Hippo Kinases Mst1 and Mst2 Sense and Amplify IL-2R-STAT5 Signaling in Regulatory T Cells to Establish Stable Regulatory Activity.

Interleukin-2 (IL-2) and downstream transcription factor STAT5 are important for maintaining regulatory T (Treg) cell homeostasis and function. Treg cells can respond to low IL-2 levels, but the mechanisms of STAT5 activation during partial IL-2 deficiency remain uncertain. We identified the serine-threonine kinase Mst1 as a signal-dependent amplifier of IL-2-STAT5 activity in Treg cells. High Mst1 and Mst2 (Mst1-Mst2) activity in Treg cells was crucial to prevent tumor resistance and autoimmunity. Mechanistically, Mst1-Mst2 sensed IL-2 signals to promote the STAT5 activation necessary for Treg cell homeostasis and lineage stability and to maintain the highly suppressive phosphorylated-STAT5+ Treg cell subpopulation. Unbiased quantitative proteomics revealed association of Mst1 with the cytoskeletal DOCK8-LRCHs module. Mst1 deficiency limited Treg cell migration and access to IL-2 and activity of the small GTPase Rac, which mediated downstream STAT5 activation. Collectively, IL-2-STAT5 signaling depends upon Mst1-Mst2 functions to maintain a stable Treg cell pool and immune tolerance.

Lipid signalling enforces functional specialization of Treg cells in tumours.

Regulatory T cells (Treg cells) are essential for immune tolerance1, but also drive immunosuppression in the tumour microenvironment2. Therapeutic targeting of Treg cells in cancer will therefore require the identification of context-specific mechanisms that affect their function. Here we show that inhibiting lipid synthesis and metabolic signalling that are dependent on sterol-regulatory-element-binding proteins (SREBPs) in Treg cells unleashes effective antitumour immune responses without autoimmune toxicity. We find that the activity of SREBPs is upregulated in intratumoral Treg cells. Moreover, deletion of SREBP-cleavage-activating protein (SCAP)-a factor required for SREBP activity-in these cells inhibits tumour growth and boosts immunotherapy that is triggered by targeting the immune-checkpoint protein PD-1. These effects of SCAP deletion are associated with uncontrolled production of interferon-γ and impaired function of intratumoral Treg cells. Mechanistically, signalling through SCAP and SREBPs coordinates cellular programs for lipid synthesis and inhibitory receptor signalling in these cells. First, de novo fatty-acid synthesis mediated by fatty-acid synthase (FASN) contributes to functional maturation of Treg cells, and loss of FASN from Treg cells inhibits tumour growth. Second, Treg cells in tumours show enhanced expression of the PD-1 gene, through a process that depends on SREBP activity and signals via mevalonate metabolism to protein geranylgeranylation. Blocking PD-1 or SREBP signalling results in dysregulated activation of phosphatidylinositol-3-kinase in intratumoral Treg cells. Our findings show that metabolic reprogramming enforces the functional specialization of Treg cells in tumours, pointing to new ways of targeting these cells for cancer therapy.

Integrated optical multi-ion quantum logic.

Practical and useful quantum information processing requires substantial improvements with respect to current systems, both in the error rates of basic operations and in scale. The fundamental qualities of individual trapped-ion1 qubits are promising for long-term systems2, but the optics involved in their precise control are a barrier to scaling3. Planar-fabricated optics integrated within ion-trap devices can make such systems simultaneously more robust and parallelizable, as suggested by previous work with single ions4. Here we use scalable optics co-fabricated with a surface-electrode ion trap to achieve high-fidelity multi-ion quantum logic gates, which are often the limiting elements in building up the precise, large-scale entanglement that is essential to quantum computation. Light is efficiently delivered to a trap chip in a cryogenic environment via direct fibre coupling on multiple channels, eliminating the need for beam alignment into vacuum systems and cryostats and lending robustness to vibrations and beam-pointing drifts. This allows us to perform ground-state laser cooling of ion motion and to implement gates generating two-ion entangled states with fidelities greater than 99.3(2) per cent. This work demonstrates hardware that reduces noise and drifts in sensitive quantum logic, and simultaneously offers a route to practical parallelization for high-fidelity quantum processors5. Similar devices may also find applications in atom- and ion-based quantum sensing and timekeeping6.

Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity.

A defining feature of adaptive immunity is the development of long-lived memory T cells to curtail infection. Recent studies have identified a unique stem-like T-cell subset amongst exhausted CD8-positive T cells in chronic infection1-3, but it remains unclear whether CD4-positive T-cell subsets with similar features exist in chronic inflammatory conditions. Amongst helper T cells, TH17 cells have prominent roles in autoimmunity and tissue inflammation and are characterized by inherent plasticity4-7, although how such plasticity is regulated is poorly understood. Here we demonstrate that TH17 cells in a mouse model of autoimmune disease are functionally and metabolically heterogeneous; they contain a subset with stemness-associated features but lower anabolic metabolism, and a reciprocal subset with higher metabolic activity that supports transdifferentiation into TH1-like cells. These two TH17-cell subsets are defined by selective expression of the transcription factors TCF-1 and T-bet, and by discrete levels of CD27 expression. We also identify signalling via the kinase complex mTORC1 as a central regulator of TH17-cell fate decisions by coordinating metabolic and transcriptional programmes. TH17 cells with disrupted mTORC1 signalling or anabolic metabolism fail to induce autoimmune neuroinflammation or to develop into TH1-like cells, but instead upregulate TCF-1 expression and acquire stemness-associated features. Single-cell RNA sequencing and experimental validation reveal heterogeneity in fate-mapped TH17 cells, and a developmental arrest in the TH1 transdifferentiation trajectory upon loss of mTORC1 activity or metabolic perturbation. Our results establish that the dichotomy of stemness and effector function underlies the heterogeneous TH17 responses and autoimmune pathogenesis, and point to previously unappreciated metabolic control of plasticity in helper T cells.

Hippo/Mst signalling couples metabolic state and immune function of CD8α+ dendritic cells.

Dendritic cells orchestrate the crosstalk between innate and adaptive immunity. CD8α+ dendritic cells present antigens to CD8+ T cells and elicit cytotoxic T cell responses to viruses, bacteria and tumours 1 . Although lineage-specific transcriptional regulators of CD8α+ dendritic cell development have been identified 2 , the molecular pathways that selectively orchestrate CD8α+ dendritic cell function remain elusive. Moreover, metabolic reprogramming is important for dendritic cell development and activation3,4, but metabolic dependence and regulation of dendritic cell subsets are largely uncharacterized. Here we use a data-driven systems biology algorithm (NetBID) to identify a role of the Hippo pathway kinases Mst1 and Mst2 (Mst1/2) in selectively programming CD8α+ dendritic cell function and metabolism. Our NetBID analysis reveals a marked enrichment of the activities of Hippo pathway kinases in CD8α+ dendritic cells relative to CD8α- dendritic cells. Dendritic cell-specific deletion of Mst1/2-but not Lats1 and Lats2 (Lats1/2) or Yap and Taz (Yap/Taz), which mediate canonical Hippo signalling-disrupts homeostasis and function of CD8+ T cells and anti-tumour immunity. Mst1/2-deficient CD8α+ dendritic cells are impaired in presentation of extracellular proteins and cognate peptides to prime CD8+ T cells, while CD8α- dendritic cells that lack Mst1/2 have largely normal function. Mechanistically, compared to CD8α- dendritic cells, CD8α+ dendritic cells exhibit much stronger oxidative metabolism and critically depend on Mst1/2 signalling to maintain bioenergetic activities and mitochondrial dynamics for their functional capacities. Further, selective expression of IL-12 by CD8α+ dendritic cells depends on Mst1/2 and the crosstalk with non-canonical NF-κB signalling. Our findings identify Mst1/2 as selective drivers of CD8α+ dendritic cell function by integrating metabolic activity and cytokine signalling, and highlight that the interplay between immune signalling and metabolic reprogramming underlies the unique functions of dendritic cell subsets.

Sensor Clustering Using a K-Means Algorithm in Combination with Optimized Unmanned Aerial Vehicle Trajectory in Wireless Sensor Networks.

We examine a general wireless sensor network (WSN) model which incorporates a large number of sensors distributed over a large and complex geographical area. The study proposes solutions for a flexible deployment, low cost and high reliability in a wireless sensor network. To achieve these aims, we propose the application of an unmanned aerial vehicle (UAV) as a flying relay to receive and forward signals that employ nonorthogonal multiple access (NOMA) for a high spectral sharing efficiency. To obtain an optimal number of subclusters and optimal UAV positioning, we apply a sensor clustering method based on K-means unsupervised machine learning in combination with the gap statistic method. The study proposes an algorithm to optimize the trajectory of the UAV, i.e., the centroid-to-next-nearest-centroid (CNNC) path. Because a subcluster containing multiple sensors produces cochannel interference which affects the signal decoding performance at the UAV, we propose a diagonal matrix as a phase-shift framework at the UAV to separate and decode the messages received from the sensors. The study examines the outage probability performance of an individual WSN and provides results based on Monte Carlo simulations and analyses. The investigated results verified the benefits of the K-means algorithm in deploying the WSN.

Cooperative Breakdown of the Oscillator Blockade in the Dicke Model.

The Dicke model, which describes the coupling of an ensemble of spins to a harmonic oscillator, is known for its superradiant phase transition, which can both be observed in the ground state in a purely Hamiltonian setting, as well as in the steady state of an open-system Dicke model with dissipation. We demonstrate that, in addition, the dissipative Dicke model can undergo a second phase transition to a nonstationary phase, characterized by unlimited heating of the harmonic oscillator. Identifying the mechanism of the phase transition and deriving the scaling of the critical coupling with the system size we conclude that the novel phase transition can be understood as a cooperative breakdown of the oscillator blockade which otherwise prevents higher excitation of the system. We discuss an implementation with trapped ions and investigate the role of cooling, by which the breakdown can be suppressed.

Role of Baseline Albumin-Bilirubin Grade on Predict Overall Survival Among Sorafenib-Treated Patients With Hepatocellular Carcinoma in Vietnam.

INTRODUCTION: Albumin-bilirubin (ALBI) grade has been recently used in evaluation of liver function and prognosis of patients with hepatocellular carcinoma (HCC). However, in Vietnam, the utility of ALBI grade in clinical setting has not been adequately investigated. METHODS: This is a retrospective study of 110 patients with HCC treated with sorafenib from January 2010 to November 2018 at 2 tertiary hospitals in Vietnam. Prognostic value of ALBI grade was evaluated by Kaplan-Meier survival analysis and Cox proportional regression model. RESULTS: Results showed that the majority of ALBI grade 1 were Child-Pugh level A (97.5%); ALBI grade 2 was seen in all Child-Pugh score groups of 5, 6, 7, ≥8, whereas ALBI grade 3 was mostly reported in Child-Pugh score ≥8 group (83.3%). Compared with ALBI grade 3, ALBI grade 1 reduced 66.4% risk of death (hazards ratio [HR] = 0.336, 95% confidence interval [CI]: 0.115-0.981; P = .046). Compared with ALBI grade 3, ALBI grade 2 reduced 67.3% risk of death (HR = 0.327, 95% CI: 0.122-0.875; P = .026). Albumin-bilirubin grade was an independent predictor of survival outcome. CONCLUSION: Baseline ALBI grade is a simple and objective approach in assessing liver functions of patients with HCC. Baseline ALBI grade is an independent predictor of survival in patients treated with sorafenib.

Epidemiological Characteristics of Advanced Hepatocellular Carcinoma in the Northern Region of Vietnam.

Epidemiological characteristics of hepatocellular carcinoma (HCC) in Southern Vietnam has been well reported as in Globocan 2018 while data from the North has still not been fully presented. Therefore, we conducted this retrospective descriptive study on 198 advanced HCC patients treated at 3 major hospitals in Northern Vietnam to describe demographic features, HCC risk factors, and correlation among them in patients with advanced HCC. This information will lead to prevention efforts and provide information for allocating funds for treatment. The median age at diagnosis was 57 years (range: 19-86) and the male/female ratio was 8.9/1. The proportions of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection were 81.3% and 5.6%, respectively. Hepatitis C virus infection rate was significantly higher in patients <50 years old (12.5% vs 3.3%, P = .016). There was no significant difference in age or viral hepatitis infection status by gender. Only 7.6% of patients diagnosed with advanced HCC were asymptomatic. In conclusion, with the high rate of HBV infection among patients with advanced HCC, it is necessary for increasing prevention efforts in HBV screening. Furthermore, HCV infection should be noticed in patients with advanced HCC younger than 50 years old.

Outage Performance Analysis and SWIPT Optimization in Energy-Harvesting Wireless Sensor Network Deploying NOMA.

Thanks to the benefits of non-orthogonal multiple access (NOMA) in wireless communications, we evaluate a wireless sensor network deploying NOMA (WSN-NOMA), where the destination can receive two data symbols in a whole transmission process with two time slots. In this work, two relaying protocols, so-called time-switching-based relaying WSN-NOMA (TSR WSN-NOMA) and power-splitting-based relaying WSN-NOMA (PSR WSN-NOMA) are deployed to study energy-harvesting (EH). Regarding the system performance analysis, we obtain the closed-form expressions for the exact and approximate outage probability (OP) in both protocols, and the delay-limited throughput is also evaluated. We then compare the two protocols theoretically, and two optimization problems are formulated to reduce the impact of OP and optimize the data rate. Our numerical and simulation results are provided to prove the theoretical and analytical analysis. Thanks to these results, a great performance gain can be achieved for both TSR WSN-NOMA and PSR WSN-NOMA if optimal values of TS and PS ratios are found. In addition, the optimized TSR WSN-NOMA outperforms that of PSR WSN-NOMA in terms of OP.

Hybrid TSR⁻PSR Alternate Energy Harvesting Relay Network over Rician Fading Channels: Outage Probability and SER Analysis.

In this research, we investigate a hybrid time-switching relay (TSR)⁻power-splitting relay (PSR) alternate energy harvesting (EH) relaying network over the Rician fading channels. For this purpose, the amplify-and-forward (AF) mode is considered for the alternative hybrid time TSR⁻PSR. The system model consists of one source, one destination and two alternative relays for signal transmission from the source to the destination. In the first step, the exact and asymptotic expressions of the outage probability and the symbol errors ratio (SER) are derived. Then, the influence of all system parameters on the system performance is investigated, and the Monte Carlo simulation verifies all results. Finally, the system performances of TSR⁻PSR, TSR, and PSR cases are compared in connection with all system parameters.

Antigen-specific TGF-ß-induced regulatory T cells secrete chemokines, regulate T cell trafficking, and suppress ongoing autoimmunity.

The ability to regulate ongoing inflammation using regulatory T cells (Tregs) is under intense investigation. Strategies to induce and expand Ag-specific Tregs are being developed, and whether various types of Tregs are suppressive in the inflammatory conditions associated with ongoing disease needs to be determined. In this study, we report that TGF-ß-induced Tregs (iTregs) and expanded Tregs specific for a major self-Ag in autoimmune gastritis suppress inflammation and associated pathology when administered late in the process of ongoing disease. Transferred iTregs localized to the stomach, maintained Foxp3 and suppressor functions, and engaged several distinct mechanisms to alleviate disease progression. In addition to suppressing the production of inflammatory cytokines in the stomach and preventing the destruction of parietal cells, we show that iTregs secrete numerous chemokines and regulate both iTreg and effector T cell trafficking into the stomach. These data support efforts to use iTregs in therapies to treat autoimmunity and inflammatory diseases and provide novel insight into the biological mechanisms of iTreg-mediated immune suppression.

Combining cohort analysis and monitoring of HIV early-warning indicators of drug resistance to assess antiretroviral therapy services in Vietnam.

Antiretroviral therapy (ART) retention and 5 early-warning indicators (EWIs) of HIV drug resistance (HIVDR) were abstracted at 27 adult and 4 pediatric clinics in Vietnam in 2009. Of 4531 adults and 313 children, 81.2% and 84.4% respectively were still on ART at 12 months. More than 90% of the clinics monitored achieved the World Health Organization (WHO) targets for lost-to-follow-up (LTFU), ART prescribing practices, and ARV supply continuity. Only 83.9% of the clinics met the target for first-line ART retention and 79.3% met the target for clinic appointment-keeping. Clinic factors (i.e. number of patients, administrative level, and geographical region) were associated with ART retention and LFTU. Data were useful in guiding public health action to optimize ART services.

A new analytical framework of 'continuum of prevention and care' to maximize HIV case detection and retention in care in Vietnam.

BACKGROUND: The global initiative 'Treatment 2.0' calls for expanding the evidence base of optimal HIV service delivery models to maximize HIV case detection and retention in care. However limited systematic assessment has been conducted in countries with concentrated HIV epidemic. We aimed to assess HIV service availability and service connectedness in Vietnam. METHODS: We developed a new analytical framework of the continuum of prevention and care (COPC). Using the framework, we examined HIV service delivery in Vietnam. Specifically, we analyzed HIV service availability including geographical distribution and decentralization and service connectedness across multiple services and dimensions. We then identified system-related strengths and constraints in improving HIV case detection and retention in care. This was accomplished by reviewing related published and unpublished documents including existing service delivery data. RESULTS: Identified strengths included: decentralized HIV outpatient clinics that offer comprehensive care at the district level particularly in high HIV burden provinces; functional chronic care management for antiretroviral treatment (ART) with the involvement of people living with HIV and the links to community- and home-based care; HIV testing and counseling integrated into tuberculosis and antenatal care services in districts supported by donor-funded projects, and extensive peer outreach networks that reduce barriers for the most-at-risk populations to access services. Constraints included: fragmented local coordination mechanisms for HIV-related health services; lack of systems to monitor the expansion of HIV outpatient clinics that offer comprehensive care; underdevelopment of pre-ART care; insufficient linkage from HIV testing and counseling to pre-ART care; inadequate access to HIV-related services in districts not supported by donor-funded projects particularly in middle and low burden provinces and in mountainous remote areas; and no systematic monitoring of referral services. CONCLUSIONS: Our COPC analytical framework was instrumental in identifying system-related strengths and constraints that contribute to HIV case detection and retention in care. The national HIV program plans to strengthen provincial programming by re-defining various service linkages and accelerate the transition from project-based approach to integrated service delivery in line with the 'Treatment 2.0' initiative.

Surgical smoke: modern mobile smoke evacuation systems improve occupational safety in the operating theatre.

OBJECTIVES: Evaluation of smoke capture efficiency of different mobile smoke evacuation devices with respect to volatile organic compounds and their noise emission. METHODS: Electrosurgical incisions were performed on fresh porcine liver in an operating room with vertical laminar flow. The generated surgical smoke was analysed with proton-transfer-reaction mass spectrometry with and without the use of a mobile smoke evacuation system consisting of a smoke evacuator machine, a suction hose and a handpiece. The inlet of the mass spectrometer was positioned 40 cm above the specimen. Various devices were compared: a hard plastic funnel, a flexible foam funnel, an on-tip integrated aspirator of an electrosurgical knife and a standard secretion suction (Yankauer). Also, sound levels were measured at a distance of 40 cm from the handpieces' inlet. RESULTS: The smoke capture efficiency of the secretion suction was only 53%, while foam funnel, plastic funnel and integrated aspirator were all significantly more effective with a clearance of 95%, 91% and 91%, respectively. The mean sound levels were 68 and 59 A-weighted decibels with the plastic and foam funnel, respectively, 66 A-weighted decibels with the integrated aspirator and 63 A-weighted decibels with the secretion suction. CONCLUSIONS: Carcinogenic, mutagenic and reprotoxic volatile organic compounds in surgical smoke can be efficiently reduced by mobile smoke evacuation system, providing improved protection for medical personnel. Devices specifically designed for smoke evacuation are more efficient than standard suction tools. Noise exposure for the surgeon was lowest with the flexible foam funnel and higher with the other handpieces tested.

Minimally invasive repair of pectus carinatum using the Abramson technique.

In the past, the treatment of pectus carinatum has been managed by open, invasive surgical procedures, which involved the resection of cartilage growth plates (Ravitch procedure). By preventing normal bony growth and maturity, this technique often led to postoperative complications, such as acquired thoracic dystrophy, chronic pain and scarring, and stiffness of the whole anterior chest. Dyspnea and exercise intolerance due to restricted thoracic space and cardiac compression were not uncommon as well. Over the last 2 decades, nonsurgical and minimally invasive approaches have gained ground because it was recognized that simple sternal compression was able to remodel the elastic anterior chest wall and therefore correct pectus carinatum adequately/efficiently, at least in children. However, failure of this compressive brace treatment is not uncommon in adolescents and older patients. Abramson therefore developed a minimally invasive technique for the correction of pectus carinatum using a pectus bar that is placed anteriorly to the sternum. The procedure is less invasive and less risky than a pectus bar inserted for pectus excavatum, but the lateral fixation of the pectus bar in the Abramson procedure remains a challenge. We demonstrate the technical aspects of the procedure step by step including our solution for fixation of the stabilizers.

Transoral Endoscopic Thyroidectomy by Vestibular Approach for Differentiated Thyroid Cancer Intraoperatively Invading Strap Muscle.

BACKGROUND: Transoral endoscopic thyroidectomy vestibular approach (TOETVA) has become increasingly popular in the surgical treatment of thyroid cancer. However, its application in T3b disease has not been well-defined. METHODS: We conducted a quasi-experimental study on patients with an intraoperative diagnosis of T3bN0M0 differentiated thyroid carcinoma from January 2019 to January 2021 in our institution. Surgical and early oncological outcomes were assessed. RESULTS: Among 326 patients who underwent TOETVA for thyroid cancer, 12 cases had T3bN0M0 disease intraoperatively. The mean operation time was 136.67±7.32 minutes, with 7.17±0.83 mL of blood loss. No patients reported symptoms of postoperatively transient hypoparathyroidism, mental nerve, or recurrent laryngeal nerve injury. After radioactive iodine therapy, all patients had undetectable thyroglobulin, negative antithyroglobulin, and normal neck ultrasound. CONCLUSIONS: TOETVA seems to be a surgically and oncological safe method for differentiated thyroid cancer patients with small tumors invading strap muscle intraoperatively. The patients can be well-managed with endoscopic total thyroidectomy and postoperative radioactive iodine therapy. Further studies with a larger sample size and longer follow-up are needed to provide more solid evidence.

Surgical Site Infections Are Associated With Higher Blood Loss and Open Access in General Thoracic Practice.

Background: Surgical site infections (SSIs) are the most costly and second most frequent healthcare-associated infections in the Western world. They are responsible for higher postoperative mortality and morbidity rates and longer hospital stays. The aim of this study is to analyze which factors are associated with SSI in a modern general thoracic practice. Methods: Data were collected from our department's quality database. Consecutive patients operated between January 2014 and December 2018 were included in this retrospective study. Results: A total of 2430 procedures were included. SSIs were reported in 37 cases (1.5%). The majority of operations were video-assisted (64.6%). We observed a shift toward video-assisted thoracic surgery in the subgroup of anatomical resections during the study period (2014: 26.7%, 2018: 69.3%). The multivariate regression analysis showed that blood loss >100 ml (p = 0.029, HR 2.70) and open surgery (p = 0.032, HR 2.37) are independent risk factors for SSI. The latter was higher in open surgery than in video-assisted thoracic procedures (p < 0.001). In the subgroup of anatomical resection, we found the same correlation (p = 0.043). SSIs are also associated with significantly longer mean hospital stays (17.7 vs. 7.8 days, p < 0.001). Conclusion: As SSIs represent higher postoperative morbidity and costs, efforts should be made to maintain their rate as low as possible. In terms of prevention of SSIs, video-assisted thoracic surgery should be favored over open surgery whenever possible.

Peuzt - Jeghers syndrome with gastric type mucinous endocervical adenocarcinoma in a young woman: A case report.

INTRODUCTION: Patients with Peutz-Jeghers syndrome (PJS) have high risk of malignancies, including gynecological cancers. Gastric type mucinous cervical adenocarcinoma might be presented in about 11-17% of PJS patients but the literature about this is limited. CASE PRESENTATION: We presented a rare case of a 39-year-old Vietnamese woman with Peutz-Jeghers syndrome who has gastric type adenocarcinoma (GAS) of the cervix. She underwent radical hysterectomy, and the diagnosis was confirmed on final pathology. CONCLUSIONS: Oncologists and pathologists should recognize this rare clinical scenario for early diagnosis and treatment. This subtype also has an aggressive nature and poor prognosis.