Tumour draining lymph node-generated CD8 T cells play a role in controlling lung metastases after a primary tumour is removed but not when adjuvant immunotherapy is used.

Surgical resection of cancer remains the frontline therapy for millions of patients annually, but post-operative recurrence is common, with a relapse rate of around 45% for non-small cell lung cancer. The tumour draining lymph nodes (dLN) are resected at the time of surgery for staging purposes, and this cannot be a null event for patient survival and future response to immune checkpoint blockade treatment. This project investigates cancer surgery, lymphadenectomy, onset of metastatic disease, and response to immunotherapy in a novel model that closely reflects the clinical setting. In a murine metastatic lung cancer model, primary subcutaneous tumours were resected with associated dLNs remaining intact, completely resected or partially resected. Median survival after surgery was significantly shorter with complete dLN resection at the time of surgery (49 days (95%CI)) compared to when lymph nodes remained intact (> 88 days; p < 0.05). Survival was partially restored with incomplete lymph node resection and CD8 T cell dependent. Treatment with aCTLA4 whilst effective against the primary tumour was ineffective for metastatic lung disease. Conversely, aPD-1/aCD40 treatment was effective in both the primary and metastatic disease settings and restored the detrimental effects of complete dLN resection on survival. In this pre-clinical lung metastatic disease model that closely reflects the clinical setting, we observe decreased frequency of survival after complete lymphadenectomy, which was ameliorated with partial lymph node removal or with early administration of aPD-1/aCD40 therapy. These findings have direct relevance to surgical lymph node resection and adjuvant immunotherapy in lung cancer, and perhaps other cancer, patients.

Bladderworts, the smallest known suction feeders, generate inertia-dominated flows to capture prey.

Aquatic bladderworts (Utricularia gibba and U. australis) capture zooplankton in mechanically triggered underwater traps. With characteristic dimensions less than 1 mm, the trapping structures are among the smallest known to capture prey by suction, a mechanism that is not effective in the creeping-flow regime where viscous forces prevent the generation of fast and energy-efficient suction flows. To understand what makes suction feeding possible on the small scale of bladderwort traps, we characterised their suction flows experimentally (using particle image velocimetry) and mathematically (using computational fluid dynamics and analytical mathematical models). We show that bladderwort traps avoid the adverse effects of creeping flow by generating strong, fast-onset suction pressures. Our findings suggest that traps use three morphological adaptations: the trap walls' fast release of elastic energy ensures strong and constant suction pressure; the trap door's fast opening ensures effectively instantaneous onset of suction; the short channel leading into the trap ensures undeveloped flow, which maintains a wide effective channel diameter. Bladderwort traps generate much stronger suction flows than larval fish with similar gape sizes because of the traps' considerably stronger suction pressures. However, bladderworts' ability to generate strong suction flows comes at considerable energetic expense.

Applied global health diplomacy: profile of health diplomats accredited to the UNITED STATES and foreign governments.

BACKGROUND: Global health diplomacy (GHD) is a burgeoning field bridging the priorities of global health and foreign affairs. Given the increasing need to mobilize disparate global health stakeholders coupled with the need to design complex public health partnerships to tackle issues of international concern, effective and timely cooperation among state actors is critical. Health Attachés represent this coordination focal point and are key diplomatic professionals at the forefront of GHD. Despite their unique mandate, little is published about this profession and the perspectives of those who work in the field. METHODS: Through purposive sampling, we performed in-depth qualitative interviews with seven Health Attachés: three foreign Health Attachés accredited to the United States and four U.S. Health Attachés accredited to foreign governments. Our interviews explored four key topics: the role and mission of Health Attachés, skills needed to perform GHD, examples of successes and challenges in accomplishing their respective missions, and suggestions for the future development of the diplomatic profession. RESULTS: We identified several lessons to apply to the growing field of GHD. First, GHD actors need to receive appropriate training to successfully negotiate the intersection of global health and foreign affairs. Participants suggested several areas of training that would benefit GHD actors: diplomacy and negotiation, applied science, and cross-cultural competency. Second, participants articulated the need for a career path for GHD practitioners, increased opportunities for on-the-job training and mentored experiences, and GHD competencies with defined levels of mastery that can be used in occupational evaluation and career development. CONCLUSIONS: Our findings indicate that skills in diplomacy and negotiation, applied science, and cross cultural competency are essential for the statecraft of Health Attachés. Additionally, establishing a clear career pathway for Health Attachés is critical for future maturation of the profession and for fostering effective global health action that aligns public health and foreign diplomacy outcomes. Achieving these goals would ensure that this special cadre of diplomats could effectively practice GHD and would also better position Health Attachés to take the lead in advancing shared global health goals among nation states in a new era of twenty-first century diplomacy.

Multi-campaign ship and aircraft observations of marine cloud condensation nuclei and droplet concentrations.

In-situ marine cloud droplet number concentrations (CDNCs), cloud condensation nuclei (CCN), and CCN proxies, based on particle sizes and optical properties, are accumulated from seven field campaigns: ACTIVATE; NAAMES; CAMP2EX; ORACLES; SOCRATES; MARCUS; and CAPRICORN2. Each campaign involves aircraft measurements, ship-based measurements, or both. Measurements collected over the North and Central Atlantic, Indo-Pacific, and Southern Oceans, represent a range of clean to polluted conditions in various climate regimes. With the extensive range of environmental conditions sampled, this data collection is ideal for testing satellite remote detection methods of CDNC and CCN in marine environments. Remote measurement methods are vital to expanding the available data in these difficult-to-reach regions of the Earth and improving our understanding of aerosol-cloud interactions. The data collection includes particle composition and continental tracers to identify potential contributing CCN sources. Several of these campaigns include High Spectral Resolution Lidar (HSRL) and polarimetric imaging measurements and retrievals that will be the basis for the next generation of space-based remote sensors and, thus, can be utilized as satellite surrogates.

The Salmonella SPI2 effector SseI mediates long-term systemic infection by modulating host cell migration.

Host-adapted strains of Salmonella enterica cause systemic infections and have the ability to persist systemically for long periods of time despite the presence of a robust immune response. Chronically infected hosts are asymptomatic and transmit disease to naïve hosts via fecal shedding of bacteria, thereby serving as a critical reservoir for disease. We show that the bacterial effector protein SseI (also called SrfH), which is translocated into host cells by the Salmonella Pathogenicity Island 2 (SPI2) type III secretion system (T3SS), is required for Salmonella typhimurium to maintain a long-term chronic systemic infection in mice. SseI inhibits normal cell migration of primary macrophages and dendritic cells (DC) in vitro, and such inhibition requires the host factor IQ motif containing GTPase activating protein 1 (IQGAP1), an important regulator of cell migration. SseI binds directly to IQGAP1 and co-localizes with this factor at the cell periphery. The C-terminal domain of SseI is similar to PMT/ToxA, a bacterial toxin that contains a cysteine residue (C1165) that is critical for activity. Mutation of the corresponding residue in SseI (C178A) eliminates SseI function in vitro and in vivo, but not binding to IQGAP1. In addition, infection with wild-type (WT) S. typhimurium suppressed DC migration to the spleen in vivo in an SseI-dependent manner. Correspondingly, examination of spleens from mice infected with WT S. typhimurium revealed fewer DC and CD4(+) T lymphocytes compared to mice infected with Delta sseI S. typhimurium. Taken together, our results demonstrate that SseI inhibits normal host cell migration, which ultimately counteracts the ability of the host to clear systemic bacteria.

IQGAP1 in cellular signaling: bridging the GAP.

IQGAP1 was identified in 1994 as a widely expressed IQ domain-containing protein with a region containing sequence similarity to the Ras GTPase-activating proteins. IQGAP1 has roles in many different aspects of cell physiology and interacts with numerous proteins. It modulates the actin cytoskeleton through Rac1 and Cdc42, and cell-cell adhesion through E-cadherin and beta-catenin. It also regulates the mitogen activated protein kinase pathway, which influences cell proliferation and differentiation. Evidence suggests that IQGAP1 is a scaffold protein that links components of signaling cascades. Here, we evaluate recent data that identify the participation of IQGAP1 in signaling networks and we illustrate how this influences diverse cellular functions. These findings suggest that IQGAP1 integrates signaling pathways and coordinates several fundamental cellular activities.

Hydrodynamics of the bladderwort feeding strike.

The aquatic bladderwort Utricularia gibba captures zooplankton in mechanically triggered underwater traps. With characteristic dimensions <1 mm, the trapping structures are among the smallest known that work by suction-a mechanism that would not be effective in the creeping-flow regime. To understand the adaptations that make suction feeding possible on this small scale, we have measured internal flow speeds during artificially triggered feeding strikes in the absence of prey. These data are compared with complementary analytical models of the suction event: an inviscid model of the jet development in time and a steady-state model incorporating friction. The initial dynamics are well described by a time-dependent Bernoulli equation in which the action of the trap door is represented by a step increase in driving pressure. According to this model, the observed maximum flow speed (5.2 m/s) depends only on the pressure difference, whereas the initial acceleration (3 × 104 m/s2 ) is determined by pressure difference and channel length. Because the terminal speed is achieved quickly (~0.2 ms) and the channel is short, the remainder of the suction event (~2.0 ms) is effectively an undeveloped viscous steady state. The steady-state model predicts that only 17% of power is lost to friction. The energy efficiency and steady-state fluid speed decrease rapidly with decreasing channel diameter, setting a lower limit on practical bladderwort size.

Effect of a school-based educational intervention on HPV and HPV vaccine knowledge and willingness to be vaccinated among Chinese adolescents : a multi-center intervention follow-up study.

BACKGROUND: Middle school students are recommended as the primary target population for human papillomavirus (HPV) vaccination. This study aimed to assess HPV and HPV vaccine knowledge, and to evaluate the effect of a school-based educational intervention, immediately and one year later, on HPV knowledge and vaccine acceptability among adolescents in mainland China. METHODS: A school-based interventional follow-up study was conducted in seven representative cities in mainland China from May 2015 to May 2017. "Train-the-trainer" strategy was employed to educate school teachers in this study. Students aged 13 to 14 years old were assigned to intervention classes and control classes. All students were required to complete the baseline questionnaire. Students in the intervention classes were given a 45-minute lecture regarding HPV and HPV vaccine knowledge and were then asked to complete a post-education questionnaire. One year later, all students were asked to complete the post-education questionnaire again. RESULTS: Baseline HPV knowledge was low among Chinese adolescents, with only 12.6% and 15.7% of students having heard of HPV and HPV vaccines, respectively. After the intervention, the level of HPV-related knowledge increased immediately, and students with higher knowledge levels of HPV and HPV vaccines were more willing to get vaccinated. One year after the intervention, the knowledge of HPV and HPV vaccines was dramatically diminished. However, knowledge was significantly higher in intervention classes compared to control classes. CONCLUSIONS: Knowledge and awareness of HPV and vaccination are generally deficient among Chinese adolescents. School-based health education was very effective in improving awareness and positive attitudes about HPV and HPV vaccines within a short time. Integrating health education on HPV into the existing school-based sexual health curriculum could be an effective way to increase HPV vaccination coverage and help to eliminate preventable HPV-associated cancers in China.

Coupling an online ion conductivity measurement with the particle-into-liquid sampler: Evaluation and modeling using laboratory and field aerosol data.

A particle-into-liquid sampler (PILS) was coupled to a flow-through conductivity cell to provide a continuous, nondestructive, online measurement in support of offline ion chromatography analysis. The conductivity measurement provides a rapid assessment of the total ion concentration augmenting slower batch-sample data from offline analysis and is developed primarily to assist airborne measurements, where fast time-response is essential. A conductivity model was developed for measured ions and excellent closure was derived for laboratory-generated aerosols (97% conductivity explained, R2 > 0.99). The PILS-conductivity measurement was extensively tested throughout the NASA Cloud, Aerosol and Monsoon Processes: Philippines Experiment (CAMP2Ex) during nineteen research flights. A diverse range of ambient aerosol was sampled from biomass burning, fresh and aged urban pollution, and marine sources. Ambient aerosol did not exhibit the same degree of closure as the laboratory aerosol, with measured ions only accountable for 43% of the conductivity. The remaining fraction of the conductivity was examined in combination with ion charge balance and found to provide additional supporting information for diagnosing and modeling particle acidity. An urban plume case study was used to demonstrate the utility of the measurement for supplementing compositional data and augmenting the temporal capability of the PILS.

Microaggressions and Islamophobia: Experiences of Muslims Across the United States and Clinical Implications.

This mixed methods exploratory study illustrates the influence of pervasive misconceptions about Islam on the experiences of 314 adult Muslims across the United States. Quantitative results suggest that Muslim stress levels are comparable to the stress levels of other marginalized groups in the United States. Qualitative analysis revealed four themes that highlight the challenges faced by Muslims as well as their resiliency in the face of microaggressions and marginalization. Family therapists may utilize these personal accounts to expand their understanding of Muslim experiences, and to reflect on their own implicit biases toward Muslims in order to reduce chances of premature termination. Clinical implications include using resiliency-based models and creating collaborative partnerships with community leaders when working with this religious minority group.

Disparities by province, age, and sex in site-specific cancer burden attributable to 23 potentially modifiable risk factors in China: a comparative risk assessment.

BACKGROUND: Understanding disparities in the burden of cancer attributable to different risk factors is crucial to inform and improve cancer prevention and control. In this report, we estimate the site-specific population-attributable fractions (PAFs) for 23 potentially modifiable risk factors across all provinces in China. METHODS: In this comparative risk assessment study, we used 2014 cancer mortality data for adults from 978 county-level surveillance points in 31 provinces of mainland China. Risk-factor prevalence estimates were obtained from representative surveys. We used summary relative risks obtained from several recent large-scale pooled analyses or high-quality meta-analyses of studies in China. We calculated PAFs using multiple formulae incorporating exposure prevalence and relative risk data stratified by age, sex and province and then combined to create summary PAFs by sex, cancer site, and risk factors. FINDINGS: About 1 036 004 cancer deaths (45·2% of all cancer deaths [95% CI 44·0-46·4]) in China in 2014 in adults aged 20 years or older were attributable to 23 evaluated risk factors. The PAF was higher in men (51·2% [95% CI 50·0-52·4]) than in women (34·9% [33·6-36·2]), with the leading risk factors being active smoking in men and low fruit intake in women. By province, the PAF in both sexes combined ranged from 35·2% in Shanghai to 52·9% in Heilongjiang, while the PAF varied from 40·9% in Shanghai to 56·4% in Guangdong among men and from 26·9% in Shanghai to 48·0% in Heilongjiang among women. The highest PAF among men was smoking in all 31 provinces, whereas among women it varied among low fruit intake (14 provinces), hepatitis B virus infection (seven provinces), smoking (six provinces), excess bodyweight (three provinces), and human papilloma virus infection (one province). INTERPRETATION: The PAFs of cancers attributable to potentially modifiable risk factors vary substantially across provinces in China. Regional adoption of effective primary cancer prevention strategies has a vast potential to reduce the burden of cancer and disparities in China. Smoking, poor diet, and infection warrant particular policy attention as they contributed a large proportion to the total cancer burden. FUNDING: National Science and Technology Basic Research Special Foundation of China.

Multiple proteins mediate IQGAP1-stimulated cell migration.

Cell migration, a highly complex physiological phenomenon that requires the co-ordinated and tightly regulated function of several proteins, is mediated by a number of signalling pathways. Elucidation of the molecular mechanisms of cell migration impacts our comprehension of numerous cell functions, ranging from development and immune surveillance to angiogenesis and metastasis. The scaffold protein IQGAP1, which binds multiple proteins and regulates their functions, promotes cell motility. Many of the IQGAP1 binding proteins have been implicated in cell migration. In this study, we employed a multifaceted strategy to identify proteins that contribute to IQGAP1-stimulated cell migration. Using specific IQGAP1 point mutant constructs, an interaction with actin was shown to be essential for IQGAP1 to increase cell migration. In contrast, eliminating the binding of Ca(2+)/calmodulin, but not Ca(2+)-free calmodulin, augmented the ability of IQGAP1 to stimulate cell migration. Consistent with these findings, selective inhibition of calmodulin function at the plasma membrane with a specific peptide inhibitor enhanced cell migration mediated by IQGAP1. Interestingly, immunofluorescence staining and confocal microscopy suggest that localization of Cdc42 at the leading edge is not necessary for maximal migration of epithelial cells. Coupled with the observations that Cdc42 and Rac1 contribute to IQGAP1-stimulated cell migration, these data suggest that IQGAP1 serves as a junction to integrate multiple signalling molecules to facilitate cell migration.

Development and characterization of a high-efficiency, aircraft-based axial cyclone cloud water collector.

A new aircraft-mounted probe for collecting samples of cloud water has been designed, fabricated, and extensively tested. Following previous designs, the probe uses inertial separation to remove cloud droplets from the airstream, which are subsequently collected and stored for offline analysis. We report details of the design, operation, and modelled and measured probe performance. Computational fluid dynamics (CFD) was used to understand the flow patterns around the complex interior geometrical features that were optimized to ensure efficient droplet capture. CFD simulations coupled with particle tracking and multiphase surface transport modelling provide detailed estimates of the probe performance across the entire range of flight operating conditions and sampling scenarios. Physical operation of the probe was tested on a Lockheed C-130 Hercules (fuselage mounted) and de Havilland Twin Otter (wing pylon mounted) during three airborne field campaigns. During C-130 flights on the final field campaign, the probe reflected the most developed version of the design and a median cloud water collection rate of 4.5 mL min-1 was achieved. This allowed samples to be collected over 1-2 min under optimal cloud conditions. Flights on the Twin Otter featured an inter-comparison of the new probe with a slotted-rod collector, which has an extensive airborne campaign legacy. Comparison of trace species concentrations showed good agreement between collection techniques, with absolute concentrations of most major ions agreeing within 30 %, over a range of several orders of magnitude.

A practice-based evaluation of the prevalence and predisposing etiology of white spot lesions.

OBJECTIVE: To use an alumni-centered, practice-based research network to evaluate white spot lesions (WSLs) among treated orthodontic patients. MATERIALS AND METHODS: An initial survey was conducted to ascertain whether orthodontic alumni from Texas A&M University Baylor College of Dentistry were willing to participate. Twenty randomly selected alumni participated, providing 158 treated cases. Each alumnus (1) obtained internal review board consent; (2) submitted pre- and posttreatment photographs of 10 consecutively finished cases; (3) completed a treatment survey; and (4) had the patient/parent complete the American Dental Association (ADA) Caries Risk Assessment. RESULTS: Almost 90% of the alumni surveyed were willing to participate in the practice-based research, primarily because a fellow alumnus asked them to. Approximately 28% of the patients developed WSLs. The average patient developed 2.4 white spots, affecting 12.7% of the teeth examined. WSLs were significantly (P < .001) more (2.3-3.2 times) likely for patients who were identified on the ADA Caries Risk Assessment. The risk of developing WSLs during treatment was also increased for those with fair (2.7 times) or poor (3.5 times) oral hygiene, poor gingival health (2.3 times), and extended treatment times (2.1 times). CONCLUSIONS: There is a substantial risk of developing WSLs among private practice patients, depending partially on the length of treatment. Patients at greatest risk can be identified prior to treatment based on the ADA Caries Risk Assessment, oral hygiene, and gingival health.

Long-term and developmental outcomes of children with complex congenital heart disease.

As short-term survival of complex congenital heart disease continues to improve dramatically with advances in medical and surgical treatment, further efforts must be made to understand the long-term outcomes of our efforts. As survival continues to improve, cardiovascular morbidity and, equally importantly, neurodevelopmental and social outcomes must be a continual focus in our treatment of these complex patients. Further study of these effects is underway, and more is certainly warranted. Understanding should lead to modification of current techniques and management strategies, all with the ultimate goal of improving our patients' quality of life.

Anomalous origin of left coronary artery from pulmonary artery - Duped by 2D; saved by color Doppler: Echocardiographic lesson from two cases.

Echocardiography is an important first-line investigation for detection of anomalous origin of a coronary artery from the pulmonary artery (ALCAPA). We report two cases of ALCAPA that illustrate the importance of systematic performance of the echocardiogram, mindful of technical artifacts that may mislead the echocardiographer color Doppler imaging in diagnosis of this condition.

Control of endothelin-a receptor expression by progesterone is enhanced by synergy with Gata2.

The endothelin-A receptor (Ednra) is involved in several physiological, pathological, and developmental pathways. Known for its function in vasoconstriction after being activated by endothelin-1, Ednra also controls cephalic neural crest cell development and appears to play a role in several pathologies, including cancer and periodontitis. However, the mechanisms regulating Ednra expression have not been identified despite its important functions. In this study, we investigated the role progesterone plays in Ednra gene expression in vivo and in vitro. In mice, pregnancy promotes Ednra expression in the heart, kidney, lung, uterus, and placenta, and the up-regulation is mediated by progesterone. We determined that the conserved region between -5.7 and -4.2 kb upstream of the mouse Ednra gene is necessary for the progesterone response. We also found that progesterone mediates Ednra activation through progesterone receptor B activation by its recruitment to PRE6, one of the 6 progesterone response elements found in that locus. However, gene activation by means of a GATA2 site was also necessary for the progesterone response. The Gata2 transcription factor enhances the progesterone response mediated by the progesterone receptor B. Together these results indicate that progesterone regulates Ednra expression by synergizing with Gata2 activity, a previously unknown mechanism. This mechanism may have an impact on pathologies involving the endothelin signaling.

Agonistic anti-CD40 antibody therapy is effective against postoperative cancer recurrence and metastasis in a murine tumor model.

Postresection recurrences of cancer arising from occult tumor deposits, either local or metastatic, represent major causes of death in patients with operable solid tumors. Thus, new therapies are required that complement existing treatments to eradicate these occult deposits. Agonistic anti-CD40 antibody is one of the most powerful new cancer immunotherapies, enhancing immune priming of effector CD8 T cells by dendritic cells, leading to increased antitumor activity. We investigated the use of anti-CD40 antibody for the treatment of postoperative recurrence and metastasis, with regional lymphadenectomy, in a murine model of cancer. Subcutaneous AB1-HA mesothelioma tumors were induced in BALB/c mice. Established tumors were surgically excised on day 16, with or without sentinel lymph node removal. On the day of surgery, animals were rechallenged with AB1-HA tumor cells at the surgical site (local recurrence) or the opposite flank (metastasis). Postoperative tumors were treated with anti-CD40 (FGK45) on emergence, delivered either intratumorally, peritumorally, or systemically. Local or systemic anti-CD40 treatment slowed postsurgical metastatic growth relative to untreated controls (P = 0.020) and improved survival from metastasis. Anti-CD40 also retarded the growth of local recurrences (P = 0.004) and improved survival from recurrence. Sentinel lymph node dissection did not impair efficacy (P > 0.05). This study demonstrates that anti-CD40 therapy, given either locally or systemically, may be a powerful and readily translatable adjuvant to cancer surgery, including in cases where regional lymphadenectomy is indicated.

Loss of antigen cross-presentation after complete tumor resection is associated with the generation of protective tumor-specific CD8(+) T-cell immunity.

An incomplete understanding on the effect of surgery on tumor-specific immunity continues to hamper efforts to combine surgery with immunotherapy in the clinic. Herein, we describe the impact of tumor resection on the tumor-specific T-cell response, showing that complete tumor resection is associated with (1) a decline in the amount of cross-presented tumor antigens, (2) a decline of cytolytic tumor-specific CD8(+) T cell activity, and (3) the development of systemic CD8(+) T cell-mediated protective immunity. Our findings are consistent with a model whereby tumor resection releases antitumor CD8(+) T cells from chronic antigen exposure, allowing a gradual differentiation toward functional antitumor memory T cells. This process depends on sentinel lymph nodes, as their removal at the time of surgery was associated with a strong negative effect on survival. We conclude that complete tumor resection provides a unique environment that boosts protective immunological memory and might provide a powerful platform for immunotherapy. Our findings also carry important implications for the design and timing of post-surgery immunotherapeutic regimens.