Efficacy of navigation system-assisted distraction osteogenesis for hemifacial microsomia based on artificial intelligence for 3 to 18 years old: study protocol for a randomized controlled single-blind trial.

BACKGROUND: Mandibular distraction osteogenesis (MDO) is a major part of the treatment for hemifacial microsomia patients. Due to the narrow surgical field of the intraoral approach, osteotomy accuracy is highly dependent on the surgeons' experience. Electromagnetic (EM) tracking systems can achieve satisfying accuracy to provide helpful real-time surgical navigation. Our research team developed an EM navigation system based on artificial intelligence, which has been justified in improving the accuracy of osteotomy in the MDO in animal experiments. This study aims to clarify the effect of the EM navigation system in improving the MDO accuracy for hemifacial microsomia patients. METHODS: This study is designed as a single-centered and randomized controlled trial. Altogether, 22 hemifacial microsomia patients are randomly assigned to the experiment and control groups. All patients receive three-dimensional CT scans and preoperative surgical plans. The EM navigation system will be set up for those in the experiment group, and the control group will undergo traditional surgery. The primary outcome is the surgical precision by comparing the osteotomy position of pre- and postoperative CT scan images through the Geomagic Control software. The secondary outcomes include mandibular symmetry (occlusal plane deviation angle, mandibular ramus height, and body length), pain scale, and complications. Other indications, such as the adverse events of the system and the satisfactory score from patients and their families, will be recorded. DISCUSSION: This small sample randomized controlled trial intends to explore the application of an EM navigation system in MDO for patients, which has been adopted in other surgeries such as orthognathic procedures. Because of the delicate structures of children and the narrow surgical view, accurate osteotomy and protection of nearby tissue from injury are essential for successful treatment. The EM navigation system based on artificial intelligence adopted in this trial is hypothesized to provide precise real-time navigation for surgeons and optimally improve patient outcomes, including function and aesthetic results. The results of this trial will extend the application of new navigation technology in pediatric plastic surgery. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200061565. Registered on 29 June 2022.

Applying artificial intelligence algorithm in the design of a guide plate for mandibular angle ostectomy.

PURPOSE: Surgical guide plates can improve the accuracy of surgery, although their design process is complex and time-consuming. This study aimed to use artificial intelligence (AI) to design standardized mandibular angle ostectomy guide plates and reduce clinician workload. METHODS: An intelligence algorithm was designed and trained to design guide plates, with a safety-ensuring penalty factor added. A single-center retrospective cohort study was conducted to test the algorithm among patients who had visited our hospital between 2020 and 2021 for mandibular angle ostectomy. We included patients diagnosed with mandibular angle hypertrophy and excluded those combined with other facial malformations. The guide plate design method acted as the primary predictor, which was AI algorithm vs. experienced residents. Moreover, the symmetry of plate-guided ostectomy was chosen as the primary outcome. The safety, shape, location, effectiveness, and design duration of the guide plate were also recorded. The independent samples t-test and Pearson's chi-squared test were used and P-values < 0.05 were considered significant. RESULTS: Fifty patients (7 men, 43 women; 27 ± 4 years) were included. The two groups differed significantly in terms of safety (7.02 vs. 5.25, P < 0.05) and design duration (24.98 vs. 1685.08, P ＜ 0.05). The ostectomy symmetry and shape, location, and effectiveness of the guide plates did not differ significantly between the two groups. CONCLUSIONS: The intelligent algorithm can improve safety and save time for guide plate design, ensuring other quality of the guide plates. It has good potential applicability in accurate mandibular angle ostectomy.

Advances in Robot-Assisted Surgery for Facial Bone Contouring Surgery.

Since our team reported the application of robot-assisted surgery in facial contouring surgery in 2020, further clinical trials with large samples have been conducted. This paper will report the interim results of a single-center, large-sample randomized controlled trial of the first robot developed by our team for facial contouring surgery. Meanwhile, this research field will be systematically reviewed and prospected.

Preliminary reports of augmented-reality assisted craniofacial bone fracture reduction.

BACKGROUND: Zygomaticomaxillary complex fractures involve four fracture ends. It is difficult to fully expose the operative area through a main coronal incision, an intraoral incision, and an eyelid incision. To address the partial visual field loss in craniofacial fracture reduction, we attempted to use an augmented reality (AR) navigation system. METHODS: Patients with zygomaticomaxillary complex fractures underwent three-dimensional (3D) computed tomography (CT) modeling before surgery, and preoperative plans were designed. The control team used traditional optical navigation to perform the surgery. The experimental team used an AR navigation system. From May 2019 to December 2019, 10 patients with zygomaticomaxillary complex fractures were included in this study. Data were collected after surgery and analyzed. RESULTS: There was a significant difference between the two groups in the fracture point error (1.35 vs. 1.61, P = 0.02) and fracture reduction time (15.40 vs. 20.40, P = 0.03). However, there was no difference in the operative duration (6.60 vs. 6.65, P = 0.92), blood loss volume (620.00 vs. 580.00, P = 0.83), or incidence of complications. CONCLUSIONS: The AR navigation system used by the research team has good auxiliary effects for reducing zygomaticomaxillary complex fractures. The new surgical method has better accuracy and a shorter reduction time than the traditional surgical method.

Challenging the fundamental conjectures in nanoparticle drug delivery for chemotherapy treatment of solid cancers.

Nanomedicines for cancer treatment have been studied extensively over the last few decades. Yet, only five anticancer nanomedicines have received approvals from the United States Food and Drug Administration (FDA) for treating solid tumors. This drastic mismatch between effort and return calls into question the basic understanding of this field. Various viewpoints on nanomedicines have been presented regarding their potentials and inefficiencies. However, the underlying logics of nanomedicine research and its inadequate translation to the successful use in the clinic have not been thoroughly examined. Tumor-targeted drug delivery was used to understand the shortfalls of the nanomedicine field in general. The concept of tumor-targeted drug delivery by nanomedicine has been based on two conjectures: (i) increased drug delivery to tumors provides better efficacy, and (ii) decreased drug delivery to healthy organs results in fewer side effects. The clinical evidence gathered from the literature indicates that nanomedicines bearing classic chemotherapeutic drugs, such as Dox, cis-Pt, CPT and PTX, have already reached the maximum drug delivery limit to solid tumors in humans. Still, the anticancer efficacy and safety remain unchanged despite the increased tumor accumulation. Thus, it is understandable to see few nanomedicine-based formulations approved by the FDA. The examination of FDA-approved nanomedicine formulations indicates that their approvals were not based on the improved delivery to tumors but mostly on changes in dose-limiting toxicity unique to each drug. This comprehensive analysis of the fundamentals of anticancer nanomedicines is designed to provide an accurate picture of the field's underlying false conjectures, hopefully, thereby accelerating the future clinical translations of many formulations under research.

Oncologic outcomes of single-incision laparoscopic surgery versus conventional laparoscopic surgery for colorectal cancer (CSILS): study protocol for a multicentre, prospective, open-label, noninferiority, randomized controlled trial.

BACKGROUND: In most previous studies, single-incision laparoscopic surgery (SILS) for colorectal cancer (CRC) was feasible and safe in the short term. However, long-term oncologic outcomes remain uncertain, as only a few studies contained long-term survival data. SILS for CRC is still in the early stages of research. Further studies, particularly large-scale, prospective randomized controlled trials, are necessary to assess the value of SILS for CRC. METHODS: This study is a prospective, multicentre, open-label, noninferiority, parallel-group randomized controlled trial that investigates the long-term oncologic outcomes of SILS compared to conventional laparoscopic surgery (CLS) for CRC. A total of 710 eligible patients will be randomly assigned to the SILS group or the CLS group at a 1:1 ratio using a central, dynamic, and stratified block randomization method. Patients with ages ranging from 18 to 85 years old, of both sexes, with CRC above the peritoneal reflection diagnosed as cT1-4aN0-2M0 and a tumour size no larger than 5 cm will be considered for the study. The primary endpoint is 3-year disease-free survival (DFS). The secondary endpoints include: intraoperative outcomes, postoperative recovery, postoperative pain assessment, pathological outcomes, early morbidity and mortality rate, cosmetic effects, quality of life, 3-year overall survival (OS), incidence of incisional hernia, 5-year DFS and 5-year OS. The first two follow-up visits will be scheduled at one month and three months postoperatively, then every three months for the first two years and every six months for the next three years. DISCUSSION: Currently, no randomized controlled trials (RCTs) have been designed to investigate the long-term oncologic outcomes of SILS for CRC. This study is expected to provide clinical evidence of the oncologic outcomes of SILS compared to CLS for CRC to promote its widespread use. TRIAL REGISTRATION: ClinicalTrials.gov:  NCT04527861 (registered on August 27, 2020).

Copy Number Analyses Identified a Novel Gene: APOBEC3A Related to Lipid Metabolism in the Pathogenesis of Preeclampsia.

Background: Preeclampsia is a heterogeneous and complex disease with its pathogenesis mechanism not fully elucidated. A certain subset of patients with preeclampsia exhibit disturbances in lipid metabolism before clinical symptoms. Moreover, there is a tendency for preeclampsia to run in families. Whether genetic factors play a role in abnormal lipid metabolism during the incidence of preeclampsia has not been well investigated. Methods: Preeclampsia patients (n = 110) and healthy age- and gravidity-matched pregnant women (n = 110) were enrolled in this study. Peripheral blood specimens were used for genomic analysis (n = 10/group) or laboratory validation (n = 100/group). We retrospectively obtained the baseline clinical characteristics of 68 preeclampsia patients and 107 controls in early pregnancy (12-14 gestational weeks). Correlation analyses between differential genes and baseline lipid profiles were performed to identify candidate genes. In vitro and in vivo gain-of-function models were constructed with lentivirus and adeno-associated virus systems, respectively, to investigate the role of candidate genes in regulating lipid metabolism and the development of preeclampsia. Results: We observed that preeclampsia patients exhibited significantly elevated plasma TC (P = 0.037) and TG (P < 0.001) levels and increased body mass index (P = 0.006) before the disease onset. Within the region of 27 differential copy number variations, six genes potentially connected with lipid metabolism were identified. The aberrant copies of APOBEC3A, APOBEC3A_B, BTNL3, and LMF1 between preeclampsia patients and controls were verified by quantitative polymerase chain reaction. Especially, APOBEC3A showed a significant positive correlation with TC (P < 0.001) and LDL (P = 0.048) in early pregnancy. Then, our in vitro data revealed that overexpression of APOBEC3A disrupted lipid metabolism in HepG2 cells and affected both cholesterol and fatty acid metabolisms. Finally, in vivo study in a hepatic-specific overexpressed APOBEC3A mouse model revealed abnormal parameters related to lipid metabolism. Pregnant mice of the same model at the end of pregnancy showed changes related to preeclampsia-like symptoms, such as increases in sFlt-1 levels and sFlt-1/PLGF ratios in the placenta and decreases in fetal weight. Conclusion: Our findings established a new link between genetics and lipid metabolism in the pathogenesis of preeclampsia and could contribute to a better understanding of the molecular mechanisms of preeclampsia.

The application of augmented reality in craniofacial bone fracture reduction: study protocol for a randomized controlled trial.

BACKGROUND: Augmented reality (AR) is a new technology that increases users' perception of the real world. The purpose of this study is to evaluate the efficacy and safety of augmented reality navigation system in treatment with craniofacial fracture reduction. METHODS: This will be a single-center prospective randomized controlled trial. Twenty-two patients will be assigned to two groups of 11, and those with zygomaticomaxillary complex fractures will undergo preoperative three-dimensional CT modeling and have operational plans designed. The control team will use traditional optical navigation to perform the surgery, and the experimental team will use an AR navigation system. The primary outcome measures will be the accuracy of the key points of surgical area between the preoperational surgical plan and post-operation. The secondary outcome measures will be the blood loss, operation time, bone reduction time, hospital time, and complication rate. The findings obtained through this study are expected to evaluate efficacy and safety of the augmented reality navigation system in the treatment of zygomaticomaxillary complex fractures. DISCUSSION: This controlled trial of augmented reality navigation system in treatment with zygomaticomaxillary complex fracture reduction will clarify the efficacy and safety of this technology by measuring the accuracy of the key points of surgical area and blood loss, operation and bone reduction times, hospital stay duration, and complication rates. This is a single-center study, and the results are expected to promote the application of augmented reality in craniofacial fracture reduction to improve surgery accuracy and efficacy. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900022626 . Registered on April 19, 2019.

Assessment of Robot-Assisted Mandibular Contouring Surgery in Comparison With Traditional Surgery: A Prospective, Single-Center, Randomized Controlled Trial.

BACKGROUND: Few clinical studies on robot-assisted surgery (RAS) for mandibular contouring have been reported. OBJECTIVES: The aim of this study was to follow the long-term effectiveness and safety of RAS for craniofacial bone surgery. METHODS: This small-sample, early-phase, prospective, randomized controlled study included patients diagnosed with mandibular deformity requiring mandibular contouring surgery. Patients of both genders aged 18 to 30 years without complicated craniofacial repair defects were enrolled and randomly assigned in a 1:1 ratio by a permuted-block randomized assignments list generated by the study statistician. The primary outcomes were the positioning accuracy and accuracy of the osteotomy plane angle 1 week after surgery. Surgical auxiliary measurement index, patient satisfaction scale, surgical pain scale, perioperative period, and complications at 1 week, 1 month, and 6 months after surgery were also analyzed. RESULTS: One patient was lost to follow-up, resulting in a total of 14 patients in the traditional surgery group and 15 in the robot-assisted group (mean [standard deviation] age, 22.65 [3.60] years). Among the primary outcomes, there was a significant difference in the positioning accuracy (2.91 mm vs 1.65 mm; P < 0.01) and angle accuracy (13.26º vs 4.85º; P < 0.01) between the 2 groups. Secondary outcomes did not significantly differ. CONCLUSIONS: Compared to traditional surgery, robot-assisted mandibular contouring surgery showed improved precision in bone shaving, as well as higher safety.

A nomogram for preoperative prediction of prolonged air leak after pulmonary malignancy resection.

BACKGROUND: Prolonged air leak (PAL) is one of the most common postoperative complications after lung surgery. This study aimed to identify risk factors of PAL after lung resection and develop a preoperative predictive model to estimate its risk for individual patients. METHODS: Patients with pulmonary malignancies or metastasis who underwent pulmonary resection between January 2014 and January 2018 were included. PAL was defined as an air leak more than 5 days after surgery, risk factors were analyzed. Forward stepwise multivariable logistic regression analysis was performed to identify independent risk factors, and a derived nomogram was built. Data from February 2018 to September 2018 were collected for internal validation. RESULTS: A total of 1,511 patients who met study criteria were enrolled in this study. The overall incidence of PAL was 9.07% (137/1,511). Age, percent forced expiratory volume in 1 second, surgical type, surgical approach and smoking history were included in the final model. A nomogram was developed according to the multivariable logistic regression results. The C-index of the predictive model was 0.70, and the internal validation value was 0.77. The goodness-of-fit test was non-significant for model development and internal validation. CONCLUSIONS: The predictive model and derived nomogram achieved satisfied preoperative prediction of PAL. Using this nomogram, the risk for an individual patient can be estimated, and preventive measures can be applied to high-risk patients.

Integration of Genomic and Transcriptomic Markers Improves the Prognosis Prediction of Acute Promyelocytic Leukemia.

PURPOSE: The current stratification system for acute promyelocytic leukemia (APL) is based on the white blood cell (WBC) and the platelet counts (i.e., Sanz score) over the past two decades. However, the borderlines among different risk groups are sometimes ambiguous, and for some patients, early death and relapse remained challenges. Besides, with the evolving of the treatment strategy from all-trans-retinoic acid (ATRA) and chemotherapy to ATRA-arsenic trioxide-based synergistic targeted therapy, the precise risk stratification with molecular markers is needed. EXPERIMENTAL DESIGN: This study performed a systematic analysis of APL genomics and transcriptomics to identify genetic abnormalities in 348 patients mainly from the APL2012 trial (NCT01987297) to illustrate the potential molecular background of Sanz score and further optimize it. The least absolute shrinkage and selection operator algorithm was used to analyze the gene expression in 323 cases to establish a scoring system (i.e., APL9 score). RESULTS: Through combining NRAS mutations, APL9 score, and WBC, 321 cases can be stratified into two groups with significantly different outcomes. The estimated 5-year overall (P = 0.00031), event-free (P < 0.0001), and disease-free (P = 0.001) survival rates in the revised standard-risk group (95.6%, 93.8%, and 98.1%, respectively) were significantly better than those in the revised high-risk group (82.9%, 77.4%, and 88.4%, respectively), which could be validated using The Cancer Genome Atlas dataset. CONCLUSIONS: We have proposed a two-category system for improving prognosis in patients with APL. Molecular markers identified in this study may also provide genomic insights into the disease mechanism for improved therapy.

Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial).

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

A Clinical Score to Predict Severe Acute Kidney Injury in Chinese Patients after Cardiac Surgery.

BACKGROUND/AIMS: Cardiac surgery-associated severe acute kidney injury (SAKI) is associated with high mortality and poor quality of life. A prognostic score for SAKI may enable prevention of complications. METHODS: This observational study of 2,552 patients undergoing cardiac surgery from January 2006 to December 2011 in our institution established associations between predictor variables and postoperative SAKI from a cohort of 1,692 patients and developed a clinical score that was assessed in a validation cohort of 860 patients. RESULTS: Postoperative SAKI occurred in 262 -patients (10.3%). We identified 7 independent and significant risk factors in the derivation model (adjusted OR 95% CI): age ≥81 years (vs. age < 40 years, 4.30, 1.52-12.21), age 61-80 years (vs. age < 40 years, 2.84, 1.24-6.52), age 41-60 years (vs. age < 40 years, 1.62, 0.68-3.87), hypertension (1.65, 1.13-2.39), previous cardiac surgery (3.62, 1.27-10.32), -hyperuricemia (2.02, 1.40-2.92), prolonged operation time (1.32, 1.17-1.48), postoperative central venous pressure < 6 mm H2O (3.53, 2.38-5.23), and low postoperative cardiac output (4.78, 2.97-7.69). The 7-variable risk prediction model had acceptable performance characteristics in the validation cohort (C statistic 0.80, 95% CI 0.74-0.85). The difference in the C statistic was 0.21 (95% CI 0.12-0.29, p < 0.001) compared with the Cleveland Clinic score. CONCLUSION: We developed and validated a practical risk prediction model for SAKI after cardiac surgery based on routinely available perioperative clinical and laboratory data. The prediction model can be easily applied at the bedside and provides a simple and interpretable estimation of risk.

Species-Specific Involvement of Integrin αIIbß3 in a Monoclonal Antibody CH12 Triggers Off-Target Thrombocytopenia in Cynomolgus Monkeys.

CH12 is a novel humanized monoclonal antibody against epidermal growth factor receptor variant III (EGFRvIII) for cancer treatment. Unfortunately, in pre-clinical safety evaluation studies, acute thrombocytopenia was observed after administration of CH12 in cynomolgus monkeys, but not rats. More importantly, in vitro experiments found that CH12 can bind and activate platelets in cynomolgus monkey, but not human peripheral blood samples. Cynomolgus monkey-specific thrombocytopenia has been reported previously; however, the underlying mechanism remains unclear. Here, we first showed that CH12 induced thrombocytopenia in cynomolgus monkeys through off-target platelet binding and activation, resulting in platelet destruction. We subsequently found that integrin αIIbß3 (which is expressed on platelets) contributed to this off-target toxicity. Furthermore, three-dimensional structural modeling of the αIIbß3 molecules in cynomolgus monkeys, humans, and rats suggested that an additional unique loop exists in the ligand-binding pocket of the αIIb subunit in cynomolgus monkeys, which may explain why CH12 binds to platelets only in cynomolgus monkeys. Moreover, this study supported the hypothesis that the minor differences between cynomolgus monkeys and humans can confuse human risk assessments and suggests that species differences can help the prediction of human risks and avoid losses in drug development.

MicroRNA-137 and microRNA-195* inhibit vasculogenesis in brain arteriovenous malformations.

OBJECTIVE: Brain arteriovenous malformations (AVMs) are the most common cause of nontraumatic intracerebral hemorrhage in young adults. The genesis of brain AVM remains enigmatic. We investigated microRNA (miRNA) expression and its contribution to the pathogenesis of brain AVMs. METHODS: We used a large-scale miRNA analysis of 16 samples including AVMs, hemangioblastoma, and controls to identify a distinct AVM miRNA signature. AVM smooth muscle cells (AVMSMCs) were isolated and identified by flow cytometry and immunohistochemistry, and candidate miRNAs were then tested in these cells. Migration, tube formation, and CCK-8-induced proliferation assays were used to test the effect of the miRNAs on phenotypic properties of AVMSMCs. A quantitative proteomics approach was used to identify protein expression changes in AVMSMCs treated with miRNA mimics. RESULTS: A distinct AVM miRNA signature comprising a large portion of lowly expressed miRNAs was identified. Among these miRNAs, miR-137 and miR-195* levels were significantly decreased in AVMs and constituent AVMSMCs. Experimentally elevating the level of these microRNAs inhibited AVMSMC migration, tube formation, and survival in vitro and the formation of vascular rings in vivo. Proteomics showed the protein expression signature of AVMSMCs and identified downstream proteins regulated by miR-137 and miR-195* that were key signaling proteins involved in vessel development. INTERPRETATION: Our results indicate that miR-137 and miR-195* act as vasculogenic suppressors in AVMs by altering phenotypic properties of AVMSMCs, and that the absence of miR-137 and miR-195* expression leads to abnormal vasculogenesis. Ann Neurol 2017;82:371-384.

Investigation of vitamin D status and its correlation with insulin resistance in a Chinese population.

OBJECTIVE: Although many studies worldwide have focused on the relationship between vitamin D and insulin resistance, results remain controversial. Furthermore, concentrations of serum 25-hydroxyvitamin D (25(OH)D) in the Chinese population are unclear. We aimed to investigate vitamin D status and its correlation with insulin resistance among a Chinese adult population. DESIGN: Serum 25(OH)D, fasting blood glucose, fasting insulin, glycated Hb (HbA1c) and other metabolic parameters were assessed. Neck circumference, waist circumference, hip circumference, weight and height were also measured. Lifestyle factors including smoking and drinking status were obtained. Diabetes mellitus was diagnosed by HbA1c according to the 2010 American Diabetes Association criteria. SETTING: Eastern China. SUBJECTS: Of 7200 residents included, 6597 individuals were ultimately analysed. RESULTS: We enrolled 2813 males (mean age 52·7 (sd 13·5) years) and 3784 females (52·3 (sd 13·5) years); mean serum 25(OH)D concentration was 43·1 (sd 11·6) and 39·6 (sd 9·8) nmol/l, respectively. Additionally, 83·3 % of participants were 25(OH)D deficient. A significant difference in 25(OH)D was observed between males and females in winter and spring (P<0·001). Furthermore, 25(OH)D concentrations were inversely associated with the homeostasis model assessment of insulin resistance (HOMA-IR) in the overweight and pre-diabetic populations. After adjusting for several variables, 25(OH)D was significantly associated with HOMA-IR in winter. When 25(OH)D values were categorized into quartiles, HOMA-IR was significantly associated with decreasing 25(OH)D. CONCLUSIONS: The majority of the Chinese population was vitamin D deficient and this deficiency was negatively associated with insulin resistance, particularly in the overweight and pre-diabetic populations. Moreover, these associations might be more evident in the winter.

The famine exposure in early life and metabolic syndrome in adulthood.

BACKGROUND & AIMS: Epidemiologic studies have revealed that early-life conditions influence later risk of chronic diseases. We aimed to explore whether exposure to Chinese famine between 1959 and 1962 during fetal and childhood period was related with metabolic syndrome (MS) in adulthood. METHODS: 6445 subjects from SPECT-China study were divided into fetal-exposed (1959-1962), childhood-exposed (1949-1958), adolescence/young adult-exposed (1921-1948), non-exposed (1963-1974) and non-exposed (after 1975). MS was defined by the International Diabetes Federation criteria. RESULTS: The prevalences of MS in the non-exposed (1963-1974), fetal and childhood-exposed were 16.4%, 20.1% and 19.1% in men and 13.5%, 23.7% and 33.5% in women, respectively. After adjustment for age, compared with non-exposed (1963-1974), fetal and childhood-exposed women had significantly higher prevalences of MS (P < 0.05), but not in men. Famine exposure during the fetal period (OR 1.47, 95% CI 1.05, 2.07) and childhood (OR 1.80, 95% CI 1.22, 2.67) was associated with higher risk of MS in women after adjusting for age (both P < 0.05). Further adjustments for age, smoking, rural/urban residence and economic status did not significantly attenuate this association. CONCLUSIONS: Exposure to famine in early life had sex-specific association with MS. It also suggests the adverse effects of malnutrition might extend beyond the 'first 1000 days' and last 9 years.

Functional lymphatic collectors in breast cancer-related lymphedema arm.

BACKGROUND: The pathophysiology of breast cancer-related lymphedema (BCRL) is poorly understood. The present study evaluated the lymphatic collectors in the arms of patients with BCRL. METHODS AND RESULTS: In total, 123 patients with ipsilateral BCRL who had undergone magnetic resonance lymphangiography using gadobenate dimeglumine as a contrast agent were enrolled in this study. Morphological changes and the numbers of collecting lymphatic vessels were recorded. Associations between the number of visualized lymphatic collectors and edema accumulation, subcutis thickness, and the BCRL duration and latency were analyzed. Tortuous and significantly dilated lymphatic collectors were visualized in the lymphedematous arms of 104 patients (85%). The median number of visualized lymphatic collectors was four. The duration of BCRL was weakly but significantly correlated with the number of lymphatic collectors (rs=0.2054, p=0.0226). The differences in the tissue water content and thickness of the subcutis between the bilateral arms demonstrated moderate correlations with the number of collecting lymphatics (rs=0.31 and 0.35, respectively; p<0.01). More lymphatic collectors tended to be seen in more advanced cases. There was no statistical difference in the amount of lymphatic vessels among different breast cancer treatment methods. CONCLUSIONS: The number of functional remaining lymphatic collectors increases with the prolongation and severity of BCRL. This may imply persistent reactions of lymphatic collectors in response to lymphostasis.

RASSF1A promoter hypermethylation is a strong biomarker of poor survival in patients with salivary adenoid cystic carcinoma in a Chinese population.

In addition to the clinicopathological parameters, molecular biomarkers are becoming increasingly important in the prognostic evaluation of cancer patients. This study aimed to determine the molecular alterations in the RAS association domain family protein1A gene (RASSF1A) in salivary adenoid cystic carcinoma (ACC) and to evaluate the potential of such alterations as prognostic markers. One hundred and sixty-seven ACC tumor tissues and 50 samples of matched normal salivary gland tissues from the same patients were analyzed for RASSF1A promoter methylation status by bisulfite sequencing PCR (BSP) and/or methylation-specific PCR (MSP). Fifty ACC tumor tissues and matched normal salivary gland tissues were analyzed for loss of heterozygosity (LOH) by examining two microsatellite markers (D3S1478, D3S1621) at 3p21. RASSF1A gene mutations were detected by direct sequencing of all six exons in 50 tumor and normal tissue specimens. Over-all, RASSF1A promoter hypermethylation was detected in 35.3% (59/167) of ACC tissues and was associated with histologically solid tumor pattern (P = 0.002) and advanced TNM stage (P = 0.014). RASSF1A LOH was observed in 18.0% (9/50) of cases, and no somatic mutation of RASSF1A was detected in any cases. RASSF1A promoter methylation was associated with the poor over-all survival (Log-rank test, P <0.001) and disease-free survival (Log-rank test, P <0.001) and identified as an independent predicator of over-all patient survival (P = 0.009) and disease-free survival (P <0.001). It was concluded that RASSF1A methylation is involved in the development, differentiation and progression of ACC and is a strong independent biomarker of poor survival in ACC patients in a Chinese population.

Synergism of PI3K/Akt inhibition and Fas activation on colon cancer cell death.

Fas and PI3K/Akt signaling pathways pivotally impact on cancer cell death and survival respectively and are considered as promising targets for innovative anticancer therapies. To better characterize the combination effect of PI3K/Akt inhibitors and Fas agonists and understand the profile of the interaction between PI3K/Akt and Fas signaling, we qualitatively and quantitatively evaluated the combination effect of PI3K/Akt inhibitors LY294002, Akt inhibitor VIII and FasL. At the concentration that can block cell cycle progression and DNA synthesis but not elicit apoptosis, these inhibitors potentiate FasL to induce apoptosis. At higher concentrations, when the PI3K/Akt inhibitors induce apoptosis, they synergize FasL to induce apoptosis. In addition, PI3K/Akt inhibition significantly facilitates the Fas-mediated apoptotic signaling. Understanding the combination effects between PI3K/Akt inhibition and Fas activation not only leads to rational design of effective combination therapy of PI3K/Akt inhibitors but also improve our knowledge about the impact of PI3K-Akt pathway on Fas signaling and the potential modulation of innate immune system by PI3K-Akt-targeting drugs in anticancer treatment.