implementation, such as lack of access to centralized laboratories, cold storage, and transport of samples. We describe a potential solution: a compact and portable, field-deployable, point-of-care system relying on digital microfluidics that can rapidly test a small volume of capillary blood for disease-specific antibodies. This system uses inexpensive, inkjet-printed digital microfluidic cartridges together with an integrated instrument to perform enzyme-linked immunosorbent assays (ELISAs). We performed a field validation of the system's analytical performance at Kakuma refugee camp, a remote setting in northwestern Kenya, where we tested children aged 9 to 59 months and caregivers for measles and rubella immunoglobulin G (IgG). The IgG assays were determined to have sensitivities of 86% [95% confidence interval (CI), 79 to 91% (measles)] and 81% [95% CI, 73 to 88% (rubella)] and specificities of 80% [95% CI, 49 to 94% (measles)] and 91% [95% CI, 76 to 97% (rubella)] (measles, n = 140; rubella, n = 135) compared with reference tests (measles IgG and rubella IgG ELISAs from Siemens Enzygnost) conducted in a centralized laboratory. These results demonstrate a potential role for this point-of-care system in global serological surveillance, particularly in remote areas with limited access to centralized laboratories.

Hypoxic Pulmonary Vasoconstriction: From Molecular Mechanisms to Medicine.

Hypoxic pulmonary vasoconstriction (HPV) is a homeostatic mechanism that is intrinsic to the pulmonary vasculature. Intrapulmonary arteries constrict in response to alveolar hypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation/perfusion matching and systemic oxygen delivery. In response to alveolar hypoxia, a mitochondrial sensor dynamically changes reactive oxygen species and redox couples in pulmonary artery smooth muscle cells (PASMC). This inhibits potassium channels, depolarizes PASMC, activates voltage-gated calcium channels, and increases cytosolic calcium, causing vasoconstriction. Sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and hypoxia-inducible factor (HIF)-1α, leading to adverse pulmonary vascular remodeling and pulmonary hypertension (PH). In the nonventilated fetal lung, HPV diverts blood to the systemic vasculature. After birth, HPV commonly occurs as a localized homeostatic response to focal pneumonia or atelectasis, which optimizes systemic Po2 without altering pulmonary artery pressure (PAP). In single-lung anesthesia, HPV reduces blood flow to the nonventilated lung, thereby facilitating thoracic surgery. At altitude, global hypoxia causes diffuse HPV, increases PAP, and initiates PH. Exaggerated or heterogeneous HPV contributes to high-altitude pulmonary edema. Conversely, impaired HPV, whether due to disease (eg, COPD, sepsis) or vasodilator drugs, promotes systemic hypoxemia. Genetic and epigenetic abnormalities of this oxygen-sensing pathway can trigger normoxic activation of HIF-1α and can promote abnormal metabolism and cell proliferation. The resulting pseudohypoxic state underlies the Warburg metabolic shift and contributes to the neoplasia-like phenotype of PH. HPV and oxygen sensing are important in human health and disease.

Nanoparticle-blood interactions: the implications on solid tumour targeting.

Nanoparticles are suitable platforms for cancer targeting and diagnostic applications. Typically, less than 10% of all systemically administered nanoparticles accumulate in the tumour. Here we explore the interactions of blood components with nanoparticles and describe how these interactions influence solid tumour targeting. In the blood, serum proteins adsorb onto nanoparticles to form a protein corona in a manner dependent on nanoparticle physicochemical properties. These serum proteins can block nanoparticle tumour targeting ligands from binding to tumour cell receptors. Additionally, serum proteins can also encourage nanoparticle uptake by macrophages, which decreases nanoparticle availability in the blood and limits tumour accumulation. The formation of this protein corona will also increase the nanoparticle hydrodynamic size or induce aggregation, which makes nanoparticles too large to enter into the tumour through pores of the leaky vessels, and prevents their deep penetration into tumours for cell targeting. Recent studies have focused on developing new chemical strategies to reduce or eliminate serum protein adsorption, and rescue the targeting potential of nanoparticles to tumour cells. An in-depth and complete understanding of nanoparticle-blood interactions is key to designing nanoparticles with optimal physicochemical properties with high tumour accumulation. The purpose of this review article is to describe how the protein corona alters the targeting of nanoparticles to solid tumours and explains current solutions to solve this problem.

Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency.

Understanding the principles governing the design of nanoparticles for tumor targeting is essential for the effective diagnosis and treatment of solid tumors. There is currently a poor understanding of how to rationally engineer nanoparticles for tumor targeting. Here, we engineered different-sized spherical gold nanoparticles to discern the effect of particle diameter on passive (poly(ethylene glycol)-coated) and active (transferrin-coated) targeting of MDA-MB-435 orthotopic tumor xenografts. Tumor accumulation of actively targeted nanoparticles was found to be 5 times faster and approximately 2-fold higher relative to their passive counterparts within the 60 nm diameter range. For 15, 30, and 100 nm, we observed no significant differences. We hypothesize that such enhancements are the result of an increased capacity to penetrate into tumors and preferentially associate with cancer cells. We also use computational modeling to explore the mechanistic parameters that can impact tumor accumulation efficacy. We demonstrate that tumor accumulation can be mediated by high nanoparticle avidity and are weakly dependent on their plasma clearance rate. Such findings suggest that empirical models can be used to rapidly screen novel nanomaterials for relative differences in tumor targeting without the need for animal work. Although our findings are specific to MDA-MB-435 tumor xenografts, our experimental and computational findings help to enrich knowledge of design considerations that will aid in the optimal engineering of spherical gold nanoparticles for cancer applications in the future.

Nanoparticle exposure in animals can be visualized in the skin and analysed via skin biopsy.

The increasing use of nanomaterials raises concerns about the long-term effects of chronic nanoparticle exposure on human health. However, nanoparticle exposure is difficult to evaluate non-invasively using current measurement techniques. Here we show that the skin is an important site of nanoparticle accumulation following systemic administration. Mice injected with high doses of gold nanoparticles have visibly blue skin while quantum dot-treated animals fluoresce under ultraviolet excitation. More importantly, elemental analysis of excised skin correlates with the injected dose and nanoparticle accumulation in the liver and spleen. We propose that skin analysis may be a simple strategy to quantify systemic nanoparticle exposure and predict nanoparticle fate in vivo. Our results suggest that in the future, dermal accumulation may also be exploited to trigger the release of ultraviolet and visible light-sensitive therapeutics that are currently impractical in vivo due to limits in optical penetration of tissues at these wavelengths.

Tumour-on-a-chip provides an optical window into nanoparticle tissue transport.

Nanomaterials are used for numerous biomedical applications, but the selection of optimal properties for maximum delivery remains challenging. Thus, there is a significant interest in elucidating the nano-bio interactions underlying tissue accumulation. To date, researchers have relied on cell culture or animal models to study nano-bio interactions. However, cell cultures lack the complexity of biological tissues and animal models are prohibitively slow and expensive. Here we report a tumour-on-a-chip system where incorporation of tumour-like spheroids into a microfluidic channel permits real-time analysis of nanoparticle (NP) accumulation at physiological flow conditions. We show that penetration of NPs into the tissue is limited by their diameter and that retention can be improved by receptor targeting. NP transport is predominantly diffusion-limited with convection improving accumulation mostly at the tissue perimeter. A murine tumour model confirms these findings and demonstrates that the tumour-on-a-chip can be useful for screening optimal NP designs prior to in vivo studies.